US3123527A

US3123527A - Antibacterkl compositions

Info

Publication number: US3123527A
Authority: US
Publication date: 1964-03-03
Anticipated expiration: 1981-03-03

Description

United States Patent 3,123,527 ANTIEBACTERIAL COMPOSITIONS Myron W. Fisher, Birmingham, Mich, assignor to Parke, Davis & Company, Detroit, Mich, a corporation of Michigan No Drawing. Filed May 2, 1958, Ser. No. 732,467 Claims. (Cl. 167-51.5)

This application is a continuation-in-part of my application Serial No. 717,300, filed February 25, 1958, now abandoned, which in turn is a continuation-in-part of my application Serial No. 654,658, filed April 24, 1957, now abandoned.

The invention relates to chemotherapeutic agents and to means of combatting bacterial infection. More particularly, the invention concerns improved sulfonamide compositions having greatly enhanced antibacterial action.

The sulfonamide compounds, now widely employed as antibacterial agents, derive their useful effect from their ability to prevent synthesis of pteroyl compounds which, it is known, are essential to the growth of many species of bacteria. In the treatment of streptococcal, meningococcal, gonococcal' and pneurnococcal infections, the sulfonamide compounds are currently agents of choice. The course of treatment ordinarily requires the repeated administration of substantial amounts of sulfonamide and in many cases where the regimen has been excessive or unduly prolonged undesirable side effects have been noted. On the other hand, insufiicient dosage often causes the emergence of resistant pathogenic infection. Consequently, at the present time there is an important need to provide means for increasing the antibacterial effectiveness of the sulfonamide compounds and for minimizing or avoiding undesirable side-effects of the type associated with the use of these compounds.

I have now found that the activity of sulfonamide compositions against pathogenic bacterial infection is greatly increased by incorporating therewith a quantity in the range from about 0.1 to 20%, preferably about 0.1 to 1%, bv weight of a dihydrotriazine compound of formula,

NH; j

I OH: N N INHQ where X is a 3-chlorophenyl, 3,5-dichloropheny1, 3,5-dibromophenyl or 3-trifluoromethylphenyl radical.

In the compositions of the invention, the antibacterial effect of the sulfonamide and the dihydrotriazine is synergistic, i.e., their combined antibacterial effect is greater than the summation of their individual effects. As near as I have been able to determine, the optimum ratio of sulfonamide to dihydrotriazine is, in general, about 100:1. However, in the case of 3-sulfanilamido-6-methoxy-pyridazine the optimum ratio appears to be about 50 to 100 parts of the sulfonamide to 1 part of the dihydrotriazine. At these ratios the effectiveness of the sulfonamide compounds is in general increased fiveto ten-fold.

Thus, means are provided in accordance with the invention of eifectively combatting pathogenic bacterial infection with a relatively lesser quantity of therapeutic agent thereby obtaining greater freedom from undesirable side effects. Conversely, for a given quantity of therapeutic agent the invention provides greater antibacterial effect. Also, the invention permits more accurate control in dosage and a shorter course of treatment with less inconvenience to the patient.

The invention contemplates broadly the use of sulfonamide compounds which per se are effective in combatting 3,123,527 Patented Mar. 3, 1964 "ice pathogenic bacterial infection and which are suitable for oral administration. In general, the sulfonamide compounds contemplated possess in common the structural As an illustration of some of the many sulfonamide compounds to which the invention is applicable, there may be mentioned sulfacetamide, sulfadiazine, sulfamerizine, sulfarnethazine, sulfathiadiazole, sulfisoxazole, sulfathiazole, p-nitrosulfathiazole, phthalysulfathiazole, salicyazo sulfapyridine, suceinylsulfathiazole, 3-sulfanilamido-6- methoxypyridazine and the like. Suitable derivatives of the sulfonamides such as amine salts or metal salts may also be employed. The invention also contemplates compositions containing more than a single sulfonamide compound, particularly compositions containing triple-sulfa combinations such as the combination of sulfacetamide, sulfadiazine and sulfamerizine and similar combinations.

The dihydrotriazines of the present compositions possess basic properties and form addition salts with acids. The invention contemplates the use of the dihydrotriazines not only in free base form but also in salt form such as the hydrohalide, sulfate, phosphate, acetate and the like. The hydrochloride salt is particularly useful in that it possesses increased water-solubility and is readily obtainable in pure form.

The compositions of the invention can be conveniently provided by physically mixing the sulfonamide and dihydrotriazine in the aforementioned proportions, either in dry form or in the form of a suspension in a suitable liquid vehicle. Conveniently, the dry mixture can be incorporated with granulating and tableting agents such as starch, magnesium stearate and the like and compounded in tablet form. The dry mixture can also be made up in powder form together with an inert diluent such as talc, starch, milk, sugar and the like, and, if desired, filled into gelatin capsules. When supplied as suspensions suitable for pediatric or other use suspending agents, flavors and stabilizing agents may be employed. Optionally, where a wider anti-bacterial effect is desired, a broad spectrum antibiotic such as chloramphenicol, oral penicillin and the like may be included in the formulation.

In administering the compositions of the invention, the course of treatment conveniently includes an initial oral dosage of about 15 to milligrams per kilogram over a twenty-four hour period followed by a daily oral dosage of about 10 to 100 milligrams per kilogram for as long as required. In the case of compositions containing 3-sulfanilamido-G-methoxypyridazine, the recommended dosage is 15 mg./kg. initially followed by 5-10 mg./kg. daily thereafter. It will be understood that the dosage regimen can be varied, as desired, to meet the particular circumstances of each case depending on the severity of infection, etc.

The preparation of compositions in accordance with the invention is illustrated by the following examples:

Example 1 A mixture consisting of 167 g. of sulfadiazine, 167 g. of sulfamerazine, 167 g. of sulfacetamide and 25 g. of l-m-trifluoromethylphenyl-4,6-diamino-1,2-dihydro-2,2-dimethyl- 1,3,5-triazine monohydrochloride is blended and the mixture is wetted with a 10% starch paste. The wet mass is granulated through an oscillating No. 6 stainless steel screen. The resultant product is dried for 16 hours .at F. and reduced to granulations passing a No. 14

stainless steel screen. The dry granulation is mixed with 3 g. of magnesium stearate and 50 g. of starch. The resulting mixture, suitable for formation into tablets, is

processed through a tableting machine to provide ap proximately 975 tablets in diameter each containing 0.5 g. total sulfonamide and 25 mg. of l-m-trifluoromethylphenyl-4,6-diamino l,2-dihydro-2,2-dirnethyl-1,3,5- triazine monohydrochloride.

The 1 m trifluoromethylphenyl-4,G-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride is prepared in the following manner:

A mixture consisting of 39.3 g. of m-aminobenzotrifluoride, 16.8 g. of dicyanidiamide, 26 ml. of concentrated hydrochloric acid (36%) and 300 ml. of acetone is placed in a 500 ml. flask and stirred at 20-25 C. Three crops of the desired product, 1-m-trifluoromethylphenyl-4,6-diamino-l,2,-dihydro-2,2-dimethyl-1,3 ,5 -triazine hydrochloride, are removed by filtration from the reaction mixture at intervals of one week, two weeks and three weeks. The product is purified by recrystallization from alcohol; M.P. 19l-193 C.

Example 2 A mixture consisting of 500 g. of sulfadiazine, and 25 g. of l-(3,5-dibromophenyl)-4,6-diamino-l,2-dihydro-2,2- dimethyl-l,3,5-triazine monohydrochloride is blended and wetted with 10% starch paste. The resultant mass is processed and tableted as in Example 1 to provide 970 tablets each containing 0.5 g. of sulfadiazine and 25 mg. of l-(3,5-dibromophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride. The 1-(3,5-diblromophenyl -4,6-diamino- 1,2-dihydro-2,2-dimethyl-1,3 S-triazine monohydrochloride (MP. 196197 C.) is pre pared as follows:

A mixture of 57.5 g. of 3,5-dibromoaniline hydrochloride, 0.22 mol. of dicyandiamide and 600 ml. of npropanol is stirred and refiuxed for five hours. The reaction mixture is cooled, filtered and the filter cake consisting of dibromophenylbiguanide hydrochloride is washed with 50l00 ml. of n-propanol to remove any trace of color present. A mixture of 18.6 g. of dibromophenylbiguanide hydrochloride, 250 ml. of acetone, 100 ml. of methanol and 0.01 mol. of hydrogen chloride in 4 N isopropanol solution is refluxed with stirring for 12 hours, cooled and filtered. Anhydrous ether (300 ml.) is added to the filtrate and the l-(3,5-dibromophenyl)-4,6- diamino-l,2dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride which separates is collected and dried; M.P. ZOO-201 C. The product can be purified by trituration in isopropanol and recrystallization from methanol.

Example 3 A mixture consisting of 500 g. of sulfaisoazole and 100 g. of 1-m-chlorophenyl-4,6-diamino-1,2-dihydro-2,2- dimethyl-1,3,5-triazine monohydrochloride is blended, compounded and tableted in accordance with the procedure of Example 1. Approximately 980 tablets each containing 0.5 g. of sulfaisoazole and 0.1 g. of l-mchlorophenyl 4,6 diamino 1,2 dihydro-2,2-dimethyl- 1,3,5-triazine monohydrochloride are obtained. The preparation of the dihydrotriazine is accomplished in the same manner set forth in Example 1 for the preparation of the trifluoromethylphenyl dihydrotriazine, starting with 38.2 g. of m-chloroaniline, 16.8 g. of dicyandiamide, 26 ml. of concentrated hydrochloric acid and 300 ml. of acetone.

Example 4 A mixture consisting of 500 g. of sulfathiazole and 5 g. of l- (3 ,5 -dichlorophenyl) -4,6-diamino-l ,2-dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride is processed and tableted as in Example 1. The yield is approximately 960 tablets each containing 0.5 g. of sulfathiazole and 5 mg. of 1-(3,5-dichlorophenyl)-4,6-diamino-1,2-dihydro- 2,2 dimethyl 1,3,5 triazine monohydrochloride. The preparation of the dihydrotriazine ingredient can be accomplished in the manner set forth in Example 2 for the preparation of the dibromophenyl dihydrotriazine, starting 4 with a mixture of 39.8 g. of 3,5-dichloroaniline hydrochloride, 0.22 mol. of dicyandiamide and 400 ml. of n-propanol and proceeding in the second step with 14.1 g. of dichlorophenylbiguanide hydrochloride, 250 ml. of acetone, ml. of methanol, and 0.01 mol. of hydrogen chloride in 4 N isopropanol solution.

Example 5 A mixture consisting of 100 g. of sulfadiazine, 100 g. of sulfamerazine, 100 g. of sulfacetamide and 15 g. of 1 m trifluorornethylphenyl 4,6 diamino 1,2 dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride is blended and filled into #1 hard gelatin capsules by standard encapsulating procedures. Approximately 980 capsules are obtained, each capsule containing 0.3 g. total sulfonamide and 15 mg. of 1-m-trifiuoromethylphenyl- 4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride.

Example 6 A mixture consisting of 83.33 g. of 3-sulfani1amido-6- methoxypyridazine, 1.67 g. of l-(3,5-dibromophenyl)- 4,6 diamino 1,2 dihydro 2,2 dimethyl 1,3,5 -triazine monohydrochloride, 2.5 g. of alginic acid and 4 g. of corn starch is blended and then wetted with an aqueous paste containing 8.17 g. of corn starch, 2.17 g. of gelatin, 0.033 g. of tartrazine (trisodium salt of 3-carboxy-5-hydroxy 1 p sulfophenyl 4 p sulfophenylazopyrazole) and 0.013 g. of Orange G (disodium salt of l-phenylazo-2-naphthol-6,8-disulfonic acid). The mixture is granulated through an oscillating No. 6 stainless steel screen and the resulting granulation dried at F. for sixteen hours. The mixture is reduced to a particle size suitable for compressing (No. 14 screen) and 0.5 g. of magnesium stearate blended into the granulation. The resulting mixture processed through a tableting machine to provide about quarter scored tablets inch in diameter each containing 0.5 g. of 3-sulfanilamido-6-methoxypyridazine and 10 mg. of 1-(3,5-dibromophenyl)-4,'6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride.

If one employs 0.84 g. of l-(3,5-dibromophenyl)-4,6- diamine-l,2-dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride in the above procedure instead of the 1.67 g. one obtains tablets which contain 0.5 g. of 3-sul'fanilamido- 6-methoxypyridazine and 5 mg. of l-(3,5-dibromophenyl)- 4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,S-triazine.

Example 7 A mixture consisting of 300 g. of finely divided 3-sulfam'lamido-S-methoxypyridazine, 6 g. of finely divided 1- (3,5 dibromophenyl) 4,6 diamino 1,2 dihydro- 2,2-dimethyl-1,3,5-triazine monohydrochloride and 30 g. of milk sugar is blended and filled into #2 hard gelatin capsules so that each capsule contains 0.5 g. of 3-sulfanilarnido-6- methoxy-pyridazine and 10 mg. 1-(3,5-dibromophenyl) 4,6 diamino 1,2 dihydro 2,2 dimethyl-1,3,5-triazine monohydrochloride.

If desired, an equal Weight of 1-(3-chlorophenyl)-4,6- diamino-l,2-dihydro-2,2-dimethyl-1,3,5-triazine, 1-(3,5-dichlorophenyl) 4,6 diamino 1,2 dihydro 2,2 dimethyl-1,3,5-triazine, l-(3-trifluoromethylphenyl) 4,6- diamino-l,2-dihydro-2,2-dirnethyl-1,3,5-triazine or an acid addition salt thereof, such as the hydrochloride salt, can be substituted for the 1-(3,5-dibromophenyl)-4,6-diamino- 1,2 dihydro 2,2 dimethyl 1,3,5 triazine monohydrochloride used in the above example.

Example 8 A mixture consisting of 300 g. of finely divided 3-sulfanilamido-6-methoxypyridazine, 300 mg. of finely divided 1 (3,5 dibromophenyl) 4,6 diamino 1,2 dihydro- 2,2-dimethyl-1,3,5-triazine monohydrochloride and 30 g. of milk sugar is blended and filled into #2 hard gelatin capsules so that each capsule contains 0.5 g. of 3-sulfa- .5 hilamido-G-methoxypyridazine and 0.5 mg. of 1-(3,5-dibromop henyl) i 4,6 diamino 1,2 dihydro 2,2 dimethyl-1,3,5-triazine monohydrochloride.

If similar preparations containing another triazine are desired, an equal weight of 1-(3-chlorophenyl)-4,6-diamino 1,2 dihydro 2,2 dimethyl 1,3,5 triazine, 1 3,5 dichlorophenyl) 4,6 diamino 1,2 dihydro- 2,2-dirnethyl-1,3,5-triazine or l-(3-trifluoromethylphenyl)- 4,6 diamino 1,2 dihydro 2,2 dimethyl 1,3,5 triazine, or an acid addition salt of any of these mentioned triazines, such as the hydrochloride salt, can be substituted for the l-(3,5-dibromophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride used above. Likewise, the mentioned 3-sulfanilamido-6-methoxy-pyridazine used above can be replaced with a like amount of any of sulfadiazine, sulfaisoxazole or sulfathiazole or with a 300 g. quantity of equal amounts of each of sulfadiazine, sulfamerazine and sulfacetamide.

Example 9 i A mixture consisting of one kilogram each of sulfadiazine, sulfamerazine and sulfacetamide and 30 g. of l m trifiuoromethylphenyl 4,6 diamino 1,2 dihydro-2,2-dimethyl1,3,5-triazine monohydrochloride is blended, wetted with 10% starch paste and granulated, while wet, through a stainless steel No. '6 mesh screen. The granulated product is dried by holding for 16 hours at 140 F. and then subdivided to pass a No. 14 stainless screen. The dry granulation is mixed with 20 g. of magnesium stearate and 300 g. of starch to provide a mixture suitable for compression into tablets. The mixture is processed through a inch tableting machine to provide about 5650 tablets each containing ca. 0.5 g. total sulfonamide and 5 mg. of 1-m-trifluoromethylphenyl-4,6-diamino-l,2-dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride.

While in the foregoing specification the invention has been described in detail, it will be realized by those skilled in the art that considerable variation can be made in such detail without departing from the spirit of the invention as set forth in the appended claims.

I claim:

1. An antibacterial composition comprising a sulfonamide having antibacterial activity and a member of the class consisting of a dihydrotriazine and acid salts thereof, said dihydrotriazine having in free base form the formula,

| NHz where X is a member of the group consisting of 3-chlorophenyl, 3,5-dichlorophenyl, 3,5-dibromophenyl and 3-trifluorornethylphenyl, the weight ratio of said sulfonamide and dihydrotriazine being in the range from about 1000:1 to :1.

2. A therapeutic composition in dosage unit form adapted for oral administration comprising 1000 parts by weight of a sulfonamide having antibacterial activity and from about 1 to 200 parts by weight of a member of the class consisting of a dihydrotriazine and acid salts thereof, said dihydrotriazine having in free base form the formula,

6 where X is a member of the group consisting of 3-ch 1orophenyl, 3,5-dichlorophenyl, 3,5-dibromophenyl and 3-trifluoromethylphenyl.

3. A composition according to claim 2 wherein the weight ratio of sulfonamide to dihydrotriazine is 100:1.

4. A therapeutic composition in dosage unit form adapted for oral administration comprising 100 parts by weight of substantially equal portions of sulfadiazine, sulfamerazine and sulfacetamide and one part of l-m-trifluoromethylphenyl-4,6-diamino-1,2-dihydro-2,2 dimethyl-1,3,5-triazine hydrochloride.

5. An antibacterial composition comprising 3-sulfanilamido-6-methoxypyridazine and a dihydrotriazine of the class consisting of l-(3-chlorophenyl)-4,6-diamino-1,2-dihydro-2,2-

dimethyl-1,3 ,5 -triazine;

1-(3,5-dichlorophenyl) -4,6-diarnino-1,2-dihydro-2,2-

dimethyl-1,3 ,5 -triazine;

1(3,5-dibromophenyl) -4,6-diamino-1,2-dihydro-2,2-

dimethyl-1,3 ,5 -triazine;

1-(3-trifluoromethylpl1enyl) -4,6-diamino-1,2-dihydro- 2,2-dimethyl-1,3,5-triazine;

and acid salts thereof, the Weight of said B-sulfanilamido- 6-methoxy-pyridazine and said dihydrotriazine being in the range of from 1000:1 to 5:1.

6. A tablet comprising 50 to 100 parts by weight of 3- sulfanilamido-6-methoxypyridazine for each part by Weight of 1-(3,5-dibromophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine monohydrochloride.

7. A capsule containing a mixture comprising 50 to 100 parts by weight of 3-sulfanilamido-6-methoxy-pyridazine for each part by weight of 1-(3,5-dibromophenyl)- 4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3 ,S-triazine monohydrochloride.

8. The method of combatting pathogenic bacterial infection which comprises administering orally a composition in dosage unit form containing 1000 parts by weight of a sulfonamide having antibacterial activity and from about 1 to 200 parts by weight of a member of the class consisting of a dihydrotriazine and acid salts thereof, said dihydrotriazine having in free base form the formula,

NHa

where X is a member of the group consisting of 3-chlorophenyl, 3,5-dichlorophenyl, 3,5-dibromophenyl and 3-trifiuoromethylphenyl.

References Cited in the file of this patent UNITED STATES PATENTS 2,484,175 Lehr Oct. 11, 1949 2,599,145 Vogel June 3, 1952 2,602,038 Vollmer July 1, 1952 (Other references on following page) 7 FOREIGN PATENTS Chemical Age, April 23, 1949, vol. 60, pp. 592 and 5 Hayman: Amer. 1. Pharmacy, vol. 122, No. 2, February 1950, pp. 72-74.

Welch et 211.: Comparison of Effects of Nine Antibiotics on Experimental Typhoid Infections in Mice,

Jour. Lab. and Clin. Med., May 1950, vol. 35, No. 5, pp. 663-666.

Hawking et a1.: The Sulphonamides, H. K. Lewis C0., London, 1950, pp. 61-64.

Chem. Abstn, v01. 48 (1954), p. 79.6.

Chem. Abstn, v01. 48 (1954), p. 7189.

Wilson et 211.: The American Drug Index, I. B. Lippincott C0., Phila., 1956, pp. 148, 175, 251, 352353, and 487.