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WO2014151719A1 - Formulations sublinguales comprenant de la géranylgéranylacétone et des dérivés de géranylgéranylacétone - Google Patents

Formulations sublinguales comprenant de la géranylgéranylacétone et des dérivés de géranylgéranylacétone Download PDF

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Publication number
WO2014151719A1
WO2014151719A1 PCT/US2014/026307 US2014026307W WO2014151719A1 WO 2014151719 A1 WO2014151719 A1 WO 2014151719A1 US 2014026307 W US2014026307 W US 2014026307W WO 2014151719 A1 WO2014151719 A1 WO 2014151719A1
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Prior art keywords
gga
alkyl
compound
mmol
optionally substituted
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PCT/US2014/026307
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English (en)
Inventor
William Boyle
Naoki Nakayama
Obsidiana Abril-Horpel
William Haag
Patricia Walicke
Florian ERMINI
Hiroaki Serizawa
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Coyote Pharmaceuticals Inc
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Coyote Pharmaceuticals Inc
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Priority claimed from US13/815,831 external-priority patent/US20140274967A1/en
Priority claimed from US13/815,792 external-priority patent/US20140275282A1/en
Application filed by Coyote Pharmaceuticals Inc filed Critical Coyote Pharmaceuticals Inc
Publication of WO2014151719A1 publication Critical patent/WO2014151719A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • 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
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • GGA geranylgeranyl acetone
  • compositions useful for the same Preferably, GGA or the GGA derivative is enriched in the all trans isomer, compared to the relative amount of the trans isomer in the mixtures of c/s and trans isomers of GGA or the GGA derivative.
  • sublingual formulations comprising geranylgeranylacetone and geranylgeranylacetone derivatives and uses thereof.
  • polyisoprenyl phosphonate derivatives pharmaceutical compositions comprising polyisoprenyl phosphonate derivatives, and uses thereof.
  • Geranylgeranyl acetone has the formula:
  • Neurodegeneration is often the result of increased age, sporadic mutations, disease, and/or protein aggregation in neural cells.
  • Neurodegenerative diseases are often characterized by a progressive neurodegeneration of tissues of the nervous system and a loss of functionality of the neurons themselves.
  • One commonality seen among most neurodegenerative diseases is the accumulation of protein aggregates intracellular ⁇ or in the extracellular space between neurons.
  • Sublingual administration of a drug involves applying the drug beneath the tongue of a subject. When the drug comes in contact with the mucous membrane beneath the tongue, it diffuses through it. Because the connective tissue beneath the epithelium contains a profusion of capillaries, the substance then diffuses into them and enters the venous circulation. In contrast, substances absorbed in the intestines are subject to "first pass metabolism" in the liver before entering the general circulation.
  • Sublingual administration has certain advantages over oral administration. Being more direct, it is often faster, and it ensures that the substance will risk degradation only by salivary enzymes before entering the bloodstream, whereas orally administered drugs must survive passage through the hostile environment of the gastrointestinal tract, which risks degrading them, either by stomach acid or bile, or by the many enzymes therein, such as monoamine oxidase (MAO). Furthermore, after absorption from the gastrointestinal tract, such drugs must pass to the liver, where they may be extensively altered; this is known as the "first pass effect" of drug metabolism. Due to the digestive activity of the stomach and intestines and the solubility of the Gl tract, the oral route is not ideal for certain substances.
  • sublingual administration requires that the drug must partition into the mucosa more favorably than water (saliva); the drug must be able to be absorbed quickly before enzymes in the saliva degrade the drug or a portion of the drug in saliva is swallowed; the drug must then be able to pass through the capillaries and into the blood.
  • the drug must be sufficiently hydrophobic to partition favorably into the mucosa relative to saliva of a subject and yet be sufficiently hydrophilic to subsequently pass from the mucosa into the subject's blood stream to exert a therapeutic effect.
  • sublingual administration of a drug will provide a bioavalability of the drug that is comparable to an i.v. administration of the drug.
  • GGA is a known anti-ulcer drug used commercially and in clinical situations. There is a need for sublingual formulations of GGA derivatives, e.g., for the treatment or prevention of disorders and diseases which can be trerated with GGA or a GGA derivative.
  • SUMMARY OF THE INVENTION in some aspects, provided herein are methods for inhibiting neural death, increasing neural activity and for treating osteopenia, including osteoporosis, or reducing the negative effects of osteopenia with the derivatives and pharmaceutical compositions provided herein. It is contemplated that these derivatives may possess one or more properties such as increased blood brain barrier penetration, enhanced activity, improved serum half-life, and/or lower toxicity.
  • methods for treating osteopenia or reducing the negative effects of bone loss comprising administering to a subject in need thereof a therapeutically effective amount of GGA or a GGA derivative.
  • subject or patient refers to a mammal, preferably humans.
  • treating osteopenia includes without limitation, modulating osteoclast and/or osteoblast function, and preferably, decreasing osteoclast function in diseases such as osteoporosis, hypercalcemia of malignancy, cancer metastasis to the bone, arthritis, Rheumatoid arthritis, bone loss due to immobilization, Paget's disease of the bone, bone loss due to hyperparathyroidism and other metabolic diseases, bone loss due to treatment with corticosteroids, bone loss due to treatment with aromatase inhibitors, periodontal disease, prosthetic loosening and the like.
  • diseases such as osteoporosis, hypercalcemia of malignancy, cancer metastasis to the bone, arthritis, Rheumatoid arthritis, bone loss due to immobilization, Paget's disease of the bone, bone loss due to hyperparathyroidism and other metabolic diseases, bone loss due to treatment with corticosteroids, bone loss due to treatment with aromatase inhibitors, periodontal disease, prosthetic loosening and the like.
  • treating osteopenia includes treating osteoporosis
  • methods for decreasing osteoclast activity and decreasing bone resorption comprising contacting an osteoclast with an effective amount of GGA or a GGA derivative.
  • methods for shifting the balance between osteoclast and osteoblast activity comprising contacting an osteoclast and/or osteoblast with an effective amount of GGA or GGA derivative.
  • the method further comprises decreasing osteoclast activity and/or increasing osteoblast activity, and/or decreasing bone resorption.
  • methods of blocking osteoclast differentiation and/or osteoclast activation of bone resorption the method comprising contacting an osteoclast with an effective amount of GGA or a GGA derivative.
  • provided herein are methods for inhibiting loss of bone density in a patient in need thereof comprising administering to the patient an effective amount of GGA or a GGA derivative.
  • methods for inhibiting bone fracture in a patient at risk thereof which bone fracture arises at least in part from pathological bone loss comprising administering to the patient an effective amount of GGA or a GGA derivative.
  • the bone fracture is fracture of the hip.
  • the bone fracture is fracture of the vertebrae.
  • provided herein are methods for inhibiting bone loss and/or facilitating bone growth in a patient at a risk of loss of bone density, comprising administering to the patient an effective amount of GGA or a GGA derivative.
  • the methods and compositions provided herein can increase bone formation and/or reduce bone resorption.
  • provided herein are methods for treating a subject who undergoes or has undergone a bone grafting procedure, where the bone grafting procedure is autologous (with bone harvested from the patient's own body) includes an allograft (with cadaveric bone usually obtained from a bone bank), or a synthetic graft.
  • the methods described herein can be used to treat a subject prior to, during and/or after a bone grafting procedure.
  • a method of a decreasing osteoclast activity or modulating osteoclast resorption by administering sublingual ⁇ a parathyroid hormone (PTH) or a PTH like receptor (PTHrP) in combination with or conjugated to a bisphosphonate provided herein.
  • PTH parathyroid hormone
  • PTHrP PTH like receptor
  • the bisphosphonates provided and/or utilized herein will reduce side effects related to elevated calcium levels, while delivering PTH or the PTHrP sublingually, and suppressing the side effects of PTH and PTHrP.
  • the ostecalst activity is decreases.
  • the osteoclast resorption is modulated.
  • the GGA or the GGA derivative includes the all-trans (hereinafter "trans") form or substantially the trans form of the GGA or the GGA derivative.
  • trans all-trans
  • substantially in the context of cis/trans configurations refers to at least 80%, more preferably at least 90%, yet more preferably at least 95%, and most preferably at least 99% of the desired configuration, which can include at least 80%, more preferably at least 90%, yet more preferably at least 95%, and most preferably at least 99% of the trans isomer. In certain embodiments, at least 90%, more preferably, at least 95%, yet more preferably at least 99%, and most preferably, at least 99.5% of the GGA or the GGA derivative is present as a trans isomer.
  • sublingual formulations of GGA or a GGA derivative are provided herein. Surprisingly, it has been discovered that GGA is efficiently provided to a subject via sublingual delivery. The bioavailability of GGA obtained via sublingual administrations is suprisingly high, and almost parallels those obtained from IV injections.
  • a method of maintaining exposure of an effective amount of GGA or a GGA derivative for a period of up to 1 hour, upto 2 hours, or up to 3 hours, in a patient comprising administering the GGA or the GGA derivative sublingually to the patinet in need thereof.
  • the effective amount of GGA or the GGA derivative varies by less that 50%, preferably by less than 25%, and more preferably by less than 10% during the period when the exopsure is maintained.
  • GGA and GGA derivatives utilized herein can be employed as a passive carier where they are not covalently bound to a drug and as covalent conjugates of drugs for administering these drugs sublingually.
  • GGA or the GGA derivative When employed as a passive carrier, GGA or the GGA derivative is mixed, but not covalently bonded, with the drug and optionally with other excipients for facilitating the sublingual delivery of that drug.
  • GGA and GGA derivatives useful for these purposes are provided herein and will be apparent to the skilled artisan upon reading this disclosure. Provided herein are compounds, compositions, and methods for sublingual administration and delivery.
  • the compounds are conjugates of GGA or GGA derivatives with other drugs where rapid onset of a therapeutic serum concentration is desired and can be tolerated
  • the conjugate are provided such that once delivered into the blood it will degrade into safe GGA (or other carrier compound) and the active drug through hydrolysis by water in the blood, through reduction by, for example, thio!-containing components of the blood such as glutathione, or through the action of endogenous enzymes such as lipases, etc.
  • provided herein are drug conjugates of GGA or drug conjugates of GGA derivatives, that are therapeutically useful for sublingual formulation and delivery to a subject.
  • compounds of formula [G-L-] v -D wherein v is 1-10, preferably 1-5, more preferably 1-3, still more preferably 1, G is GGA or a GGA derivative, L is a bond or a linker, which is preferably cleaved in vivo to provide an effective concentration of the drug G.
  • GGA or the GGA derivatives utilized herein are described herein and/or are known to the skilled artisan.
  • L is a single or a double bond.
  • the drug can be any drug, preferably one that contains one or more -C0 2 H, -OH, -NH 2 , and/or - SH, and such other groups that can be covalently conjugated as provided herein.
  • U is preferably a straight or branched chain linker group of 1 to 15 atoms consisting of carbon, nitrogen, oxygen, phosphorus, sulfur, wherein the number of heteroatoms is preferably no more than 5.
  • U comprises a Ci-Cio alkylene or Cj-Cio heteroalkylene, C3-C10 cycloalkyl, Ci-C 10 heteroaryl, C 2 - C 10 heterocyclyl moiety, which is oprinally substituted.
  • Li comprises an amino acid moiety.
  • Li is a di, tri, tetra, or pentapeptide, preferably comprising 1, more preferably 2, and still more preferably 3 or more naturally occurring amino acids.
  • the compositions provided herein contain a drug, and GGA or a GGA derivative as a non-covalently bound carrier. In these embodiments, the drug is not covalently bound to GGA or a GGA derivative directly or via a linker.
  • conjugated and admixed drugs include the following exemplary and non-limiting drugs for treating the respective indications indicated after each drug:
  • Additional drugs include but are not limited to: antibiotics, such as Vancomycin,
  • Daptomycin, Pristamycin 1A and IB, or Linezolid, etc. analgesics, such as the aminopyridine, Flupirtine, or opiates such as Morphine or Codeine, etc; and steroidal or non-steroidal anti- inflammatory drugs, such as but not limited to dexamethazone and ibuprophen, indometacin, or naproxen, respectively.
  • a method of maintaining exposure of an effective amount of a drug for a period of up to 1 hour, upto 2 hours, or up to 3 hours, in a patient comprising administering a GGA or a GGA derivative conjugate of the drug sublingually to the patinet in need thereof.
  • the effective amount of the drug varies by less that 50%, preferably by less than 25%, and more preferably by less than 10% during the period when the drug exopsure is maintained.
  • the compounds include esters of geranylgeranyl alcohol (GGOH) and such other alcohols as utilized herein.
  • esters can include the GGOH esters of NSAID carboxylic acids such as ibuprophen and naproxen.
  • carbonates can attach drugs with alcohol groups to such alcohols utilized herein, and carbamates can attach drugs with amines having at least one N-H hydrogen.
  • GGA derivatives utilized herein include, farnesyl acetone, farnesyl alcohol, farnesyl carbamate, geranyl geranyl (GG) alcohol, GG carbamate.
  • the GGA derivative is wherein r is 0, 1, 2, 3, or 4, and wherein the structures include cis and trans forms and mixtures thereof,
  • the drug that is conjugated to GGA or a GGA derivative is a small molecule, such as but not limited to Argatroban ® or Zofran ® (GlaxoSmithKline, London, U.K.) or vancomycin.
  • the drug that is conjugated to GGA or a GGA derivative is a peptide or a protein drug.
  • the drug that is conjugated to GGA or a GGA derivative is an antibody, such as but not limited to herceptin.
  • the drug that is conjugated is a nucleic acid, a nucleotide , or a nucleoside.
  • the drug conjugate is joined to GGA or the GGA derivative via a Schiff s base linkage. In some embodiments, the drug conjugate is joined to GGA or the GGA derivative via a sulfenylated amide linkage. In some embodiments, the drug conjugate is joined to GGA or the GGA derivative via an ester linkage. In some embodiments, the drug conjugate is joined to GGA or the GGA derivative via an amide linkage. In some
  • the drug conjugate is joined to GGA or the GGA derivative via an urea linkage. In some embodiments, the drug conjugate is joined to GGA or the GGA derivative via a carbonate linkage. It is contemplated that the administration of an effective amount of these sublingual formulations improves pharmaceutical activities such as a more rapid onset of biological activity, and/or a means by which GGA or a GGA derivative can bypass first pass metabolism relative to the administration of a conventional, i.e., non-sublingual formulation comprising the comparable amount of GGA or a GGA derivative.
  • sublingual formulations are better tolerated by patients having difficulty with swallowing (e.g., and without limitation, for patients that suffer from amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease).
  • ALS amyotrophic lateral sclerosis
  • the sublingual formulations of GGA or a GGA derivative avoid stomach acid induced conversion of the all trans form to a mixed cis- and trans- form.
  • at least one of the double bonds in GGA or the GGA derivative of the sublingual formulation is in the cis configuration.
  • at least two or more of the double bonds in GGA or the GGA derivative of the sublingual formulation is in the cis configuration.
  • sublingual formulations of GGA or a GGA derivative exibit bioavailablity and/or pharmacokinetic profiles that do not require the subject to fast before administration. In other words, food intake by the subject is less apt to alter the bioavailablity and/or pharmacokinetic profiles of these sublingual formulations of GGA or a GGA derivative, than corresponding oral formulations.
  • the sublingual formulation contains an effective amount of GGA or the GGA derivative. In some embodiments, these sublingual formulations of GGA or a GGA derivative exibit bioavailablity and/or
  • these sublingual formulations of GGA or a GGA derivative partition more favorably into the oral mucosa than into saliva. As such, little or none of the sublingual formulations of GGA or a GGA derivative is swallowed by the subject before it can be absorbed sublingualis It is further contemplated that these sublingual formulations of GGA or a GGA derivative are compatible with the enzymes in the oral cavity.
  • sublingual formulation of GGA or GGA derivatives such as those utilized herein, and sublingual delivery thereof to a subject.
  • GGA or the GGA derivative is the sole active agent in these formulations and methods.
  • such sublingual formulations provided herein are useful for treating or alleviating the negative effects of various neurological diseases and disorders described herein.
  • provided herein are methods for sublingual delivery of therapeutically active GGA or GGA derivatives, where the GGA or the GGA derivative is the sole therapeutically effective agent.
  • Such delivery will exclude a drug either as a mixture or a conjugate as described herein.
  • the GGA or the GGA derivative, or the drug conjugate of GGA or a GGA derivative forms a micellar or a similarly aggregated structure.
  • the drug is included in the micellar structure.
  • GGA, a GGA derivative, or a GGA-drug conjugate utilized or provided herein can form a micelle or a reverse micelle.
  • a micelle has a hydrolphilic portion exposed to a surrounding aqueous or hydrophilic phase.
  • a reverse micelle has a hydrophobic portion exposed to a surrounding hydrophobic phase.
  • both forms can be in equilibrium with each other. It is further contemplated that a conversion of a micelle to a reverse micelle and vice versa can allow a facile transportation of GGA or the GGA derivative, or the drug conjugate of GGA or a GGA derivative from an aqueous phase into the sublingual mucosal layer and further into blood in a short period of time. In the process, the drug within or associated with the micelle migrates from the salivary aqueous environment into blood.
  • sublingual pharmaceutical compositions comprising an effective amount of 5E, 9E, 13E geranylgeranyl acetone or a GGA derivative, and optionally at least one pharmaceutical excipient, wherein the effective amount is from about 1 mg/kg/day to about 12 mg/kg/day.
  • the effective amount is from about 1 mg/kg/day to about 5 mg/kg/day or from about 6 mg/kg/day to about 12 mg/kg/day, Preferably, the effective amount is about 3 mg/kg/day, about 6 mg/kg/day, or about 12 mg/kg/day.
  • GGA geranylgeranyl acetone
  • sublingual pharmaceutical compositions of isomers of geranylgeranyl acetone, preferably synthetic geranylgeranyl acetone, and GGA derivatives and methods of using such compounds and pharmaceutical compositions.
  • utilized herein is a 5-trans isomer compound of formula VI:
  • VI is at least 80% in the 5E, 9E, 13E configuration.
  • the compound utilized herein is synthetic 5E, 9E, 13E geranylgeranyl acetone.
  • the synthetic 5E, 9E, 13E geranylgeranyl acetone is free of 5Z, 9E, 13E geranylgeranyl acetone.
  • VII is at least a ketal thereof of formula XII:
  • each R 70 independently is d-C 6 alkyl, or two R 70 groups together with the oxygen atoms they are attached to form a 5 or 6 membered ring, which ring is optionally substituted with 1-3, preferably 1-2, yC 6 alkyl groups.
  • the two R 70 groups are the same.
  • R 70 is, methyl, ethyl, or propyl.
  • the cyclic ring is:
  • GGA derivatives provided and/or utilized herein are of formulas (XVIII), (XIX) or (XX), and subformulas thereof:
  • compositions comprising the compounds and uses thereof, wherein the substituents are defined herein.
  • compositions of for increasing the expression and/or release of one or more neurotransmitters from a neuron at risk of developing pathogenic protein aggregates associated with AD or ALS comprising a protein aggregate inhibiting amount of GGA, a GGA derivative, or an isomer or a mixture of isomers thereof.
  • compositions for increasing the expression and/or release of one or more neurotransmitters from a neuron at risk of developing extracellular pathogenic protein aggregates, said composition comprising an extracellular protein aggregate inhibiting amount of GGA, a GGA derivative, or an isomer or a mixture of isomers thereof.
  • sublingual compositions include without limitation lozenges, tablets, including fast dissolving and lipid matrix formulations, sprays, films, gels, granule, neat, capsules, powders, and liquid.
  • the GGA utilized herein is 5-trans GGA or substantially pure 5-trans GGA which is optionally free of cis GGA or is essentially free of cis GGA.
  • the GGA is a mixture of cis and trans isomer, or pure or substantially pure cis isomer.
  • FIG. 1 graphically demonstrates a liquid chromatography and mass spectroscopy
  • FIG. 2 graphically shows the sublingual delivery of a highly fluorescent dansyl hydrazone derivative of CNS administered in a single sublingual dose of 48 mg/kg or a single IV dose of 16 mg/kg; the concentration averages of the data from two animals per time point per treatment group are shown below along with standard deviation error bars.
  • FIG. 3 graphically shows the transportation of a dansylated peptide of approximate molecular weight of 1,3 kDa by showing the average plasma levels for each of two animals per time point per treatment group given in a single dose of 48 mg/kg by either sublingual or iv administration.
  • compositions and methods shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. "Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the invention provided herein.
  • drug conjugate of GGA or a GGA derivative refers to the covalent attachment of the drug to the GGA or GGA derivative.
  • Non-limiting covalent linkages that can be used to attach the drug to the GGA or GGA derivative include, esters, amides, cabamates, carbonates, ureas, Sen iff s bases and sulfenylated amides.
  • drug refers to approved agents for treating diseases or disorders, or agents that are undergoing development for treating such diseases or disorders.
  • the drug contains a moiety capable of forming a conjugate in the manner contemplated and provided herein.
  • neuroprotective refers to reduced toxicity of neurons as measured in vitro in assays where neurons susceptible to degradation are protected against degradation as compared to control. Neuroprotective effects may also be evaluated in vivo by counting neurons in histology sections.
  • neuroneuron refers to all electrically excitable cells that make up the central and peripheral nervous system.
  • the neurons may be cells within the body of an animal or cells cultured outside the body of an animal.
  • the term “neuron” or “neurons” also refers to established or primary tissue culture cell lines that are derived from neural cells from a mammal or tissue culture cell lines that are made to differentiate into neurons.
  • Neuroon or “neurons” also refers to any of the above types of cells that have also been modified to express a particular protein either extrachromosomally or intrachromosomally.
  • Neuroon or “neurons” also refers to transformed neurons such as neuroblastoma cells and support cells within the brain such as glia.
  • protein aggregates refers to a collection of proteins that may be partially or entirely mis-folded.
  • the protein aggregates may be soluble or insoluble and may be inside the cell or outside the cell in the space between cells. Protein aggregates inside the cell can be intranuclear in which they are inside the nucleus or cytoplasm in which they are in the space outside of the nucleus but still within the cell membrane.
  • the protein aggregates described herein are granular protein aggregates.
  • protein aggregate inhibiting amount refers to an amount of GGA that inhibits the formation of protein aggregates at least partially or entirely. Unless specified, the inhibition could be directed to protein aggregates inside the cell or outside the cell.
  • intranuclear or “intranuclearly” refers to the space inside the nuclear compartment of an animal cell.
  • cytoplasm refers to the space outside of the nucleus but within the outer cell wall of an animal cell.
  • pathogenic protein aggregate refers to protein aggregates that are associated with disease conditions. These disease conditions include but are not limited to the death of a cell or the partial or complete loss of the neuronal signaling among two or more cells. Pathogenic protein aggregates can be located inside of a cell, for example, pathogenic intracellular protein aggregates or outside of a cell, for example, pathogenic extracellular protein aggregates.
  • SBMA spinal and bulbar muscular atrophy.
  • Spinal and bulbar muscular atrophy is a disease caused by pathogenic androgen receptor protein accumulation intranuclearly.
  • ALS refers to amyotrophic lateral sclerosis disease.
  • AD Alzheimer's disease
  • neurotransmitter refers to chemicals that transmit signals from a neuron to a target cell.
  • neurotransmitters include but are not limited to: amino acids such as glutamate, aspartate, serine, ⁇ -aminobutyric acid, and glycine; monoamines such as dopamine, norepinephrine, epinephrine, histamine, serotonin, and melatonin; and other molecules such as acetycholine, adenosine, anadamide, and nitric oxide.
  • G protein refers to a family of proteins involved in transmitting chemical signals outside the cell and causing changes inside of the cell.
  • the ho family of G proteins is small G protein, which are involved in regulating actin cytoskeletal dynamics, cell movement, motility, transcription, cell survival, and cell growth.
  • RHOA, RAC1, and CDC42 are the most studied proteins of the Rho family. Active G proteins are localized to the cellular membrane where they exert their maximal biological effectiveness.
  • treatment means any treatment of a disease or condition in a patient, including one or more of: ⁇ preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop, for example, in a subject at risk of suffering from such a disease or condition, thereby substantially averting onset of the disease or condition; • inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or
  • axon refers to projections of neurons that conduct signals to other cells through synapses.
  • axon growth refers to the extension of the axon projection via the growth cone at the tip of the axon.
  • neural disease refers to diseases that compromise the cell viability of neurons.
  • Neural diseases in which the etiology of said neural disease comprises formation of protein aggregates which are pathogenic to neurons provided that the protein aggregates are not related to the disease SBMA and are not intranuclear include but are not limited to ALS, AD, Parkinson's Disease, multiple sclerosis, and prion diseases such as Kuru, Creutzfeltdt-Jakob disease, Fatal familial insomnia, and Gerstmann-Straussler-Scheinker syndrome. These neural diseases are also different from SBMA in that they do not contain polyglutamine repeats. Neural diseases can be recapitulated in vitro in tissue culture cells.
  • AD can be modeled in vitro by adding pre-aggregated ⁇ -amyloid peptide to the cells.
  • ALS can be modeled by depleting an ALS disease-related protein, TDP-43.
  • Neural disease can also be modeled in vitro by creating protein aggregates through providing toxic stress to the cell. One way this can be achieved is by mixing dopamine with neurons such as
  • An effective amount of a compound disclosed or utilized herein, including e.g., a polyisoprenyl phosphonate derivative or GGA or a GGA derivative is the amount of the compound required to produce a protective effect in vitro or in vivo. In some embodiments the effective amount in vitro is about from 0.1 nM to about 1 mM.
  • the effective amount in vitro is from about 0.1 nM to about 0.5 nM or from about 0.5 nM to about 1.0 nM or from about 1.0 nM to about 5.0 nM or from about 5.0 nM to about 10 nM or from about 10 nM to about 50 nM or from about 50 nM to about 100 nM or from about 100 nM to about 500 nM or from about 500 nM to about 1 mM.
  • the effective amount for an effect in vivo is about 0.1 mg to about 100 mg, or preferably, from about 1 mg to about 50 mg, or more preferably, from about 1 mg to about 25 mg per kg/day.
  • the effective amount in vivo is from about 10 mg/kg/day to about 100 mg/kg/day, about 20 mg/kg/day to about 90 mg/kg/day, about 30 mg/kg/day to about 80 mg/kg/day, about 40 mg/kg/day to about 70 mg/kg/day, or about 50 mg/kg/day to about 60 mg/kg/day. In some embodiments, the effective amount in vivo is from about 1 mg/kg/day to about 5 mg/kg/day, In some embodiments, the effective amount in vivo is from about 6 mg/kg/day to about 12 mg/kg/day, In one embodiment, the effective amount in vivo is about 3 mg/kg/day.
  • the effective amount in vivo is about 6 mg/kg/day. In another embodiment, the effective amount in vivo is about 12 mg/kg/day. In still some other embodiments, the effective amount in vivo is from about 100 mg/kg/day to about 1000 mg/kg/day.
  • Routes of administration refers to the method for administering a compound disclosed or utilized herein, including e.g., a polyisoprenyl phosphonate derivative or GGA or a GGA derivative to a mammal.
  • Administration can be achieved by a variety of methods. These include but are not limited to subcutaneous, intravenous, transdermal, sublingual, or intraperitoneal injection or oral administration.
  • halogenating is defined as converting a hydroxy group to a halo group.
  • halo or “halo group” refers to fluoro, chloro, bromo and iodo.
  • stereoselective ⁇ is defined as providing over 90% of the E isomer for the newly formed double bond,
  • Gaometrical isomer or “geometrical isomers” refer to compounds that differ in the geometry of one or more olefinic centers. “E” or “(E)” refers to the trans orientation and “Z” or “ ⁇ !” refers to the as orientation.
  • Geranylgeranyl acetone refers to a compound of the formula:
  • compositions comprising the compound are mixtures of geometrical isomers of the compound.
  • the 5-trans isomer of geranylgeranyl acetone refers to a compound of the formula VI:
  • the 5-cis isomer of geranylgeranyl acetone refers to a compound of the formula
  • polyisoprenyl phosphonate or “polyisoprenyl phosphonate derivative” refers to any of the compounds of Formula (XVIII), (XIX) or (XX) described herein and such other compounds known in the art.
  • C m -C n such as Ci-Cio, Ci-C 5 , or C1-C4 when used before a group refers to that group containing m to n carbon atoms.
  • alkoxy refers to— O-alkyl
  • alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms (i.e., C Cio alkyl) or 1 to 6 carbon atoms (i.e., C C6 alkyl), or 1 to 4 carbon atoms.
  • This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), r-butyl ((CH 3 ) 3 C-), rt-pentyl (CH 3 CH2CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 ) 3 CCH 2 -).
  • methyl CH 3 -
  • ethyl CH 2 -
  • n-propyl CH 2 CH 2 -
  • isopropyl ((CH 3 ) 2 CH-)
  • n-butyl CH 2 CH 2 CH 2 CH
  • alkyl refers to substituted or unsubstituted, straight chain or branched alkyl groups with C1-C12, C r C 6 and preferably Ci-C 4 carbon atoms.
  • alkenyl refers to monovalent aliphatic hydrocarbyl groups having from 2 to 25 carbon atoms or 2 to 6 carbon atoms and 1 or more, preferably 1, carbon carbon double bond. Examples of alkenyl include vinyl, allyl, dimethyl allyl, and the like,
  • alkynyl refers to monovalent aliphatic hydrocarbyl groups having from 2 to 25 carbon atoms or 2 to 6 carbon atoms and 1 or more, preferably 1, carbon carbon triple bond.
  • acyl refers to -C(0)-alkyl, where alkyl is as defined above.
  • alkoxy refers to -O-alkyl
  • nitro refers to -N0 2 .
  • cyano refers to -CN.
  • aryl refers to a monovalent, aromatic mono- or bicyclic ring having 6-10 ring carbon atoms. Examples of aryl include phenyl and naphthyl. The condensed ring may or may not be aromatic provided that the point of attachment is at an aromatic carbon atom. For example, and without limitation, the following is an aryl group:
  • aryl refers to a 6 to 10 membered, preferably 6 membered aryl group.
  • An aryl group may be substituted with 1-5, preferably 1-3, halo, alkyl, and/or— O-alkyl groups.
  • -CO2H ester refers to an ester formed between the -CO2H group and an alcohol, preferably an aliphatic alcohol.
  • a preferred example included -C0 2 R E , wherein E is alkyl or aryl group optionally substituted with an amino group.
  • Co-crystal or as sometimes referred to herein "co-precipitate” refers to a solid, preferably a crystalline solid, comprising GGA or a GGA derivative, and urea or thiourea, more preferably, where, the GGA or the GGA derivative reside within the urea or thiourea lattice, such as in channels formed by urea or thiourea.
  • chiral moiety refers to a moiety that is chiral. Such a moiety can possess one or more asymmetric centers. Preferably, the chiral moiety is enantiomerically enriched, and more preferably a single enantiomer.
  • Non limiting examples of chiral moieties include chiral carboxylic acids, chiral amines, chiral amino acids, such as the naturally occurring amino acids, chiral alcohols including chiral steroids, and the likes.
  • cycloalkyl refers to a monovalent, preferably saturated, hydrocarbyl mono-, bi-, or tricyclic ring having 3-12 ring carbon atoms, While cycloalkyl, refers preferably to saturated hydrocarbyl rings, as used herein, it also includes rings containing 1-2 carbon- carbon double bonds. Nonlimiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamentyl, and the like.
  • the condensed rings may or may not be non-aromatic hydrocarbyl rings provided that the point of attachment is at a cycloalkyl carbon atom.
  • halo refers to F, CI, Br, and/or I.
  • heteroaryl refers to a monovalent, aromatic mono-, bi-, or tricyclic ring having 2- 14 ring carbon atoms and 1-6 ring heteroatoms selected preferably from N, 0, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 5 ring atoms.
  • heteroaryl examples include furan, imidazole, oxadiazole, oxazole, pyridine, quinoline, and the like.
  • the condensed rings may or may not be a heteroatom containing aromatic ring provided that the point of attachment is a heteroaryl atom.
  • heterocyclic ring refers to a non-aromatic, mono-, bi-, or tricyclic ring containing 2-10 ring carbon atoms and 1-6 ring heteroatoms selected preferably from N, 0, S, and P and oxidized forms of N, S, and P, provided that the ring contains at least 3 ring atoms. While heterocydyl preferably refers to saturated ring systems, it also includes ring systems containing 1-3 double bonds, provided that they ring is non-aromatic.
  • heterocydyl examples include, azalactones, oxazoline, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydropyranyl.
  • the condensed rings may or may not contain a non-aromatic heteroatom containing ring provided that the point of attachment is a heterocydyl group.
  • the following is a heterocydyl group:
  • hydrolyzing refers to breaking an R H -0-CO-, R H -0-CS-, or an R H -0-S0 2 - moiety to an R H -OH, preferably by adding water across the broken bond.
  • a hydrolyzing is performed using various methods well known to the skilled artisan, non limiting examples of which include acidic and basic hydrolysis.
  • pharmaceutically acceptable refers to safe and non-toxic for in vivo, preferably, human administration.
  • pharmaceutically acceptable salt refers to a salt that is pharmaceutically acceptable.
  • salt refers to an ionic compound formed between an acid and a base.
  • salts include, without limitation, alkai metal, alkaline earth metal, and ammonium salts.
  • ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases.
  • Exemplary, and non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, NH 4 , Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids.
  • salts include, without limitation, salts of organic acids, such as caroboxylic acids and sulfonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes.
  • organic acids such as caroboxylic acids and sulfonic acids
  • mineral acids such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes.
  • pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisalfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the likes.
  • substantially pure in terms of cis or trans isomer refers to a cis or trans isomer that is by molar amount 70%, 80%, or 95%, preferably 96%, more preferably 99%, and still more preferably 99.5% or more a cis or trans isomer with the rest being the corresponding trans or cis isomer.
  • each double bond is in a trans or E configuration.
  • a cis form of GGA or a GGA derivative will contain one or more of these bonds in a cis or Z configuration.
  • Cis refers to a form where on eor more bonds in the GGA or the GGA derivative are of cis geometry, as understood by the skilled artisan.
  • Such cis isomers may be prepared following various known methods and from the mother-liquor of clathrate crystallization as disclosed in US patent application no. 61/708,570, which is incorpratd herein in its entirety by reference.
  • osteopenia refers to a disease where osteoclasts dissolve resorb more bone than produced by the bone forming cells, osteoblasts.
  • treating osteopenia includes without limitation, modulating osteoclast and/or osteoblast function, and preferably, decreasing osteoclast function in diseases such as osteoporosis, hypercalcemia of malignancy, cancer metastasis to the bone, arthritis, Rheumatoid arthritis, bone loss due to immobilization, Paget's disease of the bone, bone loss due to hyperparathyroidism and other metabolic diseases, bone loss due to treatment with corticosteroids, bone loss due to treatment with aromatase inhibitors, periodontal disease, prosthetic loosening and the like.
  • Methods for modulating and or inhibiting osteoclast function are well known to the skilled artisan, and described, for example, in Boyle et al., EP1717315.
  • the composition is suitable for the treatment of a neural disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, multiple sclerosis, a prion disease amyotrophic lateral sclerosis, damage to the spinal cord, and neural death during an epileptic seizure.
  • a neural disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, multiple sclerosis, a prion disease amyotrophic lateral sclerosis, damage to the spinal cord, and neural death during an epileptic seizure.
  • VI is at least 80% in the 5E, 9E, 13E configuration.
  • the invention utilizes a compound of formula VI wherein VI is at least 85%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.9% in the 5E, 9E, 13E configuration.
  • the compound of formula VI does not contain any of the cis-isomer of GGA.
  • VII is at least 75% in the 5Z, 9E, 13E configuration.
  • the compound utilized is of formula VII wherein VII is at least 80% in the 5E, 9E, 13E
  • the compound of formula VII does not contain any of the trans-isomer of GGA.
  • the configuration of compounds can be determined by methods known to those skilled in the art such as chiroptical spectroscopy and nuclear magnetic resonance spectroscopy.
  • the GGA derivative utilized herein is of Formula I:
  • n 1 is 1 or 2;
  • each 1 and R 2 are independently Ci-Cg alkyl, or R 1 and R 2 together with the carbon atom they are attached to form a C 5 -C 7 cycloalkyl ring optionally substituted with 1-3 C r C6 alkyl groups;
  • Q2 is hydrogen, R 6 , -O-R 6 , -NR 7 R 8 , or is a chiral moiety
  • R 6 is:
  • each R 7 and R 8 are independently hydrogen or defined as R 6 ;
  • ⁇ refers to a mixture of cis and trans isomers at the corresponding position.
  • At least 80% and, preferably, no more than 95% of the compound of Formula (I) is present as a trans isomer.
  • the GGA derivative utilized is of Formula (l-A):
  • n 1 is 1. In another embodiment, n 1 is 2.
  • the GGA derivative provided and/or utilized is of Formula (l-B);
  • the GGA derivative utilized is of Formula l-C:
  • the GGA derivative utilized is of Formula (l-D), (l-E), or (l-F):
  • R -R are defined as in Formula (I) above.
  • the GGA derivative utilized is of Formula (l-G), (l-H), or (l-l):
  • R 6 is C6-Cio aryl, such as naphthyl. In another preferred embodiment, R 6 is a heteroaryl, such as quinolinyl.
  • GGA derivative utilized herein is of Formula (II):
  • n O or 1;
  • n 0, 1, or 2;
  • each R 1 and R 2 are independently Ci-C 6 alkyl, or R 1 and R 2 together with the carbon atom they are attached to form a C 5 -C 7 cycloalkyi ring optionally substituted with 1-3 Ci-C 5 alkyl groups;
  • each of R 3 , R 4 , and R 5 independently are hydrogen or C1-C6 alkyl
  • 3 ⁇ 4 is -OH, -NR 22 R 23 -X-CO-N 24 R 25 , -X-CS-NR 24 R 25 , or -X-S0 2 -NR 24 R 25 ;
  • X is -O-, -S-, -NR 6 -, or -CR 27 R 28 ;
  • each R 22 and R 23 independently is hydrogen; Ci-C 6 alkyl, optionally substituted with Ci-C 6 alkoxy; and C3-C10 cycloalkyi;
  • each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups; -CF 3/ 1-3 halo, preferably, chloro or fluoro, groups; 1-3 nitro groups; 1-3 Ci-C 6 alkoxy groups; -CO-phenyl; or -NR 18 R 19 ;
  • each R 27 and R 28 independently are hydrogen, Ci-C 6 alkyl, -COR 81 or -C0 2 R 81 , or R 27 together with R 24 or R S and the intervening atoms form a 5-7 membered heterocyclyl ring optionally substituted with 1-3 C C6 alkyl groups.
  • the compound of Formula (II) includes optical isomers such as enantiomers and diastereomers.
  • an ester refers preferably to a phenyl or a C1-C6 alkyl ester, which phenyl or alkyl group is optionally substituted with a amino group.
  • Q3 is -N 22 R 23 -X-CO-NR 2 R 25 , -X-CS-N 24 R 25 , or -X-SOz-NR ⁇ R 25 .
  • Q3 is -X-CO-NR 24 R 25 , -X-CS- R 24 R 25 , or -X-S0 2 - R 24 R 25 .
  • Q3 is -NR 22 R 23 .
  • Q3 is -OH.
  • the compound of Formula (II) is of formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 , and Q3 are defined as in any aspect or embodiment herein.
  • the G6A derivative utilized is of formula:
  • R 1 , R 2 , R 4 , R 5 , and 3 ⁇ 4 are defined as in any aspect and embodiment here.
  • the compound of Formula (II) is of formula:
  • R 1 , R 2 , R 3 , R 4 , R s , and 3 ⁇ 4 are defined as in any aspect or embodiment herein.
  • the GGA derivative utilized is of formula:
  • R , R , R , R , m, n, X, R and R are defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R 1 , R 2 , R 4 , R 5 , m, n, and R 24 are defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R is defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R is defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R 24 is defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R 24 is defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R 24 and R 25 are defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R 24 is defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R 24 and ' are defined as in any aspect and embodiment here.
  • n is 0. In another embodiment, m is 1.
  • n is 0. In another embodiment, n is 1. In another embodiment, n is 2.
  • m+n is 1. In another embodiment, m+n is 2. In another embodiment, m+n is 3.
  • R 1 and R z are independently Ci-C 6 alkyl. In another embodiment, R 1 and R 2 independently are methyl, ethyl, or isopropyl.
  • R 1 and R 2 together with the carbon atom they are attached to form a C5-C7 cycloalkyl ring optionally substituted with 1-3 C r C 6 alkyl groups. In another embodiment, R 1 and R 2 together with the carbon atom they are attached to form a ring that is:
  • R 3 , R 4 , and R 5 are independently C r C 6 alkyl. In another embodiment, one of R 3 , R 4 , and R 5 are alkyl, and the rest are hydrogen. In another embodiment, two of R 3 , R 4 , and R 5 are alkyl, and the rest are hydrogen. In another embodiment, R 3 , R 4 , and R s are hydrogen. In another embodiment, R 3 , R 4 , and R 5 are methyl.
  • 3 ⁇ 4 is -X-CO-NR 2 R 25 . In another embodiment, 3 ⁇ 4 is -X- CS-NR 24 R 25 . In another embodiment, 3 ⁇ 4 is -X-S0 2 - R 24 R 25 . In another embodiment, 3 ⁇ 4 is - OCONHR 24 -OCONR 2 R 25 , -NHCONHR 24 -NHCONR 4 R 2S , -OCSNHR 24 -OCSNR 2 R 25 , - NHCSNHR 24 or -NHCSNR 24 R 25 .
  • X is -0-. In another embodiment, X is -NR 26 -. In another embodiment, X is or -CR 27 R 28 .
  • one of R 24 and R 25 is hydrogen. In another embodiment, one or both of R 24 and R 25 are Ci-C 6 alkyl. In another embodiment, one or both of R 24 and R 25 are C1-C6 alkyl, optionally substituted with an R 20 group, wherein R 20 is -C0 2 H or an ester thereof, C C 6 alkyl, C 3 -Ci 0 cycloalkyl, C 3 -Cs heterocyclyl, C6-Cio aryl, or C 2 -Ci 0 heteroaryl. In another embodiment, one or both of R 24 and R 25 are C3-C10 cycloalkyl.
  • R 24 and R 25 are C3-C10 cycloalkyl substituted with 1-3 alkyl groups. In another embodiment, one or both of R 24 and R 25 are C 3 -C 8 heterocyclyl. In another embodiment, one or both of R 24 and R 25 are C6-Ci 0 aryl. In another embodiment, one or both of R 24 and R 25 are C 2 -Ci 0 heteroaryl. In another embodiment, R 24 and R 25 together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.
  • R 20 is -C0 2 H or an ester thereof. In another embodiment, R 20 is C C 6 alkyl. In another embodiment, R 20 is C 3 -Ci 0 cycloalkyl. In another embodiment, R 20 is C 3 - C 8 heterocyclyl. In another embodiment, R 20 is C6- i 0 aryl. In another embodiment, R 20 is or C 2 -Cio heteroaryl.
  • the GGA derivative utilized is of formula (II): or a pharmaceutically acceptable salt thereof, wherein
  • n 0 or 1
  • each of R 3 , R 4 , and R 5 independently are hydrogen or d-C 6 alkyl
  • Q3 is -X-CO-NR 2 R 25 or -X-SOz-N ⁇ R 25 ;
  • X is -O-, -NR 26 -, or -CR 27 R 28 ;
  • R 25 is hydrogen or together with R 24 or R 25 and the intervening atoms form a 5-7 membered ring optionally substituted with 1-3 Ci-C 6 alkyl groups;
  • each R 27 and R 28 independently are hydrogen, C C G alkyl, -COR 81 or -C0 2 R 81 , or R 27 together with R 24 or R 25 and the intervening atoms form a 5-7 membered cycloalkyi or heterocyclyl ring optionally substituted with 1-3 d-C 6 alkyl groups; each R 24 and R 25 independently is
  • Ci-Ce alkyl optionally substituted with -C0 2 H or an ester thereof, C3-C10 preferably C 3 -Ce cycloalkyi, C 3 -C 8 heterocyclyl, C 6 -Ci 0 aryl, or C 2 -Ci 0 heteroaryl, C3-C10 cycloalkyi,
  • each cycloalkyi, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 Ci-C 6 alkyl groups, or R 24 and R 25 together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.
  • the GGA derivative utilized herein is of Formula
  • n 0 or 1
  • n 0, 1, or 2;
  • each 1 and R 2 are independently ⁇ alkyl, or R 1 and R z together with the carbon atom they are attached to form a C 5 -C 7 cycloalkyi ring optionally substituted with 1-3 Ci-C 6 alkyl groups;
  • each of R 3 , R 4 , and R 5 independently are hydrogen or d-C 6 alkyl
  • C is selected from the roup consisting of:
  • X 1 when X 1 is bonded via a single bond, X 1 is -0-, -NR 31 -, or -CR 32 R 33 -, and when X 1 is bonded via a double bond, X 1 is -CR 32 -;
  • Y 1 is hydrogen, -OH or -O-R 10
  • Y 2 is -OH, -OR 11 or -NHR 12
  • R 30 is Ci-C 6 alkyl optionally substituted with 1-3 alkoxy or 1-5 halo group, C 2 -C6 alkenyl, C 2 -C 6 alkynyl, C3-C10 cycloalkyi, C 6 -Ci 0 aryl, C 3 -C 8 heterocyclyl, or C 2 -Ci 0 heteroaryl, wherein each cycloalkyi or heterocyclyl is optionally substituted with 1-3 C r C6 alkyl groups, or wherein each aryl or heteroaryl is independently substituted with 1-3 C1-C6 alkyl or nitro groups, or R 30 is -NR 34 R 35 ;
  • R 31 is hydrogen or together with R 30 and the intervening atoms form a 5-7 membered ring optionally substituted with 1-3 Ci-C 6 alkyl groups;
  • each R 32 and R 33 independently are hydrogen, C r C 6 alkyl, -COR 81 or -C0 2 R 81 , or R 32 together with R 30 and the intervening atoms form a 5-7 membered cycloalkyi or heterocyclyl ring optionally substituted with oxo or 1-3 Ci-C B alkyl groups;
  • R 10 is C C 6 alkyl
  • R 11 and R 1 are independently C C 6 alkyl, C 3 -Ci 0 cycloalkyi, -C0 2 R 1S , or -CON(R 15 ) 2 , or R 10 and R 11 together with the intervening carbon atom and oxygen atoms form a heterocycle optionally substituted with 1-3 C Cs alkyl groups;
  • R 13 is Ci-C 6 alkyl or C 3 -Ci 0 cycloalkyi optionally substituted with 1-3 Ci-Ce alkyl groups;
  • R 14 is hydrogen, C 3 -C 8 heterocydyl, or C r C 6 alkyl optionally substituted with a -C0 2 H or an ester thereof or a C 6 -Ci 0 aryl, C 2 -C6 alkenyl, C 2 -C 6 alkynyl, C 3 -Ci 0 cycloalkyi, or a C 3 -C 8 heterocydyl, wherein each cycloalkyi, heterocydyl, or aryl, is optionally substituted with 1-3 alkyl groups;
  • each R 15 independently are hydrogen, C3-C10 cycloalkyi, Ci-Ce alkyl optionally substituted with 1-3 substituents selected from the group consisting of -C0 2 H or an ester thereof, aryl, or C3-C8 heterocydyl, or two R 15 groups together with the nitrogen atom they are bonded to form a 5-7 membered heterocycle;
  • R 16 is hydrogen or d-C 6 alkyl
  • R 17 is hydrogen, Ci-C 6 alkyl substituted with 1-3 hydroxy groups, -CHO, or is C0 2 H or an ester thereof;
  • each R 34 and R 35 independently is hydrogen, Ci-C 6 alkyl, optionally substituted with - C0 2 H or an ester thereof, C 3 -Ci 0 cycloalkyi, C 3 -C 8 heterocydyl, Ce-Cio aryl, or C 2 -Cio heteroaryl, or is C3-C10 cycloalkyi, C 3 -Cg heterocydyl, C6-Cio aryl, or C 2 -Ci 0 heteroarvl, wherein each cycloalkyi, heterocydyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups, or R 34 and R 35 together with the nitrogen atom they are attached to form a 5-7 membered heterocycle; and
  • each R 81 independently is C1-C6 alkyl.
  • n is 0. In another embodiment, m is 1. In another embodiment, n is 0. In another embodiment, n is 1. In another embodiment, n is 2.
  • the compound of Formula (III) is of formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 30 , X 1 , Y 1 , and Y 2 are defined as in any aspect or embodiment herein.
  • the GGA derivative utilized is of formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 ; R 30 , X 1 , Y 1 , and Y 2 are defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 30 , X 1 , and Y 2 are defined as in any aspect and embodiment herein.
  • the GGA derivative utilized is of formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 30 and X 1 are defined as in any aspect and embodiment herein.
  • the GGA derivative utilized is of formula:
  • R 1 , R 2 , R 4 , R 5 , and C are defined as in any aspect and embodiment herein.
  • the GGA derivative utilized is of formula:
  • R 1 , R 2 , R 4 , R 5 , m, n, X 1 , and R 30 are defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R 1 , R 2 , R 4 , R 5 , m, n, and R 34 are defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • each R 1 and R 2 are Ci-C 6 alkyl.
  • each R 1 and R 2 are methyl, ethyl, or isopropyl.
  • R 1 and R 2 together with the carbon atom they are attached to form a 5-6 membered ring optionally substituted with 1-3 Ci-C 6 alkyl groups.
  • R 1 and R 2 together with the carbon atom they are attached to form a ring that is:
  • R 3 , R 4 , and R 5 are Ci-C 6 alkyl. In another embodiment, one of R 3 , R 4 , and R 5 are alkyl, and the rest are hydrogen. In another embodiment, two of R 3 , R 4 , and R 5 are alkyl, and the rest are hydrogen. In another embodiment, R 3 , R 4 , and R 5 are hydrogen. In another embodiment, R 3 , R 4 , and R 5 are methyl.
  • X 1 is 0. In another embodiment, X 1 is -NR 31 . In another embodiment, R 31 is hydrogen. In another embodiment, R 31 together with R 30 and the intervening atoms form a 5-7 membered ring optionally substituted with 1-3 Ci-C 6 alkyl groups. In another embodiment, X 1 is -CR 32 R 33 -. In another embodiment, X 1 is -CR 32 -. In another embodiment, each R 32 and R 33 independently are hydrogen, Ci-C 6 alkyl, -COR 81 , or - C0 2 R 81 . In another embodiment, R 32 is hydrogen, and R 33 is hydrogen, C C 6 alkyl, -COR 81 , or -C0 2 R 81 .
  • R 33 is hydrogen. In another embodiment, R 33 C C 6 alkyl. In another embodiment, R 33 is methyl. In another embodiment, R 33 is -C0 2 R 81 . In another embodiment, R 33 is -COR 81 .
  • R 32 together with R 30 and the intervening atoms form a 5-7 membered ring.
  • R 33 is hydrogen, C r C 6 alkyl, or -C0 2 R 81 and n is 1, 2, or 3.
  • R 33 is hydrogen or d-C 6 alkyl. In one embodiment, R is hydrogen. In another embodiment, R is C1-C5 alkyl.
  • R 30 is d-C 6 alkyl. In another embodiment, R 30 is methyl, ethyl, butyl, isopropyl, or tertiary butyl. In another embodiment, R 30 is C1-C6 alkyl substituted with 1-3 alkoxy or 1-5 halo group. In another embodiment, R 30 is alkyl substituted with an alkoxy group. In another embodiment, R 30 is alkyl substituted with 1-5, preferably, 1-3, halo, preferably fluoro, groups. In another embodiment, R 30 is NR 34 R 3S . In a preferred embodiment, R 35 is H.
  • R 34 is d-C 6 alkyl, optionally substituted with a group selected from the group consisting of -C0 2 H or an ester thereof, C3-C10 cycloalkyi, C3-C8 heterocyclyl, C6-Cio aryl, or C 2 -Cio heteroaryl.
  • R 34 is C3-C10 cycloalkyi, C 3 -C 8 heterocyclyl, C6-Ci 0 aryl, or C 2 -do heteroaryl.
  • R 34 is C3-Ci 0 cycloalkyi.
  • R 30 is C 2 -C 6 alkenyl or C 2 -C 6 alkynyl. In another embodiment, R 30 is C3-C10 cycloalkyi. In another embodiment, R 30 is C3-C10 cycloalkyi substituted with 1-3 C1-C6 alkyl groups. In another embodiment, R 30 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamentyl. In another embodiment, R 30 is C6-Cio aryl or d- o heteroaryl. In another embodiment, R 30 is a 5-7 membered heteroaryl containing at least 1 oxygen atom.
  • R 30 is C 6 -Ci 0 aryl, C 3 -C 8 heterocyclyl, or C 2 -Ci 0 heteroaryl, wherein each aryl, heterocyclyl, or heteroaryl is optionally substituted with 1-3 -d alkyl groups.
  • Y 2 is -O-R 11 .
  • Q is -CR 33 COR 30 .
  • R 30 is Ci-C 6 alkyl optionally substituted with an alkoxy group.
  • R 30 is C 3 -C 8 cycloalkyi.
  • R is hydrogen.
  • R is Ci-C 6 alkyl.
  • R 33 is C0 2 R 81 .
  • R 33 is COR 81 .
  • C is -CH 2 -CH(0-CONHR 15 )-R 30 .
  • R 15 is C 3 - Cg cycloalkyl.
  • R 15 is C C 6 alkyl optionally substituted with 1-3 substiteunts selected from the group consisting of -C0 2 H or an ester thereof, aryl, or C 3 -C 8 heterocyclyl.
  • R 30 is C r C6 alkyl.
  • C is -O-CO-NHR 34 .
  • R 34 is Ci-C 6 alkyl, optionally substituted with -C0 2 H or an ester thereof, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, C 2 -Ci 0 aryl, or C 2 -Ci 0 heteroaryl.
  • R 34 is C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, C 2 -Ci 0 aryl, or C 2 -Ci 0 heteroaryl.
  • R 14 is hydrogen. In another embodiment, R 14 is C C 6 alkyl optionally substituted with a -C0 2 H or an ester thereof or a Ce-Cio aryl optionally substituted with 1-3 alkyl groups. In another embodiment, R 14 is C 2 -C 6 alkenyl. In another embodiment, R 14 is C 2 -C 6 alkynyl. In another embodiment, R 14 is C 3 -C 6 cycloalkyl optionally substituted with 1-3 alkyl groups. In another embodiment, R 14 is C 3 -C 8 heterocyclyl optionally substituted with 1-3 alkyl groups.
  • R 16 is hydrogen.
  • R 17 is C0 2 H or an ester thereof.
  • R 17 is Ci-C 6 alkyl substituted with 1-3 hydroxy groups.
  • R 17 is Ci-C 3 alkyl substituted with 1 hydroxy group.
  • R 17 is -CH 2 OH.
  • R 10 and R 11 together with the intervening carbon atom and oxygen atoms form a heteroycle of formula:
  • q is 1. In another embodiment, q is 2. In another embodiment, p is 0. In another embodiment, p is 1. In another embodiment, p is 2. In another embodiment, p is 3. In one aspect, the GGA derivative utilized herein is of Formula (IV):
  • n 0, 1, or 2;
  • each R 1 and R 2 are independently Ci-C 6 alkyl, or R 1 and R 2 together with the carbon atom they are attached to form a C 5 -C 7 cycloalkyl ring optionally substituted with 1-3 Ci-C 6 alkyl groups;
  • each of R 3 , R 4 , and R 5 independently are hydrogen or CrC 6 alkyl, or R 5 and Qs together with the intervening carbon atoms form a 6 membered aryl ring, or a 5-8 membered cycloalkenyl ring, or a 5-14 membered heteroaryl or heterocycle, wherein each aryl, cycloalkenyl, heteroaryl, or heterocycle, ring is optionally substituted with 1-2 substituents selected from the group consisting of halo, hydroxy, oxo, -N(R 40 ) 2 , and C r C s alkyl group;
  • alkyl group is optionally substituted with 1-3 substituents selected from hydroxy, H 2; C 6 -Ci 0 aryl, -C0 2 H or an ester or an amide thereof,
  • heteroaryl containing up to 3 ring heteroatoms, wherein the heteroaryl is optionally substituted with 1-3 hydroxy, -N(R 40 ) 2 , and Ci-C 6 alkyl group,
  • benzyl, and phenyl optionally substituted with 1-3 substituents selected from the group consisting of C r Ce alkyl, C1-C6 alkoxy, hydroxy, and halo groups; and
  • each R 40 independently is hydrogen or d-C 6 alkyl.
  • the compound of Formula (IV) includes tautomers and optical isomers such as enantiomers and diastereomers.
  • an ester refers preferably to a phenyl or a C C 6 alkyl ester, which phenyl or alkyl group is optionally substituted with a amino group.
  • an amide refers preferably to a moiety of formula -CON(R 40 ) 2 , wherein R 40 is defined as above.
  • (3 ⁇ 4 is selected from a group consisting of oxazole, oxadiazole, oxazoline, azalactone, imidazole, diazole, triazole, and thiazole, wherein each heteroaryl or heterocycle is optionally substituted as disclosed above.
  • the GGA derivative utilized is of formula IV-A:
  • the GGA derivative utilized is of formula IV-B:
  • R 1 , R 2 , R 4 , R 5 , and 3 ⁇ 4 are defined as in any aspect and embodiment here.
  • R 11 is Ci-C 6 alkyl, C 6 -Ci 0 aryl, C 3 -C 8 heteroaryl, C 3 -C 3 heteroaryl, C 3 -Ci 0 cycloalkyl
  • the alkyl group is optionally substituted with 1-3 C 6 -Ci 0 aryl, C3-C8 heteroaryl, C 3 -C 8 heteroaryl, C3-C10 cycloalkyl groups
  • the aryl, heteroaryl, heteroaryl, cycloalkyl groups are optionally substituted with 1-3 Ci-C 6 alkyl, d-C 6 alkoxy, halo, preferqably chloro or fluoro, C6-C10 aryl, C 3 -Cg heteroaryl, C 3 -Ce heteroaryl, C3-C10 cycloalkyl group.
  • Qs is phenyl, optionally substituted as described herein.
  • 3 ⁇ 4 is benzimidazole, benzindazole, and such other 5-6 fused 9-membered bicyclic heteroaryl or heterocycle.
  • Q5 is quinoline, isoquinoline, and such other 6-6 fused 10 membered heteroaryl or heterocycle.
  • Qs is benzodiazepine or a derivative thereof, such as, a benzodiazepinone.
  • Various benzodiazepine and derivatives thereof are well known to the skilled artisan.
  • n is 0. In another embodiment, m is 1.
  • n is 0. In another embodiment, n is 1. In another embodiment, n is 2.
  • m+n is 1. In another embodiment, m+n is 2. In another embodiment, m+n is 3.
  • R 1 and R 2 are independently Ci-Cg alkyl. In another embodiment, R 1 and R 2 independently are methyl, ethyl, or isopropyl. In another embodiment, R 1 and R z together with the carbon atom they are attached to form a C5-C7 cycloalkyl ring optionally substituted with 1-3 Ci-C 6 alkyl groups. In another embodiment, R 1 and R 2 together with the carbon atom they are attached to form a ring that is:
  • R 3 , R 4 , and R 5 are independently Ci-C 6 alkyl. In another embodiment, one of R 3 , R 4 , and R 5 are alkyl, and the rest are hydrogen. In another embodiment, two of R 3 , R 4 , and R 5 are alkyl, and the rest are hydrogen. In another embodiment, R 3 , R 4 , and R 5 are hydrogen. In another embodiment, R 3 , R 4 , and R 5 are methyl. In another embodiment, utilized herein is a compound selected from the group consisting of:
  • R 11 is defined as above.
  • GGA derivatives utilized herein are of formula (V):
  • n O or 1;
  • n 0, 1, or 2;
  • each R 1 and R 2 independently are C r C 6 alkyl, or R 1 and R 2 together with the carbon atom they are attached to form a C 5 -C 7 cycloalkyi ring optionally substituted with 1-3 Ci-C 6 alkyl groups;
  • each of R 3 , R 4 , and R 5 independently is hydrogen or C r C 6 alkyl
  • Qe is selected from the group consisting of:
  • X is bonded via a double bond, X* is -CR -;
  • Y 11 is hydrogen, -OH or -OR 55 ;
  • R S1 is C1-C6 alkyl, Ci-Cg alkyl substituted with 1-3 alkoxy or 1-5 halo groups, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C3-C10 cycloalkyl, C 3 -C 8 heterocyclyl, C 6 -Cio aryl, C 2 -Ci 0 heteroaryl, or -NR 55 R 66 , wherein each cycloalkyl or heterocyclyl is optionally substituted with 1-3 C r alkyl groups, and wherein each aryl or heteroaryl is optionally substituted independently with 1-3 nitro and d- C 5 alkyl groups;
  • R 52 is hydrogen or together with R 51 and the intervening atoms form a 5-7 membered ring optionally substituted with 1-3 C r C 6 alkyl groups;
  • each R 53 and R 54 independently are hydrogen, C r C 6 alkyl, -COR 81 , or -CONH R 82 , or R 53 together with R 51 and the intervening atoms form a 5-7 membered cycloalkyl or heterocyclyl ring optionally substituted with 1-3 Ci-C 6 alkyl groups;
  • R 55 is Ci-C 3 alkyl
  • each R 56 and R 57 independently are C r C 6 alkyl, C3-C10 cycloalkyl, -C0 2 R 62 , or -CON(R 6 ) 2 ; or R 55 and R 56 together with the intervening carbon atom and oxygen atoms form a heterocycle optionally substituted with 1-3 C_-C 6 alkyl groups;
  • R 58 is: C 3 -Cio cycloalkyl, C C B alkyl optionally substituted with -OH, C0 2 H or an ester thereof, or -C10 cycloalkyl,
  • R is hydrogen or C C 6 alkyl
  • R 60 is Ci-C 6 alkyl or C3-C10 cycloalkyl optionally substitued with 1-3 Ci-C 6 groups, or is:
  • R 51 is hydrogen, C 3 -C 8 heterocyclyl, or C r C 6 alkyl optionally substituted with a or an ester thereof or a C 6 -Ci 0 aryl, C 2 -C 6 alkenyl, C 2 -C$ alkynyl, C 3 -Ci 0 cycloalkyl, or a C 3 -C 8 heterocyclyl, wherein each cycloalkyi, heterocyclyl, or aryl, is optionally substituted with 1-3 alkyl groups;
  • each R independently are hydrogen, C 3 -Ci 0 cycloalkyi, d-C 6 alkyl optionally substituted with 1-3 substiteunts selected from the group consisting of -C0 2 H or an ester thereof, aryl, C 3 -C 8 heterocyclyl, or two R 62 groups together with the nitrogen atom they are bonded to form a 5-7 membered heterocycle;
  • R is hydrogen or C1-C6 alkyl
  • R 64 is hydrogen, Ci-C 6 alkyl substituted with 1-3 hydroxy groups, -CHO, or is
  • R 65 and R 66 independently are hydrogen, C 6 alkyl, optionally substituted with -C0 2 H or an ester thereof, C 3 -Ci 0 cycloalkyi, C 3 -C 8 heterocyclyl, C 2 - Cio aryl, or C 2 -Ci 0 heteroaryl, or is C3-C10 cycloalkyi, C 3 -C 8 heterocyclyl, C6-Cioaryl, or CrCio heteroaryl, wherein each cycloalkyi, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups, or R 65 and R G6 ether with the nitrogen atom they are bonded to form a 5-7 membered heterocycle, and if only one of R 65 and R 66 are defined as above, then the other one is
  • R ai is C r C 6 alkyl
  • R 82 is:
  • GGA derivatives useful herein are selected from:
  • the compounds provided herein utilizes the compound of formula:
  • L is 0, 1, 2, or 3, and R is C0 2 H or an ester thereof, or is -CH 2 OH, or is a Ci-C 6 alkyl ester of -CH 2 OH.
  • examples of compounds utilized herein include certain compounds tabulated below.
  • Compound ID numbers in Table 1 refer to synthetic schemes in Example 7.
  • examples of compounds utilized herein include certain compounds tabulated below. Table 2
  • Exemplary compounds include: (6E,10E,14E)-7,ll,15,19-tetramethylicosa-6,10,14,18-tetraen-3- 0
  • each R 93 , R 94 , R 95 , and R 9B is independently OH or Ci-C 6 alkoxy
  • each R 97 , R 98 and R 99 is independently hydrogen, C1-C6 alkyi or C6-C20 aryi; and each R 100 and R 101 is independently hydrogen, C C 6 alkyi or C 6 -C 20 aryi; or R 100 and R 101 together with the nitrogen to which they are attached form a C3-C7 heterocycle;
  • each aryi group of R 97 , R 98 , R 99 , R 100 and R 101 is optionally substituted with 1-3 C r C 6 alkyi, C r C 6 alkoxy, C r C 6 alkanoyl, Ci-C 6 alkanoyloxy, C C6 alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR 102 R 103 , or S(O) 2 NR 102 R 103 groups, wherein each R 102 and R 103 is independently hydrogen or Ci-C 6 alkyi;
  • R 104 and R 105 are independently selected from the group consisting of
  • R 106 and R 107 independently are hydrogen or C1-C6 alkyi
  • R 108 and R 109 are independently selected from the group consisting of a hydrogen, Ci-C 6 alkyi, and a group of Formula (XXI):
  • R -R and n are as defined herein;
  • -C0 2 R 110 or -S0 2 OR wherein R uo is selected from the group consisting of a hydrogen and C C 6 alkyl;
  • R is hydrogen or Ci-C 6 alkyl
  • A is Ci-C 5 alkylene which may have a substituent selected from -OH, halo, d-C 6 alkyl, and C r C 6 alkoxy groups on each carbon;
  • r is 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2, 3, 4 or 5.
  • the GGA derivative utilized herein is of formula:
  • R m is a lower (e.g. Ci-C 6 ) alkyl group, optionally substituted with 1 to 4 substituents selected from the group consisting of halogen, hydroxyl; lower alkyl; lower alkoxy; halogenated lower alkyl; halogenated lower alkoxy; cyano; a 5- or 6-membered (hetero) aromatic ring which may be substituted by hydroxyl, lower alkyl, lower alkoxy, halogen, amino, lower alkylamino; cyano, nitro; and other (substituted) (hetero) aromatic rings;
  • substituents selected from the group consisting of halogen, hydroxyl; lower alkyl; lower alkoxy; halogenated lower alkyl; halogenated lower alkoxy; cyano; a 5- or 6-membered (hetero) aromatic ring which may be substituted by hydroxyl, lower alkyl, lower alkoxy, halogen, amino, lower alkylamino
  • i22 is hydrogen or C1-C4 alkyl; Both the R and S configurations are encompassed.
  • Ri23 / Km and R125 are independently selected from hydrogen, substituted and
  • Ri26 is CH(O) or C m H 2m -X, wherein m is 1-3 and X is -H, -OH or a 5- or 6-membered
  • the GGA derivative utilized herein is of formula (XVIII):
  • R 100 and R 101 together with the nitrogen to which they are attached form together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring.
  • the compound is of formula (XlXa):
  • R 104 and R 105 each represent a hydrogen atom, a lower alkyl, cycloalkyl, alkenyl or alkynyl group, an aryl group which may be substituted, an arylalkyi group in which the aryl group may be substituted, or a heteroaryl or heteroarylalkyl group:
  • R 108 and R 109 each represent a hydrogen atom, a lower alkyl group or an alkali metal;
  • Y represents a group represented by the formula:
  • R 130 and R 131 each represent a hydrogen atom, a lower alkyl group or an alkali metal or a group represented by the formula: -C0 2 R 132 (wherein R 132 represents a hydrogen atom, a lower alkyl group or an alkali metal);
  • R 111 represents a hydrogen atom or a lower alkyl group
  • A represents an alkylene chain which has 1 to 5 carbon atoms and which may have a substituent on each carbon atom; and r is zero or an integer of 1 to 5); and n is zero or an integer of 1 to 5.
  • R 104 and R 105 are independently selected from the group consisting of
  • cycloalkyl ring optionally substituted with 1-3 C1-C5 alkyl groups
  • R 106 and R 107 independently are hydrogen, methyl or C 2 -C 6 alkyl, provided that, when one of R 108 and R 109 is not: and each of R and R is methyl, then R 1M and R are defined as follows: R 104 and R 105 together with the carbon atom they are attached to form a C5-C7 cycloalkyl optionally substituted with 1-3 Ci- CG alkyl groups; and R 109 are independently selected from the group consisting of a hydrogen, Ci-C 6 alkyl and a group of Formula (XXI):
  • R is selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • Z is wherein R is hydrogen or Ci-C 6 alkyl; A is C1-C5 alkylene which may have a
  • a composition comprising the compound of Formula (II), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, provided that, when one of R 108 and R 109 is not: and each of R 10b and R 10 ' is methyl, then R and R together with the carbon atom they are attached to form a C5-C7 cycloalkyi optionally substituted with 1-3 Ci-Ce alkyl groups, and the other variables are defined as above.
  • a method of: inhibiting neural death, increasing neural activity, and/or of reducing one or more negative effects of neurodegeneration, or treating osteopenia and/or reducing one or more negative effects of osteopenia comprising administering the compound of Formula (XIX), a pharmaceutically acceptable salt thereof, or a composition comprising the compound of Formula (XIX) to a patient in need thereof, provided that, when one of R 108 and R 109 is not: and each of FT" and R 1U is methyl, then R and R 1U3 ⁇ 4 together with the carbon atom they are attached to form a C5-C7 cycloalkyi optionally substituted with 1-3 Ci-Ce alkyl groups,
  • the compound of formula (XVI II) or (XIX) is selected from the group consisting of:
  • GGA derivatives useful herein include those described in the U.S. Provisional Patent Application No. 61/845,302 (Attorney Docket No. 394306-2650) entitled “GGA Derivatives,” filed herewith on the same day as the present application, US Patent Application No.
  • GGA and GGA derivatives containing substantially or solely a cis form of the compound may not be useful, without being mixed or conjugated with a drug, for treating a disease or a disorder.
  • polyisoprenyl conjugates of bisphosphonate drugs useful for treating osteopenia including osteoporosis include those shown below.
  • compositions of the present invention may be prepared using conventional methods and materials known in the pharmaceutical arts.
  • GGA or GGA derivatives such as those of Formulas (I) - (V) and sub-formulas thereof, that are therapeutically useful for sublingual delivery to a subject.
  • GGA derivatives that are drug conjugates of GGA or drug conjugates of a GGA derivative, that are therapeutically useful for sublingual delivery to a subject.
  • the sublingual dosage form comprises one or more fillers (e.g., soluble saccharides), binder, disintegrant and/or lubricant.
  • fillers e.g., soluble saccharides
  • binder e.g., mannitol, lactose, xylitol and mixtures thereof which are preferred on account of their water solubility.
  • a binder may be employed, in a minimum quantity to prevent unnecessary reduction in the rate of dissolution.
  • a preferred binder is gelatin although polyvinyl pyrolidone or hydroxymethyl polyvinyl pyrolidone may also be used.
  • Preferred binders are soluble in water. Gelatin has been found to bind tablets of good quality which disintegrate within two minutes.
  • Suitable disintegrants include starches such as maize starch and rice starch, cross-linked N- vinyl-2-pyrrolidone (CLPVP), sodium starch glycolate, croscarmelose sodium and formaldehyde casein or combinations thereof.
  • a preferred disintegrant is sodium starch glycolate.
  • Suitable lubricants include magnesium or calcium stearates or other long chain fatty acid salts. Magnesium stearate is especially preferred.
  • compositions herein can be formulated for sublingual administration.
  • Sublingual dosage forms include drops, gels, tablets, pills, powders, and oral liquids, including suspensions, solutions and emulsions. All sublingual dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16 th ed., A. Oslo editor, Easton Pa. 1980). Rapid dissolution of the dosage form which is necessary to facilitate sublingual absorption may be achieved by selection of an appropriate method of dosage form (e.g., tablet) manufacture.
  • Tablets for sublingual delivery may also include conventional excipients. These may include flavouring agents, for example flavourings such as menthol, peppermint, vanilla or fruit flavourings. Sweeteners e.g., aspartame or sodium saccharinate may be used. Further excipients may also include colouring agents, preservatives and fillers.
  • the sublingual compositions are comprised of in general, GGA or a trans-isomer compound of GGA or a mixture thereof in combination with at least one pharmaceutically acceptable excipient for sublingual administration. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compounds provided and/or utilized herein. Such excipients may be any solid, liquid, or semi-solid excipient that is generally available to one of skill in the art.
  • Sublingual pharmaceutical compositions in accordance with the invention are prepared by conventional means using methods known in the art.
  • compositions disclosed herein may be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to the sublingual preparations. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols,
  • Solid pharmaceutical excipients include starch, cellulose, hydroxypropyl cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • the concentration of the excipient is one that can readily be determined to be effective by those skilled in the art, and can vary depending on the particular excipient used.
  • the total concentration of the excipients in the solution can be from about 0.001% to about 90% or from about 0.001% to about 10%.
  • Compounds and pharmaceutical compositions provided herein maybe used alone or in combination with other compounds.
  • the coadministration can be in any manner in which the pharmacological effects of both are manifest in the patient at the same time. Thus, co-administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both the compound provided nad/or utilized herein and the other agent or that the two agents be administered at precisely the same time.
  • a compound utilized herein can be used as an adjunct to
  • a pharmaceutical composition comprising the compound of Formula (XVIII), (XIX) or (XX) and a-tocopherol.
  • a related embodiment provides for a pharmaceutical composition comprising the compound of Formula (XVIII), (XIX) or (XX), ot-tocopherol, and hydroxypropyl cellulose.
  • a pharmaceutical composition comprising the compound of Formula (XVIII), (XIX) or (XX), ⁇ -tocopherol, and gum arabic.
  • there is a pharmaceutical composition comprising the compound of Formula (XVIII), (XIX) or (XX), and gum arabic.
  • the concentration by weight can be from about 0.001% to about 1% or from about 0.001% to about 0.005%, or from about 0.005% to about 0.01%, or from about 0.01% to about 0.015%, or from about 0.015% to about 0.03%, or from about 0.03% to about 0.05%, or from about 0.05% to about 0.07%, or from about 0.07% to about 0.1%, or from about 0.1% to about 0.15%, or from about 0.15% to about 0.3%, or from about 0.3% to about 0.5%, or from about 0.5% to about 1% by weight.
  • the concentration of ⁇ -tocopherol is about 0.001% by weight, or alternatively about 0.005%, or about 0.008%, or about 0.01%, or about 0.02%, or about 0.03%, or about 0.04%, or about 0.05% by weight.
  • the concentration by weight can be from about 0.1% to about 30% or from about 1% to about 20%, or from about 1% to about 5%, or from about 1% to about 10%, or from about 2% to about 4%, or from about 5% to about 10%, or from about 10% to about 15%, or from about 15% to about 20%, or from about 20% to about 25%, or from about 25% to about 30% by weight.
  • the concentration of hydroxypropyl cellulose is about 1% by weight, or alternatively about 2%, or about 3%, or about 4%, or about 5%, or about 6%, or about 7%, or about 8%, or about 10%, or about 15% by weight.
  • the concentration by weight can be from about 0.5% to about 50% or from about 1% to about 20%, or from about 1% to about 10%, or from about 3% to about 6%, or from about 5% to about 10%, or from about 4% to about 6% by weight.
  • the concentration of hydroxypropyl cellulose is about 1% by weight, or alternatively about 2%, or about 3%, or about 4%, or about 5%, or about 6%, or about 7%, or about 8%, or about 10%, or about 15% by weight.
  • the concentration of the polyisoprenyl phosphonate derivative can be from about 1 to about 99% by weight in the pharmaceutical compositions provided herein.
  • the concentration of the polyisoprenyl phosphonate derivative in the pharmaceutical composition is about 5% by weight, or alternatively, about 10%, or about 20%, or about 1%, or about 2%, or about 3%, or about 4%, or about 6%, or about 7%, or about 8%, or about 9%, or about 11%, or about 12%, or about 14%, or about 16%, or about 18%, or about 22%, or about 25%, or about 26%, or about 28%, or about 30%, or about 32%, or about 34%, or about 36%, or about 38%, or about 40%, or about 42%, or about 44%, or about 46%, or about 48%, or about 50%, or about 52%, or about 54%, or about 56%, or about 58%, or about 60%, or about 64%, or about 68%, or about 72%, or about 76%, or about 80% by weight.
  • sustained release formulations such as drug depots or patches comprising an effective amount of the polyisoprenyl phosphonate derivative.
  • the patch further comprises gum Arabic or hydroxypropyl cellulose separately or in combination, in the presence of alpha-tocopherol.
  • the hydroxypropyl cellulose has an average MW of from 10,000 to 100,000.
  • the hydroxypropyl cellulose has an average MW of from 5,000 to 50,000.
  • the patch contains, in various embodiments, an amount of the polyisoprenyl phosphonate derivative, which is sufficient to maintain a therapeutically effective amount the
  • the methods described herein are suitable for the treatment of a neural disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, multiple sclerosis, a prion disease amyotrophic lateral sclerosis, damage to the spinal cord, and neural death during an epileptic seizure.
  • a neural disease selected from the group consisting of Alzheimer's disease, Parkinson's disease, multiple sclerosis, a prion disease amyotrophic lateral sclerosis, damage to the spinal cord, and neural death during an epileptic seizure.
  • Neurodegeneration is often the result of increased age, sporadic mutations, disease, and/or protein aggregation in neural cells.
  • Neurodegenerative diseases are often characterized by a progressive neurodegeneration of tissues of the nervous system and a loss of functionality of the neurons themselves.
  • One commonality seen in most neurodegenerative diseases is the accumulation of protein aggregates intracellular ⁇ or in the extracellular space between neurons.
  • Protein aggregation is facilitated by partial unfolding or denaturation of cellular proteins. This may be due to mutations in the sequence of the DNA, transcriptional misincorporation, modifications to the RNA, and modifications or oxidative stress to the protein.
  • protein aggregates contribute to disease progression.
  • aggregates of two non-disease proteins were formed in vitro and added to the medium of cultured cells. Addition of granular-structured, protein aggregates significantly reduced the cell viability of both the fibroblastic cell line (NIH-3T3) and neural cell line (PC12). However, addition of more organized fibrillar protein aggregates did not compromise the cell viability. (Bucciantini et al. (2002) Nature 14:507-510.)
  • Protein aggregates can be extracellular (i.e. in the space between neural cells), intracellular such as intranuclear (i.e. in the nucleus of the cell), or in the cytoplasm.
  • Extracellular and/or cytoplasm protein aggregates are a pathological characteristic of Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS).
  • AD is a progressive brain disease that destroys memory and cognitive function.
  • AD has been linked to the aggregation of the ⁇ -amyloid peptide.
  • the ⁇ -amyloid peptide is derived from the amyloid precursor protein (APP) that has been processed by two aspartyl proteases called ⁇ and ⁇ secretases.
  • APP amyloid precursor protein
  • ALS is also a progressive neurodegenerative disease and is characterized by loss of functionality of motor neurons.
  • the progressive degeneration of motor neurons results in loss of ability of the brain to initiate and control muscle movement.
  • ALS is a devastating disease, in which the last stage is complete paralysis.
  • the complete molecular mechanism of disease progression in ALS is not yet clear, but mutations in the Cu/Zn superoxide dismutase (Sod) gene, Sodl, have been linked to the degeneration of motor neurons.
  • Sod Cu/Zn superoxide dismutase
  • the disease symptoms of ALS and AD may differ, but the presence of cytotoxic aggregate proteins in both diseases suggests a common mechanism in pathogenicity. (Ross & Poirier. (2004) Nat Med. ppSlO- S17; Irvine et al. (2008) Mol Med.
  • TDP-43 protein TAR DNA binding protein or TARDBP
  • TARDBP TDP-43 protein
  • TARDBP siRNA TARDBP siRNA
  • Rho family proteins are responsible for regulating cell movement, cell survival, cell growth, transcription, and motility of cells (Iguchi et al. (2009) J. Bio Chem. Vol. 284 no. 33 pp. 22059-22066).
  • Therapies that prevent reduction in the amount and/or activity of TDP-43 or Rho family proteins may have a neuroprotective effect on cells.
  • the invention provides methods for impeding the progression of neurodegenerative diseases or injury using the polyisoprenyl phosphonate derivative.
  • the pharmaceutical compositions and/or compounds described above are useful in the methods described herein.
  • Neural diseases can result in an impairment of signaling between neurons. This can in part be due to a reduction in the growth of axonal projections.
  • Contacting neurons with the polyisoprenyl phosphonate derivative enhances axonal growth. It is contemplated that the polyisoprenyl phosphonate derivative will restore axonal grown in neurons afflicted with a neural disease.
  • the pre-contacted neurons exhibit a reduction in the axon growth ability.
  • Methods include the use of the polyisoprenyl phosphonate derivative.
  • One embodiment is directed to a method for inhibiting the cell death of neurons susceptible to neuronal cell death, which method comprises contacting said neurons with an effective amount of the polyisoprenyl phosphonate derivative.
  • Neurons susceptible to neuronal cell death include those that have the characteristics of a neurodegenerative disease and/or those that have undergone injury or toxic stress.
  • One method of creating toxic stress to a cell is by mixing dopamine with neurons such as neuroblastoma cells.
  • Another source of toxic stress is oxidative stress. Oxidative stress can occur from neuronal disease or injury, It is contemplated that contacting neurons with the polyisoprenyl phosphonate derivative will inhibit their death as measured by a MTT assay or other techniques commonly known to one skilled in the art,
  • neurode refers to both axons and dendrites.
  • Neural diseases can result in an impairment of signaling between neurons. This can in part be due to a reduction in the growth of axonal and/or dendritic projections. It is contemplated that contacting neurons with the polyisoprenyl phosphonate derivative will enhance neurite growth, It is further contemplated that the polyisoprenyl phosphonate derivative will restore neurite grown in neurons afflicted with a neural disease. In a related embodiment, the pre-contacted neurons exhibit a reduction in the neurite growth ability.
  • One embodiment is directed to a method for increasing the expression and/or release of one or more neurotransmitters from a neuron by contacting said neurons with an effective amount of the polyisoprenyl phosphonate derivative. It is contemplated that contacting neurons with an effective amount of the polyisoprenyl phosphonate derivative will increase the expression level of one or more neurotransmitters. It is also contemplated that contacting neurons with the polyisoprenyl phosphonate derivative will increase the release of one or more neurotransmitters from neurons. The release of one or more
  • neurotransmitters refers to the exocytotic process by which secretory vesicles containing one or more neurotransmitters are fused to cell membrane, which directs the
  • One embodiment is directed to a method for inducing synapse formation of a neuron by contacting said neurons with an effective amount of the polyisoprenyl phosphonate derivative.
  • a synapse is a junction between two neurons. Synapses are essential to neural function and permit transmission of signals from one neuron to the next. Thus, an increase in the neural synapses will lead to an increase in the signaling between two or more neurons. It is contemplated that contacting the neurons with an effective amount of the polyisoprenyl phosphonate derivative will increase synapse formation in neurons that otherwise experience reduced synapse formation as a result of neural disease.
  • Another embodiment is directed to a method for increasing electrical excitability of a neuron by contacting said neurons with an effective amount of the polyisoprenyl phosphonate derivative.
  • Electrical excitation is one mode of communication among two or more neurons. It is contemplated that contacting neurons with an effective amount of the polyisoprenyl phosphonate derivative will increase the electrical excitability of neurons in which electrical excitability and other modes of neural communication are otherwise impaired due to neural disease. Electrical excitability can be measured by
  • the administration of the polyisoprenyl phosphonate derivative enhances communication between neurons and accordingly provides for a method of inhibiting the loss of cognitive abilities in a mammal that is at risk of dementia or suffering from incipient or partial dementia while retaining some cognitive skills.
  • Incipient or partial dementia in a mammal is one in which the mammal still exhibits some cognitive skills, but the skills are being lost and/or diminished over time.
  • Method comprises administering an effective amount of the polyisoprenyl phosphonate derivative to said patient.
  • Another embodiment is directed to a method for inhibiting the death of neurons due to formation of or further formation of pathogenic protein aggregates between, outside or inside neurons, wherein said method comprises contacting said neurons at risk of developing said pathogenic protein aggregates with an amount of the polyisoprenyl phosphonate derivative inhibitory to protein aggregate formation, provided that said pathogenic protein aggregates are not related to SBMA.
  • the pathogenic protein aggregates form between or outside of the neurons.
  • the pathogenic protein aggregates form inside said neurons.
  • the pathogenic protein aggregates are a result of toxic stress to the cell.
  • One method of creating toxic stress to a cell is by mixing dopamine with neurons such as neuroblastoma cells.
  • Another embodiment is directed to a method for protecting neurons from pathogenic extracellular protein aggregates which method comprises contacting said neurons and/or said pathogenic protein aggregates with an amount of the polyisoprenyl phosphonate derivative that inhibits further pathogenic protein aggregation.
  • contacting said neurons and/or said pathogenic protein aggregates with an effective amount of the polyisoprenyl phosphonate derivative alters the pathogenic protein aggregates into a non-pathogenic form
  • contacting the neurons and/or the pathogenic protein aggregates with the polyisoprenyl phosphonate derivative will solu bilize at least a portion of the pathogenic protein aggregates residing between, outside, or inside of the cells. It is further contemplated that contacting the neurons and/or the pathogenic protein aggregates with the polyisoprenyl phosphonate derivative will alter the pathogenic protein aggregates in such a way that they are non-pathogenic.
  • a non-pathogenic form of the protein aggregate is one that does not contribute to the death or loss of functionality of the neuron.
  • assays known to one skilled in the art for measuring the protection of neurons either in cell culture or in a mammal.
  • One example is a measure of increased cell viability by a
  • MTT assay Another example is by immunostaining neurons in vitro or in vivo for cell death- indicating molecules such as, for example, caspases or propidium iodide.
  • in yet another embodiment is directed to a method for protecting neurons from pathogenic intracellular protein aggregates which method comprises contacting said neurons with an amount of the polyisoprenyl phosphonate derivative which will inhibit further pathogenic protein aggregation provided that said protein aggregation is not related to SBMA.
  • This method is not intended to inhibit or reduce, negative effects of neural diseases in which the pathogenic protein aggregates are intranuclear or diseases in which the protein aggregation is related to SBMA.
  • SBMA is a disease caused by pathogenic androgen receptor protein accumulation. It is distinct from the neural diseases mentioned in this application since the pathogenic protein aggregates of SBMA contain polyglutamines and are formed intranuclearly.
  • One embodiment is directed to a method of modulating the activity of G proteins in neurons which method comprises contacting said neurons with an effective amount of the polyisoprenyl phosphonate derivative. It is contemplated that contacting neurons with the polyisoprenyl phosphonate derivative will alter the sub-cellular localization, thus changing the activities of the G protein in the cell. In one embodiment, contacting neurons with the polyisoprenyl phosphonate derivative will enhance the activity of G proteins in neurons. It is contemplated that contacting the polyisoprenyl phosphonate derivative with neurons will increase the expression level of G proteins. It is also contemplated that contacting the polyisoprenyl phosphonate derivative with neurons will enhance the activity of G proteins by changing their sub-cellular localization to the cell membranes where they must be to exert their biological activities.
  • One embodiment is directed to a method of modulating or enhancing the activity of G proteins in neurons at risk of death which method comprises contacting said neurons with an effective amount of the polyisoprenyl phosphonate derivative.
  • Neurons may be at risk of death as a result of genetic changes related to ALS.
  • One such genetic mutation is a depletion of the TDP-43 protein. It is contemplated that neurons with depleted TDP-43 or other genetic mutations associated with ALS will have an increase or change in the activity of G proteins after being contacted with the polyisoprenyl phosphonate derivative. It is further contemplated that the polyisoprenyl phosphonate derivative will result in an increase in the activity of G proteins in these cells by changing their sub-cellular localization to the cell membranes where they must be to exert their biological activities.
  • Another embodiment is directed to a method for inhibiting the neurotoxicity of ⁇ -amyloid peptide by contacting the ⁇ -amyloid peptide with an effective amount of the polyisoprenyl phosphonate derivative.
  • the ⁇ -amyloid peptide is between or outside of neurons.
  • the ⁇ -amyloid peptide is part of the ⁇ -amyloid plaque. It is contemplated that contacting neurons with the polyisoprenyl phosphonate derivative will result in solubilizing at least a portion of the ⁇ -amyloid peptide, thus decreasing its neurotoxicity.
  • the polyisoprenyl phosphonate derivative will decrease the toxicity of the ⁇ -amyloid peptide by altering it in such a way that it is no longer toxic to the cell. It is also believed that the polyisoprenyl phosphonate derivative will induce the expression of heat shock proteins (HSPs) in the neurons. It is also contemplated that HSPs will be induced in support cells such as glial cells. The induced heat shock proteins in the neurons or glial cells may be transmitted extracellularly and act to dissolve extracellular protein aggregates. Cell viability can be measured by standard assays known to those skilled in the art. One such example of an assay to measure cell viability is a MTT assay. Another example is a MTS assay. The modulation of protein aggregation can be visualized by immunostaining or histological staining techniques commonly known to one skilled in the art.
  • One embodiment is directed to a method for inhibiting neural death and increasing neural activity in a mammal suffering from neural diseases, wherein the etiology of said neural diseases comprises formation of protein aggregates which are pathogenic to neurons, and which method comprises administering to said mammal an amount of the polyisoprenyl phosphonate derivative which will inhibit further pathogenic protein aggregation.
  • This method is not intended to inhibit neural death and increase neural activity in neural diseases in which the pathogenic protein aggregates are intranuclear or diseases in which the protein aggregation is related to SBMA.
  • Neural diseases such as AD and ALS disease have the common characteristic of protein aggregates either inside neural cells in cytoplasm or in the extracellular space between two or more neural cells.
  • the mammal is a human afflicted with a neural disease.
  • the negative effect of the neural disease being inhibited or reduced is ALS.
  • ALS is characterized by a loss of functionality of motor neurons. This results in the inability to control muscle movements.
  • ALS is a neurodegenerative disease that does not typically show intranuclear protein aggregates.
  • the polyisoprenyl phosphonate derivative will prevent or inhibit the formation of extracellular or intracellular protein aggregates that are cytoplasm, not intranuclear and not related to SBMA. It is also contemplated that the polyisoprenyl phosphonate derivative will alter the pathogenic protein aggregates into a form that is non-pathogenic.
  • Methods for diagnosing ALS are commonly known to those skilled in the art. Additionally, there are numerous patents that describe methods for diagnosing ALS. These include US 5851783 and US 7356521 both of which are incorporated herein by reference In their entirety.
  • AD is a neurodegenerative disease that does not typically show intranuclear protein aggregates. It is contemplated that the polyisoprenyl phosphonate derivative will prevent or inhibit the formation of extracellular or intracellular protein aggregates. It is also contemplated that the polyisoprenyl phosphonate derivative will alter the pathogenic protein aggregates into a form that is non-pathogenic. Methods for diagnosing AD are commonly known to those skilled in the art. Additionally, there are numerous patents that describe methods for diagnosing AD. These include US 6130048 and US 6391553 both of which are incorporated herein by reference in their entirety.
  • the mammal Is a laboratory research mammal such as a mouse.
  • the neural disease is ALS.
  • One such mouse model for ALS is a transgenic mouse with a Sodl mutant gene. It is contemplated that the polyisoprenyl phosphonate derivative will enhance the motor skills and body weights when administered to a mouse with a mutant Sodl gene. It is further contemplated that administering a polyisoprenyl phosphonate derivative to this mouse will increase the survival rate of Sodl mutant mice. Motor skills can be measured by standard techniques known to one skilled in the art. Sodl mutant mice provide an accepted mouse model for modeling ALS in humans. Accordingly, method aspects of this disclosure relate to a method for prolonging the survival or reducing mortality of a subject with ALS, comprising administering a therapeutically effective amount of the polyisoprenyl phosphonate derivative.
  • the neural disease is AD.
  • a transgenic mouse model for AD is a mouse that overexpresses the APP (Amyloid beta Precursor Protein). It is contemplated that administering the polyisoprenyl phosphonate derivative to a transgenic AD mouse will improve the learning and memory skills of said mouse. It is further contemplated that the polyisoprenyl phosphonate derivative will decrease the amount and/or size of ⁇ -amyloid peptide and/or plaque found inside, between, or outside of neurons. The ⁇ -amyloid peptide or plaque can be visualized in histology sections by immunostaining or other staining techniques.
  • administering the polyisoprenyl phosphonate derivative to a mammal alters the pathogenic protein aggregate present into a non-pathogenic form. In another embodiment, administering the polyisoprenyl phosphonate derivative to a mammal will prevent pathogenic protein aggregates from forming.
  • Another aspect relates to a method for reducing seizures in a mammal in need thereof, which method comprises administering a therapeutically effective amount of the polyisoprenyl phosphonate derivative, thereby reducing seizures.
  • the reduction of seizures refers to reducing the occurrence and/or severity of seizures.
  • the seizure is epileptic seizure.
  • the methods provided herein prevent neural death during epileptic seizures.
  • the severity of the seizure can be measured by one skilled in the art.
  • the methods described herein relate to administering the polyisoprenyl phosphonate derivative or the compositions of the polyisoprenyl phosphonate derivative in vitro.
  • the administration is in vivo.
  • the in vivo administration is to a mammal. Mammals include but are not limited to humans and common laboratory research animals such as, for example, mice, rats, dogs, pigs, cats, and rabbits.
  • a composition for inhibiting neural death, increasing neural activity, and/or for reducing one or more negative effects of neurodegeneration.
  • the composition includes a compound of Formula (XVIII), (XIX) or (XX), or subformulas thereof, as defined herein.
  • XVIII compound of Formula (XIX) or (XX), or subformulas thereof, as defined herein.
  • Preferred neural or a neurodegenerative diseases, and one or more negative effects of neurodegeneration treated or improved herein are described herein. Assaying Compounds
  • osteoclast culture systems or methods and bone formation assays that can be used successfully to screen potential an anti-resorptive compound provided or utilized herein. See, e.g., U.S. Pat. No. 6,080,779.
  • One osteoclast culture for use in screening is a neonatal mouse calvaria assay. Briefly, four days after birth, the front and parietal bones of neonatal mouse pups (e.g., ICR Swiss white mice) are removed by microdissection and split along the sagittal suture. The bones are then incubated in a specified medium, wherein the medium contains either test or control compounds.
  • the bones are removed from the media, and fixed in 10% buffered formalin, decalcified in EDTA, processed through graded alcohols, and embedded in paraffin wax.
  • Sections of the calvaria are prepared and assessed using histomorphometric analysis of bone formation and bone resorption. Bone changes are measured on sections. Osteoblasts and osteoclasts are identified by their distinctive morphology.
  • the effect of compounds on murine calvarial bone growth can also be tested in vivo.
  • young male mice e.g., ICR Swiss white mice
  • aged 4-6 weeks are employed, using 4-5 mice per group.
  • test compound or the appropriate control is injected into subcutaneous tissue over the right calvaria of normal mice.
  • the mice are sacrificed (after allowing for bone growth or loss to occur, e.g. on day 14), and net bone growth is measured by histomorphometric means.
  • Bone samples are cleaned from adjacent tissues and fixed in 10% buffered formalin, decalcified, processed through graded alcohols, and embedded in paraffin wax.
  • Sections of the calvaria are prepared, and representative sections are selected for histomorphometric assessment of the effects of bone formation and bone resorption. In one embodiment, sections are measured by using a camera lucida attachment to trace directly the microscopic image onto a digitizing plate.
  • Bone changes are measured on sections over adjacent lxl mm fields on both the injected and noninjected sides of calvaria. New bone may be identified by those skilled in the art by its characteristic tinctorial features, and osteoclasts and osteoblasts may be identified by their distinctive morphology or other suitable marker recognized by the skilled artisan. Histomorphometry software (OsteoMeasure, Osteometrix, Inc., Atlanta) can be used to process digitized input to determine cell counts and measure areas or perimeters.
  • Additional exemplary in vivo assays include dosing assays in intact animals, including dosing assays in acute ovariectomized (OVX) animals and assays in chronic OVX animals.
  • dosing assays in intact animals including dosing assays in acute ovariectomized (OVX) animals and assays in chronic OVX animals.
  • OVX acute ovariectomized
  • Prototypical dosing in intact animals may be accomplished by subcutaneous, intraperitoneal or oral administration, and may be performed by injection, sustained release or other delivery techniques.
  • the time period for administration of test compound may vary (for instance, 14 days, 28 days, as well as 35 days or longer may be appropriate).
  • in vivo oral or subcutaneous dosing assay may be performed as described: In a typical study, 70 three-month-old female Sprague-Dawley rats are weight-matched and divided into treatment groups, with at least several animals in each group. This includes a baseline control group of animals sacrificed at the initiation of the study; a control group administered vehicle only; a PBS or saline-treated control group; and a positive group administered a compound known to enhance net bone formation. Three dosage levels of the test compound are administered to the remaining groups. Test compound, saline, and vehicle are administered (e.g. once per day) for a number of days (for instance at least 14 days, 28 days, or 35 days - wherein an effect is expected in the positive group).
  • Test compound, saline, and vehicle are administered (e.g. once per day) for a number of days (for instance at least 14 days, 28 days, or 35 days - wherein an effect is expected in the positive group).
  • test compounds on bone remodeling or net bone formation, including bone loss and osteoclast function can thus be evaluated.
  • Test compounds can also be assayed in acute ovariectomized animals. Such assays may also include an estrogen-treated group as a control.
  • An example of the test in these animals is briefly described: In a typical study, 80 three-month-old female Sprague-Dawley rats are weight-matched and divided into treatment groups, with at least several animals in each group. This includes a baseline control group of animals sacrificed at the initiation of the study; three control groups (sham OVX and vehicle only, OVX and vehicle only, and OVX and PBS only); and a control OVX group that is administered a compound known to block or reduce bone resorption or enhance bone formation (including an anti-resorptive or anabolic compound). Different dosage levels of the test compound are administered to remaining groups of OVX animals.
  • test compound, positive control compound, PBS or saline or vehicle alone is administered orally or subcutaneously (e.g., once per day) for the treatment period.
  • test compounds can be formulated in implantable pellets that are implanted, or may be administered orally, such as by gastric gavage. All animals are injected with calcein nine days and two days before sacrifice. Weekly body weights are determined. At the end of the treatment cycle, the animals blood and tissues are processed as described above.
  • Test compounds may also be assayed in chronic OVX animals. Briefly, six month old female, Sprague-Dawley rats are subjected to sham surgery (sham OVX), or ovariectomy (OVX) at the beginning of the experiment, and animals are sacrificed at the same time to serve as baseline controls. Body weights are monitored weekly. After approximately six weeks or more of bone depletion, sham OVX and OVX rats are randomly selected for sacrifice as depletion period controls. Of the remaining animals, 10 sham OVX and 10 OVX rats are used as placebo-treated controls. The remaining animals are treated with 3 to 5 doses of test compound for a period of 35 days.
  • a group of OVX rats can be treated with a known anabolic or anti-resorptive agent in this model, such as bisphosphonate, a calcitonin, a calcitriol, an estrogen, selective estrogen receptor modulators (SER 's) and a calcium source, a supplemental bone formation agent parathyroid hormone (PTH) or its derivative (Kimmel et al., Endocrinology, 132: 1577-1584, 1993), PTHRP, a bone
  • RANKL RANK ligand
  • the animals are sacrificed and femurs, tibiae, and lumbar vertebral to 4 are excised and collected.
  • the proximal left and right tibiae are used for pQCT measurements, cancellous bone mineral density (BMD), and histology, while the midshaft of each tibiae is subjected to cortical BMD or histology.
  • the femurs are prepared for pQCT scanning of the midshaft prior to biomechanical testing.
  • LV2 are processed for BMD (pQCT may also be performed)
  • LV3 are prepared for undecalcified bone histology
  • LV4 are processed for mechanical testing.
  • osteoclast cultures containing macrophages, osteoclast precursors and osteoclasts, can be generated from bone marrow precursors, particularly from bone marrow macrophages and utilized in assessment of compounds for osteoclast modulating activity.
  • Bone marrow macrophages are cultured in 48- or 96-well cell culture dishes in the presence of M-CSF (lOng/ml), RANKL (lOOng/ml), with or without addition of compound(s) or control(s), and medium changed (e.g. on day 3).
  • Osteoclast-like cells are characterized by staining for tartrate-resistant acid phosphatase (TRAP) activity.
  • TRIP tartrate-resistant acid phosphatase
  • osteoclasts are generated on whale dentin slices from bone marrow macrophages. After three days of culture to generate osteoclasts, compound(s) or control(s) are added to the culture for two days. At the end of the experiment, cells are
  • TRAP stained and photographed to document cell number.
  • Cells are then removed from the dentin slices with 0.5M ammonium hydroxide and mechanical agitation. Maximum resorption lacunae depth is measured using a confocal microscope (Microradiance, Bio-Rad Laboratories, Hercules, CA).
  • a confocal microscope Microradiance, Bio-Rad Laboratories, Hercules, CA.
  • dentin slices are stained with Coumassie brilliant blue and analyzed with light microscopy using
  • Osteomeasure software (Osteometries, Decatur, Georgia) for quantitation.
  • osteoclast modulating ability of GGA and derivatives can be tested in an in vitro assay utilizing osteoclasts, osteoclast precursor cells or osteoclast-like cells.
  • R 75 , R 85 and each R 8 6 independently are alkyl or substituted or unsubstituted aryl, under olefination conditions to selectivel provide a compound of formula XIII:
  • Compound VIII is combined with at least an equimolar amount of a halogenating agent typically in an inert solvent.
  • an "inert solvent” is a solvent that does not react under the reaction conditions in which it is employed as a solvent. The reaction is typically run at a temperature of about 0°C to 20 °C for a period of time sufficient to effect substantial completion of the reaction.
  • Suitable solvents include, by way of example only, diethyl ether, acetonitrile, and the like.
  • Suitable halogenating agents include Br3 or PPh3/CBr 4 .
  • the resulting product, compound IX can be recovered under conventional conditions such as extraction, precipitation, filtration, chromatography, and the like or, alternatively, used in the next step of the reaction without purification and/or isolation.
  • Compound IX is combined with at least an equimolar amount of an alkyl acetoacetate, in the presence of a base and an inert solvent.
  • the reaction is typically run initially at 0°C, and then warmed up to room temperature for a period of time sufficient to effect substantial completion of the reaction.
  • Suitable solvents include, by way of example only, various alcohols, such as ethanol, dioxane, and mixtures thereof.
  • Suitable bases include, by way of example only, alkali metal alkoxides, such as sodium ethoxide.
  • Compound X is reacted with at least an equimolar amount, preferably, an excess of aqueous alkali.
  • the reaction is typically run at about 40 to 80 °C and preferably about 80°C for a period of time sufficient to effect substantial completion of the reaction.
  • Suitable solvents include, by way of examples only, alcohols, such as methanol, ethanol, and the like.
  • Compound XI is combined with at least an equimolar amount, preferably, an excess of a compound of formula XII, and at least an equimolar amount, preferably, an excess of base, in an inert solvent.
  • the reaction is typically run, initially at about -30°C for about 1-2 hours, and at room temperature for a period of time sufficient to effect substantial completion of the reaction.
  • Suitable solvents include, by way of examples only tetrahydrofuran, dioxane, and the like.
  • Suitable bases include, by way of example only, alkali metal hydrides, such as sodium hydride, or potassium hexamethyldisilazide (KHMDS), or potassium tertiary butoxide CBuOK).
  • Compound XIII is combined with a reducing agent in an inert solvent.
  • the reaction is typically run at about 0°C for about 15 minutes, and at room temperature for a period of time sufficient to effect substantial completion of the reaction.
  • Suitable reducing agents include, without limitation, LiAIH 4 .
  • Suitable solvents include, by way of examples only diethyl ether, tetrahydrofuran, dioxane, and the like.
  • the resulting product can be recovered under conventional conditions such as precipitation, filtration, chromatography, and the like or, alternatively, used in the next step of the reaction without purification and/or isolation.
  • the method further comprises repeating steps (i), (ii), and (iii) sequentially with compound of formula XIII to provide the compound of formula Vl-B, wherein m is 2.
  • the method or procedure further comprises repeating steps (i), (ii), (iii), (iv), and (v), sequentially, 1-3 times.
  • R 31 alkyl is substituted or unsubstituted alkyl
  • the method can comprise step (i) or step (ii) or steps (i) + (ii) : (i) reacting a compound of formula XV-C:
  • R31 is as defined herein, and
  • the method comprises reacting a ketal compound of formula XVII:
  • each R70 independently is C1-C6 alkyl, or two R70 groups together with the oxygen atoms they are attached to form a 5 or 6 membered ring, which ring is optionally substituted with 1-3, preferably 1-2, Ci-Ci alkyl groups, under hydrolysis conditions to provide a compound of formula II,
  • the ketal is combined with at least a catalytic amount, such as, 1-20 mole% of an aqueous acid, preferably, an aqueous mineral acid in an inert solvent.
  • a catalytic amount such as, 1-20 mole% of an aqueous acid, preferably, an aqueous mineral acid in an inert solvent.
  • the reaction is typically run about 25°C to about 80°C, for a period of time sufficient to effect substantial completion of the reaction.
  • Suitable acids include, without limitation, HCI, H2SO4, and the like.
  • Suitable solvents include alcohols, such as methanol, ethanol, tetrahydrofuran, and the like.
  • the method comprises reacting a compound of formula XVI:
  • the method comprises reacting a compound of formula XVI-C:
  • the methods further employ routine steps of separation or purification to isolate the compounds, following methods such as chromatography, distillation, or crystallization.
  • GGA or certain GGA derivatives utilized herein are described in PCT publication no. WO 2012/031028, WO 2013/052148, and WO 2013/130654, each of which is incorporated herein by reference in its entirety.
  • Other GGA derivatives can be prepared by appropriate substitution of reagents and starting materials, as will be well known to the skilled artisan upon reading this disclosure.
  • the reactions are preferably carried out in a suitable inert solvent that will be apparent to the skilled artisan upon reading this disclosure, for a sufficient period of time to ensure substantial completion of the reaction as observed by thin layer chromatography, 1 H-NMR, etc. If needed to speed up the reaction, the reaction mixture can be heated, as is well known to the skilled artisan.
  • the final and the intermediate compounds are purified, if necessary / by various art known methods such as crystallization, precipitation, column chromatography, and the likes, as will be apparent to the skilled artisan upon reading this disclosure.
  • a base such as an alkoxide
  • Keto compound (vi) is converted, following a Wittig Horner reaction with compound (vii), to the conjugated ester (viii).
  • Compound (viii) is reduced, for example with LiAIH , to provide alcohol (ix).
  • a compound of Formula (III), where n is 2 is synthesized by repeating the reaction sequence of alkylation with a beta-keto ester, hydrolysis, decarboxylation, Wittig-Horner olefination, and UAlH 4 reduction.
  • R 6 in the schemes below may also correspond to R 30 and R 51 as defined herein.
  • R 7 in the schemes below may also correspond to R 26 , R 31 and R 52 as defined herein.
  • R 8 in the schemes below may also correspond to R 27 , R 32 and R 53 as defined herein.
  • R 9 in the schemes below may also correspond to R 28 , R 33 and R 54 as defined herein.
  • R 13 in the schemes below may also correspond to R 58 as defined herein.
  • R 14 in the schemes below may also correspond to R 59 as defined herein.
  • R 15 in the schemes below may also correspond to R 50 as defined herein.
  • R 18 in the schemes below may also correspond to R 24 , R 34 and R 53 as defined herein.
  • R 19 in the schemes below may also correspond to R 25 , R 35 and R 54 as defined herein.
  • L is a leaving group as known to one of ordinary skill in the art.
  • R E is alkyl
  • Compound (ix) with alcohol functionality is an intermediate useful for preparing the compounds utilized in herein.
  • Compound (x), where L is an R S S0 2 - group is made by reacting compound (ix) with R s S0 2 CI in the presence of a base.
  • the transformation of compound (iii) to compound (x) illustrates methods of adding isoprene derivatives to a compound, which methods are suitable to make compound (iii) from compound (i).
  • Intermediate (ix) containing various R ⁇ R 5 substituents are prepared according to this scheme as exemplified herein below.
  • the transformation of compound (iii) to compound (x) illustrates methods of adding isoprene derivatives to a compound, which methods are suitable to make compound (iii) from compound (i).
  • m is 0 or 1 and R x -R 5 are as defined herein, and are preferably alkyl, or more preferably methyl.
  • Intermediate (ixa), prepared according to the scheme herein above, is converted to amino intermediate (ixb) via the corresponding bromide.
  • Intermediates (ixa) and (ixb) are converted to the compounds utilized herein by reacting with suitable isocyanates or carbamoyl chlorides, which are prepared by art known methods.
  • Intermediates for synthesizing compounds utilized herein containing various R ⁇ R 5 substituents are illustrated in the examples section and/or are well known to the skilled artisan.
  • GGA derivatives utilized herein are synthesized as schematically shown below. imines, hydazones, alkoxyimines enolcarbamates
  • Certain compounds utilized herein are obtained by reacting compound (x) with the anion Q,(-), which can be generated by reacting the compound QH with a base.
  • bases include hydroxide, hydride, amides, alkoxides, and the like.
  • Various compounds utilized herein, wherein the carbonyl group is converted to an imine, a hydrazone, an alkoxyimine, an enolcarbamate, a ketal, and the like, are prepared following well known methods.
  • the metallation is performed, by reacting the ketone with a base such as dimsyl anion, a hindered amide base such as diisopropylamide, or hexamethyldisilazide, along with the corresponding metal cation, M.
  • a base such as dimsyl anion, a hindered amide base such as diisopropylamide, or hexamethyldisilazide
  • the amino carbonyl chloride or the isocyanate is prepared, for example, by reacting the amine (R 14 ) 2 NH with phosgene or an equivalent reagent well known to the skilled artisan.
  • the beta keto ester is hydrolyzed while ensuring that the reaction conditions do not lead to decarboxylation.
  • the acid is activated with various acid activating agent well known to the skilled artisan such as carbonyl diimodazole, or 0-Benzotriazole-N,N,N N'-tetramethyl- uronium-hexafluoro-phosphate (HBTU) and reacted with the amine.
  • acid activating agent well known to the skilled artisan such as carbonyl diimodazole, or 0-Benzotriazole-N,N,N N'-tetramethyl- uronium-hexafluoro-phosphate (HBTU)
  • R E is alkyl
  • Compound (viii) is hydrolyzed to the carboxylic acid (x), which is then converted to the acid chloride (xi).
  • Compound (xi) is reacted with a suitable nucleophile such as a hydrazide, a hydroxylamine, an amino alcohol, or an amino acid, and the intermediate dehydrated to provide a compound of Formula (IV).
  • a suitable nucleophile such as a hydrazide, a hydroxylamine, an amino alcohol, or an amino acid
  • the intermediate dehydrated to provide a compound of Formula (IV).
  • the allylic alcohol (ix) is oxidized to the aldehyde (xi), which is then reacted with a cyanohydrin or cyanotosylmethane to provide further compounds utilized herein.
  • GGA derivatives utilized herein can also be synthesized employing art known methods and those disclosed here by alkene-aryl, alkene-heteroaryl, or alkene-akene couplings such as Heck, Stille, or Suzuki coupling. Such methods can use (vi) to prepare intermediate (xii) that can undergo Heck, Stille, or Suzuki coupling under conditions well known to the skilled artisan to provide compounds utilized herein.
  • L is a leaving group and Qs are as defined herein
  • Ar is a preferably an aryl group such as phenyl
  • the base employed is an alkox ' ide such as tertiarybutoxide, a hydride, or an alkyl lithium such as n-butyl lithium.
  • the metallation is performed, by reacting the ketone with a base such as dimsyl anion, a hindered amide base such as diisopropylamide, or hexamethyldisilazide, along with the corresponding metal cation, M.
  • a base such as dimsyl anion, a hindered amide base such as diisopropylamide, or hexamethyldisilazide
  • the amino carbonyl chloride or the isocyanate is prepared, for example, by reacting the amine R 13 R 14 NH with phosgene or an equivalent reagent well known to the skilled artisan.
  • the beta keto ester is hydrolyzed while ensuring that the reaction conditions do not lead to decarboxylation.
  • the acid is activated with various acid activating agent well known to the skilled artisan such as carbonyl diimodazole, or 0-Benzotriazole-N,N,N',N'-tetramethyl- uronium-hexafluoro-phosphate (HBTU) and reacted with the amine.
  • acid activating agent well known to the skilled artisan
  • HBTU 0-Benzotriazole-N,N,N',N'-tetramethyl- uronium-hexafluoro-phosphate
  • the compounds can be synthesized following methods and/or modifications thereof well known in the art. See, for example, Fieser, Mary ed. Fieser and Fieser's Reagents for Organic Synthesis. Wiley, NY; Smith and March, March's Advanced Organic Chemistry, 6 th Edition, John Wiley & Sons, Inc., New York, 2011; Larock, Comprehensive Organic
  • the reactions are preferably carried out in a suitable inert solvent that will be apparent to the skilled artisan upon reading this disclosure, for a sufficient period of time to ensure substantial completion of the reaction as observed by thin layer chromatography, ⁇ - MR, etc. If needed to speed up the reaction, the reaction mixture can be heated, as is well known to the skilled artisan.
  • the final and the intermediate compounds are purified, if necessary, by various art known methods such as crystallization, precipitation, column chromatography, and the likes, as will be apparent to the skilled artisan upon reading this disclosure. Specific non-limiting examples of bisphosphonate conjugates provided herein and their methods of synthesis are described below. Other such conjugates can be synthesized following adaptation of art known methods and those described herein.
  • PBr 3 phosphorus tribromide
  • LAH lithium aluminum hydride
  • HPC : hydroxypropyl cellulose
  • Mn number average molar mass
  • KHMDA potassium hexamethylenediamine
  • TBD S tert-butyldimethyl silyl
  • Kp RatiO Of AUCfiro/n tO AUCp/oi/na
  • Vcap 4000
  • the starting materials for the reactions described below are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce or Sigma (St. Louis, Mo., USA).
  • Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1 15 (John Wiley and Sons, 1991), Rodd's
  • the 2E,6E-farnesyl alcohol 3 (where the geometry at C2 and C6 positions is already fixed as trans- or E) was designed and used as a commercially available starting material for the synthesis of 5E,9E,13E-geranylgeranyl acetone 1.
  • the alcohol function of 2E, 6E-famesyl alcohol 3 was converted to the corresponding bromide 4 by the treatment of phosphorus tribromide (PBr 3 ) in ethyl ether (EE) or with Ph 3 P and CBr 4 in acetonitrile (ACN) at 0 e C.
  • the resulting bromide was then reacted with carbanion (derived from the reaction of ethyl acetoacetate 5 and sodium ethoxide) to yield the desired 5E,9E-farnesyl ketoester 6.
  • carbanion derived from the reaction of ethyl acetoacetate 5 and sodium ethoxide
  • the homologated ketoester 6 after hydrolysis and decarboxylation using aqueous 5N KOH yielded the expected 5E,9E-farnesyl acetone 7.
  • a one pot conversion of bromide 4 to the corresponding farnesyl acetone 7 can be possible without isolating intermediate ketoester 6.
  • the resulting 2E-conjugated ester 8 was reduced to the corresponding 2E-alcohol 9 by means of a lithium aluminum hydride (LAH) treatment, which was then converted into the corresponding 2E,6E,10E-geranylgeranyl bromide 10 by means of phosphorus tribromide (PBr 3 ) treatment in ethyl ether (EE) or with Ph 3 P and CBr 4 in acetonitrile (ACN) at 0°C.
  • LAH lithium aluminum hydride
  • PBr 3 phosphorus tribromide
  • EE ethyl ether
  • Ph 3 P and CBr 4 acetonitrile
  • the 2E,6E-farnesyl alcohol 3 (where the geometry at C2 and C6 positions is already fixed as trans- or E) was used as a commercially available starting material for the synthesis of 5Z,9E,13E-geranylgeranyl acetone 2.
  • the homologated ketoester 6 after hydrolysis and decarboxylation using aqueous 5N KOH yielded the expected 5E,9E-farnesyl acetone 7, one of the key
  • the 2Z-alcohol 13 was transformed into the corresponding 2Z,6E,10E-geranylgeranyl bromide 14 by using phosphorus tribromide (PBr3) treatment in ethyl ether (EE) or with Ph ⁇ P and CBr 4 acetonitrile (ACN) at 0"C, and then reacted with carbanion (derived from ethyl acetoacetate 5 and sodium ethoxide) at 0 e C afforded the desired 2Z,6E,10E-geranylgeranyl ketoester 15, a precursor needed for 5Z,9E,13E-geranylgeranyl acetone 2.
  • the subsequent ester hydrolysis and decarboxylation of ketoester 15 using aq. 5N KOH at 80"C yielded the requisite 5Z,9E,13E- geranylgeranyl acetone 2.
  • Example 3 5Z,9E,13E-Geranylgeranyl Acetone Synthesis Alternative synthesis of 5-c/s Isomer: 5Z,9E,13E-Geranylgeranyl acetone 2: The alternative synthesis of 5Z,9E,13E-geranylgeranyl acetone 2 can be achieved as shown in the scheme-3.
  • 5E,9E-farnesyl acetone 7 as a key intermediate, can be used to generate additional double bond with cis-(Z)-orientation.
  • the reaction of 5E,9E- farnesyl acetone 7 with the witting reagent 16 can afford the conjugated ester 12 with cis- (Z)-geometry at C2 position.
  • the subsequent reduction of ester 12 with lithium aluminum hydride (LAH) can generate the corresponding alcohol 13, which then can be converted into the corresponding bromide 14.
  • the conversion of bromide 14 to the ketoester 15 followed by hydrolysis and decarboxylation can afford the desired 5-cis (Z) isomer; 5Z,9E,13E- geranygeranyl acetone (2).
  • the 2E,6E-farnesyl alcohol 3 (where the geometry at C2 and C6 positions is already fixed as trans- or E) was used as a commercially available starting material for the synthesis of 5Z,9E,13E-geranylgeranyl acetone 2.
  • the other synthon, namely the ylide 21 can be synthesized from a commercially available starting material, ethyl levulinate 16, a sugar industry by-product.
  • the ketalization of ethyl levulinate 16 using conventional conditions can yield the desired 2-oxo-ketal 17, which then can be reduced using LAH in THF at 0 °C to the corresponding alcohol 18. Furthermore, the alcohol 18 then can be treated with Ph 3 Br in diethyl ether at 0 °C to obtain the bromide 19, which then after treatment with Ph 3 P can yield the phosphonium bromide salt 20.
  • the bromide salt 20 upon treatment with mild alkali (IN NaOH) can furnish the desired ylide 21, required to complete the synthesis of 5Z-GGA 2.
  • the 5E, 9E, 13E-geranyl geranyl acetone (1) can be prepared by reacting 6E-10E-geranyl linalool (23) with diketene (24) catalyzed by DMAP in ethyl ether to give the ester 25.
  • the ester 25 in the Carroll rearrangement using Al(OiPr)3 at elevated temperature can afford the desired 5E, 9E, 13E-geranyl geranyl acetone (1).
  • the GGA (1) can be prepared by treating geranyl linalool (23) with the Meldrum's acid 26 in the Carroll rearrangement using Al(OiPr) 3 at 160 °C.
  • the conversion of alcohol function of 28 by using Ph 3 P and CBr 4 in acetonitrile can afford the corresponding bromide 29, which then can be used to make a phosphonium bromide salt 30 by treatment with PhaP at elevated temperature.
  • the bromide salt 30 upon treatment with KHMDS in THF can afford the ylide 31, which then can be reacted in-situ with ketone 7 in a key step to establish cis geometry with the newly created double bond at C2 position and obtain the 2Z-TBDMS ether 32 (ref: Still et al, J.
  • esters (2g-k) were prepared as a mixture of trans and cis isomers.
  • LCMS MS (m/z): 432.5 (M+Na).
  • carbamates 8b to 8o were prepared according to the procedure that was used to prepare carbamate 8a.
  • the reaction of alcohol 5 (0.165g, 0.75 mmol) with n-pentyl isocyanate (0.180g, 1.4 mmol) afforded the carbamate 8b. Yield: 0.080 g (32%);
  • R Carboethoxy-2'-ethyl-
  • Piperidinyl-2'-ethyl 2E 6E,10E-geranylgeranyl thiocarbamate (101)
  • R Piperidinyl-2'-ethyl-

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Abstract

L'invention concerne des formulations sublinguales de géranylgéranylacétone, des dérivés de géranylgéranylacétone et des conjugués de médicament de chacun de ceux-ci, et leurs procédés d'utilisation. L'invention concerne des procédés de traitement de l'ostéopénie par de la géranylgéranylacétone (GGA) et des dérivés de celle-ci et des compositions utiles pour ceux-ci. L'invention concerne également des dérivés de polyphosphonate d'isoprényle, des compositions pharmaceutiques comprenant les dérivés de polyphosphonate d'isoprényle et leurs utilisations.
PCT/US2014/026307 2013-03-15 2014-03-13 Formulations sublinguales comprenant de la géranylgéranylacétone et des dérivés de géranylgéranylacétone Ceased WO2014151719A1 (fr)

Applications Claiming Priority (12)

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US13/815,831 US20140274967A1 (en) 2013-03-15 2013-03-15 Polyisoprenyl derivatives and uses thereof
US13/815,792 US20140275282A1 (en) 2013-03-15 2013-03-15 Treating osteopenia and related disorders with geranylgeranyl acetone and derivatives thereof
US13/815,792 2013-03-15
US13/815,831 2013-03-15
US201361845303P 2013-07-11 2013-07-11
US61/845,303 2013-07-11
US201361856391P 2013-07-19 2013-07-19
US61/856,391 2013-07-19
US201361878489P 2013-09-16 2013-09-16
US61/878,489 2013-09-16
US201361920441P 2013-12-23 2013-12-23
US61/920,441 2013-12-23

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017087795A1 (fr) 2015-11-19 2017-05-26 Concert Pharmaceuticals, Inc. Epi-743 deutéré

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5453524A (en) * 1991-08-27 1995-09-26 Eisai Co., Ltd. Phosphorus-containing isoprenoid derivatives
US20020082244A1 (en) * 1998-06-24 2002-06-27 Merck & Co., Inc. Compositions and methods for inhibiting bone resorption
US20080113919A1 (en) * 2003-07-29 2008-05-15 Arizona Biomedical Research Commission Conjugated Nitro Alkene Anticancer Agents Based on Isoprenoid Metabolism
US20090054623A1 (en) * 2004-12-17 2009-02-26 Neose Technologies, Inc. Lipo-Conjugation of Peptides
US20120172453A1 (en) * 2010-09-01 2012-07-05 Coyote Pharmaceuticals, Inc. Methods for treating neurodegenerative diseases

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5453524A (en) * 1991-08-27 1995-09-26 Eisai Co., Ltd. Phosphorus-containing isoprenoid derivatives
US20020082244A1 (en) * 1998-06-24 2002-06-27 Merck & Co., Inc. Compositions and methods for inhibiting bone resorption
US20080113919A1 (en) * 2003-07-29 2008-05-15 Arizona Biomedical Research Commission Conjugated Nitro Alkene Anticancer Agents Based on Isoprenoid Metabolism
US20090054623A1 (en) * 2004-12-17 2009-02-26 Neose Technologies, Inc. Lipo-Conjugation of Peptides
US20120172453A1 (en) * 2010-09-01 2012-07-05 Coyote Pharmaceuticals, Inc. Methods for treating neurodegenerative diseases

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017087795A1 (fr) 2015-11-19 2017-05-26 Concert Pharmaceuticals, Inc. Epi-743 deutéré

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