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WO2025179296A1 - Formes cristallines de nu-3 et leurs utilisations - Google Patents

Formes cristallines de nu-3 et leurs utilisations

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Publication number
WO2025179296A1
WO2025179296A1 PCT/US2025/017096 US2025017096W WO2025179296A1 WO 2025179296 A1 WO2025179296 A1 WO 2025179296A1 US 2025017096 W US2025017096 W US 2025017096W WO 2025179296 A1 WO2025179296 A1 WO 2025179296A1
Authority
WO
WIPO (PCT)
Prior art keywords
present disclosure
crystalline form
patient
cov
coronavirus
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.)
Pending
Application number
PCT/US2025/017096
Other languages
English (en)
Inventor
Kelvin Cooper
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.)
Lakewood Amedex Inc
Original Assignee
Lakewood Amedex 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 Lakewood Amedex Inc filed Critical Lakewood Amedex Inc
Publication of WO2025179296A1 publication Critical patent/WO2025179296A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • A61K9/0046—Ear
    • 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
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the crystalline form of Nu-3 may be referred to by its chemical name disodium (27?, 35, 57?)- butoxy( ⁇ 3-[butoxy(oxido)(oxo)-X 5 -phosphanyloxy]-5-(5-methyl-2,4-dioxo- 1,2,3, 4-tetrahydro-l- pyrimidinyl)tetrahydro-2-furyl (methoxy )(oxo)- -phosphanolate.
  • a crystalline form of Nu-3 is disclosed having the formula:
  • One advantage of a crystalline form of Nu-3 according to an embodiment of the present disclosure is that it is less sensitive to moisture compared to amorphous Nu-3 (herein referred to as Form 4).
  • Form 4 or amorphous Nu-3 disodium salt, is described in U.S. Patent No. 7,868,162, the entire contents of which are incorporated herein by reference.
  • Prior attempts to isolate a solid form of Nu-3 as a free acid have been challenging due to its extreme hygroscopicity (deliquescence).
  • a method of treating an infection of at least one of a wound or an ulcer in a patient in need thereof includes administering an effective amount of any crystalline form of Nu-3 disclosed herein or a pharmaceutically acceptable salt thereof, to the patient.
  • a method of treating a lung infection in a patient in need thereof includes administering an effective amount of any crystalline form of Nu-3 disclosed herein or a pharmaceutically acceptable salt thereof, to the patient.
  • the lung infection arises from a pulmonary condition.
  • the coronavirus is selected from the group consisting of porcine epidemic diarrhea virus (PEDv), scotophilus bat coronavirus 512, bat coronavirus CDPHE15, BtRF-Alpha-CoV HuB-2013, bat coronavirus HKU10, miniopterus bat coronavirus HKU8, miniopterus bat coronavirus 1, Nyctahis velutinus alphacoronavirus SC-2013, Pipistrellus kuhlii coronavirus 3398, Myotis ricketti alphacoronavirus Sax-2011, HumCoV 229E, 229E-related bat coronavirus, camel alphacoronavirus, alpaca respiratory coronavirus, HumCoV NL63, NL63- related Bat-CoV BtKYNL63-9b, HKU2, SADSr-CoV, SADS-CoV, Lucheng Rn rat coronavirus2, FIPV, TGEV, PRCV, alphacoron
  • a method of treating an infection in a burn wound in a patient in need thereof includes administering an effective amount of any crystalline form of Nu-3 disclosed herein or a pharmaceutically acceptable salt thereof, to the patient.
  • a method of treating otitis externa in a patient in need thereof includes administering an effective amount of any crystalline form of Nu-3 disclosed herein or a pharmaceutically acceptable salt thereof, to the patient.
  • a method of treating bacterial vaginosis in a patient in need thereof includes administering an effective amount of any crystalline form of Nu-3 disclosed herein or a pharmaceutically acceptable salt thereof, to the patient.
  • a method of treating impetigo in a patient in need thereof includes administering an effective amount of any crystalline form of Nu-3 disclosed herein or a pharmaceutically acceptable salt thereof, to the patient.
  • a method of treating oral mucositis in a patient in need thereof includes administering an effective amount of any crystalline form of Nu-3 disclosed herein or a pharmaceutically acceptable salt thereof, to the patient.
  • Another aspect of the present disclosure provides a crystalline form of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
  • Another aspect of the present disclosure provides the use of a crystalline form of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament.
  • FIG. 1 shows a 'H-NMR spectrum of Nu-3 di-Na salt (Form 1).
  • FIG. 2 shows a PXRD of di-Na salt of Nu-3 (Form 1).
  • FIG. 3 shows a DSC thermogram of Nu-3 di-Na salt (Form 1).
  • FIG. 4 shows a mDSC thermogram of Nu-3 di-Na salt (Form 1).
  • FIG. 15 shows PXRD data for slurry crystallization.
  • FIG. 18 shows a PXRD of amorphous Form 4.
  • FIG. 19 shows a PXRD data for slurry crystallization of amorphous Form 4.
  • FIG. 20 shows PXRD data of Form 2.
  • FIG. 21 shows DSC thermogram of Form 2.
  • FIG. 22 shows mDSC thermogram of Form 2.
  • FIG. 23 shows a 1H-NMR spectrum for Form 2.
  • FIG. 24 shows a heat-cool-heat DSC analysis of Form 2.
  • FIG. 25 shows a TGA of Form 2.
  • FIG. 26 shows a GC analysis of Form 2.
  • FIG. 27 shows a water content report of Form 2.
  • FIG. 28 shows a PXRD pattern of Form 3.
  • FIG. 29 shows a DSC thermogram of Form 3 obtained from IPA/water.
  • FIG. 30 shows a PXRD pattern of Form 3 obtained from DMF.
  • FIG. 31 shows a DSC thermogram of Form 3 obtained from DMF.
  • FIG. 32 shows an mDSC thermogram of Form 3 obtained from DMF.
  • FIG. 33 shows a TGA of Form 3 obtained from DMF.
  • a suitable commercially available trimethylsiloxysilicate is sold as a mixture with dimethicone as Dow CorningTM 593 fluid.
  • dimethiconols which are hydroxyl terminated dimethyl silicones.
  • Suitable commercially available dimethiconols are typically sold as mixtures with dimethicone or cyclomethicone (e.g., Dow CorningTM 1401, 1402, and 1403 fluids).
  • Suitable commercially available polyalkylarylsiloxanes include SF1075 methylphenyl fluid (sold by General Electric Company) and 556 Cosmetic Grade phenyl trimethicone fluid (sold by Dow Corning Corporation).
  • Hydrocarbons suitable for use in the pharmaceutical compositions of the present disclosure include without limitation straight and branched chain hydrocarbons having from about 10 to about 30 carbon atoms. In some embodiments, the straight and branched chain hydrocarbons have from about 12 to about 24 carbon atoms. In some embodiments, the straight and branched chain hydrocarbons have from about 16 to about 22 carbon atoms.
  • Non-limiting examples of such hydrocarbon materials include dodecane, squalane, cholesterol, 5 hydrogenated polyisobutylene, docosane (i.e., a C22 hydrocarbon), hexadecane, and isohexadecane (a commercially available hydrocarbon sold as PermethylTM 101A by Presperse, South Plainsfield, N.J.), among others.
  • the topical pharmaceutical compositions of the present disclosure include propylene glycol.
  • propylene glycol acts as a surfactant and assists in penetration, contact, and absorption of a compound of the present disclosure.
  • propylene glycol serves as a preservative.
  • the pharmaceutical compositions of the present disclosure include a non-ionic surfactant, such as, for example, polysorbate. Such a surfactant provides better surface contact of the pharmaceutical compositions of the present disclosure with mucosa (such as vaginal mucosa) by further reducing surface tension.
  • the topical pharmaceutical compositions of the present disclosure optionally may also be formulated with a lipophilic phase, such as, for example, emulsions and liposome dispersions.
  • liposomal formulations may extend circulation time of a compound of the present disclosure, increase permeability of a compound of the present disclosure, and improve overall efficacy of a compound of the present disclosure as an antimicrobial.
  • a compound of the present disclosure may be combined with a lipid, cationic lipid or anionic lipid.
  • the resulting emulsion or liposomal suspension in conjunction with the pH stabilizing qualities of a compound of the present disclosure can effectively increase the in vivo half-life of the activity of a pharmaceutical composition of the present disclosure.
  • anionic lipids for use with the pharmaceutical compositions of the present disclosure include, but are not limited to, cardiolipin, dimyristoyl, dipalmitoyl, dioleoyl phosphatidyl choline, phosphatidyl glycerol, palmitoyloleoyl phosphatidyl choline, phosphatidyl glycerol, phosphatidic acid, lysophosphatidic acid, phosphatidyl serine, phosphatidyl inositol, and anionic forms of cholesterol.
  • a compound of the present disclosure is incorporated into liposomes.
  • neutral lipids, cholesterol, and/or polyethylene glycol (PEG) are utilized in such liposomes.
  • the liposomal composition is composed of partially hydrogenated soy phosphatidylcholine (PHSC), cholesterol, methoxy-terminated PEG (mPEG), and/or distearoyl phosphatidyl ethanolamine (DSPE).
  • PHSC partially hydrogenated soy phosphatidylcholine
  • mPEG methoxy-terminated PEG
  • DSPE distearoyl phosphatidyl ethanolamine
  • a compound of the present disclosure may be combined with solid excipients, optionally grinding a resulting mixture, and optionally processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g., aqueous, alcoholic or oily solutions), and the like.
  • excipients suitable for use in the oral pharmaceutical compositions of the present disclosure include without limitation fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP or povidone); and oily excipients, including vegetable and animal oils, such as sunflower oil, olive oil, or cod liver oil.
  • fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol
  • cellulose preparations for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose (CMC), and/or polyvinylpyrrol
  • the oral pharmaceutical compositions of the present disclosure may also contain disintegrating agents, such as, for example, cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate; a lubricant, such as talc or magnesium stearate; a plasticizer, such as glycerol or sorbitol; a sweetening agent such as sucrose, fructose, lactose, or aspartame; a natural or artificial flavoring agent, such as, for example, peppermint, oil of Wintergreen, or cherry flavoring; or dye-stuffs or pigments, which may be used for identification or characterization of different doses or combinations.
  • disintegrating agents such as, for example, cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate
  • a lubricant such as talc or magnesium stearate
  • a plasticizer such as g
  • the oral pharmaceutical compositions of the present disclosure may also contain dragee cores with suitable coatings.
  • suitable coatings may be used, which may optionally contain, for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • the pharmaceutical compositions of the present disclosure that can be used orally include without limitation push-fit capsules made of gelatin (“gelcaps”), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain a compound of the present disclosure in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compound may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, liquid polyethylene glycols, and the like.
  • solutions may comprise propylene glycol, sterile water, ethanol, sodium chloride, and other additives, such as, for example, acid, alkali, and buffer salts.
  • solutions or suspensions may be administered by inhaling via a spray, pump, atomizer, nebulizer, and the like.
  • compositions of the present disclosure suitable for inhalation administration may also be used in combination with other inhaled therapies, including without limitation corticosteroids such as, for example, fluticasone proprionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; beta agonists such as, for example, albuterol, salmeterol, and formoterol; anticholinergic agents such as, for example, ipratroprium bromide or tiotropium; vasodilators such as, for example, treprostinal and iloprost; enzymes such as, for example, DNAase; therapeutic proteins; immunoglobulin antibodies; an oligonucleotide, such as, for example, single or double stranded DNA or RNA, siRNA; antibiotics such as, for example, tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine
  • the pharmaceutical compositions of the present disclosure are adapted for intravesical administration.
  • intravesical administration refers to delivery of a compound of the present disclosure directly into the bladder of a patient.
  • the pharmaceutical composition is administered via a catheter.
  • the catheter is a urethral catheter.
  • the pharmaceutical compositions of the present disclosure are adapted for parenteral administration.
  • parenteral administration refers to a compound of the present disclosure being injected or infused into a patient and includes without limitation intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and intrasternal injection and infusion.
  • the pharmaceutical compositions of the present disclosure suitable for parenteral administration may be formulated in sterile liquid solutions, including without limitation physiologically compatible buffers or solutions, such as, for example, saline solution, Hank’s solution or Ringer’s solution.
  • physiologically compatible buffers or solutions such as, for example, saline solution, Hank’s solution or Ringer’s solution.
  • the pharmaceutical compositions of the present disclosure suitable for parenteral administration may be prepared as dispersions in non-aqueous solutions, such as, for example, glycerol, propylene glycol, ethanol, liquid polyethylene glycols, triacetin, vegetable oils, and the like.
  • solutions may also contain a preservative, such as, for example, methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • a preservative such as, for example, methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • pharmaceutical compositions of the present disclosure suitable for parenteral administration may be formulated in solid form, including, for example, lyophilized forms, and redissolved or suspended prior to use.
  • the pharmaceutical composition is administered via a needle.
  • the present disclosure provides methods and compositions of pretreating a catheter with a compound of the present disclosure, for example, to prevent an infection after the catheter is inserted into a patient.
  • a method of the present disclosure includes coating a catheter with a compound of the present disclosure prior to inserting the catheter into a patient.
  • the present disclosure provides a composition comprising a catheter coated with a compound of the present disclosure. In some embodiments, such methods and compositions may be used as a prophylactic treatment of an infection in a patient.
  • the present disclosure also provides methods of treatment.
  • the terms “treating,” “treatment,” “therapy,” and like terms refer to administration of a compound or pharmaceutical composition of the present disclosure in an amount effective to prevent, alleviate or ameliorate one or more symptoms of a disease or condition (i.e., indication) and/or to prolong the survival of the patient being treated.
  • “treating,” “treatment,” “therapy,” and like terms also include without limitation reducing or eliminating infection in a patient.
  • an effective amount of a compound of the present disclosure is administered to a patient in need thereof.
  • the term “effective amount,” in the context of administration refers to the amount of a compound or pharmaceutical composition of the present disclosure that when administered to a patient is sufficient to prevent, alleviate or ameliorate one or more symptoms of a disease or condition (i.e., indication) and/or to prolong the survival of the patient being treated. Such an amount should result in no or few adverse events in the treated patient. Similarly, such an amount should result in no or few toxic effects in the treated patient.
  • the amount of a compound or pharmaceutical composition of the present disclosure will vary depending upon a number of factors, including without limitation the activity of a compound of the present disclosure (in vitro, e.g. a compound of the present disclosure vs. target, or in vivo activity in animal efficacy models), pharmacokinetic results in animal models (e.g., biological half-life or bioavailability), the type of patient being treated, the patient’s age, size, weight, and general physical condition, the disorder associated with the patient, and the dosing regimen being employed in the treatment.
  • the activity of a compound of the present disclosure in vitro, e.g. a compound of the present disclosure vs. target, or in vivo activity in animal efficacy models
  • pharmacokinetic results in animal models e.g., biological half-life or bioavailability
  • the type of patient being treated the patient’s age, size, weight, and general physical condition, the disorder associated with the patient, and the dosing regimen being employed in the treatment.
  • an effective amount of a compound of the present disclosure to be delivered to a patient in need thereof can be quantified by determining micrograms of a compound of the present disclosure per kilogram of patient body weight.
  • the amount of a compound of the present disclosure administered to a patient is from about 0.1 to about 1000 milligram (mg) of a compound of the present disclosure per kilogram (kg) of patient body weight.
  • the amount of a compound of the present disclosure administered to a patient is from about 0.1 to about 500 mg of a compound of the present disclosure per kg of patient body weight.
  • the amount of a compound of the present disclosure administered to a patient is from about 0.1 to about 300 mg of a compound of the present disclosure per kg of patient body weight. In some embodiments, the amount of a compound of the present disclosure administered to a patient is from about 0.1 to about 200 mg of a compound of the present disclosure per kg of patient body weight. In some embodiments, the amount of a compound of the present disclosure administered to a patient is from about 0.1 to about 100 mg of a compound of the present disclosure per kg of patient body weight. As those of ordinary skill in the art understand multiple doses may be used.
  • a compound of the present disclosure is administered as a multiple dose regimen.
  • the term “multiple dose regimen” refers to a treatment time period of more than one day.
  • the multiple dose regimen is a time period of up to about 2 days.
  • the multiple dose regimen is a time period of up to about 3 days.
  • the multiple dose regimen is a time period of up to about 4 days.
  • the multiple dose regimen is a time period of up to about 5 days.
  • the multiple dose regimen is a time period of up to about 6 days.
  • the multiple dose regimen is a time period of up to about 7 days. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about 14 days. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about one month. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about two months. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about three months. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about four months. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about five months. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about six months. Other time periods may be used herein.
  • a compound of the present disclosure is administered as part of a chronic treatment regimen.
  • chronic treatment regimen refers to treatment with a compound of the present disclosure over an extended period of time during a patient’s lifetime.
  • chronic treatment is lifelong treatment.
  • a compound of the present disclosure is administered as a single dose. In some embodiments of the present disclosure, a compound of the present disclosure is administered as a single unit dose.
  • unit dose is a predetermined amount of a compound of the present disclosure. The amount of a compound of the present disclosure is generally equal to the dosage of a compound of the present disclosure that would be administered to a patient or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • the terms “single dose” and “single unit dose” include embodiments wherein the composition can be administered as a single application and administered as multiple applications.
  • a compound of the present disclosure may also be used in combination with one or more additional active ingredients for treating the same disease or condition.
  • such combination use includes administration of a compound of the present disclosure and one or more additional active ingredient at different times, or coadministration of a compound of the present disclosure and one or more additional active ingredients.
  • dosage may be modified for a compound of the present disclosure or one or more additional active ingredients used in combination, e.g., reduction in the amount dosed relative to a compound of the present disclosure or one or more additional active ingredients used alone, by methods well known to those of ordinary skill in the art.
  • co-administration includes simultaneous administration of a compound of the present disclosure and an additional active ingredient in the same dosage form, simultaneous administration of a compound of the present disclosure and an additional active ingredient in separate dosage forms, and separate administration of a compound of the present disclosure and an additional active ingredient.
  • use in combination includes use with one or more additional active ingredients or other medical procedure in which the one or more additional active ingredients or other medical procedure may be administered at different times (e.g., within a short time, such as within hours (e.g., 1, 2, 3, 4-24 hours, etc.), or within a longer time (e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks, etc.)) than a compound or pharmaceutical composition of the present disclosure, or at the same time as a compound or pharmaceutical composition of the present disclosure.
  • a short time such as within hours (e.g., 1, 2, 3, 4-24 hours, etc.)
  • a longer time e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks, etc.
  • Use in combination also includes use with one or more additional active ingredients or other medical procedure that is administered once or infrequently, such as surgery, along with a compound or pharmaceutical composition of the present disclosure administered within a short time or longer time before or after the administration of the one or more additional active ingredients or completion of the other medical procedure.
  • the present disclosure provides for delivery of a compound or pharmaceutical composition of the present disclosure and one or more additional active ingredients delivered by a different route of administration or by the same route of administration.
  • the use in combination for any route of administration includes delivery of a compound or pharmaceutical composition of the present disclosure and one or more additional active ingredients delivered by the same route of administration together in any pharmaceutical composition, including pharmaceutical compositions in which the two compounds are chemically linked in such a way that such compounds maintain their therapeutic activity when administered.
  • the one or more additional active ingredients may be co-administered with a compound or pharmaceutical composition of the present disclosure.
  • co-formulations of a compound or pharmaceutical composition of the present disclosure and one or more additional active ingredients delivered by the same route includes preparation of the materials together such that they can be administered by one device, including the separate compounds combined in one formulation, or compounds that are modified such that the compounds are chemically joined, yet still maintain their biological activity.
  • such chemically joined compounds may have a linkage that is substantially maintained in vivo, or the linkage may break down in vivo, separating the two active components.
  • the present disclosure also provides a method of treating an infection in a patient in need thereof.
  • the method comprises administering an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the patient.
  • infection refers to any microbe infection of a patient’s body. Infection includes the invasion of a patient’s body by a microbe and subsequent multiplication in the patient’s body.
  • the present disclosure also provides a method of treating an infection of a lower extremity ulcer in a patient in need thereof.
  • the method comprises administering an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the patient.
  • infection refers to any microbe infection of a patient’s body. Infection includes the invasion of a patient’s body by a microbe and subsequent multiplication in the patient’s body.
  • lower extremity refers to a lower limb of a patient’s body, including without limitation the hip, thigh, leg, ankle, and foot.
  • the term “ulcer” refers to an open wound found anywhere on the lower extremity of a patient.
  • the present disclosure provides a method of treating an infection of a diabetic foot ulcer in a patient in need thereof.
  • the method comprises administering an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the patient.
  • the patient is suffering from Type I diabetes or Type II diabetes.
  • diabetes foot ulcer refers to an open wound located anywhere on the foot of a patient. In some embodiments, the wound is located on the heel, mid-foot, and/or forefoot of the patient’s foot.
  • the term “treating,” in the context of a diabetic foot ulcer, also includes without limitation reducing or eliminating infection in a patient, which, in some embodiments, results in limiting the progression in size, area, and/or depth of the foot ulcer; reducing the size, area, and/or depth of the foot ulcer; increasing the rate of healing and/or reducing time to healing; healing of the foot ulcer (about 100% epithelialization with no drainage); and/or decreased incidence of amputation or slowing in time to amputation.
  • the patient is a human.
  • the administration is topical administration.
  • the administration is carried out using the compound, or a pharmaceutically acceptable salt thereof, in a lotion, paste, gel, cream, ointment, oil or other viscous composition.
  • the patient is administered at least one additional active ingredient.
  • the administration is carried out as a multiple dose regimen.
  • the multiple dose regimen is a time period of up to about one month.
  • the multiple dose regimen is a time period of up to about two months.
  • the multiple dose regimen is a time period of up to about three months.
  • the multiple dose regimen is a time period of up to about four months. Other time periods may be used herein.
  • the administration is carried out one or more times per day. In some embodiments, the administration is carried out one time per day. In some embodiments, the administration is carried out two times per day. In some embodiments, the administration is carried out three times per day. In some embodiments, the administration is carried out four times per day.
  • the present disclosure also provides a method of treating a urinary tract infection in a patient in need thereof.
  • the method comprises administering an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the patient.
  • a urinary tract refers to the organs of a patient’s body that produce, store, and discharge urine and includes without limitation the kidneys, ureters, bladder, and urethra.
  • the term “urinary tract infection” refers to an infection of the urinary tract of a patient and includes without limitation an uncomplicated urinary tract infection and a complicated urinary tract infection.
  • the term “uncomplicated urinary tract infection” refers to an infection by a microbe of a structurally and functionally normal urinary tract of a patient.
  • the term “complicated urinary tract infection” refers to an infection by a microbe of an abnormal structural and functional urinary tract of a patient.
  • the complicated urinary tract infection is a catheter-associated urinary tract infection.
  • the term “catheter-associated urinary tract infection” refers to a complicated urinary tract infection that occurs in a patient having an indwelling urinary catheter.
  • the patient is a human.
  • the administration is intravesical administration.
  • the administration is carried out using a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in a liquid solution or suspension.
  • the patient is administered at least one additional active ingredient.
  • the administration is carried out as a multiple dose regimen.
  • the multiple dose regimen is a time period of up to about 2 days.
  • the multiple dose regimen is a time period of up to about 3 days.
  • the multiple dose regimen is a time period of up to about 4 days.
  • the multiple dose regimen is a time period of up to about 5 days. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about 6 days. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about 7 days. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about 14 days. In some embodiments of the present disclosure, the administration is carried out as a chronic treatment regimen. Other time periods may be used herein.
  • the administration is carried out one or more times per day. In some embodiments, the administration is carried out one time per day. In some embodiments, the administration is carried out two times per day. In some embodiments, the administration is carried out three times per day. In some embodiments, the administration is carried out four times per day.
  • Non-limiting examples of pulmonary conditions include without limitation genetic conditions, acquired conditions, primary conditions, secondary conditions, asthma, chronic obstructive pulmonary disease, cystic fibrosis, bronchiolitis, pneumonia, bronchitis, emphysema, adult respiratory distress syndrome, allergies, lung cancer, small cell lung cancer, primary lung cancer, metastatic lung cancer, bronchiestasis, bronchopulmonary dysplasia, chronic bronchitis, chronic lower respiratory diseases, croup, high altitude pulmonary edema, pulmonary fibrosis, interstitial lung disease, reactive airway disease, lymphangioleiomyomatosis, neonatal respiratory distress syndrome, parainfluenza, pleural effusion, pleurisy, pneumothorax, primary pulmonary hypertension, psittacosis, pulmonary edema secondary to various causes, pulmonary embolism, pulmonary hypertension secondary to various causes, respiratory failure secondary to various causes, sleep apnea, sarcoidosis,
  • the coronavirus is selected from the group consisting of porcine epidemic diarrhea virus (PEDv), scotophilus bat coronavirus 512, bat coronavirus CDPHE15, BtRF-Alpha-CoV HuB-2013, bat coronavirus HKU10, miniopterus bat coronavirus HKU8, miniopterus bat coronavirus 1, Nyctalus velutinus alphacoronavirus SC-2013, Pipistrellus kuhlii coronavirus 3398, Myotis ricketti alphacoronavirus Sax-2011, HumCoV 229E, 229E-related bat coronavirus, camel alphacoronavirus, alpaca respiratory coronavirus, HumCoV NL63, NL63- related Bat-CoV BtKYNL63-9b, HKU2, SADSr-CoV, SADS-CoV, Lucheng Rn rat coronavirus2, FIPV, TGEV, PRCV, alphacorona
  • the coronavirus is a betacoronavirus selected from the group consisting of HumCoV OC43 isolate TNP F1778_2, HKU23, BovCoV, SACoV, GiCoV, bovine coronavirus isolate alpaca, canine respiratory coronavirus K37, PHEV, equine coronavirus, HKU14, HKU24, myodes coronavirus 2JL14, HKU1, MHV, rat coronavirus Parker, HKU4, HKU5, human MERS-CoV, camel MERS-CoV, hedgehog coronavirus 1, HKU9, rousettus bat coronavirus GCCDC1, eidolon bat coronavirus C704, human SARS-CoV, palm civet SARS-CoV, badger SARS-CoV, bat-SL-CoV RsSHC014, bat-SL-CoV Rs3367, bat-SL-CoV WIV1, HKU3, bat-SL-CoV ZC45,
  • a method of treating a lung infection arising from cystic fibrosis in a patient in need thereof comprises administering an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the patient.
  • cystic fibrosis refers to a genetic disease that causes the production of abnormally thick mucus resulting in lung infections and damage to the lungs, digestive system, and other organs in a patient’s body.
  • the administration is inhalation administration.
  • the patient is administered at least one additional active ingredient.
  • the patient is a human.
  • the administration is carried out using a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in a liquid solution, suspension or dry powder.
  • the administration is carried out as a multiple dose regimen.
  • the multiple dose regimen is a time period of up to about one month.
  • the multiple dose regimen is a time period of up to about two months.
  • the multiple dose regimen is a time period of up to about three months.
  • the multiple dose regimen is a time period of up to about four months. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about five months. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about six months. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about seven months. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about eight months. Other time periods may be used herein.
  • the administration is carried out one or more times per day. In some embodiments, the administration is carried out one time per day. In some embodiments, the administration is carried out two times per day. In some embodiments, the administration is carried out three times per day. In some embodiments, the administration is carried out four times per day.
  • a method of treating pneumonia in a patient in need thereof comprises administering an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the patient.
  • a compound of the present disclosure or a pharmaceutically acceptable salt thereof
  • the term “pneumonia” refers to an infection by a microbe of one or both lungs of a patient resulting in inflammation of lung tissue.
  • the pneumonia is ventilator acquired pneumonia.
  • the term “ventilator acquired pneumonia” refers to pneumonia arising from a patient being connected to a mechanical ventilation machine. Ventilator acquired pneumonia includes pneumonia occurring more than about 48 hours after a patient has been intubated and received mechanical ventilation.
  • the administration is inhalation administration.
  • the patient is administered at least one additional active ingredient.
  • the patient is a human.
  • the administration is carried out using a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in a liquid solution, suspension or dry powder.
  • the administration is carried out as a multiple dose regimen.
  • the multiple dose regimen is a time period of up to about 7 days.
  • the multiple dose regimen is a time period of up to about 14 days.
  • the multiple dose regimen is a time period of up to about 21 days.
  • the multiple dose regimen is a time period of up to about one month.
  • the multiple dose regimen is a time period of up to about two months. Other time periods may be used herein.
  • the administration is carried out one or more times per day. In some embodiments, the administration is carried out one time per day. In some embodiments, the administration is carried out two times per day. In some embodiments, the administration is carried out three times per day. In some embodiments, the administration is carried out four times per day.
  • the present disclosure also provides a method of treating an infection in a burn wound in a patient in need thereof. In some embodiments, the method comprises administering an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the patient.
  • the term “bum wound” refers to a burn injury to a patient’s body involving damage to a patient’s skin and possibly tissues underlying the patient’s skin.
  • the method of treating an infection in a burn wound contemplated by the present disclosure is used to treat a first-, second-, and/or third-degree bum.
  • the patient is a human.
  • the administration is topical administration.
  • the administration is carried out using a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in lotion, cream, ointment, oil, solution, suspension, emulsion or other viscous composition.
  • the patient is administered at least one additional active ingredient.
  • the administration is carried out as a multiple dose regimen.
  • the multiple dose regimen is a time period of up to about 2 days.
  • the multiple dose regimen is a time period of up to about 3 days.
  • the multiple dose regimen is a time period of up to about 4 days.
  • the multiple dose regimen is a time period of up to about 5 days. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about 6 days. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about 7 days. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about 14 days. In some embodiments of the present disclosure, the multiple dose regimen is a time period of up to about 21 days. In some embodiments, the multiple dose regimen is a time period of up to about one month. In some embodiments, the multiple dose regimen is a time period of up to about two months. Other time periods may be used herein.
  • the administration is carried out one or more times per day. In some embodiments, the administration is carried out one time per day. In some embodiments, the administration is carried out two times per day. In some embodiments, the administration is carried out three times per day. In some embodiments, the administration is carried out four times per day.
  • the present disclosure also provides a method of treating otitis externa in a patient in need thereof.
  • the method comprises administering an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the patient.
  • otitis externa refers to an infection of the external ear canal of a patient.
  • the patient is a human.
  • the administration is topical administration directly into the patient’s external ear canal.
  • the administration is carried out using a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in a liquid solution, suspension, lotion, paste, gel, cream, ointment, oil or other viscous composition.
  • the patient is administered at least one additional active ingredient.
  • the administration is carried out as a multiple dose regimen.
  • the multiple dose regimen is a time period of up to about 7 days.
  • the multiple dose regimen is a time period of up to about 14 days.
  • the multiple dose regimen is a time period of up to about 21 days.
  • the multiple dose regimen is a time period of up to about one month. Other time periods may be used herein.
  • the administration is carried out one or more times per day. In some embodiments, the administration is carried out one time per day. In some embodiments, the administration is carried out two times per day. In some embodiments, the administration is carried out three times per day. In some embodiments, the administration is carried out four times per day.
  • the present disclosure also provides a method of treating bacterial vaginosis in a patient in need thereof.
  • the method comprises administering an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the patient.
  • bacterial vaginosis refers to an infection of the vagina of a patient caused by an overgrowth of bacteria naturally found in the vagina.
  • the patient is a female human.
  • the administration is topical administration.
  • the administration is carried out using a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in a lotion, gel, cream, ointment, oil, solution, suspension, emulsion or other viscous composition.
  • the patient is administered at least one additional active ingredient.
  • the administration is carried out as a multiple dose regimen.
  • the multiple dose regimen is a time period of up to about 7 days.
  • the multiple dose regimen is a time period of up to about 14 days.
  • the multiple dose regimen is a time period of up to about 21 days.
  • the multiple dose regimen is a time period of up to about one month. Other time periods may be used herein.
  • the administration is carried out one or more times per day. In some embodiments, the administration is carried out one time per day. In some embodiments, the administration is carried out two times per day. In some embodiments, the administration is carried out three times per day. In some embodiments, the administration is carried out four times per day.
  • the present disclosure also provides a method of treating impetigo in a patient in need thereof.
  • the method comprises administering an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the patient.
  • impetigo refers an infection of the skin of a patient that results in vesicles, pustules, yellowish crusts, and the like.
  • the patient is administered at least one additional active ingredient.
  • the administration is carried out as a multiple dose regimen.
  • the multiple dose regimen is a time period of up to about 7 days.
  • the multiple dose regimen is a time period of up to about 14 days.
  • the multiple dose regimen is a time period of up to about 21 days.
  • the multiple dose regimen is a time period of up to about one month. Other time periods may be used herein.
  • the administration is carried out one or more times per day. In some embodiments, the administration is carried out one time per day. In some embodiments, the administration is carried out two times per day. In some embodiments, the administration is carried out three times per day. In some embodiments, the administration is carried out four times per day.
  • kits comprising a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present disclosure.
  • kit refers to any manufacture, such as, for example, a package, container, and the like, containing a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present disclosure.
  • a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present disclosure is packaged in a vial, bottle, tube, flask or patch, which may be further packaged within a box, envelope, bag, or the like.
  • the pharmaceutical composition is contained in any manufacture, such as, for example, a package, container, and the like.
  • the crystalline form of any of clauses 1-8 characterized by an X-ray powder diffraction (XRPD) pattern includes one or more peaks at about 5.4°, about 5.6°, about 7.7°, about 12.4°, about 15.0°, about 15.7°, about 16.7°, about 17.2°, about 17.5°, about 18.5°, about 18.6°, about 18.9°, about 19.3°, about 21.3°, about 22.9°, about 24.0°, about 24.2°, or about 27.7°, each peak being ⁇ 0.2, ⁇ 0.1, ⁇ 0.05, ⁇ 0.02, or ⁇ 0.01 °20.
  • XRPD X-ray powder diffraction
  • a crystalline disodium monohydrate form of l-[(2R,4S,5R)-4- (Hydroxybutoxyphosphoryloxy)-5-[(hydroxybutoxyphosphoryloxy)methyl]tetrahydro-2- furyl]-5-methyl-2,4(lH,3H)-pyrimidinedione comprising less than about 0.1 wt. % of residual organic solvent.
  • a pharmaceutical composition comprising the crystalline form according to any of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • a pharmaceutical composition comprising the crystalline form according to any of clauses 37 to 42, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • a method of treating an infection in a patient in need thereof comprising administering an effective amount of a compound comprising the crystalline form according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, to the patient.
  • a method of treating an infection of at least one of a wound or an ulcer in a patient in need thereof comprising administering an effective amount of a compound comprising the crystalline form according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, to the patient.
  • a method of treating an infection of a diabetic foot ulcer in a patient in need thereof comprising administering an effective amount of a compound comprising the crystalline form according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, to the patient.
  • a method of treating a bladder and/or a urinary tract infection in a patient in need thereof comprising administering an effective compound comprising the crystalline form according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, to the patient.
  • a method of treating a lung infection in a patient in need thereof comprising administering an effective amount of a compound comprising the crystalline form according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, to the patient.
  • the lung infection arises from a pulmonary condition.
  • the pulmonary condition is selected from the group consisting of genetic conditions, acquired conditions, primary conditions, secondary conditions, asthma, chronic obstructive pulmonary disease, cystic fibrosis, bronchiolitis, pneumonia, bronchitis, emphysema, adult respiratory distress syndrome, allergies, lung cancer, small cell lung cancer, primary lung cancer, metastatic lung cancer, bronchiestasis, bronchopulmonary dysplasia, chronic bronchitis, chronic lower respiratory diseases, croup, high altitude pulmonary edema, pulmonary fibrosis, interstitial lung disease, reactive airway disease, lymphangioleiomyomatosis, neonatal respiratory distress syndrome, parainfluenza, pleural effusion, pleurisy, pneumothorax, primary pulmonary hypertension, psittacosis, pulmonary edema secondary to various causes, pulmonary embolism
  • coronavirus is selected from the group consisting of an alphacoronavirus, a betacoronavirus, a gammacoronavirus, a deltacoronavirus, and an omicroncoronavirus, or combinations thereof.
  • coronavirus is selected from the group consisting of porcine epidemic diarrhea virus (PEDv), scotophilus bat coronavirus 512, bat coronavirus CDPHE15, BtRF-Alpha-CoV HuB-2013, bat coronavirus HKU10, miniopterus bat coronavirus HKU8, miniopterus bat coronavirus 1, Nyctalus velutinus alphacoronavirus SC- 2013, Pipistrellus kuhlii coronavirus 3398, Myotis ricketti alphacoronavirus Sax-2011, HumCoV 229E, 229E-related bat coronavirus, camel alphacoronavirus, alpaca respiratory coronavirus, HumCoV NL63, NL63-related Bat-CoV BtKYNL63-9b, HKU2, SADSr-CoV, SADS-CoV, Lucheng Rn rat coronavirus2, FIPV, TGEV, PRCV, alphacor
  • PEDv porcine epidemic
  • coronavirus is a betacoronavirus selected from the group consisting of HumCoV OC43 isolate TNP F1778_2, HKU23, BovCoV, SACoV, GiCoV, bovine coronavirus isolate alpaca, canine respiratory coronavirus K37, PHEV, equine coronavirus, HKU14, HKU24, myodes coronavirus 2JL14, HKU1, MHV, rat coronavirus Parker, HKU4, HKU5, human MERS-CoV, camel MERS-CoV, hedgehog coronavirus 1, HKU9, rousettus bat coronavirus GCCDC1, eidolon bat coronavirus C704, human SARS- CoV, palm civet SARS-CoV, badger SARS-CoV, bat-SL-CoV RsSHC014, bat-SL-CoV Rs3367, bat-SL-CoV WIV1, HKU3, bat-SL-CoCo
  • a method of treating cystic fibrosis in a patient in need thereof comprising administering an effective amount of a compound comprising the crystalline form according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, to the patient.
  • a method of treating pneumonia in a patient in need thereof comprising administering an effective amount of a compound comprising the crystalline form according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, to the patient.
  • a method of treating otitis externa in a patient in need thereof comprising administering an effective amount of a compound comprising the crystalline form according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, to the patient.
  • a method of treating bacterial vaginosis in a patient in need thereof comprising administering an effective amount of a compound comprising the crystalline form according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, to the patient.
  • a method of treating impetigo in a patient in need thereof comprising administering an effective amount of a compound comprising the crystalline form according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, to the patient.
  • a method of treating oral mucositis in a patient in need thereof comprising administering an effective amount of a compound comprising the crystalline form according to any one of clauses 1 to 36, or a pharmaceutically acceptable salt thereof, to the patient.
  • clause 77 wherein the pulmonary condition arises from a coronavirus.
  • the coronavirus is selected from the group consisting of porcine epidemic diarrhea virus (PEDv), scotophilus bat coronavirus 512, bat coronavirus CDPHE15, BtRF-Alpha-CoV HuB-2013, bat coronavirus HKU10, miniopterus bat coronavirus HKU8, miniopterus bat coronavirus 1, Nyctalus velutinus alphacoronavirus SC- 2013, Pipistrellus kuhlii coronavirus 3398, Myotis ricketti alphacoronavirus Sax-2011, HumCoV 229E, 229E-related bat coronavirus, camel alphacoronavirus, alpaca respiratory coronavirus, HumCoV NL63, NL63-related Bat-CoV BtKYNL63-9b, HKU2, SADSr-CoV, SADS-CoV
  • coronavirus is selected from the group consisting of an alphacoronavirus, a betacoronavirus, a gammacoronavirus, a deltacoronavirus, and an omi croncoronavirus, or combinations thereof.
  • betacoronavirus is selected from the group consisting of HumCoV OC43 isolate TNP F1778 2, HKU23, BovCoV, SACoV, GiCoV, bovine coronavirus isolate alpaca, canine respiratory coronavirus K37, PHEV, equine coronavirus, HKU14, HKU24, myodes coronavirus 2JL14, HKU1, MHV, rat coronavirus Parker, HKU4, HKU5, human MERS-CoV, camel MERS-CoV, hedgehog coronavirus 1, HKU9, rousettus bat coronavirus GCCDC1, eidolon bat coronavirus C704, human SARS-CoV, palm civet SARS- CoV, badger SARS-CoV, bat-SL-CoV RsSHC014, bat-SL-CoV Rs3367, bat-SL-CoV WIV1, HKU3, bat-SL-CoV ZC45, bat-SL
  • pulmonary condition is selected from the group consisting of genetic conditions, acquired conditions, primary conditions, secondary conditions, asthma, chronic obstructive pulmonary disease, cystic fibrosis, bronchiolitis, pneumonia, bronchitis, emphysema, adult respiratory distress syndrome, allergies, lung cancer, small cell lung cancer, primary lung cancer, metastatic lung cancer, bronchiestasis, bronchopulmonary dysplasia, chronic bronchitis, chronic lower respiratory diseases, croup, high altitude pulmonary edema, pulmonary fibrosis, interstitial lung disease, reactive airway disease, lymphangioleiomyomatosis, neonatal respiratory distress syndrome, parainfluenza, pleural effusion, pleurisy, pneumothorax, primary pulmonary hypertension, psittacosis, pulmonary edema secondary to various causes, pulmonary embolism, pulmonary hypertension secondary to various
  • Form 1 Prior to the start of solid form screening, Form 1 was characterized by 'H NMR, PXRD, DSC, GC, KF, TGA and mDSC ( Figure 1-6).
  • a heat-cool-heat DSC analysis was planned to understand the nature of the first endotherm event observed in DSC and mDSC thermogram as shown in FIG. 3 and FIG. 4.
  • the heat-cool- heat cycle demonstrated that the first endothermic peak was associated with de-solvation.
  • the first endothermic event did not appear, but other events were reproduced (FIG. 9).
  • To understand the nature of the compound after de-solvation it was heated up to 180°C (in a TGA pan) and then subjected to PXRD and 'H-NMR analysis. Post de-solvation at 180°C, the compound became amorphous (FIG. 10A). However, no sign of degradation was observed in 'H-NMR (FIG. 10B).
  • FIG. 11 A While the compound was heated at 220°C, the amorphous material was found to be recrystallized (FIG. 11 A) at around 200°C followed by melting at 243.97 °C (as shown FIG. 3).
  • the PXRD pattern of FIG. 11A is different than Form 1.
  • FIG. 1 IB From the above set of experiments, it was evident that Form 1 undergoes de-solvation (between about 125°C to about 160°C) and becomes an amorphous material. Post de- solvation/amorphization, Form 1 went through an in-situ crystallization process (cold crystallization; at around 200°C) and then melted at about 243.97 °C.
  • Disodium crystalline solid Form 1 was exposed to 22% relative humidity (RH) at room temperature (RT) (using saturated potassium acetate solution) for 72 hrs.
  • RH relative humidity
  • RT room temperature
  • PXRD and TGA were performed on the dried material after 72 hrs.
  • the dehydrated sample did not show any change in crystallinity by PXRD (FIG. 12A) compared to the Form 1 sample input.
  • a weight loss of 4.531% was observed up to 150°C in TGA (FIG. 12B).
  • the isohume conditions did not lead to loss of water below stochiometric monohydrate.
  • Crystalline solid Form 1 was then heated at 100°C for 24 hrs. After 24 hrs., PXRD, TGA and NMR were performed on the dried material. The dehydrated sample did not show any change in PXRD pattern (FIG. 13 A). There was no change observed in the 'H-NMR spectra of Form 1 after heating (FIG. 13B). 3.212% weight loss was observed up to 150°C in TGA which was close to the theoretical weight loss for a monohydrate TGA (FIG. 13C). It strongly suggests that Form 1 is a monohydrate.
  • Form 1 was extensively characterized by PXRD, DSC, mDSC, TGA, GC, microscopy, and NMR.
  • Form 1 of Nu-3 was found to be a crystalline material with acicular morphology (as seen in FIG. 8). The compound was found to be a hydrate as there were no significant process solvents present in it (confirmed by GC) except water (confirmed by KF).
  • a series of studies were executed to understand the hydrate level of Form 1, which suggests that Form 1 of Nu-3 sodium salt is a stoichiometric monohydrate.
  • Form 1 may undergo a kinetic desolvation (suggested by heat-cool-heat DSC) that is dependent on the ramp rate and appears as an endotherm in DSC/mDSC thermogram.
  • De-solvation of Form 1 leads to the formation of an amorphous material due to the collapse of the crystal lattice (reflected in the PXRD pattern as shown in FIG. 1 OA).
  • the resulting amorphous intermediate was then cold-crystallized (at around 200°C) to another form in situ. The compound remained stable throughout the heating cycle.
  • the crystalline form, obtained after heating Form 1 up to 220°C, could possibly be a new anhydrous crystalline solid form (referred to as Form 6 (having unique 29 peaks of about 5.5°, about 7.7°, and about 12.2° with the relative intensities of 100%, 15.4% and 6.9% respectively, see Table 2) or Form 6' - see EXAMPLE 8).
  • Form 6 having unique 29 peaks of about 5.5°, about 7.7°, and about 12.2° with the relative intensities of 100%, 15.4% and 6.9% respectively, see Table 2
  • Form 6' - see EXAMPLE 8
  • Solubility of crystalline salt Form 1 was assessed in sixteen different solvents of diverse classes (ICH class 2 & 3) to facilitate the selection of solvent systems and corresponding strategies for the subsequent crystallization experiments (Table 3).
  • the solubility was visually estimated at 25°C and also at higher temperatures up to 50°C, by dosing small aliquots of the solvent into a fixed amount of Nu-3 (5 mg) until the dissolution point or a maximum volume of 1000 mL was reached.
  • Table 3 Selection of crystallization modes based on solvent screening data
  • Solid form screening with Form 1 Anti-solvent crystallization
  • co-solvents in which solubility of the Nu-3 > 50 mg/mL
  • anti-solvent in which solubility of the Nu-3 ⁇ 1 mg/mL
  • Crystalline Form 1 of Nu-3 salt was initially dissolved in different co-solvents and then an anti-solvent was added slowly into the solution under stirring conditions, at RT. The crystallized-out material in dispersion was stirred for about 4 days at RT. Results are summarized in the table below (Table 4).
  • Table 4 Crystal polymorphs isolated from Form 1 using anti-solvent crystallization
  • Form 1 three more crystalline solid forms, Form 2, 3, and 5, were identified during the anti-solvent crystallization (see FIG. 14 for the XRPD peaks).
  • Solid Form Screening of Form 1 Cooling Crystallization Based on the solubility data, MeOH, EtOH, 1 -propanol, and water were selected as solvents for cooling crystallization. Crystalline Form 1 of Nu-3 salt was dissolved in different solvents at 50°C and then their volumes were reduced by heating the clear solutions. Then the solutions were divided into two parts. Crystallization at ambient conditions and crash cooling were performed for each set of solutions. Material was isolated in MeOH, 1 -propanol and EtOH after ambient cooling and from EtOH after crash cooling. Solutions that were clear after cooling at 5°C for 24 hrs. were allowed to continue to cool at 5°C for 6 more days. After 7 days at
  • amorphous solid form (Form 4) was prepared from an aqueous solution of crystalline Form 1 by lyophilization. Briefly, solid Form 1 was dissolved in water and then subjected to lyophilization. Three different batches (0.5 g, 1 g, 2 g) were lyophilized according to details in Table 8. PXRD analysis was performed on the resulting powders and the results suggest an amorphous form (FIG. 18), with a broad diffraction peak at a low 2-theta value ( ⁇ 5.0). Results are summarized in the table below (Table 8).
  • the solubility of amorphous Form 4 was assessed in nine different solvents of diverse classes (ICH class 2 & 3) to facilitate the selection of solvent systems and corresponding strategies for the subsequent crystallization experiments. Results are shown in Table 9. The solubility was visually estimated at 50°C, by dosing small aliquots of the solvent into a fixed amount of Nu-3 (20 mg) until the dissolution point or a maximum volume of 1000 mL was reached. Table 9: Solubility data for amorphous Form 4 This solubility information was used to design the following slurry crystallization experiments. Amorphous Nu-3 salt (Form 4) was found to be soluble in NMP, EtOH, 1 -propanol and slightly soluble in ethylacetate and toluene. Salt remained insoluble in acetone, acetonitrile, THF and dioxane at 50°C.
  • the amorphous Form 4 of Nu-3 salt was slurried in solvents with relatively less to poor solubility (EtOH, n-propanol, DMF, NMP and toluene) under stirring. Slurry continued for 4 hrs. at 50°C followed by 16 hrs. stirring at RT. This process continued for the next 7 days. Results are summarized in the below Table 10. Crystalline solid Form 3 and 5 were identified during slurry crystallization (FIG. 19).
  • Amorphous Form 4 was prepared by lyophilization and then characterized by PXRD (FIG. 37), mDSC (FIG. 38), and NMR (FIG. 39). Generally, PXRD pattern resembled that of an amorphous structure; however, there was a broad diffraction peak at a low 29 value ( ⁇ 5.0).
  • Form 1 was found to be highly soluble in water irrespective of different solid forms. Solubility of Form 1 was found to be pH independent. Since the samples were not saturated, the solubility could be higher than provided in the table. EXAMPLE 20
  • Table: 14 Stability studies at variable humidity conditions No solid form transformation to another polymorph was observed at about 8-10% RH for Form 1, 4, and 6 after 1 week. Form 1, 4, and 6 became deliquescent after 48 hrs. and exposure to 84% RH. Nu-3 has not shown any tendency to form lower than a monohydrate. However, the existence of the higher hydrate could not be established due to its hygroscopic nature.
  • Form 1 was found to be converted into Form 1' after 1 week at 25°C and 60% RH.
  • a human patient is identified as having a diabetic foot ulcer.
  • a pharmaceutical composition in the form of a gel containing an effective amount of Crystalline Form 1 of Nu-3 is administered topically to the patient at the location of the diabetic foot ulcer.
  • the patient is monitored until symptoms are alleviated or ameliorated, and the pharmaceutical composition may be administered one or more additional times if it is detennined that such administration is necessary or helpful for treatment.
  • a human patient is identified as having ventilator acquired pneumonia.
  • a pharmaceutical composition containing an effective amount of Crystalline Form 1 of Nu-3 is administered via inhalation to the patient via a nebulizer.
  • the patient is monitored until symptoms are alleviated or ameliorated, and the pharmaceutical composition may be administered one or more additional times if it is determined that such administration is necessary or helpful for treatment.
  • a human patient is identified as having acne vulgaris.
  • a pharmaceutical composition in the form of a gel containing an effective amount of Crystalline Form 1 of Nu-3 is administered topically to the patient at the location of the skin lesion. The patient is monitored until symptoms are alleviated or ameliorated, and the pharmaceutical composition may be administered one or more additional times if it is determined that such administration is necessary or helpful for treatment.
  • Recrystallisation of the sodium salt was achieved by redissolving the Nu-3 disodium salt monohydrate (82.1 g, 0.142 mol in 9: 1 ethanol :water (530 ml) at 80 °C, cooling to 20 °C, clarifying through a glass fiber filter, washing the filter with 9:1 ethanokwater (41 ml), addition of acetone (74 ml) followed by a seed of crystalline Nu-3 disodium salt added as a slurry in acetone (8 ml), stirring of the seed for 1 hour, addition of acetone (739 mL) over 5 hours to induce crystallization of the disodium salt monohydrate.

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Abstract

L'invention concerne des formes cristallines et amorphes de Nu-3 et des sels pharmaceutiquement acceptables de celles-ci. L'invention concerne des compositions pharmaceutiques les contenant, et des méthodes d'utilisation.
PCT/US2025/017096 2024-02-22 2025-02-24 Formes cristallines de nu-3 et leurs utilisations Pending WO2025179296A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050107344A1 (en) * 1998-12-30 2005-05-19 Oligos Etc. Inc. Antimicrobial compounds and methods for their use
US20070053971A1 (en) * 1998-12-30 2007-03-08 Oligos Etc., Inc Antimicrobial and Antiviral Compounds and Methods for their Use
US20180353529A1 (en) * 2017-06-12 2018-12-13 Lakewood Amedex, Inc. Bisphosphocin gel formulations and uses thereof
US20210393666A1 (en) * 2018-10-17 2021-12-23 Lakewood Amedex, Inc. Methods and compositions for treating oral mucositis
WO2024226869A1 (fr) * 2023-04-26 2024-10-31 Lakewood Amedex, Inc. Composés de pyrimidinedione substitués, compositions et utilisations de ceux-ci

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050107344A1 (en) * 1998-12-30 2005-05-19 Oligos Etc. Inc. Antimicrobial compounds and methods for their use
US20070053971A1 (en) * 1998-12-30 2007-03-08 Oligos Etc., Inc Antimicrobial and Antiviral Compounds and Methods for their Use
US20180353529A1 (en) * 2017-06-12 2018-12-13 Lakewood Amedex, Inc. Bisphosphocin gel formulations and uses thereof
US20210393666A1 (en) * 2018-10-17 2021-12-23 Lakewood Amedex, Inc. Methods and compositions for treating oral mucositis
WO2024226869A1 (fr) * 2023-04-26 2024-10-31 Lakewood Amedex, Inc. Composés de pyrimidinedione substitués, compositions et utilisations de ceux-ci

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