MXPA99007910A - Pyrazine compounds - Google Patents

Abstract

A compound of formula (I) wherein R1 is selected from the group consisting of phenyl substituted by one or more halogen atoms, naphthyl and naphthyl substituted by one or more halogen atoms;R2 is selected from the group consisting of -NH2 and -NHC(=O)Ra;R3 is selected from the group consisting of -NRbRc, -NHC(=O)Ra and hydrogen, R4 is selected from the group consisting of hydrogen, -C1-4 alkyl, -C1-4 alkyl substituted by one or more halogen atoms, -CN, -CH2OH, -CH2ORd and -CH2S(O)x Rd;wherein Ra represents C1-4 alkyl or C3-7cycloalkyl, and Rb and Rc, 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 6-membered nitrogen containing heterocycle, which heterocycle can be further susbtituted with one or more C1-4 alkyl;Rd is selected from C1-4 alkyl or C1-4 alkyl substituted by one or more halogen atoms;x is an integer zero, one or two;and pharmaceutically acceptable derivatives thereof;with the proviso that R1 does not represent (a);when R2 is -NH2, and both R3 and R4 are hydrogen.

Description

PIRAZINE COMPOUNDS Field of Invention The present invention relates to cor. A series of compounds are useful in the treatment of diseases and disorders or disorders of the central nervous system (CNS) and their pharmaceutically acceptable derivatives, pharmaceutical compositions containing them, in their treatment. of such disorders to methods for preparing them.

Background of the Invention Numerous derivatives of phenylpyrazine are known in the prior art. For example, the Synthesis (1987, 101, 914-915, describes phenylpyrazine derivatives that include, inter al a, 3-y. -chlorcfeml) -p? Ra:? Hnam? Na. However, no pharmaceutical utility is disclosed in that prior art document.

The present invention relates to a series of pyrazine aerivaates which are Ref: 031082 sodium channel blockers. These compounds are particularly good anti-convulsants and as such are useful in the treatment of CNS diseases such as epilepsy.

Description of the invention.

Accordingly, the invention provides a compound of the formula (I) 0) in which R1 is selected from the group consisting of phenyl substituted by one or more halogen atoms, naphthyl and naphthyl substituted by one or more halogen atoms; R "is selected from the group consisting of -NH2 and -NHC (= 0) Rd; R3 is selected from the group consisting of -NRfcRc, -NHCX0) Ra and hydrogen; R 4 is selected from the group consisting of hydrogen, -alkyl of C i _ 4 (preferably methyl), -Cl 4 alkyl (preferably methyl) substituted by one or more halogen atoms, -CN, -CH 2 OH, -CH 2 OH -CH20Rd and -CH2S (0) xRd; in 1 to that Ra represents C? _4 alkyl or C3_7 cycloalkyl, and RD and Rc, which may be the same or different, are selected from hydrogen and C 1-4 alkyl, or together with the nitrogen atom to which they are attached, form a 6-membered heterocycle containing nitrogen, which heterocycle may to be further substituted with one or more of the C 1.4 alkyl; Ra is selected from C 1-4 alkyl or -4 alkyl substituted by one or more halogen atoms; x in a whole number of zero, one or two; and pharmaceutically acceptable derivatives thereof; with the proviso that R1 does not represent; when R2 is -NH2, and both of R3 and R4 are hydrogen.

By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt or solvate of the compounds of the formula (I), or any other compound which upon administration with the container is capable of providing (directly or indirectly) a compound of the formula (I) or an active metabolism or residue thereof (for example a pro-drug). The above reference to the compounds of the formula (I) includes the compound of the formula (I) and pharmaceutically acceptable derivatives thereof.

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 RO-CH2-n? t rógeno or R-O-C (O) -norrogen.

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 from 1 to 4 carbon atoms, and in particular includes methyl and i sopropyl.

The term C3-7 cycloalkyl includes groups containing from 3 to 7 carbon atoms, and in particular includes cyclopropyl.

The term "heterocycle" as used herein includes 6-membered heterocycles containing at least one nitrogen heteroatom, and preferably two nitrogen heteroatoms. A particularly suitable heterocycle is pipe ra zinc.

R1 is appropriately selected from unsubstituted naphthyl and phenyl substituted by one or more halogen atoms. Particularly R1 represents phenyl substituted by more than one halogen atom, such as di- or tp-halogenated phenyl. Preferably, the halogen substituted in R1 is chloro. Suitably R1 is selected from 2, 3, 5-1 ri cl or of em 1, 2, 3-di cl or of eni 1 or, 2, 5 -di chlor of eni 1 o, 1-naphthalo and 2-naft? lo. In particular, R1 is 2,3,5-trichlorophenyl.

Suitably R "" is selected from -NH2, isopropylcarbonylamino and cyclopropylcarbonylamino. R "is preferably -NH2.

Suitably R is selected from hydrogen, -NH2, dimethyl, amine, 4-methyl-1-piperazyl, acetamido, isopropylcarbonylammon, cyclopropylcarbonylamino. R3 is preferably NH2.

Suitably R is selected from hydrogen, -CN, -CH2OH or methyl. R 4 is preferably -CH 2 OH or more preferably hydrogen.

Most preferably, R 'and R are both -NH; A preferred class of compounds of the formula (I) includes those in which R1, R2 and R3 are as defined in the foregoing and R4 is selected from the group consisting of hydrogen, C? _4 alkyl (preferably methyl) and -C 4 alkyl (preferably methyl) substituted by one or more halogen atoms.

A preferred compound of the formula (I) is, wherein - R 1 is 2,3,5-trichlorophenyl; R2 is -NH2; R3 is -NH2; and R4 is hydrogen.

According to a particular modality of the s. venc? o: rooorc o a) mc u e e a formula (I a (the) in _ to Hai represents a halogen atom selected from fluorine, chlorine, bromine and iodine; N is 2 or 3; ? - is selected from the group consisting of -NH; and -N H C í = O) FX R - 'was selected from the group consisting of -NR Fc, - N H C í = 0! Rd and hidroaer.c; R is selected from the group consisting of hydrogen, - C4 alkyl (preferably methyl), - C1 alkyl- (preferably methyl) substituted by one or more halogen atoms, -CN, -CH2OH, CH2ORd and -CH2S (0) xRd; in which Ra represents C? _4 alkyl or C 3-7 cycloalkyl, and Rb and Rc, which may be the same or different, are selected from hydrogen and C 1-4 alkyl, or together with the nitrogen atom to which they are attached, form a 6-membered nitrogen-containing heterocycle, which heterocycle may to be further substituted with one or more of C 1-4 alkyl! R is selected from C? -4 alkyl or Ci-4 alkyl substituted by one or more halogen atoms; x is an integer of zero, one or two; and pharmaceutically acceptable derivatives thereof.

It will be appreciated that R ', R ° and R 4 as defined above for the formula (la), are their t ankly as described herein with reference to formula (I).

In particular, appropriately in formula (la), R 'and R3 both represent -NH2. Suitably R4 represents -CN, methyl or, more appropriately, -CH2OH or, even more appropriately, hydrogen.

Appropriately Hal in formula (la) represents chlorine. Suitably n is 3 and appropriately the t r i -us its resulting t i t uc i on represents a compound of the following formula (Ib) wherein R2, R3 and R4 are their titles as defined in the foregoing with reference to formula (la); and pharmaceutically acceptable derivatives of the same.

The preferred compounds of the present invention are 2, 6-d? Am? No-3- (2, 3-d? Chlorophen? L) p? Razma, 2, 6-d? Am? No-3- (2, 5-d? Chlorofeml) pyraz, 2, 6-d? Am? No-3- (l-naft? L) p? Razma, 2, 6-d? Am? No-3- (2-naft? L) p? Razma, 2-ammo- 6- (4-met? Llp? Perazm? L) -3- (2, 3, 5-trichlorophenyl) pyrazine, 2-am? No-6-d? Met? Lam? No-3- (2, 3- d? chlorophen? l) -pirazma, 2-ammo-6-d? met? Iam? no-3- (1-naphthyl) -pyrazine, 2,6-d? c? cloprop? lcarbon? lam? no -3- (2, 3, 5-trichlorophenyl) pyrazine, 2-am? No-6-c? Cloprop? Lcarbon? Lam? No-3- (2, 3, 5-trichlorophenyl) pyrazine, 2,6-d ??? soprop? lcarbon? lam? no-3- (2, 3, 5 -tr? chlorophen? l) p? raz? na, 2 -amino- 6-? soprop? lcarbon? lammo-3- (2, 3, 5-trichlorofeml) pyrazine, 2-? soprop? lcarbon? lammo-6-ammo-3- (2, 3, 5 -tpclorophenyl) pyrazine, 2-c? cloprop ? lcarbon? lammo-6-ammo-3- (2, 3, 5 -trichlorophenyl) p razma, 2-ammo-6-acetamido-3- (22, 3, 5. t4r? chlorophen? l pirazma, 2 -am? no-6-acetamido-3- 2, 5-d? chlorophen? l) -pirazma, 2-am? no-6-acet amido-3-2-naphthalene) pyrazma, 5-met L-2, 6-D? am? no-3- 2, 3, 5-tr? chlorophen? l) -pirazma, 5-c? ano-2, 6-D? am? no-3- (2 , 3, 5-tpclorofen? L) -pirazma, and pharmaceutically acceptable derivatives of the same.

Further preferred is the compound 5-hydrox? Met? L-2,6-d? Am? No-3- (2, 3, 5-t r? Chlorofeni 1) pi ra zma and pharmaceutically acceptable derivatives thereof.

A particularly preferred compound according to the present invention in 2,6-d? Ammo-3- (2,3,5-tr? Chlorophen? L) pyrazine, and pharmaceutically acceptable derivatives thereof.

It is understood that the present invention covers all combinations of the particular and preferred groups described herein in the foregoing.

The compounds of the formula (I) are particularly useful as an t-convul s i onant e s.

Therefore they are useful to treat epilepsy.

They can be used to improve the condition of a host typically a human being suffering from epilepsy. They can be used to alleviate the symptoms of epilepsy in a host. The "epilepsy" is intended to include the following attacks or attacks: simple partial attacks, complex partial attacks, generalized secondary attacks, generalized attacks that include absent attacks, myoclonic attacks, clonic attacks, tonic attacks, tonic-clonic attacks and atonic attacks.

The compounds of formula (I) are also useful in the treatment of bipolar disorders, alternatively known as manic depression or mania. Bipolar disorder 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 disorder. They can be used to relieve the symptoms of bipolar disorder in a host. The compounds of the formula (I) can also be used in the treatment of unipolar depression.

The compounds of the formula (I) are useful as analgesics. They are therefore useful for treating or preventing pain. They can be used to improve the condition of a host, typically a human being who suffers from pain. They can be used to relieve pain in a guest. In this way, the compounds of the formula (I) can be used as a preventive analgesic to treat acute pain such as skeletal muscle pain, post-operative pain and surgical pain, chronic pain such as chronic inflammatory pain. (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 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 disorder which include dyspepsia without ulcer, non-cardiac chest pain and in particular irritable bowel syndrome. Irritable bowel syndrome is a gastrointestinal disorder characterized by the presence of abdominal pain and alters bowel habits without any evidence of organic disease. The compounds of formula (I) in this way can be used to alleviate the pain associated with irritable bowel syndrome.

The condition of a human patient suffering from irritable bowel syndrome in this way can be improved.

The compounds of the formula (I) may also be useful in the treatment of neurodegenerative diseases, such as Alzheimer's disease, ALS, motor neuron disease and Parkinson's disease. The compounds of the formula (II) can also be useful in neuroprotection and in the treatment of the following neurological problems: attack, cardiac arrest, respiratory tract, injury to the traumatic brain, spinal cord injury or symptoms.

In addition, the compounds of the formula (I) are also useful in preventing or reducing dependence on, or preventing or reducing tolerance or tolerance against, an agent that induces dependence. Examples of dependence-inducing agents include opioids (e.g. morphine), depressing CNS (e.g., ethane.), Psi coes t imulant (e.g. cocaine), and nicotine.

Therefore, the use of a compound of the formula (I) in the manufacture of a medicament for use in the treatment of a non-junction, as described above, is also provided herein. . The present invention further comprises a method of treating a patient suffering from, or susceptible to, a disorder, his or her condition as described in the foregoing, which method comprises administering to the patient a therapeutically effective amount of a compound of the invention. formula (I). The term "treatment" as used herein includes the treatment of established disorders, and also includes prophylaxis thereof.

The compounds according to the invention are particularly useful in the treatment of epilepsy and bipolar disorder, especially epilepsy.

The precise amount of the compound of the formula (I to the salt thereof) is administered to a host, particularly a human patient, it will be the responsibility of the concomitant physician.However, the dose employed will depend on a number of factors including the age and sex of the patient. patient, the precise condition that is treated and its severity, and the route of administration.

The compound of the formula (I) and its salts can be administered at a dose from 0.1 to 10 mg / kg of body weight per day and more particularly from 0.5 to 5 mg / kg of body weight per day, calculated as the free base . The dose range for adult humans is generally 5 to 1000 mg / day, such as 5 to 200 mg / day, preferably 10 to 50 mg / day, calculated as the base lyore.

While this is possible for the compound of the formula (I) or a pharmaceutically acceptable derivative thereof to be administered as the raw chemistry, it is preferable to present it as a pharmaceutical formulation. The formulations of the present invention comprise the compound of the formula (II) or a pharmaceutically acceptable derivative thereof together with one or more acceptable carriers or diluents thereof and optionally other therapeutic ingredients. acceptable "in the sense of being compatible with the other ingredients of the formulation and not deleterious to the container thereof.

The formulations include those suitable for oral, parenteral administration (including subcutaneous by injection or by depot tablet, int radiome, intrathecal, intramuscular for example, by deposit and intravenous), rectal and topical (including dermal, buccal and sublingual), although the most appropriate routes may depend on, for example, the condition and disorder of the recipient. The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of conducting in association with the compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately conducting in association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, forming the product in the desired formulation.

Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules, trocysts or tablets (for example chewable tablets, in particular for pediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or 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 can also be presented as a bolus, electuapo or paste.

A tablet can be made by means of compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, active surface agent or dispersant. The molded tablets can be made by molding in a suitable machine a mixture of the pulverized compound moistened with an inert liquid diluent. The tablets may be optionally coated or labeled or they may be formulated to provide slow or controlled release of the active ingredient present.

Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, ba ct er i osts and solutes which give the isotonic formulation with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which include suspending agents and thickening agents. The formulations may be presented in unit dose or multiple dose containers, for example sealed vials and small vials and may be stored in a freeze-dried condition which requires only the addition of a sterile liquid carrier, for example, water for injection, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the previously described genus.

Formulations for rectal administration can be presented as a suppository with the usual carriers such as cocoa butter, hard fat or pollen 11 lengl i col.

Formulations for topical administration in the mouth, for example buccally ubiquitous, include lozenges comprising the active ingredient in a sabotex base such as sucrose and acacia or tragacanth, and lozenges comprising the active ingredient in a base such as gelatin. and glycerin or sucrose and acasia.

The compounds of the invention can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (for example subcutaneously or intimamusically) or by intramuscular injection. In this way, for example, the compounds of the invention can be formulated with suitable hydrophobic or polymeric materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as poorly soluble derivatives, for example as a low salt soluble.

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

Preferred dosage unit formulations are those that contain an effective daily dose, as listed above, or an appropriate fraction thereof, of the active ingredient. Conveniently it can be from 5 mg to 1000 mg, more conveniently from 5 mg to 200 mg (for example 5, 25 and 100 mg) and very conveniently from 10 mg to 50 mg, calculated as the free base.

When the compounds of the formula (I) are used in combination with other therapeutic agents, the compounds can be administered either sequentially or simultaneously by any convenient route.

The compounds of the formula (I) (which naturally also include compounds of the formula (Ia) and (Ib) and pharmaceutically acceptable salts and solvates thereof can be prepared by methods known in the art for the preparation of analogous examples. In particular, the compounds of the formula (I) can be prepared by the methods described in the following and which form a further aspect of the invention In the following processes R "1, R% R3 and R4, unless is specified in another form are as defined in the above for the formula (I).

According to a general process (A), a compound of the formula (I) can be prepared under suitable reaction conditions from a compound of the formula (II) (ID 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.

A compound of the formula (II) can be suitably prepared from a compound of the formula (III) (lll) by reaction with a compound of the formula (IV) RX (OH) 2. Examples of the compounds of the formula (IV) R 1 B (0H) 2 include 2,3,5-trichlorobenzoprotene acid, 2,3-di c 1obenzobenzoic acid, 2,5-dichlorobenzanboronic acid, acid 1 -naphthalenboronic and acid 2 -na ft alenboróni co. Suitably, Hal (A) in formula (III) above is more reactive than Hal (B), and suitably Hal (A) is selected from bromide and iodide, while Hal (B) is appropriately chloride. The compounds of the formula (IV) are either commercially available or can be suitably prepared from commercially available benzene analogues, for example 1-bromo-2,3-dichlorobenzene or 2-bromo-4,6-di-chloroan-1-ina. as described herein, later in greater detail in the appended Examples.

A compound of the formula (III) can be suitably prepared by further halogenation of a compound of the formula (V) for example by the reaction with a halogenating agent, such as N-bronium succinimide, with stirring at room temperature for several hours.

A compound of the formula (V) can be prepared from a di-halo compound of the formula (SAW) by the reaction with RX, where Hal (B) and Hal (c), which may be the same or different halogen substituents. Appropriately both Hal (B) and Hal (C) are chloride. The compounds of the formula (VI) are commercially available.

According to another general process (B), a compound of the formula (I) can be prepared from a compound of the formula (VII) (VII) where Hal represents a halogen atom, suitably bromide or iodide, by reaction with a compound of the formula (IV) as described above.

In the case where both of R3 and R4 represent hydrogen, a compound of the formula (VII) may be commercially available. Alternatively, a compound of the formula (VII) can be prepared from a compound of the formula (VIII) AND (VIII) where Y is a group easily convertible to R.

For example, in the case where Y represents NH2, this can be converted to -NHC (= 0) CH3 by reflux in the presence of an acetylating agent, such as acetic anhydride.

A compound of the formula (VIII) can be prepared from a compound of the formula (IX) (IX) by the reaction with R "H under suitable conditions For example a compound of the formula (IX) can be reacted with ammonia in an autoclave for several hours.

A compound of the formula (IX) can be prepared from a compound of the formula (X) (X) which in turn can be prepared from commercially available compounds of the formula (VI) described in the foregoing.

According to an additional process, C, the compounds of the formula (I), wherein R "represents NH2 can be prepared by means of hydrolysis and oxidation of a compound of the formula (XI) R1 X HN CN ./- \ NH RJ (XI) a salt of the same according to conventional procedures, for example by neutralizing a salt of a compound of the formula (XI), for example, with lithium hydroxide in a suitable solvent such as an alcohol, for example methanol, under which conditions of spontaneous oxidation with a compound of the formula (I) occurs.

The compounds of the formula (XI) can be prepared by reacting compounds of the formula (XII) R 1 C (O) H with compounds of the formula (XIII) R3 or a salt thereof, in the presence of a source of cyanide, for example potassium cyanide. The compounds of the formula (XIII), wherein R 1 is phenyl trihalido-substituted, for example 2,3,5-tpclorobenzaldehyde, are known and can be prepared according to the methods described in 095/07877. The compounds wherein R1 represents alternative values are either known or can be prepared according to known methods for the preparation of known compounds.

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

According to an additional process, D, the compounds of the formula (I) can be converted into corresponding compounds of the formula (I) using suitable reaction techniques. For example, compounds of the formula (I), wherein R 3 represents -NHC (= 0) Ra can be converted into compounds wherein R 3 represents -NH 2 by hydrolysis, for example by reaction with an aqueous hydrochloric acid. In addition, the compounds of the formula (I), in which R 4 represents hydrogen can be converted into compounds wherein R 4 represents -CN by main halogenation by reaction with a halogenating agent, such as N-bromusuccinimide, followed by the reaction with a suitable source of cyanide ions, for example a mixture of sodium cyanide and copper cyanide (I). In addition, the compounds of the formula (I), in which R 4 represents CN can be converted into compounds in which R 4 represents -CH 2 OH by the formyl derivative which can be prepared by reacting the compound -CN with di is obut hydride i 1 aluminum in toluene, followed by hydrolysis. The formyl derivative is then reduced to the compound -CH2OH using, for example, sodium borohydride in ethanol. The compounds in which R 4 represents -CH, 0H can be converted into compounds in which R "represents -CH 20 Rd by alkylation In addition, of the formula (I), in which R 4 represents -CN can be converted into compounds in which those which R4 represents methyl by the formyl derivative, prepared as described above, which is then compounded in tosylhydrazone, by the reaction with p-t ol ol uensul fonhydra z ida, followed by the reaction with ca tecolborane in chloro form / tetrahydrofuran.

The various general methods described in the above may be useful for the introduction of the desired groups at any stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different directions in such multi-step processes. The sequence of the reactions in the multi-step processes should naturally be selected for the reaction conditions using unaffected groups in the molecule which are desired in the final product.

The following Examples, which should not be construed as constituting a limitation thereof, are provided to illustrate the purpose.

EXAMPLE 1 2, 5-D? Am? No-3- (2, 3, 5-tpclorofen? L) pirazma 2, 3, 5-Tr? Chlorobromobenzene Sodium nitrite (3.88 g, 0.056 moles) is added in portions to concentrated sulfuric acid (28.16 ml) stirred below 10 ° C A solution of 2-boron-4,6-d? Oanil i na (12 g, 0.05 moles, Lancaster) in glacial acetic acid (126 ml) are added keeping the temperature below 10 ° C. The mixture is stirred below 10 ° C. For 1 hour and then slowly added to a stirring solution of cuprous chloride (10.11 g, 0.10 mole) in concentrated hydrochloric acid (101.05 ml) at room temperature. The mixture is then stirred at room temperature for 17 hours. The product is filtered, washed with water (3 X 50 ml), dissolved in chloroform (150 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo to give the desired product. Performance of lOg (77%). P.f. 55-57 ° C. 2. acid 2, 3, 5- t r i cl orobencenboróni co A solution of 2, 3, 5-trichlorobenzene (8.60 g, 0.033 mole) in dry ester (33 ml) and bromoethane (4.73 ml, 7.31 g, 0.067 mole) is added dropwise to a suspension of magnesium swarf (2.80 g, 0.12 moles) in dry ester (21.50 ml) at room temperature. The mixture is refluxed for 0.50 hours and cooled to room temperature. The mixture is then added dropwise under nitrogen to a solution of triethyl ether (5.16 ml, 5.16 g, 0.05 mol) in dry ester (8.60 ml) keeping the temperature below -60 ° C. This is heated at room temperature overnight, then cooled in a bath with ice and treated with 2M hydrochloric acid (10 ml) - the ether layer is separated, washed and the filtrate evaporated in vacuo. The residue is triturated with 40-60 ° C of petroleum ether, filtered and dried in vacuo. Yield 4.57 g (61%), m.p. 257-260 ° C.

ROUTE A 3. 2-chloro-6-amino-p? Raz? Na A suspension of 2, 6-d? Chlorophora zxine (100 g, 0.67 moles, Lancaster) in 0.880 ammonia (500 ml) is stirred and heated to 150 ° C in an aligned glass autoclave at 20 atmospheres for 20 minutes. hours. The cooled mixture is filtered, washed well with water (200 ml) and dried. The product is recrystallized from chloroform. Yield 41.98 q (48%), m.p. 150-152 ° C. . 2-Chloro-o-3-bromo-6-am? nopira zin and 2-am? no-3-bromo-6-chloropyridine A solution of 2-chloro-6-aminopropyl (20 g, 0.15 mol) in chloroform (1940 ml) is stirred at 5 ° C to 0 ° C. N-bromosuccimide (27.58 g, 0.15 mol) is added in portions maintaining the temperature between -5 and 0 ° C. The mixture is warmed to room temperature and stirred for 3.50 hours. The mixture is then washed with saturated, aqueous sodium bicarbonate (1 x 300 ml), then water (1 x 500 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated down in vacuo. The residue is purified by "flash chromatography" using chloroform as the eluent. Yield of 2-cl or o-3-bromo-6-am? Nop? Razma 13.89 g (43%), m.p. 146-147 °. Yield of 2-ammo-3-bromo-6-cl or opy a zin 4.90 g (15%), m.p. 124-125 ° C. . 2 -Amino-6-chloro-3- (2, 3, 5-trichlorophen?) Pyrazine A solution of 2,3,5-trichlorobenzanboronic acid (1.62 g, 7.18 xl0 ~ 3 moles) in absolute ethanol (2.05 ml) is slowly added to a mixture of 2-amin-3-bromo-6-chloropyrazole. Na (1 g, 5.1xl0 ~ 3 moles) and tet raki s (trif enilf os f ina) palladium (O) (0.334 g, 2.89x IX4 moles) in benzene (10.20 ml) / 2 M aqueous sodium ca bbon. (5.50 ml). The mixture is refluxed for 17 hours. The cooled reaction mixture is evaporated in vacuo and then extracted with chloroform (50 ml). The chloroform layer is washed with water (2x30 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated downwards in vacuo. The residue is triturated with 40-60 ° C of petroleum ester, filtered and dried in vacuo. Yield 0.205 g (14%), m.p. 211-214 ° C 6. 2, 6-D? Am? No-3- (2, 3, 5-tr? Chlorophen? L) pyrazine A suspension of 2-ammo-6-chloro-3 - (2, 3, 5 -tr? Chlorophen? L) p? Raz? Na (0.3 g, 9.71 x 10 ~ 4 mol) in absolute ethanol (4 ml) and 0.880 aqueous ammonia (8.24 ml) is stirred and heated in an autoclave at 180 ° C for 44 hours. The cooled mixture is evaporated in vacuo, and the residue is extracted with chloroform (3x30 ml). The combined chloroform extracts are dried over magnesium sulfate, filtered and the filtrate evaporated downwards in vacuo. The residue is purified by "flash chromatography" using chloroform to chloroform: methanol 89: 2 as the eluent. The product is triturated at 40-60 ° C with petroleum ether, filtered and dried in vacuo. Yield 0.115 g (56%), m.p. 178-180 ° C.

ROUTE B 2, 6-D? Am? No-3-bromop? Ra na A suspension of 2-chloro-3-bromo-6-aminopy ra zine (15 g, 0.072 mol) in absolute ethanol (150 ml) and 0.880 ammonia (375 ml) is stirred and heated in an autoclave at 160 ° C and 20 atmospheres, for 16 hours. The cooled mixture is evaporated in vacuo and extracted with hot methanol (3 x 1909 ml). The combined methanol extracts are evaporated in vacuo. The residue is dissolved in hot chloroform, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue is triturated with 40-60 ° C petroleum ether, filtered and dried in vacuo. Yield 5.51 g (40%), P.f. 176-178 ° C. 2-Amino-3-bromo-6-acetamidopyrazine A mixture of 2, 6-diamino-3-br omopi razi na (10.50 g, 0.056 mol) in 1. 1. dry dimethoxy ethane (1168 ml) and acetic anhydride (7.91 ml, 8.56 g, 0.084 mol) is subjected to reflux under nitrogen for 2.50 hours. The cooled mixture is evaporated in vacuo. The residue is triturated with ether, filtered and dried in vacuo. Yield 10.31 g (80%), m.p. 218-221 ° C. 2 - . 2-amino-6-acetamido-3- (2, 3, 5-tpclorofen? L oirazma A mixture of 2-ammo-3-bromo-6-ace t ami dopí razi na (7.00 g, 0.03 mol) in benzene (609.90 ml) and te tra ki s (trif eni 1 f os f ina) pa 1 adi o (0) is stirred under nitrogen at room temperature for 10 minutes. 2M aqueous sodium carbonate (30.24 ml) is added to the mixture followed by a solution of 2, 3, 5-t-chlorobenzeneboron L co (6.83 g, 0.03 mol) in absolute etl (7.07 ml) and the mixture is subjected to reflux under nitrogen for 17 hours. An additional equivalent of 2,3,5-t-chlorobenzene-2-carbon acid in absolute etl is then added and the mixture is refluxed for an additional 7.50 hours. Finally, another equivalent of 2,35-trichlorobenzeneboronic acid in absolute et is added to the mixture and is refluxed for 17 hours. The cooled mixture is evaporated IR vacuo. The residue is dissolved in chloroform (150 ml), washed with saturated aqueous sodium bicarbonate (1 x 100 ml) and water (1 x 199 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is filtered off. evaporate m vacuo The residue is purified by "flash chromatography" using chloroform to gold form: me tanol 98: 2 as the eluent. Yield 3.02 g (30%), m.p. 200-203 ° C. 2, 6-D? Am? No-3- (2, 3, 5-tr? Chlorophen?) Pyraz A suspension of 2-amino-6-ace t am-do-3- (2, 3, 5- tricl orof eni 1) pyrazam (2.97 g, 8.96 x L0 ~ 3 moles) in 12M hydrochloric acid (1.31 ml) ) and water (4.04 ml) is refluxed for 1.75 hours. The cooled mixture is then basified with 0.880 aqueous ammonia (5 ml) and extracted with chloroform (3 x 50 ml). The combined chloroform extracts are dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated m vacuo at 80 ° C. Yield 2.29 g (88%) m.p. 178-180 ° C.

ROUTE C 11 Bromhidrat or 2 -. { [c i ano- (2, 3, 5-tpclorophenyl) -methyl] -ammo} -acetamidma aminoace tamidine dibromhydrate (162.1 g, 0.774 moles) is added in portions to a solution of 2, 3, 5-tr? chlorobenzaldehyde (200.9 g, 0.851 moles) in metl (2.43 liters) at room temperature. Once the addition is complete, potassium cyanide (50.4 g, 0.774 moles) is added in one portion with the resulting mixture. The suspension is then stirred at 25 ° C for 4 hours before it is heated to 50 ° C. The mixture is stirred at 50 ° C for 24 hours. The metl is then removed m va cu, the resulting solid is suspended in water (1.5 liters) and ethyl acetate (2.5 liters) and collected by filtration. The solid is then dried m va c u o at 50 ° C overnight to give the desired product. Yield 96.31 g (33.4%), X-NMR (d-6 DMSO) d / ppm 8.72 (2H, broad r, NH); 7.99 (1H, d, J 2.3Hz, ArH); 7.79 (1H, d, J 2.3Hz, ArH); 5.39 (1H, d, j 10.6Hz, ArCH (CN) NH); 4.35 (1H, m, ArCH (CN) CH; 3.56 (2H, d, J 6.4Hz, ArCH (CN) NHCH2C? = NH) NH2). 12 2, 6-D? Am? No-3- (2, 3, 5-tr? Chlorophen? L) pyrazine 2- Hydrobromide. { [C? an- (2,35-tr? chlorophen? l? -me ti 1] -amino.}. -acetylamidine (95.36 g, 0.256 mol) is added in portions to a solution of lithium hydroxide monohydrate. (16.11 g, 0.3814 mol) in metl (1.9 liters) at room temperature The resulting solution is stirred at room temperature for 3 hours before being evaporated to dryness m vacuo.The resulting solid is suspended in water (1.15 liters and collected by After drying at 50 ° C m, the unpurified material is purified by refluxing from toluene to give the desired product Yield 69.51 g (93.8%), mp 178-180 ° C .

EXAMPLE 2 2, 6-D? Am? No-3- (2, 3-d? Chlorophen? L) p? Razma 1. Acid 2, 3-d? Chlorobenzeneboron? Co A solution of 1-bromo-2,3-di chlorobenzene (20 g, 0.088 mol, Aldrich) in dry tetrahydrofuran (44.24 ml) is added dropwise to a solution of n-butyllithium (1.6 M in hexane). , 66.36 ml, 0.11 moles) in anhydrous water (16 ml), keeping the temperature below -65 ° C. The resulting light yellow suspension is stirred at -78 ° C for 75 minutes. T rimetiborate (13.28 ml) is added in drops, 12.16 g, 0.12 moles) maintaining the temperature below -55 ° C. The resulting light yellow solution is heated at room temperature overnight. The excess of n-bu ti 1 -1 i t i o is decomposed with water (30 ml) and the reaction mixture is evaporated in vacuo. The residue obtained is suspended in water and acidified with 2M hydrochloric acid (10 ml). The insoluble solid is filtered, washed well with water and dried. The solid is suspended in 60-80 ° C petroleum ether, stirred at room temperature for 10 minutes, the filtrate is dried in vacuo. Yield 8.42 g (50%), m.p. 235-238 ° C. 2. 2 -Amino- 6-chloro-3- (2,3-dichlorophenyl) pyrazine This compound is prepared in a manner analogous to Example 1 Route A, starting from 2-amino-3-brorno-6-cl oropy r a zin. Yield 0.343 g (26%), P.f. 179-181 ° C. 3. 2, 6-Diam? No-3- (2, 3-dichlorophenyl) pyrazine This compound is prepared in a manner analogous to Example 1 Route A, starting from 2 -ami no-6-chlor or-3 - (2, 3-Dichloropheni 1) pyraz, by reaction with 0.880 ammonia. Yield 0.195 g, P.f. 169-170 ° C.

EXAMPLE 3: 2, 6-D? Am? No-3- (2, 5-d? Chlorophen? L) pyraz 1. Acid 2, 5 -di chlorobenzeboronium co This compound is prepared in a manner analogous to the compound in Example 2 starting from 2,5-di or orbromobenzene (Aldrich). Yield 2.19 g (55%), P.f. 278-280 ° C. 2-Am? No-6-acetamido-3 - (2, 5-cyclochlorophenyl) pyrazam This compound is prepared in a manner analogous to Example 1 Route A, starting from 2 -ami no-3-bromo-6-acetam? Dop? Raz.na. Renning 0.45 g, P.f. 152-154 ° C. 3. 2, 6-D? Am? No-3- (2, 5-c? Chlorophenyl) p? Raz? Na This compound is prepared in a manner analogous to Example 1 Route B, starting from 2-ammo-6-acetamido-3- (2, 5-d? Chlorophen? L) p? Razma. Yield 0.123 g, P.f. 159-160 ° C.

EXAMPLE 4: 2, 6-D? Am? No- (l-naphthalene) p? Raz? Na 2-Ammo-6-chloro-3- (1-naphthalene) pyraz This compound is prepared in a manner analogous to Example 1 Route A, starting from 2-ammo-3-bromo-6-chlorop? ra zma y. Yield 0.709 g (58%), mp 138-139 ° C. 2. 2, 6-D? Am? No- (1-naphthalene) pyrazine This compound is prepared in a manner analogous to Example 1 Route B, from 2-amino-6-chloro-3- (1 -na f talen) pi ra zine and 1-acid α-phthalate 1-boronic (Lancaster), by reaction with 0.880 ammonia. Yield 0.167 g (50%), 180-183 ° C.

EXAMPLE 5 2, 6-D? Am? No-3- (2-naphthalene) pyrazine 1. Acid 2 -na fta lenboróni co This compound is prepared in a manner analogous to the compound in Example 2 from 2-bromone phthalene (aldrich). Yield 1.71 g (40%), P.f.280-282X: 2. 2 -Ammo- 6-acetamido-3- (2-naphthalene) p razina This compound is prepared in a manner analogous to Example 1 Route B, starting from 2-amino-3-br omo-6-acetam? Dop? Razma. Yield 0.46 g, P.f.235-237 ° C. 3. 2, 6-D? Am? No-3- (2-naphthalene) p? Raz? Na This compound is prepared in a manner analogous to Example 1 Route B, from 2-amino-6-acetamido-3- (2, naphthalen) p? Razma. performance 0. 121 g, P.f. 168-170X.

EXAMPLE 6 2 - . 2 - . 2 -Arrimate- 6- (4-met? L-l-p? Perazm? L) -3- (2, 3, 5 'trichlorofeml) pyraz The 2-amino-6-chloro-3- (2, 3, 5-tr? Chlorophen? L) -pyrazine (0.215 g, 7. ox 10-3 mol) of Example 1 Route A and 1 -me 11 lpipera zma (5 ml), Aldrich), are heated at 140 ° C for 1 hour. The mixture is evaporated in vacuo and the residue is purified by "flash chromatography" eluting with ethanol: di C 1 ormeme, 0-4%. The product is dissolved in the minimum of di chloromethane and hexane (10 ml), added slowly to give yellow needles. Yield 0.247 g (95%), P.f. 185 ° C.

EXAMPLE 1: 2-Am? No-6-d? Emt? Lammo-3- (2,3-dichlorophenyl) pirazi na This compound is prepared in a manner analogous to the compound in Example 6 from 2-bromo-6-cl or o- 3 - (2, 3 -di c 1 or of eni 1) pi raz ina (Example 2? dimethylamine (Aldrich), mp 147-148 ° C EXAMPLE 8: 2 -Amino-6-d? Met? Lam no-3- (1-naphthalene) pyraz This compound is prepared in a manner analogous to the compound in Example 6 from 2-amane-6-chloro-3- (l-naphthalene) p? Razma (Example 4). P.f. 131 ° C.

EXAMPLE 9: 2, 6-D? Chloroprop? Lcarbon? Lammo-3- (2, 3, 5-tpcloro-f eni 1) pi ra zina y_ 2 -Amino-6-c? Cloporp? Lcarbon? Lammo-3- (2, 3, 5 -trichlorophenyl) pyraz Anhydrous pipdma (0.137 ml), 4-dime 111 ami nopyri di na (0.114 g) and cycloperpancarbonyl chloride (0.33 g, 0.286 ml, 3.14 x 10"moles, Aldrich) are added to a solution of 2,6-D. Ammo-3- (2, 3, 5-tri chlor of eni 1) pi raz ina (Example 1), in t there is anhydrous dro furan (12 ml) and the resulting reaction mixture is refluxed at 90 ° C. C for 2.50 hours The suspension obtained is cooled to room temperature and evaporated in vacuo The residue is extracted with ethyl acetate (3x 20 ml), washed with water (2 x 20 ml, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo) The residue is purified by "flash chromatography" using 15:25 hexane ether as the eluent. 2,6-dichloropropylcarbonyl-amino-3- (2,3,5-trichlorophenyl) pyrazine 0.340 g (51%), mp 212-214 ° C. Yield of 2-amino-6-cyclopropi 1 -carbonylamino-3 - (2, 3, 5-trichlorophenyl) pyrazine 0.174 g (31%), Mp 240-244 ° C.

EXAMPLE 10 2,6-Diisopropylcarbonylamino-3- (2, 3, 5-trichlorophenyl) -pyrazine and 2-amino-6-isopropylcarbonylamino-3- (2,3,5-trichlorophenyl) pyrazine These compounds are prepared in a manner analogous to Example 9 starting from 2,6-diamino-3- (2,3,3-tr i chlorofenyl) pi ra zine (Example 1), by the reaction with isobutyryl chloride ( Aldrich). Yield of 2,6-diisopropcarbonylamino-3- (2,3,5-trichlorophenyl) pyrazine 0.3313 g (46%), P.f. 227-229 ° C. Yield of 2-ammo-6-? Soprop? Lcarbon? Lammo-3- (2, 3, 5-trichlorophenyl) pyrazma 0.166 g (29%), P.f. 230-232 ° C.

EXAMPLE 11: 2-Isopropylcarbon - lammo-6-ammo-3- (2, 3, 5 -triclorofeml) pyrazine 1. 2-Isopropylcarbon? Lam? No-6-acetamido-3- (2, 3, 5 'trichlorophenyl) pyrazine This compound is. prepared in a manner analogous to Example 9 from 2-ammo-6-acetamido-3- (2,3,5-t-chlorophen? l) p? raz_na (Example 1) and one equivalent of isobutyryl chloride (Aldrich). Yield 0.120 g, P.f. 230-232 ° C. 2-Isopropylcarbon? Lammo-6-am? No-3- (2, 3, 51 triflorophenyl) pyrazine Stannous chloride (0.182 g, 0.0C96 moles) is added to the suspension of 2-? Soprop? Lcarbon? Lammo-6-acetam? Do-3- (2, 3, 5-tpclorofenil) pirazma (0.13 g, 3.24 x 10"4 molesX in absolute ethanol (6.59 ml) and the resulting mixtures are stirred at 50-60 [deg.] C. for 1 hour 20 minutes.The reaction mixture is cooled and evaporated in vacuo.The residue is extracted with ethyl acetate (3 x 20 ml), washed with water (2 x 20 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated m vacuo.The residue is purified by "flash chromatography" using chloroform: methanol , 99: 1 as the eluent, Yield 0.046 g (40%), Mp 105-108X.

EXAMPLE 12: 2-C? Cloprop? Lcarbon? Lam? No-6-ammo-3- (2, 3, 5 • trichlorofeml) pyrazole 2-C? Clopropylcarbon? Lam? No-6-acetamido-3 '2, 3, 5-tr? Cloroefen? L) pyrazine This compound is prepared in a manner analogous to Example 9 starting from 2-ami no- 6-a ce t ami do-3 - (2, 3, 5-tri-cl orof em L) pi razi na (Example 1) and cyclopropylcarbonyl chloride (Aldrich). Yield 0.387 g (61%) NMR (D6DMSO) d: 0.53 (2H, m), 0.7 (2H, m), 175 (1H, m), 2.18 (3H, s) 7.43 (1HHH, d), 7.87 (1H , d), 9.22 (1H, s), 10.36 (1H, b), 10.83 (1H, b). 2. Cyclopropylcarboni lamino-6-amino-3- (2, 3, 5-trichlorophenyl) pyrazine This compound is prepared in a manner analogous to Example 11 from 2-c? Clopropylcarbon? Lammo-6-acetamido-3- (2, 3, 5-trichloropheniDirazma.) Yield 0.120 g (35%), Pf 188-190 ° C.

EXAMPLE 13 2 - . 2 -Amino- 3- (2, 3, 5-tr? Chlorophen? L) pyrazole A solution of 2,3,5-tr? Chlorobenzene boronic acid (1.54 g, 6.82 mmol) in absolute ethanol (1.5 ml) is added slowly to a mixture of 2-amin-3-chloroplast (0.589 g, 4.54 mmol) and te tra ki s (trif eni 1 f or fi ne) pa ladio (0) ( 0.2399 g, 0.259 mmole) in benzene (10.5 ml) / 2M aqueous sodium carbonate (4.54 ml). The mixture is refluxed for 17 hours. The cooled reaction mixture is partitioned between water and ethyl acetate (50 ml). The organic layer is washed with water (2 x 30 ml), dried (MgSO 4) and evaporated. The unpurified product is purified by flash chromatography using chloroform at 0.5% methyl / chloro form as the eluent. The product is then crystallized from 40-60 of gasoline. Yield 0.15 g, 12% p.f. 142-143 ° C.

EXAMPLE 14 2-ammo-6-acetamido-3- (2, 3, 5-tr? Chlorophen? L) pyrazma It is prepared as described above (see example 1.9).

EXAMPLE 15 2-Ammo-6-acetamido-3- (2, 5-d? Chlorofeml) pyraz It is prepared as described in the above (see example 3.2j.

EXAMPLE 16 2-am non-6-acetamido-3- (2-naphthalene) pyrazine It is prepared as described above (see example 5.2).

EXAMPLE 17 -c? Ano-2, 6-d? Am? No-3- (2, 3, 5-tr? Chlorophen? L pirazma -Bromo-2, 6-D? Am? No-3- (2, 3, 5-tpclorofen? L pyrazine N-Bromosucchimide (0.194 g, 1.09 x 10 moles) is added for 20 minutes to a mixture of 2, 6-D? Am? No-3- (2,3,5-tpclorofen? L) p? Raz_na (0.3 g, 1.04 x 10"moles) in dimethyl sulfoxide (10 ml) and water (0.25 ml) under The resulting reaction mixture is stirred at 15 ° C for 1 hour, emptied into ice water (159 ml) and extracted with ethyl acetate (2 x 75 ml) .The extract is then washed with water. 2 M sodium carbonate solution (50 ml) and water (100 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo.The residue is purified by "flash chromatography" using 5-13% of ethyl acetate in cyclohexane as the eluent Yield 0.183 g (48%), Mp 222-224 ° C. 2. 5-C? An-2, 6-D? Am? No-3- (2, 3, 5-tr? Chlorophen? 1) - pi ra z ina A mixture of 97% sodium cyanide (0.064 g, 1,306 x 10 ~ 3 moles) and 90% copper (I) cyanide (0.135 g, 1.30 x 10"3 moles) in dime ti 1 fomami da seca (5 ml) is stirred and heated to 130 ° C. To the resulting clear solution is added 5-bromo-2,6-diamino-3 - (2, 3, 5, 1, 1-chloro-phenyl) pi-a-a (0.35 g, 0.95 × 10 ~ 3 moles) in small portions, and the solution is maintained at 140-150 ° C for 16 hours.The reaction mixture is cooled and evaporated m vacuo.The residue is extracted with ethyl acetate (100 ml), Wash with water (100 ml) and brine and 100 ml), dry over anhydrous magnesium sulfate, filter, and filter the filtrate off with vacuo.The residue is purified by "flash chromatography" using 5-17% ethyl acetate. in cyclohexane as the eluent Yield 0.152 g (51%), Mp 277-279 ° C. Analysis calculated for C H 6 N 5 Cl 3 0.02 C 6 H 2: C, 42.23 H, 1.99; N, 22.15. found: C, 42.36 H, 1.78; N, 21.79.

EXAMPLE 18 -H? Drox? Met? L-2, 6-D? Am? No-3- (2, 3, 5 tpclorophenyl) -pyrazine -Form? L-2, 6-D? Ammo-3- (2, 3, 5-tpclorofen? L) - pyrazine Dusobutyl aluminum hydride (1.5 M in toluene) (2.12 ml, 3.18 x IX3 moles) at 0 ° C ba or nitrogen is added in drops to a suspension of 5-c? Ano-2,6-d? Ammo-3 - (2, 3, 5-tpclorofen? L) piraz a (0.5 g, 1.59 x 10_i moles) in dry toluene (70 ml) and the reaction is stirred at 0 ° C for 1 hour. An additional equivalent of diiso s hydride is added then the mixture is again stirred at 0 ° C for 1 hour. Methanol (1 ml) is carefully added at 0 ° C under nitrogen to destroy the excess hydride and the reaction is warmed to room temperature. Ethyl acetate (100 ml) is added and the solution is washed with 5% citric acid solution (2 x 100 ml). The organic layer is separated, washed with brine (100 ml), dried over magnesium sulfate, filtered and the filtrate evaporated m vacuo to give the desired product. Yield 0.340 g (67%), NMR (D6DMSO) d: 7.53 (1H, d), 7.91 XH, d), 6.90-X80 (4H, d), 9.49 (1H, s). 2 5-H? Drox? Met? L-2, 6-D? Am? No-3- (2, 3, 5-tpclorofenyl) pira zma To a stirred solution of 5-formyl 1 -2,6-d? Amin-3- (2, 3, 5-trichlorophemethyl) pyrazine (0.198 g, 6.24 x 10 ~ 4 mol) in ethanol (100 ml. sodium borohydride (0.035 g, 0.35 x 10 4 moles) is added at room temperature, the reaction is stirred at room temperature under nitrogen for 1 hour, water (1 ml) is added and the solution is evaporated in vacuo. The residue is dissolved in ethyl acetate (299 ml), washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo.The product is purified by "flash chromatography" using 11-40% ethyl acetate in cyclohexane as the eluent.

Yield 0.104 g (52%, Mp 185-186 ° C. NMR (D6MMSO) d: 4.32 (2H, d), 4.98 (1H, t), 5.56 (2H, s), 5.85 (2H, s), 7.30 ( 1H, d), 7.76 (1H, d).

EXAMPLE 19 -Methyl-2,6-Diamino-3- (2, 3, 5-trichlorophenyl) pyrazine 1. 5-Formyl-2,6-Diamino-3- (2, 3, 5-trichlorophenyl) -pyrazine, cough i lhidr a zone -Formi 1 -2, 6-diamino-3 - (2, 3, 5 -trichlorophenyl-pyrazine (0.330 g, 1.04 x 10-3 moles) is added to a solution of p-toluenesulfonhydrazide (0.3 g, 1.61 x 10-3 moles) in methanol (50 ml). The solution is refluxed under nitrogen for 4 hours, cooled to room temperature and the solvent evaporated in vacuo. The residue is purified by "flash chromatography" using 0-30% ethyl acetate in cyclohexane as the eluent. Yield 0.270 g (53%).

Mass Spectrum: (elect ro-dew) 487 (MH +) Retention Time 3.33 minutes Micromass Platform Series 2 5 minutes Gradient (2mmABZ) Instrument: Red Flow Rate ml / minute Eluents A - 0.1% V / V Formic Acid + Ammonium Acetate 10 mmoles B- 95% MeCN + 0.05% Formic Acid V / V Col umna 5 cm x 2.1 mm ID ABZ + PLUS Injection Volume: 5 μl Temperature TA T lempo A% 0.00 100 0 3.50 0.0 100 5.00 0.0 100 5.50 100 o -Met? L-D? Ammo-3- (2, 3, 5-tpclorofen? L i - Add t ecolborane (1.0 M in tetrahydrofuran) drops (1.09 ml, 1.09 x 10-3 moles) at 0 ° C under nitrogen to a suspension of 5-coughs-lh? Drazone-2,6-d? Am? no-3- (2, 3, 5 -tr? chlorophen? l) p? razma (0.265 g, 5.46 x 10-4 mol) in dry chloroform (15 ml) and tetrophuran (20 ml). The reaction is stirred at 0 ° C for 1 hour, maintained and sodium acetate tphydrate (g, 5.46 x 10 -4 moles) is added. The mixture is warmed to room temperature, stirred for 1 hour and the solvents evaporated m vacuo. The residue is dissolved in ethyl acetate (100 ml), washed with 5% sodium carbonate solution, then water, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue is purified by "flash chromatography" using 10-25% ethyl acetate in cyclohexane as the eluent. Yield 0.017 g (10%), NMR (CDC1.) 5: 2.35 (3H, s) 4.10 (2H, b), 4.45 (2H, b), 7.35 (1HHH, d), 7.52 (1H, di.

Mass Spectrum: (elect ro-rocio) 305 (MH +) Retention Time 2.89 minutes (Conditions for Example 19.1) Examples of Pharmacy Sterile Formulations Example A Mg / ml Compound of the Invention 0.1 mg Sodium Chloride USP 9.0 mg Water per USP Injection the rest for 1 ml The components are dissolved in a portion of the water for injections and the solution and solution is made up to a final volume to provide 0.1 mg / ml of the compound of the invention. Where a salt of the compound is used, the amount of the compound is increased to provide 0.1 mg / ml of the free base. The solution can be packaged by injection, for example by filling and sealing in the vials, small vials and syringes. These can be aseptically filled and / or thermically and sterilized by means, for example, in the form of an autoclave at 121 ° C.

Other sterile formulations can be prepared in a similar manner to obtain alternative concentrations of the compound.

E j empl o B Mg / ml Compound of the Invention 0.5 mg Peanut tol 50.0 mg Water for Injections USP the rest for lml The components dissolve in a portion of the Water for Injections. It is made up to the final volume and mix until homogenous. The formulation of the filter during a filter and filling that sterilize in small glass jars. The small bottles are lyophilized and sealed. It is reconstituted with an appropriate solvent before use.

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

E jmplo C Understanding of the Tablet Direct Mg / Tablet Compound of the Invention 5.0 mg Magnesium Stearate 4.0 mg Microcrystalline Cellulose (Avicel PH102) the rest for 400.0 mg The compound of the invention is passed through a 30 mesh screen and mixed with the Avicel and Magnesium Stratum. The resulting mixture is compressed into tablets using a suitable tab.eta pressure setting with 11.0 mm perforated diameter to provide 5 mg of the Compound of the invention per tablet. Tablets of different resistances, for example containing 25 or 100 mg / tablet of the Compound of the invention can be prepared in a pure form.

E jmplo D Wet Granulation Tablet Mg / Tablet Compound of the Invention 5.0 mg Pregelatinized Starch 28.0 mg Sodium Starch Glycolate 16.0 mg Magnesium Stearate 4.0 mg Lactose sufficient amount for 400.0 mg The compound of the invention, Lactose, Starch Pregel to T initiate and Glycolate Sodium Starch are mixed dry and then granulated using an appropriate volume of Purified Water. The resulting granules are dried and then mixed with Magnesium Stearate. The dried granules are compressed using a suitable tablet pressure setting with 11.0 mm perforated diameter to provide 5 mg of the Compound of Invention per tablet.

Tablets of different strengths such as 25 and 100 mg / tablet are prepared.

E j empl o E Hard Gelatin Capsule mg / capsul a Compound of Invention 5.0 mg Cellulose My croen s ta 1 ina - (Avicel PH102) the rest - up to 700.0 mg The compound of the invention is passed through a 30 mesh screen and then mixed with microcrystalline cellulose to provide a homogeneous mixture. The mixture can then be filled into the size of a layer of OEL hard gelatin capsule to provide capsules containing 5.0 mg / capsule of the Compound of the Invention. Alternative resistances such as 25 or 100 mg / capsule of Compound of the Invention can be made in a similar manner.

Example F Soft Gelatin Capsule mg / capsule Compound of the Invention 10.0 mg Polyethylene glycol 90.0 mg Propylene glycol the remainder up to 200.0 mg Polyethylene glycol and Propylene glycol are mixed together using heat as necessary. It is stirred until homogeneous. The Compound of the invention is added and mixed until homogeneous. It is filled into a gelatin dough suitable for soft gelatin capsules containing 200 mg of the formulation, to provide 10.0 mg / capsule of the Compound of the Invention.

Alternative resistances, for example, 5 and 25 mg / capsule of the Compound of the Invention can be prepared in a similar manner.

E g Syrup Compound of the Invention 5.0 mg Sorbitol solution 1500.0 mg Gl i ceron 1000.0 mg Sodium Benzoate 5.0 mg Flavoring 12.5 mg Purified Water the rest for 5.0 ml The Sodium Benzoate is dissolved in a portion of the purified water and Sorbitol Solution is added. The Compound of Invention, Flavoring and Glycerol is added and mixed until homogeneous. The resulting mixture is made volume with the purified water.

Other Formulations E j us H Assumptions i tor i o mg / suppository Compound of the Invention 10.0 mg Witepsol 32, fat lasts the rest 2000.0 mg Melt Witepsol W32 at approximately 36 ° C. To a portion of this the Compound of the Invention is added and mixed. It is incorporated from the molten itepsol 32 and mixed until homogenous. The template is filled with 2000 mg of the formulation to provide 10.0 mg / suppositories of the Compound of the invention.

Implo Transmitter co Compound of the Invention 5.0 mg Silicone Fluid 90.9 mg Colloidal Silicon Dioxide 5.0 mg Mix the silicone fluid and activate it together and add the colloidal silicon dioxide. The material is then dosed into a subsequent heat sealing polymer sheet, comprising the following: release of the polyester cover, silicone compounds or acrylic polymers adhesive to skin contact, a control membrane to which is a polyolefin ( for example polyethylene or polyvinyl acetate) or polyurethane, and a waterproofing membrane of a polyester polyamide.

Biological Data The compounds of the invention have been shown to have anti-epileptic activity by means, for example, their ability to inhibit extension of the hind limb in the supraximal reading model. It is dosed í.p. in Macho Han Mistar rats (150-200 mg) with a suspension of the test compound in 0.25% of me 111 ce 1 ul to 2 hours before the test. A visual observation is carried out just before the test for the presence of ataxia. A current of 200 mA, duration of 200 milliseconds is applied using the atrial electrodes, and the presence or absence of the extension of the posterior limb is observed.

The compounds according to the invention exhibit the ED50 in the range of 1 to 20 mg / kg when tested in the previous test.

None of the apparent toxic or adverse effects are observed during the previous test due to the administration of the compounds of the invention.

It is made that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it refers.

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

Claims (12)

Claims

1. A compound of the formula (l) characterized because R1 is selected from the group consisting of phenyl substituted by one or more halogen atoms, naphthyl and naphthyl substituted by one or more halogen atoms; R is selected from the group consisting of NH 2 and NHC 1 = 0) Ra; RJ is selected from the group consisting of NRbRc, NHC (= 0) Ra and hydrogen; R ^ is selected from the group consisting of hydrogen, -Cl1alkyl substituted by one or more halogen atoms, -CN, -CH2OH, -CH2ORd and CH2S (0) xRa; in which Ra represents C 1-4 alkyl or C 3 cycloalkyl- R and Rc, which may be the same or different, are selected from hydrogen and C? - alkyl, or together with the nitrogen atom to which they are attached, form a 6-membered nitrogen-containing heterocycle, which heterocycle may to be further substituted with one or more of C 1 alkyl; R is selected from C? -4 alquiloalkyl or C? _ 4alkyl substituted by one or more halogen atoms; x is an integer of zero, one or two; and pharmaceutically acceptable derivatives thereof; with the proviso that R1 does not represent; when R ^ is -NH2, and both of R3 and R4 are hydrogen.

2. The compound according to claim 1, characterized in that R1 is phenyl substituted by one or more halogen atoms.

3. The compound according to the rei indication 2, characterized in that R1 is 2, 3, 5-trichlorofenyl.

4. The compound according to any of claims 1 to 3, characterized in that R ^ and R3 are -NH2.

5. The compound according to claims 1 to 4, characterized in that R 4 is hydrogen or -CH 2 OH.

6. The compound according to claim 5, characterized R 4 is hydrogen.

7. The compound which is 2,6-d? Am? No-3- (2,3,5-tpclorophen? L) p? Razma and pharmaceutically acceptable derivatives thereof.

8. The compound according to any of claims 1 to 7, for use in therapy.

9. A pharmaceutical composition characterized in that it comprises a compound according to any of claims 1 to 7, together with a pharmaceutically acceptable carrier.

10. The use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for use in the treatment of epilepsy, bipolar disorder or manic derangement, pain, functional bowel disorders, neurological diseases 11 va s, Neur opr opr ection, neur odegenera c ion, or prevention or reduction of dependence on, or prevention or reduction of tolreracia or inverse tolerance to an agent that induces dependence.

11. A method, characterized in that it is for treating a patient suffering from, or is susceptible to, epilepsy, bipolar disorder or manic depression, pains, functional bowel disorders, neurological diseases, neuroprotection, neurodegeneration or dependence on, or that have tolerance or inverse tolerance to, an agent that induces dependence.

12. A process for preparing a compound of the formula (I) according to claim 1, characterized in that it comprises: submit a compound of the formula (II (ll) where Hal (B) represents a halogen atom, at suitable reaction conditions; (B> reacting a compound of the formula (VII) VII) where Hal represents a halogen atom, with a compound of the formula (IV) R 1 B (OH) 2; (C) where R represents NH2, by the acylation and oxidation of a compound of the formula (XI) (XI) or a salt thereof according to conventional procedures; or (D) The compounds of the formula (I) can be converted into corresponding compounds of the formula (I), used in the appropriate reaction technique. Summary of the Invention a compound of the formula v (D in which- R ~ is selected from the group consisting of phenyl substituted by one or more halogen atoms, naphthyl and naphthyl substituted by one or more halogen atoms; is selected from the group consisting of NH2 and H Z: = 0; P " is selected from aruoo which consists of NRbRc NH C '= 0, Ra and hydrcse or It is indicated by the group consisting of hydrogen, -alq of C:. -alkyl of C; _4 s sti gone by one more halogen atoms, -CN, -: H; CH, CH; OR 'and - C H: S (0:, R3; in represented the number of C1-4: or 1 qui 1 c of Rc and R ", which may be the most different ones, are selected from hydrogen and alkyl of -, together with the nitrogen atom to which they are attached, form a 6-membered nitrogen containing heterocycle, which heterocycle it can be further substituted with one or more of alauyl of F "is selected from C 1 - alkyl or C 4 substituted alkyl: one or more halogenated atoms; I will find zero, one or two; a e r 1 v a d o s armaceutica entre: ectables de os s m o s; : c n the condition that R "does not represent; -Cl when s a N H • both of themselves, larcaen