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WO2014151697A1 - Therapeutic uses for geranylgeranyl acetone and derivatives thereof - Google Patents

Therapeutic uses for geranylgeranyl acetone and derivatives thereof Download PDF

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Publication number
WO2014151697A1
WO2014151697A1 PCT/US2014/026263 US2014026263W WO2014151697A1 WO 2014151697 A1 WO2014151697 A1 WO 2014151697A1 US 2014026263 W US2014026263 W US 2014026263W WO 2014151697 A1 WO2014151697 A1 WO 2014151697A1
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WIPO (PCT)
Prior art keywords
gga
derivative
composition
another embodiment
disease
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2014/026263
Other languages
French (fr)
Inventor
Hiroaki Serizawa
Tilmann M. Brotz
Obsidiana Abril-Horpel
William Haag
Patricia Walicke
Ankush Argade
Akash DATWANI
Natalie SPENCER
Yonghua PAN
Florian ERMINI
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Coyote Pharmaceuticals Inc
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Coyote Pharmaceuticals Inc
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Filing date
Publication date
Priority claimed from US13/815,740 external-priority patent/US20140275280A1/en
Priority claimed from US13/815,741 external-priority patent/US20140275281A1/en
Priority claimed from PCT/US2013/035333 external-priority patent/WO2014163643A1/en
Application filed by Coyote Pharmaceuticals Inc filed Critical Coyote Pharmaceuticals Inc
Publication of WO2014151697A1 publication Critical patent/WO2014151697A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/0043—Nose
    • 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
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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

Definitions

  • This invention provides therapeutic compositions suitable for intranasal administration, which include geranylgeranyl acetone (GGA) and/or derivatives thereof.
  • This invention also provides therapeutic methods for treating a neural disease, disorder or condition by the intranasal administration of compositions that include geranylgeranyl acetone (GGA) and derivatives thereof.
  • 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 cis and trans isomers of GGA or the GGA derivative.
  • This invention further provides therapeutic methods for treating inflammatory bowel disease (IBD) or a related disorder or condition by the administration of compositions that include geranylgeranyl acetone (GGA) and derivatives thereof.
  • This invention also provides therapeutic methods for treating chronic liver disease (CLD) or a related disorder or condition or acute liver injury or failure by the administration of compositions that include GGA and derivatives thereof.
  • CLD chronic liver disease
  • this invention provides therapeutic- methods for treating cardiac ischemia and repurfusion injury or a related disorder or condition by the administration of compositions that include GGA and derivatives thereof.
  • GGA Geranylgeranyl acetone
  • inflammatory bowef disease (18D) is generally characterized by diarrhea, cramping, abdominal pains, weight loss, rectal bleeding, tiredness, anemia, fistuiae, perforations, obstruction of the bowel and frequent need for surgical intervention. It encompasses a number of disorders including Crohn's disease, ulcerative colitis, indeterminate coiitis. microscopic coiitis and collagenous coiitis.
  • IBS irritable Bowel Syndrome
  • Chronic liver disease Is marked by the gradual destruction of liver tissue over time.
  • liver diseases can fall under this category, including without limitation, cirrhosis and fibrosis, the latter of which is often the precursor to cirrhosis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.
  • Cirrhosis Is the result of acute and chronic liver disease and is characterized by the replacement of liver tissue by fibrotic scar tissue and regenerative nodules leading to a progressive loss of liver function. Fibrosis and nodular regeneration results in the loss of the normal microscopic lobular architecture of the liver. Fibrosis represents the growth of scar- tissue resulting from, for example, infection, inflammation, injury, and even healing. Over time, the fibrotic scar tissue slowly replaces the norma! functioning liver tissue resulting in a decreasing amount of blood flow to the liver leaving the liver incapable of fully processing nutrients, hormones, drugs, and poisons that are found in the bloodsirearri. More common causes of cirrhosis include alcoholism, hepatitis C viral infections, ingestion of toxins, and fatty liver, but many other possible causes afso exist,
  • Liver injury is some form of trauma sustained to the liver, This can occur through either a blunt force such as a car accident, or a penetrating foreign object such as a knife. Liver injuries constitute 5% of all traumas, making it the most common abdominal injury.
  • Acute liver failure is the appearance of severe complications rapidly after the first signs of iiver disease (such as jaundice), and indicates that the liver has sustained severe damage (loss of function of 80-90% of Iiver ceils).
  • the complications are hepatic
  • hyperacute as 'within 1 week, acute as 8-28 days and subacute as 4-12 weeks. It reflects the fact that the pace of disease evolution strongly influences prognosis.
  • Acetaminophen hepatotoxicity is, by far., the most common cause of acute liver failure in both the United States and the United Kingdom. Toxicity of acetaminophen arrses often due to its quinone metabolite. Acetaminophen overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance. Signs and symptoms of paracetamol toxicity may initially be absent or vague. Untreated overdose can lead to liver failure and death within days. Renal failure is aiso a possible side effect.
  • Coronary heart disease is the narrowing or blockage of the coronary arteries, usually caused by atherosclerosis.
  • Atherosclerosis (sometimes called “hardening” or “clogging” of the arteries) is the buildup of cholesterol and fatty deposits (called piaques) on the inner wails of the arteries. These piaques can restrict blood flow to the heart muscle by physically clogging the artery or by causing abnormal artery tone and function.
  • Cardiac ischemia may be asymptomatic or may cause chest pain, known as angina pectoris. It occurs when the heart muscle, or myocardium, receives insufficient blood flow. This most frequently results from atherosclerosis, which is the long-term accumulation of cholesterol-rich plaques in the coronary arteries. Ischemic heart disease is the most common cause of death in most Western countries and a major cause of hospital
  • an intranasal composition is provided, the
  • composition comprising an effective amount of geranyigeranyl acetone (GGA) or a GGA derivative including GGA conjugates, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • GGA geranyigeranyl acetone
  • an enteric composition comprising an effective amount of geranyigeranyl acetone (GGA) or a GGA derivative including GGA conjugates, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • GGA geranyigeranyl acetone
  • the GGA or the GGA derivative includes the all-irons (hereinafter "trans") form or substantially the trans form of the GGA or the GGA derivative.
  • 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.
  • the GGA or a GGA derivative exists at least 80%, or at least 90%, or at least 95%, or at least 99% in the t ans isomer.
  • this invention relates to pharmaceutical uses, as disclosed herein, of geranylgerany! acetone (GGA) and GGA derivatives, pharmaceutical compositions of isomers of geranvlgeranyi acetone, preferably synthetic geranylgeranyl acetone, and GGA derivatives, and methods of using such compounds and pharmaceutical compositions.
  • this invention relates to a 5-trans isomer compound of formula V!:
  • VI is at least 80% in the 5E, 9E, 13E configuration.
  • this invention utilizes a compound, which is synthetic 5E, 9E, 13E geranylgeranyl acetone.
  • the synthetic 5E, 9E, 13E geranylgeranyl acetone is free of 5Z, 9E, 13E geranylgeranyl acetone.
  • this invention utilizes a pharmaceutical composition comprising synthetic GGA or synthetic 5E, 9E, 13E GGA, and at least one pharmaceutical excipient.
  • Another aspect of this invention relates to a synthetic 5-cis isomer compound of formula Vi!:
  • VI! is at leas a ketal thereof of formula XII: XVI!
  • each R 70 independently is Cr 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 optiona!!y substituted with 1-3, preferably 1-2, C r C 6 a!kyi groups.
  • the two R 70 groups are the same.
  • R 70 is, methyl, ethyl, or propyl in another embodiment, the cyclic ring is:
  • GGA and GGA derivatives utilized herein can be employed as a passive carrier where they are not covalently bound to a drug and as covalent conjugates of drugs for administering these drugs intranasally.
  • 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 intranasal 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.
  • the compounds are conjugates of GGA or GGA derivatives with other drugs where rapid onset of a therapeutic serum
  • 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, thiol-containing components of the blood such as glutathione, or through the action of endogenous enzymes such as lipases, etc.
  • utiiized herein are drug conjugates of GGA or drug conjugates of GGA derivatives, that are therapeutically useful for intranasal formulation and delivery to a subject.
  • compounds of formuia [G-L-j v -D wherein v is 1-10, preferably, 1-5, more preferably, 1-3, or 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 -CO2H, -OH, - H 3 , and/or - SH, and such other groups that can he covendingiy conjugated as provided herein.
  • Li 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.
  • Li comprises a C Ci 0 alky!ene or C Qo heteroaikylene, Q-Cio cycloalkyi, C r C10 heteroaryl, Q-Cio heterocyciyl moiety, which is oprina!iy substituted.
  • Li comprises an amino acid moiety.
  • L-. is a di, tri, tetra, or pentapeptide, preferably comprising 1, more preferably 2.. and stili more preferably 3 or more naturally occurring amino acids.
  • compositions utilized herein contain a drug, and GGA or a GGA derivative as a non-covalently bound carrier.
  • the drug is not covendingiy 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: Forteo - osteoporosis; Ceredist (TRH) -- ataxia; Byetta (GLP-1) - diabetes; Sandostatin (GHI) - acromegaly; Victoza (GLP-1) - diabetes; Gonal-f (FHS) - infertility; Neupogen (G-CSF) - neutropenia; Kepivance - mucositis in cancer; Natrecor (B type naturietic protein) ⁇ congestive heart failure; Calcitonin for hypercalcemia; ACTH for infantile spasms; Oxytocin for premature delivery in pregnancy; Copaxone for multiple sclerosis; Beta-interferon for multiple sclerosis; and Alpha-interferon for viral hepatitis.
  • 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 antiinflammatory drugs, such as but not limited to dexamethazorte and ibuprophen,
  • I n another aspect utilized herein are compounds wherein G6A or a derivative thereof is conjugated to an anti-cancer agent or another drug as disclosed herein.
  • the G6A or a derivative thereof is conjugated to an anti-cancer agent or another drug as disclosed herein.
  • the G6A or a derivative thereof is conjugated to an anti-cancer agent or another drug as disclosed herein.
  • the G6A or a derivative thereof is conjugated to an anti-cancer agent or another drug as disclosed herein.
  • R '- R 3 , m, and n are defined as in Formula (I !) herein, 1/° is a bond or a linker joining the isoprenyi portion to the Drug, and the Drug is preferably an antibiotic or a glaucoma drug, or is an anticancer agent, or is an antiviral agent.
  • the linker is a bond, methylene, or carbonyi.
  • the linker joins the isoprenyi portion to a carbonyi moiety, or an oxygen, nitrogen, or sulfur atom of the drug.
  • R 1 -R b are methyl, and m and n are 1. Such conjugates are formulated and administered in accordance with this invention.
  • 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 in this invention include, farnesyl acetone, farnesyl alcohol, farnesyl carbamate, geranyl gerany! (GG) alcohol, GG carbamate.
  • the GGA derivative is
  • r is 0, i, 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 ® (G!axoSmithKiine, London, U.K.) or vancomycin.
  • the drug that is conjugated to GGA or a GGA derivative is a peptide, such as but not limited to teriparatkie.
  • the drug that is conjugated to GGA or a GGA derivative is an antibody, such as but not limited to herceptin.
  • 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 sulfenyiated amide linkage. In some embodiments, the drug conjugate is joined to GGA or the GGA derivative via an ester linkage. In some
  • the drug conjugate is joined to GGA or the GGA derivative via an amide linkage. In some embodiments, 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.
  • intranasal 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 -intranasal formulation comprising the comparable amount of GGA or a GGA derivative
  • a conventional, i. e., non -intranasal formulation comprising the comparable amount of GGA or a GGA derivative
  • such intranasal 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 intranasal formulations of GGA or a GGA derivative avoid stomach acid induced conversion of the all cis form to a mixed cis- and cis- form.
  • at least one of the double bonds in GGA or the GGA derivative of the intranasal formulation is in the cis configuration.
  • at least two or more of the double bonds in GGA or the GGA derivative of the Intranasal formulation is in the cis configuration.
  • the surface area of the nostril is small and thus can absorb only a limited volume of any intranasal composition.
  • concentration of the GGA or the GGA derivative in the intranasal composition is contemplated to be sufficiently high e.g., 0.1-20% (weight/volume) to compensate for the small volumes, e.g., 0.01-2 mL, of the intranasal composition that are administered to each nostril, in certain embodiments, the composition includes 0.1-5%, or preferably 5-10%, or more preferably 10-15% or 15- 20% (weight/volume) of GGA or a GGA derivative, or a pharmaceutically acceptable salt thereof.
  • the intranasal compositions described herein are contemplated to be administered to each or either nostril one or more times, e.g., 1, 2, 3, 4,. 5, 6, 7 or 8 times per day. It is further contemplated that a sufficient time delay, e.g., of 1- 30 minutes or more, such as time delays of 30 minutes, 1, 2, 3, 4, 8, 12, 24 or 48 hours may be used between each administration. Without being bound by theory, it is believed that each nostril can absorb only a limited volume of any intranasal composition and thus it quickly becomes saturated by the intranasal compositions described herein .
  • an effective amount of GGA or a derivative thereof is efficiently administered by empioving the intranasal compositions described herein.
  • the intranasal formuiation of GGA or a derivative contains between 1- 55, 5-50, 10-40, or 20-30 mg/kg/day.
  • the composition is in the form of a solution or suspension .
  • said excipient comprises a bioadhesive and/or an intranasal absorption promoter.
  • Said intranasal absorption promoter in some embodiments, is one or more of a chelating agent, POE (9) Iauryi alcohol, sodium giycochoiate and !ysophosphatidy! choline.
  • 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 herein can form a micelle or a reverse micelle, A micelle has a hydroiphiiic 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 asportation of GGA or the GGA derivative, or the drug conjugate of GGA or a GGA derivative from an aqueous phase Into the intranasal 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 moist environment of the nostril Into blood.
  • a method is provided for administering intranasally an effective amount of the compositions to a subject in need thereof.
  • subject or patient refers to a mammal . , particularly preferably humans.
  • a method for treating a neural disease, disorder or condition and/or reducing one or more negative effects of a neural disease, disorder or condition comprising administering intranasally an effective amount of any of the compositions described herein to a subject in need thereof.
  • a method for delivering a GGA derivative to the brain and/or the spina! cord of a patient comprises administering an intra nas composition intranasally to said patient in an amount sufficient to introduce an effective amount of GGA derivative into the brain and/or the spina! cord.
  • an effective amount refers to a therapeutically effective amount or to a an amount effectively measured in the brain and/or the spinal cord.
  • Some embodiments provided herein describe a method for inducing expression of a heat shock protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of GGA or a GGA derivative thereof, wherein the GGA or GGA derivative thereof is administered intranasally to said subject.
  • FIG. 1 Another embodiments provided herein describe a method for inhibiting neural death in a subject in need thereof; the method comprising administering to the subject a therapeutically effective amount of GGA or a GGA derivative thereof, wherein the GGA or GGA derivative thereof is administered intranasally to said subject.
  • the administration of an effective amount of these enteric formulations improves pharmaceutical activities such as an enhanced activity,, improved serum half-life, and/or lower toxicity with reduced adverse side effects relative to the administration of a conventional, i.e., non-enteric formulation comprising the comparable amount of GGA or a GGA derivative
  • the enteric formulation is a solid-dosage form.
  • the enteric formulation comprises one or more an enteric polymer and enteric coating as suitable pharmaceutically acceptable excipients.
  • the enteric formulation contains an effective amount of GGA or the GGA derivative.
  • various bacterial and viral disorders, and cancers of the eye, the brain, and the spinal cord, and nerves, including without limitation, nerves in the brain, eye, and the spina! cord are treated in accordance with this invention, in some embodiments, the disorder is glaucoma. In another embodiment, the disorder is herpes.
  • GGA or GGA derivatives, drug conjugates, compositions thereof and related methods that are useful for the treaiment of a subject via an intramucosaf administrations, e.g., vaginal, rectal, other than the intranasal route.
  • intramucosaf administrations e.g., vaginal, rectal
  • GGA or the GGA derivatives, drug conjugates, compositions thereof can be formulated as suppositories for vaginal or rectal administration.
  • Excipien s for the treatment of intramucosal administrations, other than those described herein, are well known to the skilied artisan.
  • a method is provided of treating inflammatory bowel disease (I8D) or a related disorder or condition comprising administering a composition comprising an effective amount of geranyigeranyl acetone (GGA) or a GGA derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceuticaliy acceptable excipient to a subject in need thereof.
  • I8D inflammatory bowel disease
  • GGA geranyigeranyl acetone
  • subject or patient refers to a mammal, particularly preferably humans.
  • a method is provided of upregulating HSP70 in stomach cells affected by IBD comprising contacting the stomach cells with an effective amount of GGA.
  • a method is provided of treating chronic liver disease or a related disorder or condition comprising administering a composition comprising an effective amount of geranyigeranyl acetone (GGA) or a GGA derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a method is provided of upregulating HSP70 in hepatic cells affected by a chronic liver disease comprising contacting the hepatic cells with an effective amount of GGA,
  • the hepatic cells are affected with cirrhosis, fibrosis, nonalcoholic fatty liver disease, or non-alcoholic steatohepatitis,
  • a method is provided of treating a disorder selected from fiver injury, preferably acute fiver injury (from trauma, surgery or as a side effect of cancer treatment), acute liver failure, preferably caused by drug toxicity such as acetaminophen toxicity, cardiac ischemia, myocardial infarction, repurfusion injury and heart transplants, or a related disorder or condition, comprising administering a composition comprising an effective amount of geranyigeranyi acetone (GGA) or a GGA derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, to a su bject in need thereof,
  • the (GGA) or a GGA derivative is administered to the subject in an emergency room setting.
  • a method is provided of treating a subject diagnosed with m ild to moderate iBD following gastrectomy comprising administering a composition comprising an effective amount of geranyigeranyi acetone (GGA) or a GGA derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • GGA geranyigeranyi acetone
  • the subjects are treated for 12 weeks
  • compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
  • compositions and methods when used to define compositions and methods, shall mean excluding other eiements of any essential significance to the combination for the stated purpose. Thus, a composition or process consisting essentially of the elements as defined herein vvouid 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 eiements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
  • alkoxy refers to -O-a!kyi.
  • nitro refers to -NO ?
  • alkyl refers to monovalent saturated aliphatic hydrocarbyi groups having from 1 to 10 carbon atoms (i.e., C r Cio alkyl) or 1 to 6 carbon atoms (i.e., Ci-C 6 alkyl), or 1 to 4 carbon atoms.
  • This term includes, by way of example, linear and branched hydrocarbyi groups such as methyl (CH ) ethyl (CH 3 CHr), n-propyl (CH 3CH 2CH2-) .
  • alkenyl refers to monovalent aliphatic hydrocarbyi groups having from 2 to 25 carbon atoms or 2 to 6 carbon atoms and 1 or more, preferably 1, carbon carbon double bond.
  • alkenyl include vinyl, allyi, dimethyl ally!, and the like,
  • alkynyl refers to monovalent aliphatic hydrocarbyi groups having from 2 to 10 carbon atoms or 2 to 6 carbon atoms and 1 or more, preferably 1, carbon carbon triple bond -(C ⁇ C)-.
  • alkynyl include ethyrsyi, propargyl, dimethy!propargyl, and the like.
  • acy! refers to -C(0)-aikyl, where alkyl is as defined above.
  • 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: 10058]
  • -C0 2 H ester refers to an ester formed between the -CO ;H group and an alcohol, preferably an aliphatic alcohol. A preferred example included ⁇ C0 2 R L , wherein R l is alkyi or aryi group optionally substituted with an amino group.
  • chiraf moiety refers to a moiety that is chirai. Such a moiety can possess one or more asymmetric centers. Preferably, the chirai moiety is enantiomerically enriched, and more preferably a single enantiomer.
  • Non limiting examples of chirai moieties include chirai carboxyllc acids, chirai amines, chirai amino acids, such as the naturally occurring amino acids, chirai alcohols including chirai 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 cyciopropyl, cyclobutyi, cyc!opentyl, cyciohexyi, cycioheptyl, adamentyi, 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. For example, and without limitation , the following is a cycloalkyl group:
  • 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 heteroatorrts selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided thai the ring contains at least 5 ring atoms.
  • Nonlimiting examples of heteroaryl include furan, imidazole, oxadiazole, oxazoie, pyridine, qulnoline, and the like.
  • the condensed rings may or may not be a heteroatom containing aromatic ring provided that the point of attachment is a neteroaryi atom.
  • th oaryl group is a monovalent, aromatic mono-, bi- , or tricyclic ring having 2-14 ring carbon atoms and 1-6 ring heteroatorrts selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided thai the ring contains at
  • heterocyclyciyi 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, O, S, and P and oxidized forms of . S, and P. provided that the ring contains at !east 3 ring atoms. While heterocyclyl preferably refers to saturated ring systems, it also includes ring systems containing 1- 3 double bonds, provided that they ring is non-aromatic.
  • heterocyclyl examples include, azalactones, oxazoiine, piperidinyl, plperazinyi, pyrroiidinyl, 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 heterocyclyl group.
  • the following is a hetero
  • hydro!yzlng refers to breaking an R H -0-CO-, R H -0-CS ⁇ , or an R H -0-SO r 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
  • salt refers to an ionic compound formed between an acid and a base.
  • saits 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, b, Cs, Nli3 ⁇ 4, Ca, Ba, imidazo!ium, and ammonium cations based on naturally occurring amino acids.
  • salts include, without limitation, salts of organic acids, such as caroboxylic acids and suifonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes.
  • exemplary and non -limiting anions useful in pharmaceutically acceptable saits include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, suifate, bisalfate, mono-, dh and tribasic phosphate, mesylate, tosylate, and the likes,
  • trans isomer refers to a trans isomer that is by molar amount 95%, preferably 96%, more preferably 99%, and still more preferably 99.5% or more a trans isomer with the rest being the corresponding cis isomer.
  • each double bond is in a trans or E configuration.
  • a cis form of GG.A or a GGA derivative will contain one or more of these bonds in a cis or Z configuration.
  • neuroprotective refers to reduced toxicity of neurons as measured in vitro in assays where neurons susceptible to degradation are protected against degradation as compar ed to control. Neuroprotective effects may also be evaluated in vivo by counting neurons in histology sections.
  • neuroneuron refers to all electrically excitable ceils 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 mamma! or tissue culture ceil 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 extraehromosomally or intrachromosomally.
  • Neuroon or “neurons” also refers to transformed neurons such as neuroblastoma ceils and support cells within the brain such as glia.
  • protein aggregates '7 refers to a collection of proteins that may be partially or entirely mis-folded.
  • the protein aggregates ma 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 he intranuclear in which they are inside the nucleus or cytoplasm in which they are in the space outside of the nucleus but stili within the cell membrane.
  • the protein aggregates described in this invention are granular protein aggregates.
  • protein aggregate inhibiting amount refers to an amount of compound that inhibits the formation of protein aggregates at least partially or entirely. Unless specified, the inhibition could he directed to protein aggregates inside the cell or outside the ce!i.
  • intranuclear 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 wail of an animal cell.
  • pathogenic protein aggregate refers to protein
  • Pathogenic 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 which transmit signals from a neuron to a target cell.
  • neurotransmitters include but are not limited to: amino acids such as glutamate, aspartate, serine, y-aminobutyric acid, and glycine; monoamines such as dopamine, norepinephrine, epinephrine, histamine, serotonin, and melatonin; and other molecules such as acetychotine, adenosine, anadamide, and nitric oxide.
  • syne refers to junctions between neurons. These junctions allow for the passage of chemical signals from one cell to another,
  • G protein refers to a family of proteins involved in transmitting chemical signals outside the cell and causing changes inside of the cell.
  • the Rho 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.
  • treat ' includes alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting or suppressing the
  • deveiopment of the disease or condition relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or suppressing the symptoms of the disease or condition, and are intended to include prophylaxis.
  • the terms also include relieving the disease or conditions, e.g., causing the regression of clinical symptoms.
  • the terms further include achieving a therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • preventing refers to a reduction in risk of acquiring a disease or disorder (i.e. , causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease), The terms further include causing the clinical symptoms not to develop, for example in a subject at risk of suffering from such a disease or disorder, thereby substantially averting onset of the disease or disorder.
  • an effective amount refers to an amount that is effective for the treatment of a condition or disorder by an Intranasal administration of a compound or composition described herein
  • an effective amount of any of the compositions or dosage forms described herein is the amount used to treat a neural disease, disorder or condition and/or to reduce one or more negative effects of a neural disease, disorde or condition comprising administering intranasally any of the compositions or dosage forms described herein to a subject in need thereof
  • the condition or disorder that is treated with an effective amount of a compound or composition described herein is of the brain, spine and/or central nervous system.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into ceils or tissues
  • 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 SB A and are not intranuclear include but are not limited to ALS, AD, Parkinson's Disease, multiple sclerosis, and prion diseases such as Kuru,
  • Neural diseases can be recapitulated in vitro in tissue culture cells.
  • AD can be modeled in vitro by adding pre-aggregated 13-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 ceil. One way this can be achieved is by mixing dopamine with neurons such as neuroblastoma cells.
  • a transgenic mouse that expresses a mutant Sodl protein has similar pathology to humans with ALS.
  • a transgenic mouse that over expresses APP has similar pathology to h umans with AD.
  • This invention relates to compounds and pharmaceutical compositions of isomers of geranylgeranyi acetone, in certain aspects, this invention relates to a syn thetic 5-trans isomer compound of formula VI :
  • Vf wherein V! is at least 80% in the 5E, 9E, 13E configuration, !n some embodiments.
  • the invention utiiii-es for a compound of formuia VI wherein VI is at least 85%, or at least 90%, or at least 95%, or at least 95%, or at least 97%, or at least 98%, or at ieast 99%, or at least 99.5%, or at least 99,9% in the 5E, 9E, 13E configuration.
  • the invention for the compound of formuia VI does not contain any of the cis-tsomer of GGA.
  • Another aspect of this invention relates to a synthetic 5-cis isomer compound of formula VII :
  • VI I is at least 75% in the 51, 9E, 13 E configuration.
  • the invention utilizes a compound of formuia Vil wherein VII is at ieast 80% in the 5E, 9E, 13E configuration, or alternatively, at !east 85%, or at Ieast 90%, or at ieast 95%, or at Ieast 96%, or at Ieast 97%, or at Ieast 98%, or at least 99%, or at Ieast 99,5%, or at Ieast 99.9% in the 5E, 9E, 13E configuration.
  • the compound of formula VI! 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.
  • GGA derivatives useful in this invention include those described in in the U. S.
  • GGA derivative utilized herein is of Formula I:
  • n 1 is 1 or 2;
  • each R 1 and R 2 are independently €i-Q, alkyi, or R l and together with the carbon atom they are attached to form a C 5 -C 7 cycloalkyi ring optionally subsiituted with 1-3 QrQ alkyi groups;
  • each of R :i , R 4 , and R 5 independently are hydrogen or C Ce alkyi;
  • 3 ⁇ 4 is hydrogen, R b , -O-R", -NR' R K , or is a chiral moiety;
  • R 6 is:
  • the GGA derivative utilized is of Formula (l-A):
  • n 1 is 1. in another embodiment, n 1 is 2,
  • the GGA derivative utilized is of Formula i-C: wherein CT and Q.' are defined as in Formula (I) above,
  • the GGA derivative utilized is of Formula (l-D), (!-E), or (I
  • R 6 --R 8 are defined as in Formula (! ) above.
  • the GGA derivative utilized is of Formula (l-G), (I-H), or ⁇ I- 11:
  • R° is C 6 -Ci 0 ary!, such as naphthyl.
  • R 6 is a heteroaryi, such as quinolinyi.
  • rn 0 or 1
  • n 0, 1, or 2;
  • each R 1 and R 2 are independently d-Cg alkyl, or R 1 and R together with the carbon atom they are attached to form a C 5 -C 7 cycloalkyl ring optionally substituted with 1-3 Ci -Cg afkyl groups;
  • each of R 3 , R " , and R 5 independently are hydrogen or C r Ce alkyl
  • ⁇ 3 ⁇ 4 is -OH, -N R"R 23 -X-CO-NR M R 25 , -X-CS-NR 24 R 2S , or -X-S0 2 -NR 24 R 25 ;
  • X is -0-, -S-, -MR 26 -, or -CR 27 R 28 ;
  • each ' " " " arid R” 3 independently is hydrogen , C C g alkyl, optionally substituted with -C0 2 H or an ester thereof.
  • C r C 6 alkoxy, oxo,. -OH, -CR CR 2 , -CsCR, C3-C10 cycloaikyl, C Cg heterocyclyl, Cfi-Cio ar l, C 2 -CIQ heteroaryl, wherein each independently is hydrogen or Ci-Q alkyl;
  • each cycloaikyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl grou ps; -CF 3 , 1-3 halo, preferably, ch!oro or fluoro, groups; 1-3 nitro groups; 1-3 Ci -Cg alkoxy grou ps; -CO-phenyi; or -NR l0 R 19 ;
  • each R" and R 28 independently are hydrogen, d-Cg alkyl, -COR 81 or -COjR 81 , or R / together with R" or R * " and the intervening atoms form a 5-7 membered heterocyclyl ring optionai iy substituted with 1-3 Q-Q alkyl groups,
  • the compound of Formula (II) includes optical isomers such as enantiomers and diastereomers.
  • an ester refers prefera bly to a phenyl or a CrQ, alkyl ester, wh ich phenyl or alkyl grou p is optionally su bstitu ted with a am ino grou p.
  • 3 ⁇ 4 is -NR 22 R 23 -X-CO- R 2 R 25 , -X-CS-N R 24 R 2S , or -X-S0 2 - N R 24 R 25
  • ⁇ 1 ⁇ 4 is -X-CO-NR 24 R 25 , -X ⁇ CS-NR 2 R 25 , or -X-S0 2 -NR 24 R ⁇ in another embodiment
  • C3 ⁇ 4 is - R 22 R 23 .
  • 3 ⁇ 4 is -OH.
  • the compound of Formuia (I!) is of formula:
  • R 1 , R 2 , R ;: , W, and ⁇ 3 ⁇ 4 are defined as in any aspect or embodiment herein.
  • the GGA derivative utilized is of formula:
  • the compound of Formuia (II) is of formula:
  • R 2 ⁇ rV R 4 R 5 R 5 wherein R 1 . 2 , R 3 . R 4 , R b , and ⁇ 1 ⁇ 4 are defined as in any aspect or embodiment herein.
  • the GGA derivative utilized is of formuia:
  • R ⁇ R 2 , R", R s , m, n, X, and R i3 ⁇ 4 are defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formuia:
  • R 1 , P , R 4 , R s , m, n, and R 4 are defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R 3 ⁇ 4 is define as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • i4 is defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R *4 is defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R 24 and R 2b are defined as in any aspect and embodiment here
  • GGA derivative utilized is of formula:
  • P 4 is defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R 24 and R b are defined as in any aspect and embodiment here.
  • rn is 0. in another embodiment, m is i.
  • n is 0. in another embodiment, n is 1. In another embodiment, n is 2.
  • m+n is 1. In another embodiment, m+rt is 2. In another embodiment, m+n is 3.
  • R : and R 2 are independently C r aikyi.
  • R 1 and R" independently are methyl, ethyl, or isopropyl.
  • R " ⁇ R 4 and are independently C e aikyi.
  • one of , R 4 . and R J are aikyi, and the rest are hydrogen.
  • two of R " ⁇ R 4 , and R s are aikyi, and the rest are hydrogen, in another embodiment, R "' , R 4 , and R 5 are hydrogen.
  • R.. 3 , R 4 , and R 5 are methy!.
  • (3 ⁇ 4 is -X-CO-N R 2 R 25 .
  • (3 ⁇ 4 is "X-CS-N R 2 R 3 ⁇ 4 in another embodiment, Q 3 is -X-S0 2 -NR 24 R 25 , in another embodiment, (3 ⁇ 4 is -OCONHR 24 -OCONR 24 R 2S , -NHCO HR 2 ', -NHCONR 2 R 25 , -OCSNHR 24 , ⁇ OCSNR 2 R 25 , - NHCSNHR 24 or -NHCSNR 24 R 2S .
  • X is -0- , in another embodiment, X is -IMR i6 -. In another embodiment, X is or -CR ? R 28 .
  • one of R 3 ⁇ 4 and R : ' is hydrogen, in another embodiment, one or both of R 24 and R lb are C C 6 aikyi. in another embodiment, one or both of and R 2s are C C e aikyi, optionally substituted with an R 20 group, wherein R /C' is -C0 2 H or an ester thereof, C C 6 aikyi, C3-C10 cycioalkyi, C 3 -C 3 heterocyclyi, C 6 -Ci 0 aryl, or C 2 -Ci 0 heteroaryl. in another embodiment, one or both of R 44 and R *5 are C3-C10 cycioalkyi.
  • R 24 and R 25 are C 3 -C :l o cycioalkyi substituted with 1-3 aikyi groups, in another embodiment, one or both of R 24 and R 25 are C3-C8 heterocyclyi. In another embodiment, one or both of R -4 and R ' ° are Cs-C 10 aryl. In another embodiment, one or both of R 24 and R 26 are C2-C10 heteroaryl. in another embodiment, R / and R" together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.
  • R w is -C0 2 H or an ester thereof.
  • R 20 is C r Cr > aikyi.
  • P ° is C 2 -C 10 cycioalkyi.
  • . ⁇ ⁇ is C;rCg heterocyclyi.
  • R 2 ⁇ is C 6 -C 10 aryl.
  • R 20 is or C 2 -Cio heteroaryl.
  • the GGA derivative utilized is of formula (II):
  • n 0 or 1
  • n 0, 1, or 2;
  • each R 1 and R 2 are independently Ci-Ce alkyl, or R 1 and R* together with the carbon atom they are attached to form a C 3 -C 7 cycioaikyl ring optionally substituted with 1-3 Ci- e alkyl groups;
  • each of R 3 , R", and R s independently are hydrogen or C r C 6 alkyl
  • ⁇ 3 ⁇ 4 is -X-CO-NR 24 R 25 or -X-S0 2 -NR 24 R 2S ;
  • X is -0-., - R A ⁇ or -CR 27 R 28 ;
  • R 26 is hydrogen or together with R 24 or R' ' ⁇ b and the intervening atoms form a 5-7 membered ring optionally substituted with 1-3 C Ci, alkyl groups;
  • each R 27 and R 28 independently are hydrogen,. C r C 6 alkyl,. -COR 81 or -C0 2 R S1 , or R ""'7 together with R 2 or R 25 and the intervening atoms form a 5-7 membered cycioaikyl or heterocyciyl ring optionally substituted with 1-3 C C s alkyl groups; each R 24 and R" 5 independently is
  • Ci-Cg alkyl optionally substituted with -C0 2 H or an ester thereof, C3-C10 preferably C 3 ⁇ C 8 cycioaikyl, C 3 -C 8 heterocyciyl,. C 6 -Ci 0 aryl, or C 2 -C 10 heteroaryl, C3-C10 cycioaikyl,
  • each cycioaikyl, heterocyciyl, aryl, or heteroaryl is optionally substituted with 1-3 Ci-Cg alkyl groups, or R 24 and R 25 together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.
  • n 0 or 1
  • n 0, 1, or 2;
  • each R 1 and are independently Ci-C 6 aikyl, or R 1 and R together with the carbon atom they are attached to form a C 5 -C 7 cycioaikyl ring optionally* substituted with 1-3 C .-C 6 a iky! groups;
  • each of R " , R", and R s independently are hydrogen or C C 6 aikyl
  • QA 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 1
  • R "'& is CrQ, aikyl optionally substituted with 1-3 alkoxy or 1-5 halo group, C 2 -C 3 alkenyi, C 2 -C & aikyny!, C 3 -Ci 0 cycioaikyl, C 6 -C 10 aryl, C 3 -C 8 heterocyclyl, or C 2 -Ci 0 heteroaryl, wherein each cycioaikyl or heterocyclyl is optionally substituted with 1-3 C C b aikyl groups. or wherein each aryi or heteroaryf is independently substituted with 1-3 d-Cg alkyl or nitro groups, or R 30 is - R 34 R 35 ;
  • R 1 is hydrogen or together with R "'c' and the intervening atoms form a 5-7 membered ring optionaiiy substituted with 1-3 C r C 6 alkyl groups;
  • each R 32 and R 33 independently are hydrogen, C r -C 6 aikyl, -COR 81 or -C0 2 R 81 , or R 32 together with R 30 and the intervening atoms form a 5-7 membered cycloalkyl or heterocyciyi ring optionally substituted with oxo or 1-3 CrQ aikyl groups;
  • R 10 is C C 5 alkyl
  • R" and R 12 are independently C C 6 alkyl, C Ci 0 cycloalkyl, -C0 2 R 15 , or -CQN(R 15 ) 2 , or R " ° and R 11 together with the intervening carbon atom and oxygen atoms form a
  • R 1'3 is C1 -C5 aikyl or C 3 -C 10 cyc!oalkyi optionally substituted with 1-3 C x -C 6 aikyl groups;
  • R 14 Is hydrogen, C 3 -C 8 heterocyciyi, or C C 6 aikyl optionall substituted with a ⁇ C0 2 H or an ester thereof or a C 6 -C l0 aryi, C 2 --C c aikeny!, C C 6 alkynyl, C3-C10 cycloalkyl, or 3 C 3 -C 8 heterocyciyi, wherein each cycloalkyl, heterocyciyi, or aryi, is optionaiiy substituted with 1-3 aikyl groups;
  • each R 15 independently are hydrogen, C3-C10 cycloalkyl, Cj-Ce aikyl optionally substituted with 1-3 substituents selected from the group consisting of -C0 2 H or an ester thereof, aryi. or C 3 -C 8 heterocyciyi. or two R lb groups together with the nitrogen atom they are bonded to form a 5-7 membered heterocycle;
  • R lD is hydrogen or -C 6 aikyl
  • R 1 is hydrogen, C C 6 aikyl substituted with 1-3 hydroxy groups, -CHO, or is CQ 2 H or an ester thereof;
  • each R* s and R 55 independentiy is hydrogen, C r -C 6 alkyl, optionally substituted with - C0 2 H or an ester thereof, C3-C10 cycloalkyl, Cs-Cg heterocyciyi, Ce-Cio aryi, or C2-C10
  • heteroaryl or is CJ-CID cycloalkyl, C 3 -C 8 heterocyciyi, QrCie. aryi, or C 2 -Ci 0 heteroaryl, wherein each cycloalkyl, heterocyciyi, aryi, or heteroaryl is optionaiiy substituted with 1-3 aikyl groups, or R i4 and R & together with the nitrogen atom they are attached to form a 5-7 membered heterocycle; and
  • each R 81 independently is C C s alkyl.
  • m 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, [0132] In one embodiment, the compound of Formula (!!!) is of formula:
  • 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 utiiized 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 utiiized is of formula:
  • R s , R 4 , R s , R 0 and X 1 are defined as in any aspect and embodiment herein.
  • the GGA derivative utilized is of formula:
  • R 1 , R " ', R* R J , and G are defined as in any aspect and embodiment herein,
  • the GGA derivative utilized is of formula: wherein R 1 , R 2 , R* R 5 , m, n, X 1 , and R 3 ° are defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula: 34
  • R l , R " , R* R J , m, n, and R 3 are defined as in any aspect and embodiment here.
  • the GGA derivative utilized is of formula:
  • R 1 , R 2 . R 4 , R 5 , R 30 , m, n, and R 15 are defined as in any aspect and embodiment here.
  • each R ⁇ and R " are C Cg alkyl.
  • each R 1 and R _ are methyl, ethyl, or isopropyl.
  • R 1 and R 2 together with the carbon y are attached to form a ring that is: or .— J
  • R " , R 4 , and R s are Ci-Ce alkyl.
  • R ' ⁇ *, and R J are methyl.
  • X 1 is O. in another embodiment, X 1 is ⁇ -NR 3i .
  • R oi is hydrogen, in another embodiment, R '3i together with R 3 ° and the intervening atoms form a 5-7 membered ring optionaliy substituted with 1-3 C r C & alkyl groups.
  • X 1 is -CR 32 R " -, In another embodiment, X 1 is -CR 3 -.
  • each R 32 and R" independently are hydrogen, d-Os alk l, -COR 81 , or - C0 2 R° ⁇ in another embodiment, R 32 is hydrogen, and R 33 is hydrogen,. C r C 6 alkyl, -COR 8i , or -C0 2 R 81 .
  • R 33 is hydrogen.
  • P. 33 Ci-Q, alkyl. in another embodiment, R° 3 is methyl.
  • R 33 is -C0 2 R b l .
  • R 33 is -COR 81 .
  • R 32 together with R 3u and the Intervening atoms form a 5- 7 membered ring.
  • R 33 is hydrogen or C ; -C 6 aiky!. In one embodiment, R 33 is hydrogen, in another embodiment, R 33 is C R C 6 alkyl.
  • R* *5 is d-Ce alkyl.
  • ' U is methyl, ethyl, butyl, isopropyl, or tertiary butyl.
  • R 30 is d-d alkyl substituted with 1-3 alkoxy or 1-5 halo group, in another embodiment, R 3 is alkyl
  • R 30 is alkyl substituted with 1-5, preferably, 1-3, halo, preferably fiuoro, groups.
  • J0 is N R ⁇ ' R"
  • R 35 is H.
  • R 34 is d- alkyl, optionally substituted with a group selected from the group consisting of -C0 2 H or an ester thereof, C 3 - C 1C . cycioalkyl, C 3 -C 3 heterocyclyl, C 6 - Cioaryl, or d-Cto heteroaryi.
  • R "'4 is C 3 -Ci 0 cycioalkyl, C 3 -C 8 heterocyclyl, Ce-Cio aryl, or C 2 -Cio heteroaryi.
  • R 54 is C 3 -C10 cycioalkyl.
  • R a0 is C 2 - alkenyi or C 2 -C 3 alkynyi.
  • R M is C 3 -C J0 cycioalkyl.
  • R i0 is Cj-Cio cycioalkyl substituted with 1-3 -Ce alkyl groups.
  • R 3U is cyclopropyl, cyciobutyl, cyc!opentyi, cyclohexyl, or adamentyl.
  • R 30 is C 6 -do 3ryl or d-C :U ) heteroaryi.
  • R I0 is a 5-7 membered heteroaryi containing at least 1 oxygen atom.
  • R 3j is C 6 -Ci 0 aryl, C 3 -C 8 heterocyclyl, or C- > ⁇ Cio heteroaryi, wherein each aryl, heterocyclyl, or heteroaryi is optionally substituted with 1- 3 C d alkyl groups.
  • Y 2 is -O-R".
  • Y 1 and Y" 1 are joined to form -IMOR "1'4 .
  • Y 1 and Y" are joined to form -CR ⁇ R ⁇ .
  • ⁇ 1 ⁇ 4 is -CR 33 COR 30 .
  • R 30 is C C 6 aikyi optionaiiy substituted with an alkoxy group, in another embodiment, R 30 is C 3 -Cg cycloaikyl.
  • R" is hydrogen, in another embodiment, R 33 Is C Ce aikyi, In another embodiment, R is CO>R 81 . In another embodiment R 33 is COR s ⁇
  • QA is -CH 2 -CH
  • l 3 ⁇ 4 is C 3 -C 8 cycloaikyl.
  • R la is C C 6 aikyi optionally substituted with 1-3 substiteunts selected from the group consisting of -CO2H or an ester thereof, aryl, or C 3 - Cg heterocyclyl.
  • R 30 is C C 6 aikyi.
  • O is -O-CO-NHR 34 .
  • R 34 is C Cg aikyi, optionally substituted with -CO2H or an ester thereof, C 3 -C 8 cycloaikyl, C 3 -C 3 heterocyclyl, C 2 -Ci 0 aryl, or C 2 -Ci 0 heteroaryl.
  • R 3 * is C 3 -Cg cycloaikyl, C3-C8 heterocyclyl, C 2 -C 30 aryl, or C 2 -Cjoheteroaryl
  • R w is hydrogen
  • R' 4 is C.--C 6 aikyi optionally substituted with a - ⁇ C0 2 H or an ester thereof or a C 6 -Cio aryl optionally substituted with 1-3 aikyi groups.
  • 14 is C 2 -C 3 alkenyl.
  • R * is C 2 -C 6 alkynyl in anotner embodiment
  • R is Q-Cg cycloaikyl optionally substituted with 1-3 alkyl groups
  • R' 4 is C 3 -C 8 heterocyclyl optionally substituted with 1-3 aikyi groups.
  • R io is hydrogen.
  • R 1 ' is COjH or an ester thereof.
  • R 1 ' is Ci-C 3 aikyi substituted with 1-3 hydroxy groups.
  • R 17 is - alkyl substituted with 1 hydroxy group, in another embodiment, R i; is -CH 2 OH.
  • R 10 and R" together with the intervening carbon atom and oxygen atoms form a heteroycl f formula
  • n 0. 1, or 2;
  • each 1 and R ? are independently d-Ce aikyi, or R 1 and R 2 together with the carbon atom they are attached to form a C5-C7 cyc!oalkyl ring optionally substituted with 1-3 C Cg aikyi groups;
  • each of R ' ⁇ R", and R 5 independently are hydrogen or C r C & aikyi,. or R " and (1 ⁇ 4 together with the intervening carbon atoms form a 6 membered aryl ring, or a 5-8 membered cycioalkenyl ring, or a 5-14 membered heteroaryl or heterocycie, wherein each aryi, cycioalkenyl, heteroaryi, or heterocycie, ring is optionally substituted with 1-2 substituents selected from the group consisting of halo, hydroxy, oxo, -N(R U ) ?J and C r Cs alky! group;
  • aikyi group is optionally substituted with 1-3 substituents selected from hydroxy, NH 2 , C 5 -C 10 aryi, -C0 2 H or an ester or an amide thereof,
  • heteroaryi containing up to 3 ring heteroatoms, wherein the heteroaryi is optionally su bstituted with 1- 3 hydroxy, -N(R 4U ) 2 , and C : -C & alky! group,
  • each R 40 independently is hydrogen or C C 6 aikyi.
  • the compound of Formula (IV) includes tautomers and optical isomers such as enant!omers and diastereomers.
  • an ester refers preferably to a phenyl or a C Q, alky! ester, which phenyl or alkyl group is optionally substituted with a amino group
  • an amide refers preferably to a moiety formula -CON(R 4 °)2 , , wherein R 4 is defined as above.
  • ⁇ 1 ⁇ 4 is selected from a group consisting of oxazole, oxadiazoie, oxazoline, azalactone, imidazole, diazoie, triazole, and thiazole, wherein each beteroary! 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 J , and C3 ⁇ 4 are defined as in any aspect and embodiment here.
  • Q 5 is selected from the group consisting of:
  • R" is C r C 6 alkyl, C 6 -C 10 aryl, C3-C3 heteroaryl, C3-C3 heteroaryl, € 3 - ⁇ ⁇ cycloalkyl, and the alky! group is optionally substituted with 1-3 C 6 -C] 0 aryl, C 3 -C 8 heteroaryl, C Cg heteroaryl, C3-C10 cycloalkyi groups, and the aryl, heteroaryl, heteroaryl, cycloalkyl groups are optionally substituted with 1-3 d-Ce alkyl, d-Q alkoxy, halo, preferqably chloro or fluoro, Ce-Cio aryl, C 3 -C 8 heteroaryl, Cj-Cg heteroaryl, C3-C10 cycloalkyl group.
  • 3 ⁇ 4 is phenyl, optionally substituted as described herein, in another embodiment, ⁇ 1 ⁇ 4 is benzimidazole, benzindazole, and such other 5-6 fused 9- membered bicyciic heteroaryl or heterocycle. In another embodiment, ⁇ 3 ⁇ 4 is quinoiine. isoquinoline, and such other 6-6 fused 10 membered heteroaryl or heterocycle. In another embodiment, ⁇ 3 ⁇ 4 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 Cr alkyl.
  • R 1 and R J independently are methyl,, ethyi, or isopropyi.
  • R ;i , R 'J , and R " are independently C r C 6 alkyl.
  • one of R 3 , R 4 . and R 5 are alkyl, and the rest are hydrogen.
  • two of ⁇ R , and R b are alkyi, and the rest are hydrogen.
  • R J , and R 5 are hydrogen, in another embodiment, R 3 , R 4 , and R 3 are methyl.
  • this invention utilizes a compound selected from the group consisting of;
  • R * is defined as above.
  • GGA derivatives utilized herein are of formula (V):
  • n 0 or 1
  • n 0, 1, or 2;
  • each FT and R independently are Cj- e a!kyl, or R 1 and " together with the carbon atom they are attached to form a C 5 -C 7 cycloalkyl ring optionally substituted with 1-3 Ci-Cf, alky! groups;
  • each of R 3 , , and R b independently is hydrogen or Ci-C b alky!;
  • Qe is selected from the group consisting of:
  • X z is --Q-, -MR " " 1 -, or ⁇ -CR 53 R 4 -, and when X 3 is bonded via a double bond, X 2 is -CR 53 -;
  • Y" is hydrogen, -OH or -OR 55 ;
  • R S ;L is C Q aikyi, C Q aikyl substituted with 1-3 a!koxy or 1-5 haio groups, Q- C 6 aikenyl, C 2 -Q aikynyi, C 5 -Cj 0 cycloalkyi, C 3 -C G heterocyciyi, Q- o aryl, C 2 -CJ.J heteroaryl, or -N R T,3 ⁇ 4 R 66 , wherein each cycloalkyi or heterocyciyi is optionally substituted with 1-3 C Q alkyi groups, and wherein each ary! or heteroaryl is optionally substituted independently with 1-3 nitro and C r - C 6 alkyi 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 Q-Q alkyi groups;
  • each R 5,3 and R S4 independently are hydrogen, C,-Q alkyi, -COR 81 , -C0 2 R 81 , or -COMHR 82 , or R B3 together with R 51 and the intervening atoms form a 5-7 membered cycloalkyi or heterocyciyi ring opiionaliy substituted with 1-3 C r Q aikyl groups;
  • R 55 is C C 6 alkyi
  • each R 35 and R J independently are C Q aikyl, C 3 -C 10 cycloalkyi, -00 2 R 62 , or -CON(R 6 ) 2 ; or R 33 and R 3 ° together with the intervening carbon atom and oxygen atoms form a heterocycie optionally substituted with 1-3 Q-Q alkyi groups;
  • R 58 is: C3-C10 cycloalkyi, C r Q alkyi optionally substituted with -OH, C0 2 H or an ester thereof, or -Qo cycloalkyi.
  • R' 9 is hydrogen or C C s aikyl
  • R 60 is CrQ alkyi or C 3 -C 10 cycloalkyi optionally substitued with 1-3 C r Q alkyi groups, or is:
  • R is hydrogen, C nowadays -C 8 heterocyciyi, or Q-Q aikyl optionally substituted with a r an ester thereof or a -CXQ aryl, C 2 -C 6 aikenyl, C 2 -C 6 alkynyl, Q-Qo cycloalkyi, or a C 3 -Cg heterocyciyl, wherein each cycioalkyi, heterocyclyl, or aryi, is optionally su bstituted with 1-3 alkyi grou ps;
  • each R° 2 independently are hydrogen,.
  • C3-C10 cycioalkyi, Ci-Cg alkyl optionally su bstituted with 1-3 substiteunts selected from the grou p consisting of -C(1 ⁇ 4H or an ester thereof, aryi, C C& heterocyciyl, or two R° "'' groups together with the nitrogen atom they are bonded to form a 5 -7 mernbered heterocyde;
  • H* 3 is hydrogen or C C 6 alkyl
  • R '" is hydrogen, C r-Ce alkyl substituted with 1-3 hydroxy groups,. -CHO, or is CO2H or an ester thereof;
  • R°* and R 66 independently are hydrogen, C C 6 alkyl. optiona lly substituted with -C(1 ⁇ 2H or an ester thereof, C3-C10 cycioalkyi, C3-Q heterocyclyl, C 2 - Cio aryi, or Q-C10 heteroaryl, or is C 3 -C 10 cycioalkyi, C 3 -C 8 heterocyciyl, C&-Ci 0 aryl, or C?-CIQ heteroaryl, wherein each cycioalkyi,.
  • heterocyclyl, ary!, or heteroaryl is optionally substituted with 1-3 alkyl groups, or R 65 and R 66 gether with the nitrogen atom they are bonded to form a 5-7 membered heterocyde, and if only one of R 65 and R 66 are defined as above, then the other one is
  • o Y 22 is -0-CO-N R 58 R 59 ;
  • the GGA derivative utilized are of formula:
  • the GGA derivatives useful according to this invention is seie from:
  • L is 0, 1, 2, or 3
  • R ' is C0 2 H or an ester thereof, or is -CH?OH f or is a CrQ alkyl ester of -CH 2 OH.
  • examples of compounds utilized by this invention include certain compounds tabulated Anlagenmoi
  • examples of compounds utilized by this invention include certain compounds tabuiated beiow.
  • Exemplary compounds include:
  • the GGA derivative is a compound of Formula (XV! II), (XIX) or (XX):
  • each R 97 , R 9S and R 99 is independently hydrogen., C- aikyl or C 5 -C 20 aryl; and each R 100 and R 101 Is independently hydrogen,, C C 6 alkyl or C fi -C 20 aryl; or R 100 and R iL together with the nitrogen to which they are attached form a C3 heterocycie;
  • each aryl group of R 97 , R 98 , R 99 , R 100 and R 101 is optionally substituted with 1-3 Ci-Ce alkyl, C-.-C & alkoxy, Ci-C 6 aikanoyi, C C 6 alkanoyloxy, C r C G alkoxycarbonyl, halo,, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, N R 102 R 103 , or S(0) R 1G:' R :l03 groups, wherein each R lu2 and R ⁇ is independently hydrogen or C C e alkyl;
  • R 1" " 4 and R i0b are independently selected from the group consisting of
  • each substituted aryl or substituted heteroaryi is independently substituted with 1-3 substituents selected from -OH, halo, Cj -C G alkyl, C r C 6 alkoxy, -N0 2 , and -NR XOO R 101 groups; or P. 104 and R 1L together with the carbon atom they are attached to form a C5-C / cycioalkyi ring optionally substituted with 1-3 C r C 6 aikyl groups;
  • R 10b and R iC independently are hydrogen or C C 6 aikyl
  • each R 108 and R 10y are independently selected from the group consisting of a
  • R iL -R i07 and n are as defined herein;
  • R' u is hydrogen or C C 6 alkyi
  • A is C C 5 aikylene which may have a substituent selected from -OH, halo, C1--G5 alkyi, and C :1 -C 6 aikoxy 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 iower (e.g. C1-C6) alky! group, optionally substituted with 1 to 4 substituents selected from the group consisting of halogen, hydroxy!; Iower alkyi; iower aikoxy; ha!ogenated lower alkyi; halogenated iower aikoxy; cyano; a 5- or 6-membered (hetero) aromatic ring which may be substituted by hydroxy!,, lower alkyi, iower aikoxy,. halogen, amino, lower aikyiamino; cyano, nitro; and other (substituted) (hetero) aromatic rings;
  • iower e.g. C1-C6 alky! group, optionally substituted with 1 to 4 substituents selected from the group consisting of halogen, hydroxy!; Iower alkyi; iower aikoxy; ha!ogenated lower alkyi; halogen
  • Rt22 is hydrogen or C1-C4 alkyi; Both the R and S configurations are encompassed.
  • R t23, Rt24 and R 125 are independently selected from hydrogen, substituted and
  • j 26 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
  • Y is -C(O)- or - wherein R 127 is hydrogen or a C- : -C alkyi group
  • the compound is formula (XVIII):
  • ⁇ . 1 ⁇ and R lUl 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 thiomorpho!ino ring,
  • the GGA derivative utilized is of formula (X!Xa):
  • R" and R i J each represent a hydrogen atom, a lower aiky!, cycioalkyl, aikenyi or alkynyl group, an aryi group which may be substituted, an aryialkyi group in which the ary! group may be substituted, or a heteroaryl or heteroarylalkyl group:
  • R lu8 and lUy each represent a hydrogen atorn, a lower alkyi group or an alkali metal;
  • Y represents a group represented by the formula:
  • R i3 ° and R 31 each represent a hydrogen atom, a lower alkyi group or an alkali meta! or a group represented by the formula : --CO?
  • R 1 " (wherein R 132 represents a hydrogen atom,, a Iower alkyi group or an alkali metal );
  • R 1 represents a hydrogen atom or a Iower alkyi 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.
  • Exemplary compounds further include
  • trans forms of GGA and GGA derivatives utilized herein can be replaced with the various corresponding cis forms and utilized in accordance with this invention.
  • Such compounds can be in solely or substantially, such as at least. 90%, at seat 80%, at least 70%, at least 50% or at least 20% in the cis form.
  • various mixtures of cis and trans forms of GGA and GGA derivatives are also useful in accordance with this invention.
  • GGA and GGA derivatives containing substantially or so!e!y 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.
  • illustrative and nonlimitlng anticancer agents and conjugates and their methods of synthesis are shown below.
  • Illustrative and noniimiting viral agents, such as Vidarabine, and conjugates and their methods of synthesis are also shown below.
  • antiviral drugs may be attached in simiiar fashion to the GG-a!cohoi or GG-acetone.
  • GGA derivatives can he 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 wit! be apparent to the skilled artisan upon reading this disclosure, for a sufficient period of time to ensure substantial com pletion of the reaction as observed by thin layer chromatography, X H- R, 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 a re purified, if necessary, by various art known methods such as crystallization, precipitation, colu mn chromatography, and the likes, as will be apparent to the skilled artisan upon reading this disclosure.
  • a compound of Formula (HI ), where n is 2, is synthesized by repeating the reaction sequence of alkylatiori with a beta-keto ester, hydrolysis, decarboxylation, Wittig-Horner oSefirtation, and Li.AiH reduction.
  • R R 6 " i inn tthhee sscchheemmeess bbeell ⁇ ow may also correspond to R*° and R S : as defined herein.
  • R in the schemes below may also correspond to R 26 , R 31 and R 52 as defined herein.
  • P.° in the schemes below may also correspond to R 2 ', R : " and R 5;i as defined herein.
  • R 'J in the scheme below may also correspond to R 28 . 3I and R M as defined herein.
  • R i3 in the schemes below may also correspond to R b as defined herein.
  • * in the schemes below may also correspond to R to as defined herein.
  • R 15 in the schemes below may also correspond to R°° as defined herein.
  • R" c in the schemes below may also correspond to R ' 4 , R : and R n'! as defined herein.
  • R 19 in the schemes beiow may also correspond to R**, R 33 and R" 4 as defined herein.
  • L is a leaving group as known to one of ordinary skill in the art.
  • R E is a!kyl
  • Compound f ix) with alcohol functionality is an intermediate useful for preparing the compounds utilized in this invention.
  • Compound (x), where L is an R'S0 2 - group is made by reacting compound (ix) with R/'SC ⁇ CI in the presence of a base.
  • the transformation of compound (iii) to compound (x) illustrates methods of adding isoprerse derivatives to a compound, which methods are suitable to make compound (iii) from compound (i).
  • m is 0 or 1 and Fc-R J are as defined herein, and are preferably aikyl, 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 in this invention by reacting with suitable isocyanates or carbamoyl chlorides, which are prepared by art known methods.
  • 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, aikoxides, and the like.
  • Various compounds utilized in this invention, wherein the carbonyl group is converted to an irnine, a hydrazone, an alkoxyimine, an enolcarbamate, a ketal, and the like, are prepared following well known methods.
  • the metaliation is performed, by reacting the ketone with a base such as dimsyl anion, a hindered amide base such as diisopropy!amide, or hexarnethyidisiiazide, along with the corresponding metai cation, M.
  • a base such as dimsyl anion, a hindered amide base such as diisopropy!amide, or hexarnethyidisiiazide
  • the amino carbonyl chioride or the isocyanate is prepared, for example, by reacting the amine (R j4 ) 2 NH with phosgene or an equivalent reagent well known to the skilled artisan.
  • the beta keto ester is hydroiyzed 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 carbonyi diimodazoie, or 0-Benzotriazole-N,N,N',N'- tetramethyl-uroniurn-hexafluoro-phosphate (HBTU) and reacted with the amine.
  • acid activating agent well known to the skilled artisan such as carbonyi diimodazoie, or 0-Benzotriazole-N,N,N',N'- tetramethyl-uroniurn-hexafluoro-phosphate (HBTU)
  • R L is alkyi
  • hydrazide a hydroxyiamine, an amino alcohoi, or an amino acid
  • the allylic alcohol fix) is oxidized to the aldehyde (xi), which is then reacted with a cyanohydrin or
  • GGA derivatives utilized in this invention can also be synthesized employing art known methods and those disclosed here by a!kene-aryi, alkene-heteroaryl, or aikene-akene couplings such as Heck, Stille, or Suzuki coupling. Such methods can use (vi) to prepare intermediate fxii) that can undergo Heck, Siilie, or Suzuki coupling under conditions well known to the skilled artisan to provide compounds utilized in this invention .
  • L is a leaving group and '3 ⁇ 4 are as defined herei n
  • Ar is a preferably an aryl group such as phenyl
  • the base employed is an alkoxide such as tertiarybutoxide, a hydride, or an alky! lithium such as n-butyl lithium.
  • the metaliation is performed, by reacting the ketone with a base such as dimsyl anion, a hind ered am ide base such as diisopropylamide, or hexamethyldisiiazide, along with th e correspond ing metal cation, M.
  • a base such as dimsyl anion, a hind ered am ide base such as diisopropylamide, or hexamethyldisiiazide
  • the amino carbonyi chloride or the isocyanato is prepared, for example, by reacting the amine R l R ** 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 we!i known to the skilled artisan such as carbonyi diimodazole, or O-Benzotriazole- ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethy!-uronium-hexafluoro-phosphate (HBTU) and reacted with the amine.
  • acid activating agent we!i known to the skilled artisan such as carbonyi diimodazole, or O-Benzotriazole- ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethy!-uronium-hexafluoro-phosphate (HBTU)
  • R is a memantine or a ri!uzo!e residue.
  • Polyprenyl amine- GGA derivatives can be prepared by reductive amination employing the appropriate polyprenyl aldehyde, a primary or secondary amine and a borohydride reducing agent, as is weii known to the skilled artisan.
  • the reaction can be carried out in THF or diethyl ether, optionally in presence of a protic acid, preferably a mild protic acid catalyst,
  • Ciprofloxacin conjugate Ciprofloxacin conjugate
  • Betaxoiol Z protecting qroup
  • this invention provides and/or utilizes a composition comprising a GGA or a GGA derivative provided herein and a pharmaceutically acceptable excipient.
  • compositions can be for muiated for different routes of administration.
  • Suitable dosage forms for admin istering the GGA or GGA derivatives of this in vention include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and ora l liqu ids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used, for example, in a transdermal patch form .
  • Ail dosage forms may be prepared using methods that are standa rd in the a rt (see e.g., Rem ington's Pharmaceutical Sciences, 16 th ed ., A. Oslo ed itor, Easton Pa. 1980) .
  • Pharmaceutically acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this invention, Such excipients may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • 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 preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanoi,. 1,2- propyiene glycol, poiygiycols, dimethyisulfoxide, fatty alcohols, triglycerides, partial esters of glycerin and the like,
  • Solid pharmaceutical excipients include starch, cellulose, hydroxypropyi 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, ethanoi and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil,, mineral oil, sesame oil, etc. in certain embodiments, the compositions provided or utilized herein comprises one or more of ct-tocopherol, gum arabic, and/or hydroxypropyi cellulose,
  • this invention provides or utilizes sustained release
  • the patch further comprises gum Arabic or hydroxypropyi cellulose separately or in combination, in the presence of alpha- tocopherol.
  • the hydroxypropyi cellulose has an average MW of from 10,000 to 100,000. in a more preferred embodiment, the hydroxypropyi cellulose has an average MW of from 5,000 to 50,000.
  • this invention provides pharmaceutical compositions in the form of an enterocoated capsule or tablet that facilitates increased delivery of GGA to the intestine.
  • Compounds and pharmaceutical compositions of this invention maybe used alone or In combination with other compounds.
  • the co-administration can be in any manner in which the pharmacological effects of both are manifest in the patient at the same time.
  • 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 compou nd of this invention and the other agent or that the two agents be administered at precisely the same time.
  • co-administration will be accomplished most conveniently by the same dosage form and the same route of administration, at substantially the same time. Obviously, such administration most advantageously proceeds by delivering both active ingredients simultaneously in a novel pharmaceutical composition in accordance with the present invention.
  • a composition suitable for intranasal administration for treatment of a neural disease, disorder or condition or for reducing the negative effects of a neural disease, disorder or condition, where the composition Includes GGA, preferably ail trans GGA, or a GGA derivative as described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for introducing GGA and/or derivatives thereof via the intranasal route into a subject.
  • the intranasal dosage form may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16 Lh ed., A. Oslo editor, Easton Pa. 1980).
  • 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%.
  • intranasal administration has not gained wide acceptance.
  • all therapeutic agents cannot be effectively administered by the intranasal route.
  • the molecules which have proved suitable for this route of administration are still very few and consist essentially of only small peptide or hormone molecules (such as calcitonin, cerulean, .beta. -endorphin, glucagon, horseradish peroxidase, B-interferon , oxytocin and insulin) in special formulations.
  • small peptide or hormone molecules such as calcitonin, cerulean, .beta. -endorphin, glucagon, horseradish peroxidase, B-interferon , oxytocin and insulin
  • the ability of drug molecules to be absorbed by the nasal mucous membranes is utterly unpredictable, as is the ability of intranasal formulations to avoid irritation of the mucous nasal membranes. Mucous membrane a? irritation caused by the drug and/or excipient is the most common reason
  • compositions according to the Invention include GGA or a derivative thereof in quantities ranging from 1-55, 5-50, 10-40, or 20-30 mg/kg/day, diluted in excipienis such as huniectants, isotoning agents, antioxidants, buffers and preservatives.
  • excipienis such as huniectants, isotoning agents, antioxidants, buffers and preservatives.
  • a calcium chelating agent is also preferably included.
  • the invention makes It possible to have single-dose dosage forms, which ensure application of an optimum quantity of GGA or a derivative thereof.
  • the intranasal formulations of the invention contain concentrations of GGA or a derivative thereof ranging from 0.1 to 20%, preferably about 5-10% weight/volume. Selection of the particular excipienis depends on the desired formulation dosage form, i.e., on whether a solution to be used in drops or as a spray (aeroso! Is desired or a suspension, ointment or gel to be applied in the nasal cavity are desired.
  • Vehicles useful in the compositions according to the invention comprise solvent systems containing ethyl alcohol, isopropyi alcohol, propylene glycol, polyethylene glycol, mixtures thereof or mixtures of one or more of the foregoing with water.
  • Suitable vehicles for the formulations according to the invention include aqueous suspensions or emulsions containing an appropriate isotoning agent selected among those commonly used in pharmaceutics. Substances used for this purpose are, for instance, sodium chloride and glucose. The quantity of isotoning agent should impart to the vehicle (taking Into account the osmotic effect of the active ingredient), an osmotic pressure similar to that of biological fluids, i.e. generally from about 350 to about 850 ml!!IOsmoies (mOsm) preferably from about 270 to about 330 mOsrn,
  • Nasal mucous membranes are also capable of tolerating slightly hypertonic solutions. Should a suspension or gel be prepared instead of a solution, appropriate oily or gel vehicles may be used or one or more polymeric materials may be included, which desirably should be capable of conferring bioadhesive characteristics to the vehicle.
  • Several polymers may be used for the preparation of a gel; nonlimiting examples include hydroxypropyl celluiose ( LUCEL ® ), hydroxypropyl methyl cellulose (ETHOCEL ® ). hydroxyethyl cellulose (NATROSGL ® ), sodium carboxymethyl celluiose (BLANOSE ® ), acrylic polymers (CARBOPOL ® , POLYC A BO P H i L ® ) , gum xantban, gum tragacanth, alginates and agar-agar. [02.3.1] Some of them, such as sodium carboxymethyl cellulose and acrylic polymers, have marked bioadhesive properties and are preferred if bioadhesiveness is desired.
  • formulations suitable for intranasal administration of GGA or a derivative thereof can be obtained by adding to the aqueous vehicle polymers capable of changing the rheologic behavior of the composition in relation to the temperature.
  • These polymers make it possible to obtain low viscosity solutions at room temperature, which can be applied for instance by nasal spray and which increase in viscosity at body temperature . , yielding a viscous fluid which ensures a better and longer contact with the nasal mucous membrane.
  • Polymers of this class include without limitation polyoxyethyiene-polyoxypropylene block copolymers (POLOXA ER*).
  • the formulation is a small particle liposome or lipid complex aerosol formulation. Methods of preparing such formulation are within the skill of the skilled artisan. See, for example, US 6,090,407.
  • a pharmaceutically acceptable buffer is present to stabilize a pH range of about 4 to about 8; preferably about 5.5 to 7.5.
  • Suitable non-limiting buffers include tris (tromethamine) buffer, phosphate buffer, etc.
  • compositions according to the invention preferably contain preservatives which ensure the microbiological stability of the active ingredient. Suitable preservatives include without limitation, methyl
  • liquid formulations of GGA or a derivative thereof may be administered from a nasal spray devise of this invention comprising GGA or a GGA derivative, in the form of drops or spray, using atomizers equipped with a
  • Vehicles suitable for spray administration are water, alcohol, glycol and propylene glycol, used alone or in a mixture of two or more, in some embodiments, this invention provides muftidose nasa! spray devices, in other embodiments, this invention provides unit dose nasal spray devices.
  • illustrative and non-limiting formulations can contain the following ingredients and amounts (weight/volume):
  • ingredients such as sodium carboxymethyl cellulose and Carbopol exist in many types differing in viscosity. Their amounts are to be adjusted accordingly. Different adjustments to each formulation may aiso be necessary including omission of some optional ingredients and addition of others, !t is thus not possible to give an ail-encompassing amount range for each ingredient., but the optimization of each preparation according to the invention is within the skill of the art.
  • compositions including GGA or a derivative thereof comprises a suspension of finely micron ized active ingredient (generally from 1 to 200 micrometers, preferably from 5 to 100 micrometers) in a propellant or in an oily vehicle or in another vehicle in which the drug is not soluble.
  • the vehicle is mixed or emulsified with the propellant.
  • Vehicles suitable for this alternative are, for instance, vegetable and mineral oils and triglyceride mixtures.
  • Appropriate surfactants, suspending agents and diluents suitable for use in pharmaceutics are added to these vehicles.
  • Surfactants include without limitation sorbitan sesquioieate, sorbitanmonooieate.
  • sorbitan trioleate (amount: between about 0.25 and about 1%);
  • suspending agents include without limitation isopropylmyristate (amount: between about 0.5 and about 1%) and colloidal silica (amount: between about 0.1 and about 0.5%);
  • diluents include without limitation zinc stearate (about 0.6 to about 1%).
  • a pharmaceutical composition comprising GGA or a GGA derivative and a-tocopherol.
  • a related embodiment provides and/or utilizes a pharmaceutical composition comprising GGA or a GGA derivative, a-tocopherol, and hydroxypropyl cellulose, in another embodiment, there is provided or utilized a pharmaceutical composition comprising GGA or a GGA derivative, a-tocophero!, and optionally gum arable.
  • a pharmaceutical composition comprising GGA or a GGA derivative, and gum arable
  • 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 a- 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 hydroxypropyi 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, !n some embodiments, the
  • concentration of hydroxypropyi 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 GGA or 3 GGA 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% by weight.
  • solid dosage forms may further include, granules, pellets, beads, spheroids, a minitablet, a microtablet, granules in a capsule, pellets in a capsule, microtablets in a capsule, and minitablets in a capsule, each of which may be enteric coated, [0246]
  • the enteric formulations provide herein are useful for treating or alleviating the negative effects of various neurological diseases and disorders described herein and inflammatory bowel disease, chronic liver disease, a disorder selected from liver injury, preferably acute liver injury, acute liver failure, cardiac ischemia, myocardial infarction, repurfusion injury and heart transplants, or a related disorder or condition.
  • compositions of the present invention may be prepared using conventional methods and materials known in the pharmaceutical arts.
  • Enteric polymers used to coat pharmaceutical dosage forms include cellulose, vinyl, and acrylic derivatives. Enteric polymeric materials are primarily weak acids containing acidic functional groups, which are capable of ionization at elevated pH.
  • the enteric coating coats a core of a dosage form disclosed herein and controls the location in the digestive tract where the active agent contained in the dosage form's core Is released and absorbed.
  • the enteric coating is In the form of one or more components selected from the group including polymers, fatty acids, waxes, shellac, plastics, and plant fibers.
  • the enteric coating comprises one or more of the following: acrylates and acrylate copolymers, including methacry!ic acid/methacryiic acid methylester copolymer and methacrylic acid/ethyl acrylate copolymer; cellulose esters, including cellulose acetate phthalate, cellulose acetate trimeilitate, and cellulose acetate succinate; hydroxypropyl methylceliuiose phthalate; hydroxypropyi methy!ceflulose acetate succinate; polyvinyl derivatives, including polyvinyl acetate phthalate; and carboxymethyl ethyl cellulose.
  • the enteric coating includes one or more components sold under trade names, for example EM COAT 120 N, MARCO AT 125,
  • the enteric coating may comprise colorants, in a specific embodiment, the enteric coating comprises a EU DRAG IT ® polymer and a colorant, and is sold under the trade name ACRYL-EZE ORANGE 8 .
  • the enteric coating may further comprise a pfasticizer, !n some embodiments, the plasticizer will influence, i.e., increase or decrease, the rate of dissolution of the enteric coating.
  • the plasticizer may be lipophilic, in other embodiments, the plasticizer may be hydrophiiic.
  • the piasticizer comprises one or more of the group including cetano!, triacetin, citric acid esters such as triethy! citrate, phthalic acid esters such as diethyl phthaiate and dibutyl phthalate, dibutyl succinate, propylene glycol, polyethylene glycol (PEG), and oils and giyeerides such as fractional coconut oil.
  • Exemplary and non!lmiting coating formulations include excipients as illustrated below:
  • a compound of this invention can be used as an adjunct to conventional drug therap of the conditions described herein.
  • neural diseases are characterized by neuroinflammation.
  • neu ral diseases include, but are not limited to, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, multiple sclerosis, prion diseases such as Kuru, Creutzfeltdt-Jakob disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, and damage to the spinal cord.
  • Also provided herein in some embodiments is a method of treating visual disorders such as optic neuropathy, glaucoma, degeneration of optic nerves, age-related macular degeneration (AMD) and ophthalmoplegia.
  • Some embodiments described herein provide a pharmaceutical formulation for preventing neural death during epileptic seizures. Any pharmaceutical formulation and/or compounds described above are useful in the methods described herein.
  • GGA is the trans-GGA or the synthetic trans-GGA.
  • methods provided here in describe impeding the progression of neural diseases or injury using GGA or a derivative thereof.
  • neural diseases result in an impairment of signaling between neurons. In some cases, this impairment is due in part to a reduction in the growth of axonal projections, in some embodiments, contacting neurons with GGA or a derivative thereof enhances axonal growth. In some embodiments, GGA or a derivative thereof restores axonal grown in neurons afflicted with a neural disease, in a related embodiment, the pre-contacted neurons exhibit a reduction in the axon growth ability.
  • One embodiment provided herein describes a method for inhibiting the cell death of neurons susceptible to neuronal ceil death, which method comprises contacting said neurons with the pharmaceutical compositions provided or utilized herein.
  • Neurons susceptible to neuronal cell death include those that have the characteristics of a neural 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.
  • Oxidative stress can occur from neuronal disease or injury, it is contemplated that contacting neurons with GG.A or a derivative thereof will inhibit their death as measured by a MTT assay or other techniques commonly known to one skilled In the art.
  • GG.A GG.A
  • MTT assay MTT assay
  • the term "neurite” refers to both axons and dendrites.
  • Neural diseases can result in an impairment of signaling between neurons. In some cases, this impairment is due in part to a reduction in the growth of axonai and/or dendritic projections.
  • contacting neurons with GGA or a derivative thereof will enhance neurite growth. It is further contemplated that GGA or a derivative thereof 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 of this invention is directed to a method for increasing the expression and/or release of one or more neurotransmitters from a neuron fay contacting said neurons with the pharmaceutical compositions provided or utilized herein, it is contempiated that contacting neurons with an effective amount of GGA. and/or derivatives thereof will increase the expression level of one or more neurotransmitters. It is also contemplated that contacting neurons with GGA or a derivative thereof 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 ceil membrane, which directs the
  • neurotransmitters out of the neuron It is contemplated that the increase in the expression and/or release of neurotransmitters will lead to enhanced signaling in neurons, in which levels of expression or release of neurotransmitters are otherwise reduced due to the disease.
  • the increase in their expression and release can be measured by molecular- techniques commonly known to one skilled in the art.
  • One embodiment of this invention is directed to a method for inducing synapse formation of a neuron by contacting said neurons with the pharmaceutical compositions provided or utilized herein.
  • 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 GGA or a derivative thereof, via intranasal administration, will Increase synapse formation in neurons that otherwise experience reduced synapse formation as a result of neural disease.
  • Another embodiment of this invention is directed to a method for increasing electrical excitability of a neuron by contacting said neurons with the pharmaceutical compositions provided or utilized herein. Electrical excitation is one mode of
  • GGA GGA
  • intranasal administration contacting neurons with an effective amount of GGA or a derivative thereof, via intranasal administration, 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 electrophysiological methods commonly known to one skilled in the art.
  • the intranasal administration of GGA or a derivative thereof 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.
  • I ncipient 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 via intranasal the route to said patient an effective amount of GGA or a derivative thereof.
  • this invention 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 the pharmaceutical compositions provided or utilized herein, 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, in one embodiment of this Invention, 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 uch as neuroblastoma cells. It is contemplated that contacting neurons with an effective amount of GGA or a derivative thereof, via intranasal administration, will inhibit their death as measured by a MTT assay or other techniques commonly known to one skilled In the art.
  • Another embodiment of the invention 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 the pharmaceutical compositions provided or utilized herein, in one embodiment of this invention, contacting said neurons and/or said pathogenic protein aggregates with the pharmaceutical compositions provided or utilized herein.
  • contacting the neurons and/or the pathogenic protein aggregates with GGA or a derivative thereof, via intranasal administration will soiubifize at least a portion of the pathogenic protein aggregates residing between, outside, or inside of the ceils.
  • contacting the neurons and/or the pathogenic protein aggregates with GGA or a derivative thereof, via intranasal administration will aiter 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 ceil viability by a TT assay.
  • Another example is by immunostaining neurons in vitro or in vivo for ceil death-indicating molecules such as, for example, caspases or propidium iodide.
  • in yet another embodiment of the invention is directed to a method for protecting neurons from pathogenic intracellular protein aggregates which method comprises contacting said neurons with the pharmaceutical compositions provided herein 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.
  • SB A 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 polyglutamtnes and are formed intranucleariy. It is also distinct, from the neural diseases described in this application because the protein aggregates are formed from androgen receptor protein accumulation. It is contemplated that contacting neurons via intranasal administration with an effective amount of GGA or a derivative thereof will alter the pathogenic protein aggregate into a non-pathogenic form.
  • One embodiment of the invention is directed to a method of modulating the activity of G proteins in neurons which method comprises contacting said neurons with the pharmaceutical compositions provided or utilized herein. It is contemplated that contacting neurons via intranasal administration with an effective amount of GGA or a derivative thereof will alter the sub-ceiiutar localization, thus changing the activities of the G protein in the DCi.
  • contacting neurons via intranasal administration with an effective amount of GGA and/or derivatives thereof will enhance the activity of G proteins in neurons
  • contacting neurons via intranasal administration with an effective amount of GGA or a derivative thereof will increase the expression level of 6 proteins
  • contacting neurons via intranasal administration with an effective amount of GGA or a derivative thereof 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 of the invention 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 the pharmaceutical compositions provided or utilized herein, 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
  • 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 via intranasal administration with an effective amount of GGA or a derivative thereof
  • an effective amount of GGA or a derivative thereof 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 of the invention is directed to a method for inhibiting the neurotoxicity of ⁇ -amy!oid peptide by contacting the ⁇ -amy!oid peptide with the
  • the ⁇ - amyioid peptide is between or outside of neurons.
  • the ⁇ -amyloid peptide is part of the ⁇ -amyloid plaque, it is contemplated that contacting neurons via intranasal administration with an effective amount of GGA or a derivative thereof will result in solubilizing at least a portion of the ⁇ -amyloid peptide, thus decreasing its neurotoxicity. It is further contemplated that an effective amount of GGA or a derivative thereof will decrease the toxicity of the ⁇ -amyloid peptide by altering it in such a way that it is no longer toxic to the cell.
  • HSPs heat shock proteins
  • 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 !VITT 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 of the invention is directed to a method for inhibiting neural death and increasing neural activity in a mamma! 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 the pharmaceutical compositions provided or utilized herein.
  • This method is not intended to inhibit neura! death and increase neura! activity in neura! diseases in which the pathogenic protein aggregates are intranuclear or diseases in which the protein aggregation is related to SB A.
  • Neural diseases such as AD and ALS disease have the common characteristic of protein aggregates either inside neura! ceils in cytoplasm or in the extracellular space between two or more neural cells.
  • This invention relates to a method for using, via intranasal administration, an effective amount of GGA or a derivative thereof to inhibit the formation of the protein aggregates or alter the pathogenic protein aggregates into a nonpathogenic form, !t is contemplated that this will attenuate some of the symptoms associated with these neural diseases.
  • the mammal is a human afflicted with a neural disease
  • the negative effect ot 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. It is contemplated that an effective amount of GGA and/or derivatives thereof will prevent or inhibit the formation of extracellular or intracellular protein aggregates that are cytoplasm, not intranuclear and not related to SBMA. ft is also contemplated that an effective amount of GGA or a derivative thereof wili alter the pathogenic protein aggregates into a form that is non-pathogenic.
  • AD is a neurodegenerative disease that does not typically show intranuclear protein aggregates. It is contemplated the intranasal administration of an effective amount of GGA or a derivative thereof will prevent or inhibit the formation of extracellular or intracellular protein aggregates. St is also contemplated that the intranasal administration of an effective amount of GGA or a derivative thereof 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 U.S. 6,130,048 and U.S. 6,391,553 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 intranasal administration of an effective amount of GGA or a derivative thereof will enhance the motor skills and body weights when administered to a mouse with a mutant Sodl gene, it is further contemplated that the intranasal administration of an effective amount of GGA or a derivative thereof 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. in yet another embodiment of this invention, the neural disease is AD.
  • transgenic mouse model for AD is a mouse that overexpresses the APP (Amyloid beta Precursor Protein), It is contemplated that the intranasal administration of an effective amount of GGA or a derivative thereof to a transgenic AD mouse will improve the learning and memory skills of said mouse. It is further contemplated that the intranasal
  • ⁇ -amy!oid peptide and/or plaque found inside, between, or outside of neurons.
  • the ⁇ -amyloid peptide or plaque can be visualized in histology sections by imrnunostaining or other staining techniques.
  • the intranasal administration of an effective amount of GGA or a derivative thereof to a mammal alters the pathogenic protein aggregate present into a non-pathogenic form, in another embodiment of the invention.
  • intranasal administration of an effective amount of GGA or a derivative thereof to a mammal will prevent pathogenic protein aggregates from forming.
  • Another aspect of this invention relates to a method for reducing seizures in a mamma! in need thereof, which method comprises administering the pharmaceutical compositions provided or utilized herein, thereby reducing seizures.
  • the reduction of seizures refers to reducing the occurrence and/or severity of seizures.
  • the seizure is epileptic seizure.
  • the methods of this invention prevent neural death during epileptic seizures.
  • the severity of the seizure can be measured by one skilled in the art.
  • an intranasal formulation of GGA or a derivative thereof described herein exerts cytoprotective effects on a variety of organs, e.g., the brain and heart.
  • organs e.g., the brain and heart.
  • Tanito M, et a!. J Neurosci 2005; 25:2396-404; Fujiki , et at., J Neurotrauma 2006; 23:1164-78; Yasuda H, et a!., Brain Res 2005; 1032:176-82; Ooie T, et a!., Circulation 2001; 20; 104:1837-43; and Suzuki S, et a!., Kidney Int 2005; 67:2210-20).
  • the time course of protein expression was determined in triplicate for hippocampus, and cortex tissue samples taken from each of * 5 animals per group at each of four time points (24, 48, 72, and 96 h) after treatment with either PBS or 12 mg/kg CNS-102, administered orally.
  • the average expression for each treatment group is calculated at each time point for each tissue using PROC MIXED in SAS and are tabulated, along with the difference (delta) between treatment averages and a p- vaiue comparing the difference to zero, below.
  • HSP70 protein expression was determined for lung, testicle, spleen, liver, kidney, blood plasma, skin, peripheral blood monocytes, heart, eye, muscle, intestine,, and stomach at each of three time points (8h, 17h, 2 li),
  • Example 2 Treatment of Inflammatory Bowel Disease (IBP) with GGA or a GGA derivative.
  • IBP Inflammatory Bowel Disease
  • a pharmaceutical composition comprising GGA or a GGA derivative as described herein is prepared.
  • a subject is diagnosed with mild to moderate IBD.
  • the subject receives a daily administration of GGA or a GGA derivative, or a pharmaceutically acceptable salt thereof.
  • Subjects are treated for 12 weeks.
  • Subjects keep daily diaries and record the number and nature of bowel movements.
  • the effect of the treatments is assessed by grading clinical symptoms of fecal blood, mucus, and urgency.
  • sigmoidoscope assessment and biopsies are performed, and efficacy of treatment assessed, based on grading of sigmoidoscope and degree of histological inflammation in rectal biopsy specimens. Safet Is assessed based on spontaneous side effect reporting.
  • a pharmaceutical composition comprising GGA or a GGA derivative as described herein is prepared.
  • a subject is diagnosed with mild to moderate IBD following
  • gastrectomy The subject receives a daily administration of GGA or a GGA derivative, or 3 pharmaceutically acceptable salt thereof. Subjects are treated for 12 weeks. Subjects keep daily diaries and record the number and nature of bowel movements. The effect of the treatments is assessed by grading clinical symptoms of fecal blood, mucus, and urgency, in addition, sigmotdoscopic assessment and biopsies are performed, and efficacy of treatment assessed., based on grading of sigmoidoscopic and degree of histological inflammation in rectal biopsy specimens. Safet is assessed based on spontaneous side effect reporting.
  • GGA or a GGA derivative, or a pharmaceutically acceptable salt thereof, of this example will demonstrate efficacy in Inflam matory bowei disease IBD in terms of both treating the condition and maintaining remission from disease symptoms.
  • Example 4 GGA and derivatives thereof protect intestinal epithelial cells from oxidative stress in yit . ro.
  • Rat intestinal epithelial cell line (IEC-18) ceils are pretreated with GGA or a GGA derivative and then subjected to injury induced by H 2 CI. Ceil viabilit is assessed, and endogenous HSP70 levels are determined by enzyme-linked immunosorbent assay in IEC-18 cells. Treatment with GGA or a derivative thereof rapidly elevates HSP70 levels and protects against H 2 CI-induced injury in IEC-18 cells.
  • Example 5 GGA and GGA derivatives protect mice from dextrars sulfate sodium (OSS) - induced colitis.
  • SALS/c mice are given 3% DSS solution oraily for 7 days to induce colitis.
  • the disease activity of colitis is assessed clinically every day, and histology in the colon is evaluated at 7 days post-DSS.
  • the levels of myeloperoxidase (fvlPO) activity, tumor necrosis factor (TNF)- aipha and interferon (IFN)-gamma in the colon tissues are also examined, in addition, expression of HSPs 25, 40, 70 and 90 in the colon tissue is determined by Western blot analysis or ELISA.
  • GGA or a GGA derivalive is administered orally to mice when treatment of DSS is initiated.
  • GGA or a derivateive thereof significantly reduces the clinical severity of colitis and suppresses the levels of MPO activity, TNF-alpha and IFN-gamma induced by DSS in the colon.
  • GGA enhances the expression of HSP70 in the colon of mice given DSS.
  • j tagm!g 6 Preyjentjon of acute liver damage after hepatectomy.
  • GGA or a GGA derivative as an emulsion with 5% gum arabic and 0.004% a-tocophenoi
  • vehicle 5% gum arabic emulsion with 0,004% a- tocophenol
  • rats are anesthetized, 90% hepatectomy is performed. Briefly, the left, median, right-upper, and right-lower lobes are removed, leaving the caudate lobes, which represent 10-11% of the original liver mass.
  • liver specimens and blood samples are collected after laparotomy and exsanguinations under deep anesthesia immediately before (0) and 4, 8, 12, and 24 h after the operation.
  • Small pieces of liver tissue are immediately stored in an RNeasy stabilization kit (Gjagen, Hilden, Germany), Sera are immediately separated, and the activities of alanine (ALT) and aspartate (AST) aminotransferases are measured,
  • GGA or GGA derivative significantly suppresses the release of aminotransferases and improves survival compared with vehicle administration.
  • Gene expression and immunobiot analyses shows that, in addition to HSP70 and HSP27, GGA or GGA derivatives induce an endoplasmic reticulum chaperone, BiP.
  • acetaminophen-induced hepatotoxicity a cytotoxicity assay is employed using human hepatoma (Bel-7402) cells in the presence of S9 mixture.
  • Cell viability and mitochondrial permeability transition is assessed in the presence or absence of GGA or GGA derivatives in combination with a cytotoxic concentration of acetaminophen.
  • GGA or GGA derivatives show increased cell viability and protect from MPT disruption in the presence of acetaminophen compared with control conditions.
  • Example 8 Treatment of nori-alcohoiic steatohepatitSs.
  • a randomized, blinded, placebo-controlled study is performed on 100 patients with NAFLD diagnosed by ultrasound (US) and confirmed by liver biopsy (40 patients).
  • the patients are randomized to receive GGA or a GGA derivative (each at a daily dose of 10-200 mg for up to 12 months) or placebo. All patients participate in an identical behavioral weight loss program, and undergo monthly evaluation by abdominal US. Liver enzyme levels, lipid profiles, insulin levels, and anthropometric parameters are also monitored, and all patients undergo nutritional follow-up evaluation. Patients also undergo a further liver biopsy examination as the study progresses. Serum alanine transaminase levels and steatosis by US are measured as non-limiting endpomts. The results are analyzed following methods well known in the art.
  • Example 10 GGA and GGA derivative activity in a cardiac ischemic ischemia and reperfusion in vitro model
  • ischemia/reperfusion cardiac disease model based on the contractile HL-1 cell line. Activity is assessed via apoptosis signaling, ceil structure and energy-metabolism.
  • cardiornyocytes (murine atrial tumor cell line) are maintained in mono!ayer culture with Claycomb-medium (Sigma, Germany), Heaving reached confluence and contractile activity, cells are maintained as subcultures, induction of ischemia was carried out on vital cardiornyocytes at culture day four.
  • the subconfluent, contractile HL-1 cardiornyocytes are placed in nutrient-deficiency medium containing 2.5 mM hydrogen peroxide solution in order to enhance the oxidative stress in HL-1 cells. In control cultures the medium exchange is carried out with standard supplemented Claycomb-medium.
  • Total number of ceils are determined using 7-AAD nucleus staining, Additionally formaldehyde- fixed cells on glass coverslips are prepared for immuncytochemicai staining, TUNEL assay is performed using an In Situ Ceil Death Detection Kit, GGA and GGA derivatives reduce ischemia induced apoptosis and rescue ischemia-induced reduction of ceil proliferation.
  • Example 11 GGA and GGA derivatives protect against myocardial ischemia and
  • Anesthetized male rats are treated once orally with GGA or a GGA derivative 2.4 h before ischemia, and subjected to ischemia for 30 min, followed by reperfusion for A h. Lactate dehydrogenase (LDH), creatine kinase (CK), malondialdehyde (M DA), superoxide dismutase (SOD) activity and infarct size are measured.
  • LDH Lactate dehydrogenase
  • CK creatine kinase
  • M DA malondialdehyde
  • SOD superoxide dismutase
  • Example 12 Host shock protein 70 induced by GGA or GGA derivative protects
  • a total of 20 donor rats are randomly divided into 2 groups. One of those receives an oral dose of GGA or a GGA derivative and one is a control group.
  • Donor hearts are heterotopically transplanted into recipient rats 24h after GGA administration.
  • the levels of HSP70 expression In donor hearts and the variation of myocardial enzymes in receptor biooci or donor hearts are measured 24 h after transplantation.
  • the donated hearts are also examined under a microscope for pathological changes.
  • HSP70 expression is increase in the GGA-treated group. Lactate dehydrogenase and creatine kinase m uscle band concentrations in receptor blood are decreased in the GGA group compared to the control group.
  • the GGA group shows the lower malondialdehyde concentration and the h igher atriphosphate concentration than the control group, demonstrated by the milder inflammatory Injury in the transplanted hearts.
  • Example 13 Treatment of Cardiac Ischemia and Related indications.
  • a randomized, blinded, placebo-controlled study is performed on 100 patients diagnosed with cardiac ischemia, myocardial infarction or acute coronary syndrome based on coronary angiograms.
  • the patients are randomized to receive GGA or a GGA derivative (each at a daily dose of 10-200 mg for up to 12 months) or placebo.
  • GGA or a GGA derivative is directl administered, e.g.. in an emergency room setting, to the coronary artery via a PCI/stent catheter followed by oral administration of GGA or a GGA derivative for several weeks.
  • GGA or a GGA derivative occurs during percutanous intervention (PCI) vvhiie stenting through a catheter directly to the coronary artery and the site of infarction.
  • Oral treatment follows preferably for at least 1 month following the heart attack. The incidence of angina is ascertained , The results are analyzed following methods well known in the art.
  • GGA or a GGA derivative 0, 1-20% 10- 2, .000 g
  • the isotonicity of this composition can be adjusted, if needed, by the addition e.g.,. of 0.3% NaCI or 2.03% of glucose.
  • Example . 15 Argatroban conjugates of GGA or a GGA derivative Described below are representative synthetic routes to small molecule e.g., Argatroban conjugates of GGA or a GGA derivative. Methods for synthesizing these Argatroban conjugates will be apparent to the skilled artisan in view of this disclosure.
  • Example 16 Zofran conjugates of GGA or a GGA derivative Described vide are representative synthetic routes to small molecule e.g.,. Zofran conjugates of GGA or a GGA derivative. Methods for synthesizing these Zofran conjugates will be apparent to the skilled artisan in view of this disclosure.
  • Example 17 Representative linkages for drug conjugates of GGA or a GGA derivative
  • Z bond, O, NH, N(C i -C 6 alky!)
  • Drug small molecule, peptide, protein, antibody, etc.
  • Z bond. O, NH, N(C r C 6 aikyi)
  • Dru small mo!ecu !e, peptide, protein, antibody, etc.
  • R 14 i H or CH, Hytiro!ytic conditions
  • Drug small molecule, peptide, protein, antibody,
  • Drug small molecule, peptide, protein, antibody, etc.

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Abstract

Provided herein are compositions, including intranasal compositions, which include geranylgeranyl acetone (GGA) and/or derivatives thereof and methods for treating a neural disease, disorder or condition with the same. Also provided herein are methods of treating inflammatory bowel disease with geranylgeranyl acetone (GGA) and/or derivatives thereof. Further provided are methods of treating chronic liver disease (CLD) with geranylgeranyl acetone (GGA) and/or derivatives thereof. Still further are provided methods for treating other hepatic and cardiac disorders.

Description

THERAPEUTIC USES FOR GERANYLGERANYL ACETONE AND DERIVATIVES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a PCT application that claims the benefit of US Patent Application Nos. 13/815,740 and 13/815741, both filed on March 15, 2013, U.S. Provisional Application Nos.: 61/856,615, filed July 19, 2013, 61/808,174 filed April 3, 2013, 61/808, 177 filed April 3, 2013, and PCT application no. PCT/US2013/035333 filed April 4, 2013, the entire content of each of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention provides therapeutic compositions suitable for intranasal administration, which include geranylgeranyl acetone (GGA) and/or derivatives thereof. This invention also provides therapeutic methods for treating a neural disease, disorder or condition by the intranasal administration of compositions that include geranylgeranyl acetone (GGA) and derivatives thereof. 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 cis and trans isomers of GGA or the GGA derivative.
[0003] This invention further provides therapeutic methods for treating inflammatory bowel disease (IBD) or a related disorder or condition by the administration of compositions that include geranylgeranyl acetone (GGA) and derivatives thereof. This invention also provides therapeutic methods for treating chronic liver disease (CLD) or a related disorder or condition or acute liver injury or failure by the administration of compositions that include GGA and derivatives thereof. Furthermore this invention provides therapeutic- methods for treating cardiac ischemia and repurfusion injury or a related disorder or condition by the administration of compositions that include GGA and derivatives thereof.
STATE OF THE ART
[0004] Geranylgeranyl acetone (GGA has the formula:
Figure imgf000002_0001
and is reported to have neuroprotective and related effects. See, for example, PCT Pat. App. Pub. Nos. WO 2012/031028 , WO 2013/052148, and WO 2013/130654, each of which is incorporated herein by reference in its entirety. {00051 inflammatory bowef disease (18D) is generally characterized by diarrhea, cramping, abdominal pains, weight loss, rectal bleeding, tiredness, anemia, fistuiae, perforations, obstruction of the bowel and frequent need for surgical intervention. It encompasses a number of disorders including Crohn's disease, ulcerative colitis, indeterminate coiitis. microscopic coiitis and collagenous coiitis. Such disorders may at times begin clinically with a more benign or rniider presentation, resembling irritable Bowel Syndrome (IBS) which can subsequently progress to increasing inflammation accompanying the IBS and ma ultimately develop fu!I-bio n IBD. The precise causes of IBD and IBS remain unknown.
[0006J Chronic liver disease (CLD) Is marked by the gradual destruction of liver tissue over time. Several liver diseases can fall under this category, including without limitation, cirrhosis and fibrosis, the latter of which is often the precursor to cirrhosis, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.
[0007] Cirrhosis Is the result of acute and chronic liver disease and is characterized by the replacement of liver tissue by fibrotic scar tissue and regenerative nodules leading to a progressive loss of liver function. Fibrosis and nodular regeneration results in the loss of the normal microscopic lobular architecture of the liver. Fibrosis represents the growth of scar- tissue resulting from, for example, infection, inflammation, injury, and even healing. Over time, the fibrotic scar tissue slowly replaces the norma! functioning liver tissue resulting in a decreasing amount of blood flow to the liver leaving the liver incapable of fully processing nutrients, hormones, drugs, and poisons that are found in the bloodsirearri. More common causes of cirrhosis include alcoholism, hepatitis C viral infections, ingestion of toxins, and fatty liver, but many other possible causes afso exist,
[0008] Liver injury is some form of trauma sustained to the liver, This can occur through either a blunt force such as a car accident, or a penetrating foreign object such as a knife. Liver injuries constitute 5% of all traumas, making it the most common abdominal injury.
[0009] Acute liver failure is the appearance of severe complications rapidly after the first signs of iiver disease (such as jaundice), and indicates that the liver has sustained severe damage (loss of function of 80-90% of Iiver ceils). The complications are hepatic
encephalopathy and impaired protein synthesis (as measured by the levels of serum albumin and the prothrombin time in the blood). The 1993 classification
defines hyperacute as 'within 1 week, acute as 8-28 days and subacute as 4-12 weeks. It reflects the fact that the pace of disease evolution strongly influences prognosis.
Acetaminophen hepatotoxicity is, by far., the most common cause of acute liver failure in both the United States and the United Kingdom. Toxicity of acetaminophen arrses often due to its quinone metabolite. Acetaminophen overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance. Signs and symptoms of paracetamol toxicity may initially be absent or vague. Untreated overdose can lead to liver failure and death within days. Renal failure is aiso a possible side effect.
[0010] Coronary heart disease (CHD) is the narrowing or blockage of the coronary arteries, usually caused by atherosclerosis. Atherosclerosis (sometimes called "hardening" or "clogging" of the arteries) is the buildup of cholesterol and fatty deposits (called piaques) on the inner wails of the arteries. These piaques can restrict blood flow to the heart muscle by physically clogging the artery or by causing abnormal artery tone and function.
Without an adequate blood supply, the heart becomes starved of oxygen and the vital nutrients It needs to work properly. This can cause chest pain called angina. If blood supply to a portion of the heart muscle is cut off entirely, or if the energy demands of the heart become much greater than its blood supply, a heart attack (injury to the heart muscle) may occur.
[0011] Cardiac ischemia may be asymptomatic or may cause chest pain, known as angina pectoris. It occurs when the heart muscle, or myocardium, receives insufficient blood flow. This most frequently results from atherosclerosis, which is the long-term accumulation of cholesterol-rich plaques in the coronary arteries. Ischemic heart disease is the most common cause of death in most Western countries and a major cause of hospital
admissions.
SUMMARY OF THE INVENTION
[0012] In one aspect of the invention, an intranasal composition is provided, the
composition comprising an effective amount of geranyigeranyl acetone (GGA) or a GGA derivative including GGA conjugates, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
[0013] In another aspect of the invention, an enteric composition is provided, the composition comprising an effective amount of geranyigeranyl acetone (GGA) or a GGA derivative including GGA conjugates, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0014] Preferably,, the GGA or the GGA derivative includes the all-irons (hereinafter "trans") form or substantially the trans form of the GGA or the GGA derivative. As used herein, "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 preferred embodiments of the invention, the GGA or a GGA derivative exists at least 80%, or at least 90%, or at least 95%, or at least 99% in the t ans isomer.
[0015] In certain aspects, this invention relates to pharmaceutical uses, as disclosed herein, of geranylgerany! acetone (GGA) and GGA derivatives, pharmaceutical compositions of isomers of geranvlgeranyi acetone, preferably synthetic geranylgeranyl acetone, and GGA derivatives, and methods of using such compounds and pharmaceutical compositions. In certain aspects, this invention relates to a 5-trans isomer compound of formula V!:
Figure imgf000005_0001
VI
wherein VI is at least 80% in the 5E, 9E, 13E configuration. In one embodiment, this invention utilizes a compound, which is synthetic 5E, 9E, 13E geranylgeranyl acetone. In another embodiment, the synthetic 5E, 9E, 13E geranylgeranyl acetone is free of 5Z, 9E, 13E geranylgeranyl acetone. In another aspect, this invention utilizes a pharmaceutical composition comprising synthetic GGA or synthetic 5E, 9E, 13E GGA, and at least one pharmaceutical excipient.
[0016] Another aspect of this invention relates to a synthetic 5-cis isomer compound of formula Vi!:
13E ^ 9E J _
VII
wherein VI! is at leas a ketal thereof of formula XII:
Figure imgf000005_0002
XVI!
wherein each R70 independently is Cr alkyl, or two R70 groups together with the oxygen atoms they are attached to form a 5 or 6 membered ring, which ring is optiona!!y substituted with 1-3, preferably 1-2, Cr C6 a!kyi groups. Preferably, the two R70 groups are the same. In one embodiment, R70 is, methyl, ethyl, or propyl in another embodiment, the cyclic ring is:
Figure imgf000006_0001
[0017] GGA and GGA derivatives utilized herein can be employed as a passive carrier where they are not covalently bound to a drug and as covalent conjugates of drugs for administering these drugs intranasally. 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 intranasal 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.
[00181 Provided herein are compounds, compositions, and methods for intranasal administration and delivery. In some embodiments, 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, thiol-containing components of the blood such as glutathione, or through the action of endogenous enzymes such as lipases, etc.
[0019] In another aspect, utiiized herein are drug conjugates of GGA or drug conjugates of GGA derivatives, that are therapeutically useful for intranasal formulation and delivery to a subject. In some embodiments, provided herein are compounds of formuia [G-L-jv-D, wherein v is 1-10, preferably, 1-5, more preferably, 1-3, or 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. In one embodiment, L is a single or a double bond. In another embodiment, L is a linker of formula: =N-L CO-, -N~LrO-, ~U - LrOCCh -CO-U-CO-, -CO-L O-, -0-U-CO-, -CO-LrOCO-, -OCO- U-CO-, and the likes. The drug can be any drug, preferably one that contains one or more -CO2H, -OH, - H3, and/or - SH, and such other groups that can he covaientiy conjugated as provided herein. Li 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.
[0020J As will be apparent to the skilled artisan, compounds of formula G-L-D exclude those that have a -O-O- bond resulting from the L-G or the L-D bonding. In some embodiments, Li comprises a C Ci0 alky!ene or C Qo heteroaikylene, Q-Cio cycloalkyi, Cr C10 heteroaryl, Q-Cio heterocyciyl moiety, which is oprina!iy substituted. Certain preferred substituents include C C6 afkyl, -OH, amino, C ; -C6 alkylamino, or di Ci-C6 a!kyiamino, C C6 cycloalkyi, d-Cio heteroaryl. or C2-C10 heterocyciyl. In some embodiments, Li comprises an amino acid moiety. In some embodiments, L-. is a di, tri, tetra, or pentapeptide, preferably comprising 1, more preferably 2.. and stili more preferably 3 or more naturally occurring amino acids.
In some embodiments, the compositions utilized herein contain a drug, and GGA or a GGA derivative as a non-covalently bound carrier. In these embodiments, the drug is not covaientiy bound to GGA or a GGA derivative directly or via a linker.
[0021] In some embodiments, conjugated and admixed drugs include the following exemplary and non-limiting drugs for treating the respective indications indicated after each drug: Forteo - osteoporosis; Ceredist (TRH) -- ataxia; Byetta (GLP-1) - diabetes; Sandostatin (GHI) - acromegaly; Victoza (GLP-1) - diabetes; Gonal-f (FHS) - infertility; Neupogen (G-CSF) - neutropenia; Kepivance - mucositis in cancer; Natrecor (B type naturietic protein) · congestive heart failure; Calcitonin for hypercalcemia; ACTH for infantile spasms; Oxytocin for premature delivery in pregnancy; Copaxone for multiple sclerosis; Beta-interferon for multiple sclerosis; and Alpha-interferon for viral hepatitis.
[0022] 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 antiinflammatory drugs, such as but not limited to dexamethazorte and ibuprophen,
indometacln, or naproxen, respectively. [0023] I n another aspect utilized herein are compounds wherein G6A or a derivative thereof is conjugated to an anti-cancer agent or another drug as disclosed herein. In one embodiment,, the G
Figure imgf000008_0001
wherein R '- R3, m, and n are defined as in Formula (I !) herein, 1/° is a bond or a linker joining the isoprenyi portion to the Drug, and the Drug is preferably an antibiotic or a glaucoma drug, or is an anticancer agent, or is an antiviral agent. In certain preferred embodiments, the linker is a bond, methylene, or carbonyi. In certain other prefer red embodiments, the linker joins the isoprenyi portion to a carbonyi moiety, or an oxygen, nitrogen, or sulfur atom of the drug. In yet another preferred embodiment, R1-Rb are methyl, and m and n are 1. Such conjugates are formulated and administered in accordance with this invention.
[0024] !n some embodiments, the compounds include esters of geranylgeranyl alcohol (GGOH) and such other alcohols as utilized herein. Such esters can include the GGOH esters of NSAID carboxylic acids such as ibuprophen and naproxen. Furthermore, 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.
[0025] Certain non-limiting GGA derivatives utilized in this invention include, farnesyl acetone, farnesyl alcohol, farnesyl carbamate, geranyl gerany! (GG) alcohol, GG carbamate. In some embodiments, the GGA derivative is
Figure imgf000008_0002
wherein r is 0, i, 2, 3, or 4, and wherein the structures include cis and trans forms and mixtures thereof.
[0026] In some embodiments, the drug that is conjugated to GGA or a GGA derivative is a small molecule, such as but not limited to Argatroban® or Zofran® (G!axoSmithKiine, London, U.K.) or vancomycin. In some embodiments, the drug that is conjugated to GGA or a GGA derivative is a peptide, such as but not limited to thyrotropin-re!easing hormone, (pyro)G!u-His-Pro-N H2, having a MW=362. in some embodiments, the drug that is conjugated to GGA or a GGA derivative is a peptide, such as but not limited to teriparatkie. comprising the first 34 amino acids of human parathyroid hormone (PTH), having a MW-4,118, or a growth hormone, a 191 amino acid peptide, having a MW=22,124. In some embodiments, the drug that is conjugated to GGA or a GGA derivative is an antibody, such as but not limited to herceptin.
[0027] In some embodiments, 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 sulfenyiated 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 embodiments, 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.
[0028] It is contemplated that the administration of an effective amount of these intranasal 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 -intranasal formulation comprising the comparable amount of GGA or a GGA derivative, it Is further contemplated that such intranasal 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). By avoiding the gastrointestinal tract, the intranasal formulations of GGA or a GGA derivative avoid stomach acid induced conversion of the all cis form to a mixed cis- and cis- form. In some embodiments, at least one of the double bonds in GGA or the GGA derivative of the intranasal formulation is in the cis configuration. In some embodiments, at least two or more of the double bonds in GGA or the GGA derivative of the Intranasal formulation is in the cis configuration.
[0029| As to intranasal delivery, the surface area of the nostril is small and thus can absorb only a limited volume of any intranasal composition. As such, the concentration of the GGA or the GGA derivative in the intranasal composition is contemplated to be sufficiently high e.g., 0.1-20% (weight/volume) to compensate for the small volumes, e.g., 0.01-2 mL, of the intranasal composition that are administered to each nostril, in certain embodiments, the composition includes 0.1-5%, or preferably 5-10%, or more preferably 10-15% or 15- 20% (weight/volume) of GGA or a GGA derivative, or a pharmaceutically acceptable salt thereof. [0030] The intranasal compositions described herein are contemplated to be administered to each or either nostril one or more times, e.g., 1, 2, 3, 4,. 5, 6, 7 or 8 times per day. It is further contemplated that a sufficient time delay, e.g., of 1- 30 minutes or more, such as time delays of 30 minutes, 1, 2, 3, 4, 8, 12, 24 or 48 hours may be used between each administration. Without being bound by theory, it is believed that each nostril can absorb only a limited volume of any intranasal composition and thus it quickly becomes saturated by the intranasal compositions described herein .
[0031] it is contemplated that an effective amount of GGA or a derivative thereof is efficiently administered by empioving the intranasal compositions described herein. In some embodiments the intranasal formuiation of GGA or a derivative contains between 1- 55, 5-50, 10-40, or 20-30 mg/kg/day.
[0032] In certain embodiments, the composition is in the form of a solution or suspension . In other embod iments, said excipient comprises a bioadhesive and/or an intranasal absorption promoter. Said intranasal absorption promoter, in some embodiments, is one or more of a chelating agent, POE (9) Iauryi alcohol, sodium giycochoiate and !ysophosphatidy! choline.
[0033] In some embodiments, it is contemplated that that the GGA or the GGA derivative, or the drug conjugate of GGA or a GGA derivative, forms a micellar or a similarly aggregated structure. In some embodiments, which relate to physical mixtures of a drug and GGA or a GGA derivative, the drug is included in the micellar structure. Without being bound by theory, it is contemplated that GGA. a GGA derivative, or a GGA-drug conjugate utilized herein can form a micelle or a reverse micelle, A micelle has a hydroiphiiic portion exposed to a surrounding aqueous or hydrophilic phase. A reverse micelle has a hydrophobic portion exposed to a surrounding hydrophobic phase. As disclosed herein, 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 asportation of GGA or the GGA derivative, or the drug conjugate of GGA or a GGA derivative from an aqueous phase Into the intranasal 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 moist environment of the nostril Into blood. [0034] In another aspect of the invention,, a method is provided for administering intranasally an effective amount of the compositions to a subject in need thereof. As used herein, subject or patient refers to a mammal., particularly preferably humans.
[0035] In another aspect of the invention, a method is provided for treating a neural disease, disorder or condition and/or reducing one or more negative effects of a neural disease, disorder or condition comprising administering intranasally an effective amount of any of the compositions described herein to a subject in need thereof.
[0038] According to another aspect of this invention, a method is provided for delivering a GGA derivative to the brain and/or the spina! cord of a patient, which method comprises administering an intra nas composition intranasally to said patient in an amount sufficient to introduce an effective amount of GGA derivative into the brain and/or the spina! cord. As used herein, an effective amount refers to a therapeutically effective amount or to a an amount effectively measured in the brain and/or the spinal cord.
[0037] Some embodiments provided herein describe a method for inducing expression of a heat shock protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of GGA or a GGA derivative thereof, wherein the GGA or GGA derivative thereof is administered intranasally to said subject.
[003S] Other embodiments provided herein describe a method for inhibiting neural death in a subject in need thereof; the method comprising administering to the subject a therapeutically effective amount of GGA or a GGA derivative thereof, wherein the GGA or GGA derivative thereof is administered intranasally to said subject.
[0039] In the entenc composition aspect, it is contemplated that the administration of an effective amount of these enteric formulations improves pharmaceutical activities such as an enhanced activity,, improved serum half-life, and/or lower toxicity with reduced adverse side effects relative to the administration of a conventional, i.e., non-enteric formulation comprising the comparable amount of GGA or a GGA derivative, in one embodiment, the enteric formulation is a solid-dosage form. In another embodiment, the enteric formulation comprises one or more an enteric polymer and enteric coating as suitable pharmaceutically acceptable excipients. In another embodiment, the enteric formulation contains an effective amount of GGA or the GGA derivative. [0040] In yet other embodiments,, various bacterial and viral disorders, and cancers of the eye, the brain, and the spinal cord, and nerves, including without limitation, nerves in the brain, eye, and the spina! cord are treated in accordance with this invention, in some embodiments, the disorder is glaucoma. In another embodiment, the disorder is herpes.
[0041] Another aspect provided herein describes GGA or GGA derivatives, drug conjugates, compositions thereof and related methods that are useful for the treaiment of a subject via an intramucosaf administrations, e.g., vaginal, rectal, other than the intranasal route. For exarripie, GGA or the GGA derivatives, drug conjugates, compositions thereof can be formulated as suppositories for vaginal or rectal administration. Excipien s for the treatment of intramucosal administrations, other than those described herein, are well known to the skilied artisan.
[0042] In one aspect of the invention, a method is provided of treating inflammatory bowel disease (I8D) or a related disorder or condition comprising administering a composition comprising an effective amount of geranyigeranyl acetone (GGA) or a GGA derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceuticaliy acceptable excipient to a subject in need thereof. As used herein, subject or patient refers to a mammal, particularly preferably humans. In another aspect, a method is provided of upregulating HSP70 in stomach cells affected by IBD comprising contacting the stomach cells with an effective amount of GGA.
[0043] in another aspect of the invention, a method is provided of treating chronic liver disease or a related disorder or condition comprising administering a composition comprising an effective amount of geranyigeranyl acetone (GGA) or a GGA derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In another aspect, a method is provided of upregulating HSP70 in hepatic cells affected by a chronic liver disease comprising contacting the hepatic cells with an effective amount of GGA, In some embodiments, the hepatic cells are affected with cirrhosis, fibrosis, nonalcoholic fatty liver disease, or non-alcoholic steatohepatitis,
[0044] In another aspect of the invention, a method is provided of treating a disorder selected from fiver injury, preferably acute fiver injury (from trauma, surgery or as a side effect of cancer treatment), acute liver failure, preferably caused by drug toxicity such as acetaminophen toxicity, cardiac ischemia, myocardial infarction, repurfusion injury and heart transplants, or a related disorder or condition, comprising administering a composition comprising an effective amount of geranyigeranyi acetone (GGA) or a GGA derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, to a su bject in need thereof, In some embodiments the (GGA) or a GGA derivative is administered to the subject in an emergency room setting.
[0045] in another aspect of the invention, a method is provided of treating a subject diagnosed with m ild to moderate iBD following gastrectomy comprising administering a composition comprising an effective amount of geranyigeranyi acetone (GGA) or a GGA derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In a preferred embodiment, the subjects are treated for 12 weeks
[0046] Compounds., compositions and methods of the Invention described herein include the disclosures found in PCT application publication nos.W'O 2012/031028, WO
2013/052148, and WO2013/130654 each of which is incorporated herein in its entirety by reference. Ail citations herein are incorporated herein by reference in their entirety,
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0047] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a solvent" includes a plurality of such solvents.
[0048] As used herein, the term "comprising''' or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others.
"Consisting essentially of" when used to define compositions and methods, shall mean excluding other eiements of any essential significance to the combination for the stated purpose. Thus, a composition or process consisting essentially of the elements as defined herein vvouid 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 eiements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
[0049] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations, Each numerical parameter should at least he construed in light of the number of reported significant digits and by applying ordinary rounding techniques, [0050] As used herein, Cm-Cn, such as d-Cio, C C& or C C when used before a group refers to that group containing m to n carbon atoms.
The term "about" when used before a numerical designation, e.g., temperature, time, amount, and concentration, including range, indicates approximations which may vary by ( +
} or ( - ) 10 %, 5 % or l .
[0051] The term "alkoxy" refers to -O-a!kyi.
[0052] The term "nitro" refers to -NO?,
[00S3] The term "alkyl" refers to monovalent saturated aliphatic hydrocarbyi groups having from 1 to 10 carbon atoms (i.e., Cr Cio alkyl) or 1 to 6 carbon atoms (i.e., Ci-C6 alkyl), or 1 to 4 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyi groups such as methyl (CH ) ethyl (CH3CHr), n-propyl (CH 3CH 2CH2-) . isopropyl {(CH3)2CH~), n-butyl (CH3CH2CH2CH ), isobutyl i(CH3)2CHCHr), sec-butyl ((CH3){CH3CH2lCH~)f i-butyl {(CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCHr).
[0054] The term "alkenyl" refers to monovalent aliphatic hydrocarbyi 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, allyi, dimethyl ally!, and the like,
[0055] The term "alkynyl" refers to monovalent aliphatic hydrocarbyi groups having from 2 to 10 carbon atoms or 2 to 6 carbon atoms and 1 or more, preferably 1, carbon carbon triple bond -(C≡C)-. Examples of alkynyl include ethyrsyi, propargyl, dimethy!propargyl, and the like.
[0056] The term "acy!" refers to -C(0)-aikyl, where alkyl is as defined above.
[0057] The term "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:
Figure imgf000014_0001
10058] The term "-C02H ester" refers to an ester formed between the -CO ;H group and an alcohol, preferably an aliphatic alcohol. A preferred example included ~C02RL, wherein Rl is alkyi or aryi group optionally substituted with an amino group.
[0053] The term "chiraf moiety" refers to a moiety that is chirai. Such a moiety can possess one or more asymmetric centers. Preferably,, the chirai moiety is enantiomerically enriched, and more preferably a single enantiomer. Non limiting examples of chirai moieties include chirai carboxyllc acids, chirai amines, chirai amino acids, such as the naturally occurring amino acids, chirai alcohols including chirai steroids, and the likes.
[0060] The term "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 cyciopropyl, cyclobutyi, cyc!opentyl, cyciohexyi, cycioheptyl, adamentyi, 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. For example, and without limitation , the following is a cycloalkyl group:
Figure imgf000015_0001
[0061] The term "halo" refers to F, Ci, Br, and/or I.
[0062] The term "heteroaryl" refers to a monovalent, aromatic mono-, bi- , or tricyclic ring having 2-14 ring carbon atoms and 1-6 ring heteroatorrts selected preferably from N, O, S, and P and oxidized forms of N, S, and P, provided thai the ring contains at least 5 ring atoms. Nonlimiting examples of heteroaryl include furan, imidazole, oxadiazole, oxazoie, pyridine, qulnoline, and the like. The condensed rings may or may not be a heteroatom containing aromatic ring provided that the point of attachment is a neteroaryi atom. For example, and without limitation, th oaryl group:
Figure imgf000015_0002
[0063] The term "heterocyciyi" or heterocycle 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, O, S, and P and oxidized forms of . S, and P. provided that the ring contains at !east 3 ring atoms. While heterocyclyl preferably refers to saturated ring systems, it also includes ring systems containing 1- 3 double bonds, provided that they ring is non-aromatic. Nonlimiting examples of heterocyclyl include, azalactones, oxazoiine, piperidinyl, plperazinyi, pyrroiidinyl, 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 heterocyclyl group. For example, and without limitation, the following is a hetero
Figure imgf000016_0001
[0064] The term "hydro!yzlng" refers to breaking an RH-0-CO-, RH-0-CS~, or an RH-0-SOr moiety to an RH-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.
[0065] The term "oxo" refers to a C=0 group, and to a substitution of 2 geminal hydrogen atoms with a C--0 group.
[0066] The term "pharmaceutically acceptable" refers to safe and non -toxic for in vivo, preferably,, human administration.
[0067] The term "pharmaceutically acceptable salt" refers to a salt that is
pharmaceutically acceptable.
[0083] The term "salt" refers to an ionic compound formed between an acid and a base. When the compound provided herein contains an acidic functionality, such saits include, without limitation,, alkai metal, alkaline earth metal, and ammonium salts. As used herein, 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, b, Cs, Nli¾, Ca, Ba, imidazo!ium, and ammonium cations based on naturally occurring amino acids. When the compounds utilized herein contain basic functina!y, such salts include, without limitation, salts of organic acids, such as caroboxylic acids and suifonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the likes. Exemplary and non -limiting anions useful in pharmaceutically acceptable saits include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, suifate, bisalfate, mono-, dh and tribasic phosphate, mesylate, tosylate, and the likes,
[0069] The term "substantially pure trans isomer" refers to a trans isomer that is by molar amount 95%, preferably 96%, more preferably 99%, and still more preferably 99.5% or more a trans isomer with the rest being the corresponding cis isomer.
[0070] "Trans" in the context of GGA and GGA derivatives refer to the GGA scaffold as illustrated below:
Figure imgf000017_0001
wherein R^R3 is defined herein and q is 0-2. As shown, each double bond is in a trans or E configuration. In contrast, a cis form of GG.A or a GGA derivative will contain one or more of these bonds in a cis or Z configuration.
[0071] The term "neuroprotective" refers to reduced toxicity of neurons as measured in vitro in assays where neurons susceptible to degradation are protected against degradation as compar ed to control. Neuroprotective effects may also be evaluated in vivo by counting neurons in histology sections.
[0072] The term "neuron" or "neurons" refers to all electrically excitable ceils 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 mamma! or tissue culture ceil lines that are made to differentiate into neurons. "Neuron" or "neurons" also refers to any of the above types of cells that have also been modified to express a particular protein either extraehromosomally or intrachromosomally. "Neuron" or "neurons" also refers to transformed neurons such as neuroblastoma ceils and support cells within the brain such as glia.
[0073] The term "protein aggregates'7 refers to a collection of proteins that may be partially or entirely mis-folded. The protein aggregates ma 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 he intranuclear in which they are inside the nucleus or cytoplasm in which they are in the space outside of the nucleus but stili within the cell membrane. The protein aggregates described in this invention are granular protein aggregates.
[0074] As used herein, the term "protein aggregate inhibiting amount" refers to an amount of compound that inhibits the formation of protein aggregates at least partially or entirely. Unless specified,, the inhibition could he directed to protein aggregates inside the cell or outside the ce!i.
[0075] As used herein, the term "intranuclear" or "intranuclearly" refers to the space inside the nuclear compartment of an animal cell.
[0076] The term "cytoplasm" refers to the space outside of the nucleus but within the outer cell wail of an animal cell.
[0077] As used herein, the term "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.
[0078] As used herein, the term "SBMA" refers to the disease spinal and bulbar muscular atrophy. Spinal and bulbar muscular atrophy is a disease caused by pathogenic androgen receptor protein accumulation intranuclearly.
[0079] As used herein, the term "ALS" refers to amyotrophic lateral sclerosis disease.
[0080] As used herein, the term "AD" refers to Alzheimer's disease.
[0081] The term "neurotransmitter''' refers to chemicals which transmit signals from a neuron to a target cell. Examples of neurotransmitters include but are not limited to: amino acids such as glutamate, aspartate, serine, y-aminobutyric acid, and glycine; monoamines such as dopamine, norepinephrine, epinephrine, histamine, serotonin, and melatonin; and other molecules such as acetychotine, adenosine, anadamide, and nitric oxide.
[0082] The term "synapse" refers to junctions between neurons. These junctions allow for the passage of chemical signals from one cell to another,
[0083] The term "G protein" refers to a family of proteins involved in transmitting chemical signals outside the cell and causing changes inside of the cell. The Rho 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.
[0084] The terms "treat'", "treating" or "treatment", as used herein, include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, preventing additional symptoms,, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting or suppressing the
deveiopment of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or suppressing the symptoms of the disease or condition, and are intended to include prophylaxis. The terms also include relieving the disease or conditions, e.g., causing the regression of clinical symptoms. The terms further include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual, notwithstanding that the individual is still be afflicted with the underlying disorder, For prophylactic benefit,, the compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
[0085] The terms "preventing" or "prevention" refer to a reduction in risk of acquiring a disease or disorder (i.e. , causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease), The terms further include causing the clinical symptoms not to develop, for example in a subject at risk of suffering from such a disease or disorder, thereby substantially averting onset of the disease or disorder.
[00S6] The term "effective amount" refers to an amount that is effective for the treatment of a condition or disorder by an Intranasal administration of a compound or composition described herein, in some embodiments, an effective amount of any of the compositions or dosage forms described herein is the amount used to treat a neural disease, disorder or condition and/or to reduce one or more negative effects of a neural disease, disorde or condition comprising administering intranasally any of the compositions or dosage forms described herein to a subject in need thereof, In some embodiments, the condition or disorder that is treated with an effective amount of a compound or composition described herein is of the brain, spine and/or central nervous system.
[0087] The term "carrier" as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into ceils or tissues, [0088] The term "axon" refers to projections of neurons that conduct signals to other cells through synapses. The term "axon growth" refers to the extension of the axon projection via the growth cone at the tip of the axon.
[00891 The term "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 SB A and are not intranuclear, include but are not limited to ALS, AD, Parkinson's Disease, multiple sclerosis, and prion diseases such as Kuru,
Creutzfeitclt-Jakob disease, Fatal familial insomnia, and Gerstmann-Straussier-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. For example, AD can be modeled in vitro by adding pre-aggregated 13-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 ceil. One way this can be achieved is by mixing dopamine with neurons such as neuroblastoma cells. These neural diseases can also be recapitulated in vivo In mouse models. A transgenic mouse that expresses a mutant Sodl protein has similar pathology to humans with ALS. Similarly, a transgenic mouse that over expresses APP has similar pathology to h umans with AD.
Compounds:
GGA
10090J This invention relates to compounds and pharmaceutical compositions of isomers of geranylgeranyi acetone, in certain aspects, this invention relates to a syn thetic 5-trans isomer compound of formula VI :
Figure imgf000020_0001
Vf wherein V! is at least 80% in the 5E, 9E, 13E configuration, !n some embodiments., the invention utiiii-es for a compound of formuia VI wherein VI is at least 85%, or at least 90%, or at least 95%, or at least 95%, or at least 97%, or at least 98%, or at ieast 99%, or at least 99.5%, or at least 99,9% in the 5E, 9E, 13E configuration. In some embodiments the invention for the compound of formuia VI does not contain any of the cis-tsomer of GGA.
[0091] Another aspect of this invention relates to a synthetic 5-cis isomer compound of formula VII :
Figure imgf000021_0001
VII
wherein VI I is at least 75% in the 51, 9E, 13 E configuration. In certain embodiments, the invention utilizes a compound of formuia Vil wherein VII is at ieast 80% in the 5E, 9E, 13E configuration, or alternatively, at !east 85%, or at Ieast 90%, or at ieast 95%, or at Ieast 96%, or at Ieast 97%, or at Ieast 98%, or at least 99%, or at Ieast 99,5%, or at Ieast 99.9% in the 5E, 9E, 13E configuration. In some embodiments of the invention, the compound of formula VI! does not contain any of the trans-isomer of GGA,
[0092] 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.
[0093] The data contained in the examples herewith demonstrate at low concentrations the trans-isomer of GGA is pharmacologically active and shows a dose-dependent relationship. I n contrast, the cis-isomer of GGA does not demonstrate a dose dependent relationship and is deemed to be at best of minimal activity.
GGA derivatives
[0094] GGA derivatives useful in this invention include those described in in the U. S.
Provisional Patent Application Nos. 61/856,391, entitled 61/845,302, 61/845,303 and 13/815,831, US Patent Application Publication No. US 2006/0052347, US Patent No.
5,453, 524, PGT Publication Nos. WO 2012/026813, WO 2012/031028,. WO 2013/052148, and WO 2013/130654, each of which is incorporated herein by reference in its entirety. These and other GGA derivatives utilized herein are struc turally shown below. [0095] In one aspect, the GGA derivative utilized herein is of Formula I:
Figure imgf000022_0001
(I)
or a tautomer or pharmaceuticaliy acceptable salt thereof, wherein
n 1 is 1 or 2;
each R1 and R2 are independently€i-Q, alkyi, or Rl and together with the carbon atom they are attached to form a C5-C7 cycloalkyi ring optionally subsiituted with 1-3 QrQ alkyi groups;
each of R:i, R4, and R5 independently are hydrogen or C Ce alkyi;
Ql is -(C=0)-, -(C=S)-, or -S(02)-;
¾ is hydrogen, Rb, -O-R", -NR' RK, or is a chiral moiety;
R6 is:
C Ce alkyi, optionally substituted with -CO2H or an ester thereof, C Q, aikoxy, oxo, -OH, -CR=CR2, -C≡CR, C3-C10 cycloalkyi, C3-Cg heterocyclyl, Ce-Cio aryl, C Cio heteroaryl, wherein each R independently is hydrogen or C-Cg alkyi;
CO- C1-C5 alkyi;
C3-C10 cycloalkyi;
C3-C8 heterocyclyl;
Cg-Cio aryl; or
CrC;o heteroaryl;
wherein each cycloalkyi, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 a!kyl groups; -CF3, 1-3 haso, preferably, chloro or fluoro, groups; 1-3 nitro groups; 1-3 C C6 aikoxy groups; -CO-phenyl; or -NR18Ri9, each R18 and R '9 independently is hydrogen; CrCfc alkyi, optionally substituted with -CO2H or an ester thereof, Ci-C$ aikoxy, oxo, -CR=CR2, -CCR, C}-Cio preferably C3-C3 cycloalkyi, C3-Cg heterocyclyl, C3-C]o aryl, or C;.-C] 0 heteroaryl., wherein each R independently is hydrogen or C Ce alkyi; C3~Ci0 cycloalkyi; C3-Cg heterocyclyl; Q-Cio aryi; or C2-Cl0 heteroaryl; wherein each cycloalkyi, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 aikyl groups, optionally substituted with 1-3 halo,, preferably, fluoro, groups, where RiS and Rid together with the nitrogen atom they are attached to form a 5-7 mem be red heterocycle; each R' and R8 are independently hydrogen or defined as Ft; and refers to a mixture of s and trans isomers at the corresponding position wherein at least 80% and, preferably, no more than 95% of the compound of Formula (!) is present as a trans isomer.
[0096] In one embodiment, the GGA derivative utilized is of Formula (l-A):
Figure imgf000023_0001
(l-A)
as a substantially pure trans isomer around the 2,3 double bond wherein,
Figure imgf000023_0002
Q.1, and C are defined as in Formula (1) above,
[0097] in another embodiment; n1 is 1. in another embodiment, n1 is 2,
[0098] in another erribodiment, the GGA derivative utilized is of Formula (l-B)i I
R2 R3 R4 R5
C-B)
as a substantially pure trans isomer around the 2,3 double bond wherein, Ρ Κ", Q1, and Q2 are defined as in Formula (I ) above,
[0099] In another embodiment the GGA derivative utilized is of Formula i-C:
Figure imgf000023_0003
wherein CT and Q.' are defined as in Formula (I) above,
[0100] In another embodiment, the GGA derivative utilized is of Formula (l-D), (!-E), or (I
Figure imgf000023_0004
Figure imgf000024_0001
(i-E) (!-F)
wherein R6--R8 are defined as in Formula (! ) above.
[OlOlj In another embodiment, the GGA derivative utilized is of Formula (l-G), (I-H), or {I- 11:
Figure imgf000024_0002
Figure imgf000024_0003
(l-H) (h i) as a substantia!iy pure trans isomer around the 2,3 double bond wherein Rb-R8 are defined as in Formula (I) above.
[0102] in a preferred embodiment, R° is C6-Ci0 ary!, such as naphthyl. in another preferred embodiment, R6 is a heteroaryi, such as quinolinyi.
[0103] in another aspe ivative utilized in this invention is of Formula (II):
Figure imgf000024_0004
or a pharmaceutically acceptable salt thereof, wherein
rn is 0 or 1;
n is 0, 1, or 2;
each R1 and R2 are independently d-Cg alkyl, or R1 and R together with the carbon atom they are attached to form a C5-C7 cycloalkyl ring optionally substituted with 1-3 Ci -Cg afkyl groups;
each of R3, R", and R5 independently are hydrogen or CrCe alkyl;
·¾ is -OH, -N R"R23 -X-CO-NRMR25, -X-CS-NR24R2S, or -X-S02-NR24R25; X is -0-, -S-, -MR26-, or -CR27R28;
each R" and " independently is hydrogen; C C& alkyl, optionaiiy su bstituted with Ci~C6 alkoxy; and C3-C10 cycloaikyl;
each '"" arid R"3 independently is hydrogen , C Cg alkyl, optionally substituted with -C02H or an ester thereof. Cr C6 alkoxy, oxo,. -OH, -CR=CR2, -CsCR, C3-C10 cycloaikyl, C Cg heterocyclyl, Cfi-Cio ar l, C2-CIQ heteroaryl, wherein each independently is hydrogen or Ci-Q alkyl;
C3-C10 cycloaikyl;
C3-Cg heterocyclyl;
Cfe-Cio aryi; or
C2--C10 heteroaryl;
wherein each cycloaikyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl grou ps; -CF3, 1-3 halo, preferably, ch!oro or fluoro, groups; 1-3 nitro groups; 1-3 Ci -Cg alkoxy grou ps; -CO-phenyi; or -NRl0R19;
each R18 and R,s independently is hydrogen; Ci-C& aikyi, optionaiiy substituted with -C02H or an ester thereof, C C6 alkoxy, oxo, -CR=CR2, -CCR, C3-Cl0 preferably C3-C8 cycloaikyl, C3-C8 heterocyclyl, Cg-Cio aryl, or C2~C10 heteroaryl, wherein each R independently is hydrogen or Ci-Cg aikyi; C3-C10 cycloaikyl; C3-Q heterocyclyl; Cg-Cio aryl; or C2-C10 heteroaryl; wherein each cycloaikyl, heterocyclyl, a ryl, or heteroaryl Is optionally su bstituted with 1-3 alkyl groups, optionally substituted with 1-3 halo, preferably, fluoro, groups, where R18 and R 9 together with the nitrogen atom they are attached to form a 5-7 membered heterocycle; R' G is hydrogen or together with Rx or ^ and the intervening atoms form a 5-7 membered heterocyclic ring optionaiiy su bstituted with 1-3 C C6 alkyl groups; and
each R" and R28 independently are hydrogen, d-Cg alkyl, -COR81 or -COjR81, or R / together with R" or R*" and the intervening atoms form a 5-7 membered heterocyclyl ring optionai iy substituted with 1-3 Q-Q alkyl groups,
[0104] As used herein, the compound of Formula (II) includes optical isomers such as enantiomers and diastereomers. As also used herein, an ester refers prefera bly to a phenyl or a CrQ, alkyl ester, wh ich phenyl or alkyl grou p is optionally su bstitu ted with a am ino grou p.
[0105] In one embodiment, ¾ is -NR22R23 -X-CO- R2 R25, -X-CS-N R24R2S, or -X-S02- N R24R25, in another embodiment, <¼ is -X-CO-NR24R25, -X~CS-NR2 R25, or -X-S02-NR24R \ in another embodiment, C¾ is - R22R23. In another embodiment, ¾ is -OH. [0106] In one embodiment, the compound of Formuia (I!) is of formula:
T Ί T ' "
R2 R3 R4 R6
wherein R1, R2, R;:,
Figure imgf000026_0001
W, and <¾ are defined as in any aspect or embodiment herein.
[0107] In another embodiment, the GGA derivative utilized is of formula:
R2 R4 R5
wherein 1, R';, R", Rs, and {¾ are defined as in any aspect and embodiment here.
[0108] In one embodiment, the compound of Formuia (II) is of formula:
R2 <rV R4 R5 R5 wherein R1. 2, R3. R4, Rb, and <¼ are defined as in any aspect or embodiment herein.
[0109] In another embodiment, the GGA derivative utilized is of formuia:
Figure imgf000026_0002
wherein R\ R2, R", Rs, m, n, X, and Ri¾ are defined as in any aspect and embodiment here.
[0110] In another embodiment, the GGA derivative utilized is of formuia:
Figure imgf000026_0003
wherein R1, P , R4, Rs, m, n, and R 4 are defined as in any aspect and embodiment here.
[0111] In another embodiment, the GGA derivative utilized is of formula:
Figure imgf000026_0004
wherein R¾ is define as in any aspect and embodiment here.
[0112] In another embodiment, the GGA derivative utilized is of formula:
Figure imgf000026_0005
wherein i4 is defined as in any aspect and embodiment here.
[0113] in another embodiment, the GGA derivative utilized is of formula:
Figure imgf000027_0001
wherein R*4 is defined as in any aspect and embodiment here.
[0114] in another erTibo is of formula:
Figure imgf000027_0002
wherein "" is defined as in any aspect and embodiment here.
[0115] In another embodiment, the GGA derivative utilized is of formula:
R25
Figure imgf000027_0003
wherein R24 and R2b are defined as in any aspect and embodiment here
[0116] in another embodiment the GGA derivative utilized is of formula:
Figure imgf000027_0004
wherein P 4 is defined as in any aspect and embodiment here.
[0117] in another embodiment, the GGA derivative utilized is of formula:
H f
t ~ Ύ " r Ϊ ii R
Q
wherein R24 and R b are defined as in any aspect and embodiment here.
[0118] In one embodiment, rn is 0. in another embodiment, m is i.
[0119] in another embodiment, n is 0. in another embodiment, n is 1. In another embodiment, n is 2.
[0120] !n another embodiment, m+n is 1. In another embodiment, m+rt is 2. In another embodiment, m+n is 3.
[0121] in another embodiment, R: and R2 are independently Cr aikyi. In another embodiment, R1 and R" independently are methyl, ethyl, or isopropyl. [0122] in another embodiment, 1 and FT together with the carbon atom they are attached to form a C5-C7 cycioalkyi ring optionally substituted with 1-3 C1- 5 alkyl groups, in another embodiment, R1 and R*1 together with the carbon atom they are attached to form a ring that is:
Figure imgf000028_0001
[0123] In another embodiment, R" \ R4, and are independently C e aikyi. in another embodiment, one of , R4. and RJ are aikyi, and the rest are hydrogen. In another . embodiment, two of R"\ R4, and Rs are aikyi, and the rest are hydrogen, in another embodiment, R"', R4, and R5 are hydrogen. In another embodiment.. R.3, R4, and R5 are methy!.
[0124] in another embodiment, (¾ is -X-CO-N R2 R25. in another embodiment, (¾ is "X-CS-N R2 R¾ in another embodiment, Q3 is -X-S02-NR24R25, in another embodiment, (¾ is -OCONHR24 -OCONR24R2S, -NHCO HR2', -NHCONR2 R25 , -OCSNHR24, ~OCSNR2 R25, - NHCSNHR24 or -NHCSNR24R2S.
[0125] in another embodiment, X is -0- , in another embodiment, X is -IMRi6-. In another embodiment, X is or -CR ?R28.
[0126] In another embodiment, one of R ¾ and R :' is hydrogen, in another embodiment, one or both of R24 and Rlb are C C6 aikyi. in another embodiment, one or both of and R2s are C Ce aikyi, optionally substituted with an R20 group, wherein R/C' is -C02H or an ester thereof, C C6 aikyi, C3-C10 cycioalkyi, C3-C3 heterocyclyi, C6-Ci0 aryl, or C2-Ci0 heteroaryl. in another embodiment, one or both of R44 and R*5 are C3-C10 cycioalkyi. in another embodiment, one or both of R24 and R25 are C3-C:lo cycioalkyi substituted with 1-3 aikyi groups, in another embodiment, one or both of R24 and R25 are C3-C8 heterocyclyi. In another embodiment, one or both of R -4 and R'° are Cs-C10 aryl. In another embodiment, one or both of R24 and R26 are C2-C10 heteroaryl. in another embodiment, R/ and R" together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.
[0127] In another embodiment, Rw is -C02H or an ester thereof. In another embodiment, R20 is CrCr> aikyi. In another embodiment, P ° is C2-C10 cycioalkyi. In another embodiment,. Ρ υ is C;rCg heterocyclyi. in another embodiment, R2< is C6-C10 aryl. In another embodiment, R20 is or C2-Cio heteroaryl. In another embodiment the GGA derivative utilized is of formula (II):
Figure imgf000029_0001
(li)
or a pharmaceutically acceptable salt thereof wherein
m is 0 or 1;
n is 0, 1, or 2;
each R1 and R2 are independently Ci-Ce alkyl, or R1 and R* together with the carbon atom they are attached to form a C3-C7 cycioaikyl ring optionally substituted with 1-3 Ci- e alkyl groups;
each of R3, R", and Rs independently are hydrogen or CrC6 alkyl;
{¾ is -X-CO-NR24R25 or -X-S02-NR24R2S;
X is -0-., - R A\ or -CR27R28;
R26 is hydrogen or together with R24 or R''~b and the intervening atoms form a 5-7 membered ring optionally substituted with 1-3 C Ci, alkyl groups;
each R27 and R28 independently are hydrogen,. CrC6 alkyl,. -COR81 or -C02RS1, or R""'7 together with R2 or R25 and the intervening atoms form a 5-7 membered cycioaikyl or heterocyciyl ring optionally substituted with 1-3 C Cs alkyl groups; each R24 and R"5 independently is
hydrogen,
Ci-Cg alkyl, optionally substituted with -C02H or an ester thereof, C3-C10 preferably C3~C8 cycioaikyl, C3-C8 heterocyciyl,. C6-Ci0 aryl, or C2-C10 heteroaryl, C3-C10 cycioaikyl,
C3-C8 heterocyciyl,
C&-Cio aryi, or
C2- 10 heteroaryl,
wherein each cycioaikyl, heterocyciyl, aryl, or heteroaryl is optionally substituted with 1-3 Ci-Cg alkyl groups, or R24 and R25 together with the nitrogen atom they are attached to form a 5-7 membered heterocycle.
in another embodiment, utilized herein are compounds of formula:
Figure imgf000030_0001
m= 0, n = 1, f^ = cydohexyl, and R25 ** methyl
m = 1, n - 1 R24 - cydohexyi, and R25 = methyl
m= 1, n = 2, R2 = cydohexyi, and R25 = methyl
rn= 0, n = 1, R24 = n-perrtyL and R25 = methyl
m = 1, n = 1, R24 = n-pentyi, and R25 = methyi
m= 1, n * 2. R24 = n-penty!, and R25 · methyl
[0130] In another aspect., the GGA derivative utilized herein is of Formula
Figure imgf000030_0002
or a pharmaceutically acceptable salt of each thereof, wherein
m is 0 or 1;
n is 0, 1, or 2;
each R1 and are independently Ci-C6 aikyl, or R1 and R together with the carbon atom they are attached to form a C5-C7 cycioaikyl ring optionally* substituted with 1-3 C .-C6 a iky! groups;
each of R", R", and Rs independently are hydrogen or C C6 aikyl;
QA is selected from the roup consisting of:
Figure imgf000030_0003
when X1 is bonded via a single bond, X1 is -0-, -NR31-, or -CR32R33-, and when X1 is bonded via a double bond, X1 is -CR32-;
Y1 is hydrogen, -OH or -O-R10, Y2 is -OH, -OR11 or -NHR1 , or Y1 and Y2 are joined to form an oxo group {=0), an imine group (=NRx3), a oxime group (=N-ORl4), or a substituted or unsubstitued vinylidene (=CR16R17);
R"'& is CrQ, aikyl optionally substituted with 1-3 alkoxy or 1-5 halo group, C2-C3 alkenyi, C2-C& aikyny!, C3-Ci0 cycioaikyl, C6-C10 aryl, C3-C8 heterocyclyl, or C2-Ci0 heteroaryl, wherein each cycioaikyl or heterocyclyl is optionally substituted with 1-3 C Cb aikyl groups. or wherein each aryi or heteroaryf is independently substituted with 1-3 d-Cg alkyl or nitro groups, or R30 is - R34R35;
R 1 is hydrogen or together with R"'c' and the intervening atoms form a 5-7 membered ring optionaiiy substituted with 1-3 CrC6 alkyl groups;
each R32 and R33 independently are hydrogen, Cr-C6 aikyl, -COR81 or -C02R81, or R32 together with R30 and the intervening atoms form a 5-7 membered cycloalkyl or heterocyciyi ring optionally substituted with oxo or 1-3 CrQ aikyl groups;
R10 is C C5 alkyl;
R" and R12 are independently C C6 alkyl, C Ci0 cycloalkyl, -C02R15 , or -CQN(R15)2, or R"° and R11 together with the intervening carbon atom and oxygen atoms form a
heterocycle optionaiiy substituted with 1-3 Cj-Ce aikyl groups;
R1'3 is C1 -C5 aikyl or C3-C10 cyc!oalkyi optionally substituted with 1-3 Cx-C6 aikyl groups;
R14 Is hydrogen, C3-C8 heterocyciyi, or C C6 aikyl optionall substituted with a ~C02H or an ester thereof or a C6-Cl0 aryi, C2--Cc aikeny!, C C6 alkynyl, C3-C10 cycloalkyl, or 3 C3-C8 heterocyciyi, wherein each cycloalkyl, heterocyciyi, or aryi, is optionaiiy substituted with 1-3 aikyl groups;
each R15 independently are hydrogen, C3-C10 cycloalkyl, Cj-Ce aikyl optionally substituted with 1-3 substituents selected from the group consisting of -C02H or an ester thereof, aryi. or C3-C8 heterocyciyi. or two R lb groups together with the nitrogen atom they are bonded to form a 5-7 membered heterocycle;
RlD is hydrogen or -C6 aikyl;
R1; is hydrogen, C C6 aikyl substituted with 1-3 hydroxy groups, -CHO, or is CQ2H or an ester thereof;
each R*s and R55 independentiy is hydrogen, Cr-C6 alkyl, optionally substituted with - C02H or an ester thereof, C3-C10 cycloalkyl, Cs-Cg heterocyciyi, Ce-Cio aryi, or C2-C10
heteroaryl, or is CJ-CID cycloalkyl, C3-C8 heterocyciyi, QrCie. aryi, or C2-Ci0 heteroaryl, wherein each cycloalkyl, heterocyciyi, aryi, or heteroaryl is optionaiiy substituted with 1-3 aikyl groups, or Ri4 and R& together with the nitrogen atom they are attached to form a 5-7 membered heterocycle; and
each R81 independently is C Cs alkyl. [0131] in one embodiment, m 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, [0132] In one embodiment, the compound of Formula (!!!) is of formula:
R2 RJ R P.5
wherein 0 , R1, R2, R3, R4, Rb, R30, X1, Y1, and Y2 are defined as in any aspect or embodiment herein.
[0133] in one embodiment, the GGA derivative utilized is of formula:
Figure imgf000032_0001
wherein R1, R2., R3, R4, R5, R30, X1, Y1, and Y2 are defined as in any aspect and embodiment here.
[0134] In another embodiment,, the GGA derivative utiiized is of formula:
Figure imgf000032_0002
wherein R1, R2, R3, R4, R5, R30, X1, and Y2 are defined as in any aspect and embodiment herein.
[0135] In another embodiment, the GGA derivative utiiized is of formula:
R2 R3 R4 R5 R30
wherein R\ R2. Rs, R4, Rs, R 0 and X1 are defined as in any aspect and embodiment herein.
[0136j In another embodiment, the GGA derivative utilized is of formula:
R2 R4 R5
wherein R1, R"', R* RJ, and G are defined as in any aspect and embodiment herein,
[0137] In another embodiment, the GGA derivative utilized is of formula:
Figure imgf000032_0003
wherein R1, R2, R* R5, m, n, X1, and R3° are defined as in any aspect and embodiment here.
[0138] In another embodiment, the GGA derivative utilized is of formula: 34
FT NHR
m n
wherein Rl, R", R* RJ, m, n, and R3 are defined as in any aspect and embodiment here.
[0139] In another embodiment, the GGA derivative utilized is of formula:
Figure imgf000033_0001
wherein R1, R2. R4, R5, R30, m, n, and R 15 are defined as in any aspect and embodiment here.
[0140] in another embodiment, each R~ and R" are C Cg alkyl. in another embodiment, each R1 and R _ are methyl, ethyl, or isopropyl. in another embodiment, R1 and R2 together with the carbon atom they are attached to form a 5-6 membered ring optionaliy substituted with 1-3 C - g alkyl groups. In another embodiment, R1 and R2 together with the carbon y are attached to form a ring that is:
Figure imgf000033_0002
or .— J
[0141] In another embodiment, R", R4, and Rs are Ci-Ce alkyl. In another embodiment, one of R3, R4, and are alkyl, and the rest are hydrogen, !n another embodiment, two of R3, R4, and Rs are alky!, and the rest are hydrogen, fn another embodiment, R*, R4, and R3 are hydrogen. In another embodiment, R'\ *, and RJ are methyl.
[0142] in another embodiment, X1 is O. in another embodiment, X1 is ~-NR3i. In another embodiment, Roi is hydrogen, in another embodiment, R'3i together with R3° and the intervening atoms form a 5-7 membered ring optionaliy substituted with 1-3 CrC& alkyl groups. In another embodiment, X1 is -CR32R"-, In another embodiment, X1 is -CR3 -. In another embodiment, each R32 and R" independently are hydrogen, d-Os alk l, -COR81, or - C02R°\ in another embodiment, R32 is hydrogen, and R33 is hydrogen,. CrC6 alkyl, -COR8i, or -C02R81.
[0143] in another embodiment, R33 is hydrogen. In another embodiment, P.33 Ci-Q, alkyl. in another embodiment, R°3 is methyl. In another embodiment, R33 is -C02Rb l. In another embodiment, R33 is -COR81.
[0144] In another embodiment, R32 together with R3u and the Intervening atoms form a 5- 7 membered ring. In another embodiment, the moiety:
Figure imgf000034_0001
which is " " Has the structure:
Figure imgf000034_0002
wherein R3B is hydrogen, -Q alky!, or -C02R81 and n is 1, 2, or 3. Within these
embodiments, in certain embodiments, R33 is hydrogen or C;-C6 aiky!. In one embodiment, R33 is hydrogen, in another embodiment, R33 is CRC6 alkyl.
[0145] In another embodiment, R**5 is d-Ce alkyl. In another embodiment, 'U is methyl, ethyl, butyl, isopropyl, or tertiary butyl. In another embodiment,. R30 is d-d alkyl substituted with 1-3 alkoxy or 1-5 halo group, in another embodiment, R3 is alkyl
substituted with an aikoxy group. In another embodiment, R30 is alkyl substituted with 1-5, preferably, 1-3, halo, preferably fiuoro, groups.
[0146J In another embodiment, J0 is N R^'R" In a preferred embodiment, R35 is H. in a preferred embodiment, R34 is d- alkyl, optionally substituted with a group selected from the group consisting of -C02H or an ester thereof, C3- C1C. cycioalkyl, C3-C3 heterocyclyl, C6- Cioaryl, or d-Cto heteroaryi. In another preferred embodiment, R"'4 is C3-Ci0 cycioalkyl, C3-C8 heterocyclyl, Ce-Cio aryl, or C2-Cio heteroaryi. In a more preferred embodiment, R54 is C3-C10 cycioalkyl.
{0147] In another embodiment, Ra0 is C2- alkenyi or C2-C3 alkynyi. In another
embodiment, RM is C3-CJ0 cycioalkyl. In another embodiment, Ri0 is Cj-Cio cycioalkyl substituted with 1-3 -Ce alkyl groups. In another embodiment, R3U is cyclopropyl, cyciobutyl, cyc!opentyi, cyclohexyl, or adamentyl. In another embodiment, R30 is C6-do 3ryl or d-C:U) heteroaryi. In another embodiment, RI0 is a 5-7 membered heteroaryi containing at least 1 oxygen atom. In another embodiment, R3j is C6-Ci0 aryl, C3-C8 heterocyclyl, or C->~ Cio heteroaryi, wherein each aryl, heterocyclyl, or heteroaryi is optionally substituted with 1- 3 C d alkyl groups.
[0148] In another embodiment, Y2 is -O-R". In another embodiment, Y1 and Y4 are joined to form =NR". In another embodiment, Y1 and Y"1 are joined to form -IMOR"1'4. In another embodiment, Y1 and Y3 are joined to form (=0). In another embodiment, Y1 and Y" are joined to form -CR^R^. [01493 in another embodiment, <¼ is -CR33COR30. in another embodiment, R30 is C C6 aikyi optionaiiy substituted with an alkoxy group, in another embodiment, R30 is C3-Cg cycloaikyl. In another embodiment, R" is hydrogen, in another embodiment, R33 Is C Ce aikyi, In another embodiment, R is CO>R81. In another embodiment R33 is CORs\
[0150] in another embodiment. QA is -CH2-CH|O-CONHR; )-R30. in another embodiment, l¾ is C3-C8 cycloaikyl. in another embodiment, Rla is C C6 aikyi optionally substituted with 1-3 substiteunts selected from the group consisting of -CO2H or an ester thereof, aryl, or C3- Cg heterocyclyl. In a preferred embodiment within these embodiments, R30 is C C6 aikyi.
[0151] In another embodiment, O, is -O-CO-NHR34. withing these embodiment, in another embodiment, R34 is C Cg aikyi, optionally substituted with -CO2H or an ester thereof, C3-C8 cycloaikyl, C3-C3 heterocyclyl, C2-Ci0aryl, or C2-Ci0heteroaryl. in yet another embodiment, R3* is C3-Cg cycloaikyl, C3-C8 heterocyclyl, C2-C30 aryl, or C2-Cjoheteroaryl, [0152] In another embodiment, Rw is hydrogen, in another embodiment, R'4 is C.--C6 aikyi optionally substituted with a -~C02H or an ester thereof or a C6-Cio aryl optionally substituted with 1-3 aikyi groups. In another embodiment, 14 is C2-C3 alkenyl. In another embodiment, R * is C2-C6 alkynyl in anotner embodiment, R is Q-Cg cycloaikyl optionally substituted with 1-3 alkyl groups, in another embodiment, R'4 is C3-C8 heterocyclyl optionally substituted with 1-3 aikyi groups.
[0153] in another embodiment, preferably, Rio is hydrogen. In another embodiment, R1' is COjH or an ester thereof. In another embodiment, R1' is Ci-C3 aikyi substituted with 1-3 hydroxy groups. In another embodiment, R17 is - alkyl substituted with 1 hydroxy group, in another embodiment, Ri; is -CH2OH.
[0154] In another embodiment, R10 and R" together with the intervening carbon atom and oxygen atoms form a heteroycl f formula;
Figure imgf000035_0001
wherein q is 0 or 1, p is 0, 1, 2, or 3, and R~" is C C6 alkyl.
[0155] In another embodiment, 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. [0156] In one aspect, the GGA derivative utilized herein is of Formula (IV):
Figure imgf000036_0001
(IV)
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein rn is 0 or 1;
n is 0. 1, or 2;
each 1 and R? are independently d-Ce aikyi, or R1 and R2 together with the carbon atom they are attached to form a C5-C7 cyc!oalkyl ring optionally substituted with 1-3 C Cg aikyi groups;
each of R'\ R", and R5 independently are hydrogen or CrC& aikyi,. or R" and (¼ together with the intervening carbon atoms form a 6 membered aryl ring, or a 5-8 membered cycioalkenyl ring, or a 5-14 membered heteroaryl or heterocycie, wherein each aryi, cycioalkenyl, heteroaryi, or heterocycie, ring is optionally substituted with 1-2 substituents selected from the group consisting of halo, hydroxy, oxo, -N(R U)?J and CrCs alky! group;
Qs is ~C(=0)H, -CO2H or -CH=CHC02H, or a Ci~C6 aikyi ester or acyl haiide thereof, wherein the ester is optionally substituted with -CO-pheny!; a 5-10 membered aryi or a 5-14 membered heteroaryi or heterocycie containing up to 6 ring heteroatoms, wherein the heteroatom Is selected from the group consisting of O, , S, and oxidized forms of N and S, and further wherein the aryl, heteroaryi, or heterocyclyl ring is optionally substituted with 1 - 3 substituents selected from the group consisting of:
hydroxy, oxo, -N(R 0) , C Ce alkoxy group, and d-Q alky! group,
wherein the aikyi group is optionally substituted with 1-3 substituents selected from hydroxy, NH2, C5-C10 aryi, -C02H or an ester or an amide thereof,
a 5- 9 membered heteroaryi containing up to 3 ring heteroatoms, wherein the heteroaryi is optionally su bstituted with 1- 3 hydroxy, -N(R4U)2, and C:-C& alky! group,
benzyl, and phenyl optionally substituted with 1-3 substituents selected from the group consisting of C Q aikyi, CI-CG alkoxy, hydroxy, and halo groups: and
wherein each R40 independently is hydrogen or C C6 aikyi.
[0157] As used herein, the compound of Formula (IV) includes tautomers and optical isomers such as enant!omers and diastereomers. As also used herein, an ester refers preferably to a phenyl or a C Q, alky! ester, which phenyl or alkyl group is optionally substituted with a amino group, As used herein, an amide refers preferably to a moiety formula -CON(R4°)2,, wherein R4 is defined as above.
In some embodiment, <¼ is selected from a group consisting of oxazole, oxadiazoie, oxazoline, azalactone, imidazole, diazoie, triazole, and thiazole, wherein each beteroary! heterocycle is optionally substituted as disclosed above.
[0158J in one embodiment, the GGA derivative utilized is of formula IV-A:
R2 R3 R~ R¾
IV-A
{0159] in another embodiment, the GGA derivative utilized is of formula iV-B:
R2 R4 R5
IV-B
wherein R1, R2, R4, RJ, and C¾ are defined as in any aspect and embodiment here.
er embodiment, Q5 is selected from the group consisting of:
Figure imgf000037_0001
wherein R" is CrC6 alkyl, C6-C10 aryl, C3-C3 heteroaryl, C3-C3 heteroaryl,€3-Οιο cycloalkyl, and the alky! group is optionally substituted with 1-3 C6-C]0 aryl, C3-C8 heteroaryl, C Cg heteroaryl, C3-C10 cycloalkyi groups, and the aryl, heteroaryl, heteroaryl, cycloalkyl groups are optionally substituted with 1-3 d-Ce alkyl, d-Q alkoxy, halo, preferqably chloro or fluoro, Ce-Cio aryl, C3-C8 heteroaryl, Cj-Cg heteroaryl, C3-C10 cycloalkyl group.
[01611 In another embodiment, ¾ is phenyl, optionally substituted as described herein, in another embodiment, <¼ is benzimidazole, benzindazole, and such other 5-6 fused 9- membered bicyciic heteroaryl or heterocycle. In another embodiment, ·¾ is quinoiine. isoquinoline, and such other 6-6 fused 10 membered heteroaryl or heterocycle. In another embodiment, <¾ is benzodiazepine or a derivative thereof,, such as, a benzodiazepinone. Various benzodiazepine and derivatives thereof are well known to the skilled artisan.
[0182] In another embodiment, m is 0. in another embodiment, m is 1.
[0183] In another embodiment, n is 0. In another embodiment, n is 1. in another embodiment, n is 2.
[0164] !n another embodiment, m+n is 1. In another embodiment,, m+n is 2. In another embodiment, m+n is 3.
[0165] In another embodiment, R1 and R2 are independently Cr alkyl. In another embodiment, R1 and RJ independently are methyl,, ethyi, or isopropyi.
[0168] in another embodiment, R1 and R" together with the carbon atom they are attached to form a C5-C7 cycloaiky! ring optionally substituted with 1-3 C C6 alkyl groups, in another embodiment, R1 and R2 together with the carbon atom they are attached to form a ring that is:
Figure imgf000038_0001
[0167] In another embodiment, R;i, R'J, and R" are independently CrC6 alkyl. In another embodiment, one of R3, R4. and R5 are alkyl, and the rest are hydrogen. In another embodiment, two of Ρ R , and Rb are alkyi, and the rest are hydrogen. In another embodiment, RJ,
Figure imgf000038_0002
and R5 are hydrogen, in another embodiment, R3, R4, and R3 are methyl.
[0168] In another embodiment, this invention utilizes a compound selected from the group consisting of;
Figure imgf000039_0001
Figure imgf000039_0002
wherein R * is defined as above.
[0169] in another aspect, GGA derivatives utilized herein are of formula (V):
Figure imgf000039_0003
(V)
or a pharmaceutically acceptable salt thereof, wherein
m is 0 or 1;
n is 0, 1, or 2;
each FT and R independently are Cj- e a!kyl, or R1 and " together with the carbon atom they are attached to form a C5-C7 cycloalkyl ring optionally substituted with 1-3 Ci-Cf, alky! groups;
each of R3, , and Rb independently is hydrogen or Ci-Cb alky!;
Qe is selected from the group consisting of:
Figure imgf000039_0004
when X2 is bonded via a single bond, Xz is --Q-, -MR""1-, or ~-CR53R 4-, and when X3 is bonded via a double bond, X2 is -CR53-;
Y" is hydrogen, -OH or -OR55; Y22 is -OH, -OR55, -N H 57, or ~0-CO-NR58RSS, or YN and Y22 are joined to form an oxo group (=0), an imine group (=N R60), a oxsme group (=N-OR61), or a substituted or unsubstituted vinylidene (=CF4£,3R6 );
RS ;L is C Q aikyi, C Q aikyl substituted with 1-3 a!koxy or 1-5 haio groups, Q- C6 aikenyl, C2-Q aikynyi, C5-Cj0 cycloalkyi, C3-CG heterocyciyi, Q- o aryl, C2-CJ.J heteroaryl, or -N RT,¾R66, wherein each cycloalkyi or heterocyciyi is optionally substituted with 1-3 C Q alkyi groups, and wherein each ary! or heteroaryl is optionally substituted independently with 1-3 nitro and Cr- C6 alkyi groups;
R52 is hydrogen or together with R51 and the intervening atoms form a 5-7 membered ring optionally substituted with 1-3 Q-Q alkyi groups;
each R5,3 and RS4 independently are hydrogen, C,-Q alkyi, -COR81, -C02R81, or -COMHR82, or RB3 together with R51 and the intervening atoms form a 5-7 membered cycloalkyi or heterocyciyi ring opiionaliy substituted with 1-3 CrQ aikyl groups;
R55 is C C6 alkyi;
each R35 and RJ independently are C Q aikyl, C3-C10 cycloalkyi, -002R62, or -CON(R6 )2; or R33 and R3° together with the intervening carbon atom and oxygen atoms form a heterocycie optionally substituted with 1-3 Q-Q alkyi groups;
R58 is: C3-C10 cycloalkyi, CrQ alkyi optionally substituted with -OH, C02H or an ester thereof, or -Qo cycloalkyi.
Figure imgf000040_0001
R'9 is hydrogen or C Cs aikyl;
R60 is CrQ alkyi or C3-C10 cycloalkyi optionally substitued with 1-3 CrQ alkyi groups, or is:
Figure imgf000040_0002
R is hydrogen, C?!-C8 heterocyciyi, or Q-Q aikyl optionally substituted with a r an ester thereof or a -CXQ aryl, C2-C6 aikenyl, C2-C6 alkynyl, Q-Qo cycloalkyi, or a C3-Cg heterocyciyl, wherein each cycioalkyi, heterocyclyl, or aryi, is optionally su bstituted with 1-3 alkyi grou ps;
each R°2 independently are hydrogen,. C3-C10 cycioalkyi, Ci-Cg alkyl optionally su bstituted with 1-3 substiteunts selected from the grou p consisting of -C(¼H or an ester thereof, aryi, C C& heterocyciyl, or two R°"'' groups together with the nitrogen atom they are bonded to form a 5 -7 mernbered heterocyde;
H*3 is hydrogen or C C6 alkyl;
R'" is hydrogen, C r-Ce alkyl substituted with 1-3 hydroxy groups,. -CHO, or is CO2H or an ester thereof;
one or both of R°* and R66 independently are hydrogen, C C6 alkyl. optiona lly substituted with -C(½H or an ester thereof, C3-C10 cycioalkyi, C3-Q heterocyclyl, C2- Cio aryi, or Q-C10 heteroaryl, or is C3-C10 cycioalkyi, C3-C8 heterocyciyl, C&-Ci0aryl, or C?-CIQ heteroaryl, wherein each cycioalkyi,. heterocyclyl, ary!, or heteroaryl is optionally substituted with 1-3 alkyl groups, or R65 and R66 gether with the nitrogen atom they are bonded to form a 5-7 membered heterocyde, and if only one of R65 and R66 are defined as above, then the other one is
Figure imgf000041_0001
8i is CrC5 alkyl; and
is:
Figure imgf000041_0002
provided that, when X*' is bonded via a single bond, and R5s or RM is not
-COiMH R82, v" and Y22 are joined to form an imine roup (=NR60), and R60 is:
Figure imgf000041_0003
o Y22 is -0-CO-N R58R59;
or provided that, when (¾ is:
Figure imgf000042_0001
and 53 is not -CON HP,82, Υ" is -O-CO-N ^R^;
or provided that, when >¾ is -OCO-NR^R55, then at least one of R6Sand R°°
Figure imgf000042_0002
In one embodiment,, the GGA derivative utilized are of formula:
Figure imgf000042_0003
Figure imgf000042_0004
Figure imgf000042_0005
Figure imgf000043_0001
[0171] In another aspect, the GGA derivatives useful according to this invention is seie from:
Figure imgf000043_0002
Vi!l: R^ -OH X! V: R76= -CH2CH
Figure imgf000043_0003
wherein L is 0, 1, 2, or 3, and R ' is C02H or an ester thereof, or is -CH?OHf or is a CrQ alkyl ester of -CH2OH.
[0173] In another embodiment, examples of compounds utilized by this invention include certain compounds tabulated beiow.
Table 1
Com ound
ID Structure
Figure imgf000044_0001
Figure imgf000045_0001
44
Figure imgf000046_0001
Figure imgf000047_0001

Figure imgf000048_0002
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000053_0001
Figure imgf000054_0001
53
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000056_0001
Figure imgf000057_0001
[0174] in another embodiment, examples of compounds utilized by this invention include certain compounds tabuiated beiow.
Table 2
Figure imgf000057_0002
Figure imgf000058_0001

Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
60
Figure imgf000062_0001
61
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
65 OI753 Exemplary compounds include:
^l. ^A..- A...^A.:
{6E,10E,14E)- -tetramethyIicosa-6,10,14 8-tetraen-3-one
Figure imgf000067_0001
(61· , 10F.)-7, 11.15-trimethylhexadeca-6.10, 14-iricn~3-one
Figure imgf000067_0002
-7.11 -diracthyldodeca-6, 1 O-dien-3-οηε
Figure imgf000067_0003
(5E.9E, 13 E)- 1,3,1 -trifluoro-6, 10,14.18-lelraraelhy I nonadeca-5,9.13,17-tetraen-3-one
Figure imgf000067_0004
(5E,9E 1.3,3 -trifluoro-630.14-trimelh J nta a-5.9.33-trien-2-one
Figure imgf000067_0005
(E)-i .1,1 -trifluoro-6.30-dimelhylundeca-5,9-dien-2-onc
[0176] in certain aspects, the GGA derivative is a compound of Formula (XV! II), (XIX) or (XX):
Figure imgf000067_0006
(XVI II)
Figure imgf000067_0007
(XX)
)r a pharmaceuticaily acceptable salt thereof
wnerein FT1 is Cs-Cao aikyl or C5-C20 alkenyi optionally substituted with 1-3 C6-C20 arylene groups in the chain and that is optionally substituted with 1-3 halo, trifluoromethyl, -OR97, -P{=0)(OR93){O 99) or -NR100R101 groups;
R92 is (C3-C2ojalky! or C5~C20 alkenyi optionally substituted with 1-3 Cg-C^ aryl groups, which aryl group(s) are optionaiiy substituted with 1-3 halo, trifluoromethyl, -OR97, -P(=0)(OR9S)(OR99) or -NR10V01 groups; each R93. R9 . R95. and R96 is independently OH or C C6 a!koxy;
each R97, R9S and R99 is independently hydrogen., C- aikyl or C5-C20 aryl; and each R100 and R101 Is independently hydrogen,, C C6 alkyl or Cfi-C20 aryl; or R100 and RiL together with the nitrogen to which they are attached form a C3 heterocycie;
wherein each aryl group of R97, R98, R99, R100 and R101 is optionally substituted with 1-3 Ci-Ce alkyl, C-.-C& alkoxy, Ci-C6 aikanoyi, C C6 alkanoyloxy, Cr CG alkoxycarbonyl, halo,, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, N R102R103, or S(0) R1G:'R:l03 groups, wherein each Rlu2 and R ΛΟλ is independently hydrogen or C Ce alkyl;
R1""4 and Ri0b are independently selected from the group consisting of
hydrogen, CY-C6 alkyl, C3-C7 cycioalkyi, C2-C6 alkenyi, C C6 alkynyi, optionally substituted C3-C20 aryl, optionally substituted C6-C2o aryi-Ci - Cealkyl, optionaiiy substituted heteroaryi and optionally substituted heteroaryi-Ci-Q alkyl, each heteroaryi having 2-14 ring carbon atoms and 1-6 ring heteroatoms selected preferably from . 0, 5, and P, wherein each substituted aryl or substituted heteroaryi is independently substituted with 1-3 substituents selected from -OH, halo, Cj -CG alkyl, CrC6 alkoxy, -N02, and -NRXOOR101 groups; or P.104 and R1L together with the carbon atom they are attached to form a C5-C/ cycioalkyi ring optionally substituted with 1-3 CrC6 aikyl groups;
R10b and RiC independently are hydrogen or C C6 aikyl;
each R108 and R10y are independently selected from the group consisting of a
hydrogen, C C6 aikyl, and a group of Formula (XXI);
Figure imgf000069_0001
wherein RiL -Ri07 and n are as defined herein;
Y is -P(=O)(OR108)(OR109}, -C02R110 or -SO2ORu0, wherein Ru0 is selected from the group consisting of a hydrogen and Cj-Ce alkyi;
R111
Z js -A— — (CH2), --|- herein R' u is hydrogen or C C6 alkyi; A is C C5 aikylene which may have a substituent selected from -OH, halo, C1--G5 alkyi, and C:1-C6 aikoxy groups on each carbon;
r is 0, 1, 2, 3, 4 or 5; and
n is 0, 1, 2, 3, 4 or 5.
in one aspect,, the GGA derivative utilized herein is of formula:
Figure imgf000069_0002
wherein Rm is a iower (e.g. C1-C6) alky! group, optionally substituted with 1 to 4 substituents selected from the group consisting of halogen, hydroxy!; Iower alkyi; iower aikoxy; ha!ogenated lower alkyi; halogenated iower aikoxy; cyano; a 5- or 6-membered (hetero) aromatic ring which may be substituted by hydroxy!,, lower alkyi, iower aikoxy,. halogen, amino, lower aikyiamino; cyano, nitro; and other (substituted) (hetero) aromatic rings;
Rt22 is hydrogen or C1-C4 alkyi; Both the R and S configurations are encompassed.
R t23, Rt24 and R125 are independently selected from hydrogen, substituted and
nonsubstituted C1-C alkyi groups
j 26 is CH(O) or CmH2m-X, wherein m is 1-3 and X is -H, -OH or a 5- or 6-membered
(hetero)aromatic ring; and
Y is -C(O)- or
Figure imgf000069_0003
- wherein R127 is hydrogen or a C-: -C alkyi group,
[0178] In another aspect, the compound is formula (XVIII):
Figure imgf000070_0001
(XVI!I)
[0179] in some embodiments, Ρ.1υυ and RlUl 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 thiomorpho!ino ring,
[0180] In another aspect, the GGA derivative utilized is of formula (X!Xa):
Figure imgf000070_0002
wherein R" and Ri J each represent a hydrogen atom, a lower aiky!, cycioalkyl, aikenyi or alkynyl group, an aryi group which may be substituted, an aryialkyi group in which the ary! group may be substituted, or a heteroaryl or heteroarylalkyl group: Rlu8 and lUy each represent a hydrogen atorn, a lower alkyi group or an alkali metal; Y represents a group represented by the formula:
R130Ox OR131
¾' -o
wherein Ri3° and R 31 each represent a hydrogen atom, a lower alkyi group or an alkali meta! or a group represented by the formula : --CO? R 1 " (wherein R132 represents a hydrogen atom,, a Iower alkyi group or an alkali metal ); Z represents a group represented by the Formula: --(CH2}m · · (wherein m is an integer of 0 to 3), a group represented by the formula: --(CH2}p -CH=CH- -{CH2)q - (wherein p is 0 or 1 and q is 1 or 2} or a group represented by the Formula:
R i l l
j-A— N— -(CH2)r - - wherein R1" represents a hydrogen atom or a Iower alkyi 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. 51697
Exemplary compounds further include
3)
Figure imgf000071_0001
CH3 C Ha POi OCH3)2
H,C ' ' · ' · P ;OC H ;
; and
CH-,
Figure imgf000072_0001
and the corresponding ethyl and other C C6 a Iky I esters.
[0182] A skilled artisan will understand that trans forms of GGA and GGA derivatives utilized herein can be replaced with the various corresponding cis forms and utilized in accordance with this invention. Such compounds can be in solely or substantially, such as at least. 90%, at seat 80%, at least 70%, at least 50% or at least 20% in the cis form. As will also be understood, various mixtures of cis and trans forms of GGA and GGA derivatives are also useful in accordance with this invention. In certain preferred embodiments, GGA and GGA derivatives containing substantially or so!e!y 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.
[0183] illustrative and nonlimitlng anticancer agents and conjugates and their methods of synthesis are shown below. Illustrative and noniimiting viral agents, such as Vidarabine, and conjugates and their methods of synthesis are also shown below.
Geranylgeranyl (GG)--alcohoi/campothecin conjugate:
Figure imgf000073_0001
MOM ether of GG-a!cohol
Figure imgf000073_0002
Figure imgf000073_0003
GG-aicohol - 1 conjugate
Carbonate c
Figure imgf000073_0004
1. csrbonyl tiiimiclazoie
Figure imgf000073_0005
2 deorotect
Figure imgf000073_0006
3G-aicohO! ugaie
Carbamate GG -alcoho!/5-FU codrug or carrier conjugate: H
O - M . . 0
T
ί
5-FU
1 . carbonyl diimidazote
Figure imgf000074_0001
GG- alcohol
Figure imgf000074_0002
GG-alcohol I conjugate
Vidarabine Conjugate
Figure imgf000074_0003
vidarabine
1 · carbonyl diimidazole
Figure imgf000074_0004
2. deprotec;
i- alcohol
Figure imgf000074_0005
Other antiviral drugs may be attached in simiiar fashion to the GG-a!cohoi or GG-acetone.
[0184] Illustrative and non-limiting examples of antibiotics useful in such compounds and certain nonlimiting points of attachment (shown by an "- ") of such an tibiotics to GGA or a GGA derivative are shown beiow.
Figure imgf000075_0001
, . .., Ciprofloxacin fvioxirloxacm
[0185] illustrative and non-limiting examples of glaucoma drugs useful in such compounds and certain nonlimiting points of attachment (shown by an "->") of such drugs to GGA or a GGA d
Figure imgf000075_0002
bets blocker
Apraclonidine
alpha 2 adrenergic agonist
Figure imgf000075_0003
anticholinergic
released in cornea
Synthesis of GGA derivatives f0186] Certain methods for making GGA or certain GGA derivatives utilized herein are described in PCT publication nos. WO 2012/031028, WO 2013/052148, and WO
2013/130654, each of which are incorporated herein by reference in its entirety. Other GGA derivatives can he prepared by appropriate substitution of reagents and starting materials, as will be well known to the skilled artisan upon reading this disclosure. [0187] The reactions are preferably carried out in a suitable inert solvent that wit! be apparent to the skilled artisan upon reading this disclosure, for a sufficient period of time to ensure substantial com pletion of the reaction as observed by thin layer chromatography, XH- R, 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 a re purified, if necessary, by various art known methods such as crystallization, precipitation, colu mn chromatography, and the likes, as will be apparent to the skilled artisan upon reading this disclosure.
[0188] The compounds utilized in this invention are synthesized, e.g., from a compound of formu la (il l-A):
Figure imgf000076_0001
(Ill-A) wherein n, R -R" and ^ are defined as in Formu la (I) above, following various we!f known methods upon su bstitution of reactants and/or altering reaction conditions as will be appa rent to the skilled artisan upon reading this disclosure, The compound of Formula (III- Aj is itself prepared by methods well known to a skilled artisan, for exam ple, and without limitation, those described in PCT Pat. App. Pu b. Nos. WO 2012/031028, WO 2013/052148, and WO 2013/130654 (each supra). An illustrative and non- limiting method for synthesizing a compound of Formula (lll-A), where n is 1, is schematically shown below.
Figure imgf000077_0001
(R
C02RE
Figure imgf000077_0002
Ύ ^ ^ Y ^ ^ ^ LiAIH^ ,v nM
^ O .R ; . « γ,^^ ^ '-^' ' --^H
R2 R3 ^ R5 R2 R 3 R4 Rs
(v,ii) (ix)
[01891 Starting compound (iii), which is synthesized from compound (i) by adding isoprene derivatives as described here, is alkylated with a beta keto ester (iv), in the presence of a base such as an alkoxide, to provide the corresponding beta-ketoester (v). Compound (v) upon alkaline hydrolysis followed by decarboxylation provides ketone (vi). Keto compound (vi) is converted, following a VVittig Horner reaction with compound (vii), to the conjugated ester (viii). Compound (vi if) is reduced, for example with UAIH , to provide alcohol (ix).
[0190] As vvi!i be apparent to the skilled artisan, a compound of Formula (HI ), where n is 2, is synthesized by repeating the reaction sequence of alkylatiori with a beta-keto ester, hydrolysis, decarboxylation, Wittig-Horner oSefirtation, and Li.AiH reduction.
[0191] Certain illustrative and non-limiting synthesis of compounds utilized in this invention are schematically shown below. Compounds where 0/ is -(OS)- or --SO;- are synthesized by substituting the carbonyi group of the reactants employed, as will be apparent to the skilled artisan .
[[00113322]] R R6" i inn tthhee sscchheemmeess bbeell<ow may also correspond to R*° and RS : as defined herein. R in the schemes below may also correspond to R26, R31 and R52 as defined herein. P.° in the schemes below may also correspond to R2', R:" and R5;i as defined herein. R'J in the scheme below may also correspond to R28. 3I and RM as defined herein. Ri3 in the schemes below may also correspond to Rb as defined herein. * in the schemes below may also correspond to Rto as defined herein. R15 in the schemes below may also correspond to R°° as defined herein. R"c in the schemes below may also correspond to R' 4, R: and Rn'! as defined herein. R19 in the schemes beiow may also correspond to R**, R33 and R"4 as defined herein. L is a leaving group as known to one of ordinary skill in the art.
Q2coci R2 R3 \ R4 I R i
Base * '' m
Q': is H or R&
R' COCI
-C02F
-.3 \ f>
Figure imgf000078_0001
Figure imgf000078_0002
00 >rmuia
As shown above,. RE is a!kyl.
[0193] Compound f ix) with alcohol functionality is an intermediate useful for preparing the compounds utilized in this invention. Compound (x), where L is an R'S02- group is made by reacting compound (ix) with R/'SC^CI in the presence of a base. The transformation of compound (iii) to compound (x) illustrates methods of adding isoprerse derivatives to a compound, which methods are suitable to make compound (iii) from compound (i).
Intermediate (ix) containing various FT-R5 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).
[0194] The intermediates prepared above are converted to the compounds utilized in this invention as schematically illustrated below:
Figure imgf000079_0001
Carbamates
Figure imgf000079_0002
Alicyclic
Figure imgf000079_0003
reas
Figure imgf000079_0004
Secondary Ureas Cycle or Aiicyciic
[0195J As used herein, for example, and without limitation, m is 0 or 1 and Fc-RJ are as defined herein, and are preferably aikyl, 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 in this invention by reacting with suitable isocyanates or carbamoyl chlorides, which are prepared by art known methods. The thiocarbamates and thioureas of this invention are prepared according to the methods described above and replacing the isocyanates or the carbamoyl chlorides with isothiocyanates (Rio-N=C=S) or thiocarbamoyl chlorides (R18-NH-C(=5)CI or R18R19N-C{=S)Ci). 10196] These and other compounds utilized in this invention are also prepared by art known methods, which may require optional modifications as will be apparent to the skilled artisan upon reading this disclosure.
Intermediates for synthesizing compounds utilized in this invention containing various R^R5 substituents are illustrated in the examples section and/or are well known to the skilled artisan.
[0197} Certain GGA derivatives utilized herein are synthesized as schematically shown below. imines, hydazones. alkoxyimines
Figure imgf000080_0001
[0198] 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. Suitable noniimiting examples of bases include hydroxide, hydride, amides, aikoxides, and the like. Various compounds utilized in this invention, wherein the carbonyl group is converted to an irnine, a hydrazone, an alkoxyimine, an enolcarbamate, a ketal, and the like, are prepared following well known methods.
[0199] Other methods for making the compounds utilized in this invention are
schematically illustrated below;
Figure imgf000081_0001
Figure imgf000081_0002
[0200] The metaliation is performed, by reacting the ketone with a base such as dimsyl anion, a hindered amide base such as diisopropy!amide, or hexarnethyidisiiazide, along with the corresponding metai cation, M. The amino carbonyl chioride or the isocyanate is prepared, for example, by reacting the amine (Rj4)2NH with phosgene or an equivalent reagent well known to the skilled artisan.
Figure imgf000081_0003
activation of -ϋί¾Η
RS2NH->
Figure imgf000081_0004
[0201] The beta keto ester is hydroiyzed 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 carbonyi diimodazoie, or 0-Benzotriazole-N,N,N',N'- tetramethyl-uroniurn-hexafluoro-phosphate (HBTU) and reacted with the amine.
Figure imgf000082_0001
R JNH : 'dehydrating agent
sieves
Figure imgf000082_0002
[0202] Various other compounds utilized in this invention are prepared from the compounds made in the scheme above based on art known methods.
Figure imgf000082_0003
(viii) (X)
As shown above., RL is alkyi.
[0203] The intermediates prepared above are converted to the compounds utilized in this invention as schematically illustrated beiovv:
1 .2,4-oxadiazoie
Figure imgf000082_0004
H O 1 ^R 1
Y
H2
a-Amino Acids
(Xi) .. ft Azaloactones
HO '
NH;.
Chiral ίί-Ασ; mo t R . . O .
Aicohoe O azoles
N -
R '
OxazoSnes r r ^/OH PDC, DC M r
R3 R4 f¾. O r
Figure imgf000083_0001
recycles
.0. r
R3 R.-. R,. N J R, r
1.3-O.ozo!e- 5- substituted 1 ,4-C)xazole
[0204] Compound (viit) is hydroiyzed to the carboxyiic acid (x), which is then converted to the acid chloride (xi). Compound (xi) is reacted with a suitable nucleophile such as a
hydrazide, a hydroxyiamine, an amino alcohoi, or an amino acid, and the intermediate dehydrated to provide a compound of Formula (IV), Alternatively, the allylic alcohol fix) is oxidized to the aldehyde (xi), which is then reacted with a cyanohydrin or
cyanotosylmethane to provide further compounds utilized in this invention.
[0205] GGA derivatives utilized in this invention can also be synthesized employing art known methods and those disclosed here by a!kene-aryi, alkene-heteroaryl, or aikene-akene couplings such as Heck, Stille, or Suzuki coupling. Such methods can use (vi) to prepare intermediate fxii) that can undergo Heck, Siilie, or Suzuki coupling under conditions well known to the skilled artisan to provide compounds utilized in this invention .
Wittig olefmaiion
O Rl
R2 P.3 R4 R5 R2 R 3 R6
(xii;
(vi)
Heck/Sfiiie/Suzuki coupling
R
r f r γ-' Q-
R2 R3 R4 R5 R2 R3 R4 R5
( ii)
[0206] Higher and lower isoprenyl homologs of intermediates (x), (xi), and (xii), which are prepared following the methods disclosed here, can he similarly employed to prepare other compounds utilized in this invention.
[0207] Compounds utilized in this invention are also prepared as shown below fosse
Q^CH2-L Q¾CH=PA"-
Figure imgf000084_0001
[0208] L is a leaving group and '¾ are as defined herei n, Ar is a preferably an aryl group such as phenyl , the base employed is an alkoxide such as tertiarybutoxide, a hydride, or an alky! lithium such as n-butyl lithium. Methods of carrying out the steps shown above are well known to the skilled artisan, as are conditions, reagents, solvents, and/or additives usefu l for performing the reactions and obtaining the compound of Form ula ( IV) in the desired stereochemistry.
[0209J Other methods for making the compounds utilized in this invention are schematically ill strated below:
Figure imgf000084_0002
meta!lation
Figure imgf000084_0003
R ! JR ; !NC0C1 or Rl jNCO
Figure imgf000084_0004
[02101 The metaliation is performed, by reacting the ketone with a base such as dimsyl anion, a hind ered am ide base such as diisopropylamide, or hexamethyldisiiazide, along with th e correspond ing metal cation, M. The amino carbonyi chloride or the isocyanato is prepared, for example, by reacting the amine R l R **NH with phosgene or an equivalent reagent well known to the skilled artisan.
Figure imgf000085_0001
activation of -CQiH group;
Figure imgf000085_0002
[02111 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 we!i known to the skilled artisan such as carbonyi diimodazole, or O-Benzotriazole-Ν,Ν,Ν',Ν'- tetramethy!-uronium-hexafluoro-phosphate (HBTU) and reacted with the amine. Certain other methods of reparing the conjugates are shown below.
Figure imgf000085_0003
R ! 5NH2/debydratmg agent
es
2E, 6c ιοε-Geramy
Figure imgf000085_0004
[0212] As shown above, R is a memantine or a ri!uzo!e residue.
[0213] Polyprenyl amine- GGA derivatives can be prepared by reductive amination employing the appropriate polyprenyl aldehyde, a primary or secondary amine and a borohydride reducing agent, as is weii known to the skilled artisan. The reaction can be carried out in THF or diethyl ether, optionally in presence of a protic acid, preferably a mild protic acid catalyst,
[0214] illustrative and nonlimiting methods of making antibiotic and glaucoma drug conjugates of GGA and derivatives thereof are schematically shown below and/or can be adapted by the skilled artisan based on this disclosure. See, also, Expert Opinion on Therapeutic Patents, Prodrug strategies in nasal drug delivery, 2002 , vol. 12, No. 3 , Pages 331-340.
Ciprofloxacin conjugate.
Figure imgf000086_0001
Ciprofloxacin
2 = protecting group
Figure imgf000086_0002
2. tieprotect
GG-alcohol
Figure imgf000086_0003
GG-aiconol I conjugate
Betaxoiol conjugate
Figure imgf000087_0001
-acetone
Betaxoiol Z = protecting qroup
Figure imgf000087_0002
ketal of GG-acetone a) i
Figure imgf000087_0003
O
,0,
N
H
Beiaxoiol
2 = protecting group
carbonyl cSiimidazole
Figure imgf000088_0001
2 deprotect
GG- alcohol
Figure imgf000088_0002
Pharmaceutical Compositions
[02151 In another aspect, this invention provides and/or utilizes a composition comprising a GGA or a GGA derivative provided herein and a pharmaceutically acceptable excipient.
[0216] Such compositions can be for muiated for different routes of administration.
Although com positions suitable for oral delivery will probably be used most freq uently, other routes that may be used i nclude transdermal, intravenous,, intraa rterial, pu lmonary, rectal,, nasal, vaginal, lingual, intramuscu lar, intraperitoneal, intracutaneous, intracranial, and su bcutaneous routes. Suitable dosage forms for admin istering the GGA or GGA derivatives of this in vention include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and ora l liqu ids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used, for example, in a transdermal patch form . Ail dosage forms may be prepared using methods that are standa rd in the a rt (see e.g., Rem ington's Pharmaceutical Sciences, 16th ed ., A. Oslo ed itor, Easton Pa. 1980) . [0217] Pharmaceutically acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of this invention, Such excipients may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. Pharmaceutical compositions in accordance with the invention are prepared by conventional means using methods known in the art,
[0218] The 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 preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanoi,. 1,2- propyiene glycol, poiygiycols, dimethyisulfoxide, fatty alcohols, triglycerides, partial esters of glycerin and the like,
[0219] Solid pharmaceutical excipients include starch, cellulose, hydroxypropyi 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, ethanoi and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil,, mineral oil, sesame oil, etc. in certain embodiments, the compositions provided or utilized herein comprises one or more of ct-tocopherol, gum arabic, and/or hydroxypropyi cellulose,
[0220] in one embodiment, this invention provides or utilizes sustained release
formulations such as drug depots or patches comprising an effective amount of a compound provided or utilized herein, in another embodiment, the patch further comprises gum Arabic or hydroxypropyi cellulose separately or in combination, in the presence of alpha- tocopherol. Preferably, the hydroxypropyi cellulose has an average MW of from 10,000 to 100,000. in a more preferred embodiment, the hydroxypropyi cellulose has an average MW of from 5,000 to 50,000.
[02,21] In one embodiment, this invention provides pharmaceutical compositions in the form of an enterocoated capsule or tablet that facilitates increased delivery of GGA to the intestine. [0222] Compounds and pharmaceutical compositions of this invention, including the intranasal formulations below, maybe used alone or In combination with other compounds. When ad ministered with another agent, the co-administration 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 compou nd of this invention and the other agent or that the two agents be administered at precisely the same time. However, co-administration will be accomplished most conveniently by the same dosage form and the same route of administration, at substantially the same time. Obviously, such administration most advantageously proceeds by delivering both active ingredients simultaneously in a novel pharmaceutical composition in accordance with the present invention.
[0223] In some aspects of the invention, a composition suitable for intranasal administration is provided for treatment of a neural disease, disorder or condition or for reducing the negative effects of a neural disease, disorder or condition, where the composition Includes GGA, preferably ail trans GGA, or a GGA derivative as described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for introducing GGA and/or derivatives thereof via the intranasal route into a subject. The intranasal dosage form may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16Lh ed., A. Oslo editor, Easton Pa. 1980). 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%.
[0224] Currently, intranasal administration has not gained wide acceptance. For example, all therapeutic agents cannot be effectively administered by the intranasal route. At present, the molecules which have proved suitable for this route of administration are still very few and consist essentially of only small peptide or hormone molecules (such as calcitonin, cerulean, .beta. -endorphin, glucagon, horseradish peroxidase, B-interferon , oxytocin and insulin) in special formulations. The ability of drug molecules to be absorbed by the nasal mucous membranes is utterly unpredictable, as is the ability of intranasal formulations to avoid irritation of the mucous nasal membranes. Mucous membrane a? irritation caused by the drug and/or excipient is the most common reason for which intranasal administration has not gained wider acceptance.
[02.2.5] The compositions according to the Invention Include GGA or a derivative thereof in quantities ranging from 1-55, 5-50, 10-40, or 20-30 mg/kg/day, diluted in excipienis such as huniectants, isotoning agents, antioxidants, buffers and preservatives. A calcium chelating agent is also preferably included.
{0226] The invention makes It possible to have single-dose dosage forms, which ensure application of an optimum quantity of GGA or a derivative thereof. The intranasal formulations of the invention contain concentrations of GGA or a derivative thereof ranging from 0.1 to 20%, preferably about 5-10% weight/volume. Selection of the particular excipienis depends on the desired formulation dosage form, i.e., on whether a solution to be used in drops or as a spray (aeroso!) Is desired or a suspension, ointment or gel to be applied in the nasal cavity are desired.
[0227] Vehicles useful in the compositions according to the invention comprise solvent systems containing ethyl alcohol, isopropyi alcohol, propylene glycol, polyethylene glycol, mixtures thereof or mixtures of one or more of the foregoing with water.
[0228] Suitable vehicles for the formulations according to the invention include aqueous suspensions or emulsions containing an appropriate isotoning agent selected among those commonly used in pharmaceutics. Substances used for this purpose are, for instance, sodium chloride and glucose. The quantity of isotoning agent should impart to the vehicle (taking Into account the osmotic effect of the active ingredient), an osmotic pressure similar to that of biological fluids, i.e. generally from about 350 to about 850 ml!!IOsmoies (mOsm) preferably from about 270 to about 330 mOsrn,
[0229J Nasal mucous membranes are also capable of tolerating slightly hypertonic solutions. Should a suspension or gel be prepared instead of a solution, appropriate oily or gel vehicles may be used or one or more polymeric materials may be included, which desirably should be capable of conferring bioadhesive characteristics to the vehicle.
[0230] Several polymers may be used for the preparation of a gel; nonlimiting examples include hydroxypropyl celluiose ( LUCEL®), hydroxypropyl methyl cellulose ( ETHOCEL®). hydroxyethyl cellulose (NATROSGL®), sodium carboxymethyl celluiose (BLANOSE®), acrylic polymers (CARBOPOL®, POLYC A BO P H i L ® ) , gum xantban, gum tragacanth, alginates and agar-agar. [02.3.1] Some of them, such as sodium carboxymethyl cellulose and acrylic polymers, have marked bioadhesive properties and are preferred if bioadhesiveness is desired.
[0232] Other formulations suitable for intranasal administration of GGA or a derivative thereof can be obtained by adding to the aqueous vehicle polymers capable of changing the rheologic behavior of the composition in relation to the temperature. These polymers make it possible to obtain low viscosity solutions at room temperature, which can be applied for instance by nasal spray and which increase in viscosity at body temperature., yielding a viscous fluid which ensures a better and longer contact with the nasal mucous membrane. Polymers of this class include without limitation polyoxyethyiene-polyoxypropylene block copolymers (POLOXA ER*).
[0233] In some embodiments, the formulation is a small particle liposome or lipid complex aerosol formulation. Methods of preparing such formulation are within the skill of the skilled artisan. See, for example, US 6,090,407.
[0234] In some embodiments, a pharmaceutically acceptable buffer is present to stabilize a pH range of about 4 to about 8; preferably about 5.5 to 7.5. Suitable non-limiting buffers include tris (tromethamine) buffer, phosphate buffer, etc.
[0235] Further excipients include chemical enhancers such as intranasal absorption promoters. These include chelating agents, fatty acids, bile acid salts and other surfactants, fusidic acid, !ysophosphatides, cyclic peptide antibiotics, preservatives, carboxylic acids (ascorbic acid, amino acids), glycyrrhetinic acid, o-acylcarnitine. Preferred promoters are diisopropyladipate, POE (9) fauryi alcohol, sodium giycocholate and lysophosphatidyl- choitne which proved to be particularly active. Finally, the new compositions according to the invention preferably contain preservatives which ensure the microbiological stability of the active ingredient. Suitable preservatives include without limitation, methyl
paraoxybenzoate, propyl paraoxybenzoate, sodium benzoate, benzyl alcohol, benzalkonium chloride and chlorobutanol.
[0236] The liquid formulations of GGA or a derivative thereof, preferably in the form of solutions, may be administered from a nasal spray devise of this invention comprising GGA or a GGA derivative, in the form of drops or spray, using atomizers equipped with a
mechanical valve and possibly including a propel!ant of a type commercially available, such as butane, Nz, Ar, C02, nitrous oxide, propane, dimethyl ether, chlorofluorocarbons (e.g. FREON) etc. Vehicles suitable for spray administration are water, alcohol, glycol and propylene glycol, used alone or in a mixture of two or more, in some embodiments, this invention provides muftidose nasa! spray devices, in other embodiments, this invention provides unit dose nasal spray devices.
[0237] Generally, illustrative and non-limiting formulations can contain the following ingredients and amounts (weight/volume):
[Ingredient Broad Range {%} Preferred Range {%)] Na?EDTA 0.001-1 0.05-0.1 Nipagin 0.01-2 0.05-0.25 POE (9) Laury! alcohol 0.1-10 1-10 NaCMC (Blanose 7m8 sfd) 0, 1-5 0.3-3 Carbopol 940 0.05-2 0.1-1.5 Glycerol 1-99 Sodium glycocholate 0.05-5 0.1-1
[0238] It will be appreciated by those of ordinary skill that ingredients such as sodium carboxymethyl cellulose and Carbopol exist in many types differing in viscosity. Their amounts are to be adjusted accordingly. Different adjustments to each formulation may aiso be necessary including omission of some optional ingredients and addition of others, !t is thus not possible to give an ail-encompassing amount range for each ingredient., but the optimization of each preparation according to the invention is within the skill of the art.
[0239] An alternative for the Intranasal administration of compositions including GGA or a derivative thereof comprises a suspension of finely micron ized active ingredient (generally from 1 to 200 micrometers, preferably from 5 to 100 micrometers) in a propellant or in an oily vehicle or in another vehicle in which the drug is not soluble. The vehicle is mixed or emulsified with the propellant. Vehicles suitable for this alternative are, for instance, vegetable and mineral oils and triglyceride mixtures. Appropriate surfactants, suspending agents and diluents suitable for use in pharmaceutics are added to these vehicles.
Surfactants Include without limitation sorbitan sesquioieate, sorbitanmonooieate. sorbitan trioleate (amount: between about 0.25 and about 1%); suspending agents include without limitation isopropylmyristate (amount: between about 0.5 and about 1%) and colloidal silica (amount: between about 0.1 and about 0.5%); and diluents include without limitation zinc stearate (about 0.6 to about 1%).
[0240] In certain preferred embodiments of this invention, there is provided or utilized a pharmaceutical composition comprising GGA or a GGA derivative and a-tocopherol. A related embodiment provides and/or utilizes a pharmaceutical composition comprising GGA or a GGA derivative, a-tocopherol, and hydroxypropyl cellulose, in another embodiment, there is provided or utilized a pharmaceutical composition comprising GGA or a GGA derivative, a-tocophero!, and optionally gum arable. In a further embodiment, there is a pharmaceutical composition comprising GGA or a GGA derivative, and gum arable, in a related embodiment, there is provided or utilized GGA or a GGA derivative, gum arabic and hydroxypropyi cellulose.
[0241] When a-tocopherol is used alone or in combination with other excipients, 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. In some embodiments, the concentration of a- 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.
[0242J When hydroxypropyi cellulose is used alone or in combination with other excipients, 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. In some embodiments, the concentration of hydroxypropyi 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.
[0243] When gum arabic is used aione or in combination with other excipients, 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, !n some embodiments, the
concentration of hydroxypropyi 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.
[0244] In certain embodiments, the concentration of GGA or 3 GGA 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% by weight. [0245] In some embodiments, solid dosage forms may further include, granules, pellets, beads, spheroids, a minitablet, a microtablet, granules in a capsule, pellets in a capsule, microtablets in a capsule, and minitablets in a capsule, each of which may be enteric coated, [0246] In certain aspects, the enteric formulations provide herein are useful for treating or alleviating the negative effects of various neurological diseases and disorders described herein and inflammatory bowel disease, chronic liver disease, a disorder selected from liver injury, preferably acute liver injury, acute liver failure, cardiac ischemia, myocardial infarction, repurfusion injury and heart transplants, or a related disorder or condition.
[0247] The compositions of the present invention may be prepared using conventional methods and materials known in the pharmaceutical arts.
[0248] Certain illustrative and non- limiting enteric polymers and coatings useful in this invention are described herein.
[0249] Enteric polymers used to coat pharmaceutical dosage forms include cellulose, vinyl, and acrylic derivatives. Enteric polymeric materials are primarily weak acids containing acidic functional groups, which are capable of ionization at elevated pH.
[02501 In some embodiments, the enteric coating coats a core of a dosage form disclosed herein and controls the location in the digestive tract where the active agent contained in the dosage form's core Is released and absorbed. In certain embodiments, the enteric coating is In the form of one or more components selected from the group including polymers, fatty acids, waxes, shellac, plastics, and plant fibers.
[0251] In certain embodiments, the enteric coating comprises one or more of the following: acrylates and acrylate copolymers, including methacry!ic acid/methacryiic acid methylester copolymer and methacrylic acid/ethyl acrylate copolymer; cellulose esters, including cellulose acetate phthalate, cellulose acetate trimeilitate, and cellulose acetate succinate; hydroxypropyl methylceliuiose phthalate; hydroxypropyi methy!ceflulose acetate succinate; polyvinyl derivatives, including polyvinyl acetate phthalate; and carboxymethyl ethyl cellulose. In some specific embodiments, the enteric coating includes one or more components sold under trade names, for example EM COAT 120 N, MARCO AT 125,
AQUACOAT CPD* SEP!FILM®, AQUACOAT® ECD, METOLOSE®, SURETERIC*, AND
EUDRAGIT®. In certain embodiments, the enteric coating may comprise colorants, in a specific embodiment, the enteric coating comprises a EU DRAG IT® polymer and a colorant, and is sold under the trade name ACRYL-EZE ORANGE8. [0252] in some embodiments, the enteric coating may further comprise a pfasticizer, !n some embodiments, the plasticizer will influence, i.e., increase or decrease, the rate of dissolution of the enteric coating. In some embodiments, the plasticizer may be lipophilic, in other embodiments, the plasticizer may be hydrophiiic.
[0253] Irs other embodiments, the piasticizer comprises one or more of the group including cetano!, triacetin, citric acid esters such as triethy! citrate, phthalic acid esters such as diethyl phthaiate and dibutyl phthalate, dibutyl succinate, propylene glycol, polyethylene glycol (PEG), and oils and giyeerides such as fractional coconut oil.
[0254] Exemplary and non!lmiting coating formulations include excipients as illustrated below:
%
Hydroxyprop! methyl cellulose E5 5
Hydroxypropy! methyl cellulose E.15 2
Polyethylene Glycol 6000 1
Polyethylene Glycol 4000 1
Titanium Dioxide 6
Purified Water to 100
%
Eudragit L30D 15
Antifoam M less than 1
Acetyl Triethy! Citrate 2
Talc Micronised 3
Pumped Water to 100
[0255] In some embodiments, a compound of this invention can be used as an adjunct to conventional drug therap of the conditions described herein.
Methods of Treatment
[0256] Some embodiments provided herein describe a method of treating a neural disease via an intranasal administration of GGA or a derivative thereof. In some instances, neural diseases are characterized by neuroinflammation. Examples of such neu ral diseases include, but are not limited to, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, multiple sclerosis, prion diseases such as Kuru, Creutzfeltdt-Jakob disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, and damage to the spinal cord. Also provided herein in some embodiments is a method of treating visual disorders such as optic neuropathy, glaucoma, degeneration of optic nerves, age-related macular degeneration (AMD) and ophthalmoplegia. Some embodiments described herein provide a pharmaceutical formulation for preventing neural death during epileptic seizures. Any pharmaceutical formulation and/or compounds described above are useful in the methods described herein.
[0257] Provided herein, in some embodiments, are methods for using effective amounts of GGA or a derivative thereof preferably having the (5E, 9E, 13E) configuration or the, optionally with at least one pharmaceutically acceptable excipient for inhibiting neural death and/or increasing neural activity, in some embodiments, GGA is the trans-GGA or the synthetic trans-GGA. For example, and without limitation, methods provided here in describe impeding the progression of neural diseases or injury using GGA or a derivative thereof.
[0258] In one aspect, methods for increasing the axon growth of neurons by contacting said neurons with the pharmaceutical compositions are provided herein. In some cases, neural diseases result in an impairment of signaling between neurons. In some cases, this impairment is due in part to a reduction in the growth of axonal projections, in some embodiments, contacting neurons with GGA or a derivative thereof enhances axonal growth. In some embodiments, GGA or a derivative thereof restores axonal grown in neurons afflicted with a neural disease, in a related embodiment, the pre-contacted neurons exhibit a reduction in the axon growth ability.
[0259] One embodiment provided herein describes a method for inhibiting the cell death of neurons susceptible to neuronal ceil death, which method comprises contacting said neurons with the pharmaceutical compositions provided or utilized herein. Neurons susceptible to neuronal cell death include those that have the characteristics of a neural 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 GG.A or a derivative thereof will inhibit their death as measured by a MTT assay or other techniques commonly known to one skilled In the art. [0260] in another aspect, there are methods for increasing the neurite growth of neurons by contacting said neurons with the pharmaceutical compositions provided or utilized herein. The term "neurite" refers to both axons and dendrites. Neural diseases can result in an impairment of signaling between neurons. In some cases, this impairment is due in part to a reduction in the growth of axonai and/or dendritic projections. It is contemplated that contacting neurons with GGA or a derivative thereof will enhance neurite growth. It is further contemplated that GGA or a derivative thereof 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.
[0261] One embodiment of this invention is directed to a method for increasing the expression and/or release of one or more neurotransmitters from a neuron fay contacting said neurons with the pharmaceutical compositions provided or utilized herein, it is contempiated that contacting neurons with an effective amount of GGA. and/or derivatives thereof will increase the expression level of one or more neurotransmitters. It is also contemplated that contacting neurons with GGA or a derivative thereof 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 ceil membrane, which directs the
neurotransmitters out of the neuron. It is contemplated that the increase in the expression and/or release of neurotransmitters will lead to enhanced signaling in neurons, in which levels of expression or release of neurotransmitters are otherwise reduced due to the disease. The increase in their expression and release can be measured by molecular- techniques commonly known to one skilled in the art.
[0262] One embodiment of this invention is directed to a method for inducing synapse formation of a neuron by contacting said neurons with the pharmaceutical compositions provided or utilized herein. 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 GGA or a derivative thereof, via intranasal administration, will Increase synapse formation in neurons that otherwise experience reduced synapse formation as a result of neural disease. 10263] Another embodiment of this invention is directed to a method for increasing electrical excitability of a neuron by contacting said neurons with the pharmaceutical compositions provided or utilized herein. Electrical excitation is one mode of
communication among two or more neurons. It is contemplated that contacting neurons with an effective amount of GGA or a derivative thereof, via intranasal administration, 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 electrophysiological methods commonly known to one skilled in the art.
[0264] In each of the three previous paragraphs above, the intranasal administration of GGA or a derivative thereof 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. I ncipient 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 via intranasal the route to said patient an effective amount of GGA or a derivative thereof.
[02653 in another embodiment, this invention 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 the pharmaceutical compositions provided or utilized herein, provided that said pathogenic protein aggregates are not related to SBMA, In one embodiment of this invention, the pathogenic protein aggregates form between or outside of the neurons. In another embodiment of this invention, the pathogenic protein aggregates form inside said neurons, in one embodiment of this Invention, 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 uch as neuroblastoma cells. It is contemplated that contacting neurons with an effective amount of GGA or a derivative thereof, via intranasal administration, will inhibit their death as measured by a MTT assay or other techniques commonly known to one skilled In the art.
[0266] Another embodiment of the invention 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 the pharmaceutical compositions provided or utilized herein, in one embodiment of this invention, contacting said neurons and/or said pathogenic protein aggregates with the pharmaceutical compositions provided or utilized herein. Without being limited to any theory, it is contemplated that contacting the neurons and/or the pathogenic protein aggregates with GGA or a derivative thereof, via intranasal administration, will soiubifize at least a portion of the pathogenic protein aggregates residing between, outside, or inside of the ceils. It is further contemplated that contacting the neurons and/or the pathogenic protein aggregates with GGA or a derivative thereof, via intranasal administration, will aiter 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. There are many 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 ceil viability by a TT assay. Another example is by immunostaining neurons in vitro or in vivo for ceil death-indicating molecules such as, for example, caspases or propidium iodide.
[0267] In yet another embodiment of the invention is directed to a method for protecting neurons from pathogenic intracellular protein aggregates which method comprises contacting said neurons with the pharmaceutical compositions provided herein 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. SB A 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 polyglutamtnes and are formed intranucleariy. It is also distinct, from the neural diseases described in this application because the protein aggregates are formed from androgen receptor protein accumulation. It is contemplated that contacting neurons via intranasal administration with an effective amount of GGA or a derivative thereof will alter the pathogenic protein aggregate into a non-pathogenic form.
[0268] One embodiment of the invention is directed to a method of modulating the activity of G proteins in neurons which method comprises contacting said neurons with the pharmaceutical compositions provided or utilized herein. It is contemplated that contacting neurons via intranasal administration with an effective amount of GGA or a derivative thereof will alter the sub-ceiiutar localization, thus changing the activities of the G protein in the ceii. !n one embodiment of the invention, contacting neurons via intranasal administration with an effective amount of GGA and/or derivatives thereof will enhance the activity of G proteins in neurons, ft is contemplated that contacting neurons via intranasal administration with an effective amount of GGA or a derivative thereof will increase the expression level of 6 proteins, it is also contemplated that contacting neurons via intranasal administration with an effective amount of GGA or a derivative thereof 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.
[0269] One embodiment of the invention 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 the pharmaceutical compositions provided or utilized herein, 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 via intranasal administration with an effective amount of GGA or a derivative thereof, it is further contemplated that an effective amount of GGA or a derivative thereof 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.
[0270] Another embodiment of the invention is directed to a method for inhibiting the neurotoxicity of β-amy!oid peptide by contacting the β-amy!oid peptide with the
pharmaceutical compositions provided herein. In one embodiment of the invention the β- amyioid peptide is between or outside of neurons. In yet another embodiment of the invention, the β-amyloid peptide is part of the β-amyloid plaque, it is contemplated that contacting neurons via intranasal administration with an effective amount of GGA or a derivative thereof will result in solubilizing at least a portion of the β-amyloid peptide,, thus decreasing its neurotoxicity. It is further contemplated that an effective amount of GGA or a derivative thereof will decrease the toxicity of the β-amyloid peptide by altering it in such a way that it is no longer toxic to the cell. It is also believed that an effective amount of GGA and/or derivatives thereof 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 g!ia! cells may be transmitted
extraceilularly 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 !VITT 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.
[0271] One embodiment of the invention is directed to a method for inhibiting neural death and increasing neural activity in a mamma! 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 the pharmaceutical compositions provided or utilized herein. This method is not intended to inhibit neura! death and increase neura! activity in neura! diseases in which the pathogenic protein aggregates are intranuclear or diseases in which the protein aggregation is related to SB A.
[0272] Neural diseases such as AD and ALS disease have the common characteristic of protein aggregates either inside neura! ceils in cytoplasm or in the extracellular space between two or more neural cells. This invention relates to a method for using, via intranasal administration, an effective amount of GGA or a derivative thereof to inhibit the formation of the protein aggregates or alter the pathogenic protein aggregates into a nonpathogenic form, !t is contemplated that this will attenuate some of the symptoms associated with these neural diseases.
[0273] In one embodiment the mammal is a human afflicted with a neural disease, in one embodiment of this invention, the negative effect ot 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. It is contemplated that an effective amount of GGA and/or derivatives thereof will prevent or inhibit the formation of extracellular or intracellular protein aggregates that are cytoplasm, not intranuclear and not related to SBMA. ft is also contemplated that an effective amount of GGA or a derivative thereof wili 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 735652.1 both of which are incorporated herein by reference in their entirety.
[0274] In one embodiment of the invention the negative effect of the neural disease being inhibited or reduced is AD, AD is a neurodegenerative disease that does not typically show intranuclear protein aggregates. It is contemplated the intranasal administration of an effective amount of GGA or a derivative thereof will prevent or inhibit the formation of extracellular or intracellular protein aggregates. St is also contemplated that the intranasal administration of an effective amount of GGA or a derivative thereof 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 U.S. 6,130,048 and U.S. 6,391,553 both of which are incorporated herein by reference in their entirety.
[0275] In another embodiment, the mammal is a laboratory research mammal such as a mouse. In one embodiment of this invention, 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 intranasal administration of an effective amount of GGA or a derivative thereof will enhance the motor skills and body weights when administered to a mouse with a mutant Sodl gene, it is further contemplated that the intranasal administration of an effective amount of GGA or a derivative thereof 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. in yet another embodiment of this invention, the neural disease is AD. One example of a transgenic mouse model for AD is a mouse that overexpresses the APP (Amyloid beta Precursor Protein), It is contemplated that the intranasal administration of an effective amount of GGA or a derivative thereof to a transgenic AD mouse will improve the learning and memory skills of said mouse. It is further contemplated that the intranasal
administration of an effective amount of GGA or a derivative thereof will decrease the amount and/or size of β-amy!oid peptide and/or plaque found inside, between, or outside of neurons. The β-amyloid peptide or plaque can be visualized in histology sections by imrnunostaining or other staining techniques.
[0276J In one embodiment of the invention the intranasal administration of an effective amount of GGA or a derivative thereof to a mammal alters the pathogenic protein aggregate present into a non-pathogenic form, in another embodiment of the invention., the
intranasal administration of an effective amount of GGA or a derivative thereof to a mammal will prevent pathogenic protein aggregates from forming.
{0277} Another aspect of this invention relates to a method for reducing seizures in a mamma! in need thereof, which method comprises administering the pharmaceutical compositions provided or utilized herein, thereby reducing seizures. The reduction of seizures refers to reducing the occurrence and/or severity of seizures. In one embodiment, the seizure is epileptic seizure. In another embodiment, the methods of this invention prevent neural death during epileptic seizures. The severity of the seizure can be measured by one skilled in the art.
[027S] in some embodiments, an intranasal formulation of GGA or a derivative thereof described herein exerts cytoprotective effects on a variety of organs, e.g., the brain and heart. (See., for example Tanito M, et a!., J Neurosci 2005; 25:2396-404; Fujiki , et at., J Neurotrauma 2006; 23:1164-78; Yasuda H, et a!., Brain Res 2005; 1032:176-82; Ooie T, et a!., Circulation 2001; 20; 104:1837-43; and Suzuki S, et a!., Kidney Int 2005; 67:2210-20).
[0279] Method of treating bacterial infections, vira! infections, or cancers of the eye, brain, and spinal cord, and the nerves in the brain, eye, and the spinal cord are well known in the art and can be appropriately adapted fo practicing the methods of this invention upon reading this disclosure by the skilled artisan.
EXAMPLES
[0280] The following examples of formulations for the intranasal administration of GGA or a GGA derivative serve to illustrate the invention without limiting its scope.
Example \: Time Course of C S- 102 induced H5P70 Expression In Vivo.
[0281] The time course of protein expression,, as measured by western blot for HSP70, was determined in triplicate for hippocampus, and cortex tissue samples taken from each of* 5 animals per group at each of four time points (24, 48, 72, and 96 h) after treatment with either PBS or 12 mg/kg CNS-102, administered orally. The average expression for each treatment group is calculated at each time point for each tissue using PROC MIXED in SAS and are tabulated, along with the difference (delta) between treatment averages and a p- vaiue comparing the difference to zero, below.
10.3 HSP70 Expression Following Administration of CNS-102 vs PBS
Figure imgf000105_0001
[0282] Expression of HSP70 was observed after CNS-102 administration and the difference between CNS-102 and PBS induced expression (delta, in the table! in both the cortex at 24 h and the hippocampus at 72 h was statistically significant {bolded in the table).
[0283] These results demonstrate that CNS-102 induces expression of HSP70 as measured in the cortex 24 h after administration while in the hippocampus the !evei of HSP70 was not significant until 72 h after administration. No significant levels of HSP70 were found in the cortex after 24 h, however since no time points before 24 h were taken, it may be that HSP70 is expressed earlier, in the hippocampus the expression appears to peak after 48 h with significant levels measured at 72 hours. [0284] CNS-102 at 12 mg/kg or PBS was administered orally to Sprague-Da ley rats and the time course of HSP70 protein expression In tissues, was measured by ELISA . HSP70 protein expression was determined for lung, testicle, spleen, liver, kidney, blood plasma, skin, peripheral blood monocytes, heart, eye, muscle, intestine,, and stomach at each of three time points (8h, 17h, 2 li),
[0285} Table: Time Course of HSP70 expression as measured by ELISA in select tissues following 12mg/kg p o of CNS-102
HSP70 Fold Induction
vs. Vehicle Control
8h 17h 24h
testicle 1.10 1.03 0 94
spleen 0.64 1.09 1.04
fiver 1.24 1.00 0.89
kidney 1.11 1.08 0.92
plasma 0.88 1.09 1.05
PBMC 1.67 1.05 1.09
heart 1.89 0,60
intestine 1.63 1.26 0.64
Stomach 1.07 1.30 0.96
Example 2: Treatment of Inflammatory Bowel Disease (IBP) with GGA or a GGA derivative.
[0286] A pharmaceutical composition comprising GGA or a GGA derivative as described herein is prepared. A subject is diagnosed with mild to moderate IBD. The subject receives a daily administration of GGA or a GGA derivative, or a pharmaceutically acceptable salt thereof. Subjects are treated for 12 weeks. Subjects keep daily diaries and record the number and nature of bowel movements. The effect of the treatments is assessed by grading clinical symptoms of fecal blood, mucus, and urgency. In addition , sigmoidoscope assessment and biopsies are performed, and efficacy of treatment assessed, based on grading of sigmoidoscope and degree of histological inflammation in rectal biopsy specimens. Safet Is assessed based on spontaneous side effect reporting.
[0287] ft is contemplated that GGA or a GGA derivative, or a pharmaceutically acceptable
1 wS salt thereof, of this example will demonstrate efficacy in inflammatory bowel disease ! BD In terms of both treating the condition and maintaining remission from disease symptoms Example 3; Treatment of Inflammatory Bowel Disease (IBP) with GGA or 3 GGA derivative in gastrectomized patients.
[028S] A pharmaceutical composition comprising GGA or a GGA derivative as described herein is prepared. A subject is diagnosed with mild to moderate IBD following
gastrectomy. The subject receives a daily administration of GGA or a GGA derivative, or 3 pharmaceutically acceptable salt thereof. Subjects are treated for 12 weeks. Subjects keep daily diaries and record the number and nature of bowel movements. The effect of the treatments is assessed by grading clinical symptoms of fecal blood, mucus, and urgency, in addition, sigmotdoscopic assessment and biopsies are performed, and efficacy of treatment assessed., based on grading of sigmoidoscopic and degree of histological inflammation in rectal biopsy specimens. Safet is assessed based on spontaneous side effect reporting.
[0289] It is contempl ated that GGA or a GGA derivative, or a pharmaceutically acceptable salt thereof, of this example will demonstrate efficacy in Inflam matory bowei disease IBD in terms of both treating the condition and maintaining remission from disease symptoms.
Example 4: GGA and derivatives thereof protect intestinal epithelial cells from oxidative stress in yit.ro.
[0290] Rat intestinal epithelial cell line (IEC-18) ceils are pretreated with GGA or a GGA derivative and then subjected to injury induced by H2CI. Ceil viabilit is assessed, and endogenous HSP70 levels are determined by enzyme-linked immunosorbent assay in IEC-18 cells. Treatment with GGA or a derivative thereof rapidly elevates HSP70 levels and protects against H2CI-induced injury in IEC-18 cells.
Example 5; GGA and GGA derivatives protect mice from dextrars sulfate sodium (OSS) - induced colitis.
[0291] SALS/c mice are given 3% DSS solution oraily for 7 days to induce colitis. The disease activity of colitis is assessed clinically every day, and histology in the colon is evaluated at 7 days post-DSS. The levels of myeloperoxidase (fvlPO) activity, tumor necrosis factor (TNF)- aipha and interferon (IFN)-gamma in the colon tissues are also examined, in addition, expression of HSPs 25, 40, 70 and 90 in the colon tissue is determined by Western blot analysis or ELISA. GGA or a GGA derivalive is administered orally to mice when treatment of DSS is initiated. GGA or a derivateive thereof significantly reduces the clinical severity of colitis and suppresses the levels of MPO activity, TNF-alpha and IFN-gamma induced by DSS in the colon. On the other hand, GGA enhances the expression of HSP70 in the colon of mice given DSS.
j tagm!g 6: Preyjentjon of acute liver damage after hepatectomy.
[0292] Acute liver failure after massive hepatectorrsy remains a challenging problem.
Male ister rats weighing 230-260 g are obtained. After an overnight fast, GGA or a GGA derivative (as an emulsion with 5% gum arabic and 0.004% a-tocophenoi) or vehicle (5% gum arabic emulsion with 0,004% a- tocophenol) is intragastrically administrated into rats 4 h prior to the operation. After rats are anesthetized, 90% hepatectomy is performed. Briefly, the left, median, right-upper, and right-lower lobes are removed, leaving the caudate lobes, which represent 10-11% of the original liver mass. Liver specimens and blood samples are collected after laparotomy and exsanguinations under deep anesthesia immediately before (0) and 4, 8, 12, and 24 h after the operation. Small pieces of liver tissue are immediately stored in an RNeasy stabilization kit (Gjagen, Hilden, Germany), Sera are immediately separated, and the activities of alanine (ALT) and aspartate (AST) aminotransferases are measured,
A single oral administration of GGA or a GGA derivative significantly suppresses the release of aminotransferases and improves survival compared with vehicle administration. Gene expression and immunobiot analyses shows that, in addition to HSP70 and HSP27, GGA or GGA derivatives induce an endoplasmic reticulum chaperone, BiP.
Example 7; Protection from acetaminophen induced hepatotoxicitv in vitro,
[0293] In order to test the protective activity of GGA and GGA derivatives from
acetaminophen-induced hepatotoxicity, a cytotoxicity assay is employed using human hepatoma (Bel-7402) cells in the presence of S9 mixture. Cell viability and mitochondrial permeability transition (MPT) is assessed in the presence or absence of GGA or GGA derivatives in combination with a cytotoxic concentration of acetaminophen. GGA or GGA derivatives show increased cell viability and protect from MPT disruption in the presence of acetaminophen compared with control conditions.
Example 8: Treatment of nori-alcohoiic steatohepatitSs.
[0294] 100 adults with nonalcoholic steatohepatitis are randomly assigned to receive GGA or a GGA derivative, each at a daily dose of about 10-200 mg, or placebo, for up to 12 months. The primary outcome is an improvement in histological features of nonalcoholic steatohepatitis. The extent of lobular inflammation, hepatoceiiu!ar ballooning, and/or fibrosis is measured. The results are analyzed following methods well known in the art. Example 9 : Treatment of nori-aicohoiic fatty liver disease fNAFLP).
[0295] A randomized, blinded, placebo-controlled study is performed on 100 patients with NAFLD diagnosed by ultrasound (US) and confirmed by liver biopsy (40 patients). The patients are randomized to receive GGA or a GGA derivative (each at a daily dose of 10-200 mg for up to 12 months) or placebo. All patients participate in an identical behavioral weight loss program, and undergo monthly evaluation by abdominal US. Liver enzyme levels, lipid profiles, insulin levels, and anthropometric parameters are also monitored, and all patients undergo nutritional follow-up evaluation. Patients also undergo a further liver biopsy examination as the study progresses. Serum alanine transaminase levels and steatosis by US are measured as non-limiting endpomts. The results are analyzed following methods well known in the art.
Example 10: GGA and GGA derivative activity in a cardiac ischemic ischemia and reperfusion in vitro model,
[0296] GGA and GGA derivatives are tested for protective effects an in vitro
ischemia/reperfusion cardiac disease model based on the contractile HL-1 cell line. Activity is assessed via apoptosis signaling, ceil structure and energy-metabolism. The HL-1
cardiornyocytes (murine atrial tumor cell line) are maintained in mono!ayer culture with Claycomb-medium (Sigma, Germany), Heaving reached confluence and contractile activity, cells are maintained as subcultures, induction of ischemia was carried out on vital cardiornyocytes at culture day four. The subconfluent, contractile HL-1 cardiornyocytes are placed in nutrient-deficiency medium containing 2.5 mM hydrogen peroxide solution in order to enhance the oxidative stress in HL-1 cells. In control cultures the medium exchange is carried out with standard supplemented Claycomb-medium. 8 h after ischemia induction samples are harvested and revitalization is induced in parallel by replacing nutrient- deficiency medium with fresh Claycomb-medium and incubating cells for another 16 hours. Ceil proliferation analysis is done by flo cytometry.. Apoptosis analysis is performed by terminal desoxynuc!eotidyl transferase-rnediated dUTP nick end-labeling. Total number of ceils are determined using 7-AAD nucleus staining, Additionally formaldehyde- fixed cells on glass coverslips are prepared for immuncytochemicai staining, TUNEL assay is performed using an In Situ Ceil Death Detection Kit, GGA and GGA derivatives reduce ischemia induced apoptosis and rescue ischemia-induced reduction of ceil proliferation.
Example 11: GGA and GGA derivatives protect against myocardial ischemia and
reperfusion injury in rats.
[0297] Anesthetized male rats are treated once orally with GGA or a GGA derivative 2.4 h before ischemia, and subjected to ischemia for 30 min, followed by reperfusion for A h. Lactate dehydrogenase (LDH), creatine kinase (CK), malondialdehyde (M DA), superoxide dismutase (SOD) activity and infarct size are measured. The results show that ore-treatment with GGA or a GGA derivative significantly reduces the Infarct si2e and the levels of LDH and CK after 4 h of reperfusion. GGA also significantly inhibits the increase in MDA levels and the decrease in SOD levels.
Example 12: Host shock protein 70 induced by GGA or GGA derivative protects
heterotopically transplanted hearts in rats.
[0298] A total of 20 donor rats are randomly divided into 2 groups. One of those receives an oral dose of GGA or a GGA derivative and one is a control group. Donor hearts are heterotopically transplanted into recipient rats 24h after GGA administration. The levels of HSP70 expression In donor hearts and the variation of myocardial enzymes in receptor biooci or donor hearts are measured 24 h after transplantation. The donated hearts are also examined under a microscope for pathological changes. HSP70 expression is increase in the GGA-treated group. Lactate dehydrogenase and creatine kinase m uscle band concentrations in receptor blood are decreased in the GGA group compared to the control group.
Moreover, the GGA group shows the lower malondialdehyde concentration and the h igher atriphosphate concentration than the control group, demonstrated by the milder inflammatory Injury in the transplanted hearts.
Example 13: Treatment of Cardiac Ischemia and Related indications.
[0299] A randomized, blinded, placebo-controlled study is performed on 100 patients diagnosed with cardiac ischemia, myocardial infarction or acute coronary syndrome based on coronary angiograms. The patients are randomized to receive GGA or a GGA derivative (each at a daily dose of 10-200 mg for up to 12 months) or placebo. GGA or a GGA derivative is directl administered, e.g.. in an emergency room setting, to the coronary artery via a PCI/stent catheter followed by oral administration of GGA or a GGA derivative for several weeks. In some patients, administration of GGA or a GGA derivative occurs during percutanous intervention (PCI) vvhiie stenting through a catheter directly to the coronary artery and the site of infarction. Oral treatment follows preferably for at least 1 month following the heart attack. The incidence of angina is ascertained , The results are analyzed following methods well known in the art.
Composition % For 10 liters
GGA or a GGA derivative 0, 1-20% 10- 2, .000 g
EDTA disodium (chelating agent) 0.01-0.1 1- 10 g
NIPAGIN (preservative) ** 0.1-0,5 10-50 g
Purified water 100 10 L
Methy!paraoxybenzoate (Nipagin): BDH Chemical LTD, Poole, Dorset, UK
Method of Preparation:
in a suitable vessel equipped with mixer and heating sleeve, introduce about 9 liters of purified water and heat to a temperature of 80 °C. Dissolve Nipagin and EDTA disodium. Stir the solution constantly to complete dissolution of the components. Coo! the obtained solution to room temperature.
Dissolve or suspend GGA or a GGA derivative by stirring. Bring to volume with water. The isotonicity of this composition can be adjusted, if needed, by the addition e.g.,. of 0.3% NaCI or 2.03% of glucose.
Example .15: Argatroban conjugates of GGA or a GGA derivative Described below are representative synthetic routes to small molecule e.g., Argatroban conjugates of GGA or a GGA derivative. Methods for synthesizing these Argatroban conjugates will be apparent to the skilled artisan in view of this disclosure.
Figure imgf000111_0001
Figure imgf000112_0001
111 Example 16: Zofran conjugates of GGA or a GGA derivative Described beiow are representative synthetic routes to small molecule e.g.,. Zofran conjugates of GGA or a GGA derivative. Methods for synthesizing these Zofran conjugates will be apparent to the skilled artisan in view of this disclosure.
Figure imgf000113_0001
Bu Li
Figure imgf000113_0002
Example 17: Representative linkages for drug conjugates of GGA or a GGA derivative
Described beiow are representative synthetic routes to drug conjugates of GGA or a GGA derivative. Methods for synthesizing these drug conjugates will be apparent to the skilled artisan in view of this disclosure. Esters, amides, ureas, carbamates and carbonates:
Figure imgf000114_0001
Z = bond, O, NH, N(C i -C6alky!)
Drug = small molecule, peptide, protein, antibody, etc.
Figure imgf000114_0002
Z = bond. O, NH, N(C rC6aikyi)
Dru = small mo!ecu !e, peptide, protein, antibody, etc.
Figure imgf000114_0003
Drua
R2 / ¾ O
' m
X = O, S or NH
rug Starting Materials
Formulated for Sublingual Delivery
Figure imgf000115_0001
R 14 i = H or CH, Hytiro!ytic conditions
in vivo
Revert to Startino Materials
Drug = small molecule, peptide, protein, antibody,
Sulfenyfated amides
Figure imgf000115_0002
Starting Materials
Formulated for
Sublingual Delivery
Figure imgf000115_0003
Reductive conditions
in vivo
Revert to Starting Materials
Z = bond , Ο , ΝΗ, NiC-rC6alkyS)
Drug = small molecule, peptide, protein, antibody, etc.
[0300] All abbreviations for scientific terms used herein have their ordinary scientific meaning as known to the skilled artisan.

Claims

1. An intranasal composition, the composition comprising an effective amount of geranyigeranyl acetone (GGA) or a GGA derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient,
2. The composition of claim 1, wherein the GGA or a GG.A derivative exists at least 80%, or at least 90%, or at ieast 95%, or at Ieast 99% in the trans isomer.
3. An intranasal composition, the composition comprising an effective amount of geranyigeranyl acetone (GGA) or a GGA derivative, or a GGA derivative conjugated with a drug optionally via a linker that is labile in vivo, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient,
4. The composition of claim 3, wherein the GGA or a GGA derivative exists at Ieast 80%, or at least 90%, or at ieast 95%, or at Ieast 99% in the c/s isomer or wherein or a GGA derivative exists at Ieast 80%, or at least 90%, or at Ieast 95%, or at Ieast 99% in the trans fo m.
5. The composition of any one of claims 1-4 comprising 0.1-20% (weight/volume) of GGA or a GG.A derivative, or a pharmaceutically acceptable salt thereof,
6. The composition of any one of claims 1-4 comprising 5-10% (weight/volume} of GGA or a GGA derivative, or a pharmaceutically acceptable salt thereof.
7. The composition of any one of claims 1-6 in the form of a solution, suspension or emulsion.
8. The composition of any one of claims 1- 7 wherein said excipient comprises a bioadhesive and/or an intranasal absorption promoter,
9. The composition of claim 8, wherein said intranasal absorption promoter is selected from the group consisting of a chelating agent.
10. An enteric composition, the composition comprising an effective amount of GGA or a GGA derivative or a pharmaceutically acceptable salt thereof, and 3 pharmaceutically acceptable excipient.
11. A method comprising administering intranasal!1/ an effective amount of a
composition of any one of claims 1-9 to a subject in need thereof.
12. A method for treating a neural disease, disorder or condition and/or reducing one or more negative effects of a neural disease,, disorder or condition comprising administering intranasaiiy an effective amount of a composition of any one of claims 1-9, or administering oraliy an enteric composition of claim 10, to a subject in need thereof.
13. A method for treating inflammatory bowel disease and/or reducing one or more negative effects of inflammatory bowel disease comprising administering an effective amount of a composition of GGA or a GGA derivative to a subject in need thereof.
14. A method for treating chronic liver disease and/or reducing one or more negative effects of chronic liver disease comprising administering an effective amount of a composition of GGA or a GGA derivative to a subject in need thereof.
15. A method of treating a disorder selected from liver injury, preferably acute liver injury {from trauma, surgery or as a side effect of cancer treatment), acute liver failure, preferably caused by drug toxicity such as acetaminophen toxicity, cardiac ischemia, myocardial infarction, repurfusion injury and heart transplants, or a related disorder or condition, comprising administering a composition comprising an effective amount of geranylgeranyl acetone {GGA) or a GGA derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, to a subject in need thereof.
16. The method of any one of claims 13-15. wherein the composition is that of any one of claims 1-10.
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US201361808174P 2013-04-03 2013-04-03
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