WO2025128564A1 - Formes salines d'un modulateur du récepteur glp-1 - Google Patents

Formes salines d'un modulateur du récepteur glp-1 Download PDF

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Publication number
WO2025128564A1
WO2025128564A1 PCT/US2024/059371 US2024059371W WO2025128564A1 WO 2025128564 A1 WO2025128564 A1 WO 2025128564A1 US 2024059371 W US2024059371 W US 2024059371W WO 2025128564 A1 WO2025128564 A1 WO 2025128564A1
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Prior art keywords
compound
salt form
salt
xrpd pattern
erbumine
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Xiaoyang Wang
Xiaoyu Ma
Yanan WU
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Carmot Therapeutics Inc
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Carmot Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • FIG. 30 are TGA and DSC thermograms of Compound 1 erbumine salt Form D.
  • FIG. 34 is a 1 H NMR spectrum of Compound 1 erbumine salt Form E.
  • Compound 1 sodium salt Form B is characterized by all of the following:
  • Compound 1 sodium salt Form B is characterized by (1) an XRPD pattern substantially in accordance with FIG. 12 and at least one of the following:
  • Compound 1 sodium salt Form B is characterized by (1) an XRPD pattern substantially in accordance with FIG. 12 and:
  • Compound 1 sodium salt Form D is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising three or more peaks selected from 5.55, 11.08, 12.23, 12.47, 12.84, 13.05, 13.88, 14.10, 14.73, 15.56, 16.47, 17.09, 17.85, 18.29, 18.63,
  • Compound 1 sodium salt Form D is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising five or more peaks selected from 5.55, 11.08, 12.23, 12.47, 12.84, 13.05, 13.88, 14.10, 14.73, 15.56, 16.47, 17.09, 17.85, 18.29, 18.63,
  • Compound 1 sodium salt Form D is characterized by (1) an
  • 1 erbumine salt is characterized as Compound 1 erbumine salt Form A (1 : 1.0) (stoichiometric ratio of Compound 1 : erbumine).
  • Compound 1 erbumine salt Form A is characterized by an
  • Compound 1 erbumine salt Form A is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising peaks at 9.46, 10.26, 11.90, 19.40, and 20.28.
  • Compound 1 erbumine salt Form A is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising all of the peaks 9.46, 10.26, 11.24, 11.90, 16.94, 17.40, 18.73, 19.40, 20.28, 20.95, and 22.12.
  • Compound 1 erbumine salt Form A is characterized by the XRPD pattern substantially in accordance with FIG. 20.
  • Compound 1 erbumine salt Form A is characterized by the DSC thermogram substantially in accordance with FIG. 21 indicating decomposition upon melting.
  • Compound 1 erbumine salt Form A is characterized by the TGA thermogram substantially in accordance with FIG. 22.
  • Compound 1 erbumine salt Form A is characterized by the ’l l NMR spectrum in d6-DMSO substantially in accordance with FIG. 23 indicating no detectable residual solvent.
  • Compound 1 erbumine salt Form A is characterized by at least one of the following:
  • Compound 1 erbumine salt Form A is characterized by at least two of the following:
  • Compound 1 erbumine salt Form A is characterized by (1) an
  • Compound 1 erbumine crystalline salt is characterized as Compound 1 erbumine salt Form B.
  • the XRPD pattern of Compound 1 erbumine salt Form B was recorded in reflection geometry.
  • Compound 1 erbumine salt Form B is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising five or more peaks selected from 4.74, 5.52, 7.39, 9.40, 9.84, 11.04, 12.35, 14.29, 15.09, 16.49, 17.76, 18.09, 19.26, 20.07, 20.57, 21.06,
  • Compound 1 erbumine salt Form B is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising ten or more peaks selected from 4.74, 5.52, 7.39, 9.40, 9.84, 11.04, 12.35, 14.29, 15.09, 16.49, 17.76, 18.09, 19.26, 20.07, 20.57, 21.06,
  • Compound 1 erbumine salt Form B is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising peaks at 9.84, 11.04, and 19.26.
  • Compound 1 erbumine salt Form B is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising peaks at 9.84, 11.04, 19.26, 20.07, and 21.06.
  • Compound 1 erbumine salt Form B is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising peaks at 5.52, 9.84, 11.04, 17.76, 18.09, 19.26, 20.07, 21.06, 22.14, and 23.72.
  • Compound 1 erbumine salt Form B is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising all of the peaks 4.74, 5.52, 7.39, 9.40, 9.84, 11.04, 12.35, 14.29, 15.09, 16.49, 17.76, 18.09, 19.26, 20.07, 20.57, 21.06, 22.14, and 23.72.
  • Compound 1 erbumine salt Form B is characterized by the XRPD pattern substantially in accordance with FIG. 24. [00233] A list of the peaks from the XRPD pattern for Compound 1 erbumine salt Form B is provided in Table 6 below.
  • Compound 1 erbumine salt Form D is characterized by the TGA and DSC thermograms substantially in accordance with FIG. 30.
  • Compound 1 erbumine salt Form D is characterized by the TGA and DSC thermograms showing endothermic peak onsets at about 116 °C - 120 °C and 174 °C - 178 °C.
  • Compound 1 erbumine salt Form D is characterized by the TGA and DSC thermograms showing endothermic peak onsets at about 117.8 and about 176.3 °C.
  • Compound 1 erbumine salt Form D is characterized by the 'HNMR spectrum in d6-DMSO substantially in accordance with FIG. 31 indicating no residual solvent.
  • Compound 1 erbumine salt Form D is characterized by at least one of the following:
  • Compound 1 erbumine salt Form D is characterized by at least one of the following:
  • Compound 1 erbumine salt Form D is characterized by at least two of the following:
  • Compound 1 erbumine salt Form D is characterized by (1) an XRPD pattern substantially in accordance with FIG. 29 and at least one of the following:
  • Compound 1 erbumine salt Form D is characterized by (1) an XRPD pattern substantially in accordance with FIG. 29 and:
  • Compound 1 erbumine crystalline salt is characterized as Compound 1 erbumine salt Form E.
  • Compound 1 erbumine salt is characterized as Compound 1 erbumine salt Form E (1 :1.0) (stoichiometric ratio of Compound 1 : erbumine)
  • Compound 1 erbumine salt Form E is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising one or more peaks selected from 5.85, 7.49, 8.43, 9.62, 10.43, 11.28, 11.68, 12.53, 13.25, 13.71, 14.82, 15.12, 15.51, 16.37, 17.26, 17.61, 18.20, 18.71, 19.31, 19.91, 20.84, 21.93, 22.37, 23.26, 24.13, 25.96, 27.22, and 30.28.
  • Compound 1 erbumine salt Form E is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising three or more peaks selected from 5.85, 7.49, 8.43, 9.62, 10.43, 11.28, 11.68, 12.53, 13.25, 13.71, 14.82, 15.12, 15.51, 16.37, 17.26, 17.61, 18.20, 18.71, 19.31, 19.91, 20.84, 21.93, 22.37, 23.26, 24.13, 25.96, 27.22, and 30.28.
  • Compound 1 erbumine salt Form E is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising five or more peaks selected from 5.85, 7.49, 8.43, 9.62, 10.43, 11.28, 11.68, 12.53, 13.25, 13.71, 14.82, 15.12, 15.51, 16.37, 17.26, 17.61, 18.20, 18.71, 19.31, 19.91, 20.84, 21.93, 22.37, 23.26, 24.13, 25.96, 27.22, and 30.28.
  • Compound 1 erbumine salt Form E is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising ten or more peaks selected from 5.85, 7.49,
  • Compound 1 erbumine salt Form E is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising peaks at 11.68, 18.71, and 19.31.
  • Compound 1 erbumine salt Form E is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising peaks at 11.68, 18.20, 18.71, 19.31, and 19.91.
  • Compound 1 erbumine salt Form E is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising peaks at 5.85, 11.68, 13.25, 18.20, 18.71, 19.31, 19.91, 23.26, 24.13, and 25.96.
  • Compound 1 erbumine salt Form E is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising all of the peaks 5.85, 7.49, 8.43, 9.62,
  • Compound 1 erbumine salt Form E is characterized by the XRPD pattern substantially in accordance with FIG. 32.
  • Compound 1 erbumine salt Form E is characterized by the TGA and DSC thermograms substantially in accordance with FIG. 33.
  • Compound 1 erbumine salt Form E is characterized by a DSC thermogram showing endothermic peak onsets at about 0.6 °C - 1.0 °C and about 159 °C - 163 °C.
  • Compound 1 erbumine salt Form E is characterized by a TGA thermogram showing about 1.0 - 1.2 percent weight loss from 25 °C to 100 °C.
  • Compound 1 erbumine salt Form E is characterized by the TGA and DSC thermograms showing endothermic peak onsets at about 0.8 °C and about 161 °C and showing about 1.1 percent weight loss from 25 °C to 100 °C.
  • Compound 1 erbumine salt Form E is characterized by the T H NMR spectrum in d6-DMSO substantially in accordance with FIG. 34 indicating 0.4 percent residual solvent.
  • Compound 1 erbumine salt Form E is characterized by at least one of the following:
  • Compound 1 erbumine salt Form E is characterized by at least one of the following:
  • Compound 1 erbumine salt Form E is characterized by at least two of the following:
  • Compound 1 erbumine salt Form E is characterized by all of the following:
  • Compound 1 erbumine salt Form E is characterized by (1) an XRPD pattern substantially in accordance with FIG. 32 and at least one of the following:
  • Compound 1 erbumine salt Form E is characterized by (1) an XRPD pattern substantially in accordance with FIG. 32 and: (2) a DSC thermogram substantially in accordance with FIG. 33; and
  • Compound 1 erbumine crystalline salt is characterized as Compound 1 erbumine salt Form F.
  • Compound 1 erbumine salt is characterized as Compound 1 erbumine salt Form F (1 :1.0) (stoichiometric ratio of Compound 1 : erbumine).
  • Compound 1 erbumine salt Form F is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising one or more peaks selected from 3.17, 5.12, 5.78, 6.47, 7.67, 8.91, 9.72, 10.46, 11.24, 11.96, 13.46, 14.41, 14.80, 15.70, 16.38, 17.11, 17.40, 18.06, 18.38, 18.80, 19.59, 20.63, 20.86, 21.16, 21.94, 22.79, 23.66, 24.580 26.17, and 26.82.
  • Compound 1 erbumine salt Form F is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising three or more peaks selected from 3.17, 5.12, 5.78, 6.47, 7.67, 8.91, 9.72, 10.46, 11.24, 11.96, 13.46, 14.41, 14.80, 15.70, 16.38, 17.11, 17.40, 18.06, 18.38, 18.80, 19.59, 20.63, 20.86, 21.16, 21.94, 22.79, 23.66, 24.580 26.17, and
  • Compound 1 erbumine salt Form F is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising five or more peaks selected from 3.17, 5.12, 5.78, 6.47, 7.67, 8.91, 9.72, 10.46, 11.24, 11.96, 13.46, 14.41, 14.80, 15.70, 16.38, 17.11, 17.40, 18.06, 18.38, 18.80, 19.59, 20.63, 20.86, 21.16, 21.94, 22.79, 23.66, 24.580 26.17, and
  • Compound 1 erbumine salt Form F is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising ten or more peaks selected from 3.17, 5.12, 5.78, 6.47, 7.67, 8.91, 9.72, 10.46, 11.24, 11.96, 13.46, 14.41, 14.80, 15.70, 16.38, 17.11, 17.40, 18.06, 18.38, 18.80, 19.59, 20.63, 20.86, 21.16, 21.94, 22.79, 23.66, 24.580 26.17, and 26.82.
  • Compound 1 erbumine salt Form F is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising peaks at 11.24, 18.38, and 20.86.
  • Compound 1 erbumine salt Form F is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising peaks at 9.72, 11.24, 18.06, 18.38, and 20.86.
  • Compound 1 erbumine salt Form E is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising peaks at 3.17, 9.72, 10.46, 11.24, 13.46, 18.06, 18.38, 18.80, 20.63, and 20.86.
  • Compound 1 erbumine salt Form F is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising all of the peaks 3.17, 5.12, 5.78, 6.47, 7.67, 8.91, 9.72, 10.46, 11.24, 11.96, 13.46, 14.41, 14.80, 15.70, 16.38, 17.11, 17.40, 18.06, 18.38, 18.80, 19.59, 20.63, 20.86, 21.16, 21.94, 22.79, 23.66, 24.580 26.17, and 26.82.
  • Compound 1 erbumine salt Form F is characterized by the XRPD pattern substantially in accordance with FIG. 35.
  • Compound 1 erbumine salt Form F is characterized by the DSC and TGA thermograms substantially in accordance with FIG. 36.
  • Compound 1 erbumine salt Form F is characterized by the DSC and TGA thermograms showing endothermic peak onsets about 36 °C - 41 °C, about 116 °C - 120 °C, and about 144 °C - 148 °C and showing about 1.0 - 1.2 percent weight loss from 30 °C to 80 °C and about 6.5 - 8.5 percent weight loss from 80 °C to 150 °C.
  • Compound 1 erbumine salt Form F is characterized by the DSC and TGA thermograms showing endothermic peak onsets at about 37.9 °C, 117.7 °C, and 146.0 °C and showing about 1.1 percent weight loss from 30 °C to 80 °C and about 7.5 percent weight loss from 80 °C to 150 °C.
  • Compound 1 erbumine salt Form F is characterized by the ’H NMR spectrum in d6-DMSO substantially in accordance with FIG. 37 indicating no residual solvent.
  • Compound 1 erbumine salt Form F is characterized by at least one of the following:
  • Compound 1 erbumine salt Form F is characterized by at least one of the following:
  • Compound 1 erbumine salt Form F is characterized by at least two of the following:
  • Compound 1 erbumine salt Form F is characterized by all of the following:
  • Compound 1 erbumine salt Form F is characterized by (1) an XRPD pattern substantially in accordance with FIG. 35 and at least one of the following:
  • Compound 1 erbumine salt Form F is characterized by (1) an XRPD pattern substantially in accordance with FIG. 35 and:
  • the salt is Compound 1 L-arginine salt.
  • Compound 1 L-arginine salt is amorphous.
  • Compound 1 L-arginine salt is characterized by the XRPD pattern substantially in accordance with FIG. 38.
  • the salt is Compound 1 L-lysine salt.
  • Compound 1 L-lysine salt is crystalline.
  • Compound 1 L-lysine crystalline salt is characterized as Compound 1 L-lysine salt Form A.
  • Compound 1 L-lysine crystalline salt is characterized as Compound 1 L-lysine salt Form A (1:0.4) (stoichiometric ratio of Compound 1: lysine).
  • Compound 1 L-lysine salt Form A is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising one or more peaks selected from 9.68,
  • Compound 1 L-lysine salt Form A is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising three or more peaks selected from 9.68,
  • Compound 1 L-lysine salt Form A is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising five or more peaks selected from 9.68,
  • Compound 1 L-lysine salt Form A is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising peaks at 9.68, 19.38, and 26.03.
  • Compound 1 L-lysine salt Form A is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising peaks at 9.68, 17.71, 19.38, 22.83, and 26.03.
  • Compound 1 L-lysine salt Form A is characterized by an XRPD pattern on a 2 Theta scale, ⁇ 0.20, comprising all of the peaks 9.68, 13.32, 17.71, 17.96, 19.38, 20.47, 22.83, 23.83, 24.45, and 26.03.
  • Compound 1 L-lysine salt is characterized by the XRPD pattern substantially in accordance with FIG. 39.
  • administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intraci stemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, aerosols, and the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • compositions will include a conventional pharmaceutical excipient and an amorphous or crystalline form of the present disclosure as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, excipients, adjuvants, and so on.
  • Compositions of the disclosure may be used in combination with anticancer or other agents that are generally administered to a patient being treated for cancer.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate, and gelatin.
  • a pharmaceutical composition of the disclosure may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan, monolaurate, triethanolamine oleate, butylated hydroxytoluene, and so on.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan, monolaurate, triethanolamine oleate, butylated hydroxytoluene, and so on.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous excipients, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example, quaternary ammonium compounds
  • wetting agents as for example, cetyl alcohol, and glycerol
  • Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, and so on., crystalline forms of Compound 1, and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, and dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylenegly
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the crystalline forms of Compound 1 with for example suitable non-irritating excipients such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore melt while in a suitable body cavity and release the active component therein.
  • suitable non-irritating excipients such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable excipient and any preservatives, buffers, or propellants as may be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this disclosure.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a crystalline form of Compound 1, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a crystalline form of Compound 1, with the rest being suitable pharmaceutical excipients.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 21 st Ed., (Lippincott, Williams and Wilkins Philadelphia, PA, 2006).
  • the composition to be administered will, in any event, contain a therapeutically effective amount of a crystalline form of Compound 1 for treatment of a disease-state in accordance with the teachings of this disclosure.
  • the crystalline forms of Compound 1 are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of Compound 1, the metabolic stability and length of action of Compound 1, the age, body weight, general health, sex, diet, mode, and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the crystalline forms of Compound 1 can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
  • the compounds provided herein can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any of the solid forms provided herein can be provided in the appropriate pharmaceutical composition and be administered by a suitable route of administration.
  • the methods provided herein encompass administering pharmaceutical compositions comprising at least one solid form provided herein and one or more compatible and pharmaceutically acceptable carriers.
  • carrier includes a diluent, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils including petroleum, animal, vegetable, or oils of synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions, aqueous dextrose, and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Martin, E.W., Remington 's Pharmaceutical Sciences.
  • compositions, or compounds provided herein may be administered by any route known in the art.
  • routes of administration include, but are not limited to, inhalation, intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes.
  • a pharmaceutical composition or compound provided herein is administered parenterally.
  • compositions for parenteral administration can be emulsions or sterile solutions.
  • Parenteral compositions may include, for example, propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters (e.g., ethyl oleate). These compositions can also contain wetting, isotonizing, emulsifying, dispersing, and stabilizing agents. Sterilization can be carried out in several ways, for example, using a bacteriological filter, via radiation, or via heating.
  • Parenteral compositions can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water, or any other injectable sterile medium.
  • compositions provided herein is a pharmaceutical composition, or a single unit dosage form.
  • Pharmaceutical compositions, and single unit dosage forms provided herein comprise a prophylactically, or therapeutically effective amount of one, or more prophylactic, or therapeutic compounds.
  • the pharmaceutical composition may comprise one or more pharmaceutical excipients.
  • Any suitable pharmaceutical excipient may be used, wherein a person of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients.
  • suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like.
  • compositions, or dosage form Whether a particular excipient is suitable for incorporation into a pharmaceutical composition, or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a subject and the specific compound in the dosage form.
  • the composition, or single unit dosage form if desired, can also contain minor amounts of wetting, or emulsifying agents, or pH buffering agents. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative, and not limiting. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), incorporated by reference herein in its entirety.
  • the pharmaceutical composition comprises an anti-foaming agent.
  • Any suitable anti-foaming agent may be used.
  • the anti-foaming agent is selected from an alcohol, an ether, an oil, a wax, a silicone, a surfactant, and combinations thereof.
  • the anti-foaming agent is selected from a mineral oil, a vegetable oil, ethylene bis stearamide, a paraffin wax, an ester wax, a fatty alcohol wax, a long-chain fatty alcohol, a fatty acid soap, a fatty acid ester, a silicon glycol, a fluorosilicone, a polyethylene glycol-polypropylene glycol copolymer, polydimethylsiloxane-silicon dioxide, ether, octyl alcohol, capryl alcohol, sorbitan trioleate, ethyl alcohol, 2-ethyl-hexanol, dimethicone, oleyl alcohol, simethicone, and combinations thereof.
  • the pharmaceutical composition comprises a co-solvent.
  • co-solvents include ethanol, poly(ethylene) glycol, butylene glycol, di methyl acetamide, glycerin, and propylene glycol.
  • the pharmaceutical composition comprises a buffer.
  • buffers include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate.
  • the pharmaceutical composition comprises a carrier, or filler.
  • carriers, or fillers include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.
  • the pharmaceutical composition comprises a surfactant.
  • surfactants include /-alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, glyceryl behenate, glyceryl monooleate, lauric acid, macrogol 15 hydroxystearate, myristyl alcohol, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, poly oxylglyceri des, sodium lauryl sulfate, sorbitan esters, and vitamin E polyethylene(glycol) succinate.
  • the pharmaceutical composition comprises an anti-caking agent.
  • anti -caking agents include calcium phosphate (tribasic), hydroxymethyl cellulose, hydroxypropyl cellulose, and magnesium oxide.
  • Other excipients that may be used with the pharmaceutical compositions include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, controlled release agents, diluents, dispersing agents, dissolution enhancers, emulsifying agents, gelling agents, ointment bases, penetration enhancers, preservatives, solubilizing agents, solvents, stabilizing agents, and sugars.
  • the pharmaceutical composition comprises a solvent.
  • the solvent is saline solution, such as a sterile isotonic saline solution, or dextrose solution.
  • the solvent is water for injection.
  • the pharmaceutical compositions are in a particulate form, such as a microparticle or a nanoparticle.
  • Microparticles, and nanoparticles may be formed from any suitable material, such as a polymer, or a lipid.
  • the microparticles, or nanoparticles are micelles, liposomes, or polymersomes.
  • anhydrous pharmaceutical compositions, and dosage forms comprising a compound, since, in some embodiments, water can facilitate the degradation of some compounds.
  • Anhydrous pharmaceutical compositions, and dosage forms provided herein can be prepared using anhydrous, or low moisture containing ingredients, and low moisture, or low humidity conditions.
  • Pharmaceutical compositions, and dosage forms that comprise lactose, and at least one active ingredient that comprises a primary, or secondary amine can be anhydrous if substantial contact with moisture, and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • Lactose-free compositions can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopeia (USP) SP (XXI)/NF (XVI).
  • USP U.S. Pharmocopeia
  • XXI XXI/NF
  • lactose-free compositions comprise an active ingredient, a binder/fdler, and a lubricant in pharmaceutically compatible, and pharmaceutically acceptable amounts.
  • Exemplary lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.
  • compositions, and dosage forms that comprise one, or more excipients that reduce the rate by which a compound will decompose.
  • excipients which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically sterile, or capable of being sterilized prior to administration to a subject. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose, and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose, and Sodium Chloride Injection, and Lactated Ringer’s Injection
  • Excipients that increase the solubility of one, or more of the antibodies disclosed herein can also be incorporated into the parenteral dosage forms.
  • the doctor will determine the posology which he considers most appropriate according to a preventive, or curative treatment, and according to the age, weight, condition, and other factors specific to the subject to be treated.
  • compositions provided herein is a pharmaceutical composition, or a single unit dosage form.
  • Pharmaceutical compositions, and single unit dosage forms provided herein comprise a prophylactically, or therapeutically effective amount of one, or more prophylactic, or therapeutic antibodies, or antigen binding fragments thereof.
  • the amount of the compound, or composition which will be effective in the prevention, or treatment of a disorder, or one, or more symptoms thereof will vary with the nature, and severity of the disease, or condition, and the route by which the compound is administered.
  • the frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro, or animal model test systems.
  • exemplary doses of a composition include milligram, or microgram amounts of the compound per kilogram of subject, or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram).
  • the dosage of the compound provided herein, based on weight of the compound, administered to prevent, treat, manage, or ameliorate a disorder, or one, or more symptoms thereof in a subject is 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 10 mg/kg, or 15 mg/kg or more of a subject’s body weight.
  • the dosage of the composition, or a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one, or more symptoms thereof in a subject is 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.25 mg to 2.5 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 0.5 to 12 mg, 0.5 to 10 mg, 0.5 mg to 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 0.5 to 10 mg, 0.5 mg to 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20
  • the dose can be administered according to a suitable schedule, for example, once, two times, three times, or four times weekly. It may be necessary to use dosages of the compound outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician, or treating physician will know how, and when to interrupt, adjust, or terminate therapy in conjunction with subject response.
  • treatment, or prevention can be initiated with one, or more loading doses of a compound, or composition provided herein followed by one, or more maintenance doses.
  • a dose of a compound, or composition provided herein can be administered to achieve a steady-state concentration of the compound in blood, or serum of the subject.
  • the steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical characteristics of the subject such as height, weight, and age.
  • administration of the same composition may be repeated, and the administrations may be separated by at least one day, two days, three days, five days, ten days, fifteen days, thirty days, forty-five days, two months, seventy-five days, three months, or six months.
  • administration of the same prophylactic, or therapeutic agent may be repeated, and the administration may be separated by at least one day, two days, three days, five days, ten days, fifteen days, thirty days, forty-five days, two months, seventy-five days, three months, or six months.
  • the compounds are administered to a mammal, in certain embodiments, a human, in a pharmaceutically acceptable dosage suitable for administration form such as those known in the art, and those discussed herein, intravenously as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intra-cerebrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, or intratumoral routes.
  • the compounds also are suitably administered by peritumoral, intralesional, or perilesional routes, to exert local as well as systemic therapeutic effects.
  • the compounds are administered to a mammal, in certain embodiments, a human, in a pharmaceutically acceptable dosage suitable for oral administration form such as those known in the art, and those discussed herein.
  • a pharmaceutically acceptable dosage suitable for oral administration form such as those known in the art, and those discussed herein.
  • the compounds of this disclosure may be administered orally to a human as a liquid, or solid form.
  • Solid dosage forms include capsules, tablets, pills, powders, and granules.
  • the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonit
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • Non-limiting examples of disorders associated with diabetes include, obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious disease (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infections, inferior limb infection), diabetic gangrene, xerostomia, hypacusis, cerebrovascular disorder, diabetic cachexia, delayed wound healing, diabetic dyslipidemia peripheral blood circulation disorder, cardiovascular risk factors, (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, and risk factors related to unmanaged cholesterol, and/or lipid levels, and/or inflammation), NASH, bone fracture, and cognitive dysfunction
  • nephropathy e.g., diabetic nephropathy
  • retinopathy diabetic cardiomyopathy
  • cataract cataract
  • macroangiopathy osteop
  • diseases, or conditions related to diabetes include, pre-diabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL- cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipemia), metabolic syndrome (e.g., metabolic disorder where activation of GLP-1R is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.
  • hyperlipidemia e.g., hypertriglyceridemia, hypercholesterolemia, high LDL- cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipemia
  • metabolic syndrome e.g., metabolic disorder where activation of GLP-1R is beneficial
  • metabolic syndrome X e.g., metabolic disorder where activation of GLP-1R is beneficial
  • hypertension e.g., impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.
  • ITT impaired glucose tolerance
  • the disease, or condition is diabetes, and obesity (diabesity).
  • the compounds described herein are useful in improving the therapeutic effectiveness of metformin.
  • the disease or condition is a disorder of a metabolically important tissue.
  • the disease, or condition is a fatty liver disease.
  • Fatty liver diseases include, but are not limited to, non-alcoholic fatty acid liver disease (NAFLD) or metabolic dysfunction-associated fatty liver disease (MAFLD) , steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease resulting from hepatitis, fatty liver disease resulting from obesity, fatty liver disease resulting from diabetes, fatty liver disease resulting from insulin resistance, fatty liver disease resulting from hypertriglyceridemia, Abetalipoproteinemia, glycogen storage diseases, Weber-Christian disease, Wolman’s disease, acute fatty liver of pregnancy, and lipodystrophy.
  • NAFLD non-alcoholic fatty acid liver disease
  • MAFLD metabolic dysfunction-associated fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • fatty liver disease resulting from obesity fatty liver disease resulting from diabetes
  • fatty liver disease resulting from insulin resistance fatty liver disease resulting from
  • Non-alcoholic fatty liver disease represents a spectrum of disease occurring in the absence of alcohol abuse, and is typically characterized by the presence of steatosis (fat in the liver).
  • NAFLD is believed to be linked to a variety of conditions, e.g., metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia), and insulin resistance. It can cause liver disease in adults and children, and may ultimately lead to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9).
  • NAFLD nonalcoholic fatty liver or NAFL
  • NAFL nonalcoholic fatty liver or NAFL
  • NASH non-alcoholic steatohepatitis
  • the subject is a pediatric subject (e.g., 6-16 years old; or 6-12 years old; or 6-10 years old). In certain embodiments, the subject is an adult subject.
  • diseases, or conditions in metabolically important tissues include, joint disorders (e.g., osteoarthritis, secondary osteoarthritis), steatosis (e.g. in the liver); gall stones; gallbladder disorders; gastroesophageal reflux; sleep apnea; hepatitis; fatty liver; bone disorder characterized by altered bone metabolism, such as osteoporosis, including post-menopausal osteoporosis, poor bone strength, osteopenia, Paget's disease, osteolytic metastasis in cancer patients, osteodystrophy in liver disease, and the altered bone metabolism caused by renal failure, or hemodialysis, bone fracture, bone surgery, aging, pregnancy, protection against bone fractures, and malnutrition polycystic ovary syndrome; renal disease (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease);
  • renal disease e.g.,
  • the chemical entities described herein can be used for treating surgical trauma by improving recovery after surgery, and/or by preventing the catabolic reaction caused by surgical trauma.
  • the disease, or condition is a cardiovascular disease.
  • cardiovascular disease include, congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, or peripheral artery disease, stroke, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, cardiac failure, cerebrovascular disorder (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, elevated blood pressure (e.g., 130/85 mm Hg or higher), and prothrombotic state (exemplified by high fibrinogen, or plasminogen activator inhibitor in the blood).
  • the disease, or condition is a neurological disorder (e.g., neurodegenerative disorder), or a psychiatric disorder.
  • neurological disorders include, brain insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's chores, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson, steel-Richard syndrome, Down's syndrome, myasthenia gravis, nerve trauma, brain trauma, vascular amyloidosis, cerebral hemorrhage I with amyloidosis, brain inflammation, Friedrich's ataxia, acute confusion disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeld-Jakob Disease, bovine spongiform encephalopathy (mad cow disease),
  • MCI mild cognitive impairment
  • AD Alzheimer'
  • Non-limiting examples of psychiatric disorders include drug dependence/addiction (narcotics, amphetamines, and attention deficit/hyperactivity disorder (ADHD).
  • drug dependence/addiction narcotics, amphetamines, and attention deficit/hyperactivity disorder (ADHD).
  • ADHD attention deficit/hyperactivity disorder
  • the chemical entities described herein can be useful in improving behavioral response to addictive drugs, decreasing drug dependence, prevention drug abuse relapse, and relieving anxiety caused by the absence of a given addictive substance.
  • the chemical entities described herein are useful in improving learning, and memory by enhancing neuronal plasticity, and facilitation of cellular differentiation, and also in preserving dopamine neurons, and motor function in Morbus Parkinson.
  • the disease, or condition is impaired fasting glucose (IFG), impaired fasting glycemia (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood levels of fatty acids, or glycerol, a hypoglycemic condition, insulin resistant syndrome, paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesteremia, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., hyperlipidemia, atherogenic dyslipidemia characterized by high triglycerides and low HDL cholesterol), glucagonoma, hyperuric acidemia, hypoglycemia (e.g., nighttime hypoglycemia), and concomitant comatose endpoint associated with insulin.
  • IGF impaired fasting glucose
  • IGF impaired fasting glycemia
  • hyperglycemia insulin resistance
  • hyperinsulinemia elevated blood levels of fatty acids
  • glycerol a hypoglyce
  • the compounds described herein can reduce, or slow down the progression of borderline type, impaired fasting glucose, or impaired fasting glycemia into diabetes.
  • the disease, or condition is an autoimmune disorder.
  • autoimmune disorders include, multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorder is associated with immune rejection, graft versus host disease, uveitis, optic neuropathies, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves’ disease.
  • the disease, or condition is a stomach, or intestine related disorder.
  • these disorders include, ulcers of any etiology (e.g. peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers related to infections, or other pathogens), digestion disorders, malabsorption, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel diseases (Crohn’s disease, and ulcerative colitis), celiac sprue, hypogammaglobulinemic sprue, chemotherapy, and/or radiation therapy-induced mucositis, and diarrhea, gastrointestinal inflammation, short bowel syndrome, ulcerative colitis, gastric mucosal injury (e.g., gastric mucosal injury caused by aspirin), small intestinal mucosal injury, and cachexia (e.g., cancerous cachexia, tuberculous cachexia, cachexia associated with blood disease, cachexia associated with endocrine disease, cachexia associated with infectious
  • the compounds described herein can be used to reduce body weight (e.g., excess body weight), prevent body weight gain, induce weight loss, decrease body fat, or reduce food intake in a subject (e.g., a subject in need thereof).
  • the weight increase in a subject may be attributed to excessive ingestion of food, or unbalanced diets, or may be weight increase derived from a concomitant drug (e.g., insulin sensitizers having a PPARy agonist-like action, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, and the like).
  • the weight increase may be weight increase before reaching obesity, or may be weight increase in an obese subject.
  • the weight increase may also be medication-induced weight gain, or weight gain subsequent to cessation of smoking.
  • the compounds described herein can be used to maintain body weight following weight loss,
  • the weight loss is caused by injectable medications.
  • the injectable medication is selected from the group consisting of CT-388, CT-868, Mounjaro®, Zepbound®, Wegovy®, Ozempic®, Zepbound®, and Saxenda®, as well as others.
  • the condition, disease, or disorder is an eating disorder, such as hyperphagia, binge eating, bulimia, or compulsive eating.
  • the disease, or condition is an inflammatory disorder.
  • inflammatory disorders include, chronic rheumatoid arthritis, spondylitis deformans, arthritis deformans, lumbago, gout, post-operational or post-traumatic inflammation, bloating, neuralgia, laryngopharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory large bowel disease), inflammation in metabolically important tissues including liver, fat, pancreas, kidney, and gut, and a proinfl ammatory state (e.g., elevated levels of proinflammatory cytokines or, markers of inflammation-like C-reactive protein in the blood).
  • a proinfl ammatory state e.g., elevated levels of proinflammatory cytokines or, markers of inflammation-like C-reactive protein in the blood.
  • kits for the treatment that include the administration of an effective amount of compounds provided herein.
  • the methods encompass the step of administering to the subject in need thereof an amount of a compound described herein effective for the treatment of disease, or condition in combination with a second agent effective for the treatment, or prevention of the disease, or condition.
  • the compound is in the form of a pharmaceutical composition, or dosage form, as described elsewhere herein.
  • the subject is a treatment naive subject.
  • the subject has previously received therapy. For instance, in certain embodiments, the subject has not responded to a single agent treatment regimen. In some embodiments, the subject has received a prior incretin treatment.
  • the incretin treatment is selected from exenatide (Byetta®, Bydureon®), liraglutide (Victoza®), sitagliptin (Januvia®, Janumet®, Janumet® XR, Juvisync®), saxagliptin (Onglyza®, Kombiglyze® XR), alogliptin (Nesina®, Kazano®, Oseni®), linagliptin (Tradjenta®, Jentadueto®), semaglutide, Wegovy®, Mounjaro®, and Rybelsus®, as well as others.
  • the subject is a subject that discontinued some other therapy because of one or more adverse events associated with the other therapy.
  • the subject has received some other therapy and discontinued that therapy prior to administration of a method provided herein.
  • the subject has received therapy and continues to receive that therapy along with administration of a compound provided herein.
  • the compounds described herein can be co-administered with other therapy for treatment of the disease or condition according to the judgment of one of skill in the art.
  • the methods or compositions provided herein can be co-administered with a reduced dose of the other therapy for the treatment of the disease or condition.
  • a compound provided herein is provided in the form of a kit
  • the procedure is a diagnostic assay. In certain embodiments, the procedure is a therapeutic procedure.
  • the kit further comprises a solvent for the reconstitution of the compound.
  • the compound is provided in the form of a pharmaceutical composition.
  • kits can include a compound, or composition provided herein, an optional second agent, or composition, and instructions providing information to a health care provider regarding usage for treating the disorder. Instructions may be provided in printed form, or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained.
  • a unit dose of a compound, or a composition provided herein, or a second agent, or composition can include a dosage such that when administered to a subject, a therapeutically, or prophylactically effective plasma level of the compound, or composition can be maintained in the subject for at least one day.
  • a compound, or composition can be included as a sterile aqueous pharmaceutical composition, or dry powder (e.g., lyophilized) composition.
  • suitable packaging includes a solid matrix, or material customarily used in a system, and capable of holding within fixed limits a compound provided herein, and/or a second agent suitable for administration to a subject.
  • materials include glass, and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, plastic-foil laminated envelopes, and the like. If e- beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents.
  • Another aspect relates to labeled crystalline forms of the present disclosure (radio- labeled, fluorescent-labeled, and so on) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo.
  • the present disclosure further includes isotopically-labeled crystalline forms of the present disclosure.
  • An “isotopically” or “radio-labeled” compound is a crystalline form of the present disclosure where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (that is, naturally occurring).
  • Suitable radionuclides that may be incorporated in crystalline forms of the present disclosure include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), n C, 13 C, 14 C, 13 N, 15 N, 1?
  • radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro metalloprotease labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 123 I, 131 I, or 35 S will generally be most useful. For radio-imaging applications "C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br, or 77 Br will generally be most useful.
  • the crystalline forms described herein in which one or more hydrogens is/are replaced by deuterium, such as hydrogen bonded to a carbon atom exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. They can also be useful as tools for pharmacokinetic studies.
  • a “radio-labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 1, 35 S, and 82 Br.
  • the present disclosure can further include synthetic methods for incorporating radioisotopes into crystalline forms of the present disclosure. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and a person of ordinary skill in the art will readily recognize the methods applicable for the compounds of disclosure.
  • a labeled compound of the disclosure can be used in a screening assay to identify/evaluate compounds. For example, a newly synthesized or identified compound (that is, test compound) which is labeled can be evaluated. Conversely, in some other screening assays, the standard compound is labeled, and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.
  • X-ray diffraction patterns were recorded at ambient conditions in transmission geometry with a STOE STADI P diffractometer (Cu Kai radiation, primary Ge-monochromator, Mythen IK silicon strip detector, angular range 1.5° to 50.5° 2Theta, 0.02° 2Theta step size, 48 seconds step time).
  • Compound 1 was used as starting material in preparation of the salt forms.
  • Antisolvents were added to the clear solutions and the hazy solutions from the cooling experiments. Suspensions obtained after antisolvent addition were filtered through a 0.45 pm nylon membrane filter by centrifugation at 14,000 rpm. After being dried at 50 °C under vacuum for two hours, the collected solids were analyzed by XRPD. Solids obtained: Compound 1 erbumine salt Form A, Compound 1 erbumine salt Form B, Compound 1 TRIS salt.
  • Example 2G Preparation of Compound 1 Sodium Salt Form C and Sodium Salt Form D
  • Compound 1 400 mg was weighed into a 20 mL glass vial and 29 mg of (1.05 equivalent) NaOH was added into the glass vial. 4 mL Acetonitrile (5% water) was added into the glass vial under stirring at 25 °C and a small amount of Compound 1 sodium salt Form C crystal seed was added to the suspension. After stirring for one day, solids were collected by filtration and dried to afford Compound 1 sodium salt Form C as a hydrate at 86.39% yield. Compound 1 sodium salt Form D was obtained by the same process.
  • erbumine salt Form E is the most thermodynamically stable salt form among Compound 1 Erbumine Salt Form A, Form E, and Form F.
  • Example 5 Solubility of Compound 1 Erbumine Salt Form E and Sodium Salt Form C
  • Compound 1 Erbumine Salt Form E and Sodium Salt Form C (8 mg each) were each weighed into a 8 mL glass vial. 4mL of solubility medium was added. Obtained suspensions were stirred at 37°C at 600 rpm and sampled at 2 hours and at 24 hours. Filtration and supernatants were analyzed by HPLC for solubility.

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  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des sels d'un agoniste de GLP-1R, le composé 1. L'invention concerne également des sels cristallins ou amorphes du composé 1. L'invention concerne également des compositions pharmaceutiques comprenant les sels du composé 1. L'invention concerne en outre des méthodes de traitement d'une maladie, d'un trouble ou d'un syndrome à l'aide d'un sel du composé 1 tel que figurant dans la description.
PCT/US2024/059371 2023-12-11 2024-12-10 Formes salines d'un modulateur du récepteur glp-1 Pending WO2025128564A1 (fr)

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CNPCT/CN2023/137926 2023-12-11
CN2023137926 2023-12-11

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WO2025128564A1 true WO2025128564A1 (fr) 2025-06-19

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AR (1) AR134641A1 (fr)
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022165076A1 (fr) 2021-01-28 2022-08-04 Carmot Therapeutics, Inc. Agonistes du récepteur gpcr, compositions pharmaceutiques les comprenant, et leurs procédés d'utilisation
WO2023182869A1 (fr) * 2022-03-25 2023-09-28 Ildong Pharmaceutical Co., Ltd. Nouveau sel de composé agoniste du récepteur glp-1, son procédé de préparation et composition pharmaceutique le comprenant
WO2024008174A1 (fr) * 2022-07-07 2024-01-11 杭州德睿智药科技有限公司 Sel d'agoniste de glp-1r, son procédé de préparation et son utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022165076A1 (fr) 2021-01-28 2022-08-04 Carmot Therapeutics, Inc. Agonistes du récepteur gpcr, compositions pharmaceutiques les comprenant, et leurs procédés d'utilisation
WO2023182869A1 (fr) * 2022-03-25 2023-09-28 Ildong Pharmaceutical Co., Ltd. Nouveau sel de composé agoniste du récepteur glp-1, son procédé de préparation et composition pharmaceutique le comprenant
WO2024008174A1 (fr) * 2022-07-07 2024-01-11 杭州德睿智药科技有限公司 Sel d'agoniste de glp-1r, son procédé de préparation et son utilisation

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