KR20050019935A - Pharmaceutical compositions comprising pyrazine compounds - Google Patents

Abstract

A compound of formula (1) and a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, comprising: epilepsy, bipolar disorder or manic depression, pain, functional defecation disorder, neurodegenerative disease, neuroprotection, neurodegeneration Or a pharmaceutical composition for use in preventing or reducing dependence on a dependency-inducing agent or for preventing or reducing resistance or adverse resistance thereto.

<Formula I>

Where

R ¹ is phenyl, naphthyl and one or more substituted by one or more halogen atoms

Selected from the group consisting of naphthyl substituted by halogen atoms;

R ² is selected from the group consisting of —NH ₂ and —NHC (═O) R ^a ;

R ³ is selected from the group consisting of —NR ^b R ^c , —NHC (═O) R ^a and hydrogen;

R ⁴ is hydrogen, -C _1-4 alkyl, at least one halogen atom substituted with -C _1-4 alkyl, -CN,

-CH ₂ OH, -CH ₂ OR ^d and -CH ₂ S (O) _x R ^d ;

here,

R ^a represents C _1-4 alkyl or C _3-7 cycloalkyl,

R ^b and R ^c may be the same or different and selected from hydrogen and C _1-4 alkyl

Or one or more C _1-4 together with the nitrogen atom to which they are attached

To form a six-membered nitrogen-containing heterocycle which may be further substituted with alkyl

To;

R ^d is C _1-4 alkyl substituted by C _1-4 alkyl or one or more halogen atoms

Is selected from;

x is an integer of 0, 1 or 2,

Provided that when R ² is -NH ₂ and both R ³ and R ⁴ are hydrogen, then R ¹ is

Does not indicate.

Description

Pharmaceutical composition containing a pyrazine compound {PHARMACEUTICAL COMPOSITIONS COMPRISING PYRAZINE COMPOUNDS}

The present invention relates to a group of pyrazine compounds and pharmaceutically acceptable derivatives thereof useful for the treatment of central nervous system (CNS) diseases and disorders, pharmaceutical compositions comprising them, their use in the treatment of the disease and methods of preparation thereof.

Many phenyl pyrazine derivatives are known in the prior art. For example, Synthesis (1987), (10), 914-915 describe phenyl pyrazine derivatives, especially including 3- (4-chlorophenyl) -pyrazineamine. However, the prior art literature does not describe any pharmaceutical utility.

The present invention relates to a series of pyrazine derivatives which are sodium channel blockers. In particular, there is provided a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, which is effective in the treatment of certain diseases including CNS diseases such as epilepsy.

The present invention provides a compound of formula (1) and a pharmaceutically acceptable derivative thereof;

Where

R ¹ is phenyl, naphthyl and one or more substituted by one or more halogen atoms

Selected from the group consisting of naphthyl substituted by halogen atoms;

R ² is selected from the group consisting of —NH ₂ and —NHC (═O) R ^a ;

R ³ is selected from the group consisting of —NR ^b R ^c , —NHC (═O) R ^a and hydrogen;

R ⁴ is hydrogen, —C _1-4 alkyl (preferably methyl), at least one halogen atom

With substituted -C _1-4 alkyl (preferably methyl), -CN, -CH ₂ OH, -CH ₂ OR ^d and -CH ₂ S (O) _x R ^d

Selected from the group consisting of;

here,

R ^a represents C _1-4 alkyl or C _3-7 cycloalkyl,

R ^b and R ^c may be the same or different and are selected from hydrogen and C _1-4 alkyl

One or more, in addition to the nitrogen atoms selected or to which they are attached

A 6-membered nitrogen containing heterocycle which may be further substituted with C _1-4 alkyl

Form;

R ^d is C _1-4 alkyl substituted by C _1-4 alkyl or one or more halogen atoms

Is selected from;

x is an integer of 0, 1 or 2;

Provided that when R ² is -NH ₂ and both R ³ and R ⁴ are hydrogen, then R ¹ is

Does not indicate.

A pharmaceutically acceptable derivative means any pharmaceutically acceptable salt or solvate of a compound of formula (1), or a compound of formula (1) or an active metabolite or moiety thereof when administered to a patient (eg, Prodrug) is any other compound capable of providing (directly or indirectly). References made below to the compounds of formula (1) include the compounds of formula (1) and their pharmaceutically acceptable salts.

Suitable prodrugs are well known in the art and include, for example, N-acyl derivatives, such as simple acyl derivatives such as acetyl, propionyl, or RO-CH ₂ − in any of the nitrogens of the compound of formula (1). Groups such as N or ROC (O) -N are included.

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

As used herein, the term C _1-4 alkyl includes straight and branched chain alkyl groups having 1 to 4 carbon atoms, in particular methyl and isopropyl.

The term C _3-7 cycloalkyl includes groups having 3 to 7 carbon atoms and especially cyclopropyl.

As used herein, the term heterocycle includes a 6 membered heterocycle containing at least one nitrogen heteroatom, preferably two nitrogen heteroatoms. Particularly suitable heterocycles are piperazinyl.

R ¹ is suitably selected from unsubstituted naphthyl and phenyl substituted by one or more halogen atoms. In particular R ¹ represents phenyl substituted with one or more halogen atoms, for example di- or tri-halogenated phenyl. Preferred halogen substituent of R ¹ is chlorine. Suitably R ¹ is selected from 2,3,5-trichlorophenyl, 2.3-dichlorophenyl, 2.5-dichlorophenyl, 1-naphthyl and 2-naphthyl. It is especially preferable that R ¹ is 2,3,5-trichlorophenyl.

Suitably R ² is selected from —NH ₂ , isopropylcarbonylamino and cyclopropylcarbonylamino. R ² is preferably -NH ₂ .

Suitably R ³ is hydrogen, -NH ₂ , dimethylamino, 4-methyl-1-piperazinyl, acetamido, isopropylcarbonylamino, cyclopropylcarbonylamino. R ³ is preferably -NH ₂ .

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

More preferably, both R ² and R ³ are —NH ₂ .

Preferred classes of compounds of formula (1) include R ¹ , R ² and R ³ as defined above and R ⁴ is substituted by hydrogen, —C _1-4 alkyl (preferably methyl) and one or more halogen atoms Those selected from -C _1-4 alkyl (preferably methyl).

Preferred compounds of formula (1) are those in which R ¹ is 2,3,5-trichlorophenyl; R ² is -NH ₂ ; R ³ is -NH ₂ ; And R ⁴ is hydrogen

According to a specific embodiment of the present invention, a compound of formula 1a and pharmaceutically acceptable derivatives thereof are obtained.

here,

Hal represents a halogen atom selected from fluorine, chlorine, bromine and iodine;

n is 2 or 3;

R ² is selected from the group consisting of —NH ₂ and —NHC (═O) R ^a ;

R ³ is selected from the group consisting of —NR ^b R ^c , —NHC (═O) R ^a and hydrogen;

R ⁴ is hydrogen, -C _1-4 alkyl (preferably methyl), substituted by one or more halogen atoms -C _1-4 alkyl (preferably methyl), -CN, -CH ₂ OH, CH ₂ OR ^d and —CH ₂ S (O) _× R ^d ;

here

R ^a represents C _1-4 alkyl or C _3-7 cycloalkyl, and

R ^b and R ^c (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, wherein said heterocycle is one or more May be further substituted with C _1-4 alkyl;

R ^d is selected from a C _1-4 alkyl substituted by C _1-4 alkyl or one or more halogen atoms;

x is an integer of 0, 1 or 2.

It can be seen that R ² , R ³ and R ⁴ for Formula (1a) as defined above are described as substantially related to Formula (1) as above.

Especially suitably in formula (1a), both R ² and R ³ represent —NH ₂ . Suitably R ⁴ is —CN, methyl or more suitably —CH ₂ OH or even more suitably hydrogen.

Suitably Hal in formula (1a) represents chlorine. Suitably n is 3 and suitably the tri-substitution formed represents a compound of formula (1b) below and a pharmaceutically acceptable derivative thereof.

Wherein R ² , R ³ and R ⁴ are described as substantially related to formula (1a) as above.

Preferred compounds of the present invention

2,6-diamino-3- (2,3-dichlorophenyl) pyrazine,

2,6-diamino-3- (2,5-dichlorophenyl) pyrazine,

* 2,6-diamino-3- (1-naphthyl) pyrazine,

2,6-diamino-3- (2-naphthyl) pyrazine,

2-amino-6- (4-methyl-1-piperazinyl) -3- (2,3,5-trichlorophenyl) pyrazine,

2-amino-6-dimethylamino-3- (2,3-dichlorophenyl) pyrazine,

2-amino-6-dimethylamino-3- (1-naphthyl) pyrazine,

2,6-dichloropropylcarbonylamino-3- (2,3,5-trichlorophenyl) pyrazine,

2-amino-6-cyclopropylcarbonylamino-3- (2,3,5-trichlorophenyl) pyrazine,

2,6-diisopropylcarbonylamino-3- (2,3,5-trichlorophenyl) pyrazine,

2-amino-6-isopropylcarbonylamino-3- (2,3,5-trichlorophenyl) pyrazine,

2-isopropylcarbonylamino-6-amino-3- (2,3,5-trichlorophenyl) pyrazine,

2-cyclopropylcarbonylamino-6-amino-3- (2,3,5-trichlorophenyl) pyrazine,

2-amino-6-acetamido-3- (2,3,5-trichlorophenyl) pyrazine,

2-amino-6-acetamido-3- (2,5-dichlorophenyl) pyrazine,

2-amino-6-acetamido-3- (2-naphthalene) pyrazine,

5-methyl-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine,

5-cyano-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine,

And pharmaceutically acceptable derivatives thereof.

More preferred are 5-hydroxymethyl-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine and pharmaceutically acceptable derivative compounds thereof.

Particularly preferred compounds according to the invention are 2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine and pharmaceutically acceptable derivatives thereof.

It is to be understood that the present invention encompasses almost all of the specific and preferred combinations mentioned above.

Compounds of formula (1) are particularly useful as anticonvulsants. Therefore, they are useful for treating epilepsy. They can be used to improve the condition of a host, generally human, with epilepsy. They can be used to relieve epilepsy from the host. “Epilepticism” may include epileptic seizures, such as: simple partial seizures, complex partial seizures, secondary generalized seizures, generalized seizures including lacking seizures, myoclonial seizures, myepic seizures, tonic seizures, Tonic hepatic seizures and laxative seizures.

Compounds of formula (1) are also useful on the one hand in the treatment of bipolar disorder known as manic depression. Bipolar disorder type I or II can be treated. Therefore, the compound of formula (1) can be used to improve the condition of a patient suffering from bipolar disorder. These can be used to alleviate the host's bipolar disorder. The compounds of formula (1) may also be used to treat unipolar depression.

Compounds of formula (1) are useful as analgesics. Therefore, they are useful for treating or preventing pain. They can be used to improve the condition of a suffering host, generally a human. These can be used to relieve pain in the host. Thus, the compounds of formula (1) may be used for acute pain, eg, musculoskeletal pain, postoperative pain and surgical pain, chronic pain, such as chronic inflammatory pain (eg, rheumatoid arthritis and osteoarthritis), neuropathic pain (eg , Post-herpes neuralgia, trigeminal neuralgia and sympathetic lasting pain) and pain associated with cancer and fibromyalgia. The compounds of formula (1) may also be used for the treatment or prevention of pain associated with migraine headaches.

The compounds of formula (1) are also effective in the treatment of functional bowel disorders, including non-ulcer dyspepsia, non-cardiac chest pain and especially irritable bowel syndrome. Irritable bowel syndrome is a gastrointestinal disorder characterized by abdominal pain and altered bowel habits without any evidence of organic disease. Therefore, the compound of formula (1) can be used to relieve pain associated with irritable bowel syndrome. Therefore, the condition of a patient suffering from irritable bowel syndrome can be improved.

The compounds of formula (1) may also be useful in the treatment of neurodegenerative diseases such as Alzheimer's disease, ALS, motor neuron disorders and Parkinson's disease. Compounds of formula (1) may also be useful for neuroprotection and treatment of neurodegeneration following seizures, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury, and the like.

In addition, the compounds of formula (1) are also useful for preventing or reducing dependence on dependency-inducing agents, or for preventing or reducing resistance or reverse resistance to them. Examples of dependency causing agents include opioids (eg morphine), CNS inhibitors (eg ethanol), stimulants (eg cocaine) and nicotine.

Therefore, the use of the compound of formula (1) in the manufacture of a medicament for use in the treatment of a disease substantially as described above is also provided by the present invention. The present invention also encompasses the treatment of a patient suffering from or susceptible to a disease substantially as described above, which method comprises administering to a patient a therapeutically effective amount of a compound of formula (1). As used herein, the term “treatment” includes the treatment of, and prevention from, the constructed disease.

In particular the compounds according to the invention are useful for the treatment of epilepsy and bipolar diseases, in particular epilepsy.

The precise dosage of the compound of formula (1) or salt from them administered to the host, in particular human, will be the responsibility of the assistant physician. However, the amount used will be influenced by various factors, including the age and sex of the patient, the exact condition and severity thereof to be treated, and the method of administration.

The compound of formula (1) and salts thereof can be administered in an amount of 0.1 to 10 mg / kg body weight per day, preferably in an amount of 0.5 to 5 mg / kg body weight per day, calculated as the free base. The dosage range for adults is generally 5 to 1000 mg / day, for example 5 to 200 mg / day, preferably 10 to 50 mg / day, calculated as the free base.

Although the compound of formula (1) or a pharmaceutically acceptable derivative thereof may be administered as a raw chemical, it is preferred to supply it as a pharmaceutical preparation. The formulations of the present invention consist of a compound of formula (1) or a pharmaceutically acceptable derivative thereof in addition to at least one acceptable carrier or diluent therefor and any other therapeutic ingredient. The carrier (s) should be "acceptable" in the sense that it may be combined with other ingredients of the formulation and from which it is not harmful to the patient.

Although the most appropriate method may depend, for example, on the condition and disease of the patient, the formulation may be administered orally, parenterally (eg, by subcutaneous administration by injection or by depot tablets, intradermal administration, intradermal administration, eg depots and Including intravenous administration by intravenous), rectal and topical administration (including skin, buccal and sublingual administration). The formulations may conveniently be supplied in a single dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of combining the compound of formula (1) or a pharmaceutically acceptable acid addition salt thereof (“active ingredient”) with a carrier consisting of one or more accessory ingredients. In general, formulations are prepared by allowing the active ingredient to be uniformly and intimately combined with a liquid carrier or a finely divided solid carrier or both, followed by molding the product into the desired formulation, if necessary.

Formulations of the invention suitable for oral administration may be presented as discrete units, for example capsules, cassienans or tablets (e.g. chewable tablets, particularly for pediatric administration), each containing a predetermined amount of the active ingredient; As a powder or particles; As a solution or a suspension in an aqueous or non-aqueous liquid; Or as oil-in-water liquid emulsions or water-in-oil liquid emulsions. The active ingredient may also be provided as a large pill, a low agent or a paste.

Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form, such as a powder or particles, optionally mixed with a binder, lubricant, inert diluent, lubricious surface activity or dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets may optionally be coated or scored and formulated so that the active ingredient is liberated slowly or with control.

Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may include anti-oxidants, buffers, bacteriostatics, and solutes of the patient's blood and preparation to make isotonic solution; And aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be provided in single or multiple dose containers, eg sealed ampoules and vials, and freeze-dried (freeze-dried) just prior to use to add a sterile liquid carrier such as distilled water for injection. Can be stored in a lyophilised state. Instant infusion solutions and suspensions can be prepared from sterile powders, particles, and tablets of the kind described above.

In preparations for rectal administration, conventional carriers such as cocoa butter, hardened oil or polyethylene glycol can be supplied as suppositories.

Formulations for oral topical administration, for example topically orally or sublingually, include lozenges containing the active ingredient in a flavoring base such as sucrose and acacia or tragaconte, and gelatin and glycerin or Pastilles containing the active ingredient in a substrate such as sucrose and acacia.

The compounds of the invention can also be prepared as depot preparations. Such long-acting agents can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present invention may be formulated with suitable polymerizable or hydrophobic materials (eg as emulsifiers in acceptable oils) or ion exchange resins and formed as little soluble derivatives, for example little soluble salts. Can be.

In particular, in addition to the components mentioned above, the preparations may include other preparations customary in the art with respect to the form of the preparations, for example, those suitable for oral administration may be included as flavoring agents.

Preferred unit dose formulations are those comprising an effective dose of the active ingredient or a suitable portion thereof, as described above. When calculated with free base, it will preferably be 5 mg to 1000 mg, more preferably 5 mg to 200 mg (eg 5, 25 to 100 mg) and best 10 mg to 50 mg.

When the compound of formula (1) is used in combination with other therapeutic agents, the compound may be administered continuously or simultaneously by any convenient method.

Compounds of formula (1) (which of course also include compounds of formulas (1a) and (Ib)) and pharmaceutically acceptable salts and solvates thereof may be prepared by methods well known in the art for the preparation of similar examples. have. In particular, the compound of formula (1) may be prepared by the method disclosed below, which is another aspect of the present invention. In the following procedure, unless otherwise indicated, R ¹ , R ² , R ³ and R ⁴ are as defined above for Formula (1).

According to the general procedure (A), the compound of formula (1) can be prepared from the compound of formula (2) under appropriate reaction conditions.

Here, Hal (B) represents a halogen atom, suitably chlorine. For example, Hal (B) can be converted to —NR ^b R ^c by reaction with a suitable amine in a solvent such as ethanol.

Compounds of formula (2) may be prepared from compounds of formula (3), suitably by reacting with compounds of formula (4) R ¹ B (OH) ₂ .

Examples of compounds of formula (4) R ¹ B (OH) ₂ include 2,3,5-trichlorobenzene boric acid, 2,3-dichlorobenzene boric acid, 2,5-dichlorobenzene boric acid, 1-naphthalene boric acid and 2- Naphthalene boric acid is included. Suitably, Hal (A) of formula (3) is more reactive than Hal (B) and suitably Hal (A) is selected from bromine and iodine, while Hal (B) is preferably chlorine. Compounds of formula (4) are commercially available or commercially available benzene analogs, such as 1-bromo-2,3-dichlorobenzene or 2-bromo-4,6-dichloro, as described in more detail in the Examples appended below. It may be appropriately prepared from aniline.

Compounds of formula (3) can be suitably prepared by further halogenation of compounds of formula (5) with stirring for several hours at room temperature, for example by reaction with halogenated agents such as N-bromosuccinimide.

Compounds of formula (5) can be prepared from di-halo compounds of formula (6) by reacting with R ² H,

Hal (B) and Hal (C) in the above may be the same or different halogen substituents. Suitably, both Hal (B) and Hal (C) are chlorine. Compounds of formula (6) are commercially available.

According to a further general process (B), compounds of formula (1) can be prepared from compounds of formula (7) by reacting with compounds of formula (4) mentioned above

Here, Hal represents a halogen atom, suitably bromine or iodine.

When both R ³ and R ⁴ represent hydrogen, the compound of formula (7) is commercially available. On the other hand, the compound of formula (7) can be prepared from the compound of formula (8),

Y is a group which can be easily converted to R ³ . For example, when Y represents NH ₂ , it can be converted to —NHC (═O) CH ₃ by reflux in the presence of an acetylation agent, for example acetic anhydride.

Compounds of formula (8) can be prepared from compounds of formula (9) by reacting with R ² H under suitable conditions. For example, the compound of formula 9 may react with ammonia for several hours in an autoclave.

Compounds of Formula (9), Table of Contents Can be prepared from compounds of formula (10) which can be prepared sequentially from the commercially available compounds of formula (6) mentioned above.

According to a further procedure C, the compound of formula (1) in which R ² represents NH ₂ is prepared in a conventional manner, for example a salt of the compound of formula (11), in an appropriate solvent, For example, by neutralization with lithium hydroxide in an alcohol such as methanol (spontaneous oxidation of the compound of formula (1) under these conditions), by cyclization and oxidation.

The compound of formula (11) may be prepared by reacting a compound of formula (12) R ¹ C (O) H in the presence of a compound of formula (13), or a salt thereof, with a cyanide source, such as potassium cyanide have.

Compounds of formula (12) 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 WO 95/07877. Compounds in which R ¹ represents other substituents are known or can be prepared according to known methods for the preparation of known compounds.

Compounds of formula (13), such as aminoacetamidine, are known procedures, for example as described in Chem. Berichte, 89, 1185 (1956).

According to further process D, the compound of formula (1) can be converted to the corresponding compound of formula (1) by introducing an appropriate reaction technique. For example, a compound of formula (1) in which R ³ represents NHC (= 0) R ^a can be converted to a compound in which R ³ represents -NH ₂ by hydrolysis, for example by reaction with aqueous hydrochloric acid. . In addition, compounds of formula (1) in which R ⁴ represents hydrogen are first reacted with halogenating agents, for example N-bromosuccinimide, and then halogenated, followed by suitable cyanide ion sources such as sodium cyanide and copper cyanide (I). R ⁴ can be converted to a compound representing -CN by reaction with a mixture of In addition, R ⁴ is via the formyl derivative which may be prepared after the compound of formula (1) represents the CN R ⁴ is -CN is reacted with a compound with diisobutylaluminium hydride in toluene, by hydrolysis -CH ₂ It can be converted to a compound showing OH. The formyl derivative is then reduced to -CH ₂ OH using, for example, sodium borohydride in ethanol. R ⁴ is -CH ₂ OH to the compound represented by alkylation is a R ⁴ it can be converted to the compound showing the -CH ₂ OR ^d. In addition, R ^4, and then the compound of formula (1) representing R ⁴ is -CN is via the formyl derivative prepared as described above can be converted to the compound showing the methyl, followed by p- toluenesulfonamide hydrazide and reaction Conversion to tosylhydrazone by reaction with catecholborane in chloroform / tetrahydrofuran.

The various general methods mentioned above may be useful for introducing the desired groups at any stage in the stepwise formation of the required compounds, which can be combined with other methods of the multi-step process. Of course, the reaction sequence of the multi-step process should be chosen so that the reaction conditions used do not affect the groups in the molecule that are needed in the final product.

The following examples are provided to illustrate the invention, but should not be limited thereto.

EXAMPLE

<Example 1>

2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine

1.2,3,5-trichlorobromobenzene

Sodium nitrite (3.88 g, 0.056 mole) was added in portions of concentrated concentrated sulfuric acid (28.16 ml) at 10 ° C or lower. A solution of 2-bromo-4,6-dichloroaniline (12 g, 0.05 mole, purchased from Lancaster) of glacial acetic acid (126 ml) was added while maintaining the temperature at 10 ° C or lower. The mixture was stirred at 10 ° C. or lower for 1 hour and then slowly added to a stirred solution of cuprous chloride of concentrated hydrochloric acid (101.05 ml) (10.11 g, 0.10 mole) at room temperature. The mixture was then stirred at rt for 17 h. The product was filtered, washed with water (3 x 50 ml), dissolved in chloroform (150 ml), dried over anhydrous magnesium sulfide and filtered and the filtrate was evaporated in vacuo to afford the desired product. Yield 10g (77%), melting point 55-57 degreeC.

2. 2,3,5-trichlorobenzeneboric acid

A 2,3,5-trichlorobromobenzene (8.60 g, 0.033 mole) solution of anhydrous ether (33 ml) and bromoethane (4.73 ml, 7.31 g, 0.067 mole) was turned into magnesium turning of anhydrous ether (21.50 ml) at room temperature. (turning) (2.80 g, 0.12 mole) was added dropwise to the suspension. The mixture was refluxed for 0.50 hours and cooled to room temperature. The mixture was then added dropwise to a trimethylborate (5.16 ml, 5.16 g, 0.05 mole) solution of dry ether (8.60 ml) while maintaining the temperature below −60 ° C. under nitrogen. It was warmed to room temperature overnight and then cooled in an ice-water bath and treated with 2M hydrochloric acid (10 ml). The ether layer was separated, washed with water (2 x 20 ml), dried over anhydrous magnesium sulfide, filtered and the filtrate was evaporated in vacuo. The residue was triturated with 40-60 ° C. petroleum ether, then filtered and dried in vacuo. Yield 4.57 g (61%), melting point 257-260 ° C.

Method A

3. 2-Chloro-6-amino-pyrazine

A suspension of 2,6-dichloropyrazine (100 g, 0.67 mole, purchased from Lancaster) of 0.880 ammonia (500 ml) was stirred and heated for 16 h at 150 ° C. and 20 atm in an autoclave with a glass array. The cooled mixture was filtered, washed well with water (200 ml) and dried. The product was recrystallized from chloroform. Yield 41.98 g (48%), melting point 150-152 占 폚.

4. 2-Chloro-3-bromo-6-aminopyrazine and 2-amino-3-bromo-6-chloropyrazine

A 2-chloro-6-aminopyrazine (20 g, 0.15 mole) solution of chloroform (1940 ml) was stirred at -5 ° C to 0 ° C. N-bromosuccinimide (27.58 g, 0.15 mole) was added in portions keeping the temperature between -5 and 0 ° C. The mixture was allowed to warm to rt and stirred for 3.5 h. The mixture was then washed with aqueous saturated sodium bicarbonate (1 × 300 ml) followed by water (1 × 500 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated under vacuum. The residue was purified by "flash chromatography" using chloroform as eluent. Yield 13.89 g (43%) of 2-chloro-3-bromo-6-aminopyrazine, melting point 146-147 ° C. Yield 4.90 g (15%) of 2-amino-3-bromo-6-chloropyrazine, melting point 124-125 ° C.

5. 2-amino-6-chloro-3- (2,3,5-trichlorophenyl) pyrazine

A solution of 2,3,5-trichlorobenzeneboric acid (1.62 g, 7.18 x 10 ^-3 mole) in anhydrous ethanol (2.05 ml) was added with 2-amino-3 in benzene (10.20 ml) / 2M aqueous sodium carbonate (5.50 ml). Add slowly to a mixture of bromo-6-chloropyrazine (1 g, 5.1 × 10 ⁻³ mole) and tetrakis (triphenylphosphine) palladium (O) (0.334 g, 2.89 × 10 ⁻⁴ mole) did. The mixture was refluxed for 17 hours. The cooled reaction mixture was evaporated in vacuo and then extracted with chloroform (50 ml). The chloroform layer was washed with water (2 x 30 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated under vacuum. The residue was triturated with 40-60 ° C. petroleum ether, filtered and dried in vacuo. Yield 0.205 g (14%), melting point 211-214 ° C.

6. 2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine

Stirring 2-amino-6-chloro-3- (2,3,5-trichlorophenyl) pyrazine (0.3 g, 9.71 x 10 ^-4 mole) suspension of anhydrous ethanol (4 ml) and 0.880 aqueous ammonia (8.24 ml) And heated in a 180 ° C. autoclave for 44 h. The cooled mixture was evaporated in vacuo and the residue was extracted with chloroform (3 × 30 ml). The combined chloroform extracts were dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated under vacuum. The residue was purified by 'flash chromatography' using chloroform with chloroform: methanol as 98: 2 as the eluate. The product was triturated with 40-60 ° C. petroleum ether, filtered and dried in vacuo. Yield 0.155 g (56%), Melting Point 178-180 ° C.

Method B

7. 2,6-diamino-3-bromopyrazine

A 2-chloro-3-bromo-6-aminopyrazine (15 g, 0.072 mole) suspension of anhydrous ethanol (150 ml) and 0.880 ammonia (375 ml) was stirred and heated for 16 h at 160 ° C. and 20 atm autoclave. The cooled mixture was evaporated in vacuo and extracted with hot methanol (3 × 100 ml). The mixed methanol extracts were evaporated in vacuo. The residue was dissolved in hot chloroform, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was triturated with 40-60 ° C. petroleum ether, filtered and dried in vacuo. Yield 5.51 g (40%), melting point 176-178 ° C.

8. 2-Amino-3-bromo-6-acetamidopyrazine

A mixture of 2,6-diamino-3-bromopyrazine (10.50 g, 0.056 mole) of anhydrous 1,1-dimethoxyethane (168 ml) and acetic anhydride (7.91 ml, 8.56 g, 0.084 mole) was added in the presence of nitrogen. It was refluxed for hours. The cooled mixture was evaporated in vacuo. The residue was triturated with ether, filtered and dried in vacuo. Yield 10.31 g (80%), melting point 218-221 ° C.

9. 2-Amino-6-acetamido-3- (2,3,5-trichlorophenyl) pyrazine

A 2-amino-3-broro-6-acetamidopyrazine (7.00 g, 0.03 mole) mixture of benzene (60.90 ml) and tetrakis (triphenylphosphine) palladium (O) was added at room temperature under nitrogen for 10 minutes. Stirred. 2M aqueous sodium carbonate (30.24 ml) was added to the mixture followed by a 2,3,5-trichlorobenzene boric acid (6.83 g, 0.03 mole) solution of anhydrous ethanol (7.07 ml) and the mixture refluxed under nitrogen for 17 hours. did. Then an equal amount of 2,3,5-trichlorobenzeneboric acid in anhydrous ethanol was added and the mixture was refluxed for an additional 7.50 hours. Finally, 2,3,5-trichlorobenzeneboric acid of anhydrous ethanol was added again to the same amount mixture and reflux was continued for 17 hours. The cooled mixture was evaporated in vacuo. The residue was dissolved in chloroform (150 ml) and washed with aqueous saturated sodium bicarbonate (1 × 100 ml) and water (1 × 100 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. . The eluate was purified by flash chromatography using chloroform with chloroform: methanol at 98: 2. Yield 3.02 g (30%), melting point 200-203 캜.

10.2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine

A suspension of 2-amino-6-acetamido-3- (2,3,5-trichlorophenyl) pyrazine (2.97 g, 8.96 × 10 ⁻³ mole) of 12M hydrochloric acid (1.31 ml) and water (4.04 ml) It was refluxed for 1.75 hours. The cooled mixture was then basified with 0.880 aqueous ammonia (5 ml) and extracted with chloroform (3 × 50 ml). The combined chloroform extracts were dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated under vacuum at 80 ° C. Yield 2.29 g (88%), Melting Point 178-180 ° C.

Method C

11. 2-{[cyano- (2,3,5-trichlorophenyl) -methyl] amino} -acetamide hydrobromide

Aminoacetamidine dihydrobromide (162.1 g, 0.774 mole) was added in part to a 2,3,5-trichlorobenzaldehyde (200.0 g, 0.851 mole) solution of methanol (2.43 L) at room temperature. Once addition was complete, potassium cyanide (50.4 g, 0.774 mole) was added in part to the resulting mixture. The suspension was then stirred at 25 ° C. for 4 hours before warming to 50 ° C. The mixture is stirred at 50 ° C. for 24 hours. Methanol was then removed in vacuo, and the solid formed was suspended with water (1.5 L) and ethyl acetate (2,5 L) and concentrated by filtration. The solid was then dried overnight under vacuum at 50 ° C. to obtain the desired product. Yield 96.31 g (33.4%), ¹ H nmr (d-6 DMSO) δ / ppm 8.72 (3H, br, NH); 7.99 (1H, doublet, J 2.3 Hz, ArH); 7.79 (1H, doublet, J 2,3 Hz, ArH); 5.39 (1H, doublet, J 10.6 Hz, ArCH (CN) NH); 4.35 (1H, m, ArCH (CN) NH); 3.56 (2H, doublet, J 6.4 Hz, ArCH (CN) NHCH ₂ C (= NH) NH ₂ ).

12. 2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine

Lithium hydroxide monohydrate of methanol (1.9 L) in 2-{[cyano- (2,3,5-trichlorophenyl) -methyl] -amino} -acetamidine hydrobromide (95.36 g, 0.256 mole) at room temperature (16.11 g, 0.384 mole) was added in part to the solution. The resulting solution was stirred at room temperature for 3 hours before evaporating until drying in vacuo. The solid formed was suspended in water (1.5 L) and integrated by filtration. After vacuum drying at 50 ° C., the crude material was purified by recrystallization from toluene to obtain the desired product. Yield 69.51 g (93.8%), melting point 178-180 ° C.

<Example 2>

2,6-diamino-3- (2,3-dichlorophenyl) pyrazine

1.2,3-dichlorobenzene boric acid

Anhydrous tetrahydrofuran (44.24 ml) of 1-bromo-2,3-dichlorobenzene (20 g, 0.088 mole, purchased from Aldrich) was dissolved in anhydrous tetra while maintaining the temperature below -65 ° C. Hydrofuran (16 ml) was added dropwise to a solution of n-butyllithium (1.6 M in hexane, 66.36 ml, 0.11 mole). The pale yellow suspension formed was stirred at −78 ° C. for 75 minutes. Trimethylborate (13.28 ml, 12.16 g, 0.12 mole) was added dropwise keeping the temperature below -55 deg. The pale yellow solution formed was warmed to room temperature overnight. Excess n-butyllithium was decomposed with water (30 ml) and the reaction mixture was evaporated in vacuo. The residue formed was suspended in water and oxidized with 2M hydrochloric acid (10 ml). The insoluble solid was filtered off, washed well with water and dried. The solid was suspended in 60-80 ° C. petroleum ether, then stirred at room temperature for 10 minutes, filtered and dried in vacuo. Yield 8.42 g (50%), melting point 235-238 ° C.

2. 2-amino-6-chloro-3- (2,3-dichlorophenyl) pyrazine

This compound was prepared from 2-amino-3-bromo-6-chloropyrazine by a method similar to Example 1 Method A by reacting with 0.880 ammonia. Yield 0.343 g (26%), melting point 179-181 ° C.

3. 2,6-diamino-3- (2,3-dichlorophenyl) pyrazine

This compound was prepared from 2-amino-6-chloro-3- (2,3-dichlorophenyl) pyrazine in a similar manner to Example 1 Method A. Yield 0.195 g, melting point 169-170 ° C.

<Example 3>

2,6-diamino-3- (2,5-dichlorophenyl) pyrazine

1.2,5-dichlorobenzene boric acid

The compound was prepared in a similar manner to Example 2 from 2,5-dichlorobromobenzene (purchased from Altrihisa). Yield 2.19 g (55%), melting point 278-280 ° C.

2. 2-Amino-6-acetamido-3- (2,5-dichlorofetyl) pyrazine

This compound was prepared from 2-amino-3-bromo-6-acetamidopyrazine in a similar manner to Example 1 Method B. Yield 0.45 g, Melting point 152-154 占 폚.

3. 2,6-diamino-3- (2,5-dichlorophenyl) pyrazine

The compound was prepared from 2-amino-6-acetamido-3- (2,5-dichlorophenyl) pyrazine in a similar manner to Example 1 Method B. Yield 0.123 g, melting point 159-160 ° C.

<Example 4>

2,6-diamino- (1-naphthalene) pyrazine

1.2 -Amino-6-chloro-3- (1-naphthalene) pyrazine

This compound was prepared from 2-amino-3-bromo-6-chloropyrazine and 1-naphthaleneboronic acid (available from Lancaster) in a similar manner to Example 1 Method A. Yield 0.709 g (58%), melting point 138-139 ° C.

2. 2,6-diamino- (1-naphthalene) pyrazine

This compound was prepared from 2-amino-6-chloro-3- (1-naphthalene) pyrazine by reaction with ammonia (0.880) in a similar manner to Example 1 Method A. Yield 0.167 g (50%), Melting point 180-183 占 폚.

Example 5

2,6-diamino-3- (2-naphthalene) pyrazine

1. 2-naphthalene boric acid

The compound was prepared in a similar manner to the compound of Example 2 from 2-bromonaphthalene (purchased from Altrihysa). Yield 1.71 g (40%), melting point 280-282 ° C.

2. 2-amino-6-acetamido-3- (2-naphthalene) pyrazine

This compound was prepared from 2-amino-3-bromo-6-acetamidopyrazine in a similar manner to Example 1 Method B. Yield 0.46 g, melting point 235-237 ° C.

3. 2,6-diamino-3- (2-naphthalene) pyrazine

This compound was prepared from 2-amino-6-acetamido-3- (2-naphthalene) pyrazine in a similar manner to Example 1 Method B. Yield 0.121 g, melting point 168-70 ° C.

<Example 6>

2-amino-6- (4-methyl-1-piperazinyl) -3- (2,3,5-trichlorophenyl) pyrazine

Example 1 2-Amino-6-chloro-3- (2,3,5-trichlorophenyl) pyrazine (0.215 g, 7.0 × 10 ⁻³ mole) and 1-methylpiperazine (5 ml, altree of Method A Purchased from Hisa) was heated at 140 ° C. for 1 hour. The mixture was evaporated in vacuo and the residue was purified by 'flash chromatography' eluting with ethanol: dichloromethane, 0-4%. The product was dissolved in a minimum amount of dichloromethane and hexane (10 ml) and added slowly to get a yellow needle. Yield 0.247 g (95%), melting point 185 캜.

<Example 7>

2-amino-6-dimethylamino-3- (2,3-dichlorophenyl) pyrazine

This compound was prepared in a similar manner to the compound of Example 6 from 2-amino-6-chloro-3- (2,3-dichlorophenyl) pyrazine (Example 2) and dimethylamine (purchased from Altrihysa). Melting point 147-148 ° C.

<Example 8>

2-amino-6-dimethylamino-3- (1-naphthalene) pyrazine

This compound was prepared from 2-amino-6-chloro-3- (1-naphthalene) pyrazine (Example 4) in a similar manner to the compound of Example 6. Melting point 131 캜.

Example 9

2,6-dicyclopropylcarbonylamino-3- (2,3,5-trichlorophenyl) pyrazine and 2-amino-6-cyclopropylcarbonylamino-3- (2,3,5-trichlorophenyl Pyrazine

Anhydrous pyridine (0.137 ml), 4-dimethylaminopyridine (0.114 g) and cyclopropanecarbonylchloride (0.33 g, 0.286 ml, 3.14 x 10 ^-3 mole, purchased from Altrihisa) are anhydrous tetrahydrofuran (12 ml) Was added to a 2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine (Example 1) solution and the reaction mixture formed was refluxed at 90 ° C. for 2.50 hours. The resulting suspension was cooled to rt and evaporated in vacuo. The residue was extracted with ethyl acetate (3 × 20 ml), washed with water (2 × 20 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by 'flash chromatography' using hexane: ether of 15:25 to 5:35 as the eluate. 0.340 g (51%) of 2, 6- dicyclopropyl carbonylamino-3- (2, 3, 5- trichlorophenyl) pyrazine, melting | fusing point 212-214 degreeC. Yield 0.174g (31%) of 2-amino-6-cyclopropylcarbonylamino-3- (2,3,5-trichlorophenyl) pyrazine, melting | fusing point 240-244 degreeC.

<Example 10>

2,6-diisopropylcarbonylamino-3- (2,3,5-trichlorophenyl) pyrazine and 2-amino-6-isopropylcarbonylamino-3- (2,3,5-trichlorophenyl Pyrazine

This compound is similar to Example 9 from 2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine (Example 1) by reacting with isobutyryl chloride (purchased from Altrihysa). Prepared by the method. Yield 0.313 g (46%) of 2, 6- diisopropyl carbonylamino-3- (2, 3, 5- trichlorophenyl) pyrazine, melting | fusing point 227-229 degreeC. Yield 0.166 g (29%) of 2-amino-6-isopropylcarbonylamino-3- (2,3,5-trichlorophenyl) pyrazine, melting point 230-232 캜.

<Example 11>

2-isopropylcarbonylamino-6-amino-3- (2,3,5-trichlorophenyl) pyrazine

1. 2-isopropylcarbonylamino-6-acetamido-3- (2,3,5-trichlorophenyl) pyrazine

The compound was prepared from Example 9 from 2-amino-6-acetamido-3- (2,3,5-trichlorophenyl) pyrazine (Example 1) and the same amount of isobutyryl chloride (purchased from Altrihysa). Prepared in a similar manner. Yield 0.120 g, melting point 230-232 ° C.

2. 2-isopropylcarbonylamino-6-amino-3- (2,3,5-trichlorophenyl) pyrazine

Tin chloride (0.182 g, 0.0096 mole) was dissolved in anhydrous ethanol (6.50 ml) of 2-isopropylcarbonylamino-6-acetamido-3- (2,3,5-trichlorophenyl) pyrazine (0.13 g, 3.24 X10 ^-4 mole) suspension was added and the resulting mixture was stirred at 50-60 ° C for 1 h 20 min. The reaction mixture was cooled down and evaporated in vacuo. The residue was extracted with ethyl acetate (3 × 20 ml), washed with water (2 × 20 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by 'flash chromatography' using 99: 1 chloroform: methanol as eluent. Yield 0.046 g (40%), melting point 105-108 ° C.

<Example 12>

2-cyclopropylcarbonylamino-6-amino-3- (2,3,5-trichlorophenylpyrazine)

1. 2-cyclopropylcarbonylamino-6-acetamido-3- (2,3,5-trichlorophenyl) pyrazine

This compound is prepared from Example 9 from 2-amino-6-acetamido-3- (2,3,5-trichlorophenyl) pyrazine (Example 1) and cyclopropylcarbonyl chloride (purchased from Altrihisa). Prepared in a similar way. Yield 0.387 g (61%) Nmr (D6DMSO) δ: 0.53 (2H, m), 0.7 (2H, m), 1.75 (1H, m), 2.18 (3H, s), 7.43 (1H, d), 7.87 ( 1H, d), 9.22 (1H, s), 10.36 (1H, b), 10.83 (1H, b).

2. Cyclopropylcarbonylamino-6-amino-3- (2,3,5-trichlorophenyl) pyrazine

The compound was prepared in a similar manner to Example 11 from 2-cyclopropylcarbonylamino-6-acetamido-3- (2,3,5-trichlorophenyl) pyrazine. Yield 0.120 g (35%), Melting Point 188-190 ° C.

Example 13

2-amino-3- (2,3,5-trichlorophenyl) pyrazine

A solution of 2,3,5-trichlorobenzeneboric acid (1.54 g, 6.82 mmol) in anhydrous ethanol (1.5 ml) was added with 2-amino-3-chloropyrazine (10.5 ml) / 2M aqueous sodium carbonate (4.54 ml). 0.589 g, 4.54 mmol) and tetrakis (triphenylphosphine) palladium (O) (0.299 g, 0.259 mmol) were added slowly to the mixture. The mixture was refluxed for 17 hours. The cooled reaction mixture was separated between water and ethyl acetate (50 ml). The organic layer was washed with water (2 × 30 ml), dried (MgSO ₄ ) and evaporated. The crude product was purified by flash chromatography using chloroform, 0.5% methanol / chloroform as eluent. The product was then recrystallized from 40-60 petroleum. Yield 0.15 g, 12%, melting point 142-143 degreeC.

<Example 14>

2-amino-6-acetamido-3- (2,3,5-trichlorophenyl) pyrazine

Prepared as described above (see Example 1.9).

<Example 15>

2-amino-6-acetamido-3- (2,5-dichlorophenyl) pyrazine

Prepared as described above (see Example 3.2).

<Example 16>

2-amino-6-acetamido-3- (2-naphthalene) pyrazine

Prepared as described above (see Example 5.2).

<Example 17>

5-cyano-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine

5-bromo-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine

N-bromosuccinimide (0.194 g, 1.09 × 10 ⁻³ mole) was added to 2,6-diamino-3- (2,3,) of dimethyl sulfoxide (10 ml) and water (0.25 ml) at 15 ° C. or lower. To a mixture of 5-trichlorophenyl) pyrazine (0.3 g, 1.04 × 10 ⁻³ mole) was added over 20 minutes. The reaction mixture formed was stirred at 15 ° C. for 1 h and then poured onto ice water (150 ml) and extracted with ethyl acetate (2 × 75 ml). The extract was then washed with 2M sodium carbonate solution (50 ml) and water (100 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was dried in vacuo. The residue was purified by 'flash chromatography' using 5-13% ethyl acetate of cyclohexane as eluent. Yield 0.183 g (48%), melting point 222-224 ° C.

2. 5-cyano-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine

A mixture of 97% sodium cyanide (0.064 g, 1.306 × 10 ⁻³ mole) and 90% copper cyanide (I) (0.135 g, 1.306 × 10 ⁻³ mole) of anhydrous dimethylformamide (5 ml) was stirred and brought to 130 ° C. Heated. 5-bromo-2.6-diamino-3- (2,3,5-trichlorophenyl) pyrazine (0.35 g, 0.95 × 10 ⁻³ mole) was added in part to the formed clear solution and the solution was added at 140-150 ° C. Stored for 16 hours. The reaction mixture was cooled down 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, filtered and the filtrate was evaporated in vacuo. The residue was purified by 'flash chromatography' using 5-17% ethyl acetate of cyclohexane as eluent. Yield 0.152 g (51%), melting point 277-279 ° C. Analytical calculation for C ₁₁ H ₆ N ₅ Cl ₃ 0.02C ₆ H ₁₂ : C, 42.23; H, 1.99; N, 22.15. Observations: C, 42.36; H, 1.78; N, 21.79.

Example 18

5-hydroxymethyl-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine

1. 5-formyl-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine

(1.5M of toluene) Diisobutylaluminum hydroxide (2.12 ml, 3.18 × 10 ⁻³ mole) was added to anhydrous toluene (70 ml) of 5-cyano-2,6-diamino-3- (2) at 0 ° C. under nitrogen. To the suspension of, 3,5-trichlorophenyl) pyrazine (0.5 g, 1.59 × 10 ⁻³ mole) was added dropwise and the reaction was stirred at 0 ° C. for 1 hour. Then further 1 equivalent of diisobutylaluminum hydroxide was added and the mixture was stirred at 0 ° C. for 1 hour. Methanol (1 ml) was carefully added in the presence of 0 ° C. nitrogen to destroy excess hydroxide and the reaction was allowed to warm to room temperature. Ethyl acetate (100 ml) was added and the solution was washed with 5% citric acid solution (2 × 100 ml). The organic layer was separated, washed with brine (100 ml), dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo to afford the desired product. Yield 0.340 g (67%), Nmr (D6DMSO) δ: 7.53 (1H, d), 7.91 (1H, d), 6.90-7.80 (4H, b), 9.49 (1H, s).

2. 5-hydroxymethyl-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine

Sodium borohydride (0.035 g, 9.35 x 10 ^-4 mole) was added to ethanol (100 ml) of 5-formyl-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine (0.198) at room temperature. g, 6.24 × 10 ⁻⁴ mole), was added to the stirred solution at room temperature. The reaction was stirred for 1 h in the presence of nitrogen, water (1 ml) was added and the solution was evaporated in vacuo. The residue was dissolved in ethyl acetate (200 ml), washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The product was purified by 'flash chromatography' using 11-40% ethyl acetate of cyclohexane as eluent. Yield 0.140 g (52%), melting point 185-186 ° C. Nmr (D6DMSO) δ: 4.32 (2H, d), 4.98 (1H, t), 5.56 (2H, s), 5.58 (2H, s), 7.30 (1H, d), 7.76 (1H, d).

Example 19

5-methyl-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine

1. 5-formyl-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine, tosylhydrazone

5-formyl-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine (0.330 g, 1.04 × 10 ⁻³ mole) was added to p-toluenesulfonhydrazide (50 ml) in methanol. 0.3 g, 1.61 × 10 ⁻³ mole). The solution was refluxed in the presence of nitrogen for 4 hours and cooled to room temperature before the solvent was evaporated in vacuo. The residue was purified by 'flash chromatography' using 0-30% ethyl acetate of cyclohexane as eluent. Yield 0.270 g (53%)

Mass spectrometry: (electrospray) 487 (MH ⁺ )

Retention time: 3.33 minutes

Micromass Platform Series 2

5 minutes Grad. (2mm ABZ)

Instrument: Red Flow rate: 0.8 ml / min

Eluent: A-0.1 vol% formic acid + 10 mmol ammonium acetate

        B-95% MeCN + 0.05 volume% formic acid

Column: 5cm × 2.1mm ID ABZ + PLUS

Injection volume: 5 μl Temperature: room temperature

Time A% B%

0.00 100 0

3.50 0.0 100

5.00 0.0 100

5.50 100 0

2. 5-Methyl-2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine

(1.0 M of tetrahydrofuran) Catecholborane (1.09 ml, 1.09 × 10 ⁻³ mole) was added to 5-tosylhydrazone-2,6 of anhydrous chloroform (15 ml) and tetrahydrofuran (20 ml) at 0 ° C. under nitrogen. -To a suspension of diamino-3- (2,3,5-trichlorophenyl) pyrazine (0.265 g, 5.46 x 10 ^-4 mole). The reaction was stirred at 0 ° C. for 1 hour, allowed to settle and sodium acetate trihydrate (g, 5.46 × 10 ⁻⁴ mole) was added. The mixture was allowed to warm to rt, stirred for 1 h and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed with 5% sodium carbonate solution, washed with water, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by 'flash chromatography' using 10-25% ethyl acetate in cyclohexane as eluent. Yield 0.017 g (10%), Nmr (CDCl ₃ ) δ: 2.35 (3H, s), 4.10 (2H, b), 4.45 (2H, b), 7.35 (1H, d), 7.52 (1H, d).

Mass spectrometry: (electrospray) 305 (MH ⁺ )

Retention time 2.89 minutes

(Conditions corresponding to Example 19.1)

Preparation Example

Sterile preparations

Example A

mg / ml

0.1 mg of compound of the present invention

Sodium Chloride USP 9.0mg

Sufficient fill up to 1ml of water for USP injection

The solution is prepared to a final volume to dissolve the components in an amount of water for injection and to give 0.1 mg / ml of the compound of the present invention. Using salts of such compounds, the amount of compound is increased to give 0.1 mg / ml of free base. The solution may be packaged for injection, for example by filling in ampoules, vials or syringes and then sealing. They may be aseptically filled and / or finally sterilized by heating under pressure at 121 ° C., for example.

Other formulations can be prepared in a similar manner to prepare another concentration solution of the compound.

<Example B>

mg / ml

0.5 mg of compound of the present invention

Mannitol 50.0mg

Fill as far as 1.0ml of water for injection

Dissolve the ingredients in a portion of the water for infusion. Mix until the final volume is formed and homogeneous. Filter the formulation through a sterilization filter and fill into glass vials. Lyophilize and seal the vial. Recycle with a suitable solvent before use.

Formulations for Oral Administration

Tablets may be prepared by conventional methods, for example by direct compression or wet granulation. Tablets may be film coated with a suitable film to form a material, such as Opadry, using conventional techniques. Tablets can, on the other hand, be sugar encoded.

Example C

Direct compression tablets

mg / tablet

5.0 mg of compound of the present invention

Magnesium Stearate 4.0mg

Microcrystalline cellulose (Avicel PH 102) up to 400 mg

Fill

The compound of the present invention is passed through a 30 mesh sieve and mixed with Avicel and magnesium stearate. The resulting blend is compressed into tablets using a suitable tablet press fixed with a 11.0 mm diameter punch to provide 5 mg of the compound of the invention per tablet. For example, other concentrations of tablets containing Compound 25 or 100 mg / tablet of the present invention may be prepared in a similar manner.

Example D

Wet granulation tablets

mg / tablet

5.0 mg of compound of the present invention

Pregelled Starch 28.0mg

Sodium Starch Glycollate 16.0 mg

Magnesium Stearate 4.0mg

Sufficient Lactose 400.0mg

Compounds of the invention, lactose, pregelled starch and sodium starch glycolate were dry mixed and then granulated using an appropriate volume of purified water. The granules formed were dried and mixed with magnesium stearate. The dried granules were compressed using a suitable tablet press fixed with a 11.0 mm diameter punch to provide 5 mg of the compound of the invention per tablet.

Tablets of different concentrations, such as for example 25-100 mg / tablet, were prepared.

Example E

Hard Gelatin Capsules

mg / capsules

5.0 mg of compound of the present invention

Sufficient amount to 700.0 mg of microcrystalline cellulose (avicel PH 102)

Compounds of the invention are mixed with microcrystalline cellulose to pass through a 30 mesh sieve and provide a homogeneous blend. The blend can then be filled into a size 0EL hard gelatin capsule shell to form a capsule containing 5.0 mg / capsule of the compound of the invention. On the other hand, concentrations such as, for example, compound 25 or 100 mg / capsule of the invention can be prepared in a similar manner.

<Example F>

Soft gelatin capsules

mg / capsules

10.0 mg of the compound of the present invention

Polyethylene Glycol 90.0mg

Sufficient amount to be 200.0mg of propylene glycol

If necessary, use heat to mix polyethylene glycol and propylene glycol together. Stir until homogeneous. Add compounds of the invention and mix until homogeneous. To provide 10.0 mg / capsule of the compound of the present invention, fill a suitable gelatin mass to obtain a soft gelatin capsule comprising 200 mg of the formulation.

Another concentration, for example 5 to 25 mg / capsule, of the compounds of the present invention can be prepared in a similar manner.

Example G

syrup

5.0 mg of the compound of the present invention

Sorbitol Solution 1500.0mg

Glycerol 1000.0mg

Sodium benzoate 5.0mg

12.5 mg flavoring agent

Sufficient to be 5.0mg of purified water

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

Other formulations

Example H

suppository

mg / suppositories

10.0 mg of the compound of the present invention

Whitepsol W32, sufficient to 2000.0 mg of cured fat

Dissolve Uthepsol W32 at approximately 36 ° C. Add a compound of the present invention to a portion of the material and then mix. Combine the remaining dissolved Utopsol W32 and mix until homogeneous. Fill the mold with 2000 mg of the formulation to provide 10.0 mg / suppository of the compound of the invention.

<Example 1>

Transdermal

5.0 mg of compound of the present invention

90.0 mg of silicone liquid

Colloidal Silicon Dioxide 5.0mg

Mix the silicone liquid and active substance together and add colloidal silicon dioxide. The material is then administered to successive heat sealed polymeric laminates consisting of: polyester release liners, skin contact adhesives comprised of silicone or acrylic polymers, polyolefins (eg polyethylene or polyvinyl acetate), or Control membranes that are polyurethanes and non-penetrating background membranes of polyester multilaminates.

Biological data

The compounds of the present invention are known to have anti-epileptic activity, for example, by their ability to inhibit posterior limb swelling in the maximum electric shock model. First, an experimental compound suspension of 0.25% methylcellulose was administered to one Han Wistar male rat (150-200 mg) 2 hours prior to the experiment. Before the experiment, we visually observed whether there was ataxia. After using the biceps muscle electrode plate for 200 milliseconds at a current of 200 mA, the presence or absence of posterior limb extension was observed.

When tested in the above experiments, the compounds according to the invention appeared as ED ₅₀ in the range of 1-20 mg / kg.

No adverse or toxic effects were observed during administration of the compound of the present invention.

The present invention provides a group of pyrazine compounds useful for the treatment of central nervous system (CNS) diseases and disorders and pharmaceutically acceptable derivatives thereof, and pharmaceutical compositions comprising them.

Claims (7)

A compound of formula (1) and a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, comprising: epilepsy, bipolar disorder or manic depression, pain, functional defecation disorder, neurodegenerative disease, neuroprotection, neurodegeneration Or a pharmaceutical composition for preventing or reducing a dependency on a dependency-inducing agent or to prevent or reduce resistance or reverse resistance to it. <Formula 1> Where R ¹ is phenyl, naphthyl and one or more substituted by one or more halogen atoms Selected from the group consisting of naphthyl substituted by halogen atoms; R ² is selected from the group consisting of —NH ₂ and —NHC (═O) R ^a ; R ³ is selected from the group consisting of —NR ^b R ^c , —NHC (═O) R ^a and hydrogen; R ⁴ is hydrogen, -C _1-4 alkyl, at least one halogen atom substituted with -C _1-4 alkyl, -CN, -CH ₂ OH, -CH ₂ OR ^d and -CH ₂ S (O) _x R ^d ; here, R ^a represents C _1-4 alkyl or C _3-7 cycloalkyl, R ^b and R ^c may be the same or different and selected from hydrogen and C _1-4 alkyl Or one or more C _1-4 together with the nitrogen atom to which they are attached To form a six-membered nitrogen-containing heterocycle which may be further substituted with alkyl To; R ^d is C _1-4 alkyl substituted by C _1-4 alkyl or one or more halogen atoms Is selected from; x is an integer of 0, 1 or 2, Provided that when R ² is -NH ₂ and both R ³ and R ⁴ are hydrogen, then R ¹ is Does not indicate. The pharmaceutical composition of claim 1, wherein R ¹ is phenyl substituted by one or more halogen atoms. The pharmaceutical composition of claim 2, wherein R ¹ is 2,3,5-trichlorophenyl. The pharmaceutical composition according to any one of claims 1 to 3, wherein R ² and R ³ are -NH ₂ . The pharmaceutical composition of claim 1, wherein R ⁴ is hydrogen or —CH ₂ OH. The pharmaceutical composition of claim 5, wherein R ⁴ is hydrogen. 2,6-diamino-3- (2,3,5-trichlorophenyl) pyrazine and its pharmaceutically acceptable derivatives and pharmaceutically acceptable carriers, comprising epilepsy, bipolar disorder or mood swings, pain, functional A pharmaceutical composition for preventing or reducing, or preventing or reducing resistance to or defecation of defecation disorders, neurodegenerative diseases, neuroprotection, neurodegeneration or dependence on dependency-inducing agents.