Butyramide derivatives

Process for preparing new butvramide derivatives (Inventors t Jean MEIER and Anne FARTNOUAT)

Société Anonyme called-: ROUSSEL-UCLAF • International Convention - Priority of a patent application filed in France on September 3, 1973 under N ° 73-31699. *

The present invention relates to a process for the preparation of new derivatives of butyramide of 'formula I s'

<img file="LU70832A1_D0001.tif" />

where X '^, X' ^, X '₂ and X₂ represent a hydrogen atom, a halogen atom, an alkyl, alkyloxy or alkylthio group having 1 to 5 carbon atoms, a trifluoromethyl, trifiuoromethoxy or trifluoromethylthio group, a hydroxy group or a dialkoylamino group having 1 to 5 carbon atoms , X, Y and Z represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, R ^ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, R₂ represents a hydroxy group or an alkyloxy group having 1 to 5 carbon atoms and the dotted line indicates the possible presence of a double bond, either in αβ or in βy of the oarboxylic group.

- 2 In formula 1 ^ the substituents X'p X ^, X'g ^ 2 may be in any position on the benzene rings. When X'p X ^, or X¹^ represents a halogen atom, it is preferably a fluorine or chlorine atom; when X'p X ^, X'2 or X2 represents an alkyl, alkyloxy or alkylthio group, these are in particular methyl or ethyl, methoxy or ethoxy, methylthio or ethylthio groups. The substituents X, Y and Z preferably represent a hydrogen atom or a methyl group. .

The invention relates in particular to a process for the preparation of those derivatives of formula I which correspond to formula I.

<img file="LU70832A1_D0002.tif" />

wherein X ^ represents a halogen atom, X2 represents an alkyl group having 1 to 5 carbon atoms, and X, Y, Z, P ^ and Rg are defined as above.

The substituent X ^ preferably represents a fluorine or chlorine atom; the substituent X_£ preferably represents a methyl group

The invention relates in particular to a process for the preparation of those of the derivatives of formula I or I ^, for which X, Y and Z represent a hydrogen atom, as well as those for which Rz | represents a hydrogen atom or a methyl group and R2 represents a hydroxy or methoxy group.

The invention relates in particular to a process for preparing the derivatives of formula I described below in Examples i to 4.

The compounds of formula I possess valuable pharmacological properties. They exhibit in particular analgesic and anti-inflammatory activity.

- 3 They can be used in therapy / for example, in the treatment of muscle, joint or nerve pain, rheumatic ailments, dental pain, zonas and migraines, as well as osteoarthritis, lumbago and also as a complementary treatment in infectious states and feverish.

Therapeutically active compounds of formula I can therefore be used as a medicament.

The new butyramide derivatives of formula I, obtained by the process of the invention, can be used for the preparation of pharmaceutical compositions containing as active principle at least one of the products of formula I defined above.

These pharmaceutical compositions can be administered parenterally, buccally or rectally, or locally in topical application to the skin or mucous membranes.

To this end, they can be presented in the form of injectable solutions or suspensions, tablets, capsul.es, capsules, oral solutions or emulsions, suppositories, ointments, creams or topical powders. These pharmaceutical forms are prepared according to the usual methods.

The dosage varies in particular depending on the route of administration and the desired therapeutic effect. For example, in adults, it can vary, orally, between 100 mg and 1 g of active principle per day.

The process of the invention is characterized in that an acid of formula II is subjected:

<img file="LU70832A1_D0003.tif" />

the substituents of which are defined as above, or a functional derivative thereof, for the action of a compound of formula III:

<img file="LU70832A1_D0004.tif" />

(Ill)

R ^ and R ^ being defined as above. .

The functional derivatives of the acids of formula II can be the anhydride, the acid chloride, a mixed anhydride or a lower alkyl ester.

When using the acid II itself, the reaction is carried out, for example, in the presence of a dehydrating agent. The dehydrating agent is, for example, dicyclohexylcarbodiimide.

When using a lower alkyl ester of acid II, the reaction can be carried out by simple heating with the compound of formula III.

When the acid chloride, the anhydride or a mixed anhydride is used, the reaction is carried out, for example, in an organic solvent. The organic solvent is, for example, dimethylformatnide, an aromatic hydrocarbon (benzene, xylene or toluene), or an ether, for example, ethyl ether or tetrahydrofuran.

The compounds of formula II can be prepared by applying the methods described in Belgian Patent No. 788,316. ​​The following examples illustrate the invention without, however, limiting it.

<img file="LU70832A1_D0005.tif" />

- 5 Example 1: 4- (3'-P-chlorobenzoyl 2'-methyl) phenyl N-methoxy butyramide

10 g of 4- (3'-p-chlorobenzoyl 2'-methyl) phenyl butyric acid and 30 cm 3 of thionyl chloride are mixed. The mixture is slowly brought to 80 ° 0 and maintained at this temperature until the evolution of gas has ceased and the excess of SOC ^ is removed by evaporation and entrainment with benzene. The residue is dissolved in 50 cm3 of benzene and the solution obtained is gradually added to a mixture of 8.5 cm3 of O-methylhydroxylamine and 50 cm3 of benzene, while maintaining the temperature at approximately 10 ° C. Allowed to stand for half an hour, the precipitate formed is removed by filtration, and the benzene evaporated. The residue is purified by dissolving in toluene, adding hot petroleum ether (bp 40 ° C.-75 ° C.) then cooling. The 4- (3'-p-chlorobenzoyl 2'-methyl) phenyl li-methozy butyramide which crystallizes is then separated; Mp = 104 ° C-105 ° C. ·

Example 2: 4- (3'-p-chlorobenzoyl 2'-methyl) phenyl LT-methyl N-methoxy butyramide

By operating in a manner analogous to that described in the example. above, by reaction of 4- (3'-p-chlorobenzoyl 2'-methyl) phenyl butyric acid chloride and Ν, Ο-dimethyl hydroxyl amine in tetrahydrofuran, we obtain 4- (3'- p-chlorobenzoyl 2'-methyl) phenyl N-methyl N-methoxy butyramide which is purified by chromatography on silica gel, eluting with a methylene chloride-acetone mixture (4-1). The product is characterized in this system by Rf. = 0.5. Example 3: 4- (3'-p-chlorobenzoyl 2'-methyl) phenyl N-hydroxy butyramide

By operating in a manner analogous to that of Example 1, but by reacting the acid chloride with hydroxylamine, in dimethylformamide, 4- (3'-p-chlorobenzoyl 2'-methyl) phenyl N is obtained. -hydroxy butyramide.

the product is recrystallized by concentrating a solution

- .6 in benzene; Mp = 125 ° C.

Example 4 s 4- (3'-p-chlorobenzoyl 2'-methyl) phenyl Ν'-hydroxy N ~ methyl butyramide

By operating in a manner analogous to that described in Example 1, but by reacting the acid chloride (dissolved in benzene) with N-methyl hydroxylamine (in a benzened.imethylformamide mixture (5-1), 4- (3 '-p-chlorobenzoyl 2'-methyl) phenyl N-hydroxy N-methyl butyramide is obtained, which is purified by washing with hexane and recrystallization from isopropyl ether-methylene chloride (7 -3) the product melts at 116 ° C.

'Preparation of tablets

Tablets were prepared corresponding to the following formula: Compound of Example 1 .......................... 50 mg

Excipient qs ,. for one tablet, finished at .............. 350 mg (Details of the excipient: lactose, starch, talc, magnesium stearate).