Complexes of nickel-pimaricin
United States Patent 11 1 Aszalos et al.  
 [ COMPLEXES OF NICKEL-PIMARICIN [75] Inventors: Adorjan Aszalos, Princeton; John Vandeputte, Milltown, both of NJ.  
 [73] Assignee: E. R. Squibb &amp; Sons, Inc., New  
 York, NY.  
  22 Filed: Dec. 21, 1970 21 Appl. No.: 100,492  
 [52] US. Cl. 260/210 AB; 424/115; 424/1 I7;  
  424/118; 424/1 I9; 424/120; 424/121; 424/122 [51] Int. Cl C07c 47/18; C07g 11/00 [58] Field of Search 260/210 R, 210 AB 1451 Apr. 22, 1975 &#39;4/1965 France 260/210 AB I2/196l United Kingdom 260/210 R OTHER PUBLICATIONS Meyer, Chem. Abst., Vol. 69, 1968 p. 6765m.  
 Primary [hammer-Johnnie R. Brown Attorney, Agent, or Firm-Lawrence S. Levinson;  
 Merle J. Smith; Stephen B. Davis [57] ABSTRACT Disclosed herein are complexes of polyene antibiotics which are soluble in alcohol or in water and alcohol. These complexes are prepared in alcoholic solutions and have been found to be useful as antifungal agents which can be orally administered.  
 1 Claim, No Drawings COMPLEXES OF NICKEL-PIMARICIN BACKGROUND OF INVENTION Many complexes of antibacterial agents have been prepared. however. those antimicrobial agents which possess antifungal activity and fall within the polyene series have been difficult to form successfully. The literature shows various attempts to form the salts or complexes of these antimicrobial agents and the difficulty involved therein. Titanium was utilized to complex nystatin in order to make a colorimetric determination of nystatin. This attempt appears in ACTA. PHARM. HUNG. Vol. 32. page 59 1962 Examination and Colorimetric Determination of the Titanium (IV) Complex of the Antibiotic Nystatin.&#34; by Laszlo Mazor and Maria Papay. In this publication. however. the complex is in fact never separated from the solution. Other attempts to form complexes with a polyene type antibiotic is disclosed in an article appearing in CHEMOTHERAPlA. Vol. 6. pages 326 to 343 (1963). entitled Biologically Active. Water-soluble Derivatives of Nystatin Chemical Studies. by G. Rapi. P. Cocchi and E. Belgodere. In this article it is clearly stated that the water-soluble derivatives of a polyene macrolide antibiotic is extremely difficult to obtain. However. the article teaches the formulation of a nystatin monohydrochloride which is water soluble but an unstable preparation.  
 THE INVENTION The invention relates to a complex ofa polyene antibiotic which heretofore was unknown. It is prepared by the reaction of a polyvalent cation with a polyene antibiotic such as nystatin in the presence of an aliphatic alcohol and recovering the desired complex. Complexes of this invention have the formula:  
 Z-polyene macrolide wherein Z is a polyvalent cation.  
  As mentioned herein the reactants are reacted in the presence of an alcohol and thereafter the complex of this reaction is precipitated by adding an ether or other nonpolar solvents. such as hexane. benzene. cyclohexane. and so forth. to the reaction solution. The precipitate can then be removed in any convenient manner as by centrifugation. filtering. and the like. The ratio of antibiotic to applied ion is from about :1 to about 1:] to form complexes of the instant invention.  
  The trivalent cations of this invention are the aluminium. iron. cobalt. chromium. gallium. cerium. tungsten and other halides and nitrates such as aluminum chloride. aluminum bromide. ferric nitrate. cobalt bromide. gallium chloride. cerium iodide. and so forth. The divalent cations of this invention are copper. ferrous. chromium. nickel. zinc and others. Tetravalent ions which may be utilized in the instant invention are stannic and zirconium. such as stannic chloride and zirconium nitrate.  
  The polyene macrolides are nystatin. pimaricin. rimocidin. amphotericin A. amphotericin B. etruscomycin. lagosin. azacalutin. hamycine. candidin. filipin. fungichromin. pentamycin. flavacid, candicidin. and tylosin.  
  Alcohols that can be utilized to carry out the reaction are the lower alkyl alcohols of from 1 to 6 carbons such as methanol. ethanol. isopropanol. isobutanol. butanol.  
 plexes of polyenes having antifungal activity were not water soluble. therefore. they had to be applied topically. It has been discovered that the complexes of this invention when formulated for oral administration to animals (e.g.. dogs. cows. pigs. and so forth) yield a high level of the polyene in the blood. Heretofore such results could not be achieved as some of the water soluble salts were unstable and the polyenes per se could not cross into the blood from the digestive system. Utilizing complexes of the instant invention in from between l.000 to 40.000 units per Kg of weight per day formulations can be prepared in the usual manner. as for example. those described in US. Pat. NO. 3.491.187.  
  The following examples are illustrative of the invention. All temperatures are in degrees Centigrade. unless otherwise stated:  
 EXAMPLE 1 Procedure for Preparing Ferric-Nystatin Complex Dissolve FECIg-OHgO (273 g.) in methanol (2500 ml.) and add nystatin (2850 g.) to it. Practically all nystatin goes into solution within 5 to 10 minutes. The solution is filtered. The pH of this solution is about 3.4. It is adjusted to about pH of 5.4 with methanolic NaOH.  
  The ferric-nystatin is precipitated by adding ether or ethylacetate to the above solution. The precipitate is separated by centrifuging and is washed with the precipitating solvent. The compound is vacuum dried and has the following properties:  
 Soluble in H 0 and alcohols In vitro activity (S. cerevisiae) equal to nystatin lron content 1.8 percent (wt.)  
 MW 3000 (ultracentrifuge pH3 buffer) EXAMPLE 2 Procedure for Preparing Alumina-Nystatin The procedure is the same as for Example 1. except that g. aluminum chloride is dissolved in the 2500 ml. MeOH or EtOH and 6650 g. nystatin is added instead of the FeCl .6H- .O.  
  The alumina-nystatin formed has the following propcrties:  
 Soluble in H 0 and methanol In vitro activity (S. cerevisiae) about equal to nystatin EXAMPLE 3 Procedure for Preparing C hromium-Nystatin The procedure is the same as for Example 1 except that268 g. CrCl;,.6H O is mixed into 2500 ml. alcohol and 9550 g. of nystatin is added.  
 C hromium-nystatin has the following properties:  
 soluble in H and methanol ln vitro activity (S. .cerevisiae) about equal to nystatin.  
 EXAMPLE Cobalt Amphotericin B Following the procedures of Example I but utilizing I65 g. cobalt chloride in lieu of ferric chloride and 2850 g. amphotericin B in lieu of nyst&#39;atin. the desired product is re&#39;co vered.  
 EXAMPLE 5 Gallium Azacalutin&#39; Utilizing the procedures of Example I but substituting.l7 6 g. gallium chloride for ferric chloride and 3000 g. azacalutin in lieu of nystatin. the desired product is recovered.  
 EXAMPLE 6 Cerium Candidin Utilizing the procedure of Example l but substituting 296 g cerium chloride for ferric chloride and 2500 g. candidin for amphotericin B. the desired product is recovered.  
 EXAMPLE 7 Stannic Amphotericin A Following the procedures of Example lbut utilizing 438 g. stannic bromide in lieu of ferric chloride and 3900 g. of amphotericin A in lieu of nystatin. the desired product is recovered.  
 EXAMPLE 8 Procedure for Preparing Fe&#39;rrous- N \&#39;statin Dissolve Fe(NO=,) 6H- |O (288* g.) in. MeOH (2500 ml.) and nystatin 1900 g.) to it...Practically all nystatin goes into solution within 5 to -l0minutes. The solution is filtered. The pH of the solution .is-about 6.0.  
 The ferrous-nystatin is precipitated out by adding.  
 ether or ethylacctate to the above solution. The precipitate is separated by centrifuging and is washed with the precipitating solvent. The compound is-vacuum dried.  
 Ferrous-nystatin is soluble in methanol.  
  EXAMPLE 10. Copper Etruscomycin Utilizing the procedure of Example I but substituting l70 g. cuppric chloride for ferrous chloride and I000 g. etruscomycin for nystatin. the desired product is recovered.  
 What is claimed is:  
 1. The complex of the formula nickel-pimaricin.