United States Patent [191 [11] Patent Number: 4,617,293 Wahlig et al. [45] Date of Patent: Oct. 14, 1986 [54] FLAVONOID PI-IOSPHATE SALTS OF [52] us. c1. ...................................... .. 514/41; 514/37; AMINOGLYCOSIDE ANTIBIOTICS 514/39; 536/8; 536/13.2; 536/13.3; 536/13.8; 536/14; 536/l6.8 [75] Inventors: Helmut Wahlig, Darmstadt; Elvira [58] Field of Search .............. .. 536/8, 13.2, 13.3, 13.8, Dingeldein, Dreieich; Richard 536/16.6, 14; 514/37, 41, 39 Kirchlechner, Rott a. Inn; Dieter ()rth, Darmstadt; Werner Rogalski, [56] References Cited Alsbach, all of Fed. Rep. of U.S. PATENT DOCUMENTS Germany 2,962,495 11/1960 Ferno et al. .......................... .. 536/8 [73] Assignee: Merck Patent Gesellschaft mit 3,091,572 5/1963 Luedemann et al. .'. .......... .. 536/l3.6 beschraenkter Haftung, Darmstadt, Fed. Rep. of Germany OTHER PUBLICATIONS Rinehart, Jr. and Suami, Ed., Aminocyclitol Antibiot [21] Appl.N0.: 613,131 ics, ACS Symposium Series 125, Washington, D.C., [22] Filed: May 23,1984 1980. Primary Examiner-Johnnie R. Brown Related US. Application Data Assistant Examiner-Elli Peselev [63] Continuation-impart of Ser. No. 377,779, May 13, Attorney, Agent, or Firm—Millen & White 1982, abandoned. [57] ABSTRACT [30] Foreign Application Priority Data Flavonoid phosphates of aminoglycoside antibiotics are useful sparingly soluble salts, e.g., for achieving a depot May 13, 1981 [DE] Fed. Rep. of Germany ..... .. 3118856 effect. Feb. 25, 1982 [DE] Fed. Rep. of Germany ..... .. 3206725 [51] Int. 01.4 ..................... .. A61K 31/71; 00711 15/22 12 Claims, N0 Drawings 4,617,293 1 2 ?avane system, but can also be in the 4-, 8-, 2’-, 5'- or FLAVONOID PHOSPHATE SALTS OF 6’-position. The 3’- and S-positions are preferred. AMINOGLYCOSIDE ANTIBIOTICS One or more of the hydroxy groups can be esteri?ed with phosphoric acid. This, for example, the 3'- and This application is a continuation-in-part of US. Ser. 5 5-monophosphates and the 3',5-diphosphate of hesperi No. 377,779, ?led on May 13, 1982, now abandoned, din can be used as salt-forming component. In all of the May 24, 1984 and whose disclosure is incorporated by following text, the expression “hesperidin-phosphoric reference herein. acid” relates to the 3',5-diphosphate and the expression "hesperidin-phosphate(s)” relates to the salts derived BACKGROUND OF THE INVENTION therefrom. The present invention relates to new sparingly solu In addition to the phosphorylated and free OH ble salts of aminoglycoside antibiotics. groups, the ?avonoid phosphoric acids can also carry Aminoglycoside antibiotics such as gentamycin or other substituents, for example etheri?ed OH groups, tobramycin are usually employed in the form of their such as alkoxy groups of, preferably, 1-4 C atoms, sulfates, which are readily soluble in water. The antibi above all methoxy groups (as a rule not more than otics are rapidly released from these salts and distribute three, preferably one, and preferably in the 4’-position, themselves around the body. In some cases, this prop but also in the 3-, 3'-, 5-, 6- and/or 7-position), and, in erty is a disadvantage, in particular if a locally limited particular, glycosidated OH groups. These can be infection is to be combatted, for example an infected glycosidated with mono-, di-, tri- or tetra-saccharides. bone. In these cases, more sparingly soluble salts, from Preferred glycoside components are monosaccharides, which the antibiotic is released more slowly and which e.g., D-glucose, and also D-galactose, D-glucuronic therefore can display a certain depot action, are desir acid, D-galacturonic acid, D-xylose, D-apiose, L-rham able. nose and L-arabinose, and disaccharides, e.g., rham Some sparingly soluble salts of aminoglycoside anti nosylglucoses, particularly preferably rutinose and neo biotics are known. Thus, for example, U.S. Pat. No. 25 hesperidose, and also, for example, rungiose, robinobi 3,091,572 mentions various sparingly soluble salts of ose, sophorose, gentiobiose, apiobiose, vicianose, sam gentamycin (for example, salts of fatty acids containing bubiose, primverose or latyrose. Glycosidated OH groups are preferably in the 7- and/or 3-position; at 8 or more C atoms, e.g., lauric acid, stearic acid, palmi tic acid or oleic acid; aralkanoic acids, e.g., phenyl most 2, and preferably one, glycosidated OH group is as a rule present in the molecule of the ?avonoid phos- ' butyric acid; arylcarboxylic acids, e.g., naphthalene-l phoric acid. Examples of other possible substituents (as carboxylic acid; and sulfuric and sulfonic acids, e.g., a rule not more than 3, preferably only one) include laurylsulfuric acid and dodecylbenzenesulfonic acid). alkyl of, for example, 1-4 C atoms, preferably methyl, It has been found that these salts display certain dis halogen, preferably F or Cl, and hydroxyalkoxy of, for advantages when used For example, they have a waxy, 35 example, l-4 C atoms, preferably 2-hydroxyethoxy. clearly hydrophobic nature which impedes their galeni Examples of speci?c ?avonoid phosphates include cal processing. phosphoric acid half-esters of hydroxy?avanes, e.g., SUMMARY OF THE INVENTION 6-hydroxy-4’-methoxy?avane, 6-hydroxy-3,4'-dime thoxy?avane, 6-hydroxy-4'-methoxy-3-methyl?avane, Accordingly, it is an object of this invention to pro 40 catechol ((+)-3,3’,4’,5,7-pentahydroxy?avane) and vide new salts of antibiotics which are sparingly soluble leucocianidol (3,3',4,4’,5,7-hexahydroxy?avane) and and which do not have the adverse properties of the glycosides thereof, e.g., 2,3,3',4,4',5,7-heptahydroxyfla known antibiotic salts or display them only to a minor vane glucoside; hydroxy?avanones, e.g., liquiritigenin degree. (4‘,7-dihydroxy?avanone), pinocembrin (dihydrochry Upon further study of the speci?cation and appended 45 sin, 5,7-dihydroxyflavanone), naringenin (4',5,7-trihy claims, further objects and advantages of this invention droxy?avanone), eriodictyol (3',4',5,7-tetrahydroxy will become apparent to those skilled in the art. flavanone), dihydroquercetin (taxifolin, 3,3',4',5,7-pen These objects have been achieved by this invention tahydroxy?avanone), 6-hydroxy-4'-methoxy?avanone, and the ?nding that a slower release of the antibiotics sacuranetin (4’,5-dihydroxy-7-methoxy-flavanone), can be achieved if the sparingly soluble ?avonoid phos isosacuranetin (5,7-dihydroxy-4'-methoxy-?avanone), phates, in particular the hesperidin-phosphates, of the hesperetin (3',5,7-trihydroxy-4'-methoxy?avanone) and aminoglycoside antibiotics are used instead of the men silibinin (2-[trans-2-(4-hydroxy-3-methoxyphenyl)-3 tioned sulfates or other readily soluble salts. hydroxymethyl-1,4-benzodioxan-6-yl]-3,5,7-trihydrox This invention accordingly relates to the ?avonoid ychroman-4-one) and glycosides thereof, e.g., pinocem phosphates, in particular the hesperidin-phosphates, of 55 brin 7-rutinoside, sarothanoside (pinocembrin 7-neohes aminoglycoside antibiotics. peridoside), salipurposide (naringenin 5glucoside), pru nin (naringenin 7-glucoside), narirutin (naringenin 7 DETAILED DISCUSSION rutinoside), naringin (naringenin 7-neohesperiodoside), Suitable anionic components of the salts of this inven eriodictin (eriodictyol 7-rhamnoside), eriocitrin (erio tion include phosphoric acid half-esters of hydroxy 60 dictyol 7-rutinoside), eriodictyol 7-neohesperidoside, ?avonoids, for example of hydroxy-?avanes, -?avenes, didymin (isosacuranetin 7-rutinoside), poncirin -?avanones, -flavones or -?avylium salts. The flavanone (isosacuranetin 7-neohesperidoside), persicoside (hes and ?avone derivatives are preferred. peritin glucoside), hesperidin (hesperetin 7-rutinoside), The hydroxyflavonoids can contain one or more, for and neohesperidin (hesperetin 7-neohesperidoside); hy example 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2, 3 or 4, 65 droxy?avones, e.g., chrysin (5,7-dihydroxy?avone), hydroxy groups, which are preferably of a phenolic primetin (5,8-dihydroxyflavone), galangin (3,5,7-trihy nature, but can also be of the alcoholic type. They are as droxy?avone), baicalein (5,6,7-trihydroxy?avone), a rule in the 3-, 5-, 6-, 7-, 3’- and/or 4’-position of the apigenin (4',5,7-trihydroxyflavone), datiscetin (2',3,5,7 4,617,293 3 4 tetrahydroxy?avone), loto?avin (2’,4',5,7-tetrahydrox polybasic acids, it is furthermore possible for acid, neu yflavone), caempferol (3,4’,5,7-tetrahydroxyflavone), tral and/or basic salts to be formed. All these possible ?setin (3,3',4’,7-tetrahydroxyflavone), luteolin (3',4’,5,7~ salts and their mixtures with one another are included in tetrahydroxy?avone), scutellarein (4',5,6,7tetrahydrox the term “a flavonoid phosphate of an aminoglycoside yflavone), morin (2',4,4',5,7-pentahydroxy?avone), ro antibiotic” and analogous terms used herein. binetin (3,3',4’5‘,7-pentahydroxyflavone), quercetin The neutral salts and mixtures containing these are (3,3',4',5,7-pentahydroxy?avone), tectochrysin (5 preferred. In the case of the gentamycin hesperidin hydroxy-7-methoxyflavone), genkwanin (4',5-dihy phosphates, for example, the salt (mixture) of 2 moles of droxy-7-methoxyflavone), acacetin (5,7-dihydroxy-4’ gentamycin and 5 moles of hesperidin-phosphoric acid methoxyflavone), diosmetin (3 ’,5,7-trihydroxy-4' is particularly preferred. (“Neutral” in this context methoxy?avone), chrysoeriol (4’,5,7-trihydroxy-3' means that there is one basic amino group per phos methoxyflavone), rhamnetin (3,3',4’,5-tetrahydroxy-7 phoric acid radical). methoxy?avone), isorhamnetin (3,4',5,7-tetrahydroxy The invention also relates to a process for the prepa