Substituted benzoylphenyl butyramide derivatives, process for preparing them and pharmaceutical compositions

The invention relates, in particular, to those amongst the derivatives of formula I, which correspond to formula

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*¹a’ in which X^ represents a halogen atom, Xp represents an alkyl group having 1 to 5 carbon atoms, and-X-,—¥ך2~ץ R^ and Rg ^aredefined as above.

Preferably the substituent represents a fluorine or chlorine atoiiTf. pnefej:auly--the-^xubs±i.tu£trLu_Xg._reprasex±a_a״ methyl-gnnup—

The invention relates, in particular, to those amongst the derivatives of formula I or fQr_jd1ich-lX,_y._and_^__ -n®prsse-nt--a--b-yds’4>gQ-n--atG1n₁--as-wel.l-£S—to--th0££. for which R^ represents a hydrogen atom or 8 methyl group and Eg represents a hydroxy or methoxy group.

In particular, the invention relates to the derivatives of formula I described below in Examples 1 to 4.

The compounds of formula I possess interesting pharmacological properties. They have, in particular, analgesic and. anti-inflammatory activity.

They can be .used in therapy, for example, in the treatment of muscular, articular or nervous pains, rheumatic complaints, toothache, shingles and migraines, as well as arthoses, lumbago and also as further treatment in infectious and febrile conditions.

The therapeutically active compounds of formula I can, consequently, be employed as a medicament.

The invention extends to pharmaceutical compositions containing as active principle at least one of the products of formula I defined above.

These pharmaceutical compositions can te administered ty. patenterally, orally,־־arrectally, or locally as a topical application to the skin or the mucous membranes.

For this purpose they can be presented in the form of injectable solutions or suspensions, compressed tablets, capsules, gelatin capsules, drinkable solutions or emulsions, suppositories, ointments, creams or topical powders. These pharmaceutical forms are prepared according to the usual processes.

The posology varies in particular depending upon the route of administration and the therapeutic effect sought. For example, in the adult, it can vary, by oral route, between 100 mg and 1 g of active principle per day.

The invention also relates to a process for preparing the confounds of formula 1.

This process 1s characterized In that an acid of formula Π;

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(Π) the substituents of which are defined as before, or a functional derivative of this latter, 1s subjected to the action of a compound of formula III:

Rj and Rg being defined as above.

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(III)

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 the acid II itself is used, the reaction is carried out, for example, in the presence of a dehydrating agent.

The. dehydrating agent is, for example, dicyclohexylcarbodiimide.

When a lower alkyl ester of the acid II is used, 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. 1'he organic solvent is, for example, dimethylformamide,, 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 processes described in Belgian Patent 788,516.

The following Examples, illustrate the invention without, however, limiting it.

Example 4-(3'-n-chlorobenzoyl 2'-methyl)phenyl N-methoxy butyramide

ICg of 4-(5'-p־chlorobenzoyl 2'-methyl)phenyl butyric acid .ל brought up and 3° cnr of thienyl chloride are mixed. The mixture is t-eteenslowly to 80°C and maintained at this temperature until the evolution of gas ceases, and the excess SCCl.? ^,is eliminated by evaporation and entrainment with benzene. The residue is dissolved in 50 of benzene and the solution obtained is׳ x added, progressively, to a mixture of 8.5 err of 0methylhydroxylamine and 50 cm^ of benzene, the temperature being maintained at about 10°C. ׳ The mixture is allowed, to stand for half an hour, the precipitate formed is eliminated by filtration . and the benzene is evaporated. The residue is purified by dissolving in toluene, adding hot petroleum ether (B.F. 40°C75°C) then cooling. 4-(j-p-chlorobenzoyl 2^,-methyl)phenyl N-methoxy butyramide is then separated, which crystallizes;

Ji.Pt 104° ־C-105°C.

Example ^-(^¹־P-chlorobenzoyl 2¹-methyl)phenyl N-methyl N-methoxy butyramide

In a manner similar to that described, in the previous Example, by the reaction of the chloride of 4-(5'-p-chlorobenzoyl 2'-methyl)phenyl butyric acid and of Ν,Ο-dimethyl hydroxylamine in tetrahydrofuran, 4-(5'-p-chlorobenzoyl 2^,-methyl)phenyl N-methyl N-methoxy butyramide is obtained, which is purified by chromatography on silica gel, eluting with a methylene chloride/ acetone mixture (4־Ί). The product is characterized in this system by Pf = 0.5. Example . 4-(3'-p-chlorobenzoyl ?¹-methyl) phenyl N-hydroxy butyramide

In a manner similar to that of Example 1 but causing the . acid chloride to react with the hydroxylamine, in dimethylformamide,

4-(3’~p-chlorobenzoyl. 2'-methyl) phenyl N-hydroxy butyremide iJ obtained,.

The product is recrystallized by concentrating a solution in benzene; M.Pt= 125°C.

Example 4-(3'-P“chlorobenzoyl 2¹-methyl) phenyl N-hydroxy N-methyl butyramide

In a manner similar to that described, in Example 1, but causing the acid chloride (in solution in benzene) to react with N-methyl hydroxylamine (in a benzene/dimethylformamide mixture (55)-4 ,(1־’-p־chlorobenzoyl 2’-methyl) phenyl N-hydroxy N-methyl.butyramide is obtained, which is purified by washing with hexane and recrystallizing in an isopropyl ether/methylene chloride mixture (75־). ^The product melts at 116°C.

Preparation of compressed tablets

Compressed tablets corresponding to the following formula were prepared:

Compound of Example 1 ...... ng

Excipient, q.s. for a compressed tablet, up to .... 35^ (Detail of the excipient: lactose, starch, talc, magnesium stearate).