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WO2025043108A1 - Co-cristaux de composés donneurs de nitroxyle - Google Patents

Co-cristaux de composés donneurs de nitroxyle Download PDF

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Publication number
WO2025043108A1
WO2025043108A1 PCT/US2024/043471 US2024043471W WO2025043108A1 WO 2025043108 A1 WO2025043108 A1 WO 2025043108A1 US 2024043471 W US2024043471 W US 2024043471W WO 2025043108 A1 WO2025043108 A1 WO 2025043108A1
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WIPO (PCT)
Prior art keywords
crystal
compound
pharmaceutical composition
proline
former
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Inventor
Scott A. Savage
Bhupinder Kaur SANDHU
Hyunsoo Park
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Publication of WO2025043108A1 publication Critical patent/WO2025043108A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/64—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom

Definitions

  • Nitroxyl has been shown to have positive cardiovascular effects in in vitro and in vivo models of failing hearts. However, at physiological pH, nitroxyl dimerizes to hyponitrous acid, which subsequently dehydrates to nitrous oxide. Due to this metastability, nitroxyl for therapeutic use must be generated in situ from donor compounds. A variety of compounds capable of donating nitroxyl have been described and proposed for use in treating disorders known or suspected to be responsive to nitroxyl. See, e.g., U.S.
  • U.S. Patent 8,987,326 describes nitroxyl donating compounds that are highly efficacious in treating cardiovascular diseases (e.g., heart failure) and have suitable toxicological profiles.
  • N-hydroxy-5-methylfuran-2-sulfonamide has been evaluated in preclinical models and in Phase I/IIa studies. In these studies, N-hydroxy-5-methylfuran-2-sulfonamide demonstrated peripheral vasodilation and increased inotropy and improved lusitropy. Cowart D. et al., J Am Coll Cardiol 201565 A876; and European Heart Failure 2016 Congress in Florence, Italy, May 21–24, 2016. Formulating nitroxyl donating compounds has proven to be a considerable challenge. Many of the current nitroxyl donating compounds are insoluble in aqueous solutions and/or are insufficiently stable in solution and as crystalline solids.
  • Nitroxyl donating compounds can be a challenge to formulate as a stable crystalline product.
  • Appropriate stability is a critical attribute of any pharmaceutical, with the identification of stable storage conditions being required to ensure that it can be successfully delivered to patients with appropriate quality. Solubility and stability problems often preclude the use of such compounds in pharmaceutical compositions for parenteral and/or oral administration. Accordingly, there is a need to develop new solid forms of nitroxyl donating compounds that are sufficiently stable in solution and in the solid state.
  • U.S. Patent 10,245,249 describes enhancing stability and/or solubility of nitroxyl donating compounds with a cyclodextrin.
  • Nitroxyl donating compounds gradually release nitroxyl and at least one byproduct in the pharmaceutical composition, which can compromise the efficacy and safety of the composition.
  • the presence of cyclodextrin can mitigate or eliminate the release of nitroxyl and byproducts in the pharmaceutical composition during storage, prior to administration to a patient.
  • Pharmaceutical co-crystals have emerged over the past two decades as a new solid form.
  • a pharmaceutical co-crystal is a crystalline solid composed of at least two co-formers, in which one of the co-formers is an active pharmaceutical ingredient (API) and the other is a pharmaceutically acceptable compound found in the generally regarded as safe (GRAS) list.
  • API active pharmaceutical ingredient
  • GRAS pharmaceutically acceptable compound found in the generally regarded as safe
  • Co-crystals have the advantage of forming stable crystalline form as compared to amorphous solids. There is no need to make or break covalent bonds and there is theoretical capability of all types of API molecules (weakly ionizable/non-ionizable) to form co-crystals.
  • co-crystals can be used for those drugs that are non-ionizable or weakly ionizable in nature.
  • co-formers food additives, preservatives, pharmaceutical excipients, and other APIs that can form co-crystals with the API via weak interactions. Yadav, A. V. et al., Indian Journal of Pharmaceutical Sciences 2009, 71 (4), 359-370.
  • co-crystals offer the unique advantages of potentially retaining the pharmacological properties of the API and simultaneously benefiting from the physicochemical properties of the co- former.
  • the present disclosure relates to the discovery of co-crystals of nitroxyl donating compounds, such as N-hydroxylsulfonamide compounds, that are highly stable as compared to their free form(s) and to formulations with a cyclodextrin.
  • the co-crystals described herein are IV compatible (both physically and biologically).
  • the co-crystals described herein also provide manufacturing advantages relative to their free form(s).
  • the co-crystal approach when used in manufacturing, avoids the step of isolating the neat form of the nitroxyl donating compound, which is thermally unstable.
  • a co-crystal of the disclosure comprises a compound of the formula (1): and a co-crystal former selected group alanine, and proline.
  • the present disclosure provides a pharmaceutical composition comprising a co-crystal described above; and at least one pharmaceutically acceptable excipient.
  • the present disclosure provides a method of making a co-crystal of a nitroxyl donating compound and a co-crystal former.
  • the method comprises: (a) contacting a solution comprising the nitroxyl donating compound with a co-crystal former under crystallization conditions so as to form the co-crystal in solid phase; and optionally (b) isolating the co- crystal formed in step (a).
  • the co-crystals and compositions of the disclosure can be used in treating a variety of conditions that are responsive to nitroxyl therapy.
  • the co-crystals or compositions of the disclosure can be used to treat or prevent the occurrence of cardiovascular diseases.
  • the co-crystals or compositions of the disclosure can be used to treat cardiovascular disease, ischemia/reperfusion injury, pulmonary hypertension or another condition responsive to nitroxyl therapy.
  • the co-crystals or compositions of the disclosure can be used to treat heart failure.
  • the co-crystals or compositions of the disclosure can be used to treat decompensated heart failure (e.g., acute decompensated heart failure).
  • the co-crystals or compositions of the disclosure can be used to treat systolic heart failure.
  • the co-crystals or compositions of the disclosure can be used to treat diastolic heart failure.
  • FIG.2 shows the crystal structure of Co-Crystal 11 (a co-crystal of Compound 1 and glycine).
  • FIG.3 shows the crystal structure of Co-Crystal 12 Form B (a co-crystal of Compound 1 and proline).
  • FIG.4 shows the crystal structure of Co-Crystal 12 Form C (a co-crystal of Compound 1 and proline).
  • FIG.5 shows the crystal structure of Co-Crystal 13 (a co-crystal of Compound 2 and proline).
  • FIG.6 shows the crystal structure of Co-Crystal 14 (a co-crystal of Compound 3 and proline).
  • FIG.7 shows the crystal structure of Co-Crystal 15 (a co-crystal of Compound 4 and proline).
  • FIG.8 shows the crystal structure of Co-Crystal 16 (a co-crystal of Compound 5 and proline).
  • FIG.9 shows the crystal structure of Co-Crystal 17 (a co-crystal of Compound 6 and proline).
  • FIG.10 shows the crystal structure of Co-Crystal 18 (a co-crystal of Compound 7 and proline).
  • FIG.11 shows the crystal structure of Co-Crystal 19 (a co-crystal of Compound 8 and proline).
  • FIG.12 shows PXRD data for Compound 1 (Form A).
  • FIG.13 shows PXRD data for Co-Crystal 12 Form B/C.
  • FIG.14 shows the experimental PXRD patterns for Compound 1 (Form A), L-proline and Co-Crystal 12 Form B/C, together with simulated patters for Co-Crystal 12 Forms B and C.
  • FIG.15 shows DSC data for Compound 1 (Form A).
  • FIG.16 shows DSC data for Co-Crystal 12 Form B/C.
  • FIG.17 shows TGA data for Compound 1 (Form A).
  • FIG.18 shows TGA data for Co-Crystal 12 Form B/C.
  • FIG.19 shows Moisture-Sorption Isotherms for Form B/C.
  • FIG.20 shows PXRD data for Compound 2.
  • FIG.21 shows PXRD data for Co-Crystal 13 (a co-crystal of Compound 2 and proline).
  • FIG.22 shows PXRD data for Compound 3.
  • FIG.23 shows PXRD data for Co-Crystal 14 (a co-crystal of Compound 3 and proline).
  • FIG.24 shows PXRD data for Compound 4.
  • FIG.25 shows PXRD data for Co-Crystal 15 (a co-crystal of Compound 4 and proline).
  • FIG.26 shows PXRD data for Compound 6.
  • FIG.27 shows PXRD data for Co-Crystal 17 (a co-crystal of Compound 6 and proline).
  • FIG.28 shows PXRD data for Compound 7.
  • FIG.29 shows PXRD data for Co-Crystal 18 (a co-crystal of Compound 7 and proline).
  • FIG.30 shows PXRD data for Compound 8.
  • FIG.31 shows PXRD data for Co-Crystal 19 (a co-crystal of Compound 8 and proline).
  • FIG.32 shows a melting point analysis or decomposition temperature of neat form API (left), L- proline (right) and the corresponding co-crystal (middle). 4.
  • the invention includes the following: (1.) A co-crystal comprising a nitroxyl donating compound and a co-crystal former, wherein the co-crystal former is selected from the group consisting of glycine, alanine and proline. (2.) The co-crystal of the above (1.), wherein the nitroxyl donating compound is an N- hydroxysulfonamide compound.
  • a method of treating a cardiovascular disease responsive to nitroxyl therapy comprising administering an effective amount of a co-crystal of any one of the above (1.) to (11.) or the pharmaceutical composition of any one of the above (12.) to (15.) to a patient in need thereof.
  • the method of the above (23.), wherein the cardiovascular disease is heart failure.
  • the method of the above (23.) or the above (24.), wherein the cardiovascular disease is acute decompensated heart failure.
  • a kit comprising a co-crystal of any one of the above (1.) to (11.) in dry form or the pharmaceutical composition of any one of the above (12.) to (15.) in dry form; and a pharmaceutically acceptable liquid diluent.
  • a co-crystal of any one of the above (1.) to (11.) in dry form or the pharmaceutical composition of any one of the above (12.) to (15.) in dry form; and a pharmaceutically acceptable liquid diluent Use of the co-crystal of any one of the above (1.) to (11.) or use of the pharmaceutical composition of any one of the above (12.) to (15.) for the manufacture of a medicament useful for treating a cardiovascular disease.
  • beneficial or desired results include but are not limited to inhibiting and/or suppressing the onset and/or development of a condition or reducing the severity of such condition, such as reducing the number and/or severity of symptoms associated with the condition, increasing the quality of life of those suffering from the condition, decreasing the dose of other medications required to treat the condition, enhancing the effect of another medication a patient is taking for the condition, and/or prolonging survival of patients having the condition.
  • Prevent”, “preventing” and the like refers to reducing the probability of developing a condition in a patient who does not have but is at risk of developing a condition.
  • a patient “at risk” may or may not have a detectable condition and may or may not have displayed a detectable condition prior to the treatment methods disclosed herein.
  • N-hydroxysulfonamides have a pH dependent first-order decomposition to form HNO.
  • An example of an N-hydroxysulfonamide nitroxyl donating compound is a compound of the formula (1): H 3 C SO 2 NHOH
  • Compound 1 decomposes to O O O - S OH pKa ⁇ 8.5 S O + S OH the compound will be both in solution and as an isolated solid.
  • Compound 1 which has a pKa of ⁇ 8.5, is relatively unstable in solution ( ⁇ 60 min half-life) and as a crystalline solid. Because HNO is so reactive, there is a secondary degradation in the solid state that results in a non-linear and catastrophic decomposition of the API at standard temperature storage conditions.
  • the co-former is a compound selected from the group consisting of glycine, alanine, and proline.
  • a co-crystal of the disclosure comprises a compound listed in Table 1 and the co-crystal former is glycine.
  • a co-crystal of the disclosure comprises a compound listed in Table 1 and the co-crystal former is alanine.
  • a co-crystal of the disclosure comprises a compound listed in Table 1 and the co-crystal former is proline.
  • the co-crystal comprises Compound 1 and proline and is characterized by an X-ray powder pattern having peaks at two or more of 9.72, 11.7, and 12.9 (2-theta degrees) ⁇ 0.2.
  • the co-crystal comprises Compound 1 and proline and is characterized by a DSC plot substantially similar to that in FIG.16.
  • the co-crystal comprises Compound 1 and proline and is characterized by a TGA plot substantially similar to that in FIG.18.
  • a co-crystal of the disclosure comprises Compound 2 and the co- crystal former is proline.
  • a co-crystal of the disclosure comprises Compound 3 and the co-crystal former is proline.
  • a co-crystal of the disclosure comprises Compound 4 and the co-crystal former is proline.
  • a co- crystal of the disclosure comprises Compound 5 and the co-crystal former is proline.
  • a co-crystal of the disclosure comprises Compound 6 and the co-crystal former is proline.
  • a co-crystal of the disclosure comprises Compound 7 and the co- crystal former is proline.
  • a co-crystal of the disclosure comprises Compound 8 and the co-crystal former is proline.
  • the present disclosure provides a method of making a co-crystal of a N-hydroxylsulfonamide compound and a co-former.
  • the method comprises: (a) contacting a solution comprising the N-hydroxylsulfonamide compound with a co-former under crystallization conditions so as to form the co-crystal in solid phase; and optionally (b) isolating the co- crystal formed in step (a).
  • the N-hydroxylsulfonamide compound and co-former used in the methods of making co-crystals can be any disclosed herein.
  • step (a) comprises substep (i) adding a suitable amount of the N- hydroxylsulfonamide compound to a suitable solvent system to obtain a solution of N- hydroxylsulfonamide.
  • the suitable solvent system comprises a solvent selected from the group consisting of methyl isobutyl ketone (MIBK), ethyl acetate, toluene, tetrahydrofuran, acetonitrile, methanol, isopropyl alcohol, cyclopentyl methyl ether (CPME), water, and mixtures thereof.
  • substep (i) is performed at room temperature.
  • compositions can be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, as drenches (for example, aqueous or non-aqueous solutions or suspensions), tablets (for example, those targeted for buccal, sublingual and systemic absorption), caplets, boluses, powders, granules, pastes for application to the tongue, hard gelatin capsules, soft gelatin capsules, mouth sprays, troches, lozenges, pellets, syrups, suspensions, elixirs, liquids, emulsions and microemulsions; or (2) parenteral administration by, for example, subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension.
  • oral administration for example, as drenches (for example, aqueous or non-aqueous solutions or suspensions), tablets (for example, those targeted for buccal, sublingual and systemic absorption), caplets, boluses, powders, gran
  • co-crystals and pharmaceutical compositions disclosed herein can be prepared as any appropriate unit dosage form, such as capsules, sachets, tablets, powder, granules, solution, suspension in an aqueous liquid, suspension in a non-aqueous liquid, oil-in-water liquid emulsion, water-in-oil liquid emulsion, liposomes, or bolus. Tablets can be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the therapeutic agent or agents in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets can be optionally coated or scored and can be formulated so as to provide slow or controlled release of the active ingredient therein. Methods of formulating such slow or controlled release compositions of pharmaceutically active ingredients, such as the therapeutic agents herein and other compounds known in the art, are known in the art and disclosed in issued U.S.
  • compositions suitable for topical administration include, without limitation, lozenges comprising the ingredients in a flavored basis, such as sucrose, acacia and tragacanth; and pastilles comprising the active ingredient in a flavored basis or in an inert basis, such as gelatin and glycerin.
  • compositions administered parenterally can be administered in an acidic, neutral, or basic solution.
  • pharmaceutical compositions of the disclosure can be formulated in an acidic solution having a pH of from about 4 to about 5, for instance, a pH of about 4, about 4.5, about 4.8, or about 5, including values there between.
  • pharmaceutical compositions of the disclosure can be formulated for parenteral use at a pH of from about 5 to about 6.2 (e.g., pH of about 5, about 5.5, about 5.8, about 6, or about 6,2, including values there between).
  • cardiovascular diseases and symptoms that can usefully be treated with the co- crystals and compositions disclosed herein include cardiovascular diseases that are responsive to nitroxyl therapy, coronary obstructions, coronary artery disease (CAD), angina, heart attack, myocardial infarction, high blood pressure, ischemic cardiomyopathy and infarction, pulmonary congestion, pulmonary edema, cardiac fibrosis, valvular heart disease, pericardial disease, circulatory congestive states, peripheral edema, ascites, Chagas’ disease, ventricular hypertrophy, heart valve disease, heart failure, diastolic heart failure, systolic heart failure, congestive heart failure, acute congestive heart failure, acute decompensated heart failure, and cardiac hypertrophy.
  • CAD coronary artery disease
  • the co-crystals and pharmaceutical compositions of the disclosure can be used to treat patients suffering from heart failure.
  • the heart failure can be of any type or form, including any of the heart failures disclosed herein.
  • Nonlimiting examples of heart failure include early-stage heart failure, Class I, II, III and IV heart failure, acute heart failure, congestive heart failure (CHF) and acute congestive heart failure.
  • the co-crystals and compositions of the disclosure can be used to treat acute decompensated heart failure.
  • another active agent that treats heart failure can also be administered.
  • the co-crystal or pharmaceutical composition can be administered in conjunction with a positive inotrope such as a beta-agonist.
  • beta-agonists include, without limitation, dopamine, dobutamine, isoproterenol, analogs of such compounds and derivatives of such compounds.
  • the co-crystal or pharmaceutical composition can be administered in conjunction with a beta-adrenergic receptor antagonist (also referred to herein as beta-antagonist or beta-blocker).
  • beta-antagonists include, without limitation, propranolol, metoprolol, bisoprolol, bucindolol, and carvedilol.
  • the disclosure provides a method of treating, preventing or delaying the onset and/or development of ischemia/reperfusion injury, comprising administering an effective amount of a co-crystal or a pharmaceutical composition as disclosed herein to a subject in need thereof.
  • the method is for preventing ischemia/reperfusion injury.
  • a co-crystal or a pharmaceutical composition of the disclosure is administered prior to the onset of ischemia.
  • a co-crystal or a pharmaceutical composition of the disclosure is administered prior to procedures in which myocardial ischemia can occur, for example an angioplasty or surgery, such as a coronary artery bypass graft surgery.
  • a co-crystal or a pharmaceutical composition of the disclosure is administered after ischemia but before reperfusion.
  • a co-crystal or a pharmaceutical composition of the disclosure is administered after ischemia and reperfusion.
  • a co-crystal or a pharmaceutical composition of the disclosure can be administered to a patient who is at risk for an ischemic event.
  • a co-crystal or a pharmaceutical composition of the disclosure is administered to a patient at risk for a future ischemic event, but who has no present evidence of ischemia.
  • the determination of whether a patient is at risk for an ischemic event can be performed by any method known in the art, such as by examining the patient or the patient’s medical history.
  • the patient has had a prior ischemic event.
  • the patient can be at risk of a first or subsequent ischemic event.
  • Examples of patients at risk for an ischemic event include patients with known hypercholesterolemia, EKG changes associated with ischemia (e.g., peaked or inverted T-waves or ST segment elevations or depression in an appropriate clinical context), abnormal EKG not associated with active ischemia, elevated CKMB, clinical evidence of ischemia (e.g., crushing sub-sternal chest pain or arm pain, shortness of breath and/or diaphoresis), prior history of myocardial infarction, elevated serum cholesterol, sedentary lifestyle, angiographic evidence of partial coronary artery obstruction, echocardiographic evidence of myocardial damage, or any other evidence of a risk for a future ischemic event.
  • EKG changes associated with ischemia e.g., peaked or inverted T-waves or ST segment elevations or depression in an appropriate clinical context
  • abnormal EKG not associated with active ischemia e.g., elevated CKMB
  • clinical evidence of ischemia e.g., crushing sub-sternal chest pain or arm
  • ischemic events include, without limitation, myocardial infarction (MI) and neurovascular ischemia, such as a cerebrovascular accident (CVA).
  • the subject of treatment is an organ that is to be transplanted.
  • a co-crystal or a pharmaceutical composition of the disclosure can be administered prior to reperfusion of the organ in a transplant recipient.
  • a co-crystal or a pharmaceutical composition of the disclosure can be administered prior to removal of the organ from the donor, for example through the perfusion cannulas used in the organ removal process.
  • the organ donor is a live donor, for example a kidney donor, the co-crystals or pharmaceutical compositions of the disclosure can be administered to the organ donor.
  • the co-crystals or pharmaceutical compositions of the disclosure are administered by storing the organ in a solution comprising the co-crystal or pharmaceutical composition.
  • a co-crystal or pharmaceutical composition of the disclosure can be included in the organ preservation solution, such as the University of Wisconsin “UW” solution, which is a solution comprising hydroxyethyl starch substantially free of ethylene glycol, ethylene chlorohydrin and acetone (see U.S. Pat. No.4,798,824).
  • a co-crystal or a pharmaceutical composition of the disclosure that is administered is such that ischemia/reperfusion injury to the tissues of the organ is reduced upon reperfusion in the recipient of transplanted organ.
  • the method reduces tissue necrosis (the size of infarct) in at-risk tissues.
  • Ischemia/reperfusion injury can damage tissues other than those of the myocardium and the disclosed subject matter embraces methods of treating or preventing such damage.
  • the ischemia/reperfusion injury is non-myocardial.
  • the method reduces injury from ischemia/reperfusion in the tissue of the brain, liver, gut, kidney, bowel, or any part of the body other than the myocardium.
  • the patient is at risk for such injury. Selecting a person at risk for non-myocardial ischemia could include a determination of the indicators used to assess risk for myocardial ischemia.
  • risk factors for stroke could demonstrate a patient’s risk for ischemia of brain tissue: hypertension, cigarette smoking, carotid artery stenosis, physical inactivity, diabetes mellitus, hyperlipidemia, transient ischemic attack, atrial fibrillation, coronary artery disease, congestive heart failure, past myocardial infarction, left ventricular dysfunction with mural thrombus, and mitral stenosis.
  • risk factors for stroke could demonstrate a patient’s risk for ischemia of brain tissue: hypertension, cigarette smoking, carotid artery stenosis, physical inactivity, diabetes mellitus, hyperlipidemia, transient ischemic attack, atrial fibrillation, coronary artery disease, congestive heart failure, past myocardial infarction, left ventricular dysfunction with mural thrombus, and mitral stenosis.
  • risk factors for stroke could demonstrate a patient’s risk for ischemia of brain tissue: hypertension, cigarette smoking, carotid artery steno
  • complications of untreated infectious diarrhea in the elderly can include myocardial, renal, cerebrovascular and intestinal ischemia. Slotwiner-Nie et al., Gastroenterol. Clin. N. Amer.30(3):625-635 (2001).
  • patients could be selected based on risk factors for ischemic bowel, kidney and/or liver disease. For example, treatment would be initiated in elderly patients at risk of hypotensive episodes (such as surgical blood loss). Thus, patients presenting with such an indication would be considered at risk for an ischemic event.
  • the patient has any one or more of the conditions listed herein, such as diabetes mellitus and hypertension.
  • a co-crystal or pharmaceutical composition of the disclosure can be used to prevent or delay the onset and/or development of pulmonary hypertension.
  • a co-crystal or a pharmaceutical composition of the disclosure can be used to prevent or delay the onset and/or development of pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • the disclosure provides a method of reducing mean pulmonary arterial pressure (MPAP), comprising administering an effective amount of a co-crystal or a pharmaceutical composition disclosed herein to a patient in need thereof.
  • the MPAP is reduced by up to about 50%.
  • the MPAP is reduced by up to about 25%. In another embodiment, the MPAP is reduced by up to about 20%. In another embodiment, the MPAP is reduced by up to about 15%. In another embodiment, the MPAP is reduced by up to 10%. In another embodiment, the MPAP is reduced by up to about 5%. In another embodiment, the MPAP is reduced to be from about 12 mmHg to about 16 mmHg. In another embodiment, the MPAP is reduced to be about 15 mmHg. 4.6 Administration Modes, Regimens, and Dose Levels
  • the co-crystals and pharmaceutical compositions of the disclosure can be administered via parenteral (e.g., subcutaneous, intramuscular, intravenous or intradermal) administration.
  • the co-crystal or pharmaceutical composition is administered by intravenous infusion.
  • the co-crystals and pharmaceutical compositions of the disclosure can be administered by oral administration.
  • dosages are expressed based on the amount of active pharmaceutical ingredient, i.e., the amount of co-crystal of the disclosure present in the pharmaceutical composition.
  • the dose can usefully be expressed per unit time, either as a fixed amount per unit time or as a weight-based amount per unit time.
  • a co-crystal or pharmaceutical composition of the disclosure is administered intravenously in an amount of at least about 0.1 ⁇ g/kg/min, at least about 0.2 ⁇ g/kg/min, at least about 0.3 ⁇ g/kg/min, at least about 0.4 ⁇ g/kg/min, at least about 0.5 ⁇ g/kg/min, at least about 1 ⁇ g/kg/min, at least about 2.5 ⁇ g/kg/min, at least about 5 ⁇ g/kg/min, at least about 7.5 ⁇ g/kg/min, at least about 10 ⁇ g/kg/min, at least about 11 ⁇ g/kg/min, at least about 12 ⁇ g/kg/min, at least about 13 ⁇ g/kg/min, at least about 14 ⁇ g/kg/min, at least about 15 ⁇ g/kg/min, at least about 16 ⁇ g/kg/min, at least about 17 ⁇ g/kg/min, at least about 18 ⁇ g/kg/min, at least about 19 ⁇
  • the co-crystal or pharmaceutical composition of the disclosure is administered intravenously in an amount of no more than about 100 ⁇ g/kg/min, no more than about 90 ⁇ g/kg/min, no more than about 80 ⁇ g/kg/min, no more than about 70 ⁇ g/kg/min, no more than about 60 ⁇ g/kg/min, no more than about 50 ⁇ g/kg/min, no more than about 49 ⁇ g/kg/min, no more than about 48 ⁇ g/kg/min, no more than about 47 ⁇ g/kg/min, no more than about 46 ⁇ g/kg/min, no more than about 45 ⁇ g/kg/min, no more than about 44 ⁇ g/kg/min, no more than about 43 ⁇ g/kg/min, no more than about 42 ⁇ g/kg/min, no more than about 41 ⁇ g/kg/min, no more than about 40 ⁇ g/kg/min, no more than about 39 ⁇ g/kg/min, no more than about 38 ⁇ g
  • the co-crystal or pharmaceutical composition of the disclosure is administered intravenously in an amount ranging from about 10 ⁇ g/kg/min to about 50 ⁇ g/kg/min, about 20 ⁇ g/kg/min to about 40 ⁇ g/kg/min, about 25 ⁇ g/kg/min to about 35 ⁇ g/kg/min, or about 30 ⁇ g/kg/min to about 40 ⁇ g/kg/min.
  • the co-crystal or pharmaceutical composition of the disclosure is administered intravenously in an amount of from about 20 ⁇ g/kg/min to about 30 ⁇ g/kg/min.
  • the co- crystals or pharmaceutical compositions of the disclosure are administered according to a weight-based daily dosing regimen, either as a single daily dose (QD) or in multiple divided doses administered, e.g., twice a day (BID), three times a day (TID), or four times a day (QID).
  • QD single daily dose
  • BID twice a day
  • TID three times a day
  • QID four times a day
  • the co-crystal or pharmaceutical composition of the disclosure is administered in a dose of at least about 0.5 mg/kg/d, at least about 0.75 mg/kg/d, at least about 1.0 mg/kg/d, at least about 1.5 mg/kg/d, at least about 2 mg/kg/d, at least about 2.5 mg/kg/d, at least about 3 mg/kg/d, at least about 4 mg/kg/d, at least about 5 mg/kg/d, at least about 7.5 mg/kg/d, at least about 10 mg/kg/d, at least about 12.5 mg/kg/d, at least about 15 mg/kg/d, at least about 17.5 mg/kg/d, at least about 20 mg/kg/d, at least about 25 mg/kg/d, at least about 30 mg/kg/d, at least about 35 mg/kg/d, at least about 40 mg/kg/d, at least about 45 mg/kg/d, at least about 50 mg/kg/d, at least about 60 mg/kg/d, at least about 70 mg
  • the co-crystal or pharmaceutical composition of the disclosure is administered at a dose of no more than about 100 mg/kg/d, no more than about 100 mg/kg/d, no more than about 90 mg/kg/d, no more than about 80 mg/kg/d, no more than about 80 mg/kg/d, no more than about 75 mg/kg/d, no more than about 70 mg/kg/d, no more than about 60 mg/kg/d, no more than about 50 mg/kg/d, no more than about 45 mg/kg/d, no more than about 40 mg/kg/d, no more than about 35 mg/kg/d, no more than about 30 mg/kg/d.
  • the dose is from about 0.001 mg/kg/d to about 10,000 mg/kg/d. In certain embodiments, the dose is from about 0.01 mg/kg/d to about 1,000 mg/kg/d. In certain embodiments, the dose is from about 0.01 mg/kg/d to about 100 mg/kg/d. In certain embodiments, the dose is from about 0.01 mg/kg/d to about 10 mg/kg/d. In certain embodiments, the dose is from about 0.1 mg/kg/d to about 1 mg/kg/d. In certain embodiments, the dose is less than about 1 g/kg/d.
  • the co-crystal or pharmaceutical composition of the disclosure is administered in a dose range in which the low end of the range is any amount from about 0.1 mg/kg/day to about 90 mg/kg/day and the high end of the range is any amount from about 1 mg/kg/day to about 100 mg/kg/day (e.g., from about 0.5 mg/kg/day to about 2 mg/kg/day in one series of embodiments and from about 5 mg/kg/day to about 20 mg/kg/day in another series of embodiment).
  • the co-crystal or pharmaceutical composition of the disclosure is administered in a dose range of about 3 to about 30 mg/kg, administered from once a day (QD) to three times a day (TID).
  • the co-crystal or pharmaceutical composition of the disclosure is administered according to a flat (i.e., non-weight-based) dosing regimen, either as a single daily dose (QD) or in multiple divided doses administered, e.g., twice a day (BID), three times a day (TID), or four times a day (QID).
  • a flat dosing regimen either as a single daily dose (QD) or in multiple divided doses administered, e.g., twice a day (BID), three times a day (TID), or four times a day (QID).
  • the co-crystal or pharmaceutical composition of the disclosure is administered at a dose of at least about 0.01 grams/day (g/d), at least about 0.05 g/d, at least about 0.1 g/d, at least about 0.5 g/d, at least about 1 g/d, at least about 1.5 g/d, at least about 2.0 g/d, at least about 2.5 g/d, at least about 3.0 g/d, or at least about 3.5 g/d.
  • the co-crystal or pharmaceutical composition of the disclosure is administered at a dose of no more than about 5 g/d, no more than about 4.5 g/d, no more than about 4 g/d, no more than about 3.5 g/d, no more than about 3 g/d, no more than about 2.5 g/d, or no more than about 2 g/d.
  • the co-crystal or pharmaceutical composition of the disclosure is administered in a dose of about 0.01 grams per day to about 4.0 grams per day.
  • the co-crystal or pharmaceutical composition of the disclosure can be administered at a dose in which the low end of the range is any amount from about 0.1 mg/day to about 400 mg/day and the high end of the range is any amount from about 1 mg/day to about 4000 mg/day.
  • the co-crystal or pharmaceutical composition is administered in a dose of about 5 mg/day to about 100 mg/day.
  • the co-crystal or pharmaceutical composition is administered at a dose of from about 150 mg/day to about 500 mg/day.
  • the dosing interval for parenteral or oral administration can be adjusted according to the needs of the patient. For longer intervals between administrations, extended release or depot formulations can be used.
  • a co-crystal or pharmaceutical composition as disclosed herein can be administered prior to, at substantially the same time with, or after administration of an additional therapeutic agent.
  • the administration regimen can include pretreatment and/or co-administration with the additional therapeutic agent.
  • the compound or pharmaceutical composition and the additional therapeutic agent can be administered simultaneously, separately, or sequentially.
  • Examples of administration regimens include without limitation: administration of each co- crystal, pharmaceutical composition or therapeutic agent in a sequential manner; and co-administration of each co-crystal, pharmaceutical composition or therapeutic agent in a substantially simultaneous manner (e.g., as in a single unit dosage form) or in multiple, separate unit dosage forms for each compound, pharmaceutical composition or therapeutic agent.
  • dose level will depend on various factors such as the particular administration mode, administration regimen, compound, and pharmaceutical composition selected, as well as the particular condition and patient being treated.
  • dose level can vary depending upon the activity, rate of excretion and potential for toxicity of the specific compound or pharmaceutical composition employed; the age, body weight, general health, gender and diet of the patient being treated; the frequency of administration; the other therapeutic agent(s) being co-administered; and the type and severity of the condition.
  • the kit comprises a co-crystal or a pharmaceutical composition disclosed herein, each in dry form, and a pharmaceutically acceptable liquid diluent.
  • a co-crystal in dry form or a pharmaceutical composition in dry form contains about 2.0% or less water by weight, about 1.5% or less water by weight, about 1.0% or less water by weight, about 0.5% or less water by weight, about 0.3% or less water by weight, about 0.2% or less water by weight, about 0.1% or less water by weight, about 0.05% or less water by weight, about 0.03% or less water by weight, or about 0.01% or less water by weight.
  • liquid diluents include but are not limited to sterile water, saline solutions, aqueous dextrose, glycerol, glycerol solutions, and the like. Other examples of suitable liquid diluents are disclosed by Nairn, "Solutions, Emulsions, Suspensions and Extracts," pp.721-752 in Remington: The Science and Practice of Pharmacy, 20th Ed. (Lippincott Williams & Wilkins, Baltimore, MD, 2000).
  • the kit further comprises instructions for using the co-crystal or pharmaceutical composition.
  • the instructions can be in any appropriate form, such as written or electronic form. In another embodiment, the instructions can be written instructions.
  • the instructions are contained in an electronic storage medium (e.g., magnetic diskette or optical disk).
  • the instructions include information as to the compound or pharmaceutical composition and the manner of administering the compound or pharmaceutical composition to a patient.
  • the instructions relate to a method of use disclosed herein (e.g., treating, preventing and/or delaying onset and/or development of a condition selected from cardiovascular diseases, ischemia/reperfusion injury, pulmonary hypertension and other conditions responsive to nitroxyl therapy).
  • the kit further comprises suitable packaging. Where the kit comprises more than one co-crystal or pharmaceutical composition, the co-crystals or pharmaceutical compositions can be packaged patiently in separate containers or combined in one container when cross-reactivity and shelf-life permit. 5.
  • Example 1.1 - Co-Crystals of Compound 1 with Carboxylic Acid Co-Formers Carboxylic acids are common co-formers and traditionally used in biologics as buffers. Following the general procedure described in Example 1, unsuccessful attempts were made to crystallize Compound 1 with a variety of carboxylic acid co-formers and solvents.
  • the unsuccessful co-formers include benzoic acid, citric acid, fumaric acid, L-maleic acid, succinic acid, L-tartaric acid, maleic acid, salicylic acid, L-arginine, L-valine, L-isoleucine, L-leucine hydrochloride, L-serine, L- threonine, monosodium succinate, EDTA, EDTA di-sodium salt, glutamic acid, glutamine, asparagine, valine, gluconic acid sodium salt, malic acid sodium salt, malic acid sodium salt, sodium citrate, sodium succinate, and sodium tartrate.
  • Example 1.2 Co-Crystal 10 (Co-Crystal of Compound 1 and Alanine) To a round bottom flask was charged L-alanine (14g, 157 mmol) and water (60 mL). While stirring, the mixture was heated to 60°C to dissolve the majority of L-alanine. The thin slurry was cooled to 40°C and Compound 1 (13g, 73 mmol) was added.
  • MIBK methyl isobutyl ketone
  • ethyl acetate toluene
  • CPME cyclopentyl methyl ether
  • Example 1.4 - Co-Crystal 12 (Co-Crystal of Compound 1 and Proline) Form B: To a round bottom flask was charged Compound 1 (12g, 68 mmol) and water (100 mL). The mixture was stirred until a clear solution persisted. In a separate flask, L-proline (10g, 87 mmol) was mixed with water (30 mL) and heated until clear. The aqueous L-proline solution was then added in small portions to the aqueous Compound 1 solution over 1 hour while stirring.
  • Form C A second polymorph of Compound 1-Pro was obtained by dissolving Compound 1 (12g, 68 mmol) in aqueous medium, water (100 mL) or water/alcohol mixture. The mixture was stirred until a clear solution persisted.
  • L-proline (10g, 87 mmol) was mixed with water (30 mL) and heated until clear. The aqueous L-proline solution was then added in small portions to the aqueous Compound 1 solution over 1 hour while stirring. The solution was slowly evaporated at ⁇ 40°C. During the reaction, excess proline (4 eq) was used to drive equilibrium towards co-crystal formation and provide increased yield.
  • Example 1.6 - Co-Crystal 14 (Co-Crystal of Compound 3 and Proline) 1g of L-proline was dissolved in 5 mL of methanol.0.5 eq ( ⁇ 1g) of Compound 3 was dissolved separately in 5 mL of methanol. The two streams were combined, first passing through syringe filters to remove any solids. The vial was loosely capped to allow for slow evaporation of the mother liquor. The resulting Co-Crystal 14 was confirmed by SCXRD.
  • Example 1.7 - Co-Crystal 15 (Co-Crystal of Compound 4 and Proline) 1g of L-proline was dissolved in 5 mL of methanol.0.5 eq ( ⁇ 1g) of Compound 4 was dissolved separately in 5 mL of methanol. The two streams were combined, first passing through syringe filter to remove any solids. The vial was loosely capped to allow for slow evaporation of the mother liquor. The resulting Co-Crystal 15 was confirmed by SCXRD.
  • Example 1.8 Co-Crystal 16 (Co-Crystal of Compound 5 and Proline) 25 mg of Compound 5 and 32mg of L-proline were almost completely dissolved in ⁇ 200uL of ethanol/AcN (1:1) at 50°C at ambient conditions. Full dissolution of the input solid was ultimately observed. The vial was loosely capped to allow for slow evaporation of the mother liquor. The resulting Co-Crystal 16 was confirmed by SCXRD.
  • Example 1 0.5 eq ( ⁇ 1g) of Compound 6 was dissolved separately in 5 mL of methanol/water (1:1). The two streams were combined, first passing through a syringe filter to remove any solids. The vial was returned to ambient conditions and loosely capped to allow for slow evaporation of the mother liquor. The resulting Compound 6-Pro co-crystal was confirmed by SCXRD.
  • Example 1.10 - Co-Crystal 18 (Co-Crystal of Compound 7 and Proline) 17.8 mg of Compound 7 and 32mg of L-proline were fully dissolved in ⁇ 200 ⁇ L of methanol at room temperature. The vial was loosely capped to allow for slow evaporation of the mother liquor.
  • Co-Crystal 18 crystallized from these conditions and was used for SCXRD analysis. The resulting Co-Crystal 18 was confirmed by SCXRD.
  • Example 1.11 - Co-Crystal 19 (Co-Crystal of Compound 8 and Proline) Three stoichiometries, 1:1 (19mg:13mg), 1:2(19mg:22mg) and 1:3(19mg:32mg), of Compound 8 and L-proline, respectively, were each ground in a drop of methanol solvent. After 20 seconds, the mixtures were dissolved in methanol solvent at room temperature. The vial was loosely capped to allow for slow evaporation of the mother liquor. The resulting Co-Crystal 19 was confirmed by SCXRD.
  • Example 2 Crystallography
  • Example 2.1 Single-crystal X-ray Diffraction (SCXRD)
  • SCXRD Single-crystal X-ray Diffraction
  • Co-Crystal 10 (Compound 1-Ala co-crystal): The single-crystal structure of Co-Crystal 10 contains two molecules of alanine per one molecule of API.
  • Co-Crystal 12 (Compound 1-Pro co-crystal): Two crystal structures of Co-Crystal 12 were obtained, Form B and Form C. The asymmetric unit of both structures consists of two pairs of Compound 1-Pro units. There are two hydrogen-bond donors in the API, the secondary amine group and the hydroxyl group (OH). There are two hydrogen-bond donors in proline, the two protons of the primary amine.
  • the resulting two-dimensional diffraction arcs were integrated to create a traditional 1-dimensional PXRD pattern with a step size of 0.05 degrees 2 ⁇ in the approximate range of 2 to 32 degrees 2 ⁇ .
  • PXRD patterns of Form B/C were recorded on an Empyrean (PANalytical) X-ray powder diffractometer with Cu K ⁇ radiation. The diffractometer was equipped with a ceramic tube which was set at the power level of 45kV and 40mA, and a RTMS PIXcel ID detector.
  • Incident optics consisted of a 0.02rad soller slit; 10mm beam mask; 1o antiscatter slit; and auto-divergence slit set to 10mm illuminated length.
  • the PXRD patterns for Compound 1 and L-proline show significant differences from those of the co-crystal forms, thereby indicating the formation of new phases.
  • the experimental patterns obtained here exhibit a good fit with the combination of the simulated patters of both crystal forms. Slight differences could be due to disorder or preferred orientation effects.
  • DSC Differential Scanning Calorimetry
  • DSC Differential scanning calorimetry experiments were performed on Compound 1 (Form A) and Co-Crystal 12 Form B/C using a TA Instrument - model Q2000 or Q1000.
  • the sample (about 1-10 mg) was weighed in an aluminum pan and the weight recorded accurately to a hundredth of a milligram before transferring the sample to the DSC.
  • the instrument was purged with nitrogen gas at 50mL/min. Data were collected between room temperature and 300 °C at a heating rate of 10 °C/min. DSC plots were generated such that the endothermic peaks pointed down.
  • FIG.17 shows the TGA plot for Compound 1 (Form A) and FIG.18 shows the TGA plot for Co-Crystal 12 Form B/C. Compound 1 exhibited ⁇ 0.5% weight loss at 95 °C (results not shown).
  • Example 7 Moisture Sorption Isotherms Moisture sorption isotherms were collected in a VTI SGA-100 Symmetric Vapor Analyzer or TA Instrument VTI-SA+ Vapor Sorption Analyzer using approximately 10 mg of sample. The sample was dried at 60°C until the loss rate of 0.0005 wt %/min was obtained for 10 minutes.
  • FIG.19 show moisture-sorption isotherms for Co-Crystal 12 Form B/C.
  • Dynamic Vapor Sorption (DVS) measures how much and how soon water can be absorbed into or desorbed from a sample as a function of humidity.
  • Co-Crystal 12 Form B/C exhibited a ⁇ 0.1% moisture uptake in the range of 5-85% relative humidity (RH).
  • Example 8 General Procedure for Determining Solid State Stability
  • DSC, TGA, and PXRD physical stability analyses
  • Table 5 Chemical stability of Compound 1 (Form A) vs Co-Crystal 12 Form B/C. Data is color coded based on the stability results with light gray as poor stability, medium gray as intermediate and dark gray indicating good stability.
  • the examples described herein show that co-crystals with L-proline as a co-former provide a dramatic increase in chemical stability through strong heteromeric hydrogen-bonded interactions between the API and L-proline.
  • Co-crystallization of Compound 1 with L-proline provided a straightforward, inexpensive, and commercially viable approach to improve the melting point, solid state stability, and no-hygroscopicity of the neat API. Comparable improvements in decomposition temperatures were seen in Co-Crystals 13 - 19. Proline co-crystal forms of N-hydroxysulfonamides clearly demonstrate better chemical and physical stability over neat forms.
  • REFERENCES The following references are hereby incorporated by reference in their entireties: 1. Aizawa, K.; Nakagawa, H.; Matsuo, K.; Kawai, K.; Ieda, N.; Suzuki, T.; Miyata, N., Piloty’s acid derivative with improved nitroxyl-releasing characteristics.

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Abstract

L'invention concerne des co-cristaux de composés/V-hydroxysulfonamide, des compositions pharmaceutiques et des kits comprenant de tels co-cristaux, et des procédés d'utilisation de tels co-cristaux ou compositions pharmaceutiques les comprenant. En particulier, l'invention concerne des procédés d'utilisation de tels co-cristaux ou compositions pharmaceutiques pour traiter une insuffisance cardiaque.
PCT/US2024/043471 2023-08-23 2024-08-22 Co-cristaux de composés donneurs de nitroxyle Pending WO2025043108A1 (fr)

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