NO137728B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRASIN-4-OXYDIDE DERIVATIVES - Google Patents

Description

The present invention relates to a process for the production of new pyrazine derivatives which have hypoglycemic and hypolipemic effects.

The use of nicotinic acid and related compounds is known from hypolipemic therapy [Altschul, Hoffer and Stephen, Arch.

Biochem. Biophys., 1955, 54, 558], At the beginning of the treatment, however, the use of nicotinic acid constantly causes unwanted peripheral vasodilatory effects, which persist in 10-15% of the patients after the initial period, although with lower intensity. However, it is advisable not to

use this product on patients with a disease picture of peptic ulcer, diabetes or hyperuricaemia; in fact, at the dose administered, nicotinic acid can cause gastro-intestinal disturbances, hyperglycemia, hyperuricemia and disturbances in liver function.

It has now been found that by replacing the pyridine nucleus of the nicotinic acid with the pyrazine nucleus, it is possible to obtain compounds with hypoglycemic and hypolipemic action which do not cause the side effects induced by the pyridine derivatives.

The invention provides a compound of general formula

(IN)

12 3

wherein each of R , R , and R , which may be the same or different, is a hydrogen or halogen atom or a C 1-6 alkyl or alkoxy group, and at least one of R<1>, R 2 , and R<3> is different from a hydrogen atom,

R 4 is a hydroxy or C 1 , alkoxy group or a

5 6 5 6

group of the formula -NR R , where each of R and R , which may be the same or different, is a hydrogen atom or an alkyl group; or, when R 4 is a hydroxy group, a pharmaceutically acceptable salt of said compound.

12 3

Preferably, at least one of R, R and R is a methyl group and the others are hydrogen atoms.

The alkyl groups can be straight-chain or branched.

The salts can be with a suitable organic or inorganic base.

The preferred salt is with ethanolamine.

The compounds can be produced by a method which consists of

in that one oxidizes a compound with the general formula (II)

12 3 4 where R , R , R and R are as defined above, and converts, if desired, an obtained compound of general formula (I), where R 4 is a hydroxy group into a compound of general formula 4 5 6 (I) , where R is an alkoxy group or a -NR R group, or converts an obtained compound of general form (I), where

4 5 6

R is an alkoxy group, or a -NR R group to eru compound

4

with general formula I, where R is a hydroxy group, or converts an obtained compound of formula (I), where R 4 is an alkoxy group into a compound of general form (I),

where R^ is a -NR^R^ group, or converts an obtained for-

bond of general formula (I), where R is a -NR 5 R 6 group, '! 5 6 where one or both of R and R are hydrogen atoms of a for-4 5 6 bond of general formula (I), where R is a -NR R group, 5 6 where one or both of R and R are alkyl groups and, if , desired, reacts a compound of general formula (I), where R 4 is a hydroxy group, with a base to a pharmaceutically acceptable salt, or the carboxy group is protected in the usual way.

Compounds of general formula (II), where R 4 is a hydroxy group, are known compounds and can be prepared according to methods known per se. 2-carboxy-5-methylpyrazine can, for example, be obtained by oxidizing 5-methyl-2-hydroxymethylpyrazine with potassium permanganate, according to Pitré, Boveri and Grabitz, Chem.

Ber., 1966, 99, 364. The compounds of general formula (II),

4

where R is an alkoxy group "can be prepared from the compounds of general formula (II), where R 4 is a hydroxy group by esterification according to usual methods in organic chemistry. The compounds of general formula (II), where R 4 is a -NR 5 R 6 group , can be prepared from the compounds of general formula (II), where R^ is a hydroxy or alkoxy group, by usual methods in organic chemistry, for example by

to react a compound with general formula

where X is a carboxy group or a functional derivative thereof, e.g. a halide or a mixed anhydride,

5 6

with ammonia or an amine of the formula HNR R .

The oxidation of the compounds of general formula (II) is preferably carried out with per acids, which can be prepared in situ. The preferred peracids are per-acetic acid, m-chloro-perbenzoic acid and per-maleic acid. When the oxidation is carried out with a compound

IN

with general formula (II), where R <4> is a hydroxy group, the carboxy group is preferably protected in the usual way, i.e. by using one of the protecting groups that are usually used for this purpose in organic chemistry. The methyl and ethyl esters can, for example, be suitably used as protecting groups; these protective groups which can be removed under mild reaction conditions, e.g. benzyl, t-butyl, p-methoxy-benzyl or phthalimidomethyl esters can also be used.

The conversion of the compounds of general formula (I), where R 4 is a hydroxy group, to a compound of general formula (I), where R 4 is an alkoxy group, can be carried out according to 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.

4 The conversion of the compound of general formula (I), where R is a hydroxy group, into a compound of general formula

4 5 6

(I), where R is a -NR R group can be carried out according to methods known per se, e.g. by activating the carboxyl group

(e.g. by forming a mixed anhydride or active ester)

and reacting it with ammonia yields an amine of formula NHR 5 R 6. The conversion of the compounds msd general formula (I), where

4 5 6

R is an alkoxy group or a -NR R group, to a compound-4

Else with general formula (I), where R is a hydroxy group, can also be carried out by 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<4> is an alkoxy group, to a compound of general formula (I), where R <4> is a -NR <5> R <6> group, can be carried out by methods known per se, for example by reflux treatment with concentrated ammonia or with an amine of general formula NHR<5>R<6>.

Finally, the conversion of a compound of general formula (I), where R 4 is an NR 5 R 6 group, where one or both of R 5 and R ( i are hydrogen atoms, to a compound of general formula (I), where one or both R and R are alkyl groups, is carried out according to methods known per se, for example by alkylation with an alkyl halide in dimethylsulfoxide in the presence of powdered potassium hydroxide.

The compounds of general formula (I) have hypoglycemic and hypolipemic effects, as shown by the samples given in the following table, where the values in parentheses indicate the time (in minutes) when the highest effects were observed.

The effect of these compounds was assessed on groups of

6 "weaned" SPF CFE rats, each weighing 140-160 g. The animals fasted but were allowed to drink water 18 hours before the test. For each compound examined, three groups of animals were treated and killed after 60, 120, and 240 minutes, respectively. The test substances were administered at a dose of 50 mg/kg by means of a throat probe, suspended in 0.5% methylcellulose 400, and the dose does not exceed the volume of 0.2 mg/100 g. The sodium nicotinate was used as a reference substance at the same dose. Groups of animals treated only with the suspension agent served as controls. At the indicated times, the animals were decapitated. Their blood was immediately cooled and centrifuged. The glycemic titre and levels of free fatty acids were assessed in plasma. When glycemic 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 Troiif's modification of Dole's method (Trout, Estes and Friedberg, J. Lipid. Res., 1950, 1, 199-202).

The invention is illustrated by the following examples.

EXAMPLE 1

2-Carboxy-5-methylpyrazine (9.7 g) in dry dioxane (114 mL) and tributylamine (17.7 mL) was treated with ethyl chloroformate

(7.5 ml), and the temperature is maintained at 0-5°C. After 10 minutes, dioxane (190 ml) saturated with ammonia was added. The mixture. was stirred for 3 hours at room temperature, then dioxane was distilled off and the residue was taken up in saturated aqueous sodium bicarbonate (20 mL). The mixture was filtered and the product washed with water and gives 2-carbamoyl-5-methylpyrazine (9.2 g) m.p. 204-206°c. This amide (7 g) in glacial acetic acid (30 ral) and 35% hydrogen peroxide (20 ml) was heated with stirring at 70°C for 7 hours. The reaction mixture was cooled, the product which separated was filtered and washed with water to give 2-carbamoyl-5-methylpyrazine-4-oxide (5.5 g), m.p. 206-208°C.

Proceeding in the same way gave 2-carboxy-5,6-dimethylpyrazine 2-carbamoyl-5,6-dimethylpyrazine-4-oxide (m.p. 248-249°C),

while 2-carboxy-6-methylpyrazine-2-carboxylic acid gave 2-carbamoyl-6-methylpyrazine-4-oxide (m.p. 225°C).

EXAMPLE 2

2-Carboxy-5-methylpyrazine (9.4 g) suspended in methylene chloride (100 ml) was treated with triethylamine (9.8 ml). The mixture was cooled to 0-5°C, ethyl chloroformate (7.4 ml) was added dropwise, and after 10 minutes diethylamine (9.48 ml) was added. The mixture was stirred for 5 hours at room temperature, the triethylamine hydrochloride thus obtained was filtered, the methylene chloride was distilled off and the crude diethylamide thus obtained was oxidized. The crude diethylamide (3.5 g) was added to glacial acetic acid (107 mL)/30% hydrogen peroxide (7.25 mL). The reaction mixture was heated at 70°C for 6 1/2 hours, then cooled and the product that separated was filtered to give 2-(N,N-diethylcarbamoyl)-5-methylpyrazine-4-oxide (2.5 g) sm. p. 110-112°C.

In the same way, 2-carboxy-5-methylpyrazine and monoethylamine were converted to 2-(N-ethylcarbamoyl)-5-methylpyrazine-4-oxide (m.p. 191-193°C).

EXAMPLE 3

2-Carbamoyl-5-methylpyrazine-4-oxide (5 g) was added to 10% sodium hydroxide (50 ml) and then refluxed for 30 minutes. The reaction mixture was acidified with dilute hydrochloric acid and extracted in a continuous extractor with ethyl acetate. The ethyl acetate extract was concentrated to a small volume, and after filtration gave 2-carboxy-5-methylpyrazine-4-oxide (3.2 g), m.p. 178-180°C,

Proceeding in the same way gave 2-carbamoyl-6-methylpyrazine-4-oxide 2-carboxy-6-methylpyrazine-4-oxide (m.p. 187-190°C),

while 2-carbamoyl-5,6-dimethylpyrazine-4-oxide gave 2-carboxy-5,6-dimethylpyrazine-4-oxide (m.p. 177-180°C).

EXAMPLE 4

2-Carboxy-5-methylpyrazine-4-oxide (2.5 g) was added to methanol (60 ml) and ethanolamine (1.1 ml). The mixture was refluxed for 20 minutes, then cooled and filtered and 2-carboxy-5-methylpyrazine-4-oxide-ethanolamine salt (2.1 g), m.p. 177-180°C is obtained, after crystallization from methanol.

In the same way, 2-carboxy-5,6-dimethylpyrazine-4-oxide and ethanolamine were converted to 2-carboxy-5,6-dimethylpyrazine-4-oxide-ethanolamine salt, m.p. 178-180°C.

EXAMPLE 5

2-Carboxy-5-methylpyrazine-4-oxide (6.5 g) was heated in a sealed stirrer with absolute ethanol (15 mL) and thionyl chloride (1 mL) for 5 h at 60 °C to give 2-carboxy-5-methylpyrazine -4-oxide ethyl ester (4 g).

EXAMPLE 6

2-Carboxy-5,6-dimethylpyrazine-4-oxide ethyl ester (5 g) was refluxed with 28 Be ammonium hydroxide (20 ml) to give 2-carbamoyl-5,6-dimethylpyrazine-4-oxide (3.5 g) , sm.p. 248-249°C.

EXAMPLE 7

2-Carboxy-5-methylpyrazine-4-oxide ethyl ester (4.5 g) was added to 10% sodium hydroxide (45 ml) and the mixture was refluxed for 5 hours. The reaction mixture was acidified with dilute hydrochloric acid and extracted in a continuous extractor with ethyl acetate. The ethyl acetate extract was concentrated to a small volume and after filtration gives 2-carboxy-5-methylpyrazine-4-oxide (3.5 g), m.p. 178-180°C.

EXAMPLE 8

30% hydrogen peroxide (40 ml) was added with cooling and stirring to maleic anhydride (78 g) in chloroform (60 ml). After two hours, 2-carboxy-5-methylpyrazine (4.8 g) was added and the mixture was kept for two days at 0-5°C. The maleic acid was filtered off. After concentration to a small volume, the product was treated with ethyl acetate to give, after filtration, 2-carboxy-5-methyl-pyrazine-4-oxide (1.1 g), m.p. 178-180°C.

EXAMPLE 9

(A) 2-carboxy-5-methylpyrazine potassium salt (6 g) suspended in dimethylformamide (80 ml) was treated with p-methoxybenzyl bromide

(8g). After 12 hours, the mixture was poured into ice water; the aqueous solution was extracted with chloroform, washed with saturated sodium bicarbonate and then with water. Drying gave 2-carboxy-5-methylpyrazine-p-methoxybenzyl ester (10 g).

(B) The product (4.5 g) of (A) in chloroform (100 ml) was treated dropwise with 90% m-chloroperbenzoic acid (3.32 g) in

chloroform (100 ml). After four hours, the reaction mixture was washed with saturated sodium bicarbonate and then with water. Drying over sodium sulfate and then under reduced pressure gave 2-carboxy-5-methylpyrazine-4-oxide-p-methoxybenzyl ester (3.8 g).

(C) The product (3 g) of (B) was treated with trifluoroacetic acid (3 ml) and benzene (30 ml). The mixture was stirred

1 hour at room temperature and the benzene and trifluoroacetic acid were removed under reduced pressure. The rest was treated with water, . and pH brought to 3. Extraction with ethyl acetate, concentration and filtration gave 2-carboxy-5-methylpyrazine-4-oxide (1.6 g), m.p. 178-180°C.

EXAMPLE 10

Powdered potassium hydroxide (1.7 g) was added to 2-carbamoyl-5-methylpyrazine-4-oxide (4 g) in dimethyl sulfoxide (20 mL). Ethyl bromide (6.55 g) was added dropwise while cooling;

after 4 hours water (80 ml) was added and the precipitate was filtered to give 2-(N,N-diethylcarbamoyl)-5-methylpyrazine-4-oxide (2.8 g), m.p. 110-112°C.

EXAMPLE 11

2-Carbamoyl-6-methoxypyrazine (2 g» m.p. 2o4-2o"7°C) was dissolved "in a mixture of glacial acetic acid (8 ml) and H 2 O 2 35% (5.5 ml). After stirring and heating at 7o°C for six and a half hours, the reaction mixture was cooled, the precipitated product filtered and washed with water to give 2-carbamoyl-6-methoxy-pyrazine-4-oxide (1.8 g» m.p. 248-25o °C). In the same way, starting from 2-carbamoyl-5-n-butylpyrazine (m.p. 139-141°c), after crystallization from ethanol 2-carbamoyl-5-n-butylpyrazine-4-oxide (m.p. 183-184 °c) obtained and from 2-carbamoyl-5-tert-butylpyrazine 2-carbamoyl-5-tert-butylpyrazine-4-oxide was obtained after crystallization from methanol (m.p. 178-180°C).

EXAMPLE 12

2-carbamoyl-6-chloropyrazine (4.73 gm. m.p. 165-167°c) was dissolved in glacial acetic acid (50 ml). A suspension of m-chloroperbenzoic acid (10.35 g) in glacial acetic acid (44 ml) was added portionwise. After stirring for three hours at 60°C, the reaction mixture was poured into ice water (75 mL), filtered, and the mother liquor was concentrated to a small volume. Filtration of the crude product, drying and crystallization from dimethylsulfoxide gave 2-carbamoyl-6-chloro-pyrazine-4-oxide (3.3 g > m.p. 238-24o°C).

EXAMPLE 13

2-Carbamoyl-6-methoxypyrazine-4-oxide (1.7 g) was dissolved in a mixture of concentrated H 2 SO 4 in water (1:1) (25 ml). A mixture of NaN02 (1 <3) in water (5 ml) was added dropwise with stirring at a temperature maintained at 2o-25°C, and then

stirred for two hours at 7o°C. The reaction mixture was pre-

diluted with water, repeatedly extracted with ethyl acetate, and then

the ethyl acetate was concentrated to dryness. Crystallization of the remaining product from dioxane gave 2-carboxy-6-methoxy-pyrazine-4-oxide (0.9 g > m.p. 242°c cleavage),

in the same way, starting from 2-carbamoyl-6-chloropyrazine-4-

oxide was obtained after crystallization from dioxane 2-carboxy-6-chloropyrazine-4-oxide (m.p. 2o5-2o7°C.

EXAMPLE 14

2-carbamoyl-5-n-butylpyrazine-4-oxide (4.4 g) was refluxed with HCl 8% (70 ml) for one and a half hours. The reaction mixture was repeatedly extracted with chloroform, the chloroform extracts were then concentrated to dryness, and the crude

product was recrystallized from water and gives 2-carboxy-5-n-butylpyrazine-4-oxide (3.2 g > m.p. 126-127°C).

EXAMPLE 15

2-Carbamoyl-5-tert-butylpyrazine-4-oxide (1.9 g) was refluxed for one hour with NaOH 10% (20 ml). The reaction mixture was cooled, then acidified with dilute hydrochloric acid. Filtration and crystallization from ethanol at 95°C gave 2-carboxy-5-tert-butylpyrazine-4-oxide (1.2 g, m.p. 122-123°C).

EXAMPLE 16

To a suspension of 2-carboxy-5-methyl-pyrazine-4-oxide (32.5

g) in methyl alcohol (15 ml) boron trifluoride etherate (1.2 ml) was added. After 1 hour at room temperature, the solution was refluxed for 1 night and then poured into ice water (50 ml). After alkaline adjustment with sodium bicarbonate, extraction with chloroform and drying on sodium sulfate, the solvent was evaporated. The residue, crystallized from methyl alcohol, gave

2-carboxy-5-methyl-pyrazine-4-oxide methyl ester (9 g; m.p.

145-146°C).

EXAMPLE 17

2-Carboxy-3-methyl-pyrazine-4-oxide ethyl ester (3.6 g) was refluxed in hydrochloric acid 20% (25 ml) for 2 1/2 hours. After evaporation of the solution and crystallization of the residue from water, 2-carboxy-3-methyl-pyrazine-4-oxide (1.3 g; m.p. 164-

165°C) achieved.

EXAMPLE 18

16.8 g of 2-carboxy-5-methylpyrazine-4-oxide methyl ester are heated in a closed stirrer with diethylamine (21 ml) for 6 hours at 80°C. At the end of the reaction, the methanol and excess amine are distilled off.

The residue is crystallized from dioxane. 17 g of 2-(N,N-diethylcarbamoyl)-5-methylpyrazine-4-oxide, m.p. 112-114°C (yield 81.3%) obtained

Dec.

Claims (1)

Analogous process for the preparation of a therapeutically active compound of general formula (I) where each of R<1>, R<2> and R<3>, which may be the same or different, denotes a hydrogen or halogen atom or a C1* alkyl or alkoxy group, and at least one of R<1>, R and R<3> is different from a hydrogen atom, R4 is a hydroxy or C1_6 alkoxy group or a group of the formula -NR R , where each of R<5> and R<6>, which may be the same or different , is a hydrogen atom or an alkyl group5 or, when R<4> is a hydroxy group, a pharmaceutically acceptable salt of said compound, characterized by oxidizing a compound of the general formula (II) 12 3 4 where R , R , R and R are as defined above, and convert, if desired, an obtained compound of general formula (I), where R 4 is a hydroxy group into a compound of general formula 4 5 6 (I), where R is an alkoxy group- or a -NR R group, or converts an obtained compound of general formula (I), where 4 5 6 R is an alkoxy group, or a -NR R group to a compound of general formula I, where R<4>is a hydroxy group, or converts an obtained compound of formula (I), where R 4 is an alkoxy group to a compound of general formula (IN), where R 4 is a -NR 5 R 6 group, or converts an obtained for-4 5 6 bond with general formula (I), where R is a -NR R group, 5 6 where one or both of R and R are hydrogen atoms of a compound of general formula (I), where R is a -NR R group, wherein one or both of R and R are alkyl groups and, if desired, reacts a compound of general formula (I), wherein R 4 is a hydroxy group, with a base to a pharmaceutically acceptable salt, or the carboxy group is protected in the usual manner.