DE3816794A1 - NEW PYRAZIN-N-OXIDE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, MEANS THAT CONTAIN AND USE THEREOF - Google Patents

Abstract

Substituted 2,5-pyrazinedimethanol derivatives of formula (I> <IMAGE> wherein each of the R and R2 groups which may be the same or different, represents a hydrogen atom or C1-C6 alkyl group, and each of R1 and R3, which may be the same or different, is hydrogen or a straight or branched chain, saturated or unsaturated, C1-C8 aliphatic hydrocarbon group are chained. They are useful in the treatment of a primary or secondary hyperlididaemia or of ventricular arrhythmia in an infarct patient.

Description

The present invention relates to new substituted 2,5-pyrazine dimethanol derivatives, a process for their Manufacture and pharmaceutical means of this included, and their use.

The compounds of the invention have the following general formula (I)

wherein the groups R and R₂, the same or different can be, each a hydrogen atom or a C₁-C₆- Mean alkyl group, and R₁ and R₃, the same or can be different, each hydrogen or one linear or branched, saturated or unsaturated, represent aliphatic C₁-C₈ hydrocarbon group.

The invention also encompasses all possible isomers the compound of formula (I), their mixtures and the Metabolites of the compounds of formula (I).  

The alkyl groups can be linear or branched groups represent. If one or each of the groups R and R₂ C₁-C₆-alkyl means, this is preferably C₁-C₃- Alkyl, and particularly preferably methyl. If one or each of the groups R₁ and R₃ is a branched or linear, saturated, aliphatic C₁-C₈ hydrocarbon group means, this is especially C₁-C₆-alkyl, preferred Methyl or ethyl.

Preferred compounds of formula (I) are those wherein R and R₂ are both hydrogen and R₁ and R₃ independently are hydrogen or C₁-C₄ alkyl.

Particularly preferred compounds according to the invention are those compounds of formula (I) in which R and R₂ are both hydrogen and R₁ and R₃ independently Represent hydrogen or methyl.

Examples of particularly preferred compounds according to the invention are:
2,5-pyrazine dimethanol 1-oxide;
5-methoxymethylpyrazine methanol 1-oxide;
5-methoxymethylpyrazine methanol-4-oxide.

The compounds according to the invention can be prepared by a process which is characterized by the following steps:
Oxidizing a compound of formula (II)

wherein R, R₁, R₂ and R₃ are the above Have meanings and - if desired - convert a connection made in this way Formula (I) into another compound of formula (I) and / or - if desired - separating one Isomer mixture of compounds of formula (I) in the individual isomers.

The oxidation of a compound of formula (II) can e.g. B. with the help of 30 to 36% (w / v) hydrogen peroxide in the presence of Na₂WO₄ at a temperature in the range from 20 ° C to 80 ° C and reaction times from approx. 1 h to 20 h, or with the help of organic peracids, e.g. B. Peracetic acid, permaleic acid, monoperphthalic acid or m-chloroperbenzoic acid are carried out, the the latter, if necessary, in situ by implementing Hydrogen peroxide, e.g. B. 30 to 36% (w / v) Hydrogen peroxide, with the corresponding acid at temperatures in the range of approx. 20 ° C to Reflux temperature of the reaction mixture and Reaction times from 1 h to 12 h can be produced can.

As indicated above, a connection of the Formula (I) optionally in another compound of Formula (I) can be converted; this procedure can follow known methods can be carried out.

So z. B. a compound of formula (I) wherein one or both groups R₁ and R₃ are an alkyl group represent, in a compound of formula (I), wherein one or both of the groups R₁ and R₃ are hydrogen,  according to the following common procedures in organic Chemistry are known to be converted. This conversion z. B. by treatment with a strong mineral acid, such as HCl, HBr, HI, preferably HBr, at a temperature in the range of 30 ° C to Reflux temperature, preferably at reflux temperature, or by treatment with a Lewis acid, e.g. B. AlCl₃ or BF₃, in a suitable solvent, e.g. B. CH₂Cl₂ or nitrobenzene, at temperatures in the range of Room temperature up to approx. 80 ° C. A compound of the formula (I), wherein one or both groups R₁ and R₃ are hydrogen can mean a compound of formula (I) wherein represent one or both groups R₁ and R₃ alkyl, e.g. B. can be converted as follows: a) by reaction with a C₁-C₆ alkyl halide, preferably chloride, bromide or iodide, in the presence of a base such as potassium tert-butoxide, where the reaction takes place in a suitable solvent, e.g. B. tert-butanol, at temperatures in the range of 10 ° C. to the reflux temperature of the reaction mixture; or b) by reacting the sodium or potassium alkoxide ion Compound of formula (I) obtained in situ by treatment with a strong suitable base, e.g. B. sodium hydride or potassium hydride, with a C₁-C₆ alkyl halide, preferably chloride, bromide or iodide takes place, wherein the reaction in a suitable solvent is carried out, e.g. B. anhydrous dimethylformamide or dimethylacetamide, at temperatures in the range of approx. 0 ° C to approx. 60 ° C, and reaction times of approx. 30 min until 18 h.

The possible separation of a Isomer mixture in the individual isomers can be after usual known methods are carried out, for. B.  by column chromatography or by crystallization.

Compounds II, wherein both R₁ and R₃ are hydrogen can mean, according to Liebigs, Ann. Chem. 1981, (6), 1065.

Compound II, wherein one or both substituents R₁ and R₃ are alkyl groups can from corresponding chloromethyl derivatives according to e.g. B. the one in J. Org. Chem. 26 (3), 2356 (1960) getting produced.

The compounds of the invention have one enhanced lipid lowering effect, especially a anti-lipolytic activity (decrease in free plasma Fatty acids), as well as an activity to lower the Triglycerides, cholesterol and plasma phospholipid. The the above-mentioned effects of the invention Connections were made e.g. B. examined on rats, namely on groups of 5, 6 or 12 male OFA-Ico: SD (IOPS Caw) rats with an average weight of 180 g, which fasted for 18 h and water ad libitum received.

The compounds to be examined were in Methocel® (0.5% in distilled water) and suspended administered a stomach tube, in doses of 1 to 50 mg / kg body weight, each in a volume of 0.5 ml per 100 g body weight. The animals were after a period from the first to the seventh hour after the treatment was enough, killed.  

For each time interval tested, animals were identified as Control groups with only the suspension agent treated. After the specified times, both the treated animals as well as the control animals were killed and collected their blood.

The plasma of the blood samples obtained by centrifugation, with the addition of 1% heparin in physiological Saline (0.1 ml for 5 ml blood) was following Checked values:

• a) Free fatty acids: according to the Dole method, modified by Trout: Dole V. P. - Clin. Invest., 35, 150, (1956); Trout D.L. - J. Lip. Res., 1, 199, (1960);
• b) Triglycerides: according to the method of Mendez J. - Clin. Chem., 21, N. 6, 768, (1975);
• c) Total cholesterol: according to the Allain method: Allain C. et al - Clin. Chem., 20, 470, (1974);
• d) Phospholipids: according to the Takayama method: Takayama M. - Clin. Chim. Acta, 79, 93, (1977).

Suitable for lowering lipids due to their high activity the new connections to the therapy of primary and secondary hyperlipidemia.

They can be particularly due to their antilipolytic Activity the occurrence of ventricular arrhythmias Reduce infarct patients (Rowe H. J., 1975, LANCET 1, 295). The compounds of the invention can in a variety of forms of administration are given e.g. B. orally in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or Suspensions; rectally, in the form of suppositories; parenterally, e.g. B. intramuscularly or by intravenous  Injection or infusion. The dosage depends on Age, weight, condition of the patient and the Mode of administration; so is z. B. the dosage for oral administration in an adult of approximately 100 up to approx. 250 mg per dose, one to three times Every day.

The toxicity of the compounds according to the invention is almost negligible, so this for therapy can be used safely. The determination of Toxicity (as orientative acute toxicity, i.e. LD₅₀) z. B. Performed as follows: mice that were 9 h long who had not been fed were given orally with a treated with single dose of increasing doses, and then in fed the cage normally; the LD₅₀ value was on determined seventh day after treatment.

There were e.g. B. receive the following data: 5-methoxymethylpyrazine methanol 1-oxide: LD₅₀ <800 mg / kg.

The invention also includes pharmaceutical preparations which comprise a compound of formula (I), these optionally present in any isomeric form can, and in combination with a pharmaceutical acceptable excipient (which is a carrier or a Can be used as a diluent).

The pharmaceutical preparations that the Containing compounds of the invention can according to usual methods and are manufactured in one administered pharmaceutically suitable form. So can e.g. B. solid oral forms together with the active ingredient  Contain extenders, e.g. B. lactose, dextrose, Sucrose, cellulose, corn starch and potato starch; Lubricants, e.g. B. silicon dioxide, talc, stearic acid, Magnesium or calcium stearate, and / or Polyethylene glycols; Binders, e.g. B. strengths, Gum arabic, gelatin, methyl cellulose, Carboxymethyl cellulose and polyvinyl pyrrolidone; Explosives, e.g. B. starch, alginic acid, alginates or Sodium starch glycolate; Shower mixes; Dyes; Sweeteners; Wetting agents such as lecithin, polysorbates or lauryl sulfates; and generally non-toxic and pharmacologically inactive substances such as them commonly used in pharmaceutical formulations will. These pharmaceutical preparations can be found in are made in a known manner, e.g. B. by Mixing, granulating, tableting, Sugar coating or film coating processes. The liquid dispersions for oral administration e.g. B. solutions, syrups, emulsions or suspensions represent. The solutions for oral administration may contain a carrier e.g. B. water with a suitable amount of a dye and / or Sweetener. The syrups can be used as a carrier e.g. B. Sucrose or sucrose with glycerin and / or mannitol and / or contain sorbitol; especially diabetic Syrup administered to patients can only be used as a carrier Contain products that do not metabolize to glucose or only in a small amount to glucose metabolize like sorbitol.

The suspensions and emulsions can be used as carriers e.g. B. natural gum, agar, sodium alginate, pectin, Methyl cellulose, carboxymethyl cellulose or Contain polyvinyl alcohol.  

The solutions for intravenous injections or infusions can as a carrier z. B. contain sterile water, or they can preferably be in the form of sterile, aqueous, Isotonic saline solutions are available.

The following examples are intended to illustrate the invention explain. The NMR spectrum was preferably in solution of CDCl₃-dimethyl sulfoxide-d₆ using a 90 M Hertz Bruker HFX apparatus added.

Example 1

Sodium tungstate (Na₂WO₄ · 2 H₂O; 0.6 g) is added to a solution of 2,5-pyrazine dimethanol (6.0 g) in hydrogen peroxide (36% w / v; 30 ml). The reaction mixture is stirred at 40 ° C for 8 h, then it is diluted with water to twice the original volume and a small amount of sodium bicarbonate is added. The solution, which was concentrated to half volume under reduced pressure and diluted again with water, is extracted with a mixture of chloroform-isopropanol (2: 1). The combined organic extracts are then evaporated to dryness to form a solid residue which, after crystallization from isopropanol, gives 4.0 g of 2,5-pyrazine dimethanol-1-oxide.
Melting point: 142-144 ° C.
Analysis:

Found: C 46.13; H 5.17; N 17.95. Calculated for C₆H₈N₂O₃: C 46.15; H 5.16; N 17.94. NMR (DMSO-dc): delta ppm4.55 (s; 2 H, CH₂)
4.63 (s; 2H; CH₂)
8.18 (s; 1 H, pyrazine H)
8.53 (s; 1 H, pyrazine H)

The following compounds were obtained in the same way:
2,5-bis (methoxymethyl) pyrazine-1-oxide
5-methoxymethylpyrazine methanol 1-oxide
5-methoxymethylpyrazine methanol-4-oxide

Example 2

M-Chloroperbenzoic acid (2.6 g) was added to a solution of 2.5 g of 2,5-bis (methoxymethyl) pyrazine [melting point 45 ° C. from n-hexane] in chloroform (150 ml). The reaction mixture was heated under reflux for 4 hours, then cooled and washed with 2% aqueous sodium hydroxide solution. The organic phase was dried with sodium sulfate and evaporated. The solid residue, crystallized from acetone, gives 2.0 g of 2,5-bis (methoxymethyl) pyrazine-1-oxide as a white solid with a melting point of 54-56 ° C.
Analysis:

Found: C 52.10; H 6.58; N 15.22 Calculated for C₈H₁₂N₂O₃: C 52.12; H 6.57; N, 15.20. NMR (CDCl₃): delta ppm3.49 (s; 3 H; CH₂-O- CH ₃)
3.54 (s; 3 H; CH₂-O- CH ₃)
4.57 (s; 2 H; CH ₂-O-CH₃)
4.66 (s; 2 H; CH ₂-O-CH₃)
8.20 (s; 1H; H-6)
8.53 (s; 1H; H-3)

The following connections were made in an analogous manner:
2,5-pyrazine dimethanol 1-oxide
5-methoxymethylpyrazine methanol 1-oxide
5-methoxymethylpyrazine methanol-4-oxide

Example 3

A mixture of 4.0 g of 2,5-bis (methoxymethyl) pyrazine-1-oxide and 25 ml of concentrated hydrobromic acid is heated under reflux for 2 h. After cooling, the reaction mixture is poured into crushed ice. The acidic solution is neutralized with sodium bicarbonate and extracted with chloroform. The organic layer is dried and evaporated to dryness to give a solid residue which is chromatographed on a silica gel column, eluting with chloroform-methanol (90: 5). The eluate evaporated to dryness gives 2.5 g of 5-methoxymethylpyrazine-methanol-1-oxide as a white solid with a melting point of 74 to 76 ° C.
Analysis:

Found: C 49.39; H 5.91; N 16.47 Calculated for C₇H₁₀N₂O₃: C 49.41; H 5.92; N 16.46 NMR (CHCl₃): delta ppm3.52 (s; 3 H; CH₂-O- CH ₃)
4.58 (s; 2 H; CH ₂-O-CH₃)
4.82 (s; 2 H; CH ₂-OH)
8.28 (s; 1H; H-6)
8.48 (s; 1H; H-3)

The following compounds were obtained in an analogous manner:
2,5-pyrazine dimethanol 1-oxide
5-methoxymethylpyrazine methanol-4-oxide.

Example 4

A solution of 2,5-pyrazine dimethanol-1-oxide (2.35 g) in anhydrous dimethylformamide (20 ml) with a Suspension of sodium hydride (0.40 g) in anhydrous Dimethylformamide (5 ml) treated.

The reaction mixture is kept at room temperature stirred until hydrogen formation ceases; Then it will be a solution of methyl iodide (2.13 g) in anhydrous Dimethylformamide (10 ml) was added in portions.

After stirring for 2 hours at room temperature The reaction mixture was evaporated to dryness in vacuo and the residue was taken up in water (30 ml) and  extracted repeatedly with chloroform. The United Extracts are dried and evaporated to dryness, whereby a solid residue is obtained, which on a Silica gel column is chromatographed; eluting done with chloroform-methanol (90: 5). The first Fraction gives 0.8 g of 5-methoxymethylpyrazine-methanol-1- oxide (melting point 74 to 76 ° C, N.M.R. (CDCl₃): likewise as obtained in Example 3).

Further elution gives 0.7 g of 5-methoxymethylpyrazine-methanol-4-oxide.
Analysis:

Found: C 49.43; H 5.93; N 16.44 Calculated for C₇H₁₀N₂O₃: C 49.41; H 5.92; N 16.46 NMR (CDCl₃): delta ppm3.57 (s; 3 H; CH₃)
4.71 (s; 2H; CH₂)
4.79 (s; 2H; CH₂)
8.22 (s; 1 H; pyrazine H)
8.60 (s; 1 H; pyrazine H)

The following connection is obtained in an analogous manner:
2,5-bis (methoxymethyl) pyrazine-1-oxide

Formulation examples Formulation I: tablet

Tablets, each weighing 300 mg, the  Containing 100 mg of active ingredient can be prepared as follows will:

Preparation (for 10,000 tablets)

5-methoxymethylpyrazine-methanol-1-oxide 1000 g Lactose1420 g Corn starch 475 g Talc powder 75 g Magnesium stearate 30 g

5-methoxymethylpyrazine methanol 1-oxide, lactose and the Half of the corn starch is mixed together; the mixture is then passed through a sieve with openings from 0.5 mm driven. Corn starch (18 g) is made in warm water (180 ml) suspended. The paste obtained becomes Granulation of the powder used. The granules will dried through a sieve with a mesh size of Given 1.4mm and then the remaining amount of thickness, Talc and magnesium stearate added, mixed thoroughly and processed into tablets with a diameter of 10 mm.

Claims (12)

1. Compound of the general formula (I) wherein R and R₂, which may be the same or different, each represent a hydrogen atom or a C₁-C₆ alkyl group, and R₁ and R₃, which may be the same or different, each represent hydrogen or a straight-chain or branched, saturated or unsaturated, aliphatic C₁ -C₈ hydrocarbon group mean. 2. Compound of formula (I) according to claim 1, characterized in that R and R₂ both Represent hydrogen, and R₁ and R₃ each independently of one another hydrogen or a C₁-C₄- Mean alkyl group. 3. Compound of formula (I) according to claim 1, characterized in that R and R₂ both hydrogen and R₁ and R₃ each independently are hydrogen or methyl.   4. Connection selected from the group:
2,5-pyrazine dimethanol 1-oxide;
5-methoxymethylpyrazine methanol 1-oxide;
5-methoxymethylpyrazine methanol-4-oxide. 5. A process for the preparation of a compound of formula (I) according to claim 1, characterized by oxidizing a compound of formula (II) wherein R, R₁, R₂ and R₃ have the meaning given in claim 1, and - if desired - converting the compound of the formula (I) thus prepared into another compound of the formula (I) and / or - if desired - separation an isomer mixture of compounds of formula (I) in the individual isomers. 6. pharmaceutical agent, characterized in that there is a Carrier and / or an extender and, as active ingredient, a compound of formula (I) according to claim 1. 7. A compound of formula (I) according to claim 1 as it is specified above and via which in claim 4 mentioned connections goes beyond.   8. Use of a compound of formula (I) according to Claim 1 in a method for treating the human or animal body through surgery or therapy, or for diagnosis, on human or animal body. 9. Use of a compound of formula (I) according to Claim 1 for the manufacture of a medicament for the Treatment of a primary or secondary Hyperlipidemia. 10. Use of a compound of formula (I) according to Claim 1 for the manufacture of a medicament for Treatment of ventricular arrhythmia in one Infarct patients. 11. Process for the preparation of a compound of formula (I) according to claim 1, characterized in that this in essentially corresponds to one of Examples 1 to 4. 12. Pharmaceutical agent, characterized in that this in essential to the formulation I Corresponds to formulation examples.