US20170056352A1 - PHARMACEUTICALLY ACCEPTABLE SALTS OF beta-GUANIDINOPROPIONIC ACID WITH IMPROVED PROPERTIES AND USES THEREOF - Google Patents

PHARMACEUTICALLY ACCEPTABLE SALTS OF beta-GUANIDINOPROPIONIC ACID WITH IMPROVED PROPERTIES AND USES THEREOF Download PDF

Info

Publication number
US20170056352A1
US20170056352A1 US15/245,750 US201615245750A US2017056352A1 US 20170056352 A1 US20170056352 A1 US 20170056352A1 US 201615245750 A US201615245750 A US 201615245750A US 2017056352 A1 US2017056352 A1 US 2017056352A1
Authority
US
United States
Prior art keywords
gpa
pharmaceutically acceptable
salt
acceptable salt
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US15/245,750
Other languages
English (en)
Inventor
Eduardo J. Martinez
Andreas G. GRILL
Aniruddh Singh
Padmini Kavuru
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Inspirna Inc
Original Assignee
Rgenix Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rgenix Inc filed Critical Rgenix Inc
Priority to US15/245,750 priority Critical patent/US20170056352A1/en
Priority to US15/281,329 priority patent/US9827217B2/en
Publication of US20170056352A1 publication Critical patent/US20170056352A1/en
Priority to US15/795,540 priority patent/US10512623B2/en
Priority to US16/675,669 priority patent/US20200138759A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • ⁇ -Guanidinopropionic acid also referred to as guanidinopropionic acid, beta-guanidinopropionic acid or, N-(aminoiminomethyl)-beta-alanine is a creatine analog.
  • acidic guanidine derivatives such as ⁇ -GPA can ameliorate hyperglycemia in animal models of noninsulin-dependent diabetes. Accordingly, it is sometimes used as a dietary supplement in diabetic patients to regulate blood sugar levels.
  • ⁇ -GPA is a white crystalline powder that is highly soluble in water (>50 mg/mL).
  • ⁇ -GPA has recently been found to be effective for the suppression of metastasis, particularly liver metastasis in gastrointestinal cancers, e.g., see International Patent Publication WO2014/071067.
  • ⁇ -GPA salts and formulations with improved physical properties and handling characteristics.
  • the present invention features new pharmaceutical salts of ⁇ -GPA which exhibit improved physical properties.
  • the invention features salts of ⁇ -GPA with improved flow properties (e.g., improved Carr's index and/or Hausner ratio), such as fumarate salts, succinate salts, and oxalate salts.
  • the invention also features pharmaceutical compositions including a pharmaceutically effective amount of one or more salts of ⁇ -GPA, as well as methods of treating cancer including administration of a formulation including a ⁇ -GPA salt of the invention to a subject in need thereof.
  • the invention features a pharmaceutically acceptable salt of ⁇ -guanidinopropionic acid having a Carr's Index of less than 20 (e.g., less than 15, less than 10, less than 6) and/or a Hausner ratio of less than 1.25 (e.g., less than 1.2, less than 1.15, less than 1.1).
  • the pharmaceutically acceptable salt is a salt of a dicarboxylic acid (e.g., fumaric acid, succinic acid, or oxalic acid).
  • the pharmaceutically acceptable salt is a fumarate salt (e.g., a 1:1 fumarate salt), a succinate salt (e.g., a 2:1 succinate salt), or an oxalate salt (e.g., a 1:1 oxalate salt).
  • the pharmaceutically acceptable salt is crystalline (e.g., a 1:1 fumarate salt with rod-like crystal morphology.
  • the pharmaceutically acceptable salt includes less than 40% by weight (e.g., less than 30%, less than 20%, less than 10%, less than 5%, less than 1% or between 30-40%, 25-35%, 20-30%, 15-25%, 10-20%, 5-15%, 1-10%) of amorphous compound.
  • the pharmaceutically acceptable salt is substantially free of amorphous compound.
  • the pharmaceutically acceptable salt is substantially free of any other salt or crystal form of ⁇ -GPA.
  • the pharmaceutically acceptable salt is a 1:1 fumarate salt.
  • the pharmaceutically acceptable salt has an endothermic onset at about 171° C. (e.g., from 169° C. to 173° C., 170° C. to 173° C., 169° C. to 172° C., 170° C. to 172° C.) in differential scanning calorimetry (DSC) profile.
  • the pharmaceutically acceptable salt has a loss of weight from 31° C. to 140° C. of less than 5% (e.g., less than 4%, less than 3%, less than 2%, less than 1%) as measured by thermal gravimetric analysis.
  • the pharmaceutically acceptable salt has at least one peak at diffraction angle 2 ⁇ (°) of 20 ⁇ 0.5 as measured by X-ray powder diffractometry. In some embodiments, the pharmaceutically acceptable salt further has at least one peak at diffraction angle 2 ⁇ (°) of 20 ⁇ 0.5, 20.5 ⁇ 0.5, and/or 23 ⁇ 0.5 as measured by X-ray powder diffractometry. In some embodiments, the pharmaceutically acceptable salt has one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more) peaks listed in Table 1 as measured by X-ray powder diffractometry. In some embodiments, the pharmaceutically acceptable salt has all of the peaks listed in Table 1 as measured by X-ray powder diffractometry.
  • the pharmaceutically acceptable salt has at least one peak at 3300 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 3188 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 3049 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 2941 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 2886 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy.
  • the pharmaceutically acceptable salt has at least one peak at 1713 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 1653 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 1483 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 1421 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 1382 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy.
  • the pharmaceutically acceptable salt has at least one peak at 1305 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 1268 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 1190 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 1084 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 997 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy.
  • the pharmaceutically acceptable salt has at least one peak at 896 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 681 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 625 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 555 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has at least one peak at 486 ⁇ 1 cm ⁇ 1 as measured by Raman spectroscopy.
  • the pharmaceutically acceptable salt has one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more) peaks listed in Table 2 as measured by Raman spectroscopy. In some embodiments, the pharmaceutically acceptable salt has all of the peaks listed in Table 2 as measured by Raman spectroscopy.
  • the pharmaceutically acceptable salt is a 1:1 oxalate salt. In some embodiments, the pharmaceutically acceptable salt has at least one peak at diffraction angle 2 ⁇ (°) of 27.5 ⁇ 0.5 as measured by X-ray powder diffractometry. In some embodiments, the pharmaceutically acceptable salt has one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more) peaks listed in Table 3. In some embodiments, the pharmaceutically acceptable salt has all of the peaks listed in Table 3 as measured by X-ray powder diffractometry.
  • the pharmaceutically acceptable salt is a 2:1 succinate salt.
  • the pharmaceutically acceptable salt has at least one peak at diffraction angle 2 ⁇ (°) of 27 ⁇ 0.5 as measured by X-ray powder diffractometry.
  • the pharmaceutically acceptable salt has one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more) peaks listed in Table 4.
  • the pharmaceutically acceptable salt has all of the peaks listed in Table 4 as measured by X-ray powder diffractometry.
  • the invention features a composition (e.g., an aqueous composition) including any of the foregoing pharmaceutically acceptable salts and a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable salt contains less than 10% by weight (e.g., less than 5%, less than 1%) of amorphous compound.
  • the pharmaceutically acceptable salt is substantially free of amorphous compound.
  • the invention features a composition (e.g., an aqueous composition) including the fumarate salt of ⁇ -guanidinopropionic acid, wherein at least 80% (at least 85%, at least 90%, at least 95%, at least 99%) of the fumarate salt of ⁇ -guanidinopropionic acid is a 1:1 salt (e.g., wherein the composition is substantially free of the 2:1 fumarate salt of ⁇ -guanidinopropionic acid) and a pharmaceutically acceptable excipient.
  • a composition e.g., an aqueous composition
  • the fumarate salt of ⁇ -guanidinopropionic acid wherein at least 80% (at least 85%, at least 90%, at least 95%, at least 99%) of the fumarate salt of ⁇ -guanidinopropionic acid is a 1:1 salt (e.g., wherein the composition is substantially free of the 2:1 fumarate salt of ⁇ -guanidinopropionic acid) and a pharmaceutically acceptable
  • the pharmaceutically acceptable excipient includes 1,3-butanediol, mannitol, water, Ringer's solution, or isotonic sodium chloride solution. In some embodiments of any of the foregoing compositions, the composition is formulated for intravenous infusion.
  • the invention features a method for treating cancer (e.g., gastrointestinal cancer such as colon cancer or gastric cancer, pancreatic cancer, liver cancer, breast cancer, prostate cancer, lung cancer, and melanoma) in a subject in need thereof, including administering to the subject an effective amount of any of the foregoing pharmaceutically acceptable salts or compositions.
  • cancer e.g., gastrointestinal cancer such as colon cancer or gastric cancer, pancreatic cancer, liver cancer, breast cancer, prostate cancer, lung cancer, and melanoma
  • the invention features a method for treating metastatic cancer (e.g., metastatic gastrointestinal cancer such as colon cancer or gastric cancer) in a subject in need thereof, including administering to the subject an effective amount of any of the foregoing pharmaceutically acceptable salts or compositions.
  • the effective amount includes an amount effective to suppress metastatic colonization (e.g., metastatic colonization in the liver) of the cancer (e.g., gastrointestinal cancer such as colorectal cancer or gastric cancer).
  • the invention features a method for treating cancer (e.g., gastrointestinal cancer such as colon cancer or gastric cancer) in a subject in need thereof, comprising injecting into the subject an effective amount of an aqueous composition comprising any of the foregoing pharmaceutically acceptable salts and a pharmaceutically acceptable excipient.
  • cancer e.g., gastrointestinal cancer such as colon cancer or gastric cancer
  • the cancer is metastatic cancer.
  • the effective amount is an amount effective to suppress metastatic colonization of the cancer.
  • the invention features a method of treating metastatic cancer (e.g., gastrointestinal cancer such as colorectal cancer, esophageal cancer, or gastric cancer, pancreatic cancer, liver cancer, breast cancer, prostate cancer, lung cancer, and melanoma) in a subject in need thereof comprising: (a) providing a subject identified to have, or to be at risk of having, metastatic cancer on the basis of the expression level of miR-483-5p and/or miR-551a is below a predetermined reference value or the expression level of CKB and/or SLC6a8 is above a predetermined reference value; and (b) administering to the subject an effective amount of any of the foregoing pharmaceutically acceptable salt or compositions.
  • metastatic cancer e.g., gastrointestinal cancer such as colorectal cancer, esophageal cancer, or gastric cancer, pancreatic cancer, liver cancer, breast cancer, prostate cancer, lung cancer, and melanoma
  • metastatic cancer e.g., gastrointestinal cancer such as colore
  • any of the foregoing methods further include administering an additional therapy (e.g., an additional therapeutic agent) to the subject.
  • the additional therapy is a therapeutic agent such as cyclocreatine, a RNAi agent, a nucleic acid, a vector, 5-fluorouracil, Oxaliplatin, Irinotecan, Capecitabine, Gemcitabine, Cetuximab, Taxol, Avastin, folinic acid (leucovorin), Regorafenib, Zaltrap, topoisomerase I inhibitors, NKTR-102, Tivantinib, PX-866, Sorafenib, Linifanib, kinase inhibitors, Telatinib, XL281 (BMS-908662), Robatumumab, or IGF1-R inhibitors.
  • a therapeutic agent such as cyclocreatine, a RNAi agent, a nucleic acid, a vector, 5-fluorouracil, Oxalip
  • the invention features a method of producing a pharmaceutically acceptable 1:1 fumarate salt of ⁇ -guanidinopropionic acid.
  • This method includes combining ⁇ -guanidinopropionic acid and fumaric acid in an amount sufficient to produce a pharmaceutically acceptable 1:1 fumarate salt of ⁇ -guanidinopropionic acid.
  • the method includes dissolving the ⁇ -guanidinopropionic acid and the fumaric acid in a solvent and the 1:1 fumarate salt of ⁇ -guanidinopropionic acid precipitates from the solvent.
  • the method further includes recrystallization of the 1:1 fumarate salt of ⁇ -guanidinopropionic acid.
  • FIG. 1 is an image depicting X-ray powder diffraction (XRPD) pattern obtained for a crystalline form of the 1:1 fumarate salt of ⁇ -GPA.
  • XRPD X-ray powder diffraction
  • FIG. 2 is an image depicting X-ray powder diffraction (XRPD) pattern obtained for a crystalline form of ⁇ -GPA.
  • FIG. 3 is an image of ⁇ -GPA crystals under a polarized microscope.
  • FIG. 4 is an image depicting a DSC thermogram obtained for a crystalline form of ⁇ -GPA.
  • FIG. 5 is an image depicting TGA analysis obtained for a crystalline form of ⁇ -GPA.
  • FIG. 6 is an image depicting a 1 H NMR spectra of a crystalline form ⁇ -GPA.
  • FIG. 7 is an image depicting a DVS analysis for a crystalline form of ⁇ -GPA.
  • FIG. 8 is an image depicting X-ray powder diffraction (XRPD) pattern obtained for a crystalline form of the 1:1 hydrochloride salt of ⁇ -GPA.
  • XRPD X-ray powder diffraction
  • FIG. 9 is an image depicting X-ray powder diffraction (XRPD) pattern obtained for a crystalline form of the 1:1 maleate salt of ⁇ -GPA.
  • FIG. 10 is an image depicting X-ray powder diffraction (XRPD) pattern obtained for a crystalline form of the 1:1 fumarate salt of ⁇ -GPA.
  • XRPD X-ray powder diffraction
  • FIG. 11 is an image depicting X-ray powder diffraction (XRPD) pattern obtained for a crystalline form of the 1:1 L-malic acid salt of ⁇ -GPA.
  • XRPD X-ray powder diffraction
  • FIG. 12 is an image depicting X-ray powder diffraction (XRPD) pattern obtained for a crystalline form of the 2:1 succinate salt of ⁇ -GPA.
  • XRPD X-ray powder diffraction
  • FIG. 13 is an image depicting X-ray powder diffraction (XRPD) pattern obtained for a crystalline form of the 1:1 oxalate salt of ⁇ -GPA.
  • XRPD X-ray powder diffraction
  • FIG. 14 is an image depicting X-ray powder diffraction (XRPD) pattern obtained for a crystalline form of the 2:1 maleate salt of ⁇ -GPA.
  • XRPD X-ray powder diffraction
  • FIG. 15 is an image depicting a 1 H NMR spectra of a crystalline form of the 2:1 maleate salt of ⁇ -GPA.
  • FIG. 16 is an image depicting a DSC thermogram obtained for a crystalline form of the 1:1 hydrochloride salt of ⁇ -GPA.
  • FIG. 17 is an image of a crystalline form of the 1:1 hydrochloride salt of ⁇ -GPA by hot stage microscopy.
  • FIG. 18 is an image depicting a DSC thermogram obtained for a crystalline form of the 1:1 maleate salt of ⁇ -GPA.
  • FIG. 19 is an image depicting a DSC thermogram obtained for a crystalline form of the 1:1 fumarate salt of ⁇ -GPA.
  • FIG. 20 is an image depicting TGA analysis obtained for a crystalline form of the 1:1 fumarate salt of ⁇ -GPA.
  • FIG. 21 is an image depicting a 1 H NMR spectra of a crystalline form of the 1:1 fumarate salt of ⁇ -GPA.
  • FIG. 22 is an image depicting a DSC thermogram obtained for a crystalline form of the 2:1 succinate salt of ⁇ -GPA.
  • FIG. 23 is an image of a crystalline form of the 2:1 succinate salt of ⁇ -GPA by hot stage microscopy.
  • FIG. 24 is an image depicting TGA analysis obtained for a crystalline form of the 2:1 succinate salt of ⁇ -GPA.
  • FIG. 25 is an image depicting a 1 H NMR spectra of a crystalline form of the 2:1 succinate salt of ⁇ -GPA.
  • FIG. 26 is an image depicting a DSC thermogram obtained for a crystalline form of the 1:1 oxalate salt of ⁇ -GPA.
  • FIG. 27 is an image depicting TGA analysis obtained for a crystalline form of the 1:1 oxalate salt of ⁇ -GPA.
  • FIG. 28 is an image depicting a 1 H NMR spectra of a crystalline form of the 1:1 oxalate salt of ⁇ -GPA.
  • FIG. 29A - FIG. 29J are images of crystalline forms of ⁇ -GPA salts.
  • FIG. 29A 1:1 hydrochloride salt of ⁇ -GPA
  • FIG. 29B 1:1 phosphate salt of ⁇ -GPA
  • FIG. 29C 1:1 mesylate salt of ⁇ -GPA
  • FIG. 29D 1:1 maleate salt of ⁇ -GPA
  • FIG. 29E 1:1 maleate of ⁇ -GPA
  • FIG. 29F 2:1 maleate salt of ⁇ -GPA
  • FIG. 29G 1:1 fumarate salt of ⁇ -GPA
  • FIG. 29H 1:1 malate salt of ⁇ -GPA
  • FIG. 29I 2:1 succinate salt of ⁇ -GPA
  • FIG. 29J 1:1 oxalate salt of ⁇ -GPA.
  • FIG. 30 is an image depicting the rod-like crystal morphology of 1:1 fumarate salt of ⁇ -GPA (Pattern 7A).
  • FIG. 31 is an image depicting a comparison of XRPD analysis before and after DVS of 1:1 fumarate salt of ⁇ -GPA (Pattern 7A).
  • FIG. 32 is an image depicting X-ray powder diffraction (XRPD) pattern obtained for a crystalline form of the 1:1 fumarate salt of ⁇ -GPA after slow evaporation of solvent.
  • XRPD X-ray powder diffraction
  • FIG. 33 is an image depicting an X-ray powder diffraction (XRPD) pattern obtained for a crystalline form of the 1:1 fumarate salt of ⁇ -GPA after slurry experiment in tetrahydrofuran:water (1:1) for 48 hours.
  • XRPD X-ray powder diffraction
  • FIG. 34 is an image depicting X-ray powder diffraction (XRPD) pattern obtained for a crystalline form of the 2:1 fumarate salt of ⁇ -GPA.
  • XRPD X-ray powder diffraction
  • FIG. 35 is an image depicting a 1 H NMR spectra of a crystalline form of the 2:1 fumarate salt of ⁇ -GPA.
  • FIG. 36 is an image depicting a DSC thermogram obtained for a crystalline form of the 2:1 fumarate salt of ⁇ -GPA.
  • FIG. 37 is an image depicting the Raman spectra of a crystalline form of the 1:1 fumarate salt of ⁇ -GPA.
  • the present inventors carried out salt screening experiments with 19 different counterions and eight different solvent systems. Ten of the counterions were prepared in crystalline forms and their properties assessed. Following identification of preferred salts with optimal properties, polymorph screening of these salts was conducted.
  • ⁇ -GPA has the structure:
  • ⁇ -GPA is zwitterionic and highly soluble in water (>50 mg/mL), but has low solubility in organic solvents.
  • ⁇ -GPA possesses a basic guanidino group, and is thus capable of forming both 1:1 ( ⁇ -GPA:acid) and 2:1 ( ⁇ -GPA:acid) salts with diacids.
  • a “2:1 salt” of ⁇ -GPA with a diacid e.g., a 2:1 succinate salt
  • a “2:1 salt” of ⁇ -GPA with a diacid e.g., a 2:1 succinate salt
  • a “2:1 salt” of ⁇ -GPA with a diacid e.g., a 2:1 succinate salt
  • a “2:1 succinate salt” includes two molecules of ⁇ -GPA and one molecule of succinic acid.
  • Free ⁇ -GPA in solid state is highly crystalline and is generally present as an anhydrate.
  • the crystalline form is non-hygroscopic (e.g., with ⁇ 0.3% water uptake at 80% humidity at 25° C.) with a sharp melting point at 219° C. and an endothermic event at 235° C. by DSC.
  • the crystals of ⁇ -GPA have a plate-like crystal morphology. No degradation was observed in experiments at 40° C. at 75% humidity after 4 weeks.
  • the flow properties of ⁇ -GPA are sub-optimal.
  • the bulk density is 0.389 g/cc and the tapped density is 0.627 g/cc.
  • These measurements can be used to calculate the Carr's index and Hausner ratio for a substance.
  • the Carr's index and Hausner ratio are indicators of flowability of a powder. As known in the art, e.g., as described in Carr R. L. Chem. Eng. 1965, 72, 163-168, the relationship to flowability of a powder to the Carr's index and Hausner ratio is based on the scale shown in Table 5 below.
  • the hydrochloric acid, L-malic acid, phosphoric acid, methanesulfonic acid, and ethanesulfonic acid salts were found to be stable in dry conditions, but deliquesced under high humidity conditions.
  • the maleic acid, fumaric acid, succinic acid, and oxalic acid salts were found to be stable in both dry and humid conditions.
  • the maleic acid, fumaric acid, and oxalic acid salts were found to have 1:1 ( ⁇ -GPA:acid) stoichiometry, whereas the succinic acid salt was found to have 2:1 ( ⁇ -GPA:acid) stoichiometry.
  • Further experiments to generate 2:1 salts with fumaric, oxalic, and maleic acid were conducted, resulting in the preparation of 2:1 salts with maleic acid and fumaric acid.
  • the 2:1 fumarate salt of ⁇ -GPA was formed upon lypohilization of the 1:1 salt and fast evaporation, or lyophilization of ⁇ -GPA and fumaric acid in 2:1 ( ⁇ -GPA:acid) stiochiometry.
  • the crystalline form of the 2:1 salt was found to contain some amorphous material, and was unstable.
  • the 2:1 fumarate salt converted to the 1:1 salt when slurried in water, heated, or under high humidity conditions.
  • Crystalline ⁇ -GPA is defined as a solid comprising ⁇ -GPA, or a pharmaceutically acceptable salt thereof, in which the constituent molecules are packed in a regularly ordered repeating pattern extending in all three spatial dimensions. Identification of crystallinity is readily accomplished in a number of ways known to those skilled in the art. Microscopic examination of a test composition will reveal the presence of regular shapes suggesting ordered internal structure, e.g., the 1:1 fumarate salt of ⁇ -GPA produced in Example 1 has rod-like morphology.
  • XRPD is another method for identifying crystalline ⁇ -GPA, or pharmaceutically acceptable salts thereof.
  • the regularly ordered structure of constituent molecules in crystal diffracts incident X-rays in a distinct pattern depicted as a spectrum of peaks. This pattern of peaks for the 1:1 fumarate salt of ⁇ -GPA is shown in FIG. 1 . While the XRPD peaks for a particular crystal may vary in intensity, the same general pattern will be present in replicate XRPD analysis.
  • Crystalline 1:1 fumarate salt of ⁇ -GPA exhibits an XRPD dominant peak at about 27 2 ⁇ (°), ordinarily about 26.7.
  • about is meant within the typical variation in measurement of XRPD peaks. Such variations may result from the use of different instruments, instrument settings, batches of product, post-crystallization processing such as micronization or milling, and with varying sample preparation methods. In general, about means ⁇ 0.5 2 ⁇ (°).
  • Illustrative examples of other dominant peaks for crystalline 1:1 fumarate salt of ⁇ -GPA are at about 19, 20, 21, 23, and 29 2 ⁇ (°), ordinarily 19.2, 19.7, 20.6, 22.9, and 28.8 2 ⁇ (°).
  • Representative peaks for crystalline 1:1 fumarate salt of ⁇ -GPA are shown in Table 1.
  • the identification of a crystalline form of ⁇ -GPA, or a pharmaceutically acceptable salt thereof need not require the presence of any one or more of the dominant peaks seen in FIG. 1 or listed in Table 1.
  • the presence or absence of dominant peaks is ordinarily taken into account with other diagnostic characteristics, e.g., DSC thermogram or TGA graph, to identify a candidate as a particular crystalline form of ⁇ -GPA, or a pharmaceutically acceptable salt thereof.
  • Crystalline 1:1 fumarate salt of ⁇ -GPA is also characterized by DSC thermogram which reveals an endothermic onset at 171° C. in differential scanning calorimetry profile. Typically, some variation in this measurement also will be encountered (e.g., ⁇ 1-3° C.).
  • Crystalline 1:1 fumarate salt of ⁇ -GPA may also be characterized by thermal gravimetric analysis, e.g., by a loss of weight from 31° C. to 140° C. of less than 1%.
  • ⁇ -GPA has recently been found to be effective for the suppression of metastasis.
  • the mechanism of action has been hypothesized as inhibition of creatine transport and/or creatine kinase.
  • the phosphocreatine system promotes metastasis by enhancing the survival of disseminated cancer cells in the liver by acting as an energetic store for ATP generation to endure hepatic hypoxia.
  • Inhibition of creatine transport into cancer cells limits the amount of phosphocreatine available to use in the production of ATP.
  • Inhibition of creatine kinase inhibits the production of ATP through conversion of phosphocreatine to creatine.
  • Typical vascularized tumors that can be treated with the method include solid tumors, particularly carcinomas, which require a vascular component for the provision of oxygen and nutrients.
  • Exemplary solid tumors include, but are not limited to, carcinomas of the lung, breast, bone, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate, thyroid, squamous cell carcinomas, adenocarcinomas, small cell carcinomas, melanomas, gliomas, glioblastomas, neuroblastomas, Kaposi's sarcoma, and sarcomas.
  • Treating cancer can result in a reduction in size or volume of a tumor.
  • tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to its size prior to treatment.
  • Size of a tumor may be measured by any reproducible means of measurement.
  • the size of a tumor may be measured as a diameter of the tumor.
  • Treating cancer may further result in a decrease in number of tumors.
  • tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment.
  • Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2 ⁇ , 3 ⁇ , 4 ⁇ , 5 ⁇ , 10 ⁇ , or 50 ⁇ ).
  • Treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site.
  • the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment.
  • the number of metastatic nodules may be measured by any reproducible means of measurement.
  • the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2 ⁇ , 10 ⁇ , or 50 ⁇ ).
  • Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days).
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the invention.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.
  • Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population.
  • the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%).
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of the invention.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.
  • compositions that contains a suitable excipient and one or more of the pharmaceutically acceptable salts described above.
  • the composition can be a pharmaceutical composition that contains a pharmaceutically acceptable excipient, a dietary composition that contains a dietarily acceptable suitable excipient, or a cosmetic composition that contains a cosmetically acceptable excipient.
  • composition refers to the combination of an active agent with a excipient, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • a “pharmaceutically acceptable excipient,” after administered to or upon a subject, does not cause undesirable physiological effects.
  • the excipient in the pharmaceutical composition must be “acceptable” also in the sense that it is compatible with the active ingredient and can be capable of stabilizing it.
  • One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an active compound.
  • examples of a pharmaceutically acceptable excipient include, but are not limited to, biocompatible vehicles, adjuvants, additives, and diluents to achieve a composition usable as a dosage form.
  • examples of other excipients include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic response, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below.
  • a free base function can be reacted with a suitable acid.
  • suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, fumaric, or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, fumaric, or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • the pharmaceutical compositions of the present invention additionally include a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable excipient includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
  • materials which can serve as pharmaceutically acceptable excipients include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; natural and synthetic phospholipids, such as soybean and egg yolk phosphatides, lecithin, hydrogenated soy lecithin, dimyristoyl lecithin, dipalmitoyl lecithin, distearoyl lecithin, dioleoy
  • lecithin which are preferred include those which are available under the trade name Phosal® or Phospholipon® and include Phosal 53 MCT, Phosal 50 PG, Phosal 75 SA, Phospholipon 90H, Phospholipon 90G and Phospholipon 90 NG; soy-phosphatidylcholine (SoyPC) and DSPE-PEG2000 are particularly preferred; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • buffering agents such as magnesium hydroxide and aluminum hydrox
  • compositions in any of the forms described above, can be used for treating cancer, or any other disease or condition described herein.
  • An effective amount refers to the amount of an active compound/agent that is required to confer a therapeutic effect on a treated subject. Effective doses will vary, as recognized by those skilled in the art, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment.
  • a pharmaceutical composition of this invention can be administered parenterally, orally, nasally, rectally, topically, or buccally.
  • parenteral refers to subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique.
  • a sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • solutions include, but are not limited to, 1,3-butanediol, mannitol, water, Ringer's solution, and isotonic sodium chloride solution.
  • fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides).
  • Fatty acids such as, but not limited to, oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as, but not limited to, olive oil or castor oil, orpolyoxyethylated versions thereof.
  • oil solutions or suspensions also can contain a long chain alcohol diluent or dispersant such as, but not limited to, carboxymethyl cellulose, or similar dispersing agents.
  • a long chain alcohol diluent or dispersant such as, but not limited to, carboxymethyl cellulose, or similar dispersing agents.
  • Other commonly used surfactants such as, but not limited to, Tweens or Spans or other similar emulsifying agents or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms also can be used for the purpose of formulation.
  • a composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions.
  • commonly used excipients include, but are not limited to, lactose and corn starch.
  • Lubricating agents such as, but not limited to, magnesium stearate, also are typically added.
  • useful diluents include, but are not limited to, lactose and dried corn starch.
  • compositions for topical administration can be formulated as solutions, ointments, creams, suspensions, lotions, powders, pastes, gels, sprays, aerosols, or oils.
  • topical formulations can be in the form of patches or dressings impregnated with active ingredient(s), which can optionally include one or more excipients or diluents.
  • the topical formulations include a material that would enhance absorption or penetration of the active agent(s) through the skin or other affected areas.
  • a topical composition contains a safe and effective amount of a dermatologically acceptable excipient suitable for application to the skin.
  • a “cosmetically acceptable” or “dermatologically-acceptable” composition or component refers a composition or component that is suitable for use in contact with human skin without undue toxicity, incompatibility, instability, or allergic response.
  • the excipient enables an active agent and optional component to be delivered to the skin at an appropriate concentration(s).
  • the excipient thus can act as a diluent, dispersant, solvent, or the like to ensure that the active materials are applied to and distributed evenly over the selected target at an appropriate concentration.
  • the excipient can be solid, semi-solid, or liquid.
  • the excipient can be in the form of a lotion, a cream, or a gel, in particular one that has a sufficient thickness or yield point to prevent the active materials from sedimenting.
  • the excipient can be inert or possess dermatological benefits. It also should be physically and chemically compatible with the active components described herein, and should not unduly impair stability, efficacy, or other use benefits associated with the composition.
  • the pharmaceutical composition may further include an additional compound having antiproliferative activity.
  • the additional compound having antiproliferative activity can be selected from a group of antiproliferative agents including those shown in Table 8.
  • the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same disorder, or they may achieve different effects (e.g., control of any adverse effects).
  • antiproliferative agent any antiproliferative agent, including those antiproliferative agents listed in Table 8, any of which can be used in combination with a pharmaceutically acceptable salt of the invention to treat the medical conditions recited herein.
  • Antiproliferative agents also include organo-platine derivatives, naphtoquinone and benzoquinone derivatives, chrysophanic acid and anthroquinone derivatives thereof.
  • TGA Thermal Gravimetric Analysis
  • Samples were analyzed using an Aquadyne DVS-2 gravimetric water sorption analyzer. The relative humidity was adjusted between 2-95% and the weight of the sample was continuously monitored and recorded.
  • Sample was prepared by dissolving the compound in deuterated dimethylsulfoxide with 0.05% (v/v) tetramethylsilane (TMS). Spectra were collected at ambient temperature on a Bruker Avance 300 MHz NMR with TopSpin software. The number of scans was 16 for proton NMR.
  • Samples were analyzed using an Olympus BX53 polarized light microscope equipped with a PAXcam 3 digital microscope camera.
  • Solid-state ⁇ -GPA was analyzed by XRPD ( FIG. 2 ) and was also observed under a polarized microscope ( FIG. 3 ). The material was found to be crystalline
  • a DSC thermogram of ⁇ -GPA is illustrated in FIG. 4 .
  • the melting onset of ⁇ -GPA was found to be around 219° C. followed by an endothermic event at around 237° C. and immediate possible degradation. However, another tiny endothermic event at 187° C. was also exhibited by the material (possible traces of another form of ⁇ -GPA).
  • TGA analysis reveals that there is less than 0.1% weight loss in the sample from 30 to 145° C. as illustrated in FIG. 5 .
  • the 1 H NMR of ⁇ -GPA is shown in FIG. 6 .
  • the DVS experiment of ⁇ -GPA revealed around 0.1% moisture absorbed and desorbed when exposed to relative humidity between 0-95 percent ( FIG. 7 ). No change in the solid form was observed after the DVS experiment as confirmed by XRPD.
  • Table 10 illustrates the selected counter ions for the salt screening of ⁇ -GPA. Salt screening experiments were designed in 1:1.1 equivalence (eq) for ⁇ -GPA to counter ion.
  • FIGS. 8 through 13 represents the XRPDs of the new crystalline forms isolated from slurry/slow evaporation experiments.
  • Crystalline forms were prepared with phosphoric acid (from ethyl acetate and trifluoroethanol), methanesulfonic acid (from ethyl acetate), ethanesulfonic acid (from all four solvents), and L-malic acid (from trifluoroethanol).
  • the DSC of ⁇ -GPA-HCl salt revealed the presence of an endothermic event at around 135° C. followed by an exothermic event at around 185° C. and an endotherm at 265° C. ( FIG. 16 ).
  • the exothermic event in the DSC arises from the recrystallization of the sample as confirmed by hot stage microscopy ( FIG. 17 ).
  • the TGA analysis revealed a weight loss of around 11% from 31° C. to 210° C.
  • the ⁇ -GPA-maleic acid salt (Sample ID: 2162-42-21) exhibited three endotherms at the following temperatures: 90, 124 and 141° C. ( FIG. 18 ).
  • TGA analysis revealed a weight loss of around 1.2% from 31 to 105° C. (1st endotherm) and a weight loss of around 5.4% from 105 to 138° C. (2nd endotherm).
  • the ⁇ -GPA-maleic acid salt (Sample ID: 2162-48-6) exhibited two endotherms at 85 and 155° C. respectively. However, the dried sample exhibited only one endotherm at 155° C. From the DSC analysis it is evident that a hydrate was formed in the prior case whereas an anhydrous form was yielded as a result of drying. TGA analysis revealed a weight loss of ⁇ 0.1% from 31 to 145° C.
  • ⁇ -GPA—fumaric acid salt (Sample ID: 2162-42-25) exhibited an endotherm at 171° C. ( FIG. 19 ) followed by possible decomposition of the salt.
  • TGA analysis revealed a weight loss ⁇ 1% from 31° C. to 145° C. ( FIG. 20 ).
  • the 1 H NMR of the 1:1 fumarate salt is shown in FIG. 21 .
  • ⁇ -GPA—L-malic acid salt (Sample ID: 2162-42-45) exhibited an endotherm at 110° C. followed by possible decomposition of the salt. TGA analysis revealed a weight loss ⁇ 1% from 31° C. to 145° C. The 1 H-NMR of the salt confirmed it was a 1:1 salt.
  • the DSC of ⁇ -GPA—succinic acid salt revealed the presence of an endothermic event at around 130° C. followed by another endothermic event at around 175° C. An exothermic event was observed at around 179° C. ( FIG. 22 ) followed by an endothermic event at 232° C.
  • hot stage microscopy was performed on the sample and illustrated in FIG. 23 .
  • the TGA analysis revealed a weight loss of around 0.4% from 31° C. to 135° C. and 13% from 135 to 215° C. ( FIG. 24 ).
  • the 1 H-NMR revealed that the salt formed between ⁇ -GPA and succinic acid was in 2:1 ( ⁇ -GPA:acid) molar ratio ( FIG. 25 ).
  • the ⁇ -GPA—oxalic acid (Sample ID: 2162-42-69) when analyzed by DSC revealed a presence of an endothermic event at around 217° C. followed by an exothermic peak at around 224° C. and an endotherm at 268° C. as represented in FIG. 26 .
  • the TGA analysis revealed a weight loss of ⁇ 0.3% from 31 to 195° C. ( FIG. 27 ).
  • FIG. 28 The 1 H-NMR of ⁇ -GPA oxalate is presented in FIG. 28 . From the elemental analysis the stoichiometric ratio of ⁇ -GPA to oxalic acid was found to be 1:1 (Intertek).
  • Salts of ⁇ -GPA were also analyzed by optical microscopy. Optical microscopic images of ⁇ -GPA salts are presented from FIG. 29A to 29J . As shown in FIG. 30 , ⁇ -GPA fumarate (1:1) has a rod-like crystal morphology.
  • 1:1 ⁇ -GPA oxalate and 1:1 ⁇ -GPA fumarate salts retained their XRPD pattern after 48 hours slurry in water.
  • 2:1 ⁇ -GPA succinate started showing up peaks from ⁇ -GPA after 6 hours slurry in water and thus the experiment was stopped after 6 hours.
  • the mobile phase was prepared by dissolving 2.72 g of monobasic potassium phosphate in 1 L of deionized water and the adjusting the desired pH by 85% (w/w) phosphoric acid.
  • the counterions were also analyzed by HPLC under the same concentrations as they were present in the respective salts.
  • the bulk density of ⁇ -GPA oxalate (Pattern 18 B), succinate (Pattern 15A), and fumarate (Pattern 7A) were determined by pouring in a known amount of salt (g) into a measuring cylinder. The volume (Vi) occupied by the salt was recorded and the bulk density ( ⁇ B ) was determined using equation 1.
  • the tapped densities of the salts were determined using a Tap density analyzer.
  • a known amount of salt was poured (g) into a measuring cylinder and the initial volume was recorded and tapped using a Tap density analyzer.
  • the final volume (V f ) after tapping was recorded and the tapped density ( ⁇ T ) was calculated by using equation 2.
  • Table 15 lists the bulk and tapped density of ⁇ -GPA and salts thereof.
  • Carr's index or Carr's compressibility index (C) is an indication of the compressibility of a powder. It can be calculated using the equation below:
  • a Carr's index greater than 25 is considered to be an indication of poor flowability while a value below 15 is an indication of good flowability.
  • the Hausner ratio is a number that is correlated to the flowability of a powder or granular material. It is calculated by using the equation below:
  • Table 16 lists the Carr's index and Hausner ratio corresponding to the flow character of a powder proposed by R. L. Carl.
  • Table 17 lists the Carr's index and Hausner ratio for ⁇ -GPA and salts thereof.
  • a cylindrical vessel is secured to the stand and above that a funnel is also secured such that the bottom of the funnel is close to the vessel.
  • a powder load of ⁇ 50-60 g is then poured through the funnel into the middle of the cylinder.
  • the lever device is pulled to open the hole in the disk quickly and without vibration. If a powder slowly flows through the small-diameter holes, leaving a cavity shaped like an upside-down, truncated cone, the test is considered positive. If a powder flocculates in bulk and falls abruptly, forming a cylindrical cavity, the test is considered negative. If a powder does not fall through the small-diameter holes, the test is considered negative. If the experiment is negative, the powder is tested again with a disk having a larger hole. Tables 18-21 list the flowability test results for ⁇ -GPA and salts thereof.
  • Sample 2162-64-1 was analyzed by DVS in triplicate and the post DVS samples were characterized by XRPD to identify the form at the end of the experiment.
  • the moisture uptake by ⁇ -GPA fumarate was found to be less than 0.1%.
  • the XRPDs were found to be identical to ⁇ -GPA fumarate (Pattern 7A) and no appearance of ⁇ -GPA peaks were observed, unlike sample 2162-42-3 post DVS ( FIG. 30 ).
  • ⁇ -GPA maleate (1:1), fumarate (1:1), succinate (2:1) and oxalate (1:1) Three salts of ⁇ -GPA were selected after performing the DVS experiments: ⁇ -GPA maleate (1:1), fumarate (1:1), succinate (2:1) and oxalate (1:1) and the form stability was determined by XRPD.
  • ⁇ -GPA fumarate, succinate and oxalate retained their XRPD after the DVS experiment.
  • ⁇ -GPA fumarate revealed the presence of two peaks from the ⁇ -GPA indicating dissociation of the salt.
  • the purity assessment for the salts was carried out by HPLC and the purity of the salts was as follows: ⁇ -GPA fumarate—97.7%, ⁇ -GPA succinate—98.1% and ⁇ -GPA oxalate—98.4%.
  • ⁇ -GPA oxalate Patterns 18A and B
  • fumarate fumarate
  • succinate was determined using density analyzer unit.
  • flowability measurements for the salts were measured using Hanson Flodex unit.
  • Solubility of ⁇ -GPA fumarate was measured gravimetrically in fifteen different solvents and solvent mixtures at 15 and 45° C. About 100 mg of the compound was dispensed in ten volumes (1 mL) of the solvent/solvent mixture and slurried for 48 hours. Table 23 represents the solubility of ⁇ -GPA fumarate in different solvents. After 48 hours the vials were centrifuged. The supernatant was collected and left for slow evaporation under vacuum at 45° C. and solubility was determined. The solids obtained after centrifugation and evaporation were analyzed by XRPD. The XRPD analysis of the precipitates after 48 hours slurries revealed no form transformations for 1:1 ⁇ -GPA fumarate.
  • ⁇ -GPA fumarate was slurried in tetrahydrofuran:water (1:1) for 48 hours. The filtrate was set up for evaporation at 45° C. under vacuum, and after overnight evaporation an off-white solid was obtained. Both the solids from the slurry and the solids obtained after slow evaporation were analyzed by XRPD ( FIG. 33 ).
  • Pattern 7B obtained by slow evaporation (45° C.) of the filtrate of ⁇ -GPA fumarate from the slurry experiment in tetrahydrofuran:water (1:1), was analyzed by DSC and 1 H-NMR. The DSC revealed the presence of an endotherm at 161° C. and also traces of Pattern 7A (the original ⁇ -GPA fumarate salt).
  • Anti-solvent addition experiments for 1:1 ⁇ -GPA fumarate were performed by using different anti-solvents. A given amount of 1:1 ⁇ -GPA fumarate was dissolved in the solvent at 50° C. Around 1 mL of ice cold anti-solvent was added to salt solution and continued stirring in ice bath for 2 hours followed by overnight stirring at 20° C. None of the experiments resulted in a new form of ⁇ -GPA fumarate.
  • Neat and solvent drop grinding experiments were also performed as a part of polymorph screening. Around 30 mg of the sample was ground in the presence of 20 ⁇ L of solvent (tetrahydrofuran, isopropanol, acetone, water, or t-butylmethylether) for 5 minutes using mortar and pestle. After grinding, the samples were analyzed by XRPD. All the experiments resulted in XRPDs that were identical to Pattern 7A.
  • solvent tetrahydrofuran, isopropanol, acetone, water, or t-butylmethylether
  • the microscopic image of the sample revealed the presence of some amorphous material. It could be possible that excess of fumaric acid after the formation of 2:1 ⁇ -GPA fumarate salt might have transformed to amorphous as seen in the microscopic image of the lyophilized sample
  • Pattern 7C was slurried in 0.2 mL of Pattern 7C to water.
  • Pattern 7A (within 10 minutes)
  • the DSC of the lyophilized sample revealed the presence of an exothermic event (possible recrystallization or solid phase transformation) followed by two endothermic events ( FIG. 36 ).
  • the first endothermic event could be the 1:1 ⁇ -GPA fumarate salt followed by the melting of possible side product which might have formed after the melting of 1:1 ⁇ -GPA fumarate salt.
  • Pattern 7D Heating of ⁇ -GPA fumarate (2162-84-7) at 160-165° C. resulted in a yellow to brownish solid (possible side reaction followed by decomposition) which was further analyzed by 1H-NMR and XRPD.
  • Pattern 7A (the original 1:1 ⁇ -GPA fumarate form) appears to be the most stable form.
  • Raman spectroscopy of the 1:1 ⁇ -GPA fumarate salt was carried out on a Bruker IFS 66V/S FT-IR/FT-Raman spectrometer equipped with a 1064 nm laser ( FIG. 37 ).
  • the peak list of the Raman spectra is listed in Table 26.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Oncology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US15/245,750 2015-08-25 2016-08-24 PHARMACEUTICALLY ACCEPTABLE SALTS OF beta-GUANIDINOPROPIONIC ACID WITH IMPROVED PROPERTIES AND USES THEREOF Abandoned US20170056352A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US15/245,750 US20170056352A1 (en) 2015-08-25 2016-08-24 PHARMACEUTICALLY ACCEPTABLE SALTS OF beta-GUANIDINOPROPIONIC ACID WITH IMPROVED PROPERTIES AND USES THEREOF
US15/281,329 US9827217B2 (en) 2015-08-25 2016-09-30 Pharmaceutically acceptable salts of B-guanidinopropionic acid with improved properties and uses thereof
US15/795,540 US10512623B2 (en) 2015-08-25 2017-10-27 Pharmaceutically acceptable salts of B-Guanidinopropionic acid with improved properties and uses thereof
US16/675,669 US20200138759A1 (en) 2015-08-25 2019-11-06 Pharmaceutically acceptable salts of beta-guanidinopropionic acid with improved properties and uses thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562209624P 2015-08-25 2015-08-25
US15/245,750 US20170056352A1 (en) 2015-08-25 2016-08-24 PHARMACEUTICALLY ACCEPTABLE SALTS OF beta-GUANIDINOPROPIONIC ACID WITH IMPROVED PROPERTIES AND USES THEREOF

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/281,329 Continuation US9827217B2 (en) 2015-08-25 2016-09-30 Pharmaceutically acceptable salts of B-guanidinopropionic acid with improved properties and uses thereof

Publications (1)

Publication Number Publication Date
US20170056352A1 true US20170056352A1 (en) 2017-03-02

Family

ID=58100994

Family Applications (4)

Application Number Title Priority Date Filing Date
US15/245,750 Abandoned US20170056352A1 (en) 2015-08-25 2016-08-24 PHARMACEUTICALLY ACCEPTABLE SALTS OF beta-GUANIDINOPROPIONIC ACID WITH IMPROVED PROPERTIES AND USES THEREOF
US15/281,329 Active US9827217B2 (en) 2015-08-25 2016-09-30 Pharmaceutically acceptable salts of B-guanidinopropionic acid with improved properties and uses thereof
US15/795,540 Active US10512623B2 (en) 2015-08-25 2017-10-27 Pharmaceutically acceptable salts of B-Guanidinopropionic acid with improved properties and uses thereof
US16/675,669 Abandoned US20200138759A1 (en) 2015-08-25 2019-11-06 Pharmaceutically acceptable salts of beta-guanidinopropionic acid with improved properties and uses thereof

Family Applications After (3)

Application Number Title Priority Date Filing Date
US15/281,329 Active US9827217B2 (en) 2015-08-25 2016-09-30 Pharmaceutically acceptable salts of B-guanidinopropionic acid with improved properties and uses thereof
US15/795,540 Active US10512623B2 (en) 2015-08-25 2017-10-27 Pharmaceutically acceptable salts of B-Guanidinopropionic acid with improved properties and uses thereof
US16/675,669 Abandoned US20200138759A1 (en) 2015-08-25 2019-11-06 Pharmaceutically acceptable salts of beta-guanidinopropionic acid with improved properties and uses thereof

Country Status (16)

Country Link
US (4) US20170056352A1 (OSRAM)
EP (1) EP3340973B1 (OSRAM)
JP (2) JP6880023B2 (OSRAM)
KR (1) KR102707964B1 (OSRAM)
CN (2) CN114057611A (OSRAM)
AU (1) AU2016311368B2 (OSRAM)
CA (1) CA2996520C (OSRAM)
DK (1) DK3340973T3 (OSRAM)
ES (1) ES2843561T3 (OSRAM)
HR (1) HRP20210044T1 (OSRAM)
HU (1) HUE053963T2 (OSRAM)
PL (1) PL3340973T3 (OSRAM)
PT (1) PT3340973T (OSRAM)
RS (1) RS61804B1 (OSRAM)
SI (1) SI3340973T1 (OSRAM)
WO (1) WO2017035331A1 (OSRAM)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9884813B1 (en) * 2017-03-01 2018-02-06 Rgenix, Inc. Pharmaceutically acceptable salts of B-guanidinopropionic acid with improved properties and uses thereof
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US10512623B2 (en) 2015-08-25 2019-12-24 Rgenix, Inc. Pharmaceutically acceptable salts of B-Guanidinopropionic acid with improved properties and uses thereof
WO2021119316A1 (en) * 2019-12-11 2021-06-17 Rgenix, Inc. Methods of treating cancer

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3950673A1 (en) 2014-04-30 2022-02-09 Inspirna, Inc. Inhibitors of creatine transport and uses thereof
US20190125745A1 (en) * 2014-12-17 2019-05-02 Rgenix, Inc. Treatment and diagnosis of cancer
EP3713575A4 (en) 2017-11-21 2021-08-25 Rgenix, Inc. POLYMORPHS AND THEIR USES
HUE067466T2 (hu) 2019-12-13 2024-10-28 Inspirna Inc Fémsók és alkalmazásuk
KR102615692B1 (ko) 2021-10-13 2023-12-19 주식회사 휴엔켐 베타-구아니디노프로피온산을 포함하는 간섬유화 예방 또는 치료용 조성물
CN119421865A (zh) * 2022-04-21 2025-02-11 默沙东有限责任公司 制备附聚的结晶中链脂肪酸钠盐的方法
KR102822799B1 (ko) 2022-11-09 2025-06-20 충남대학교산학협력단 베타-구아니디노프로피온산을 포함하는 장내 미생물 개선용 조성물

Family Cites Families (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA101653A (en) 1906-08-30 1906-10-23 Herman Besser Mould
BE794886A (fr) * 1972-02-22 1973-08-02 Pfizer Acides 6-(alpha-(omega-guanidinoalcanoylamino)acylamino)-penicillaniques
US3933797A (en) * 1972-02-22 1976-01-20 Pfizer Inc. 6-[α-(ω-QUANIDINOALKANOYLAMIDO)ACYLAMIDO]PENICILLANIC ACIDS
US3972872A (en) 1974-09-23 1976-08-03 Pfizer Inc. 6-[α-(ω-Guanidinoalkanoylamido)acylamido]penicillanic acids
ATE70048T1 (de) 1986-09-10 1991-12-15 Syntex Inc Selektive amidinierung von diaminen.
US5676978A (en) * 1989-02-14 1997-10-14 Amira, Inc. Methods of inhibiting undesirable cell growth using a combination of a cyclocreatine compound and a hyperplastic inhibitory agent
CA2028593C (en) * 1989-10-31 2007-08-21 Douglas R. Brandt Stabilized enzyme compositions
DE4334639A1 (de) 1993-10-11 1995-04-13 Inst Neue Mat Gemein Gmbh Verfahren zur Herstellung von TiN-Sinterkörpern und -Schichten
DE793646T1 (de) 1994-11-23 1999-12-30 Pharmacia & Upjohn Co., Kalamazoo Carboxylierte aminoguanidine zum behandlung von insulin-unabhängigem diabetes mellitus
US5994577A (en) 1994-11-23 1999-11-30 Larsen; Scott D. Aminoguanidine carboxylates for the treatment of non-insulin-dependent diabetes mellitus
JP3745439B2 (ja) 1995-07-06 2006-02-15 花王株式会社 皮膚外用剤
TW453881B (en) 1995-10-16 2001-09-11 Kao Corp Cosmetic composition comprising amide derivatives
JPH09202710A (ja) * 1995-11-20 1997-08-05 Kao Corp しわ改善剤
AU3117497A (en) 1996-05-21 1997-12-09 Pharmacia & Upjohn Company Aminoguanidine carboxylate lactams for the treatment of non-insulin-dependent diabetes mellitus
JP4317599B2 (ja) 1996-06-26 2009-08-19 武田薬品工業株式会社 徐放性製剤
EP1093370B1 (en) 1998-06-30 2006-02-22 Takeda Pharmaceutical Company Limited Pharmaceutical composition for the treatment of diabetes
EP1656945A1 (en) 1999-06-05 2006-05-17 The Board Of Trustees Of The Leland Stanford Junior University Pharmaceutical composition comprising oligoarginine
US6605115B1 (en) 1999-06-05 2003-08-12 Board Of Trustees Of The Leland Stanford Junior University Method and composition for inhibiting cardiovascular cell proliferation
US6242491B1 (en) 1999-06-25 2001-06-05 Rima Kaddurah-Daouk Use of creatine or creatine compounds for skin preservation
US20020082448A1 (en) 1999-11-08 2002-06-27 The Upjohn Company Aminoguanidine carboxylates for the treatment of non-insulin-dependent diabetes mellitus
US7335723B2 (en) 2001-08-08 2008-02-26 Merck & Co., Inc. Melanin-concentrating hormone antagonists
EP1465609A2 (en) 2001-11-07 2004-10-13 Medical Research Council Modulation of dopaminergic neurons
CA2473229A1 (en) 2002-01-09 2003-07-24 Merck & Co., Inc. Selective melanin-concentrating hormone type -1 receptor agonists
US20120245211A1 (en) 2002-06-04 2012-09-27 Children's Hospital Medical Center Methods of Treating Cognitive Dysfunction by Modulating Brain Energy Metabolism
EP1567180A4 (en) 2002-06-04 2010-03-10 Avicena Group Inc METHODS OF TREATING COGNITIVE DYSFUNCTIONS BY MODULATING BRAIN ENERGY METABOLISM
GB0302882D0 (en) 2003-02-07 2003-03-12 Univ Cardiff Improvements in or relating to agents for the treatment of cardiovascular dysfunction and weight loss
EP1746099A1 (en) 2004-12-23 2007-01-24 DeveloGen Aktiengesellschaft Mnk1 or Mnk2 inhibitors
JP4865251B2 (ja) 2005-05-09 2012-02-01 株式会社 資生堂 不全角化抑制剤、毛穴縮小剤及び皮膚外用組成物
KR101355868B1 (ko) 2005-08-02 2014-01-27 알즈켐 아게 구아니디노아세트산 성분에 기반한 액체 제제
WO2008054544A2 (en) 2006-05-22 2008-05-08 Immune Disease Institute, Inc. Method for delivery across the blood brain barrier
WO2008043024A2 (en) 2006-10-04 2008-04-10 Kalypsys, Inc. Oral pharmaceutical formulation comprising a sulfonyl bicyclic modulator of ppar for the treatment of disease
CN101594778A (zh) 2006-12-11 2009-12-02 凯姆制药公司 苯丙胺的非标准氨基酸结合物及其制备和使用的方法
DE102007004781A1 (de) 2007-01-31 2008-08-07 Alzchem Trostberg Gmbh Verwendung von Guanidinoessigsäure(-Salzen) zur Herstellung eines gesundheitsfördernden Mittels
CA2674020A1 (en) 2007-02-08 2008-08-14 Kempharm, Inc. Polar hydrophilic prodrugs of amphetamine and other stimulants and processes for making and using the same
EP2197890A1 (en) 2007-09-07 2010-06-23 Gencia Corporation Mitochondrial compositions and uses thereof
WO2009098142A1 (en) 2008-02-06 2009-08-13 Helm Ag Prasugrel salts with improved properties
BRPI0907287B1 (pt) 2008-12-19 2018-01-02 L'oréal "processo de clareamento ou de coloração das fibras queratínicas e dispositivo com vários comportamentos"
FR2940077B1 (fr) 2008-12-19 2012-07-20 Oreal Procede de coloration eclaircissante de matieres keratiniques mettant en oeuvre une composition anhydre colorante comprenant un agent alcalin et une composition oxydante.
FR2940104B1 (fr) 2008-12-19 2011-08-19 Oreal Procede de traitement des cheveux mettant en oeuvre une emulsion directe comprenant un agent oxydant et une composition contenant un agent alcalin
JP5866137B2 (ja) 2009-04-30 2016-02-17 ロレアル アミノトリアルコキシシランまたはアミノトリアルケニルオキシシラン化合物を含む組成物を用いたヒトケラチン繊維の明色化および／または着色ならびに装置
WO2011031308A1 (en) 2009-09-09 2011-03-17 Cytokinetics, Incorporated Novel combinations
CN102573888A (zh) 2009-09-18 2012-07-11 诺和诺德公司 长效y2 受体激动剂
FR2954160B1 (fr) 2009-12-22 2012-03-30 Oreal Composition de coloration ou d'eclaircissement comprenant un corps gras et un polymere amphotere
CN104586859B (zh) 2009-12-31 2017-12-05 凯姆制药公司 喹硫平的氨基酸缀合物、其制备和使用方法
DE102010012199A1 (de) 2010-03-19 2011-09-22 Fresenius Medical Care Deutschland Gmbh Molekular geprägte Polymere für die Eliminierung von Metaboliten
FR2958161B1 (fr) 2010-04-02 2012-04-27 Oreal Procede de traitement des cheveux mettant en oeuvre une emulsion directe comprenant un agent oxydant et une emulsion directe contenant un agent alcalin
WO2011127933A1 (en) 2010-04-16 2011-10-20 Nuevolution A/S Bi-functional complexes and methods for making and using such complexes
WO2011133150A1 (en) 2010-04-21 2011-10-27 Pharmacofore, Inc. Compositions comprising enzyme-cleavable prodrugs of active agents and inhibitors thereof
EP2560489A4 (en) 2010-04-21 2014-01-22 Signature Therapeutics Inc COMPOSITIONS WITH ENZYMSPALTBAR OPIOID PRODRUGS AND HEMMER FOR THIS
US20110262359A1 (en) 2010-04-21 2011-10-27 Jenkins Thomas E Compositions comprising enzyme-cleavable prodrugs of active agents and inhibitors thereof
US20110262355A1 (en) 2010-04-21 2011-10-27 Jenkins Thomas E Compositions comprising enzyme-cleavable opioid prodrugs and inhibitors thereof
US20130059914A1 (en) 2010-04-21 2013-03-07 Signature Therapeutics, Inc. Compositions Comprising Enzyme-Cleavable Amphetamine Prodrugs and Inhibitors Thereof
RU2012151500A (ru) 2010-05-03 2014-06-10 Дженентек, Инк. Композиции и способы, пригодные для снижения вязкости белковосодержащих составов
WO2011143534A1 (en) 2010-05-13 2011-11-17 The Mclean Hospital Corporation Methods for the treatment of psychiatric disorders
EP2399885A1 (en) 2010-06-22 2011-12-28 Ulrich Dietz Device and method for solubilizing, separating, removing and reacting carboxylic acids in aqueous or organic solutions by means of micro- or nanoemulsification
WO2012024611A1 (en) 2010-08-20 2012-02-23 Natural Alternatives International, Inc. Methods of treating sarcopenia and frailty
WO2012047630A2 (en) 2010-09-27 2012-04-12 Martin Teintze N-alkyl or n-aryl substituted guanide and biguanide compounds and methods of their use
US8765115B2 (en) 2010-12-01 2014-07-01 National Institute of Agrobiological Scienses Method of treatment of gastrointestinal disorders with IL-10
US20120232066A1 (en) 2011-03-09 2012-09-13 Jenkins Thomas E Compositions for reducing risk of adverse events caused by drug-drug interactions
WO2012122420A2 (en) 2011-03-09 2012-09-13 Pharmacofore, Inc. Opioid prodrugs with heterocyclic linkers
EP2683394B1 (en) 2011-03-09 2021-01-06 Signature Therapeutics, Inc. Active agent prodrugs with heterocyclic linkers
WO2012138214A1 (en) 2011-04-08 2012-10-11 Brewster Lizzy Maritza Beta-guanidinopropionic acid for the treatment of hypertension
WO2012173846A2 (en) 2011-06-06 2012-12-20 Aileron Therapeutics, Inc. Peptidomimetic macrocycles
CN102850242A (zh) * 2011-06-27 2013-01-02 天津天成制药有限公司 胍基丙酸硝酸盐的制备方法
US8427223B2 (en) 2011-07-19 2013-04-23 Lsi Corporation Voltage level translator circuit for reducing jitter
BR112014002084B1 (pt) 2011-07-28 2022-03-29 Kempharm, Inc Composição de pró-fármaco e uso de conjugado de metilfenidato
TW201806968A (zh) 2011-10-18 2018-03-01 艾利倫治療公司 擬肽巨環化合物
FR2983407B1 (fr) 2011-12-06 2014-01-03 Oreal Composition aqueuse riche en huile et son utilisation dans un procede de coloration d'oxydation ou de decoloration
BR112014020103A2 (pt) 2012-02-15 2018-10-09 Aileron Therapeutics, Inc. macrociclos peptidomiméticos
CA2864120A1 (en) 2012-02-15 2013-08-22 Aileron Therapeutics, Inc. Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles
MX2014014902A (es) 2012-06-05 2015-03-04 Neuroderm Ltd Composiciones que comprenden apomorfina y acidos organicos y usos de las mismas.
US9221789B2 (en) 2012-06-22 2015-12-29 Basf Se Multicomponent crystals comprising imatinib mesilate and selected co-crystal formers
CN114177166B (zh) * 2012-10-31 2024-07-30 洛克菲勒大学 结肠癌的治疗和诊断
FR2997846B1 (fr) 2012-11-09 2023-10-20 Oreal Composition comprenant un derive dicarbonyle et un acide, le procede de lissage des fibres keratiniques a partir de cette composition
WO2014138492A1 (en) 2013-03-08 2014-09-12 Solan, LLC Methods for fabricating graphite-based structures and devices made therefrom
CN103288685B (zh) * 2013-07-03 2015-02-18 郭礼强 一种3-胍基丙酸的制备方法
US20170056352A1 (en) 2015-08-25 2017-03-02 Rgenix, Inc. PHARMACEUTICALLY ACCEPTABLE SALTS OF beta-GUANIDINOPROPIONIC ACID WITH IMPROVED PROPERTIES AND USES THEREOF
WO2018160178A1 (en) 2017-03-01 2018-09-07 Rgenix, Inc. Pharmaceutically acceptable salts of b-guanidinopropionic acid with improved properties and uses thereof

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10512623B2 (en) 2015-08-25 2019-12-24 Rgenix, Inc. Pharmaceutically acceptable salts of B-Guanidinopropionic acid with improved properties and uses thereof
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US10385130B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US11535670B2 (en) 2016-05-11 2022-12-27 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US12122833B2 (en) 2016-05-11 2024-10-22 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US9884813B1 (en) * 2017-03-01 2018-02-06 Rgenix, Inc. Pharmaceutically acceptable salts of B-guanidinopropionic acid with improved properties and uses thereof
WO2021119316A1 (en) * 2019-12-11 2021-06-17 Rgenix, Inc. Methods of treating cancer
US12011427B2 (en) 2019-12-11 2024-06-18 Inspirna, Inc. Methods of treating cancer

Also Published As

Publication number Publication date
DK3340973T3 (da) 2021-01-11
RS61804B1 (sr) 2021-06-30
CA2996520A1 (en) 2017-03-02
US20180243248A1 (en) 2018-08-30
HK1257822A1 (en) 2019-11-01
JP2021121597A (ja) 2021-08-26
JP7134294B2 (ja) 2022-09-09
PL3340973T3 (pl) 2021-06-14
SI3340973T1 (sl) 2021-07-30
CA2996520C (en) 2024-11-19
CN108472269B (zh) 2021-11-02
EP3340973A4 (en) 2019-04-03
KR20180059446A (ko) 2018-06-04
AU2016311368A1 (en) 2018-03-29
KR102707964B1 (ko) 2024-09-20
CN114057611A (zh) 2022-02-18
ES2843561T3 (es) 2021-07-19
EP3340973A1 (en) 2018-07-04
AU2016311368B2 (en) 2020-10-08
CN108472269A (zh) 2018-08-31
PT3340973T (pt) 2021-01-19
JP6880023B2 (ja) 2021-06-02
US20200138759A1 (en) 2020-05-07
EP3340973B1 (en) 2020-10-14
US10512623B2 (en) 2019-12-24
JP2018531280A (ja) 2018-10-25
HRP20210044T1 (hr) 2021-04-30
HUE053963T2 (hu) 2021-07-28
US9827217B2 (en) 2017-11-28
US20170056353A1 (en) 2017-03-02
WO2017035331A1 (en) 2017-03-02

Similar Documents

Publication Publication Date Title
US10512623B2 (en) Pharmaceutically acceptable salts of B-Guanidinopropionic acid with improved properties and uses thereof
US9884813B1 (en) Pharmaceutically acceptable salts of B-guanidinopropionic acid with improved properties and uses thereof
US20220054664A1 (en) Pharmacokinetic enhancements of bifunctional chelates and uses thereof
US8293726B2 (en) Treatment of cancer and other diseases
ES2542647T3 (es) Derivados de pirido[2,3 b]pirazina y sus usos terapéuticos
EP3068443B1 (en) Residualizing linkers and uses thereof
WO2022087375A1 (en) Novel heterocyclic compounds
WO2022087371A1 (en) Novel bicyclic compounds
EP3137447B1 (en) Inhibitors of creatine transport and uses thereof
US20250114488A1 (en) Psma-targeted radiopharmaceuticals and checkpoint inhibitor combination therapy
WO2004007676A2 (en) Combination therapy for the treatment of neoplasms
WO2016176636A1 (en) Inhibitors of creatine transport and uses thereof
PT1963295E (pt) Derivados de 3,6-di-hidro-2-oxo-6h(1,3,4)-tiadiazina
HK1257822B (en) Pharmaceutically acceptable salts of beta-guanidinopropionic acid with improved properties and uses thereof
US20230150976A1 (en) 4-Amino Pyrimidine Compounds for the Treatment of Cancer
US20250177581A1 (en) Ntsr1-targeted radiopharmaceuticals and dna damage response inhibitor combination therapy
TW202506204A (zh) Psma靶向放射性藥物及dna損傷反應抑制劑之組合療法
US20250099633A1 (en) Ntsr1-targeted radiopharmaceuticals and checkpoint inhibitor combination therapy
EA045232B1 (ru) Усиление фармакокинетики бифункциональных хелатов и их применения
WO2005117847A2 (en) Methods and compounds for the treatment of neoplasms
HK1235391B (en) Inhibitors of creatine transport and uses thereof

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION