WO2006083687A1 - Sel cristallin d'inhibiteurs de xanthine oxydase - Google Patents

Sel cristallin d'inhibiteurs de xanthine oxydase Download PDF

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Publication number
WO2006083687A1
WO2006083687A1 PCT/US2006/002833 US2006002833W WO2006083687A1 WO 2006083687 A1 WO2006083687 A1 WO 2006083687A1 US 2006002833 W US2006002833 W US 2006002833W WO 2006083687 A1 WO2006083687 A1 WO 2006083687A1
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Prior art keywords
oxypurinol
choline salt
crystalline
disease
salt
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PCT/US2006/002833
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English (en)
Inventor
Bertrand M.C. Plouvier
Lewis Siu Leung Choi
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Cardiome Pharma Corp.
Wagner, Emily W.
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Application filed by Cardiome Pharma Corp., Wagner, Emily W. filed Critical Cardiome Pharma Corp.
Publication of WO2006083687A1 publication Critical patent/WO2006083687A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • Allopurinol and oxypurinol are poorly resorbed, and there have been a number of fo ⁇ nulations developed for treatment of gout and chronic inflammatory intestinal diseases to address this problem.
  • These formulations include oral dosage forms of oxypurinol alkali or alkaline earth salts, in an amorphous or crystalline, non-micronized state; and oxypurinol or its alkali or alkaline earth salts in the form of a solids dispersion with pharmacologically inert adjuvants in a specified ratio (U.S. Patent Nos. 5,661,154 and 5,368,864).
  • the present invention relates to a stable crystalline form of a choline salt of oxypurinol.
  • the crystalline oxypurinol choline salts of the invention have both in vitro and in vivo biological activity.
  • the crystralline choline salts of oxypurinol have enhanced solubility and stability properties as compared to the oxypurinol free acid, and have properties which may enable faster dissolution and targeting than the oxypurinol free acid. Therefore, salts of the present invention provide improved pharmaceutical compositions.
  • a crystalline oxypurinol choline salt is provided that extends the stability and solubility of oxypurinol compared to oxypurinol free acid.
  • a further aspect of the invention resides in obtaining certain choline salts of oxypurinol in sufficient quality to determine the three dimensional (tertiary) structure of the compound by X-ray diffraction methods. Accordingly, the invention provides crystals of sufficient quality to obtain a determination of the three-dimensional structure of a choline salt of oxypurinol to high resolution.
  • crystals of the invention are Diffraction Quality Crystals.
  • the invention contemplates a composition, in particular a pharmaceutical composition, comprising an oxypurinol choline salt of the invention.
  • a solid form pharmaceutical composition is provided (e.g., tablets, capsules, or a powdered or pulverized form) comprising a crystalline oxypurinol choline salt.
  • the present invention contemplates crystalline forms of oxypurinol as a choline salt, which can be processed galenically as stable, well-defined solid substances. Such crystalline forms allow for prolonged stability in storage and for oral and intravenous administration of the drug. Therefore, the invention provides a crystalline form of oxypurinol as a choline salt as a solid formulation.
  • a solid formulation may be in the form of a powder (e.g., a sterile packaged powder, capsule (soft and hard capsules), sachet, tablet, pill, buccal, or lozenge).
  • the invention further contemplates a method for preventing and/or treating a condition and/or disease discussed herein in a subject comprising administering an effective amount of an oxypurinol choline salt of the invention.
  • the invention also relates to the use of an oxypurinol choline salt of the invention in the preparation of a medicament for preventing and/or treating a condition and/or disease discussed herein.
  • the knowledge obtained concerning the choline salts of oxypurinol may be used to model the tertiary structure of the compounds and related compounds i.e. analogs and derivatives of oxypurinol and salts thereof.
  • the invention provides compounds having substantially the same three-dimensional structure of an oxypurinol choline salt of the invention.
  • the knowledge of the structure of the choline salts of oxypurinol provides a means of investigating the mechanism of action of these compounds in the body. For example, the ability of compounds to inhibit xanthine oxidase activity may be predicted by various computer models.
  • Another aspect of the invention is to provide material which is a starting material in the rational design of drugs which mimic the action of oxypurinol compounds. These drugs may be used as therapies that are beneficial in the prevention and/or treatment of conditions and/or diseases discussed herein.
  • Figure 1 shows the ORTEP molecular representations of molecules of oxypurinol choline salt obtained from the two batches of the oxypurinol choline salt obtained from the crystallization process set forth in Preparation Method 1.
  • Figure 2 shows some resonance forms for oxypurinol.
  • Figures 3-5 show the powder X-ray diffraction patterns of the two batches of oxypurinol choline salt obtained from Preparation Method 1 and the batch of oxypurinol choline salt obtained from Preparation Method 2.
  • Figures 6-8 show comparisons between the powder X-ray diffraction patterns of the two batches of oxypurinol choline salt obtained from Preparation Method 1 and the batch of oxypurinol choline salt obtained from Preparation Method 2.
  • Figure 9 shows the simulated powder diffraction pattern generated from the single crystal structure solution of the first batch of oxypurinol choline salt obtained from Preparation Method 1.
  • Figure 10 shows a molecular representation (ORTEP) of a molecule of an oxypurinol choline salt with 50 % probability thermal ellipsoids shown; selected H-atoms are shown with the other H-atoms omitted for clarity.
  • ORTEP molecular representation
  • Figure 11 is a representation of the hydrogen bonding in the solid state of an oxypurinol choline salt.
  • Oxypurinol refers to a compound of the Formula I
  • R 1 is hydrogen or lower alkyl
  • R 2 is hydrogen, hydroxyl or lower alkyl.
  • “Lower alkyl” refers to a branched or linear hydrocarbon radical, typically containing from 1 through 10 carbon atoms, more preferably 1 to 6 carbon atoms. Typical alkyl groups include but are not limited to methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, tert-butyl, pentyl, hexyl, and the like.
  • oxypurinol in particular refers to (4,6-dihydroxypyrazole[3,4- djpyrimidine], functional derivatives, or tautomeric forms thereof. Tautomeric forms of oxypurinol are shown in Table 20.
  • a “functional derivative” of oxypurinol refers to a compound that possesses a biological activity (either functional or structural) that is substantially similar to the biological activity of oxypurinol.
  • the term “functional derivative” is intended to include “variants” “analogs” or “chemical derivatives” of oxypurinol.
  • variant is meant to refer to a molecule substantially similar in structure and function to oxypurinol or a part thereof.
  • a molecule is “substantially similar” to oxypurinol if both molecules have substantially similar structures or if both molecules possess similar biological activity.
  • the term “analog” refers to a molecule substantially similar in function to an oxypurinol molecule.
  • the term “chemical derivative” describes a molecule that contains additional chemical moieties which are not normally a part of the base molecule. .
  • substantially pure or “high purity” includes a purity of at least 95%, and preferably at least 97% by weight (e.g., at least 99% to 99.5% by weight). Impurities include by-products of synthesis or degradation.
  • “Therapeutically effective amount” relates to a dose of an active ingredient (i.e. oxypurinol) that will lead to the desired pharmacological and/or therapeutic effect.
  • the desired pharmacological effect is, to alleviate a condition or disease described herein, or symptoms associated therewith.
  • a therapeutically effective amount of a substance may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance to elicit a desired response in the individual. Dosage mita may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a therapeutically effective amount may be estimated from cell culture assays or animal cell models.
  • a dose maybe formulated in animal models to achieve a circulating concentration range of compound that includes an effective concentration as initially determined in a cell culture. This information may be used to more accurately determine useful doses in humans.
  • a therapeutically effective dose can also be estimated from pharmacokinetic data. For example, a dose that has an area under the blood concentration-time curve (AUC) within about 50%, 60%, 70%, 80% or 90% or more of the AUC of a dose known to be effective for the indication being treated is expected to be effective.
  • AUC blood concentration-time curve
  • subject refers to an animal including a warmblooded animal such as a mammal, which is afflicted with or suspected of having or being predisposed to a condition and/or disease as discussed herein.
  • the terms refer to a human.
  • the terms also include but are not limited to domestic animals bred for food, sports, or as pets, including horses, cows, sheep, poultry, fish, pigs, cats, dogs, and zoo animals.
  • Typical subjects for treatment include persons susceptible to, suffering from or that have suffered a condition and/or disease described herein.
  • suitable subjects for treatment in accordance with the invention include persons that are susceptible to, suffering from or that have suffered heart failure, particularly congestive heart failure or acute cardiogenic shock.
  • patients are selected where an increase in myocardial contractility with reduced energy requirements is desirable. More particularly, patients are selected where increased cardiac efficiency is desirable.
  • pharmaceutically acceptable vehicle includes a medium which does not interfere with the effectiveness or activity of an active ingredient and which is not toxic to the hosts to which it is administered.
  • Excipients include diluents, binders, adhesives, lubricants, disintegrates, bulking agents, and miscellaneous materials such as absorbants, that may be needed in order to prepare a particular formulation.
  • preventing and/or treating and “prophylactic and/or therapeutic” refer to administration to a subject of biologically active ingredients either before or after onset of a condition or disease. If the agent is administered prior to exposure to a factor causing a condition or disease the treatment is preventive or prophylactic (i.e., protects the host against damage). If the agent is administered after exposure to the factor causing a condition or disease the treatment is therapeutic (i.e., alleviates the existing damage). A treatment may be either performed in an acute or chronic way.
  • condition and/or disease refers to an indication that requires modulation of xanthine oxidase or which utilizes xanthine oxidase inhibitors for treatment, intervention, or prevention.
  • the condition and/or disease is a cardiovascular disease and related diseases, ischaemia-reperfusion injury in tissues including the heart, lung, kidney, gastrointestinal tract, and brain, diabetes, inflammatory joint diseases such as rheumatoid arthritis, respiratory distress syndrome, kidney disease, liver disease, sickle cell disease, sepsis, burns, viral infections, hemorrhagic shock, gout, hyperuricaemia, and conditions associated with excessive resorption of bone.
  • Cardiovascular and related diseases include, for example, hypertension, hypertrophy, congestive heart failure, heart failure subsequent to myocardial infarction, arrhythmia, myocardial ischemia, myocardial infarction, conditions associated with poor cardiac contractility, conditions associated with poor cardiac efficiency, ischemia reperfusion injury, and diseases that arise from thrombotic and prothrombotic states in which the coagulation cascade is activated.
  • the condition or disease is congestive heart failure.
  • Heart failure may arise from any disease that affects the heart and interferes with the circulation.
  • a disease that increases the workload of the heart muscle, such as hypertension may eventually weaken the force of the contractions of the heart.
  • the methods, compositions and formulations of the invention are suitable for the treatment of congestive heart failure of idiopathic, ischemic, or other causes.
  • Diffraction Quality Crystal refers to a crystal that is well-ordered and of a sufficient size, i.e., at least 10 ⁇ m, at least 50 ⁇ m, or at least 100 ⁇ m in its smallest dimension such that it produces measurable diffraction to at least 3 A resolution, preferably to at least 2 A resolution, and most preferably to at least 1.5 A resolution or lower.
  • Diffraction quality crystals include native crystals, heavy-atom derivative crystals, and co-crystals.
  • Unit Cell refers to the smallest and simplest volume element (i.e., parallelepiped- shaped block) of a crystal that is completely representative of the unit or pattern of the crystal, such that the entire crystal may be generated by translation of the unit cell.
  • the dimensions of the unit cell are defined by six numbers: dimensions a, b and c and the angles are defined as ⁇ , ⁇ , and ⁇ (Blundell et al., Protein Crystallography, 83-84, Academic Press. 1976).
  • a crystal is an efficiently packed array of many unit cells.
  • Space Group refers to the set of symmetry operations of a unit cell.
  • space group designation e.g., C2
  • the capital letter indicates the lattice type and the other symbols represent symmetry operations that may be carried out on the unit cell without changing its appearance.
  • Structure coordinates refers to mathematical coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of X-rays by the atoms (scattering centers) of an oxypurinol choline salt in crystal form.
  • the diffraction data are used to calculate an electron density map of the repeating unit of the crystal.
  • the electron density maps are used to establish the positions of the individual atoms within the unit cell of the crystal.
  • Structural coordinates can be slightly modified and still render nearly identical three dimensional structures. A measure of a unique set of structural coordinates is the root- mean-square deviation of the resulting structure.
  • Structural coordinates that render three dimensional structures that deviate from one another by a root-mean-square deviation of less than 2 A, preferably less than 0.5 A, more preferably less than 0.3 A, may be viewed by a person of ordinary skill in the art as identical.
  • Variations in structural coordinates may be generated because of mathematical manipulations of the structural coordinates of an oxypurinol choline salt described herein.
  • the structural coordinates of Table 5 or Table 14 may be manipulated by crystallographic permutations of the structural coordinates, fractionalization of the structural coordinates, integer additions or substractions to sets of the structural coordinates, inversion of the structural coordinates or any combination of the above.
  • Variations in structure resulting from changes in any of the components that make up a structure of the invention may also account for modifications in structural coordinates. If such modifications are within an acceptable standard error as compared to the original structural coordinates, the resulting structure may be the same.
  • Having substantially the same three-dimensional structure refers to a compound that is characterized by a set of molecular structure coordinates that have a root mean square deviation (r.m.s.d.) of up to about or equal to 1.5 A, preferably 1.25 A, preferably 1 A, and preferably 0.5 A, and preferably 0.25 A, when superimposed onto the molecular structure coordinates of Table 5 or Table 14 when at least 50% to 100% of the coordinates are included in the superposition.
  • the program MOE may be used to compare two structures (Chemical Computing Group, Inc., Montreal, Canada).
  • a choline salt of oxypurinol may be represented by the following structure:
  • a choline salt of oxypurinol of the invention may have greater solubility than oxypurinol free acid.
  • a choline salt of oxypurinol may have a solubility in water or alcohol that is 2, 3, 4, or 5 fold greater than the oxypurinol free acid.
  • the solubility of a crystalline choline salt of oxypurinol is about 130- 160 mg/mL, in particular 140-155 mg/mL, more particularly 150-155 mg/mL.
  • a choline salt of oxypurinol of the invention may have long-term stability to UV light, oxidation, heat and humidity.
  • a choline salt of oxypurinol may have greater thermal stability than oxypurinol free acid.
  • a crystalline choline salt of oxypurinol may be more stable than oxypurinol free acid when exposed to atmospheric oxygen or nitrogen at about 15-30 0 C for about 3-80 days.
  • Oxypurinol choline salts of the invention may have a particle size in the range from 10 to 2000 ⁇ m, preferably from 50 to 1000 ⁇ m, particularly preferably from 100 to 800 ⁇ m, very particularly preferably in the range from 100 to 600 ⁇ m.
  • both sieve analysis and laser diffraction spectrometry are suitable for determining the size distribution of oxypurinol choline salt crystals.
  • a crystalline choline salt of oxypurinol may comprise molecules of oxypurinol choline in a unit cell held together by hydrogen bond interactions.
  • the crystalline choline salt comprises 8 molecules of oxypurinol choline in a unit cell.
  • a crystalline oxypurinol choline salt which comprises molecules of oxypurinol choline salt in a unit cell held together by hydrogen bond interactions from the deprotonated pyrimidine nitrogen atom of a molecule of oxypurinol to the quaternary ammonium of choline.
  • the distances between the nitrogen and quarternary ammonium is about 3-5 A, in particular 4 A.
  • the ratio of oxypurinol and choline in a crystalline oxypurinol choline salt of the invention may be 1:2, in particular 1:1.
  • a crystal of the invention may take any crystal symmetry form based on the type of choline salt molecule, the hydrogen bond interactions, and/or the space group.
  • a crystalline oxypurinol choline salt has space group symmetry C2/c.
  • the crystal of oxypurinol choline salt comprises monoclinic unit cells.
  • An oxypurinol choline salt of the invention may be further characterized by having one or more of the following properties: a) at least 1, 5, 10, 15, or 18 of the atomic coordinates as shown in Table 5 or Table 14; b) at least 1, 5, 10, 15, 20, 30, 40, 50, 60, 70-, 80, 90, or 95 of the bond lengths and angles as shown in Table 6 or Table 15; c) at least 1 , 5, 10, 15, or 18 of the anisotropic displacement parameters as shown in Table 7 or Table 16; d) at least 1, 5, 10, 15, or 17 of the hydrogen coordinates and isotropic displacement parameters as shown in Table 8 or Table 17; e) at least 1, 5, 10, 15, 20, 25 of the torsion angles as shown in Table 9 or Table 18; f) at least 1, 2, or 3 of the hydrogen bonds as shown in Table 10 or Table 19; g) a melting point of about 160 0 C to 175°C, in particular 163 0 C to 174°C, more particularly 164°C to 173 0 C, most particularly 17
  • a crystalline choline salt of oxypurinol is characterized by (a); (a) and (b); (a), (b) and (c); (a), (b), (c), and (d); (a) through (e); (a) through (f); (a) through (g); (a) through (h); (a) through (i); (a), (g) and (h); (a) and (h); and (a) (b), (g) and (h).
  • a crystalline salt of the invention may be prepared by treating oxypurinol free acid with a choline compound, and purifying the salt by crystallization.
  • a stable and/or substantially pure crystalline choline salt may be formed as described in the Examples.
  • the invention relates to a process for preparing crystalline oxypurinol choline salt by reacting oxypurinol free acid with choline hydroxide.
  • the process may be carried out in water, a water-miscible organic solvent, or in a mixture of water and a water- miscible organic solvent.
  • the proportion of water in a solvent may be about 0 to 50% by weight, in particular from about 0 to 10% by weight.
  • a water-miscible solvent maybe selected that is water-miscible, thermally stable, or a volatile solvent containing only carbon, hydrogen and oxygen, such as alcohols, ethers, esters, ketones and acetals.
  • solvents examples include methanol, ethanol, ⁇ -propanol, isopropanol, l-methoxy-2-butanol, l-propoxy-2-propanol, tetrahydrofuran or acetone is used.
  • the molar ratio of the reaction substrates oxypurinol free acid and choline hydroxide in the process is in the range 1:3, 1:2, 1:1.5, 1:1, 1:0.95 or 1:0.9 or any ratio in between the ranges indicated above.
  • protecting groups may be used to block reactive groups.
  • Appropriate blocking and deblocking schemes are known to the skilled artisan (See T. W. Greene and P. G. M. Wuts, 2.sup.nd ed., Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991).
  • particular protective groups are selected which adequately protect the reactive groups in question during subsequent synthetic steps and which are readily removable under conditions which will not cause degradation of the desired product.
  • some protecting groups are cleaved or metabolically converted into the active functional group (e.g., via hydrolysis or oxidation). Metabolically cleaved protecting groups are preferred, in some cases. Examples of protecting groups that may be used include hydroxyl protecting groups such as methyl ethers including methoxymethyl, methylthiomethyl, and t-butylthiomethyl.
  • the invention also encompasses compounds identical to the oxypurinol salts of the invention except that one or more conventional protecting groups are used, such as the hydroxyl protecting groups described herein.
  • a crystalline oxypurinol choline salt may be formed by, for example, dissolving oxypurinol choline salt in a solvent as discussed above, and evaporating the solvent.
  • the crystals may also be prepared by diffusion using standard methods.
  • crystalline choline salts of functional derivatives of oxypurinol may be prepared using the methods described herein, and the salts of such derivatives prepared by the methods are contemplated in the present invention.
  • a crystal of a choline salt of oxypurinol may be used to model the three dimensional structure of the salts and related compounds i.e., analogs and derivatives of oxypurinol and salts thereof. Therefore, the invention provides a method for determining the three-dimensional structure of an oxypurinol choline salt crystal, comprising the steps of providing a crystal of the present invention; and analyzing the crystal by x-ray diffraction to determine the three- dimensional structure. In an aspect, the invention provides for the production of three- dimensional structural information (or "data") from the crystals of the invention.
  • Such information may be in the form of structural coordinates that define the three-dimensional structure of an oxypurinol choline salt in a crystal or a portion thereof (see Table 5 and Table 14).
  • An example of a portion of an oxypurinol choline salt includes the site that interacts with a xanthine oxidase.
  • the information on structural coordinates may include other structural information, such as vector representations of the molecular structures coordinates.
  • the invention provides methods of producing a computer readable database comprising the three-dimensional molecular structural coordinates of an oxypurinol choline salt.
  • the methods may comprise obtaining three-dimensional structural coordinates defining an oxypurinol choline salt or portion thereof from a crystal of the salt (see Table 5 and Table 14); and introducing the structural coordinates into a computer to produce a database containing the molecular structural coordinates of an oxypurinol choline salt.
  • the invention also contemplates databases produced by such methods.
  • the invention also provides computer machine-readable media embedded with the three-dimensional structural information obtained from the oxypurinol choline crystals of the invention, or portions thereof.
  • the types of machine- or computer-readable media into which the structural information is embedded include without limitation magnetic tape, floppy discs, hard disc storage media, optical discs, CD-ROM, electrical storage media such as RAM or ROM, and hybrids of any of these storage media.
  • Machine-readable media of the invention may also comprise additional information that is useful for representing the three-dimensional structure, including, but not limited to, isotropic displacement parameters.
  • a machine-readable medium is provided that is embedded with information defining a three- dimensional structural representation of any of the crystals of the present invention, or a fragment or portion thereof.
  • the information may be in the form of molecular structure coordinates, such as, for example, those of Table 5 and Table 14.
  • the coordinates may be used to solve the three-dimensional X-ray diffraction and/or solution structures of other pyrazole xanthine oxidase inhibitors, and unrelated structures, to high resolution.
  • the information may also be used in molecular modeling and computer-based screening applications to, for example, intelligently design modulators (e.g., agonists) of pyrazole xanthine oxidase inhibitors.
  • the modulators may be used directly or as lead compounds in pharmaceutical efforts to identify compounds that modulate xanthine oxidase activity.
  • Compounds that are agonists of oxypurinol or antagonists of xanthine oxidase may be incorporated in pharmaceutical compositions and used to prevent and/or treat a condition and/or disease discussed herein.
  • Also provided in the present invention is a method for obtaining structural information about a molecule of unknown structure comprising: crystallizing the molecule or molecular complex; generating an x-ray diffraction pattern from the crystallized molecule or molecular complex; and using a molecular replacement method to inteipret the structure of said molecule; wherein said molecular replacement method uses the structure coordinates of Table 5 or Table 14, or structure coordinates having a root mean square deviation for the atoms of the structure coordinates of up to about 2.0 A, preferably up to about 1.75 A, preferably up to about 1.5 A, preferably up to about 1.25 A, preferably up to about 1.0 A, preferably up to about 0.75 A.
  • the coordinates of the resulting structure may be stored in a computer readable database as described herein.
  • the invention provides pharmaceutical compositions formulated from an oxypurinol choline salt of the invention (e.g., in particular, a crystalline choline salt of oxypurinol), a combination of the oxypurinol choline salts of the invention, or a combination of oxypurinol and oxypurinol choline salt(s) of the invention.
  • an oxypurinol choline salt of the invention e.g., in particular, a crystalline choline salt of oxypurinol
  • a combination of the oxypurinol choline salts of the invention e.g., in particular, a crystalline choline salt of oxypurinol
  • Routes of administration of a composition of the invention include oral, pulmonary, topical, body cavity (e.g., nasal eye, buccal), transdermal, and parenteral (e.g., intravenous, intramuscular, and subcutaneous routes).
  • Externally activated drug delivery systems include those activated by heat, ultrasound, electrical pulse, iontophoresis, electrophoresis, magnetic modulation, and light.
  • Compositions include solids (tablets, soft or hard gelatin capsules), semi-solids (gels, creams), or liquids (solutions, colloids, or emulsions), preferably solids.
  • Colloidal carrier systems include microcapsules, emulsions, microspheres, multi-lamellar vesicles, nanocapsules, uni-lamellar vesicles, nanoparticles, microemulsions, and low-density lipoproteins.
  • Systems for parenteral administration include lipid emulsions, liposomes, mixed micellar systems, biodegradable fibers, and fibrin-gels, and biodegradable polymers for implantation.
  • Systems for pulmonary administration include metered dose inhalers, powder inhalers, solutions for inhalation, and liposomes.
  • a composition can be formulated for sustained release (multiple unit disintegrating particles or beads, single unit non-disintegrating system), controlled release (oral osmotic pump), and bioadhesives or liposomes.
  • Controlled release compositions include those, which release intermittently, and those that release continuously.
  • a composition of the invention includes one or more pharmaceutical carriers, and optionally one or more bioactive agents.
  • Pharmaceutical carriers include inorganics such as calcium phosphate and titanium dioxide; carbohydrates such as -lactose monohydrate and - cyclodextrin; surfactants such as sodium lauryl sulfate and poloxamers; polymers such as starch, ethyl cellulose, hydrogels, and polyacrylic acids; lipids such as polylactides, stearic acid, glycerides, and phospholipids; or amino acids and peptides such as leucine and low density lipoprotein.
  • compositions formulated from a salt of oxypurinol of the invention may include: (a) a tablet including an oxypurinol choline salt of the invention, a pharmaceutical carrier and may also include an absorption enhancer, (b) a capsule containing a crystalline, powder, microspheres, or pellets made from an oxypurinol choline salt of the invention, even though, in the capsule, oxypurinol choline salt is no longer in the form of clear crystals (e.g., prisms), (c) a soft gel capsule made from an oxypurinol choline salt of the invention, (d) an aqueous solution of an oxypurinol choline salt of the invention, wherein the dissolved oxypurinol choline salt is no longer crystalline, and may for example, no longer be associated with either the choline, and (e) other parenteral, transdermal, intranasal or oral administration forms known to those skilled in the art.
  • Oxypurinol derived from a salt of the invention is also useful in certain methods of treatment of the invention. Pure oxypurinol alone (e.g., oxypurinol free acid), however, is not contemplated for use in a composition of the invention.
  • the pharmaceutical composition is a solid form composition wherein the active ingredient i.e., salt of the invention is in crystalline form.
  • the composition can be in the form of a tablet, capsule, or powder.
  • a particularly preferred solid form composition of the invention having enhanced solubility and/or stability properties comprises a crystalline choline salt of oxypurinol.
  • a composition of the invention is typically formulated so that it remains active at physiologic pH.
  • the composition may be formulated in the pH range 4 to 7.
  • the oxypurinol salts of the invention may be converted into pharmaceutical compositions using customary methods.
  • a crystalline oxypurinol choline salt of the invention may be mixed in with other pharmaceutically acceptable excipients.
  • the active ingredient is also mixed with a substantially inert, pharmaceutically acceptable substance (or substances) which creates a "micro-pH" around each particle of pyrazole xanthine oxidase inhibitor of not less than pH 7, in particular not less than pH 8, when water is adsorbed to the particles of the mixture or when water is added in small amounts to the mixture.
  • a substantially inert, pharmaceutically acceptable substance or substances which creates a "micro-pH" around each particle of pyrazole xanthine oxidase inhibitor of not less than pH 7, in particular not less than pH 8, when water is adsorbed to the particles of the mixture or when water is added in small amounts to the mixture.
  • Examples of pharmaceutically acceptable substances include without limitation sodium, potassium, calcium, magnesium, and aluminum salts of phosphoric acid, carbonic acid, citric acid, or other suitable weak inorganic or organic acids; substances typically used in antacid preparations such as aluminum, calcium, and magnesium hydroxides; magnesium oxide or composite substances such as, for example, MgOAl 2 O 3 or like compounds; organic pH-buffering substances such as trihydroxy-methylamino-methane or other similar, pharmaceutically acceptable pH-buffering substances.
  • the powder mixture may then be formulated into small beads, i.e., pellets or tablets, by conventional pharmaceutical procedures. The pellets, tablets, or gelatin capsules may then be used as cores for further processing.
  • the cores containing may be separated from enteric coating polymer(s) by applying a pre-coating or insulating coating.
  • the pre-coating protects the core from degradation and discoloration during the coating process and/or during storage, and also serves as a pH- buffering zone.
  • the pH-buffering properties of a pre-coating layer may be further strengthened by introducing in the layer substances chosen from a group of compounds usually used in antacid formulations discussed above.
  • the pre-coating layer typically comprises of one or more water soluble inert layers, optionally containing pH-buffering substances.
  • the enteric coating layer may be applied on to the pre-coated cores by conventional coating techniques.
  • coating techniques include pan coating or fluidized bed coating using solutions of polymers in water and/or suitable organic solvents, or using latex suspensions of the polymers.
  • Suitable enteric coating polymers include, for example, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, copolymerized methacrylic acid/methacrylic acid methyl esters (e.g., Eudragit®L12,5 or Eudragit®L100 available from Rohm Pharma of Darmstadt, Germany), or other similar compounds.
  • the enteric coating may also be applied using water- based polymer dispersions including Aquateric®. (FMC Corporation of Chicago, 111.), Eudragit®Ll 00-55 (Rohm Pharma of Darmstadt, Germany), Coating CE 5142 (BASF of Mount Olive, N.J.).
  • Pharmaceutically acceptable plasticizers may also be included in the enteric coating including cetanol, triacetin, citric acid esters such as, for example, those known under the trade name Citroflex® (Pfizer of New York, N. Y.), phthalic acid esters, dibutyl succinate or similar plasticizers.
  • the enteric coating may also include dispersants such as talc, colorants and pigments.
  • Oxypurinol was purchased from DSM (lot # C) and choline hydroxide, 50 wt. % solution in water was purchased from Aldrich (Cat. # 292257, lot # 15727BA).
  • a choline salt of oxypurinol was prepared from oxypurinol free acid and choline hydroxide as depicted in Scheme 1 :
  • a second batch was prepared using the same procedure to prepare an oxypurinol choline salt as a light orange fine crystalline solid with dark orange larger crystals after grinding. (8.65 g, 64 % yield), mp 164-166 0 C; 1 H-NMR (DMSO-d 6 ): ⁇ 3.11 (9H, s, CH 3 ), 3.42 (2H, t, CH 2 ), 3.85 (2H, br s, CH 2 ), 7.48 (IH, s, Ar), 9.25 (3H, br s, OH); MS (ESI " , CH 3 OH): m/z 150.9; MS (ESI + , CH 3 OH): m/z 103.9.
  • Equimolar amounts of oxypurinol hemihydrate and choline hydroxide concentrated aqueous solution are mixed at ambient or other suitable conditions.
  • the solution is spray dried or spray coated onto a pharmaceutically acceptable support as exemplified by, but not limited to, lactose, such that the solvent is removed by controlled means as exemplified by, but not limited to, spray drying, tray drying, or lyophilization.
  • a pharmaceutically acceptable support as exemplified by, but not limited to, lactose, such that the solvent is removed by controlled means as exemplified by, but not limited to, spray drying, tray drying, or lyophilization.
  • the resulting solid support containing the oxypurinol salt either crystalline in nature as a single or multiple polymorphs or amorphous in nature or some mixed ratio of these, may be further incorporated into pharmaceutical dosage forms according to methods practiced by those skilled in the art.
  • Table 1 summarizes the characterization data for the two batches of oxypurinol choline salt obtained from Preparation Method 1 above, and the batch of oxypurinol choline salt obtained from Preparation Method 2 above.
  • the material from the two batches obtained from Preparation Method 1 and the batch obtained from Preparation Method 2 had identical melting points of 173 ° C by DSC .
  • Analysis of X-ray powder diffraction (XRPD) and scanning electron microscopy (SEM micrograph,) showed that the material from the two batches obtained from Preparation Method 1 and the batch obtained from Preparation Method 2 was crystalline and identical (see below and Table
  • the choline crystalline salts of oxypurinol prepared had an increased solubility ( ⁇ 500 mg/mL at room temperature) compared to oxypurinol free acid ( ⁇ 0.1 mg/mL at 37°C).
  • the material from the two batches obtained from Preparation Method 1 and the batch obtained from Preparation Method 2 had identical melting points of 173° C by DSC.
  • the analysis was carried out using a TA Instruments 2910 Modulated Differential Scanning Calorimeter (DSC) (Mil #A11913).
  • the instrument was calibrated on 2004-09-28 using a heating rate of 10 °C/min and a nitrogen atmosphere of 50 cc/min, with a calibration due date of 2004-12-28.
  • the analysis was performed in nitrogen at atmospheric pressure, flowing at a rate of 50 cc/min.
  • a portion of each sample was accurately weighed and hermetically sealed into aluminum pans for the analysis.
  • the first sample was heated at 10 °C/min from ambient to approximately 300 0 C. There were indications of decomposition prior to 250 0 C. Accordingly, the second and third samples were heated to approximately 210 0 C.
  • X-Rav Powder Diffraction TXRPD X-Rav Powder
  • the samples were ground with a mortar and pestle and packed into standard sample holders.
  • the samples were rotated during data collection to reduce any undesired effects caused by the preferred orientation of crystallites.
  • Tables 2-10 summarize the data for the first batch of oxypurinol choline salt obtained from Preparation Method 1.
  • a pale orange prism crystal of C 1O H 17 N 5 O 3 from the first batch obtained from Preparation Method 1 having approximate dimensions of 0.20 x 0.12 x 0.07 mm was mounted on a glass fiber. All measurements were made on a Rigaku/ADSC diffractometer with graphite monochromated Mo-Ka radiation.
  • the data were collected at a temperature of -100.0 + 0.1 0 C to a maximum 2 ⁇ value of 55.7°. Data were collected in a series of ⁇ and ⁇ scans in 0.50° oscillations with 23.0 second exposures. The crystal-to-detector distance was 38.24 mm.
  • Neutral atom scattering factors were taken from Cromer and Waber [Cromer, D. T. & Waber, J. T.; "International Tables for X-ray Crystallography", Vol. IV, The Kynoch Press, Birmingham, England, Table 2.2 A (1974)].
  • Anomalous dispersion effects were included in Fcalc [Ibers, J. A. & Hamilton, W. C; Acta Crystallogr., 17, 781 (1964)]; the values for ⁇ f and ⁇ f ' were those of Creagh and McAuley [Creagh, D. C. & McAuley, WJ .; "International Tables for Crystallography", VoI C, (A.J.C.
  • Neutral atom scattering factors were taken from Cromer and Waber [Cromer, D. T. & Waber, J. T.; "International Tables for X-ray Crystallography", Vol. IV, The Kynoch Press, Birmingham, England, Table 2.2 A (1974)].
  • Anomalous dispersion effects were included in Fcalc [Ibers, J. A. & Hamilton, W. C; Acta Crystallogr., 17, 781 (1964)]; the values for ⁇ f and ⁇ f" were those of Creagh and McAuley [Creagh, D. C. & McAuley, WJ .; "International Tables for Crystallography", VoI C, (A.J.C.

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Abstract

L'invention concerne des sels de choline d'oxypurinol, des procédés de préparation desdits sels, des compositions pharmaceutiques contenant de tels sels ainsi que des méthodes de traitement d'affections ou de pathologies au moyen de ces sels et compositions.
PCT/US2006/002833 2005-01-28 2006-01-26 Sel cristallin d'inhibiteurs de xanthine oxydase WO2006083687A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010049525A1 (fr) * 2008-10-31 2010-05-06 C-A-I-R Biosciences Gmbh Sel de choline et de trométhamine du licofelone
WO2011022757A1 (fr) * 2009-08-24 2011-03-03 Queensland University Of Technology Diagnostic et thérapie des plaies ciblant les purines
US20120004237A1 (en) * 2006-02-22 2012-01-05 Medigene Ag Salt of cd 80 antagonist
EP3001814A4 (fr) * 2013-03-15 2017-02-15 Allen, Davidoff Formulations d'inhibiteur de xanthine oxydase
WO2021235283A1 (fr) * 2020-05-18 2021-11-25 Jsr株式会社 Composition de résine sensible aux rayonnements, procédé de formation de motif et composé de sel d'onium

Citations (4)

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Publication number Priority date Publication date Assignee Title
EP0237348A1 (fr) * 1986-03-13 1987-09-16 The Wellcome Foundation Limited Protection cellulaire
DE3839839A1 (de) * 1988-11-25 1990-05-31 Henning Berlin Gmbh Mittel zur behandlung von chronisch entzuendlichen darmerkrankungen
WO1991009600A1 (fr) * 1989-12-28 1991-07-11 Biokinet Chemisches Laboratorium Gesellschaft M.B.H. Composition de sel d'oxypurinol a administration par voie orale pour le traitement d'hyperuricemie
WO2004019903A1 (fr) * 2002-08-29 2004-03-11 Novadel Pharma Inc. Capsule ou vaporisateur buccal, polaire et non polaire, contenant des medicaments pour le traitement de troubles metaboliques

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Publication number Priority date Publication date Assignee Title
EP0237348A1 (fr) * 1986-03-13 1987-09-16 The Wellcome Foundation Limited Protection cellulaire
DE3839839A1 (de) * 1988-11-25 1990-05-31 Henning Berlin Gmbh Mittel zur behandlung von chronisch entzuendlichen darmerkrankungen
WO1991009600A1 (fr) * 1989-12-28 1991-07-11 Biokinet Chemisches Laboratorium Gesellschaft M.B.H. Composition de sel d'oxypurinol a administration par voie orale pour le traitement d'hyperuricemie
WO2004019903A1 (fr) * 2002-08-29 2004-03-11 Novadel Pharma Inc. Capsule ou vaporisateur buccal, polaire et non polaire, contenant des medicaments pour le traitement de troubles metaboliques

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Title
DUESEL, B.F. ET AL.: "Substituted xanthines. I. Preparation and properties of some choline theophyllinates", JOURNAL OF THE AMERICAN PHARMACEUTICAL ASSOCIATION, vol. 43, no. 10, 1954, pages 619 - 622, XP009067847 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120004237A1 (en) * 2006-02-22 2012-01-05 Medigene Ag Salt of cd 80 antagonist
WO2010049525A1 (fr) * 2008-10-31 2010-05-06 C-A-I-R Biosciences Gmbh Sel de choline et de trométhamine du licofelone
JP2012506899A (ja) * 2008-10-31 2012-03-22 ツェー・アー・イー・エルバイオサイエンスシーズ、ゲーエムベーハー リコフェロンのコリンおよびトロメタミン塩
US8519155B2 (en) 2008-10-31 2013-08-27 C-A-I-R Biosciences Gmbh Choline and tromethamine salt of licofelone
WO2011022757A1 (fr) * 2009-08-24 2011-03-03 Queensland University Of Technology Diagnostic et thérapie des plaies ciblant les purines
EP3001814A4 (fr) * 2013-03-15 2017-02-15 Allen, Davidoff Formulations d'inhibiteur de xanthine oxydase
US11406713B2 (en) 2013-03-15 2022-08-09 Xortx Therapeutics, Inc. Xanthine oxidase inhibitor formulations
WO2021235283A1 (fr) * 2020-05-18 2021-11-25 Jsr株式会社 Composition de résine sensible aux rayonnements, procédé de formation de motif et composé de sel d'onium

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