NO124370B - - Google Patents

Description

Analogy method for the preparation of pharmacodynamically active 3-aryl-5-methylhydantoins.

The present invention relates to a process for the production of new 3-aryl-5-methylhydantoins with pharmacodynamic action. More particularly, the present invention relates to the production of certain new 3-phenyl-5-methylhydantoins which are substituted in the phenyl ring.

It has surprisingly been found that compounds of formula I where R is a fluorine atom, a trifluoromethyl group or •. a lower ayloxy group,

has interesting pharmacological properties. Thus, pharmacological experiments have shown that said compounds of formula I possess anti-inflammatory, analgesic and antipyretic properties in mammals which make them valuable in the treatment of pain, inflammation or fever. Moreover, they are used in pathological conditions, the symptomatology of which is characterized by a combination of the aforementioned symptoms, such as dermatitis, inflammation of the joints, arthritis and rheumatism. They prove to be well tolerated and remarkably free of side effects, especially of allergic origin.

The term "lower alkoxy"" and "lower alkyl" as used in the present description and in the appended claims includes alkoxy and alkyl groups containing up to and including 6 carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl and isopro -pyl groups, also the butyl group, the pentyl group and the hexyl group and their branched isomers. Alkoxy groups are, for example, methoxy, ethoxy, propoxy and isopropoxy groups, further butoxy, pentyloxy and hexyloxy groups and their branched isomers. Methyl is preferred and methoxy groups.

Certain 3-phenyl-5-alkylhydantoins are described in the literature. Thus, 3-phenyl-5-methylhydantoin is a well-known compound and 3-phenylhydantoins substituted in the 5-positions with alkyl groups of up to and including 8 carbon atoms are described in French Patent No. 1,389,841, Monatshefte 85, 1060 - 1076 (1954) and J. Chinese Chem. Soc. 15, 46-54 (1947). No biological properties have been shown for said hydantoins in the aforementioned publications. Furthermore, 3-phenyl-5-methyl- and -isobutylhydantoins comprising a chlorine or a methyl substituent in the phenyl ring have been described in J. Med. Chem. 7, 97-101 (1964); when testing for pharmacological properties with the aim of showing hypoglycemic activity, none could be detected. Thus, no 3-(substituted phenyl)-5-methylhydantoins possessing valuable pharmacological properties have so far been found to be known.

The compounds of formula I are prepared by cyclization of a racemic or optically active compound of formula II

where "alkyl" is an alkyl group with up to 6 carbon atoms, preferably methyl or ethyl, and

R has the meaning stated above.

The cyclization of compounds of formula II occurs at a moderately elevated temperature. However, it is advantageous to carry out said cyclization in the presence of an acid and preferably in a homogeneous solution. Suitable acids are mineral acids, preferably aqueous hydrohalic acids, especially hydrochloric acid. Addition of an organic solvent, such as a lower alkanol, e.g. methanol, ethanol or propanol to achieve a homogeneous solution is appropriate. Other solvents miscible with water can also be used, e.g. dioxane, dimethylformamide or dimethylsulfoxide. The procedure is carried out at temperatures from room temperature to boiling temperature over the course of several hours. On cooling, the product crystallizes and can be isolated by simple filtration. Its subsequent purification is achieved by conventional technique.

Starting compounds of formula II are prepared using well-known methods from a phenyl isocyanate substituted in accordance with the meaning of R and an alkyl ester of alanine.

The 3-phenyl-5-methylhydantoins according to the present invention

come as optical isomers, and both the racemates and the individual isomers are included within the scope of the present invention. While the racemate is usually used, the individual isomers can be obtained through the use of the corresponding optical isomer of the alanine alkyl ester starting material.

The following examples further illustrate the invention. The temperatures are indicated in degrees Celsius.

EXAMPLE 1

p-fluorophenyl isocyanate (0.12 mol, 16.48 g) is added to a suspension of D,L-alanine methyl ester hydrochloride (0.12 mol,

16.74 g) and sodium bicarbonate (0.12 mol, 10.08 g) in anhydrous benzene (120 mL). The reaction mixture is heated under reflux for 5 hours and then cooled. The reaction mixture is filtered and the collected solid is washed well with water to remove salts and dried, m.p. 155 - 168°. A solution of this material, containing mostly D,L-N-(p-fluorophenyl)carbamoylalanine methyl ester in 3-n hydrochloric acid (150 mL) and ethanol (150 mL), is heated at reflux for 4 hours. The reaction mixture is cooled and the resulting 3-(p-fluorophenyl)-5-methyl-hydantoin is collected by filtration.

One recrystallization from ethanol and three recrystallizations from isopropanol (with charcoal purification) gives the pure product, m.p.

183 - 186°C.

EXAMPLE 2

To a suspension of D,L-alanine methyl ester hydrochloride (0.13 mol, 18.09 g) and sodium bicarbonate (0.13 mol, 10.94 g) in anhydrous benzene (130 ml) is added p-methoxyphenyl isocyanate (0 .13 mol, 19.3 g). This mixture is heated at reflux for 10 hours and then cooled. The product is collected by filtration, washed with water and recrystallized twice from methanol (200 ml) and once from ethanol. This material is dissolved in boiling 6-n sodium hydroxide solution (165 ml) and the insoluble material is removed by filtering the hot solution through a sintered glass funnel. The filtrate is cooled and the sodium salt, which precipitates, is collected by filtration, washed with 6-n sodium hydroxide solution and redissolved in water. This solution is adjusted to pH 4 with 50% acetic acid and a solid settles to the bottom. A suspension of this solid in ethanol (110 ml) and 1-n hydrochloric acid (110 ml) is heated at reflux for 4 hours and cooled to give 3-(p-methoxyphenyl)-5-methylhydantoin, which after recrystallization from ethanol melts at 179 - 180°C.

EXAMPLE 3

a) m-trifluoromethylphenyl isocyanate (0.09 mol, 16.8 g), D,L-alanine methyl ester hydrochloride (0.09 mol), 12.4 g) and sodium bicarbonate (0.09 mol, 7, 56 g) in anhydrous benzene (90 ml) is heated at reflux for 5 hours and cooled. The reaction mixture is filtered and the combined solid is washed with water. The mother liquor is evaporated to dryness and the residue is dissolved in chloroform and water. The organic phase is separated, dried over sodium sulfate and evaporated to dryness to give D,L-N-(m-trifluoromethylphenyl)carbamoyl-alanine methyl ester as an oil.

A solution of this oil in 3N hydrochloric acid (112.5 ml) is heated at reflux for 4 hours and then cooled. The product is collected by filtration and the mother liquor is refiltered to give a second quantity. The combined solid is suspended in ether, stirred at room temperature and filtered. 3-(m-trifluoromethylphenyl)-5-methyl-hydantoin, m.p. 135 - 137°, is thus collected and further purified by recrystallization from benzene. b) In a similar way, the product 3-(p-trifluoromethylphenyl)-5-methylhydantoin, mp. 180 - 181°C.

The pharmacological properties of the compounds of formula I can be demonstrated and measured in standard samples, accepted and recognized by pharmacologists as consistent with a therapeutic effect. E.g. anti-inflammatory activity can be observed in rodents, especially in rats, in which inflammation and oedema, which results from it, is produced with the help of carrageenin, etc.

J. Pharmacol. 16, 810-816 (1964) as well as in other conventional animal models.

As a measure of analgesic activity, the reduction of writhing produced by the administration of acetic acid as observed in the so-called "stretch test", cf. Fed. Pro. 18, 412 (1959) can be used.

Antipyretic activity can be observed in the well-established sample according to Smith & Hamburger, J. Pharmacol. Exp. Therap. 54, 346

(1935).

The following compounds produced according to the invention have been examined in one or more of the test processes as mentioned above:

A. 3-(p-fluorophenyl)-5-methylhydantoin (ex. 1)

B. 3-(p-Methoxyphenyl)-5-methylhydantoin (Ex. 2)

C. 3-(m-trifluoromethylphenyl)-5-methylhydantoin (ex. 3)

The results obtained are as follows:

These results show that the test compounds after oral administration reduce carrageenin-induced edema and thus have interesting anti-inflammatory properties.

These results show that after oral administration of the test compounds the extent of torsion produced by acetic acid is substantially reduced and thus that the test compounds show interesting analgesic activity.

The anti-pyretic effect of compound A by oral administration amounts to -23°C at 50 mg/kg. By comparison, the effect of antipyrine at 200 mg/kg p.o. amounts to -21°C.

For the purpose of oral administration, the compounds of formula I are incorporated into mixtures suitable for oral administration to animals in solid or liquid dosage unit forms, such as tablets, capsules, powders, granules, syrups, elixirs and the like. The term dosage unit form as used in this description and claims refers to physically separate units suitable as uniform dosages for animals, each unit containing a predetermined amount of active material calculated to provide the desired therapeutic effect, especially analgesic, anti-inflammatory and/or or

antipyretic activity in mammals, in conjunction with the desired pharmaceutical diluent, carrier or excipient.

Claims (1)

Analogy method for the preparation of pharmacodynamically active compounds of the general formula I where R denotes a fluorine atom, a trifluoromethyl group or a lower alkoxy group, in racemic or optical, active form, character! by cyclizing a racemic or optically active compound of formula II where "alkyl" is an alkyl group with up to 6 carbon atoms, preferably methyl or ethyl, and R has the above meaning, at a moderately elevated temperature, preferably in the presence of a strong acid, e.g. a hydrohalic acid and in an inert solvent.