3,375,165 United States Patent Office Patented Mar. 26, 1968 2 3,375,165 safe but effective amount of a salt of fusidic acid and an FUSDIC ACD SALTS OF TETRACYCLINE antibiotic of the tetracycline group. BASES AND THERAPY These and other objects of the invention will become Guy Hagemann, Nogent-sur-Marne, and Lucien Penasse, more apparent as the description thereof proceeds. Paris, France, assignors to Roussel-UCLAF, Paris, We have found that salts formed between fusidic acid France, a corporation of France No Drawing. Filed Aug. 11, 1964, Ser. No. 388,954 and antibiotics of the tetracycline group exhibit a remark Claims priority, application France, Oct. 22, 1963, able antibiotic activity, superior to that of fusidic acid 951,378; Jan. 22, 1964, 96,75 and the antibiotic of the tetracycline group, included in 6 Claims. (Cl. 167-65) the salt. 0. In addition to this starting synergistic effect, the said The present invention relates to a novel salts of fusidic salts, and more particularly the fusidic acid salt of tetra acid and of antibiotics, as well as to a process for the cycline, are distinguished by a favorable tolerance, a very preparation of these compounds, compositions contain slight solubility in water and the absence of a bitter ing them and their therapeutic utilization. taste. The latter is unpleasant in pharmaceutical presen In particular, the invention relates to the salts formed 5 tations in the form of granules, syrups, etc. from fusidic acid and antibiotics of the tetracycline group, The process for the preparation of these compounds, such as chlorotetracycline, oxytetracycline, demethyl which is also the subject of the present invention, is char chlorotetracycline, and especially tetracycline itself. acterized principally in that fusidic acid is allowed to act It is known that the fusidic acid, despite its satisfactory on an antibiotic of the tetracycline group while operating activity in vitro and in vivo on Gram positive bacteria 20 in an organic solvent such as an alcohol, an ether, a ke and in particular on staphylococci only slightly sensitive tone, an ester, or a chlorinated solvent. to penicillin or to other antibiotics, has the disadvantage The products, resulting from this process of prepara of giving rise to resistant strains rather fast, and in ad tion, are advantageously isolated either by precipitation dition, its activity is exceedingly diminished in the pres by means of water, or by evaporation of the solvent or by ence of serum. 25 adding a second organic solvent in which the salt of On the other hand, it is known that the association of fusidic acid and an antibiotic of the tetracycline group are the fusidic acid with certain antibiotics, for example of insoluble. the macrollide group or of the penicillin group produces As a variant, these same compounds may be prepared a synergetic effect. by double decomposition between a soluble salt of fusidic This phenomenon is, however, not general, and the as 30 acid, such as an alkaline metal or ammonium salt, and a sociation of the fusidic acid with other antibiotics such soluble salt of an antibiotic of the tetracycline group, as tetracycline does not bring about any particular ad such as the hydrochloride or the sulfate, by advantageous vantage. The mixtures thus formed possess only the addi ly utilizing as a reaction media either water or a tive activity of the antibiotics which make up their com water miscible solvent or any other media in which the position (see especially Godtfredsen et al., Lancet, 1962, 35 initial salts are soluble and the salt formed is insoluble 1, page 928). or may be rendered insoluble by the addition of a suit An object of the present invention is the production of able diluent, a salt of fusidic acid and an antibiotic of the tetracycline For the performance of the process for the preparation group. of the compounds of the present invention, it is advan A further object of the invention is the development of 40 tageous to introduce approximately equimolecular quanti a process for the production of a salt of fusidic acid and ties of the starting antibiotics. If a precipitation by a sec an antibiotic of the tetracycline group which comprises ond organic solvent is to be effected, it is preferable to the steps of reacting fusidic acid with a compound of the utilize an excess of fusidic acid. When effecting the proc tetracycline group in the form of its free base in an or ess in the presence of an organic solvent, it is preferable ganic solvent and recovering said salt of fusidic acid and to utilize an alcohol, such as the lower alkanols; an ether, an antibiotic of the tetracycline group. such as a dialkyl ether, for example, ethyl ether, a cyclo A further object of the invention is the development of alkyl ether, for example, tetrahydrofurane, a cycloalkyl a process for the production of a salt of fusidic acid and diether, for example, dioxane; a ketone, such as a lower an antibiotic of the tetracycline group which comprises alkanone, for example, acetone; an ester, such as the low reacting a soluble salt of fusidic acid with a soluble salt 50 er-alkyl lower alkanoates, for example, ethyl acetate; or of an antibiotic of the tetracycline group in the presence a chlorinated solvent, such as a chlorinated lower alkane, for example, chloroform. When effecting the process of of a solvent in which the salt of fusidic acid and an anti precipitating the salt of fusidic acid and an antibiotic of biotic of the tetracycline group is insoluble and recover the tetracycline group from an organic solvent by means ing said salt of fusidic acid and an antibiotic of the tetra of an organic compound in which the salt is insoluble, it cycline group. is preferable to utilize as such organic compound, an Another object of the invention is the obtension of a ether, such as a dialkyl ether for example isopropyl ether. therapeutic composition comprising a minor amount of Fusidic acid and its soluble salts are described in a salt of fusidic acid and an antibiotic of the tetracycline United States Patent No. 3,072,531. group and a major amount of an inert pharmaceutically 60 The terms "antibiotic of the tetracycline group” and acceptable excipient. “tetracyclines' as used herein include all antibiotics which A yet further object of the invention is the development have as the fundamental nucleus that of tetracene. These of a process for the treatment of bacilliary infections compounds include, but are not limited to, tetracy which comprises administering to the infected organism a cline, 5 - oxytetracycline, 7-chlorotetracycline, 7-bromo 3,375,165 3. 4. tetracycline, anhydrotetracycline, 6-deoxytetracycline, 6 thus obtained, the product being identical to that described demethyltetracycline, etc. in Example I, and having a specific rotation The invention is described in more detail in the ex amples with the preparation of the salt of fusidic acid and tetracycline, but it is evident that the process is ap 5 (c. = 1% acetone). plicable in the same manner to the preparation of the Analysis confirmed the presence of equimolecular fusidic acid salts with other antibiotics of the tetracycline quantities of fusidic acid and tetracycline in the product. group. EXAMPLE V-PREPARATION OF THE FUSDIC The following examples are illustrative of the practice ACID SALT OF TETRACYCLINE BY DOUBLE of the invention. It is to be understood, however, that 0 DECOMPOSITION they are not to be deemed limitative. 516 mg. of fusidic acid were placed in suspension in 10 EXAMPLE I-PREPARATION OF THE FUSIDIC cc. of water, and the stoichiometric amount of an aqueous solution of normal NaOH was added. Then, under agita ACID SALT OF TETRACYCLINE tion, 10 cc. of an aqueous solution of 480 mg. of tetra 516 mg. of fusidic acid and 444 mg. of tetracycline 5 cycline hydrochloride were added. The solution was al were dissolved in 10 cc. of acetone and the filtrate was lowed to stand at rest for a period of 12 hours, then the concentrated to a low volume. product formed was vacuum filtered, washed with water The solution was poured into water. The precipitate was and dried under vacuum. 865 mg. (yield; 90%) of the filtered, washed with water and dried under vacuum. 607 crystallized fusidic acid salt of tetracycline were obtained, mg. (yield; 63%) of the fusidic acid salt of tetracycline 20 identical to the product described in Example I. were obtained having a specific rotation a 0--62 The fusidic acid salt of tetracycline presents in vitro, (c.'=1 acetone). with reference to various strains of pathogenic staphyl The fusidic acid salt of tetracycline occurred in the ococci, a superior activity to that of either fusidic acid or form of light yellow microcrystals and was insoluble in tetracycline, which are used in its preparation. Even in water and isoproyl ether, slightly soluble in ethyl ether, 2 5 the cases of strains resistant to penicillin, tetracycline or and soluble in acetone, ethanol, chloroform, dioxane and fusidic acid, the fusidic acid salt of tetracycline remains tetrahydrofuran. active at a very weak concentration. Ultraviolet spectra: As it has already been indicated, the fusidic acid salts of antibiotics of the tetracycline group possess interesting X max. =366 mu, E=148.4 30 pharmacological properties. In particular they possess an X max. =264mu, E=159 important antibiotic and bactericidal action. They can be used for the treatment of staphylococcal A max. = 220mp, E=235 infections, streptococcal infections and infections caused Analysis (CHON) : Molecular weight=961.12. 35 by the Gram negative bacteria, as for example, the coli Calculated: C, 66.22%; H, 7.55%; N, 2.91%.