Claims
- 1. A compound of the formula ##STR5## wherein at least one of R.sub.1, R.sub.2 and R.sub.3 is C.sub.1-6 alkyl and the others are hydrogen atoms; each of R.sup.5 and R.sup.6, which may be the same or different, is hydrogen or C.sub.1-6 alkyl.
- 2. A compound according to claim 1 wherein at least one of R.sup.1, R.sup.2 and R.sup.3 is a methyl group and the others are hydrogen atoms.
- 3. 2-Carbamoyl-5-methylpyrazine 4-oxide.
- 4. 2-Carbamoyl-5,6-dimethylpyrazine 4-oxide.
- 5. 2-Carbamoyl-6-methylpyrazine 4-oxide.
- 6. 2-(N,N-diethylcarbamoyl)-5-methylpyrazine 4-oxide.
- 7. 2-(N-ethylcarbamoyl)-5-methylpyrazine 4-oxide.
- 8. A pharmaceutical composition consisting essentially of a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
- 9. Composition of claim 8, wherein said compound is a compound wherein at least one of R.sub.1, R.sub.2 and R.sub.3 is a methyl group and the others are hydrogen atoms.
- 10. Composition of claim 8, wherein said compound is 2-carbamoyl-5-methylpyrazine 4-oxide.
- 11. Composition of claim 8, wherein said compound is 2-(N,N-diethylcarbamoyl)-5-methylpyrazine 4-oxide.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 23663/72 |
Apr 1972 |
IT |
|
Parent Case Info
This is a division of application Ser. No. 578,820, filed May 19, 1975, now U.S. Pat. No. 4,002,750 granted Jan. 11, 1977, which is a continuation of Ser. No. 354,909, filed Apr. 26, 1973, now abandoned.
This invention relates to new pyrazine derivatives having hypoglycaemic and hypolipaemic activity, to a process for their preparation, and to pharmaceutical compositions containing them.
The use of the nicotinic acid and related compounds is known in hypolipaemic therapy [Altschul, Hoffer and Stephen, Arch. Biochem, Biophys., 1955, 54, 558]. However, at the beginning of the treatment, the use of nicotinic acid constantly causes undesired peripheral vasodilatory effects, which persist in 10 - 15% of patients after the initial period even if with lower intensity. It is advisable, anyway, not to use this product in patients with a history of peptic ulcers, diabetes or hyperuricaemia; in fact, at the dose administered, the nicotinic acid may cause gastrointestinal troubles, hyperglycaemia, hyperuricaemia and liver function disorders.
We have now found that replacing the pyridine nucleus of nicotinic acid by the pyrazine nucleus, it is possible to obtain compounds with hypoglycaemic and hypolipaemic activity which do not cause the side-effects caused by the pyridine derivatives.
The invention provides a compound of general formula (I) ##STR2## wherein each of R.sup.1, R.sup.2 and R.sup.3, which may be the same or different, is a hydrogen or halogen atom or a C.sub.1-6 alkyl or alkoxy group, at least one of R.sup.1, R.sup.2 and R.sup.3 being other than a hydrogen atom; R.sup.4 is a hydroxy or C.sub.1-6 alkoxy group or a group of formula --NR.sup.5 R.sup.6 wherein each of R.sup.5 and R.sup.6, which may be the same or different, is a hydrogen atom or a C.sub.1-6 alkyl group; or, when R.sup.4 is a hydroxy group, a pharmaceutically acceptable salt of said compound.
Preferably at least one of R.sup.1, R.sup.2 and R.sup.3 is a methyl group, and the others are hydrogen atoms.
The alkyl groups may be branched or unbranched.
The salts can be with a suitable organic or inorganic base. The preferred salt is with ethanolamine.
The compounds can be prepared by a process comprising oxidising a compound of general formula (II) ##STR3## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above, and then if desired converting by methods known per se the compound of general formula (I) so produced into another compound of general formula (I), and if desired, when R.sup.4 is a hydroxy group, reacting the compound of general formula (I) with a base to give a pharmaceutically acceptable salt.
For example, a compound of general formula (I), wherein R.sup.4 is a hydroxy group can be converted into a compound of general formula (I), wherein R.sup.4 is an alkoxy group or a --NR.sup.5 R.sup.6 group; or a compound of general formula (I), wherein R.sup.4 is an alkoxy group or a --NR.sup.5 R.sup.6 group can be converted into a compound of general formula (I), wherein R.sup.4 is a hydroxy group; or a compound of formula (I), wherein R.sup.4 is an alkoxy group, may be converted into a compound of general formula (I), wherein R.sup.4 is a --NR.sup.5 R.sup.6 group. A compound of general formula (I), wherein R.sup.4 is a --NR.sup.5 R.sup.6 group, wherein one or both of R.sup.5 and R.sup.6 are hydrogen atoms can be converted into a compound of general formula (I) wherein R.sup.4 is a --NR.sup.5 R.sup.6 group wherein one or both of R.sup.5 and R.sup.6 are alkyl groups.
The compounds of general formula (II), wherein R.sup.4 is a hydroxy group, are known compounds and can be prepared by methods known per se. For example, 2-carboxy-5-methylpyrazine may be obtained by oxidising 5-methyl-2-hydroxymethylpyrazine with potassium permanganate, according to Pitre, Boveri and Grabitz, Chem. Ber., 1966, 99, 364. The compounds of general formula (II), wherein R.sup.4 is an alkoxy group may be prepared from the compounds of general formula (II), wherein R.sup.4 is a hydroxy group by esterification according to the usual methods of organic chemistry. The compounds of general formula (II), wherein R.sup.4 is a --NR.sup.5 R.sup.6 group, may be prepared from the compounds of general formula (II), wherein R.sup.4 is a hydroxy or alkoxy group, by the usual methods of organic chemistry, for example by reacting a compound of general formula ##STR4## wherein X is a carboxy group or a functional derivative thereof, e.g. a halide or a mixed anhydride, with ammonia or an amine of formula HNR.sup.5 R.sup.6.
The oxidation of the compounds of general formula (II) is preferably performed with peracids, which may be prepared in situ. The preferred peracids are peracetic, m-chloro perbenzoic and permaleic acid. When the oxidation is performed on a compound of general formula (II), wherein R.sup.4 is a hydroxy group, the carboxy group is preferably protected in a conventional way, i.e. by using one of the protecting groups commonly employed for this purpose in organic chemistry. For example, the methyl and ethyl esters may be conveniently used as protecting groups; those protecting groups which can be removed under mild reaction conditions, e.g. benzyl, t-butyl, p-methoxybenzyl or phthalimidomethyl esters, can also be used.
The conversion of the compound of general formula (I), wherein R.sup.4 is a hydroxy group into a compound of general formula (I), wherein R.sup.4 is an alkoxy group, may be performed by methods known per se, for example by adding dry hydrogen chloride to a solution of the starting material in methyl alcohol or absolute ethyl alcohol, heating it in a sealed tube with methanol or ethanol and thionyl chloride, or treating with a diazoalkane, e.g. diazomethane.
The conversion of the compound of general formula (I), wherein R.sup.4 is a hydroxy group into a compound of general formula (I), wherein R.sup.4 is a --NR.sup.5 R.sup.6 group can be performed by methods known per se such as activating the carboxy group (e.g. by forming a mixed anhydride or active ester) and reacting it with ammonia or an amine of formula NHR.sup.5 R.sup.6. The conversion of the compounds of general formula (I), wherein R.sup.4 is an alkoxy group or a --NR.sup.5 R.sup.6 group into a compound of general formula (I), wherein R.sup.4 is a hydroxy group, may be also performed by means of methods known per se, for example by saponification with an aqueous alkali or by hydrolysis.
The conversion of a compound of general formula (I), wherein R.sup.4 is an alkoxy group, into a compound of general formula (I), wherein R.sup.4 is a --NR.sup.5 R.sup.6 group, may be performed by methods known per se, for example by refluxing with concentrated ammonia or with an amine of general formula NHR.sup.5 R.sup.6.
Finally, the conversion of a compound of general formula (I), wherein R.sup.4 is a --NR.sup.5 R.sup.6 group wherein one or both of R.sup.5 and R.sup.6 are hydrogen atoms, into a compound of general formula (I) wherein one or both of R.sup.5 and R.sup.6 are alkyl groups, may be performed by methods known per se, for example by alkylation with an alkyl halide in dimethylsulphoxide in the presence of powdered potassium hydroxide.
The compounds of general formula (I) have hypoglycaemic and hypolipaemic activity, as is shown by the tests reported in the following Table, in which the values given in brackets indicate the times (in minutes) at which the highest effects were observed.
The activity of these compounds was evaluated on groups of six "outbred" SPF CFE rats each weighing 140-160 g. The animals were fasted but allowed to drink water 18 hours before the test. For each compound tested, three groups of animals were treated and sacrificed after 60, 120 and 240 minutes, respectively. The test substances were administered at a dose of 50 mg/kg by gavage, suspended in 0.5% methylcellulose 400, the dose not exceeding the volume of 0.2 ml/100 g. The sodium nicotinate was used as a reference substance at the same dose. Groups of animals treated only with the suspending agent acted as controls. At the indicated times, the animals were decapitated. Their blood was immediately cooled and centrifuged. The glycaemic titres and level of free fatty acids were evaluated in plasma. The glycaemic values were determined by the o-toluidine method according to Wenk, Creno, Loock and Henry, Clin. Chem., 1969, 15, (12). The plasma free fatty acids were determined according to Trout's modification of Dole's method (Trout, Estes and Friedberg, J. Lipid. Res., 1960, 1, 199-202).
The invention also provides a pharmaceutical composition comprising a compound of general formula (I) and a pharmaceutically acceptable carrier or diluent.
The compounds of the present invention can be conveniently incorporated with pharmaceutical carriers or diluents such as, for instance, gelatine capsules; microcrystalline cellulose; lactose; natural gums; starches, such as corn starch and potato starch; cellulose derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; as well as other non-toxic compatible substances used in pharmaceutical formulations.
The compositions are preferably in a form suitable for oral administration, for example tablets, capsules, liquid solutions or suspensions.
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
|
4002750 |
Ambrogi et al. |
Jan 1977 |
|
Divisions (1)
|
Number |
Date |
Country |
| Parent |
578820 |
May 1975 |
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Continuations (1)
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Number |
Date |
Country |
| Parent |
354909 |
Apr 1973 |
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Patent Grant
4051245
