WO2019051207A1 - Analogues d'agonistes du récepteur activé par les proliférateurs de proxisomes (ppar) et leurs procédés d'utilisation - Google Patents

Analogues d'agonistes du récepteur activé par les proliférateurs de proxisomes (ppar) et leurs procédés d'utilisation Download PDF

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WO2019051207A1
WO2019051207A1 PCT/US2018/049927 US2018049927W WO2019051207A1 WO 2019051207 A1 WO2019051207 A1 WO 2019051207A1 US 2018049927 W US2018049927 W US 2018049927W WO 2019051207 A1 WO2019051207 A1 WO 2019051207A1
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mmol
etoac
nmr
mhz
methyl
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PCT/US2018/049927
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English (en)
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Bruce E. HECK
Dong Hyun Kim
Paul Erhardt
Brian Kress
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The University Of Toledo
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Priority claimed from US15/699,054 external-priority patent/US10181018B2/en
Application filed by The University Of Toledo filed Critical The University Of Toledo
Publication of WO2019051207A1 publication Critical patent/WO2019051207A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/26—Radicals substituted by sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms

Definitions

  • the present disclosure relates to the field of compounds, compositions, and methods useful for the treatment or prevention of osteoporosis, osteoarthritis, metabolic bone disorders, fracture management, and other musculoskeletal disorders.
  • Osteoporosis is a silent disease of bones that affects tens of millions of people over the age of 50. The disease results in decreased bone mineral density and ultimately bone fracture. Osteoporosis can lead to acute and chronic fractures, causing significant morbidity and mortality to patients. Other metabolic bone diseases can similarly result in weakened bones and fractures.
  • the best medications available can reduce recurrent fracture risk only 65% of the time, and are associated with significant risks such as avascular necrosis of the
  • Osteoarthritis is the most common joint disorder in the world, and affects the majority of people over the age of 65. Osteoarthritis is a disease of cartilage and bone that results in the wearing away of the lining of the joint, and ultimately bone-on-bone changes. Osteoarthritis can lead to crippling joint pain and deformity, causing significant morbidity to patients. Currently, there are no medical treatments available to prevent or halt the progression of osteoarthritis. The standard of care for treating osteoarthritis dictates supportive pain management measures such as medications, physical therapy, braces, lifestyle changes, and activity modifications, until a patient can no longer tolerate the pain, at which point a joint fusion or replacement may be performed.
  • a method of inducing osteogenesis or chondrogenesis comprising treating mammalian stem cells with an effective amount of one or more of a PPAR5 agonist and a 2O-OH-PGE2 antagonist, whereby the mammalian stem cells differentiate into a cell of osteoblast or chondroblast lineage.
  • a method of inducing osteogenesis or chondrogenesis which includes: administering an effective amount of a pharmaceutical composition to a mammalian patient in need thereof, where the pharmaceutical composition comprises a peroxisome proliferator activated receptor (PPAR) compound in an amount sufficient to prompt stem cells in the patient to contribute toward bone formation, and a pharmaceutically acceptable carrier, excipient, diluent or adjuvant; wherein the PPAR compound has a chemical structure of Formula I:
  • PPAR peroxisome proliferator activated receptor
  • Ri is H;
  • R2 is H;
  • R3 is H or CF 3 ;
  • R4 is H or CF 3 ;
  • R5 is H or CH 3 ; and salts, isomers, solvates, hydrates, polymorphs, and prodrugs thereof.
  • the administration is by surgical implantation including allograft bone, bone substitutes or bone scaffold matrices, or by localized injection of liquid or gel formulations or delivery systems to or near the bone.
  • the administration is by an intravenous, intramuscular or subcutaneous injection of liquid or gel formulations or delivery systems.
  • a method of inducing osteogenesis or chondrogenesis which includes administering induced stem cells to a mammalian patient in need thereof; wherein the induced stem cells are derived from incubating stem cells with a pharmaceutical composition comprising a peroxisome proliferator activated receptor (PPAR) compound having a chemical structure of Formula I.
  • PPAR peroxisome proliferator activated receptor
  • the mammalian patient is a human and the stem cells are either harvested from the same patient or supplied from another mammalian donor.
  • the stem cells are present in a human patient in need of therapy for osteoarthritis, cartilage disorder, bone fracture, osteoporosis, metabolic bone disease, avascular necrosis, or concurrent with skeletal surgery.
  • the stem cells are present in a culture media after either being harvested from a human patient or another mammal; and wherein after treatment are administered to a human patient as a therapy for osteoarthritis, bone fracture, osteoporosis, metabolic bone disease, avascular necrosis or concurrent with skeletal surgery.
  • the patient has one or more of: injury to articular cartilage; osteoarthritis; costochondritis; herniation; achondroplasia; relapsing polychondritis; benign or non-cancerous chondroma; and, malignant or cancerous chondrosarcoma.
  • Ri is H;
  • R2 is H;
  • R3 is H or CF 3 ;
  • R4 is H or CF 3 ;
  • R5 is H or CH 3 ; and salts, isomers, stereoisomers, enantiomers, racemates, solvates, hydrates, polymorphs, and prodrugs thereof.
  • a pharmaceutical composition comprising: a compound of Formula I; and one or more of a pharmaceutically acceptable carrier, excipient, diluent or adjuvant.
  • FIG. 2 Increased osteogenic formation from MSCs treated with BK-4-03
  • FIG. 4 Increased osteogenic formation from MSCs treated with BK-4-15
  • FIG. 5 Table I - Structure of GW0742, chemical template for test agents, and summary of results for several compounds tested in the MSC assay with concomitant assessment of fat cell formation.
  • FIG. 6 Scheme 1 - Eastern half synthesis.
  • FIG. 7 Scheme 2 - O-series synthesis.
  • FIG. 8 Scheme 3 - S-series synthesis.
  • FIG. 9 Scheme 4 - NH-series synthesis.
  • FIG. 10 Scheme 5 - N-Methyl synthesis.
  • FIG. 11 Scheme 6 - N- Alkyl synthesis.
  • FIG. 12 Scheme 7 - Ri& R 2 Western Ring Analogs Group #1.
  • FIG. 13 Scheme 8 - Ri& R 2 Western Ring Analogs Group #2.
  • FIG. 14 Scheme 9 - Central Heterocycle "Thiazole-flip".
  • FIG. 15 Scheme 10 -Central Heterocycle Triazole Synthesis.
  • FIG. 16 Scheme 11- Carboxylic Acid Bioisostere 44.
  • FIG. 17 Scheme 12 - Carboxylic Acid Bioisosteres 49 and 51.
  • FIG. 18 Scheme 13 - Carboxylic Acid Bioisosteres 53, 56, and 57 Syntheses.
  • FIG. 19 Scheme 14 - Naphthalene Sulfonic Acid 61 and Amide 61 Syntheses.
  • PPAR Peroxisome Proliferator Activated Receptors, which are orphan receptors belonging to the steroid/retinoid receptor superfamily of ligand-activated transcription factors.
  • PPARa Three mammalian PPARs have been identified, termed PPARa, PPARy, and PPAR5.
  • PPARs regulate expression of target genes by binding to DNA response elements as heterodimers with the retinoid X receptor.
  • pharmacophoric mimic refers to a compound or functional group having the steric and electronic features necessary for molecular recognition by a biological macromolecule similar to that of another compound or functional group.
  • alkyl refers to monovalent alkyl groups, which are saturated hydrocarbons, preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, n-hexyl, and the like.
  • Some of the crystalline forms for the compounds may exist as polymorphs and as such are included.
  • some of the compounds herein may form solvates with water (i.e., hydrates) or common organic solvents, which are also included.
  • Prodrugs of the compounds herein are included.
  • such prodrugs are functional derivatives of the compounds that are readily convertible in vivo into the required compound.
  • the term “administering” includes the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a subject in need thereof.
  • solvate refers to a pharmaceutically acceptable solid form of a specified compound containing solvent molecules as part of the crystal structure.
  • a solvate typically retains at least some of the biological effectiveness of such compound.
  • Solvates can have different solubilities, hygroscopicities, stabilities, and other properties. Examples of solvates include, but are not limited to, compounds in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine. Solvates are sometimes termed “pseudopolymorphs.”
  • hydrate refers to a solvate with water.
  • racemate refers to a mixture that contains an equal amount of enantiomers.
  • the compounds may be in the form of an individual enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers.
  • the compounds are enantiopure compounds.
  • mixtures of stereoisomers or diastereomers are provided.
  • the compounds encompass both (Z) and (E) double bond isomers (or cis and trans isomers) unless otherwise specifically designated.
  • compounds generally depicted in structures herein encompass those structures in which double bonds are (Z) or (E).
  • substituted whether preceded by the term “optionally” or not, and substituents contained in formulas, refer to the replacement of hydrogen atoms in a given structure with a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • Mesenchymal stem cells are stem cells that can develop into connective tissue throughout the body, such as bone, fat, and cartilage.
  • the present disclosure is aimed at directing mesenchymal stem cells toward osteogenesis or chondrogenesis as opposed to adipogenesis, thereby inducing bone formation over fat formation.
  • the compounds, compositions, and methods described herein are thus useful in the treatment and/or prevention of musculoskeletal disorders such as osteoporosis, osteoarthritis, metabolic and bone disease, as well as for fracture management and prosthetic integration.
  • a method of inducing osteogenesis comprising: contacting a mammalian cell with an effective amount of at least one pharmaceutical composition described herein, whereby the mammalian cell differentiates into a cell of an osteoblast lineage, or whereby the mammalian cell differentiates into a cell of a chondroblast lineage.
  • the mammalian cell is an in vivo mammalian cell.
  • the mammalian cell is a mesenchymal stem cell.
  • the stem cell is isolated from a primate.
  • the primate is a human.
  • the step of contacting is by oral administration of the compound to the mammal.
  • the step of contacting is by intravenous administration of the compound to the mammal.
  • the step of contacting is by subcutaneous administration of the compound to the mammal.
  • the method further comprises detecting differentiation of the mammalian cell into an osteocyte cell of an osteoblast lineage.
  • the method further comprises detecting differentiation of the mammalian cell into a chondrocyte cell of a chondroblast lineage.
  • the solid support is a three dimensional matrix.
  • the solid support is a planar surface.
  • a method of treating a bone disorder comprising: contacting a mammalian cell with a pharmaceutical composition as described herein, whereby the mammalian cell differentiates into a cell of an osteoblast lineage, wherein the bone disorder is associated with defective osteoblasts.
  • the bone disorder is osteoporosis.
  • the method further comprises administering the cell of an osteoblast lineage to an individual with the disorder, thereby treating the disorder.
  • the administration is by surgical implantation.
  • a method of treating a cartilage disorder comprising: contacting a mammalian cell with a pharmaceutical composition as described herein, whereby the mammalian cell differentiates into a cell of a chondroblast lineage, wherein the bone disorder is associated with defective chondroblasts.
  • the cartilage disorder is one or more of: injury to articular cartilage; osteoarthritis; costochondritis; herniation; achondroplasia; relapsing polychondritis; benign or non-cancerous chondroma; and, malignant or cancerous chondrosarcoma.
  • a method for inducing chondrogenesis leading to cartilage formation or chondrogenesis leading to cartilage formation that further mediates formation of new bone tissue in a vertebrate comprising administering a
  • the administration is local or systemic.
  • a method for promoting chondrogenesis at a site of skeletal surgery in a vertebrate comprising delivering a pharmaceutical composition as described herein at the site of skeletal surgery wherein such delivery induces chondrogenesis leading to cartilage formation at the site or chondrogenesis leading to cartilage formation that further mediates formation of new bone tissue at the site.
  • MSCs Human bone marrow-derived mesenchymal stem cells
  • the plates were cultured in a-MEM with 20% FBS for 1 day at 37°C.
  • the medium was switched to osteogenic media (Stem X- Vivo, R&D System, Minneapolis, MN) containing 10% FBS plus 50 ⁇ g/ml ascorbic acid and 3 mM ⁇ - glycerol -phosphate.
  • MSCs were cultured in the osteogenic medium without (vehicle negative control) or with test agents at 1, 2, 4, 10 or 20 ⁇ supplied every 2nd day for 21 days.
  • GW 0427 standard PPAR ligand as positive control
  • FIG. 5 - Table I provides a structural key for these compounds and a summary of biological data for several additional members within each of the four linkage types.
  • FIG. 5 - Table I shows the structure of GW0742, chemical template for test agents, and summary of results for several compounds tested in the MSC assay with concomitant assessment of fat cell formation.
  • 'AD' indicates formation of fat cells analogous to those in adipose tissue
  • 'OS' indicates formation of mineral deposits indicative of osteogenesis ('OS')
  • generalized scaling was '0' for none observed, '+' for modest, '++' for moderate, '+++' for significant, and '++++' for extensive
  • 'Toxic' indicates that cell viability was affected by the test agent such that assignment of a scale for either AD or OS became compromised
  • Blank entries indicate that the corresponding dose either was not tested or assessed, the latter generally being due to the observation of toxicity from the preceding dose.
  • a mix of fat and osteogenic effects is regarded as acceptable as long as bone predominates during dose progression, e.g. BK-4-15 exhibits the most preferred profile while the profile for BK-4-30 is not as suitable. While GW0742 initially demonstrates such a preference, its OS activity typically decreased as its dose range was continued to 10 and 20 uM such that all of its estimated, averaged effects at these higher doses have been placed in parentheses.
  • any of the compounds disclosed herein could be used in a medication, a food additive, an injection, or a surgical implant designed to treat, ameliorate, or modify, osteoporosis, osteoarthritis, metabolic bone disease, and/or fracture management problems.
  • the compounds of the present disclosure could be used to enhance the natural pathways to direct a patient' s own mesenchymal stem cells toward bone and cartilage formation over adipose formation, thereby preventing and/or treating these underlying conditions.
  • the compounds could also be incorporated into a pharmaceutical composition, or could be used to treat isolated stem cells that are then administered to a patient in need thereof.
  • compositions of the present disclosure comprise an effective amount of a compound disclosed herein, and/or additional agents, dissolved or dispersed in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable refers to molecular entities and compositions that produce no adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human.
  • the preparation of a pharmaceutical composition that contains at least one compound or additional active ingredient will be known to those of skill in the art in light of the present disclosure, as exemplified by Remington's Pharmaceutical Sciences, 2003, incorporated herein by reference.
  • preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biological Standards.
  • compositions disclosed herein may comprise different types of carriers depending on whether it is to be administered in solid, liquid or aerosol form, and whether it need to be sterile for such routes of administration as injection.
  • Compositions disclosed herein can be administered intravenously, intradermally, transdermally, intrathecally, intraarterially, intraperitoneally, intranasally, intravaginally, intrarectally, intraosseously, periprosthetically, topically, intramuscularly, subcutaneously, mucosally, intraosseosly, periprosthetically, in utero, orally, topically, locally, via inhalation (e.g., aerosol inhalation), by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, via a catheter, via a lavage, in cremes, in lipid compositions (e.g., liposomes), or by other method or any combination of the forgoing as would be known to one of ordinary skill in the art (see, for example,
  • the actual dosage amount of a composition disclosed herein administered to an animal or human patient can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. Depending upon the dosage and the route of administration, the number of administrations of a preferred dosage and/or an effective amount may vary according to the response of the subject. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.
  • compositions may comprise, for example, at least about 0.1 % of an active compound.
  • an active compound may comprise between about 2% to about 75% of the weight of the unit, or between about 25% to about 60%, for example, and any range derivable therein.
  • the amount of active compound(s) in each therapeutically useful composition may be prepared is such a way that a suitable dosage will be obtained in any given unit dose of the compound. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations will be contemplated by one skilled in the art of preparing such pharmaceutical formulations, and as such, a variety of dosages and treatment regimens may be desirable.
  • a dose may also comprise from about 1 microgram kg/body weight, about 5 micro gram/kg/body weight, about 10 microgram kg/body weight, about 50 microgram kg/body weight, about 100 microgram/kg/body weight, about 200 microgram/kg/body weight, about 350 microgram/kg/body weight, about 500 microgram/kg/body weight, about 1 milligram/kg/body weight, about 5 milligram/kg/body weight, about 10 milligram/kg/body weight, about 50 milligram/kg/body weight, about 100 milligram/kg/body weight, about 200 milligram/kg/body weight, about 350 milligram/kg/body weight, about 500 milligram/kg/body weight, to about 1000 mg/kg/body weight or more per administration, and any range derivable therein.
  • a range of about 5 mg/kg/body weight to about 100 mg/kg/body weight, about 5 microgram/kg/body weight to about 500 milligram/kg/body weight, etc. can be administered, based on the numbers described above.
  • a composition herein and/or additional agent is formulated to be administered via an alimentary route.
  • Alimentary routes include all possible routes of administration in which the composition is in direct contact with the alimentary tract.
  • the pharmaceutical compositions disclosed herein may be administered orally, buccally, rectally, or sublingually.
  • these compositions may be formulated with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard- or soft- shell gelatin capsules, they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • a composition described herein may be administered via a parenteral route.
  • parenteral includes routes that bypass the alimentary tract.
  • the pharmaceutical compositions disclosed herein may be administered, for example but not limited to, intravenously, intradermally, intramuscularly, intraarterially, intrathecally, subcutaneous, or intraperitoneally (U.S. Patents 6,753,514, 6,613,308, 5,466,468, 5,543,158; 5,641,515; and 5,399,363 are each specifically incorporated herein by reference in their entirety).
  • compositions disclosed herein as free bases or pharmacologically acceptable salts may be prepared in water suitably mixed with a surfactant, such as
  • Dispersions may also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (U.S. Patent 5,466,468, specifically incorporated herein by reference in its entirety). In most cases, the form must be sterile and must be fluid to the extent that easy injectability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (i.e., glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and/or vegetable oils.
  • polyol i.e., glycerol, propylene glycol, liquid polyethylene glycol, and the like
  • suitable mixtures thereof and/or vegetable oils.
  • Proper fluidity may 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 dispersion, and/or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, such as, but not limited to, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • various antibacterial and antifungal agents such as, but not limited to, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption such as, for example, aluminum monostearate or gelatin.
  • aqueous solution for parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration.
  • sterile aqueous media that can be employed is known to those of skill in the art in light of the present disclosure.
  • one dosage may be dissolved in 1 mL of isotonic NaCl solution and either added to 1000 mL of hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, "Remington's Pharmaceutical Sciences” 15th Edition, pages 1035-1038 and 1570-1580).
  • Some variation in dosage will necessarily occur depending on the condition of the subject being treated.
  • the person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards.
  • Sterile injectable solutions are prepared by incorporating the compositions in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized compositions into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • some methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • a powdered composition is combined with a liquid carrier such as, e.g., water or a saline solution, with or without a stabilizing agent.
  • compositions may be formulated for administration via various miscellaneous routes, for example, topical (i.e., transdermal) administration, mucosal administration (intranasal, vaginal, etc.) and/or via inhalation.
  • topical i.e., transdermal
  • mucosal administration intranasal, vaginal, etc.
  • inhalation via inhalation.
  • compositions for topical administration may include the compositions formulated for a medicated application such as an ointment, paste, cream, or powder.
  • Ointments include all oleaginous, adsorption, emulsion, and water-soluble based compositions for topical application, while creams and lotions are those compositions that include an emulsion base only.
  • Topically administered medications may contain a penetration enhancer to facilitate adsorption of the active ingredients through the skin. Suitable penetration enhancers include glycerin, alcohols, alkyl methyl sulfoxides, pyrrolidones and luarocapram.
  • compositions for topical application include polyethylene glycol, lanolin, cold cream and petrolatum as well as any other suitable absorption, emulsion or water-soluble ointment base.
  • Topical preparations may also include emulsifiers, gelling agents, and antimicrobial preservatives as necessary to preserve the composition and provide for a homogenous mixture.
  • Transdermal administration of the compositions may also comprise the use of a "patch.”
  • the patch may supply one or more compositions at a predetermined rate and in a continuous manner over a fixed period of time.
  • the compositions may be delivered by eye drops, intranasal sprays, inhalation, and/or other aerosol delivery vehicles.
  • Methods for delivering compositions directly to the lungs via nasal aerosol sprays has been described in U.S. Patents 5,756,353 and 5,804,212 (each specifically incorporated herein by reference in their entirety).
  • the delivery of drugs using intranasal microparticle resins (Takenaga et al., 1998) and lysophosphatidyl-glycerol compounds (U.S. Patent 5,725,871, specifically incorporated herein by reference in its entirety) are also well-known in the pharmaceutical arts and could be employed to deliver the compositions described herein.
  • transmucosal drug delivery in the form of a polytetrafluoroethylene support matrix is described in U.S. Patent 5,780,045 (specifically incorporated herein by reference in its entirety), and could be employed to deliver the
  • compositions disclosed herein may be delivered via an aerosol.
  • aerosol refers to a colloidal system of finely divided solid or liquid particles dispersed in a liquefied or pressurized gas propellant.
  • the typical aerosol for inhalation consists of a suspension of active ingredients in liquid propellant or a mixture of liquid propellant and a suitable solvent.
  • Suitable propellants include hydrocarbons and hydrocarbon ethers.
  • Suitable containers will vary according to the pressure requirements of the propellant.
  • Administration of the aerosol will vary according to subject's age, weight and the severity and response of the symptoms.
  • kits containing a single or separate containers. Many embodiments of such kits are possible.
  • a kit could house two containers, the first container comprising a compound of Formula I, and the second container comprising a compound of Formula II.
  • a kit could have a first container housing a solution comprising one or more compounds of Formula I and Formula II, and a second container comprising a syringe configured to inject the solution.
  • kits for the preparation of a pharmaceutical composition could have a first container housing one or more compounds of Formula I and Formula II, and a second container housing a pharmaceutically acceptable carrier, excipient, diluent, or adjuvant.
  • the kits typically further include instructions for using the components of the kit to practice the subject methods.
  • the instructions for practicing the subject methods are generally recorded on a suitable recording medium.
  • the instructions may be present in the kits as a package insert or in the labeling of the container of the kit or components thereof.
  • the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, such as a flash drive, CD-ROM, or diskette.
  • the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, such as via the internet, are provided.
  • An example of this embodiment is a kit that includes a web address where the instructions can be viewed and/or from which the instructions can be downloaded. As with the instructions, this means for obtaining the instructions is recorded on a suitable substrate.
  • Acetal 6 (0.909g, 3.968 mmol) was dissolved in THF (15mL) and cooled to -
  • the aqueous phase was extracted using two portions of EtOAc and the organic phases were combined and washed with water, brine, and dried over Na 2 S0 4 . After evaporation of the solvent, a crude product was isolated as a sticky yellow solid. The crude product was purified by column chromatography using a 5-20% EtOAc/Hexane gradient to give7b as a yellow solid (0.658g, 1.504 mmol, 38.2 %).
  • Acetal 7b (0.589 g, 1.346 mmol) was dissolved in THF (20 mL) and 3N HC1 (5 mL) was added. The reaction mixture was stirred at r.t. for 2 hours and was concentrated under reduced pressure. The residue was neutralized with IN NaOH and extracted with EtOAc. The organic extract was washed with water, brine, and dried with Na 2 S04. After evaporation of the solvent, the product was purified with column chromatography using a gradient of 5-20%
  • Acetal 6 (1.079 g, 4.710 mmol) was dissolved in THF (15 mL) and cooled to -
  • Acetal 6 (0.915g, 3.99 mmol) was dissolved in THF (15mL) and cooled to -78°C.
  • Methyl ester 9d (0.053g, 0.113 mmol) was dissolved in 95% EtOH (10 mL) with heat. Mixture was allowed to cool to room temperature before 3N NaOH (1 mL) was added.
  • Ethyl 4-(N-ierf-Butoxycarbonyl)aminocinnamate 10 (1.336 g, 4.586 mmol), thiazole 4a (1.027 g, 4.590 mmol), and Nal (0.690 g, 4.603 mmol) were dissolved in anhydrous DMF (30 mL) under inert gas and cooled in an icebath.
  • NaH 50% dispersion in mineral oil, 0.281 g, 7.025 mmol
  • the reaction mixture was stirred for 3 hours at room temperature and quenched with a 50% dilution of sat. NaHC03.
  • BOC protected amine lib (1.140 g, 2.085 mmol) was dissolved in anhydrous DCM (15 mL) and cooled in an ice bath. Trifluoroacetic acid (3 mL) was added slowly and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then washed with a chilled saturated NaHCC solution, water, brine, and dried with Na2S04. After filtration and evaporation of the solvent, the crude product was purified with column chromatography using a gradient of 10% EtOAc hexane to 25% EtOAc/hexane. The purified productl2b was collected as an ivory solid (0.793 g, 1.776 mmol, 85.2 %).
  • Ethyl ester 10 (1.274 g, 4.373 mmol) and thiazole 4d (1.314 g, 4.250 mmol) were dissolved in anhydrous DMF (35 mL) and cooled to 0°C. Nal (0.677 g, 4.520 mmol) was added and the mixture was warmed to room temperature and stirred for 1.5 hours. The solution was then quenched with water and extracted with ether/NaHCOs solution three times. The ether extracts were combined and washed with brine and dried with Na2S04. The crude yellow-orange oil was concentrated and purified using column chromatography with a 100% hexane to 15%
  • Ethyl 4-N-ferf-butoxycarbonyl)aminocinnamate 10 (0.935 g, 3.211 mmol) was dissolved in anhydrous DMF (17 mL) and cooled in an icebath. NaH (60% dispersion in oil, 0.198 g, 4.95 mmol) was added and the mixture was stirred for 60 minutes followed by addition of iodomethane (0.60 mL, 9.63 mmol). The reaction mixture was stirred overnight at room temperature and quenched with a 50% aqueous solution of NaHCC and extracted twice with ether.
  • Ethyl 4-[N-(ierf-butoxycarbonyl)methyl]aminocinnamate 14 (0.775 g, 2.538 mmol) was dissolved in anhydrous DCM (20 mL) and cooled in an icebath. Trifluoroacetic acid (5 mL) was slowly added and the mixture was allowed to warm to room temperature. The mixture was stirred for 90 minutes and the solvent was removed under reduced pressure. The residue was taken up into EtOAc and washed with chilled saturated NaHC(3 ⁇ 4, brine, dried with Na2S04, filtered, and concentrated. The crude material was purified by column chromatography using 10%
  • Ethyl 4-(N-Methyl)aminocinnamate 15 (0.430 g, 2.094 mmol), thiazole 4b (0.661 g, 2.265 mmol), and Nal (0.336 g, 2.241 mmol) were dissolved in anhydrous DMF (15 mL) and cooled in an icebath. NaH (60% dispersion in oil, 0.132 g, 3.300 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water, diluted with ether, and washed with a 10% aqueous NaHCC solution. The organic phase was collected and the aqueous phase was extracted with ether three times.
  • N-isopropyl ester 18b (0.490g, 2.100 mmol), thiazole4b (0.745 g, 2.554 mmol) and Nal (0.41g, 2.735mmol) were dissolved in dry DMF (25mL) and cooled to 0°C. NaH (0.107 g, 2.675 mmol) was added and the reaction mixture was stirred for 4 hours at room temperature. The mixture was diluted with a solution of NaHC(3 ⁇ 4 and extracted with ether three times. The ether extracts were combined and washed with brine, water, dried with Na 2 S0 4 , and filtered.
  • N-isopropyl esterl9b (0.168 g, 0.344 mmol) was dissolved in EtOH (5 mL) and
  • Methyl ester 23b (1.359 g, 4.450 mmol) was dissolved in anhydrous DCM (25 mL) under nitrogen gas and cooled in ice bath. Trifluoroacetic acid (7 mL, 91.48 mmol) was carefully added and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was then quenched with an aqueous saturated solution of NaHC03. The organic phase was collected and washed with water, brine, and dried with Na2S04. After filtration, the solution was concentrated and column chromatography was attempted to purify the crude material along with recrystallization.
  • Trifluoroacetic acid (7.4 mL, 96.70 mmol) was slowly added and the mixture was stirred at r.t. for 2 hours.
  • the reaction mixture was diluted with DCM and neutralized with chilled saturated NaHC03.
  • the organic phase was collected and washed with water, brine, dried with Na2S04, and concentrated.
  • the crude material was purified by column chromatography using a gradient of 5% EtOAc/hexane to 50% EtOAc/hexane and appeared to oxidize upon collection to give the desired product 29b as a crude black oil with trace EtOAc (1.733 g). This material was used in the next step without further purification.
  • TLC R f (25% EtOAc/Hexane) 0.51.
  • Ethyl ester 33 (3.284 g, 10.416 mmol) was dissolved in anhydrous THF (30 mL) under nitrogen gas. The mixture was cooled in icebath and a chilled 2.0 M solution of LAH in THF (5.2 mL, 10.4 mmol) was added slowly. The reaction mixture was stirred in ice bath for 15 minutes before removing the ice bath to allow warming to room temperature. The reaction mixture stirred for 90 minutes and was quenched with water and dried with Na 2 S0 4 .
  • Alcohol 34 (1.606 g, 5.877 mmol) was dissolved in anhydrous DCM (40 mL) under nitrogen gas and triethylamine (1.65 mL, 11.838 mmol) was added at room temperature. The mixture was cooled in an ice bath and methanesulfonyl chloride (0.69 mL, 8.915 mmol) was added and the reaction mixture was stirred at 4 °C overnight. The reaction mixture was diluted with DCM and washed with sat. NaHCCb solution, water, brine, and dried with Na2S04.

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Abstract

L'invention concerne des composés de type récepteur activé par les proliférateurs de peroxysomes (PPAR), et leurs procédés d'utilisation pour le traitement des fractures osseuses, le traitement de l'ostéoporose et/ou des maladies osseuses métaboliques, et l'induction de l'ostéogenèse et/ou de la chondrogenèse.
PCT/US2018/049927 2017-09-08 2018-09-07 Analogues d'agonistes du récepteur activé par les proliférateurs de proxisomes (ppar) et leurs procédés d'utilisation WO2019051207A1 (fr)

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US15/699,054 US10181018B2 (en) 2013-03-14 2017-09-08 Analogs of proxisome proliferator activated receptor (PPAR) agonists and methods of using the same
US15/699,054 2017-09-08

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113461491A (zh) * 2021-07-14 2021-10-01 山东华安新材料有限公司 一种三氟异丙醇的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040248951A1 (en) * 2003-06-06 2004-12-09 Jean Ackermann Aniline derivatives, their manufacture and use as pharmaceuticals
US20080207685A1 (en) * 2003-11-20 2008-08-28 Eli Lilly And Company Heterocyclic Compounds As Modulators Of Peroxisome Proliferator Activated Receptors, Useful For The Treatment And/Or Prevention Of Disorders Modulated By A Ppar
US20160016920A1 (en) * 2013-03-14 2016-01-21 The University Of Toledo Analogs of Peroxisome Proliferator Activated Receptor (PPAR) Agonists, and Methods of Using the Same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040248951A1 (en) * 2003-06-06 2004-12-09 Jean Ackermann Aniline derivatives, their manufacture and use as pharmaceuticals
US20080207685A1 (en) * 2003-11-20 2008-08-28 Eli Lilly And Company Heterocyclic Compounds As Modulators Of Peroxisome Proliferator Activated Receptors, Useful For The Treatment And/Or Prevention Of Disorders Modulated By A Ppar
US20160016920A1 (en) * 2013-03-14 2016-01-21 The University Of Toledo Analogs of Peroxisome Proliferator Activated Receptor (PPAR) Agonists, and Methods of Using the Same

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113461491A (zh) * 2021-07-14 2021-10-01 山东华安新材料有限公司 一种三氟异丙醇的制备方法

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