NO135525B - - Google Patents

Description

The present invention relates to an analogue method for the production of new anti-inflammatory and analgesic agents.

Various anti-inflammatory agents, e.g. certain steroids (cortisone and its derivatives), acetylsalicylic acid (hereinafter called "Aspirin"), phenylbutazone and "Indomethacin", are known.

However, most of these known compounds have unpleasant side effects, for example they cause ulcers.

It has thus been desirable to find compounds which are useful anti-inflammatory agents, which are largely as effective as the known anti-inflammatory agents, but have less unpleasant side effects.

V.' Ett el and J. Hebky, Cali. Czech. Chem. Commun. , 15, 639

(1950) and J. Hebky, Cali. Czech. Chem. Commun., 16, 348 (1951),

have described the preparation of 2,6-dimethyl-3,5-dicarboethoxy-N-(4'-hydroxyphenyl)-4-pyridone and 2,6-dimethyl-3,5-dicarboethoxy-N-(3'-hydroxyphenyl)- 4-pyridone and their acid salts. The compounds serve as starting materials for the production of their mono- and

diiodo derivatives, as part of an investigation to find new X-ray contrast agents for a similar application to the known diethanolamine salt of 3,5-diiodo-4-pyridone-N-acetic acid.

It has now surprisingly been shown that certain esters of 2,6-dimethyl-N-4-alkoxyphenyl-substituted-4-pyridone-3,5-dicarboxylic acid have good anti-inflammatory properties essentially without having the unpleasant side effects that they known anti-inflammatory agents.

In addition, some of the pyridones mentioned have useful analgesic properties, and some have β-blocking properties.

The known 2,6-dimethyl-3,5-dicarboethoxy-(4*-hydroxyphenyl)-4-pyridone does not have these properties.

The present invention thus relates to an analogous method for the production of therapeutically active pyridone derivatives with the general formula:

where R 1 and R are the same or different alkyl or alkenyl groups with 1-4 carbon atoms, cycloalkyl groups with 5 or 6 carbon atoms or benzyl groups, and R is a straight-chain or branched alkyl, cycloalkyl, benzyl or alkenyl group with 1 - 20 carbon atoms, which method is characterized in that a pyrone with the general formula:

where R, and R„ are as indicated above,

is reacted with a 4-alkoxyaniline with the general formula:

where R is as above,

and, if desired, the resulting pyridone derivative of formula I is subjected to transesterification by boiling with a suitable alcohol, or alternatively, if desired, when both R 1 and R 2 are methyl or ethyl, the resulting pyridone derivative of formula I is hydrolyzed, and the resulting free carboxyl groups are esterified with a suitable alcohol.

The reaction of the pyrone of formula II with the amine with

formula III can be carried out in an inert solvent such as acetic acid, at elevated temperatures, e.g. 100 - 120°C, and the desired pyridone obtained is isolated in a manner known per se.

Any esterification is preferably carried out by first preparing the acid chloride, e.g. by reacting the 2,6-dimethyl-3,5-dicarboxy-N-phenyl-4-pyridone with thionyl chloride in benzene and then reacting the acid chloride with the desired alcohol.

Compounds of formula I show anti-inflammatory properties when tested in the carrageenin-induced hindpaw edema test. rats or in the cotton pellet granuloma test in rats.

Considerable anti-inflammatory activity and a good dose response were found at doses between 100 mg/kg body weight and 200 mg/kg when administered orally or intraperitoneally.

Moreover, the compounds of the pyridone derivatives of formula I have a low ulcerogenic index at the effective anti-inflammatory dose.

Some of the compounds exhibit analgesic properties as assessed by measuring the pain threshold in rats by the method of Randall and Selitto.

The toxicity of the investigated compounds was quite low.

The invention will now be illustrated with reference to the following examples.

Example 1

1>5 g of 4-butoxyaniline and 2 g of 2,6-dimethyl-3,5-dicarboethoxy-4-pyrone (M. Conrad and M. Guthzeit , Chem. Ber., 1°_, 19-26 (1886), which compound will hereafter be called "the pyridone") was dissolved in 10 ml of glacial acetic acid. The mixture was stirred and heated for 1 hour at 110°C, then cooled and poured into 50 g of ice and then neutralized with concentrated ammonia to pH 7. The precipitate was filtered off with suction, washed with water and dried, giving 3 g 2,6-dimethyl-3,5-dicarboethoxy-N-(4<*->butoxyphenyl)-4-pyridone, m.p. 134 - 135°C.

The compound has a good inhibitory effect on the development of carrageenin-induced edema in rats at a dose of 100 mg/kg, and a very good effect at a dose of 200 mg/kg. The compound also inhibited granuloma formation in intact and adrenolectomized rats at doses of 100 mg/kg and 200 mg/kg.

A low ulcerogenic index was observed at the dose described above.

At a dose of 200 mg/kg, the compound had a good effect on adjuvant arthritis in rats, compared to "Indomethacin". A good analgesic activity was observed at a dose of 200 mg/kg compared to aminopyrine.

Example 2

1.5 g of the pyronet and 1 g of p-isobutoxyaniline were dissolved in 20 ml of acetic acid, and the resulting mixture was heated for 30 minutes at 110°C. The mixture was cooled, poured into ice water and neutralized to pH 7 with ammonium hydroxide. The precipitate formed was filtered off and dried in air. Yield was 1 g of 2,6-dimethyl-3,5-dicarboethoxy-N-(4'-isobutoxyphenyl)-4-pyridone, m.p. 110°C.

The compound had a very good inhibitory effect on the development of carrageenin-induced edema in rats at a dose of 200 mg/kg. A moderate analgesic effect was observed at the same dose.

The following compounds were prepared in the same manner:

2,6-dimethyl-3,5-dicarboethoxy-N-(4'-methoxyphenyl)-4-pyridone,

m.p. 159 - 16o°C,

2,6-dimethyl-3,5-dicarboethoxy-N-(4'-ethoxyphenyl)-4-pyridone,

m.p. l65°C,

2,6-dimethyl-3,5-dicarboethoxy-N-(4'-propoxyphenyl)-4-pyridone,

m.p. 122°C.

Example 3

In the same way as described in example 2, 2.78 g of the pyronet and 2 g of p-isopentyloxy-aniline were reacted, whereby 4.5 g of 2,6-dimethyl-3,5-dicarboethoxy-N-(4' -isopentyloxyphenyl)-4-pyridone, m.p. 168°C.

A considerable analgesic effect was observed at a dose of 200 mg/kg.

The compound had a very good inhibitory effect on carrageenin-induced edema in rats at a dose of 200 mg/kg.

Example 4

In the same way as described in example 2, 2.75 g of the pyronet and 2 g of p-n-pentylaniline were reacted, whereby 4>3 g of 2,6-dimethyl-3,5-dicarboethoxy-N-(4'-pentyloxyphenyl) were obtained )-4-pyridone, m.p. 92°C.

The compound had a moderate inhibitory effect on carrageenin-induced edema in rats at a dose of 200 mg/kg.

Example 5

in the same way as described in example 2, 2.53 g of the pyrone was reacted with 2 g of p-heptyloxyaniline, whereby 4 g of 2,6-dimethyl-3,5-dicarboethoxy-N-(4'-heptyloxyphenyl)- 4-pyridone, m.p. 102°C.

At a dose of 200 mg/kg, a persistent and strong anti-inflammatory effect was observed with a rapid onset of carrageenin-induced oedema.

Example 6

In the same way as described in example 2, 17.2 g of the pyronet was reacted with 2 g of p-octyloxyaniline in 15 ml of acetic acid, whereby 2.5 g of 2,6-dimethyl-3,5-dicarboethoxy-N-( 4'-octyloxyphenyl)-

4-pyridone, m.p. 86°C.

The compound has a good inhibitory effect on carrageenin-induced edema in rats at a dose of 200 mg/kg.

Example 7

In the same way as described in example 2, 2 g of the pyronet were reacted with 2,99 p-octadecyloxyaniline in 15 ml of acetic acid, whereby 5 g of 2,6-dimethyl-3,5-dicarboethoxy-N-(4' -octadecyloxy-phenyl)-4-pyridone, m.p. 90°C.

The compound delayed the development of the inflammation. It had a very good inhibitory effect on carrageenin-induced edema in rats at a dose of 200 mg/kg.

Example 8

In the same way as described in example 2, 2 g of the pyrone was reacted with 2.5 g of p-tetradecyloxyaniline in 15 ml of acetic acid, whereby 3.8 g of 2,6-dimethyl-3,5-dicarboethoxy-N-( 4<*->tetradecyloxy-phenyl)-4-pyridone, m.p. 87°C.

Example 9

In the same way as described in example 2, 1.04 g of the pyronet was reacted with 2 g of p-decyloxyaniline in 15 ml of acetic acid, whereby 2.7 9 2,6-dimethyl-3,5-dicarboethoxy-N-( 4'-decyloxyphenyl)-4-pyridone, m.p. 87°C.

Example 10

In the same way as described in example 2, 1.3 g of the pyronet was reacted with 1 g of p-cyclohexyloxyaniline in 15 ml of acetic acid, whereby 1 g of 2,6-dimethyl-3,5_dicarboethoxy-N-(4'-cyclohexyloxyphenyl) was obtained )-4-pyridone, m.p. 170°C.

Example 11

In the same manner as described in Example 2, 2.1 g of the pyrone was reacted with 3 9 p-heptadecyloxyaniline in 15 ml of acetic acid, which gave 5 g of 2,6-dimethyl-3,5-dicarboethoxy-N-(4<* ->heptadecyloxyphenyl)-4-pyridone, m.p. 85°C.

Example 12

In the same manner as described in Example 2, 2.5 g of the pyronet was reacted with p-(3'-hexyloxy)-aniline in 15 ml of acetic acid, yielding 4 g of 2,6-dimethyl-3,5-dicarboethoxy-N -[4'-(3"-hexyloxy)-phenyl]-4-pyridone, mp 145°C.

The compound showed good inhibitory activity against carrageenin-induced edema in rats at a dose of 200 mg/kg.

Example 13

In the same manner as described in Example 2, 2.5 g of the pyrone was reacted with p-pentadecyloxyaniline in 15 ml of acetic acid, yielding 5.5 g of 2,6-dimethyl-3,5-dicarboethoxy-N-(4"- pentadecyloxyphenyl)-4-pyridone, mp 95°C.

The compound showed a very good inhibitory effect on carrageenin-induced edema in rats at a dose of 200 mg/kg.

Example 14

In the same manner as described in Example 2, 2.53 g of the pyrone was reacted with 2 g of p-(4'-heptyloxy)-aniline in 15 ml of acetic acid, which gave 3.5 g of 2,6-dimethyl-3,5 -dicarboethoxy-N-[4'-(4"-heptyl-oxy)-phenyl]-4-pyridone, mp 116°C.

The compound showed very good inhibitory effect on carrageenin-induced edema in rats at a dose of 200 mg/kg.

Example 15

in the same manner as described in Example 2, 2.5 g of the pyrone was reacted with 2 g of p-(2•-heptyloxy)-aniline in 15 ml of acetic acid, yielding 3.5 g of 2,6-dimethyl-3,5 -dicarboethoxy-N-[4'-(2"-heptyloxy)-phenyl]-4-pyridone, mp 90°C.

The compound showed good inhibitory effect on carrageenin-induced edema in rats at a dose of 200 mg/kg.

Example 16

in the same manner as described in Example 2, 2 g of the pyronet was reacted with 2 g of p-(4'-octyloxy)-aniline in 15 ml of acetic acid, yielding 3.5 g of 2,6-dimethyl-3,5-dicarboethoxy -N-[4'-(4"-octyloxy)-phenyl]-4-pyridone, mp 104°C

At a dose of 200 mg/kg, a good anti-inflammatory effect was observed on carrageenin-induced edema in rats. A mild analgesic effect was also observed.

Example 17

in the same manner as described in Example 2, 2.95 g of the pyrone was reacted with 2 g of p-(3'-pentyloxy)-aniline in 15 ml of acetic acid^ which gave 4.5 g of 2,6-dimethyl-3, 5-dicarboethoxy-N-[4<*->(3"-pentyl-

oxy)-phenyl]-4-pyridone, m.p. 172°C.

At a dose of 200 mg/kg, a very good anti-inflammatory effect was observed on carrageenin-induced edema in rat

the paw. A good analgesic effect was also observed.

The compound also exhibited (3-blocking effects on a

isolated rat uterus (standard dose 200 µg/kg) and on rat blood jerk (standard dose 20 mg/kg).

Example 18

In the same way as described in example 2, 2.5 g of

the pyronet reacted with 2 g of p-hexyloxyaniline in 15 ml of acetic acid, which gave 4.3 g of 2,6-dimethyl-3,5-dicarboethoxy-N-(4'-hexyloxyphenyl)-4-

pyridone, m.p. 104°C.

The compound showed moderate inhibitory effect on carrageenin-induced edema in rats at a dose of 200 mg/kg.

Claims (1)

Analogous procedure for the preparation of therapeutically active pyridone derivatives with the general formula: where R 1 and R 2 are the same or different alkyl or alkenyl groups with 1-4 carbon atoms, cycloalkyl groups with 5 or 6 carbon atoms or benzyl groups, and R is a straight-chain or branched alkyl, cycloalkyl, benzyl or alkenyl group with 1 - 20 carbon atoms, characterized in that a pyrone with the general formula: where R and R^ are as indicated above, is reacted with a 4-alkoxyaniline with the general formula: where R is as above, and, if desired, the obtained pyridone derivative of formula I is subjected to transesterification by boiling with a suitable alcohol, or alternatively, if desired, when both R^ and R^ are methyl or ethyl, the obtained pyridone derivative of formula I is hydrolyzed, and the obtained free carboxyl groups are esterified with a suitable alcohol.