GB2205099A

GB2205099A - New pyrazine n-oxide derivatives

Info

Publication number: GB2205099A
Application number: GB08811764A
Authority: GB
Inventors: Paolo Cozzi; Pierpaolo Lovisolo; Antonio Pillan
Original assignee: Farmitalia Carlo Erba SRL; Carlo Erba SpA
Current assignee: Pfizer Italia SRL
Priority date: 1987-05-26
Filing date: 1988-05-18
Publication date: 1988-11-30
Anticipated expiration: 2008-05-18
Also published as: GB8712368D0; GB2205099B; DE3816794A1; JPS63307861A; GB8811764D0; IT8820693A0; IT1219693B

Description

NEW PYRAZINE N-OXIDE DERIVATIVES 22050,99 The present invention relates to

new substituted 2,5pyraz ine dime th anol derivatives, to a processfor their preparation and to pharmaceutical compositions containing them. The compounds of the invention have the following general formula (1) 0 11 R l-Q-CH 2 2 R N CH 2 -C-R 3 (1) wherein each of the R and R 2 groups which may be the sane or different, represents a hydrogen atom or C 1-C 6 alkyl group, and each of R I and R 3' which may be the same or different, is hydrogen or a straight or branched chain, saturated or unsaturated, C 1-C 8 aliphatic hydrocarbon group.

is Also the possible isomers of the compounds of formula (1), their mixtures and the metabolites of the compounds of formula (1) are included in the scope of the present Invention. The alkyl groups may be branched or straight chain groups.

When one --or each of R and R 2 's C 1 'C6 alkyl, it is preferably C,-C3 alkyl and more preferably mthyl- When one or each of R1 and R3 2 - is a branched or straight chain saturated C 1-C 8 aliphati hydrocarbon group, in particular it is C 1-C 6 alkyl, preferably methyl or ethyl.

A preferred class of compounds is that represented by the compounds of formula (I), wherein R and R are both hydro2 gen, and each of R 1 and R 3 Independently is hydrogen or C 1-C 4 alkyl. More particularly preferred compounds of the invention are the compounds of formula (I) wherein R and R 2 are both hydrogen and each of R 1 and R 3 is independently hydrogen or methyl. Examples of particularly preferred compounds of the invention are: 2,5- pyrazined,,i.methanol 1-oxide 5-methoxymethylpyrazi-nemethanol 1-oxide 4nemethanol 4-oxide 5-methoxymethylpyraz The compounds of the invention can be prepared by a process comprising: oxidizing a compound of formula (II) R 1 -0-CH 2 N R 2 ZS. 1 (11) R CN) CH 2 -0-R 3 n - 3 ?wherein R, R19 R 2 and R 3 are as defined above, and, if " formula (1) so pro- desired, transforming a compound ol. duced into another compound of formula (1) and/or, if _desired, separating a mixture of isomers of compounds of 5 formula (11) into the single isomers. The oxidation of a compound of formula (II) may, for example, be carried out through 30-36 %,w/v hydrogen per- ure ranging from oxide in presence of Na WO at temperat 2- 4 about 200C to SOOC for reaction times ranging from about 1 hour to about 20 hours, or through organic peracids, e.g., peracetic acid, permaleic acid, monoperphthalic acid or m-chloroperbenzoic acid, if desired, prepared in situ by reaction of hydrogen peroxide, for example 30-36 % w/v hydrogen peroxide, with the corresponding acid, at temperatures rangng from about 200C to the reflux, temperature of the reacting mixture, for reaction times ranging from about 1 hour up to about 12 hours.

As stated above a compound of formula (1) may be converted, if desired, into another compound of formula this optional process may be carried out by methods known in 4hemselves. Thus, for example, a compound of formula (I) wherein one or both of R 1 and R 3 is an alkyl group may be converted into a compound of formula (1), where one or both of R, and R 3 is a hydrogen group, by following conventional procedures well known in organic chemistry. For example by treatment with a strong mineral acid, i.e. HC1, HBr, - 4 HI, preferably HBr, at temperature ranging from 30 0 C to the reflux temperature, preferably at reflux temperature, or by treatment with a Lewis.acid, for example Alel 3 or BF 3' in a suitable solvent, i.e. CH 2 cl 2 or nitrobenzene, at temperatures ranging from the room temperature to about 80 0 C. A compound of formula (I) wherein one or both of R 1 and R 3 is a hydrogen may be converted into a compound of formula (1) where one or both of R 1 and R. is an alkyl group, e.g. a) by reaction with a C l-C 6 alkylhalide, preferably chloride, bromide or iodide in the presence of a base as potassium tert-butoxide operating in a suitable solvent, e.g. tert- butanol at temperatures ranging from about 10 0 C to reflux temperature of the reacting mixture; or b) by reacting the alkoxide ion of sodium or potassium of the compound of formula (I), performed in situ by treatment with a strong appropriate base, e.g. sodium hydride or potabsium hydride, with a C 1- C 0 alkylhalide, preferably chloride, bromide or iodide, operating in a suitable solvent e.g. anhydrous dimethylformamide or dimethylacetamide, at temperatures ranging from about 0 0 C to about 60 0 C, for reaction times ranging approximately from 30 minutes to 18 hours.

Also the optional separation of a mixture of isomers into the single isomes may be carried out by conventional methods, e.g. by column chromatography or by crystallization.

il 1 -- 5 - is Compounds II, where both R 1 and R 3 are hydrogen can be prepared according to Liebigs, Ann. Chem. 1981, (6)q -1065. Compounds II, where one or both R 1 and R 3 are alkyl groups can be prepared from corresponding chloromethyl thods described in J. der,ivaltives following e.g. 4%-.he met Org. Chem. 26 (3), 2356, (1960). The compounds of the invention possess an elevated lipidlowering activity, in particular an anti-lipolytic activity (decrease of plasma free fatty acids), triglyceride-, cholesterol- and plasma phospholipid-lowering activity. The above activities of the compounds of the 4 nvention, for example, were evaluated, on groups of five, six or.welve male OFA-Ico: SD (-TOPS Caw) rats, of average weight -h water ad lfb",um.

g, fasted for 18 hours, wit R) --ested were suspended in Methocel' The compounds to be 41. (0.5 % in distilled water) and administered by stomach tube and in doses ranging from 1 to 50 mg/kg body weight, each in a volume of 0.5 ml per 100 g of body weight.

imes ranging fr - to The animals were killed at t om the 1st -rea4-ment.

ter %Ihe 76h hour aft 'ed wit -he suspending agent only Groups of animals treat Ih t 4ng time.

(control groups) were available for each sampl. At the times indicated, treated and control animals were -ed.

slaughtered and blood collect 6 - The plasma obtained by centrifugation of the blood samples, with addition to 1 % heparin in saline (0.1 ml for 5 ml of blood), was assayed for the following variables: a) Free fatty acids: by the method of Dole modified by 'rnvest., 35, 150, (1956); Trout: Dole V.P. - Clin..

Trout D.L. - J. Lip. Res., 1, 199, (1960).

-he method of Mendez: Mendez J.

b) Trlaglycerides: by At. C1.4n. Chem., 21, N.6, 768, f1975).

-al cholesterol: by -he method of Allain: Allal c) Tot #1 t W n C.

et al. - Clin. Chem., 20, 470, (1974) -he met d) Phospholipids: by t hod of Takayama: Takayama M.

Clin. Chim. Acta, 79, 93, (1977).

_Y, In view of their high lipid-lowering actiVit these new compounds are useful in the therapy of primary and secondary hype rl ipi daemi as.

heir antilipolytic activity In particular, because of 1'. W they can reduce the incidence of ventricular arrhythmias in infarct patients (Rowe H.J., 1975, LANCET 1, 295).

They may be administered in a variety of dosage forms, 4e.g. 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. intramuscularly or by intravenous injection or infusion. The dosage depends on the age, weight, conditions of the patient and administration route; for example the dosage adopted for oral administration in adult hxmis ranges fran about 100 to about 250 mg pro dose, from I to 3 times daily.

4 - 7 The toxicity of the compounds of the invention was found to be quite negligible and therefore they can be safely used in therapy. The evaluation of the toxicity (as orientative acute toxicity, i.e. LD so), was carried out, e.g., as follows: nine hours food-deprived mice were treated orally with single administration of increasing doses, then housed and normally fed; the LD 50 was assessed on the seventh day after treatment.

For example, the following data was obtained:

5-methoxymethylpyrazinemethanol 1-oxide: LD 50 > 800 mg/kg.

The scope of this invention includes also pharmaceutical compositions comprising a compound of formula (I) which may, if desired, be in any isomeric form, in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent).

The pharmaceutical compositions containing the compounds of the invention can be usually prepared by conventional methods and administered in a pharmaceutically suitable form. For example, the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. s, tarches, arabic gums, gelatin, methyl- cellulose, carboxymethyl cellulose or polyvinyl pyrrolidone; - 8 is disaggregating agents, e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as, lecithin, polysorbates or laurylsulphates; and in general, non-toxic and pharmacologically inactive substances generally used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugarcoating, or film-coating processes. The liquid dispersions for oral administration may be e.g. solutions, syrups, emulsions or suspensions. The solutions for oral administration may contain as carrier, for example, water with a suitable amount of a dyestuffs and/or sweeteners agents. The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol; in particular, a syrup to be administered to diabetic patients can contain as carriers only products not metabolizable to glucose, or metabolizable in only very small amounts to glucose, such as sorbitol. The suspensions and the emulsions may contain as carrier, for- example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

t AL The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

The following Examples serve to illustrate the invention. The N.M.R. Spectrum was measured preferably in solution of CDC1 3 dimethyl sulphoxide-d 6' using a 90 M-Hertz Bruker HFX apparatus.

Example 1 "0 Sodium tungstate (Na 2 WO 42H 2 0; 0.6 g) is added to a solution of 2,5-pyrazinedimethanol (6.0 g) in hydrogen peroxide (36 % w/v; 30 ml). The reaction mixture is stirred for 8 hours at 400C, then it is diluted with water to twice the original volume and a small amount of sodium bicarbonate is added. The solution, concentrated to half the volume under reduced pressure and diluted again with water, is extracted with a mixture of chloroformisopropanol (2:1). The combined organic extracts are evaporated to dryness to a solid residue that after crystallization from isopropanol yields 4.0 g of 2,5-pyrazine- dimethanol 1-oxide. m.p. 142-1440C Analysis: found: C 46.13; H 5.17; N 17. 95. Calculated for C 6 H a N 2 0 3: C 46.15; N.M.R. (DMSO-dc): 6' p.p.m.

H 5.16; N 17.94.

4.55 (S; 2H; CH 2 4.63 (s; 2H; CH 2 8.18 (s; 1H; pyrazine H) 8.53 (s; 1H, pyrazine H) By proceeding analogously the following compounds can be obtained: 2,5- Bis (methoxymethyl)-pyrazine 1-oxide 5-methoxymethylpyrazinemethanol 1- oxide 5-methoxymethylpyrazinemethanol 4-oxide is Example 2

To a solution of 2.5 g of 2,5-Bis(methoxymethyl)pyrazine [m.p. 450C from n-hexane] in chloroform (150 ml), mchloroperbenzoic acid (2.6 g) is added. The reaction mixture is refluxed for 4 hours, then cooled and washed with 2 % aqueous sodium hydroxide. The organic phase is dried with sodium sulphate and evaporated. The solid residue, cristallized from acetone, yields 2.0 g of 2,5-Bis(methoxymethyl)pyrazine 1-oxide as white solid, m. p. 54-56C.

1.

"7; Analysis: Found: C 52.10; H 6.58; N 15.22. Calculated for C 8 H 12 N 2 0 3: C 52.12; H 6.57; N 15.20.

N.M.R. (CDC1 3 ppm 3.49 (s; 3H; CH 2-0-:3H 3) 3.54 (S; 3H; CH 2-0-CH3) 4.57 (S; 2H; CH 2-0-CH 3) 4.66 2H; CH 2 -0-CH 3) 8.20 1H; H-6) 8.53 (S; 1H; H-3) By proceeding analogously the following compounds can be obtained: 2,5- pyrazinedimethanol 1-oxide 5-methoxymethylpyrazinemethanol 1-oxide 5- methoxymethylpyrazinemethanol 4-oxide is 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 at reflux for 2 hours. 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 yields 2. 5 _g of 5-methoxymethylpyrazinwethanol 1-oxide as white solid. m.p. 74-760C. Analysis: Found: C 49.39; H 5.91; N 16.47 calculated for C 7 H 10 N 2P3: C 49.41; H 5.92; N 16.46 NMR (CHCl 3):2C-'s m 3.52 (s; 3H; CH 2-0-CH 3 4.58 (s; 2H; CH 2-0-CH 3 4. 82 (s; 2H; CH 2-OH) 8.28 (s; IH; H-6) 8.48 (s; 1H; H-3) By proceeding analogously the following compounds can be obtained: 2,5 pyraz ine dime thanol 1-oxide 5-wethoxymethylpyrazinemethanol-4-oxide.

Example 4

A solution of 2,5-pyrazinedimethanol 1-oxide (2.35 g) in anhydrous dimethylformamide (20 ml) Is treated with a suspension of sodium hydride (0.40 g) in anhydrous di- b - 13 methylformamide (5 ml). The reaction mixture is stirred at room temperature until the hydrogen production is ceased, then a solution of methyl iodide (2.13g) in anhydrous dimethylformamide (10 ml) is added portionwise. After two hours stirring at room temperature, the reaction mixture is evaporated to dryness under vacuum and the residue is taken up with water (30 ml) and repeatedly extracted with chloroform. The combined extracts are dried and evaporated to dryness to give a solid residue which is chromatographed on a silica gel column, eluiting with chloroform-methanol (90:5).The first fraction gives O.S g of 5-methoxymethylpyrazinemethancl 1-oxide (m.p. 74-7611C, N.M.R. (CDC1 3): the same of that obtained in the Example 3).

Further elution gives 0.7 g of 5-methoxymethylpyrazinemethanol 4-oxide Analysis:

Found: C 49.43; H 5.93; N 16.44 Calculated for C 7 H 10 N 2 0 3: C 49.41 N.M.R. (CDCL 3): P.P.M. 3.57 (s, 3H. CH 3 4.71 (s, 2H, CH 2 4.79 (s, 2H, CH 2) 8.22 (s, 1H, pyrazine H) 8.60 (s, 1H, pyrazine H) j H 5.92 N 16.46 By proceeding analogously the following compound can be obtained: 2,5Bis(methoxymethyl)pyrazine 1-oxide 1 - 14. - Formulation Examples Formulation I: Tablet Tablets, each weighing 300 mg and containing 100 mg of the active substance can /Knufactured as follows:

Composition (for 10,000 tablets) 5-Methoxymethylpyrazinemethanoll-oxide Lactose Corn starch Talc powder Magnesium stearate 1000 g 1420 g 475 g 75 g 30 g 5-Methoxymethylpyrazinemethanol-l-oxide, lactose, and half of the corn starch are mixed; the mixture is then forced through a sieve of 0.5 mm openings. Corn starch (18 g) 'is suspended in warm water (180 ml). The resulting paste is used to granulate the powder. The granules are dried, comminuted on a sieve of-sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets using punches of 10 mm diameter.

1 - is -

Claims

CLAIMS 1. A ccnpound having the following general formila (1)

0 It R, -)"JCH 2 R 2 3 '.00 R N CH 3 (I) wherein each of the Rk and R 2 groups which may be the same or different, represents a hydrogen atom or C 1-C 6 alkyl group, and each of R 1 and R 3' which may be the same or different, is hydrogen or a straight or branched chain, saturated or unsaturated, C 1-C 8 aliphatic hydrocarbon group.

2. A compound of formula (I) according to claim 1 wherein R and R 2 are both hydrogen, and each of R 1 and R 3 independently is hydrogen or C 1-C 4 alkyl.

3. A compound of formula (I) according to claim 1 wherein R and R 2 are both hydrogen and each of R 1 and R 3 is 15. independently hydrogen or methyl.

4. A compound selected from the group consisting of: 2,5pyrazipedimethanol 1-oxide; 5-methoxymethylpyrazinemethanol 1-oxide; 5methoxymethylpyrazinemethanol 4-oxide.

1 5. A process for the preparation of a compound of úormula (I), according to claim 1. the process comprising x)xidizing a compound of formula (II) R -0-CH N 1 2 2 1 1 RX v X CH 2 -0-R 3 (11) wherein R, R,, R. and 1R3 are as defined in claim 1 and, If desired, transforming a compound of formula (1) so produced Into another compound of formula (I) and/or, If desired, separating a mixture of isomers of compounds of formula (I) into the single isomers.

6. A pharmaceutical composition containing a suitable carrier and/or diluent and, as an active principle, a compound of formula (1) according to claim 1.

7. A compound of formula (I) as defined in claim 1, hereinbefore specified other than a compound claimed in claim 4.

a.' A-compound of formula (1) as defined In claim 1 for use In a method of treatment of the human or animal body by therapy..

- 9. A compound according to claim 8 for use In the treatment of a primary or secondary hyperlipidaemia.

10. A compound according to claim 9 for use in the treatment of ventricular arrhythmia in an infarct patien t.

11. A process for the preparation of a compound of formula (1) as defined in claim 1, said process being substantially as hereinbefore defined in any one of Examples 1 to 4.

12. A pharmaceutical composition substantially as hereinbefore described with reference to Formulation 1 of the Formulation examples.

Published 1988 at The Patent Office, State I-louse, 66-71 I-1-igh Holborn, London WClR 4TP. Further copies may be obtained from The Patent office, Sales Branch, St Mary Cray, Orpington, Kent BI-15 3RD. Printed by Multiplex techniques ltd. St Mary Cray, Kent. Con- 1/87.