IL31917A - 3-aryl-5-methylhydantoins,process for the preparation thereof,and therapeutic compositions containing them - Google Patents

Description

on1 K D' »3Dn o"nsi">r» o 'wni Novel 3-aryl-5-methylhydantoins process for the preparation thereof, and therapeutic compositions containing them CIBA-GEIGY A.G.

C. 30156 4-2796 /GC 307* J. R. G E I G Y A.G. ; B A S E L ; S C H E I Z NOVEL 3-ARYL-5-METHYLHYDANTOINS AND PROCESS FOR THE PREPARATION THEREOF This invention pertains to certain novel 3-aryl-5-methyl-hydantoins, to a process for their preparation and to compositions of matter containing them. More in particular, this invention pertains to certain novel 3-phenyl-5-methylhydantoins which are substituted in the phenyl ring and which have therapeutic utility.

It has been surprisingly found that compounds of the formula I 0 CH wherein R represents a fluorine atom, a trifluoromethyl group or a lower alkoxy group, possess interesting pharmacological properties. Thus, pharmacological experiments have revealed that said compounds of formula I possess anti- inflammatory, analgesic and antipyretic properties in mammals which indicates them to be useful in the treatment of pain, inflammation or fever; moreover, they are indicated in pathological conditions the symptomatology of which is characterized by a combination of the aforesaid symptoms, such as dermatitis, in- flammation of the joints , arthritis, rheumatism.

They appear to be well tolerated and remarkably free of side effects, particularly of allergenic origin.

The terms "lower alkoxy" and "lower alkyl" as used in this specification and the appended claims define alkoxy and alkyl groups comprising up to and including 6 carbon atoms. Examples of such alkyl groups are the methyl, ethyl, propyl and isopropyl groups, also the butyl group, the pentyl group and the hexyl group and their branched-chain isomers. Alkoxy groups are, for example, the methoxy, ethoxy, propoxy and isopropoxy groups, ^ branched chain furthermore the butoxy, pentyloxy and hexyloxy groups and their/ isomers. Preferred are the methyl and methoxy groups.

Certain 3-phenyl-5-alkylhydantoins have been described in the literature. Thus, 3-phenyl-5-methylhydantoin is a well-known compound and 3-phenylhydantoins substituted in the 5-positions by alkyl groups up to and including 8 carbon atoms have been 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 revealed for said hydantoins in the aforementioned publications. Furthermore, 3-phenyl-5-methyl- and -isobutylhydantoins comprising a chloro or a methyl substituent in the phenyl ring have been described in J. Med. Chem. _7, 97 - 101 (1964) ; when tested for pharmacological property with the object of demonstrating hypoglycemic activity, none could be detected. Thus, no 3- (substituted phenyl) -5-me-thylhydantoins possessing useful pharmacological property appear to have become known to date .

The compounds of formula I may be prepared by cyclization of a compound of formula II COOalkyl (ID wherein R and "alkyl" have the meanings defined above.

Cyclization of compounds of formula II will occur at moderately elevated temperature. However, it is advantageous to perpreferably form said cyclization in the presence of an acid and/in homogeneous solution. Suitable acids are mineral acids, preferably aqueous hydrohalic acids, particularly hydrochloric acid. Addition of an organic solvent, such as a lower alkanol , e. g. methanol , ethanol or propanol , in order to achieve homogeneous solution is convenient . Other solvents miscible with water may also be used, e. g. dioxane, dimethylformamide or dimethyl- sulfoxide. The process is performed at temperatures ranging from room temperature to boiling temperature for periods of several hours. On cooling , the product crystallizes and can be isolated by simple filtration. Its subsequent purification 19 achieved by conventional techniques .

Starting compounds of formula II are prepared by known The 3-phenyl-5-methylhydantoins of the present invention exist as optical isomers and both the racemates and the individual isomers are within the scope of the present invention. V/hile the racemate is generally employed, the individual isomers can be obtained through use of the corresponding optical isomer of the alanine alkyl ester starting material.

The following examples further illustrate the invention without in any way limiting the scope thereof. Temperatures are in degrees centigrade.

EXAMPLE 1 b-Fluorophenylisocyanate (0,12 mole, 16,48 g) is added to a suspension of D,L-alanine methyl ester hydrochloride (0,12 mole, 16,74 g) and sodium bicarbonate (0,12 mole, 10,08g) in anhydrous benzene (120 ml) . The reaction mixture is heated at 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, consisting essentially of D ,L-N- (p- fluorophenyl) car-bamoylalanine methyljester in 3N hydrochloric acid (150 ml) and ethanol (150 ml) is heated at reflux for four hours. The reaction mixture is cooled and the resulting 3- (p- fluorophenyl) -5-methylhydantoin is collected by filtration.

One recrystallization from ethanol and three recrystalli-zations from isopropanol (with charcoal clarification) afforded the pure product, m. p. 183 - 186 °C .

EXAMPLE 2 To a suspension of D,L-alanine methyl ester hydrochloride (0,13 mole, 18,09 g) and sodium bicarbonate (0,13 mole, 10,94 g) in anhydrous benzene (130 ml) is added p-methoxyphenylisocyanate (0,13 mole, 19,3 g) . This mi¾/¾re 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 6N sodium hydroxide solution (165 ml) and the insoluble material is removed by filtration of the hot solution through a sintered glass funnel. The filtrate is cooled and the sodium salt lution is adjusted to pH 4 with 50 % acetic acid and a solid precipitates. A suspension of this solid in ethanol (110 ml) and IN hydrochloric acid (110 ml) is heated at reflux for four hours and cooled to yield 3- (p-methoxyphenyl) -5-methyl-hydantoin which after one recrystallization from ethanol melts at 179 - 180 °C.

EXAMPLE 3 (a) m-Trifluoromethylphenyljisocyanate (0,09 mole, 16,8 g) , D,L-alanine methyl ester hydrochloride (0,09 mole, 12,4 g) , and sodium bicarbonate (0,09 mole, 7,56 g) in anhydrous benzene (90 ml) is heated at reflux for 5 hours and cooled. The reaction mixture is filtered and the collected 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 yield 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 crop. The combined solid is suspended in ether, stirred at room temperature and filtered. 3- (m-Trifluoromethylphenyl) -5-methylhydantoin, m. p. 135 - 137 °C, is thus collected and further purified through recrystallization from benzene. (b) In a similar manner there was obtained from N- (p-Tri-fluoromethylphenyl) carbamoylalanine methyl ester (m. p. 127 -131 °) the product 3- (p-trifluoromethylphenyl) -5-methylhydantoin, m. p. 180 - 181 °C.

The pharmacological properties of the compounds of formula I can be demonstrated and measured in standard tests, accepted and recognized by pharmacologists as correlating with a therapeutic effect. For example anti-inflammatory activity can be observed in rodents, generally in the rat , in which inflammation and edema resulting therefrom is induced by means of carrageenin, cf. J. Pharmacol. JL6 , 810 - 816 (1964) as well as in other conventional tests on experimental animals.

As a measure for analgesic activity, reduction of writhing induced by administration of acetic acid as observed in the so-called "stretch test", cf. Fed. Proc. 18 , 412 (1959) may be used Antipyretic activity may be observed in the well-established test according to Smith & Hamburger, J. Pharmacol. Exp. Therap. 54 , 346 (1935) . vention have been examined in one or more of the test procedures 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: Table I Effect on Carrageenin-induced Edema Compound Dose (mg/kg) Reduction of Induced and Route Edema (% of Control) A 100 p. o. - 46 50 p . o . - 31 p. o. - 30 12.5 . o . - 24 B 100 p. o. - 27 These results demonstrate that the test compounds after oral administration reduce carrageenin-induced edema and thus have interesting anti-inflammatory property.

Table II Effect on Writhing induced by Acetic Acid ("Stretch Test") „ , Dose (mg/kg) Reduction of D Compound ^ *> Writhing (% df Control) Ratin§~ A 12.5 p. o. - 83 2 6.25 p . o . - 85 2 B 25 p. o. - 71 2 12.5 p. o. - 77 2 C 25 p. o. - 57 2 12.5 p. o. - 49 1 " " These results demonstrate that after oral administration of the test compounds the extent of writhing induced by acetic acid is extensively reduced and thus that the test compounds exhibit interesting analgesic activity.

The anti-pyretic effect of Compound A on oral administration was found to amount to - 9.1 °F at 50 mg/kg. By comparison, the effect of antipyrine at 200 mg/kg p. o. amounts to - 5,7 °F.

For the purpose of oral administration, the compounds of formula I are incorporated in compositions suitable for oral administration to animals in solid and liquid unit dosage forms, such as tablets, capsules, powders, granules, syrups, elixirs and the like. The term unit dosage form as used in this specification and claims refers to physically discrete units suita-ble as unitary dosages for animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in particular analgesic , antiinflammatory and/or antipyretic activity in mammals, in association with the required pharmaceutical diluent carrier or vehicle.

Powders are prepared by comminuting a compound of this invention to a suitable fine size and mixing with a similarly comminuted diluent. The diluent can be an edible carbohydrate material such as starch. A sweetening agent or sugar may also be present as well as flavoring oil.

Granules for reconstitution into a liquid oral preparation are prepared utilizing water-soluble diluents. A powder mixture of the finely divided compound and a water-soluble diluent such as sucrose, glucose, and the like, is wetted with a binder such as acacia mucilage, gelatin solution, methyl- cellulose solution and forced through a screen to form granules which are allowed to dry. A suspending agent such as traga- canth may be included in the composition.

Capsules are made by preparing a powder mixture as des- cribed above and filling formed gelatin sheaths. As an aj-juvant to the filling operation, a lubricant such as talc, magnesium stearate and calcium stearate may be added to the powder mixture before the filling operation.

Tablets are made by preparing a powder mixture, granu-lating or slugging, adding a lubricant and pressing into tablets. The powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base such as starch, sucrose, kaolin, dicalcium phosphate and the like.

The powder mixture can be granulated by wetting with a binder such as syrup, starch paste or acacia mucilage and forcing through a screen. As an alternative to granulating, the powder mixture can be slugged, i. e., run trough the tablet machine and the resulting imperfectly formed tablets broken into pieces (slugs) . The slugs can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricating mixture is then compressed into tablets. A protective coating consisting of a sealing coat of shellac, a coating of sugar and methylcellulose, and a polish coating of carbauba wax may be provided.

Oral fluids are prepared in unit dosage forms such as syrups and elixirs wherein each teaspoonful of composition contains a predetermined amount of the compound for administratior The following examples illustrate the production of unit dosage forms.

Ingredient Quantity/capsule 3- (p-Fluorophenyl) -5-methylhydantoin.... 100 mg Corn Starch 200 mg The foregoing ingredients are mixed and introduced into a two-piece No. 1 hard gelatin capsule.

EXAMPLE 6 Ingredient Quantity/tablet 3- (m-Trifluoromethylphenyl) -5-methylhydantoin 50 mg Corn Starch : 130 mg Lactose 160 mg Silicium dioxide (colloidal) 4 mg Gelatin 5 mg Magnesium Stearate 1 mg The foregoing ingredients are thoroughly mixed and pressed into tablets suitable for oral administration of 50 mg of active ingredient. The tablets may be scored to permit administration of fractional doses.

EXAMPLE 7 Ingredient Quantity/tablet 3- (p-Methoxyphenyl) -5-methylhydantoin ... 250 mg Lactose 80 mg Corn Starch 70 mg Soluble Starch 15 mg Magnesium Stearate 5 mg The first three ingredients are thoroughly mixed and granulated with a solution of the soluble starch. This granu

Claims (10)

1. What is claimed is: A compound of the formula wherein R represents a fluori' Le atom, a trifluoromethyl group or a lower alkoxy group in racemic or optically active form.
2. 2. A compound as claimed in claim 1 wherein R is a fluorine atom.
3. 3. A compound as claimed in claim 2 wherein the fluorine atom is in the 4-position.
4. 4. A compound as claimed in claim 1 wherein R is a methoxy grou .
5. 5. A compound as claimed in claim 4 wherein the methoxy group is in the 4-position.
6. 6. A compound as claimed in claim 1 wherein R is the tri-fluoromethyl group.
7. 7. A compound as claimed in claim 6 wherein the trifluoro-methyl group is in the 3-posii ion or in the 4-position.
8. 8. Process for the productic n of compounds of formula I wherein R represents a fluorine atom, a tri luoromethyl group which comprises cyclization of a racemic or optically active compound of formula II CH„ - CH - COOalkyl (II) wherein "alkyl" represents an alkyl group comprising up to and including 6 carbon atoms and R has the meaning defined above, at moderately elevated temperature, preferably in the presence of a strong acid and in an inert solvent.
9. 9. Process as claimed in claim 8 wherein cyclization is effected in the presence of a mineral acid in aqueous medium.
10. 10. Process as claimed in claim 9 wherein the mineral acid is a hydrohalic acid. 12. Process as claimed in claim 9 wherein in a compound of formula II the group "alkyl" is a methyl group or an ethyl group . 13. Process as claimed in claims 8 to 12 substantially as hereinbefore described with reference to any one of the Examples 1 to 3. 14. A compound having the formula I as defined in claims .1 to 7 whenever prepared by a process as claimed in any one of the claims 8 to 12 and 13. 15. A therapeutic composition capable of exerting an analgesic, antipyretic anti-inflammatory and/or/effeet , comprising a therapeutically effective amount of a 3-aryl-5-methylhydantoin as defined in claim 1, together with a pharmaceutically acceptable diluent or carrier therefor and compounded as a dosage form suitable for internal administration. 16. A therapeutic composition as claimed in claim 15 wherein the 3-aryl-5-methylhydantoin is as defined in claim 3. nts