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United States Patent (19) 11 Patent Number: 5,847,110 Dragsten Et Al

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United States Patent (19) 11 Patent Number: 5,847,110 Dragsten Et Al USOO584711 OA United States Patent (19) 11 Patent Number: 5,847,110 Dragsten et al. (45) Date of Patent: Dec. 8, 1998 54 METHOD OF REDUCING ASCHIFF BASE 4,217,338 8/1980 Ouash ......................................... 424/1 4,419,444 12/1983 Quash ......................................... 435/7 (75) Inventors: Paul R. Dragsten, Chanhassen; 4,699.784 10/1987 Shih et al. ..... ... 424/85 Gregory J. Hansen, Fridley, both of 4,975,533 12/1990 Kondo et al. ... ... 536/55.3 Minn. 5,057,313 10/1991 Shih et al. ........................... 424/85.91 73 Assignee: Biomedical Frontiers, Inc., Minneapolis, Minn. OTHER PUBLICATIONS 21 Appl. No.: 911,991 Pelter, A. et al., “Reductive Aminations of Ketones and 1-1. Aldehydes using Borane-Pyridine”, J. Chem. Soc., Perkins 22 Filed: Aug. 15, 1997 Trans. 1, pp. 717–720 (1984). 51 Int. Cl. ........................... C08B 30/00; CO8B 37/00; C08B 37/02; CO7C 209/00 52 U.S. Cl. ........................ 536,124. 536/179536/185. Primary Examiner Howard C. Lee 536/18.7; 536/102; 536/112; 536/123.1; Attorney, Agent, Or Firm-Merchant, Gould, Smith, Edell, 564/123; 564/488; 564/489 Welter & Schmidt, PA. 58 Field of Search .................................. 536/17.9, 18.5, 536/18.7, 102, 112, 123.1, 124; 564/8, 57 ABSTRACT 123,489, 488 The invention relates to methods of reducing Schiff bases 56) References Cited and making chelator conjugates by treating with borane pyridine complex. U.S. PATENT DOCUMENTS 3,706,633 12/1972 Katchalski et al. ....................... 195/63 47 Claims, No Drawings 5,847,110 1 2 METHOD OF REDUCING ASCHIFF BASE includes Steps of reacting a water Soluble carrier with an amine, and treating reacted water Soluble carrier with BACKGROUND OF THE INVENTION borane-pyridine complex. This embodiment of the invention can also include addi Schiff bases can be reduced by a variety of known tional Steps, Such as modifying a water Soluble carrier to reducing agents, for example, Sodium borohydride, Sodium introduce groups that react with an amine and/or reducing cyanoborohydride, and the like. However, Selective reduc Species present after the treating Step. A water Soluble carrier tion of Schiff bases in molecules with other functional can be modified by, for example, oxidation or reaction with groups remains problematic. It is particularly difficult to a linking group to produce or incorporate carbonyl groups Selectively reduce Schiff bases in an aqueous Solvent. For on the water Soluble carrier. The reduction can be accom example, Selective reduction of Schiff bases in a water plished by treating with sodium borohydride. Soluble macromolecule at an acceptable yield has been The water Soluble carrier, the initial product from reacting difficult to achieve. water Soluble carrier with amine, the product from treating Amine complexes of borane are a family of reducing with borane-pyridine complex, or any other form of the agents that have been shown to have broad reactivity under 15 water Soluble carrier can be purified as part of the method. a variety of conditions. For example, borane-amine com Purifying includes procedures Such as diafiltering. Purifying plexes can reduce carbonyl compounds in a variety of also includes purifying the conjugate into a pharmaceuti Solvents. Typically though, borane-amine complexes are cally acceptable vehicle. much more effective reducing agents in Strong aqueous acid, The present invention also includes products of the meth Such as a mineral acid or a Lewis acid, than in water. Mild ods of the invention. These products include a reduced conditions for reduction with borane-amine complexes Schiff base produced by a proceSS including the Step of include use of glacial acetic acid as a Solvent, and borane treating the Schiff base with borane-pyridine complex in an amine complexes reduce Schiff bases in glacial acetic acid. aqueous Solution at a non-acid pH, Such as pH at least about 4. Another product of the methods of the invention includes In glacial acetic acid, borane-pyridine complex causes a covalently bonded conjugate of an amine and a water reductive amination of aldehyde or ketone and reduction of 25 Soluble carrier produced by a proceSS including the Steps of Schiff bases. Introduction of polar or hydrophilic cosolvents reacting a water Soluble carrier with an amine, and treating typically reduces or eliminates reduction of a Schiff base. the reacted water Soluble carrier with borane-pyridine com Furthermore, some Schiff bases are reduced less readily than plex. others. Although borane-pyridine complex was found to be effective for reducing Schiff bases formed from acetophe The water soluble carrier of the invention is preferably a none or benzaldehyde, it was not effective in reducing Schiff large molecule that has characteristics Such that conjugating bases derived from more hindered or leSS reactive ketones. a chelator with the water Soluble carrier results in desirable For example, yields as high as 93% were obtained for biological properties Such as increasing efficacy, prolonging reductive amination of acetaldehyde or cyclohexanone, but the circulating half-life, decreasing toxicity, and the like. no reduction was observed when the Schiffbase was derived 35 Preferably, the water soluble carrier is a polysaccharide, for from the reaction of aniline with camphor or of acetophe example, Starch, a Starch derivative, dextran, or hyaluronic none with a hindered amine Such as octylamine or cyclo acid. In a preferred embodiment, the water Soluble carrier is hexylamine. hydroxyethyl starch. Advantageously, the amine of the invention is a chelator. Given the shortcomings of the current methods for reduc Preferably the chelator is effective to chelate iron so that the ing Schiff bases described above, a need exists for a method 40 iron can be excreted from the body of a patient. In a to reduce Schiff bases in aqueous Solvents, in the presence preferred embodiment, the chelator is deferoxamine. of carbonyl groups, on unreactive molecules, or on hindered In a preferred embodiment, a conjugate of deferoxamine molecules, Such as a water Soluble carrier. with hydroxyethyl starch (HES-DFO) is effective to SUMMARY OF THE INVENTION 45 decrease iron load in a patient Suffering from an iron overload disorder. Preferably, the conjugate of the invention The present invention relates to a method for reducing a can be administered to a patient without unacceptable Schiff base and meets the needs described above. The adverse Side effects. method includes treating a Schiff base with borane-pyridine Preferably, a chelator conjugate of the invention can be complex (or borane-pyridine) in an aqueous Solution at a 50 formulated as a Solution, Suspension, or emulsion, or similar non-acid pH, Such as pH at least about 4. The method can liquid based form, preferably in a formulation suitable for also include one or more Steps for making the Schiff base, administration to a patient. Preferably, the chelator conju Such as oxidizing a water Soluble carrier to form a modified gate is formulated in a pharmaceutically accepted vehicle. water Soluble carrier comprising a dialdehyde moiety, and/or Preferably, the pharmaceutically acceptable vehicle is water reacting a modified water Soluble carrier with an amine to 55 including about 0.9% sodium chloride or lactated Ringer's form the Schiff base. Solution. Preferably, the chelator conjugate is formulated as This embodiment of the invention can also include addi a Solution with chelator conjugate concentration of about 5 tional Steps, Such as reducing aldehyde present after treating g/L to about 250 g/L. Preferably, the chelator conjugate is a Schiff base with borane-pyridine complex. This reduction administered as a Solution with a total chelator concentration can be accomplished by treating with Sodium borohydride. 60 of about 5 mM to about 250 mM. Products of and reactants in the method can be purified as DETAILED DESCRIPTION OF THE part of the method. For example, purifying the Schiffbase or INVENTION the treated Schiff base can be accomplished by a method Such as diafiltering or diafiltration. Reducing Schiff Bases With Borane-Pyridine In another embodiment of the invention, the method 65 Complex makes a covalently bonded conjugate of an amine and a Although previous methods for reducing Schiff bases with water Soluble carrier. In this embodiment the method borane complexes require an acidic, non-aqueous Solvent 5,847,110 3 4 Such as glacial acetic acid, reduction of Schiff bases with formed in Situ or can be formed in another reaction and, borane-pyridine complex can be accomplished in an aque optionally, purified prior to reaction with an amine and ous Solution at a non-acid pH, Such as pH at least about 4. reduction with borane-pyridine complex. A preferred alde The present method can Specifically reduce a Schiff base in hyde or ketone includes a water Soluble aldehyde or ketone an aqueous Solvent in the presence of a dialdehyde without Such as a natural or a modified water Soluble carrier. Substantially reducing the dialdehyde. Such a specific reduc tion can be readily accomplished by treating the Schiff base The water Soluble carrier is preferably a natural polymer, with borane-pyridine complex. Treatment with borane a modified natural polymer, or another pharmaceutically pyridine complex is also useful to make a stable, covalently acceptable organic polymer. Such water Soluble carriers bonded conjugate of an amine and a water Soluble carrier. include polysaccharides Such as dextrans and hyaluronic The water Soluble carrier is reacted with an amine, and then acid, Starch and Starch derivatives, and proteins Such as the product of this reaction is treated with borane-pyridine human Serum albumin, and the like. Polymer Starting mate complex. Prior to reaction with the amine, the water soluble rials. Such as the dextrans, human albumin and plasma carrier can be modified to introduce groups that will react protein fraction are commercially available as water-Soluble with an amine.
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