WO2021011723A1 - Composés d'hydantoïne contre l'arthrose, compositions et méthodes associées - Google Patents

Composés d'hydantoïne contre l'arthrose, compositions et méthodes associées Download PDF

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Publication number
WO2021011723A1
WO2021011723A1 PCT/US2020/042238 US2020042238W WO2021011723A1 WO 2021011723 A1 WO2021011723 A1 WO 2021011723A1 US 2020042238 W US2020042238 W US 2020042238W WO 2021011723 A1 WO2021011723 A1 WO 2021011723A1
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WIPO (PCT)
Prior art keywords
compound
microspheres
acid
arthritis
biodegradable
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PCT/US2020/042238
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English (en)
Inventor
Ang Li
Robert A. Volkmann
Anthony Marfat
Frederick R. NELSON
Panayiotis F. ZAGOURAS
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Avidence Therapeutics, Inc.
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Publication of WO2021011723A1 publication Critical patent/WO2021011723A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to new compounds and methods of using them to treat joint-related disorders like osteoarthritis.
  • the aggrecan resides in the extracellular matrix of joints. Aggrecanases degrade aggrecan, and contribute to the development of osteoarthritis. Thus, inhibiting aggrecanases is a strategy for treating osteoarthritis.
  • aggrecanase inhibitors include, for example, using osmotic pumps to establish pharmacokinetic-pharmacodynamic relationships and define desirable human performance characteristics for aggrecanase inhibitors. They also include identifying potent and selective hydantoin inhibitors of aggrecanase-1 and aggrecanase-2 that are effective in both chemical and surgical models of osteoarthritis. They further include a highly selective hydantoin inhibitor of aggrecanase-1 and aggrecanase-2 with a low projected human dose.
  • Galapagos patent applications (e.g., WO 2017/211666, WO 2016/102347, WO 2017/211667, and WO 2017/211668) and Merck’s patents (e.g., U.S. Patent No. 8,859,529) are also germane to aggrecanase inhibitors.
  • This invention provides a compound having the following structure:
  • This invention also provides a prodrug of the present compound, and a pharmaceutically acceptable salt thereof.
  • This invention further provides the present compound (in both active and prodrug forms), wherein one, two, three, over three, or all hydrogen atoms are replaced by deuterium atoms.
  • This invention also provides a composition comprising the present compound and a pharmaceutically acceptable carrier.
  • This invention still further provides a method for treating a disorder in a subject comprising administering to the subject a therapeutically effective amount of the present compound, wherein the disorder is selected from the group consisting of osteoarthritis, synovitis, hemophilic arthropathy, rheumatoid arthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, scleroderma, ankylosing spondylitis, algodystrophy, achondroplasia, Paget’s disease, Tietze syndrome or costal chondritis, fibromyalgia, neurogenic or neuropathic arthritis, arthropathy, sarcoidosis, amylosis, cartilage injury, hydarthrosis, periodical disease, rheumatoid spondylitis, osteochondritis dissecans, hypertropic arthritis, Yersinia arthritis, pyrophosphat
  • This invention provides a biodegradable microsphere, wherein the microsphere (i) has a diameter of from 1 pm to 500 pm; (ii) comprises a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carries the present compound; and (iv) when present in a suitable joint-related tissue, releases the compound for at least one month.
  • the microsphere (i) has a diameter of from 1 pm to 500 pm; (ii) comprises a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carries the present compound; and (iv) when present in a suitable joint-related tissue, releases the compound for at least one month.
  • PLGA polylactic-co-glycolic acid copolymer
  • This invention also provides a plurality of biodegradable microspheres, wherein the microspheres (i) have a d9o value from 1 pm to 500 pm; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of the present compound; and (iv) when present in a suitable joint-related tissue, release the compound for at least one month.
  • the microspheres (i) have a d9o value from 1 pm to 500 pm; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of the present compound; and (iv) when present in a suitable joint-related tissue, release the compound for at least one month.
  • PLGA polylactic-co-glycolic acid copolymer
  • This invention provides an injectable formulation comprising (a) a
  • microspheres (i) have a d9o value from 1 pm to 500 pm; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of the present compound; and (iv) when present in a suitable joint-related tissue, release the compound for at least one month.
  • PLGA polylactic-co-glycolic acid copolymer
  • This invention also provides a method for treating a joint-related disorder in a subject comprising introducing biodegradable microspheres into suitable tissue in or around one or more of the subject’s joints, wherein the microspheres (i) have a d9o value from 1 pm to 500 pm; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of the present compound; and (iv) when present in a suitable joint-related tissue, release the compound for at least one month.
  • PLGA polylactic-co-glycolic acid copolymer
  • this invention further provides an article of manufacture (kit) comprising, in separate compartments, (a) a diluent, and (b) a plurality of biodegradable microspheres, wherein the microspheres (i) have a d9o value from 1 pm to 500 pm; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of the present compound; and (iv) when present in a suitable joint-related tissue, release the compound for at least one month.
  • kit comprising, in separate compartments, (a) a diluent, and (b) a plurality of biodegradable microspheres, wherein the microspheres (i) have a d9o value from 1 pm to 500 pm; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of the present compound; and (iv) when present
  • This figure shows the inhibitory activity of the active form of the present compound on glycosaminoglycan (GAG) release by human healthy
  • the EC50 for inhibiting GAG release (indicating activity of cartilage degradation) is 37.8 nM.
  • This figure shows the FI-NMR spectrum of the active form of the present compound.
  • This invention provides new compounds and methods of using them to treat joint-related disorders like osteoarthritis, as well as numerous other disorders.
  • each present compound is preferably“administered” (also referred to as“introduced”) in the form of a pharmaceutical composition (i.e. , the compound (alone or as a pharmaceutically acceptable salt) in combination with a pharmaceutically acceptable carrier).
  • Administering the instant pharmaceutical compositions can be effected or performed using any of the various methods and delivery systems known to those skilled in the art.
  • the administering can be performed, for example, intravenously, orally, intra- articularly, via implant, transmucosally, transdermally, intramuscularly, and subcutaneously.
  • pharmaceutically acceptable carriers are well known to those skilled in the art (including, e.g., the diluents disclosed herein).
  • the following delivery systems, which employ a number of routinely used carriers, are only representative of the many embodiments envisioned for administering the instant compositions.
  • Oral delivery systems include, for example, tablets and capsules. These can contain excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials),
  • binders e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch
  • diluents e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials
  • disintegrating agents e.g., starch polymers and cellulosic materials
  • lubricating agents e.g., stearates and talc.
  • Solutions, suspensions and powders for reconstitutable delivery systems include vehicles such as
  • suspending agents e.g., gums, zanthans, cellulosics and sugars
  • humectants e.g., sorbitol
  • solubilizers e.g., ethanol, water, PEG and propylene glycol
  • surfactants e.g., sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine
  • preservatives and antioxidants e.g., parabens, vitamins E and C, and ascorbic acid
  • anti-caking agents e.g., gums, zanthans, cellulosics and sugars
  • solubilizers e.g., ethanol, water, PEG and propylene glycol
  • surfactants e.g., sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine
  • preservatives and antioxidants e.g., parabens, vitamins E and
  • Transdermal delivery systems include patches, gels, tapes and creams, and can contain excipients such as solubilizers, permeation enhancers (e.g., fatty acids, fatty acid esters, fatty alcohols and amino acids), hydrophilic polymers (e.g., polycarbophil and polyvinylpyrolidone), and adhesives and tackifiers (e.g., polyisobutylenes, silicone-based adhesives, acrylates and polybutene).
  • solubilizers e.g., permeation enhancers (e.g., fatty acids, fatty acid esters, fatty alcohols and amino acids), hydrophilic polymers (e.g., polycarbophil and polyvinylpyrolidone), and adhesives and tackifiers (e.g., polyisobutylenes, silicone-based adhesives, acrylates and polybutene).
  • permeation enhancers e.g., fatty acids, fatty acid esters
  • Transmucosal delivery systems include patches, tablets, suppositories, pessaries, gels and creams, and can contain excipients such as solubilizers and enhancers (e.g., propylene glycol, bile salts and amino acids), and other vehicles (e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropyl-methylcellulose and hyaluronic acid).
  • solubilizers and enhancers e.g., propylene glycol, bile salts and amino acids
  • other vehicles e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropyl-methylcellulose and hyaluronic acid.
  • Injectable drug delivery systems include solutions, suspensions, gels, microspheres (detailed herein) and polymeric injectables, and can comprise excipients such as solubility-altering agents (e.g., ethanol, propylene glycol and sucrose) and polymers (e.g., polycaprylactones and PLGA's).
  • Implantable systems include rods and discs, and can contain excipients such as PLGA and polycaprylactone.
  • “introducing” preferably means delivering to a specified part of the body, such as joint fluid or a disc. Methods of introducing biodegradable microspheres to joint fluid are known and include, for example, intra-articular injection.
  • the instant pharmaceutical compositions can be packaged in the form of pharmaceutical kits or packages in which the daily (or other periodic) dosages are arranged for proper sequential administration. Accordingly, this invention further provides a drug delivery system comprising a pharmaceutical package containing a plurality of dosage units, adapted for successive daily (or other periodic) administration (e.g., oral administration), each dosage unit comprising at least one of the instant pharmaceutical compositions.
  • a“biodegradable microsphere” comprises a polylactic-co- glycolic acid copolymer (PLGA) matrix, which matrix can include solely polylactic acid (PLA), solely polyglycolic acid (PGA), or a combination of PLA and PGA.
  • PLA polylactic-co- glycolic acid copolymer
  • PGA solely polyglycolic acid
  • PLA polylactic-co- glycolic acid copolymer
  • PLA polylactic-co- glycolic acid copolymer
  • PGA solely polyglycolic acid
  • biodegradable microsphere contains a combination of PLA and PGA wherein the molar ratio of PLA to PGA (i.e. , the“lactic acid to glycolic acid ratio”, or“L:G ratio”) is 0:100, 5:95, 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, 80:20, 85:15, 90:10, 95:5, or 100:0.
  • the molar ratio of PLA to PGA i.e. , the“lactic acid to glycolic acid ratio”, or“L:G ratio”
  • the biodegradable microsphere contains a combination of PLA and PGA wherein the molar ratio of PLA to PGA is from 5:95 to 20:80, from 20:80 to 40:60, from 40:60 to 50:50, from 50:50 to 60:40, from 60:40 to 80:20, from 80:20 to 100:0, from 50:50 to 100:0, from 60:40 to 90:10, from 70:30 to 80:20, from 50:50 to 80:20, from 50:50 to 90:10, from 60:40 to 70:30, from 80:20 to 90: 10, or from 90: 10 to 100:00.
  • the population of biodegradable microspheres used in this invention can be homogeneous or heterogeneous with respect to the microspheres’ molar ratio of PLA to PGA. In one
  • the population of biodegradable microspheres is homogeneous with respect to the microspheres’ molar ratio of PLA to PGA (e.g., the population includes only microspheres wherein the molar ratio of PLA to PGA is at least 75:25).
  • the population of biodegradable microspheres is heterogeneous (e.g., the population includes both (i) microspheres wherein the molar ratio of PLA to PGA is 70:30, and (ii) microspheres wherein the molar ratio of PLA to PGA is 80:20).
  • the instant microspheres contain PLGA having an inherent viscosity of 0.1 to 2.0 dl/g (e.g., 0.16 to 1.7 dl/g), and a molecular weight from 1 ,000 to 500,000 (e.g., from 7,000 to 240,000).
  • the present biodegradable microsphere has a diameter of, for example, from 1 pm to 500 pm, (ii) can non-covalently carry the present compound, and (iii) depending on its polymeric composition, degrades over a period lasting, for example, from one month to over twelve months when placed in suitable joint- related tissue.
  • Microsphere diameters include, for example, the following: (i) from 1 pm to 20 pm, from 20 pm to 40 pm, from 40 pm to 60 pm, from 60 pm to 80 pm, from 80 pm to 100 pm, from 100 pm to 120 pm, from 120 pm to 140 pm, from 140 pm to 160 pm, from 160 pm to 180 pm, from 180 pm to 200 pm, from 200 pm to 250 pm, from 250 pm to 300 pm, from 300 pm to 350 pm, from 350 pm to 400 pm, from 400 pm to 450 pm, or from 450 pm to 500 pm; and (ii) 20 pm, 40 pm, 60 pm, 80 pm, 100 pm, 120 pm, 140 pm, 160 pm, 180 pm, 200 pm, 250 pm, 300 pm, 350 pm, 400 pm, 450 pm, or 500 pm.
  • the present biodegradable microspheres can further comprise polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • Biodegradable PLGA microspheres including homogeneous and heterogeneous populations thereof having defined molar ratios of PLA to PGA) are commercially available from, among other sources, Millipore-Sigma in the form of Degradex ® products (Burlington, MA).
  • the term“carry”, with respect to the present compound and a biodegradable microsphere, means that the present compound is non- covalently bound to, or otherwise contained in or on, the biodegradable microsphere in a manner permitting release from the microsphere during its biodegradation.
  • the term“diluent” includes, without limitation,
  • carboxymethylcellulose sodium carboxymethylcellulose sodium, mannitol (which can optionally be incorporated on and/or into the microspheres to improve suspendability), and water.
  • biodegradable microspheres having a specified size range means that 90% of the biodegradable microspheres have a diameter in the specified range.
  • a“pharmaceutically acceptable salt” includes, without limitation, a salt formed by any of the following acids: 1-hydroxy-2-naphthoic acid, 2,2- dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4- acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2-disulfonic
  • acid ethanesulfonic acid
  • formic acid fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric
  • DL lactobionic acid
  • lauric acid maleic acid, malic acid (- L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1 ,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid (- L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+ L), thiocyanic acid, toluenesulfonic acid (p), or undecylenic acid.
  • a“prodrug” is a biologically inactive form of a drug that, when metabolized in the body, yields the active form of the drug.
  • both hydantoin hydrogen atoms i.e., the hydrogen atoms on the five-membered hydantoin ring
  • the prodrug form of the present compound one or both of the hydantoin hydrogen atoms are replaced with a prodrug moiety.
  • each of the hydantoin hydrogen atoms is replaced with a prodrug moiety, and these moieties may be the same or different.
  • the hydantoin hydrogen atom bound to the ring nitrogen atom in turn bound to the two carbonyl groups is replaced with a prodrug moiety.
  • the other hydantoin hydrogen atom is replaced with a prodrug moiety.
  • Prodrug moieties include, without limitation, ester groups (e.g., with a CH 2 linker), and sulfonamide groups.
  • Prodrug moieties that can replace one or more of the hydantoin hydrogen atoms (ideally the preferred hydantoin hydrogen atom) of the present compound are exemplified below, wherein the present compound is represented by the following formula:
  • the active form of the present compound is shown when both R 2 moieties are H (i.e., when both hydantoin hydrogen atoms are present).
  • the prodrug form is shown when at least one R 2 moiety is not H.
  • each R 4 is the same or different and is independently selected from the group consisting of
  • a biodegradable microsphere “releases” the present compound when some, or all, of the present compound contained by the microsphere is freed into the microsphere’s surrounding milieu.
  • the release is continuous.
  • the release is continuous.
  • biodegradable microspheres having an average release per day of X mg the present compound released per day is, e.g., from 0.1X mg to 10X mg, from 0.2X mg to 5X mg, or from 0.5X mg to 2X mg.
  • the present compound released per week is, e.g., from 0.2X mg to 5X mg, or from 0.5X mg to 2X mg.
  • present compound release into the joint-related tissue precedes, and is distinct from, its efficacy (e.g., pain relief or improvement in physical function) in that tissue.
  • biodegradable microspheres that release a therapeutically effective amount of pharmaceutical present compound into a joint’s synovial fluid for two months might yield a therapeutic effect for three months.
  • present compound release into the joint-related tissue is
  • the term“subject” includes, without limitation, a mammal such as a human, a non-human primate, a dog, a cat, a horse, a sheep, a goat, a cow, a rabbit, a pig, a rat and a mouse.
  • the subject is human.
  • the subject is a dog, a cat, or a horse.
  • suitable joint-related tissue includes any portion of a joint, or the joint’s surrounding tissue, which is capable of holding the instant present compound-containing biodegradable microspheres such that the present compound released therefrom can act on the joint.
  • Suitable joint- related tissue includes, without limitation, (i) articular and periarticular spaces;
  • treating a subject afflicted with a disorder shall include, without limitation, (i) slowing, stopping or reversing the disorder's progression, (ii) slowing, stopping or reversing the progression of the disorder’s symptoms (e.g., pain), (iii) reducing the likelihood of the disorder’s recurrence, and/or (iv) reducing the likelihood that the disorder’s symptoms will recur.
  • treating a subject afflicted with a disorder means (i) reversing the disorder's progression, ideally to the point of eliminating the disorder, and/or (ii) reversing the progression of the disorder’s symptoms, ideally to the point of eliminating the symptoms.
  • This invention solves an unmet need in the art by providing novel hydantoin compounds to treat disorders like osteoarthritis. These compounds inhibit both aggrecanase 1 (Adamts4) and aggrecanase 2 (Adamts5).
  • This invention also provides related compositions for systemic delivery (such as tablets and capsules) and those for local delivery (such as biodegradable microsphere compositions), as well as methods and kits for treating inflammatory diseases, diseases involving degradation of cartilage, and diseases involving the disruption of cartilage homeostasis.
  • this invention provides a compound having the following structure:
  • salts of the active form of the present compound include, without limitation, the following: a salt of X formed by 1 -hydroxy-2-naphthoic acid; a salt of X formed by 2,2- dichloroacetic acid; a salt of X formed by 2-hydroxyethanesulfonic acid; a salt of X formed by 2-oxoglutaric acid; a salt of X formed by 4-acetamidobenzoic acid; a salt of X formed by 4-aminosalicylic acid; a salt of X formed by acetic acid; a salt of X formed by adipic acid; a salt of X formed by ascorbic acid (L); a salt of X formed by aspartic acid (L); a salt of X formed by benzenesulfonic acid; a salt of X formed by benzoic acid; a salt of X formed by camphoric acid (+); a salt of X formed by camphor-10-
  • This compound (and its salt forms) is referred to herein as the“active form” of the present compound, or simply the“present active form.”
  • This invention also provides a prodrug of the compound having the following structure:
  • This compound is referred to herein as the“prodrug form” of the present compound, or simply the“present prodrug form.”
  • the active and prodrug forms of the present compound are collectively referred to herein as the“present compound” or the“present compounds.”
  • This invention further provides the present compound (in both active and prodrug forms), wherein one, two, three, over three, or all hydrogen atoms are replaced by deuterium atoms.
  • This invention further provides a composition comprising the present compound (preferably the present prodrug form) and a pharmaceutically acceptable carrier.
  • the present composition is formulated for oral
  • the present composition is formulated for intravenous administration.
  • the present composition is formulated for intravenous administration.
  • composition is formulated for injection into a joint or a disc.
  • the present compound is envisioned for use, without limitation, in the
  • This invention provides a method for treating a disorder in a human subject comprising administering to the subject a therapeutically effective amount of the present compound (preferably the present prodrug form), wherein the disorder is selected from the group consisting of osteoarthritis, synovitis, hemophilic arthropathy, rheumatoid arthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, scleroderma, ankylosing spondylitis, algodystrophy, achondroplasia, Paget’s disease, Tietze syndrome or costal chondritis, fibromyalgia, neurogenic or neuropathic arthritis, arthropathy, sarcoidosis, amylosis, cartilage injury, hydarthrosis,
  • This invention also provides a method for treating a disorder in a non-human mammal (preferably a cat, a dog, or a horse) comprising administering to the mammal a therapeutically effective amount of the present compound (preferably the present prodrug form), wherein the disorder is selected from the group consisting of osteoarthritis, synovitis, hemophilic arthropathy, rheumatoid arthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, scleroderma, ankylosing spondylitis, algodystrophy, achondroplasia, Paget’s disease, Tietze syndrome or costal chondritis, fibromyalgia, neurogenic or neuropathic arthritis, arthropathy, sarcoidosis, amylosis, cartilage injury, hydarthrosis, periodical disease, rheumatoid s
  • dosages of the present compound include, for example, 0.1 mg - 10 g per day.
  • dosages of the present compound i.e. , therapeutically effective amounts
  • for oral delivery include, without limitation, the following: (i) 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg,
  • Dosages of the present compound (i.e., therapeutically effective amounts) for intravenous delivery include, without limitation, the following: (i) 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg,
  • Dosages of the present compound (i.e. , therapeutically effective amounts) for subcutaneous delivery include, without limitation, the following: (i) 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1 .5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg,
  • therapeutically effective amounts) for local intra-articular delivery to the knee or intra disc delivery include, without limitation, the following: (i) 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg; (ii) from 1 mg to 25 mg, from 25 mg to 50 mg, from 50 mg to 75 mg, from 75 mg to 100 mg, from 100 mg to 150 mg, from 150 mg to 200 mg, from 200 mg to 250 mg, from 250 mg to 300 mg, from 300 mg to 350 mg, from 350 mg to 400 mg, from 400 mg to 450
  • the present compound is locally administered in the form of biodegradable microspheres.
  • this invention provides a biodegradable microsphere, wherein the microsphere (i) has a diameter of from 1 pm to 500 pm; (ii) comprises a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carries the present compound (preferably the present prodrug form); and (iv) when present in a suitable joint-related tissue, releases the compound for at least one month.
  • the present biodegradable microsphere has a lactic acid to glycolic acid molar ratio of from 100:0 to 50:50. In another embodiment, the present biodegradable microsphere (i) has a diameter of from 20 pm to 200 pm; and (ii) has a lactic acid to glycolic acid molar ratio of at least 75:25 (e.g., 75:25, 80:20, 85:15, 90:10, 95:5, or 100:0). In yet another embodiment, the present biodegradable microsphere further comprises polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • the microsphere when it is present in a suitable joint-related tissue, it releases the present compound for longer than one month.
  • the microsphere when present in a suitable joint-related tissue, releases the present compound for at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months.
  • This invention provides a plurality of biodegradable microspheres, wherein the microspheres (i) have a d9o value from 1 pm to 500 pm; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of the present compound (preferably the present prodrug form); and (iv) when present in a suitable joint-related tissue, release the compound for at least one month.
  • the microspheres (i) have a d9o value from 1 pm to 500 pm; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of the present compound (preferably the present prodrug form); and (iv) when present in a suitable joint-related tissue, release the compound for at least one month.
  • PLGA polylactic-co-glycolic acid copolymer
  • the present plurality of biodegradable microspheres further comprise polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • the present plurality of biodegradable microspheres (i) have a d9o value from 20 pm to 200 pm; (ii) have a lactic acid to glycolic acid molar ratio of from 100:0 to 50:50; and (iii) carry from 1 mg to 500 mg of the compound.
  • the microspheres when present in a suitable joint-related tissue, release the present compound for longer than one month.
  • the microspheres when present in a suitable joint-related tissue, releases the present compound for at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months.
  • This invention provides an injectable formulation comprising (a) a
  • the microspheres further comprises polyethylene glycol (PEG).
  • This invention provides a method for treating a joint-related disorder in a subject comprising introducing biodegradable microspheres into suitable tissue in or around one or more of the subject’s joints, wherein the microspheres (i) have a d9o value from 1 pm to 500 pm; (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix; (iii) carry a therapeutically effective amount of the present compound (preferably the present prodrug form); and (iv) when present in a suitable joint-related tissue, release the compound for at least one month (and optionally release the present compound for at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months).
  • the microspheres (i) have a d9o value from 1 pm to 500 pm; (ii) comprise a polylactic-co-glycolic acid copo
  • the present microspheres further comprise polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • the subject is human. In another embodiment of this method, the subject is human. In another
  • the subject is a non-human mammal (preferably a cat, a dog, or a horse).
  • the disorder is arthritis, such as osteoarthritis or rheumatoid arthritis.
  • this method comprises intra-articularly injecting the biodegradable microspheres into one or both of the subject’s knees.
  • the microspheres (i) have a d9o value from 20 pm to 200 pm; (ii) have a lactic acid to glycolic acid molar ratio of from 100:0 to 50:50; and (iii) carry from 1 mg to 500 mg of the compound.
  • the microspheres have an average lactic acid to glycolic acid molar ratio of at least 75:25 (e.g., 75:25, 80:20, 85:15, 90:10, 95:5, or 100:0).
  • the biodegradable thermoplastic material in another preferred embodiment of this method, the biodegradable thermoplastic material
  • microspheres have a d9o value from 20 pm to 150 pm.
  • per injection dosages of the present compound for local intra-articular delivery to the knee via biodegradable microspheres include, without limitation, the following: (i) 1 mg,
  • the biodegradable microspheres can be introduced into the suitable tissue in or around one or more of the subject’s joints using any known method appropriate for the tissue in question.
  • the method comprises intra-articularly injecting the biodegradable microspheres into the synovial fluid of one or both of the subject’s knees.
  • the instant method is performed a plurality of times (e.g., two times, three times, four times, five times, or more). In that embodiment, each subsequent time the method is performed, it is performed after a suitable period has lapsed since the preceding time the method was performed.
  • This suitable time can be, for example, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, or longer.
  • Microsphere-based drug products and methods of delivering them are known, at least generally (e.g., Zilretta ® (triamcinolone acetonide extended-release injectable suspension for intra- articular use (Flexion)); and Sandostatin LAR ® Depot (octreotide acetate for injectable suspension) (Novartis)).
  • This invention further provides an article of manufacture (kit) comprising, in separate compartments, (a) a diluent, and (b) a plurality of biodegradable microspheres, wherein the microspheres (i) have a d9o value from 1 pm to 500 pm (e.g., from 20 pm to 200 pm, or from 50 pm to 150 pm); (ii) comprise a polylactic-co-glycolic acid copolymer (PLGA) matrix (preferably having a lactic acid to glycolic acid molar ratio of from 100:0 to 50:50 (e.g., 75:25, 80:20, 85:15, 90:10, 95:5, or 100:0)); (iii) carry a therapeutically effective amount of the present compound (preferably the present prodrug form) (e.g., from 1 mg to 500 mg of the present compound); and (iv) when present in a suitable joint-related tissue, release the compound for at least one month (and optionally release the present compound for at least two months, at
  • the microspheres further comprise polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • the instant kit is supplied as a single-dose kit, and contains (i) a single dose vial of the present compound-carrying biodegradable microspheres, and (ii) a single dose vial of diluent (e.g., sterile, clear liquid solution of 0.9% w/w sodium chloride, 0.5% w/w sodium carboxymethylose, and 0.1 % w/w polysorbate-80).
  • diluent e.g., sterile, clear liquid solution of 0.9% w/w sodium chloride, 0.5% w/w sodium carboxymethylose, and 0.1 % w/w polysorbate-80.
  • this invention provides synthetic intermediates formed in the synthesis of the present active form. Specifically, this invention provides compound 6 as described in the examples that follow. This invention also provides compound 24 as described in the examples that follow. This invention further provides a method for making the active form of the present compound comprising the steps of (i) contacting compounds 6 and 24 under amide-forming conditions, and (ii) chirally resolving the resulting racemic mixture to obtain the active form of the present compound.
  • amide-forming conditions is set forth below in the examples.
  • i-Pr2NH (0.46 mL, 3.3 mmol).
  • amine was slowly added 2.5 M n-BuLi in hexanes (1.25 mL, 3.1 mmol).
  • the LDA reagent was diluted with dry THF (20 mL).
  • imide 3 (0.65 g, 25 mmol) was dissolved in THF (16 mL) and cooled to -70 °C.
  • the LDA solution was slowly added via syringe such that the internal
  • MMPs matrix metalloproteinases
  • adamts4 enzyme concentration of 50 mM. Twenty-five microliters of adamts4 enzyme is added to each well of a 96-well black plate, to which 5 mI of inhibitor or DMSO control is added and incubated at room temperature for 10 minutes to allow binding. Final inhibitor concentrations range from 0.1 nM, 1 nM, 10 nM, 100 nM, 1 mM, 10 mM, 100 mM, and 1 mM. Then, 25 mI of WAAG-3R substrate is added to the enzyme-inhibitor mixture, and incubated at 37 °C. The fluorescence is read on a Molecular Device SpectraMax i3 instrument every 10-15 minutes with excitation at 340 nm and emission at 420 nm.
  • human recombinant MMP-1 enzyme 901 -MP, R&D Systems
  • the MMP-1 enzyme is activated by adding P-aminophenylmercuric acetate (Sigma, #A- 9563) to a concentration of 1 mM followed by incubation at 37 °C for 2 hours. Then, the activated MMP-1 is diluted to 1 ng/mI in assay buffer, and the substrate ES001 (R&D Systems) is diluted to 20 mM in assay buffer.
  • MMP-2 enzyme is activated by adding P- aminophenylmercuric acetate (Sigma, #A-9563) to a final concentration of 1 mM, followed by incubation at 37 °C for 1 hour.
  • the activated MMP-2 enzyme is diluted to 0.2 ng/mI in assay buffer, and the substrate ES001 (R&D Systems) is diluted to 20 mM in assay buffer.
  • the assay is conducted with a MMP-3 Fluorometric Drug Discovery Kit (BML- AK401 , Enzo Life Sciences) according to manufacturer instructions. Briefly, human recombinant MMP3 enzyme is diluted 100X fold from the manufacturer stock, and the substrate is diluted 10X fold from the manufacturer stock. In a black 96-well plate, sequentially add 10 mI MMP3 enzyme, 5 mI substrate, 30 mI assay buffer, and 5 mI of tested compound dissolved in DMSO. The plate is incubated at 37 °C, and fluorescence is read on a Molecular Device SpectraMax Gemini XS instrument every 10 minutes with excitation at 328 nm and emission at 420 nm. 3.6 - Enzyme Assay for Inhibitory Activities on Human MMP-7
  • MMP-7 907-MP, R&D Systems
  • MMP-7 is activated by adding P-aminophenylmercuric acetate (Sigma, #A-9563) to final concentration of 1 mM, followed by incubation at 37 °C for 1 hour.
  • the activated MMP-7 is diluted to 0.4 ng/mI in assay buffer, and the substrate ES001 (R&D Systems) is diluted to 20 mM in assay buffer.
  • MMP-8 908-MP, R&D Systems
  • MMP-8 is activated by adding P-aminophenylmercuric acetate (Sigma, #A-9563) to final concentration of 1 mM, followed by incubation at 37 °C for 1 hour.
  • the activated MMP-8 is diluted to 1 ng/mI in assay buffer, and the substrate ES001 (R&D Systems) is diluted to 20 mM in assay buffer.
  • MMP-9 is activated by adding P- aminophenylmercuric acetate (Sigma, #A-9563) to final concentration of 1 mM, followed by incubation at 37 °C for 24 hours.
  • the activated MMP-9 is diluted to 0.4 ng/mI in assay buffer, and the substrate ES001 (R&D Systems) is diluted to 20 mM in assay buffer.
  • the assay is conducted with a MMP-14 Fluorometric Drug Discovery Kit (BML- AK417, Enzo Life Sciences) according to manufacturer instructions. Briefly, human recombinant MMP14 enzyme is diluted 100X fold from the manufacturer stock, and the substrate is diluted 10X fold from the manufacturer stock. In a black 96-well plate, sequentially add 10 mI MMP14 enzyme, 5 mI substrate, 30 mI assay buffer, and 5 mI of tested compound dissolved in DMSO. The plate is incubated at 37 °C, and fluorescence is read on a Molecular Device SpectraMax Gemini XS instrument every 10 minutes with excitation at 328 nm and emission at 420 nm.
  • MMP-14 Fluorometric Drug Discovery Kit BML- AK417, Enzo Life Sciences
  • the assay is conducted with a TACE Inhibitor Screening Assay Kit (K366-100, Biovision) according to manufacturer instructions. Briefly, human recombinant TACE enzyme is diluted 25X fold from manufacturer stock, and the TACE substrate is diluted 12.5X fold from manufacturer stock. In a black 96-well plate, sequentially add 20 mI TACE enzyme, 5 mI tested compound dissolved in
  • chondrocytes Primary human healthy chondrocytes are expanded and made into cell aggregates by adding 200,000 cells per well into a 96-well U-bottomed deep- well plate followed by centrifugation at 300 g for 5 minutes.
  • the condensed cell aggregates are cultured in chondrogenic differentiation medium (MesenCultTM- ACF Chondrogenic Differentiation Medium, Stem Cell Technologies) for 1 week, and grown into a cartilage pellet.
  • the chondrogenic medium is removed, and the cartilage pellets are washed with PBS.
  • 250 mI of DMEM medium (11965, ThermoFisher) was added to each cartilage pellet for overnight incubation at 37 °C.
  • Glycosaminoglycan GAG is released by the cartilage pellets into the DMEM medium, and 40 mI of the conditioned medium are used for GAG quantification.
  • DMMB dye To make DMMB dye, first dissolve 2 g sodium formate into 980 ml water. 2 ml formic acid is then added and pH is adjusted to 3.5 as a buffer solution. In a separate tube, 16 mg dimethylmethylene blue (Santa Cruz Biotechnology) is mixed with 5 ml ethanol and added to the buffer. The volume of the DMMB dye is adjusted to 1 L. For GAG quantification, 40 mI of the sample is added to a clear 96-well plate, and 200 pi of DMMB dye is added to each well. The absorbance at 540 nm and 595 nm is read by a Molecular Device SpectraMax Plus 384 plate reader.
  • the active form of the present compound showed no inhibition on the hERG ion channel, which indicates good cardiac safety.
  • 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 are all greater than 10 micromolar, indicating lack of inhibition of these liver CYP enzymes and low risk of potential drug-drug interactions.
  • the half-life of the active form of the present compound in the presence of liver microsomes is 40.34 minutes, which indicates fast metabolic degradation by the liver.
  • the systemic exposure of the drug it is desirable that the systemic exposure of the drug be low.
  • Fast metabolic degradation is a favorable property of the active form of the present compound, if administered as a long-acting (e.g., prodrug-containing microcapsule) knee injection for osteoarthritis.
  • the active form of the present compound is stable in human plasma with a half- life of over 10 hours. Since the synovial fluid is an ultra-filtrate of plasma, this compound would be expected to be stable in human synovial fluid as well. This is a desirable property for a long-acting depot injection in the knee.
  • Human healthy chondrocytes were cultured for three weeks in the presence of the active form of the present compound (10 ng/ml to 10 pg/ml) or DMSO as a negative control. DNA was quantified as an indicator of cell number.
  • Glycosaminoglycan GAG
  • OHP hydroxy-proline
  • Healthy human synoviocytes and chondrocytes were cultured in the presence of the active form of the present compound (0.1 ng/ml to 10 pg/ml) or DMSO control for 7 days.
  • the cell proliferation and metabolism were quantified with a brief incubation of resazurin.
  • the active form of the present compound had no negative effects on cell proliferation or metabolism.

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Abstract

La présente invention concerne des composés d'hydantoïne qui inhibent à la fois l'aggrécanase 1 (Adamts4) et l'aggrécanase 2 (Adamts5). La présente invention concerne également des compositions et des méthodes associées pour le traitement de maladies inflammatoires, de maladies impliquant la dégradation du cartilage et de maladies impliquant la rupture de l'homéostasie du cartilage.
PCT/US2020/042238 2019-07-18 2020-07-16 Composés d'hydantoïne contre l'arthrose, compositions et méthodes associées WO2021011723A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080262045A1 (en) * 2001-03-15 2008-10-23 Anders Eriksson Metalloproteinase Inhibitors
US20110288054A1 (en) * 2008-09-24 2011-11-24 Schering Corporation Compounds for the treatment of inflammatory disorders
US20150218107A1 (en) * 2012-10-26 2015-08-06 Eli Lily And Company Aggrecanase inhibitors
WO2016102347A1 (fr) * 2014-12-22 2016-06-30 Galapagos Nv Dérivés 5-[(pipérazine-1-yl) -3-oxo-propyl]-imidazolidine -2,4-dione comme inhibiteurs d'adamts pour le traitement de l'arthrose
WO2018080521A1 (fr) * 2016-10-28 2018-05-03 SpineThera Compositions pharmaceutiques et utilisations correspondantes

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7504424B2 (en) * 2004-07-16 2009-03-17 Schering Corporation Compounds for the treatment of inflammatory disorders
TW201332989A (zh) * 2011-12-23 2013-08-16 Millennium Pharm Inc 雜芳基化合物及其用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080262045A1 (en) * 2001-03-15 2008-10-23 Anders Eriksson Metalloproteinase Inhibitors
US20110288054A1 (en) * 2008-09-24 2011-11-24 Schering Corporation Compounds for the treatment of inflammatory disorders
US20150218107A1 (en) * 2012-10-26 2015-08-06 Eli Lily And Company Aggrecanase inhibitors
WO2016102347A1 (fr) * 2014-12-22 2016-06-30 Galapagos Nv Dérivés 5-[(pipérazine-1-yl) -3-oxo-propyl]-imidazolidine -2,4-dione comme inhibiteurs d'adamts pour le traitement de l'arthrose
WO2018080521A1 (fr) * 2016-10-28 2018-05-03 SpineThera Compositions pharmaceutiques et utilisations correspondantes

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