WO2023096854A1 - Agonistes du récepteur de l'acétylcholine et procédés de traitement de troubles neurologiques et de la douleur neuropathique - Google Patents

Agonistes du récepteur de l'acétylcholine et procédés de traitement de troubles neurologiques et de la douleur neuropathique Download PDF

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WO2023096854A1
WO2023096854A1 PCT/US2022/050553 US2022050553W WO2023096854A1 WO 2023096854 A1 WO2023096854 A1 WO 2023096854A1 US 2022050553 W US2022050553 W US 2022050553W WO 2023096854 A1 WO2023096854 A1 WO 2023096854A1
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alkyl
acetylcholine receptor
receptor agonist
acid
pharmaceutically acceptable
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PCT/US2022/050553
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Jonnie R. Williams
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Miralogx Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • Acetylcholine (ACh), a neurotransmitter, can regulate neuronal excitability by acting on the cys-loop cation-conducting ligand-gated nicotinic ACh receptor (nAChR) channels.
  • nAChR nicotinic ACh receptor
  • CNS central nervous system
  • these receptors are widely distributed throughout the central nervous system (CNS), being expressed on neurons and non-neuronal cells, where they participate in a variety of physiological responses such as anxiety, the central processing of pain, food intake, and cognitive functions.
  • CNS central nervous system
  • nine different subunits have been identified, which assemble into pentameric complexes with much subunit diversity. The 0.7 and 0.402 subtypes predominate in the CNS.
  • Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders.
  • the a7* and non-a7 nAChR subtypes are active targets for therapeutic development in neurodegenerative disease, neurodevelopmental disorders, and chronic pain. These receptors play a role in the etiology and treatment of such neurological disorders as Alzheimer’s disease (AD), autism, schizophrenia, neuropathic pain, and addiction.
  • AD Alzheimer’s disease
  • autism schizophrenia
  • schizophrenia neuropathic pain
  • addiction addiction
  • an acetylcholine receptor agonist has a structure selected from the group consisting of: or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt.
  • an acetylcholine receptor agonist has a structure selected from the group consisting of:
  • an acetylcholine receptor agonist has a structure selected from the group consisting of: and or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt.
  • a pharmaceutical composition comprises a therapeutically effective amount of at least one acetylcholine receptor agonist depicted above and a pharmaceutically acceptable vehicle therefor.
  • a method of treating a neurological disorder comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a acetylcholine receptor agonist having the structure: and a pharmaceutically acceptable vehicle therefor.
  • a method of treating a neurological disorder comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a acetylcholine receptor agonist having the structure: and a pharmaceutically acceptable vehicle therefor.
  • a method of treating a neurological disorder comprises administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a acetylcholine receptor agonist having the structure: and a pharmaceutically acceptable vehicle therefor.
  • the disorder is Alzheimer’s disease (AD), autism, schizophrenia, or neuropathic pain.
  • the disorder is depression, anxiety, or an addiction.
  • the present disclosure provides a method for treatment or remedy of smoking addiction or promoting smoking cessation, comprising administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a acetylcholine receptor agonist disclosed herein.
  • the present disclosure relates to an acetylcholine receptor agonist having a structure selected from the group consisting of
  • the present disclosure relates to an acetylcholine receptor agonist having a structure according to Formula la or Formula lb set forth below:
  • X is an ion of an acid forming a pharmaceutically acceptable salt
  • a and B are independently selected from nitrogen (N) or Carbon (C)
  • Ri, R2, R3, and R5 are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle
  • RHs selected from the group consisting of ketone, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle
  • the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, NR A R B
  • the present disclosure relates to an acetylcholine receptor agonist having a structure according to Formula Ila or Formula lib set forth below:
  • X is an ion of an acid forming a pharmaceutically acceptable salt
  • a and B are independently selected from nitrogen (N) or Carbon (C)
  • Ri, R2, R3, R5, and Re are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle
  • R4 is selected from the group consisting of ketone, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle
  • the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, NR A R B
  • Ri has the structure according to Formula Illa or Formula Illb:
  • A is N
  • B is C
  • one of - is a double bond.
  • both A and B are N.
  • B is N, and R2 is nothing.
  • Ri, R2, and/or R3 is methyl.
  • R4 is a ketone
  • one of > - is a double bond.
  • the acetylcholine receptor agonist has the structure:
  • the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof. [25] In some embodiments, the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.
  • the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.
  • the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.
  • the present disclosure relates to an acetylcholine receptor agonist comprising
  • acetylcholine receptor agonist having a structure selected from the group consisting of:
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an acetylcholine receptor agonist disclosed herein and a pharmaceutically acceptable vehicle therefor.
  • the present disclosure relates to a method of treating a neurological disorder comprising administering to an individual in need thereof the pharmaceutical composition disclosed herein.
  • the disorder is depression.
  • the disorder is anxiety.
  • the disorder is neuropathic pain.
  • the disorder is Alzheimer’s disease.
  • the disorder is an addiction.
  • the addiction is tobacco or nicotine addiction.
  • the present disclosure relates to a method of treating a neurological disorder comprising administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure:
  • X is an ion of an acid forming a pharmaceutically acceptable salt, and a pharmaceutically acceptable vehicle therefor.
  • the disorder is depression.
  • the disorder is anxiety.
  • the disorder is neuropathic pain.
  • the disorder is Alzheimer’s disease.
  • the disorder is an addiction.
  • the addiction is tobacco or nicotine addiction.
  • the present disclosure relates to a method of treating nicotine addiction associated with smoking tobacco or promoting smoking cessation in a subject in need thereof, comprising administering a therapeutically effective amount of an acetylcholine receptor agonist or the pharmaceutical composition disclosed herein to the subject in need thereof.
  • the method of treating tobacco or nicotine addiction, or treating nicotine addiction associated with smoking tobacco or promoting smoking cessation comprises administering the acetylcholine receptor agonist having the structure: or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt and a pharmaceutically acceptable vehicle therefor.
  • the methods disclosed herein result in at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% reduction in an intensity of smoking tobacco or nicotine self-administration by a subject, or the subject no longer smokes tobacco or selfadministers tobacco.
  • the reduction in an intensity of smoking tobacco or nicotine selfadministration or cessation of smoking is observed after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.
  • treatment may continue for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 or more days; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 or weeks months; or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more months; or 1, 2, or 3 or more years or until the subj ect no long experiences nicotine cravings or other nicotine withdrawal symptoms, or has ceased smoking or using other tobacco products.
  • reduction in smoking intensity is determined by measuring expired carbon monoxide levels, or a biochemical marker of smoking intensity in biological fluids obtained from the subject.
  • the acetylcholine receptor agonist is administered at a dose of from about 0.01 to about 50 mg/kg.
  • the present disclosure relates to a composition for use in a method of treating a neurological disorder in a subject in need thereof, wherein the composition comprises an acetylcholine receptor agonist disclosed herein or is the pharmaceutical compositions disclosed herein, and wherein the method comprises administering the composition to the subject.
  • the present disclosure relates to an acetylcholine receptor agonist disclosed herein for use in the manufacture of a medicament for treating a neurological disorder.
  • Nicotinic acetylcholine receptors belong to the superfamily of cys-loop receptors, which also includes serotonin 5-HT3, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (GABA)A, GAB AC, and glycine receptors, and participate in a variety of physiological functions, including regulation of neuronal excitability and neurotransmitter release.
  • GABA a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
  • GABA a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
  • GABA a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
  • GABA a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
  • GABA a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
  • GAB AC glycine receptors
  • nAChR subunits In the mammalian brain, nine different nAChR subunits are known to exist (a2-7 and [32— 4), which combine as either homo- or heteromeric complexes into multiple functionally diverse pentameric receptors.
  • the predominant subtypes functionally expressed in the brain are categorized as a7* subunit-containing receptors (either homo- or heteromeric) or those composed of both a and P subunits, including the a4p2* and a3p4* subtypes (the * denotes that these nAChRs can contain other a and P subunits as well).
  • the a4p2* receptor subtype was initially found to be the maj or nAChR subtype in the brain (where it comprises 90% of the high affinity nicotine binding sites, while the a3p4* nAChR is known primarily as a ganglionic receptor in the PNS.
  • the a3p4* nAChR is also expressed in a variety of brain areas, including the interpeduncular nucleus and medial habenula.
  • the a2, a5, a6, and 03 subunits participate in nAChRs expressed in various brain regions, although they represent a minority population of the total.
  • the al* nAChR subunit is a key therapeutic target as these receptors are expressed on a variety of cell types in the periphery, including immune cells and neurons, as well as in the brain regions that underlie learning and memory. Further, these receptors are highly permeable to calcium, implicating them as significant modulators of intracellular signaling and neurotransmitter release from neurons. In the brain, al* receptors are expressed on both neurons and non-neuronal cells, including astrocytes, microglia, oligodendrocyte precursor cells, endothelial cells, and chondroitin sulfate proteoglycan NG2-expressing (NG2) cells, among others.
  • NG2 chondroitin sulfate proteoglycan NG2-expressing
  • al* receptors in these non-neuronal cells suggests a possible role in brain innate immunity, inflammation, and neuroprotection. Immune cell expression of al* receptors has been shown to modulate inflammatory responses by regulating the production of inflammatory cytokines and chemokines.
  • al* nAChR was initially thought to be functionally expressed as homomeric receptors, it recently has been shown to be capable of co-assembling with other subunits, which provides an explanation for the incongruent properties of in situ a7-containing receptors and in vitro expressed homomeric al receptors. Dineley et al., Trends in Pharm. Sci., Feb. 2015, Vol. 36, No. 2, reported that al and 02 subunits co-assembled in vitro, and that basal forebrain cholinergic neurons express functional a702 receptors with an enhanced sensitivity to the amyloid-0 (A0) peptide associated with AD.
  • A0 amyloid-0
  • the present disclosure relates to an acetylcholine receptor agonist having a structure selected from the group consisting of:
  • the present disclosure relates to an acetylcholine receptor agonist having a structure selected from the group consisting of
  • the present disclosure relates to an acetylcholine receptor agonist having a structure according to Formula la or Formula lb set forth below:
  • Formula la or a pharmaceutically acceptable ester or solvate thereof wherein X" is an ion of an acid forming a pharmaceutically acceptable salt, where A and B are independently selected from nitrogen (N) or Carbon (C), wherein Ri, R2, R3, and R5 are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein RHs selected from the group consisting of ketone, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, NR A R
  • the present disclosure relates to an acetylcholine receptor agonist having a structure according to Formula Ila or Formula lib set forth below: or a pharmaceutically acceptable ester or solvate thereof, wherein X" is an ion of an acid forming a pharmaceutically acceptable salt, where A and B are independently selected from nitrogen (N) or Carbon (C), wherein Ri, R2, R3, R5, and Re are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein R4 is selected from the group consisting of ketone, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted
  • Ri has the structure according to Formula Ila or Formula lib :
  • A is N
  • B is C
  • one of - is a double bond.
  • both A and B are N.
  • B is N, and R2 is nothing.
  • RI, R2, and/or R3 is methyl.
  • R4 is a ketone
  • one of > - is a double bond.
  • the acetylcholine receptor agonist has the structure:
  • the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.
  • the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.
  • the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.
  • the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.
  • X" may be an ion formed from l-hydroxy-2-naphthoic acid, 2,2- di chloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor- 10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2- disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic
  • the acetylcholine receptor agonist has the structure: or a pharmaceutically acceptable ester or solvate thereof.
  • an acetylcholine receptor agonist has a structure selected from the group consisting of:
  • X is an ion of an acid forming a pharmaceutically acceptable salt.
  • X may be an ion formed from 1- hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2- oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor- 10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, e
  • the present disclosure relates to an acetylcholine receptor agonist comprising
  • an acetylcholine receptor agonist has a structure selected from the group consisting of: or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt.
  • X may be an ion formed from 1- hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2- oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor- 10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic
  • acetylcholine receptor agonist having the structure selected from the group consisting of:
  • the present disclosure relates to an acetylcholine receptor agonist having a structure selected from the group consisting of: or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt.
  • compositions containing the acetylcholine receptor agonists disclosed herein and uses thereof are disclosed herein and uses thereof.
  • a pharmaceutical composition may include a pharmaceutically acceptable carrier that facilitates processing of an active ingredient into pharmaceutically acceptable compositions.
  • a pharmaceutically acceptable carrier is synonymous with “pharmacological carrier” and means any carrier that has substantially no long term or permanent detrimental effect when administered and encompasses terms such as “pharmacologically acceptable vehicle,” “stabilizer,” “diluent,” “additive,” “auxiliary” or “excipient.”
  • Such a carrier generally is mixed with an active compound or permitted to dilute or enclose the active compound and can be a solid, semi-solid, or liquid agent. It is understood that the active ingredients can be soluble or can be delivered as a suspension in the desired carrier or diluent.
  • aqueous media such as, e.g., water, saline, glycine, hyaluronic acid and the like
  • solid carriers such as, e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like
  • solvents dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredient.
  • Selection of a pharmacologically acceptable carrier can depend on the mode of administration.
  • any pharmacologically acceptable carrier is incompatible with the active ingredient, its use in pharmaceutically acceptable compositions is contemplated.
  • Nonlimiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed. 1999); REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & Gilman’s The Pharmacological Basis of Therapeutics (Joel G.
  • Purity refers to the ratio of a compound’s mass to the total sample mass following any purification steps.
  • the level of purity is at least about 95%, more usually at least about 96%, about 97%, about 98%, or higher.
  • the level of purity may be about 98.5%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher.
  • Compound described herein that exist in more than one optical isomer form may be provided either as a racemic mixture or by isolating one of the enantiomers, the latter case in which purity as described above may refer to enantiomeric purity.
  • the compounds described herein may be prepared synthetically using such techniques as those described in K. Huang et al., “A New and Efficient Approach to the Synthesis of Nicotine and Anabasine Analogues,” J Heterocycl Chem.
  • a compound may be converted into a pharmaceutically acceptable salts using techniques well known to persons skilled in the art.
  • salts such as sodium and potassium salts may be prepared by treating the compound with a suitable sodium or potassium base, such as sodium hydroxide or potassium hydroxide, respectively.
  • Esters and ethers of the compound may be prepared as described, e.g., in Advanced Organic Chemistry, 1992, 4th Edition, J. March, John Wiley & Sons, or J. Med. Chemistry, 1992, 35, 145-151.
  • a pharmaceutical composition may optionally include, without limitation, other pharmaceutically acceptable components (or pharmaceutical components), including, without limitation, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifying agents, wetting agents, sweetening or flavoring agents, and the like.
  • buffers include, without limitation, acetate buffers, citrate buffers, phosphate buffers, neutral buffered saline, phosphate buffered saline and borate buffers.
  • antioxidants include, without limitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • Useful preservatives include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilized oxy chloro composition and chelants, such as, e.g., DTPA or DTPA-bisamide, calcium DTP A, and CaNaDTPA-bisamide.
  • Tonicity adjustors useful in a pharmaceutical composition include, without limitation, salts such as, e.g., sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonicity adjustor.
  • the pharmaceutical composition may be provided as a salt and can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. It is understood that these and other substances known in the art of pharmacology can be included in a pharmaceutical composition.
  • auxiliaries and/or excipients examples include cremophor, poloxamer, benzalkonium chloride, sodium lauryl sulfate, dextrose, glycerin, magnesium stearate, polyethylene glycol, starch, dextrin, lactose, cellulose, carboxymethylcellulose sodium, talc, agar-agar, mineral oil, animal oil, vegtetable oil, organic and mineral waxes, paraffin, gels, propylene glycol, benzyl alcohol, dimethylacetamide, ethanol, polyglycols, tween 80, solutol HS 15, and water. It is also possible to administer the active substances as such, without vehicles or diluents, in a suitable form, for example, in capsules.
  • compositions described herein may be administered orally, nasally, topically, subcutaneously, intramuscularly, intravenously, or by other modes of administration known to persons skilled in the art.
  • compositions may be formulated for delivery by inhaler, e-cigarette/vape, gum, transdermal patch, or similar techniques.
  • the compositions may be used as a nicotine substitute for individuals afflicted with tobacco addiction, inclusive of smoking addiction and smokeless tobacco addiction.
  • a pharmaceutical composition may comprise a therapeutic compound in an amount sufficient to allow customary administration to an individual.
  • a unit dose form may have, e.g., at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a therapeutic compound.
  • a unit dose form may have, e.g., at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of a therapeutic compound.
  • a pharmaceutical composition disclosed herein may include, e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg to about 1,500 mg of a therapeutic compound.
  • a pharmaceutical composition disclosed herein may include, e.g., about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about 1,000 mg, or about 5 mg to about 250 mg of a therapeutic compound.
  • the acetylcholine receptor agonists disclosed herein have antiinflammatory activity.
  • a compound may have an anti-inflammatory activity capable of reducing the levels of an inflammation-inducing molecule, such as substance P(SP), calcitonin gene-related peptide (CGRP), glutamate, or a combination thereof.
  • an inflammation-inducing molecule such as substance P(SP), calcitonin gene-related peptide (CGRP), glutamate, or a combination thereof.
  • a compound may have an anti-inflammatory activity capable of reducing the levels of SP, CGRP, glutamate, or a combination thereof released from a sensory neuron by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.
  • Prostaglandins mediate a local inflammatory response and are involved in all inflammatory functions through action on prostaglandin receptors and mediate inflammatory signaling including chemotaxis (macrophages, neutrophils and eosinophils), vasodilation and algesia.
  • chemotaxis macrophages, neutrophils and eosinophils
  • vasodilation vasodilation
  • the principle resolution factor is a prostaglandin called 15dPGJ2, which is an endogenous agonist of peroxisome proliferator-activator receptor-y (PPAR-y) signaling.
  • PPAR-y signaling pathway 1 induces apoptosis of macrophage Ml cells, thereby reducing the levels of Thl pro-inflammatory cytokines and 2) promotes differentiation of monocytes into macrophage M2 cells. Macrophage M2 cells produce and release Th2 anti-inflammatory cytokines.
  • Compounds disclosed herein may have an anti-inflammatory activity capable of reducing the levels of an inflammation inducing prostaglandin.
  • a compound may have an antiinflammatory activity capable of reducing the levels of an inflammation inducing prostaglandin released from a sensory neuron by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.
  • an antiinflammatory activity capable of reducing the levels of an inflammation inducing prostaglandin released from a sensory neuron by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.
  • a compound may have an anti-inflammatory activity capable of reducing the levels of an inflammation inducing prostaglandin released from a sensory neuron in a range from, e.g., about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.
  • the peroxisome proliferator-activated receptors are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. All PPARs are known to heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes called peroxisome proliferator hormone response elements (PPREs). PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms. The family comprises three members, PPAR-a, PPAR-y, and PPAR-6 (also known as PPAR-P).
  • PPAR-a is expressed in liver, kidney, heart, muscle, adipose tissue, as well as other tissues.
  • PPAR-6 is expressed in many tissues but markedly in brain, adipose tissue, and skin.
  • PPAR-y comprises three alternatively-spliced forms, each with a different expression pattern.
  • PPAR-yl is expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen.
  • PPAR-y2 is expressed mainly in adipose tissue.
  • PPAR- y3 is expressed in macrophages, large intestine, and white adipose tissue. Endogenous ligands for the PPARs include free fatty acids and eicosanoids.
  • a compound may have an anti-inflammatory activity capable of reducing the levels of IFN- y, TNF-a, IL-12, or a combination thereof released from a Thl cell and increasing the levels of IL-10 released from a Th2 cell.
  • a compound may have an anti-inflammatory activity capable of reducing the levels of IFN-y, TNF-a, IL-12, or a combination thereof released from a Thl cell by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%, and capable of increasing the levels of IL-10 released from a Th2 cell by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.
  • a compound may have an anti-inflammatory activity capable of stimulating some or all PPAR signaling pathways. It is contemplated that such a compound therefore may act as a PPAR pan-agonist or possibly as a selective PPAR agonist.
  • a compound may have an anti-inflammatory activity capable of modulating Thl and Th2 cytokines.
  • a compound may have an anti-inflammatory activity capable of reducing the levels of Interferon-y (IFN-y), tumor necrosis factor-a (TNF-a), interleukin- 12 (IL-12), or a combination thereof released from a Thl cell.
  • a compound may have an anti-inflammatory activity capable of reducing the levels of IFN-y, TNF-a, IL-12, or a combination thereof released from a Thl cell by, e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.
  • a compound may have an anti-inflammatory activity capable of reducing the levels of IFN-y, TNF-a, IL-12, or a combination thereof released from a Thl cell in a range from, e.g., about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, or about 10% to about 90.
  • a compound may have an anti-inflammatory activity capable of increasing the levels of IL- 10 released from a Th2 cell.
  • a compound may have an anti-inflammatory activity capable of increasing the levels of IL- 10 released from a Th2 cell by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%.
  • the compounds herein may be useful for treating acute or chronic inflammation.
  • a chronic inflammation symptom can be associated with a large, otherwise unrelated group of disorders which underlay a variety of diseases and disorders.
  • the immune system is often involved with chronic inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation.
  • Non-immune diseases with etiological origins in chronic inflammatory processes include cancer, atherosclerosis, and ischaemic heart disease.
  • Non-limiting examples of disorders exhibiting chronic inflammation as a symptom include, without limitation, acne, acid reflux/heartburn, age related macular degeneration (AMD), allergy, allergic rhinitis, Alzheimer’s disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune disorders, balanitis, blepharitis, bronchiolitis, bronchitis, a bullous pemphigoid, burn, bursitis, cancer, cardiac arrest, carditis, celiac disease, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, colitis, congestive heart failure, conjunctivitis, Crohn’s disease, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, common cold, dac
  • the acetylcholine receptor agonist is administered at a dose of from about 0.01 to about 50 mg/kg, about 0.01 to about 40 mg/kg, about 0.01 to about 30 mg/kg, about 0.01 to about 20 mg/kg, about 0.1 mg/kg to about 18 mg/kg, about 1 mg/kg to about 16 mg/kg, about 2 mg/kg to about 14 mg/kg, or about 5 mg/kg to about 10 mg/kg.
  • the acetylcholine receptor agonist is administered at a dose of about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 8/5 mg/kg, about 9 mg/kg, about
  • the acetylcholine receptor agonist is administered at a dose of about 0.5 mg, about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100, about 2150 mg, about
  • compositions as described herein may include a pharmaceutically acceptable solvent.
  • a solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous (the solute), resulting in a solution.
  • Solvents useful in the pharmaceutical compositions include, without limitation, a pharmaceutically acceptable polar aprotic solvent, a pharmaceutically acceptable polar protic solvent and a pharmaceutically acceptable non-polar solvent.
  • a pharmaceutically acceptable polar aprotic solvent includes, without limitation, di chloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO).
  • a pharmaceutically acceptable polar protic solvent includes, without limitation, acetic acid, formic acid, ethanol, n-butanol, 1 -butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol, n-propanol, isopropanol, 1,2 propan-diol, methanol, glycerol, and water.
  • a pharmaceutically acceptable non-polar solvent includes, without limitation, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-di oxane, chloroform, n-methyl- pyrrolidone (NMP), and diethyl ether.
  • the method of administration as well as the dosage range which are suitable in a specific case depend on the species to be treated and on the state of the respective condition or disease, and may be optimized using techniques known in the art. Most often, the daily dose of active compound in a patient may range from 0.0005 mg to 15 mg per kg, more usually 0.001 mg to 7.5 mg per kg. Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art. For instance, treatment may comprise a one-time administration of an effective dose of a pharmaceutical composition as disclosed herein.
  • treatment may comprise multiple administrations of an effective dose of a pharmaceutical composition carried out over a range of time periods, such as, e.g., once daily, twice daily, trice daily, once every few days, or once weekly.
  • time periods such as, e.g., once daily, twice daily, trice daily, once every few days, or once weekly.
  • the timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual’s symptoms.
  • an effective dose of a pharmaceutical composition disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy.
  • a person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a pharmaceutical composition disclosed herein that is administered can be adjusted accordingly.
  • compositions may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles.
  • pH of the formulation may be adjusted with acceptable pharmaceutical or food grade acids, bases or buffers to enhance the stability of the formulated composition or its delivery form.
  • Liquid dosage forms for oral administration include acceptable pharmaceutical or food grade emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylsulfoxide (DMSO) dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water
  • Solid dosage forms for oral administration include capsules, tablets, lozenges, pills, powders, and granules.
  • the active compound is mixed with at least one inert, acceptable pharmaceutical or food grade excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agaragar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyce
  • the dosage form may also comprise buffering agents.
  • the solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract or, optionally, in a delayed or extended manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Tablet formulations for extended release are also described in U.S. Pat. No. 5,942,244.
  • compositions may contain a compound as disclosed herein, alone or with other therapeutic compound(s).
  • a therapeutic compound is a compound that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals.
  • a therapeutic compound disclosed herein may be used in the form of a pharmaceutically acceptable salt, solvate, or solvate of a salt, e.g., a hydrochloride. Additionally, therapeutic compound disclosed herein may be provided as racemates, or as individual enantiomers, including an R- or S-enantiomer.
  • the therapeutic compound disclosed herein may comprise an R-enantiomer only, a S-enantiomer only, or a combination of both an R- enantiomer and a S-enantiomer of a therapeutic compound.
  • the therapeutic compound may have anti-inflammatory activity, such as a non-steroidal anti-inflammatory drug (NSAID).
  • NSAIDs are a large group of therapeutic compounds with analgesic, antiinflammatory, and anti-pyretic properties. NSAIDs reduce inflammation by blocking cyclooxygenase.
  • NSAIDs include, without limitation, aceclofenac, acemetacin, actarit, alcofenac, alminoprofen, amfenac, aloxipirin, aminophenazone, antraphenine, aspirin, azapropazone, benorilate, benoxaprofen, benzydamine, butibufen, celecoxib, chlorthenoxacin, choline salicylate, clometacin, dexketoprofen, diclofenac, diflunisal, emorfazone, epirizole; etodolac, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen, glafenine, hydroxylethyl salicylate, ibuprofen, indometacin, indoprofen, ketoprofen, ketorolac, lactyl phenet
  • NSAIDs may be classified based on their chemical structure or mechanism of action.
  • Nonlimiting examples of NSAIDs include a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclooxygenase (COX) inhibitor, a selective cyclooxygenase- 1 (COX-1) inhibitor, and a selective cyclooxygenase-2 (COX-2) inhibitor.
  • COX non-selective cyclooxygenase
  • COX-1 selective cyclooxygenase- 1
  • COX-2 selective cyclooxygenase-2
  • An NSAID may be a profen.
  • Examples of a suitable salicylate derivative NSAID include, without limitation, acetylsalicylic acid (aspirin), diflunisal, and salsalate.
  • Examples of a suitable p-amino phenol derivative NSAID include, without limitation, paracetamol and phenacetin.
  • Examples of a suitable propionic acid derivative NSAID include, without limitation, alminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, and suprofen.
  • acetic acid derivative NSAID examples include, without limitation, aceclofenac, acemetacin, actarit, alcofenac, amfenac, clometacin, diclofenac, etodolac, felbinac, fenclofenac, indometacin, ketorolac, metiazinic acid, mofezolac, nabumetone, naproxen, oxametacin, sulindac, and zomepirac.
  • a suitable enolic acid (oxicam) derivative NSAID examples include, without limitation, droxicam, isoxicam, lomoxicam, meloxicam, piroxicam, and tenoxicam.
  • a suitable fenamic acid derivative NSAID examples include, without limitation, flufenamic acid, mefenamic acid, meclofenamic acid, and tolfenamic acid.
  • a suitable selective COX-2 inhibitors include, without limitation, celecoxib, etoricoxib, firocoxib, lumiracoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib.
  • the present disclosure relates to a method of treating a neurological disorder comprising administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure: or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt, and a pharmaceutically acceptable vehicle therefor.
  • a method of treating a neurological disorder comprises administering to an individual in need thereof a pharmaceutical composition comprising a compound having the structure: or a pharmaceutically acceptable ester or solvate thereof.
  • the present disclosure relates to a method of treating a neurological disorder comprising administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound having a structure according to Formula la or Formula lb:
  • X is an ion of an acid forming a pharmaceutically acceptable salt
  • a and B are independently selected from nitrogen (N) or Carbon (C)
  • Ri, R2, R3, and R5 are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle
  • RHs selected from the group consisting of ketone, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle
  • the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, — OH, alkyl, — O-alkyl, NR
  • the present disclosure relates to an acetylcholine receptor agonist having a structure according to Formula Ila or Formula lib set forth below: or a pharmaceutically acceptable ester or solvate thereof, wherein X" is an ion of an acid forming a pharmaceutically acceptable salt, where A and B are independently selected from nitrogen (N) or Carbon (C), wherein Ri, R2, R3, R5, and Re are independently selected from the group consisting of nothing, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein R4 is selected from the group consisting of ketone, H, OH, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, and heterocycle; wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted
  • the disorder is depression.
  • Depression may be manifested by depressive symptoms. These symptoms may include psychological changes such as changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts or attempts, and/or self-deprecation.
  • Physical symptoms of depression may include insomnia, anorexia, appetite loss, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, aches, pains, headaches, cramps, digestive issues, and/or abnormal hormonal circadian rhythms.
  • the disorder is anxiety.
  • the disorder is neuropathic pain.
  • the disorder is Alzheimer’s disease.
  • the disorder is an addiction.
  • the addiction includes addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites.
  • Nicotine addiction includes nicotine addiction of all known forms, such as smoking cigarettes, cigars and/or pipes, and addiction to chewing tobacco.
  • the compounds disclosed herein may be particularly suitable for treating neurological disorders such as Alzheimer’s Disease (AD), autism, schizophrenia, addiction, anxiety, depression, and neuropathic pain.
  • Addiction is inclusive of addictions to controlled substances (opioid, heroin, cocaine, barbiturate, methamphetamine, etc.) addiction as well as addiction to tobacco, inclusive of smoking and smokeless tobacco addiction.
  • the present disclosure relates to a method of treating nicotine addiction associated with smoking tobacco comprising administering a therapeutically effective amount of an acetylcholine receptor agonist disclosed herein.
  • Some embodiments include a method of treating nicotine addiction associated with smoking tobacco comprising administering an acetylcholine receptor agonist disclosed herein.
  • the method of treating tobacco or nicotine addiction, or promoting smoking cessation comprises administering a therapeutically effective amount of an acetylcholine receptor agonist disclosed herein.
  • the method of treating tobacco or nicotine addiction, or treating nicotine addiction associated with smoking tobacco or promoting smoking cessation comprises administering the acetylcholine receptor agonist having the structure: or a pharmaceutically acceptable ester or solvate thereof, where X" is an ion of an acid forming a pharmaceutically acceptable salt and a pharmaceutically acceptable vehicle therefor.
  • the therapeutically effective amount of a acetylcholine receptor agonist disclosed herein is administered once a day, once every two days, once every three days, once every four days, once every five days, once every six days, or once every seven days.
  • the methods comprise administering an acetylcholine receptor agonist (or composition comprising the same) three or more times a day, twice a day, or once a day.
  • the method of treating tobacco or nicotine addiction, or promoting smoking cessation comprises administering a therapeutically effective amount of an acetylcholine receptor agonist disclosed herein results in at least 10% reduction in an intensity of smoking tobacco or nicotine self-administration by a subject.
  • the reduction in an intensity of smoking tobacco or nicotine selfadministration by a subject is reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 100%, or the subject no longer smokes tobacco or self-administer nicotine.
  • the methods comprise administering a single dose of an acetylcholine receptor agonist (or composition comprising the same).
  • the method comprises administering repeated doses, such as for a predetermined period of time of until the symptoms or effects of nicotine addiction are reduced, ameliorated, or eliminated or until the subject has ceased smoking or otherwise consuming
  • the nicotine-degrading enzyme variant may be a long-acting nicotine-degrading enzyme variant as described above.
  • treatment is repeated with additional doses if signs/symptoms/effects persist or if the subject continues to have nicotine cravings or experiences them anew.
  • treatment may continue for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 or more days; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 or weeks months; or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 or more months; or 1, 2, or 3 or more years or until the subject no long experiences nicotine cravings or other nicotine withdrawal symptoms, or has ceased smoking or using other tobacco products.
  • administration of the compounds disclosed herein to human beings results in the reduction of smoking intensity as measured using the number of cigarettes smoked per day, assessed via daily smoking diaries.
  • the reduction in smoking intensity is determined by measuring expired carbon monoxide levels, or a biochemical marker of smoking intensity (such as nicotine or cotinine) in biological fluids obtained from the subject.
  • the therapeutically effective dosage of the acetylcholine receptor agonist disclosed herein may depend on the weight or age of the subject, the intensity of smoking, and/or the level of nicotine in the subject's brain or plasma at the time of treatment.
  • the acetylcholine receptor agonist is administered at a dose of from about 0.01 to about 50 mg/kg, about 0.01 to about 40 mg/kg, about 0.01 to about 30 mg/kg, about 0.01 to about 20 mg/kg, about 0.1 mg/kg to about 18 mg/kg, about 1 mg/kg to about 16 mg/kg, about 2 mg/kg to about 14 mg/kg, or about 5 mg/kg to about 10 mg/kg.
  • the acetylcholine receptor agonist is administered at a dose of about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 8/5 mg/kg, about 9 mg/kg, about
  • the acetylcholine receptor agonist is administered at a dose of about 0.5 mg, about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100, about 2150 mg, about
  • a subject in need of treatment for nicotine addiction or promoting smoking cessation is a human subject who consumes nicotine products, such as smoking tobacco, chewing tobacco, electronic cigarettes, and/or other nicotine delivery devices. Such a subject may or may not be physically addicted to nicotine and/or psychologically addicted to consuming nicotine products.
  • Typical subjects in need of smoking cessation treatment smoke or use tobacco or other nicotine products daily, such as smoking at least 1 cigarette a day, or more, such as at least about 5, at least about 10, at least about 15, at least about 20, or more, cigarettes per day, including fewer than 10, 10-20, 20-30, 30-40, or 40 or more (or the equivalent use of other tobacco or nicotine products).
  • the phrases “therapeutically effective amount” and “therapeutic level” mean an acetylcholine receptor agonist disclosed herein dosage or plasma concentration in a subject that provides the specific pharmacological effect for which the acetylcholine receptor agonist disclosed herein is administered to a subject in need of such treatment, i.e. to promote smoking cessation and/or treat tobacco or nicotine addiction.
  • the therapeutically effective amount may vary based on the route of administration and dosage form, the age and weight of the subject, and/or the subject's condition.
  • the subject’s condition may for example include the degree of nicotine addiction, amount of nicotine generally consumed/ingested by the subject, and/or the subject's plasma levels of nicotine at the time of treatment and/or the amount of nicotine localized in the brain at the time of treatment.
  • treatment refers to one or more of: reducing, ameliorating or eliminating one or more symptoms or effects of the disease or condition.
  • symptoms may include nicotine withdrawal; reducing the number of cigarettes or the amount of nicotine consumed by a subject; and/or reducing the subject's plasma levels of nicotine and/or reducing the amount of nicotine localized in specific tissues of the subject (e.g., brain/central nervous system, heart and vasculature, etc.), and/or reducing the subject’s levels of expired carbon monoxide, and/or reducing the subject’s levels of a biochemical marker of tobacco smoking or nicotine self-admini strati on in a biological fluid.
  • the terms “individual,” “subject,” and “patient” are used interchangeably herein, and refer to any individual mammal subject, e.g., bovine, canine, feline, equine, or human.
  • child refers to a human subject from 0 through about 19 years of age. A child can be a subject that begins a course of treatment prior to turning about 19 years of age, even if the subject continues treatment beyond 19 years of age.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Addiction (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés agonistes du récepteur de l'acétylcholine et des procédés de traitement. Une composition pharmaceutique peut comprendre une quantité thérapeutiquement efficace d'un ou plusieurs agonistes du récepteur de l'acétylcholine et d'un véhicule pharmaceutiquement acceptable. L'invention concerne également des méthodes de traitement d'un trouble neurologique impliquant l'administration de la composition pharmaceutique à un individu en ayant besoin, pour le traitement de la dépendance au tabac ou à la nicotine.
PCT/US2022/050553 2021-11-23 2022-11-21 Agonistes du récepteur de l'acétylcholine et procédés de traitement de troubles neurologiques et de la douleur neuropathique WO2023096854A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202163282568P 2021-11-23 2021-11-23
US202163282616P 2021-11-23 2021-11-23
US63/282,616 2021-11-23
US63/282,568 2021-11-23
US202263299320P 2022-01-13 2022-01-13
US63/299,320 2022-01-13

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WO2023096854A1 true WO2023096854A1 (fr) 2023-06-01

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Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM COMPOUND ANONYMOUS : "(+)-Nicotine", XP093071194, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "(R)-nicotinium(1+)", XP093071201, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "(S)-nicotinium(1+)", XP093071329, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "1-methyl-2-pyridin-3-yl-2H-pyrrol-5-one", XP093071311, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "1-Methyl-5-(3-pyridinyl)-2pyrrolidinone", XP093071334, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "2-(1-Methyl-2,5-dihydropyrrol-2yl)pyridine", XP093071297, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "2,5-Dihydro-2-phenyl-1H-pyrrole", XP093071331, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "2-phenyl-2,5-dihydro-1H-imidazole", XP093071308, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "3-(1-Methylpyrrolidin-2-yl)pyridine", XP093071300, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "3-(2,3-dihydro-1H-pyrrol-5-yl)pyridine", XP093071330, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "3-(2-Methylcyclopentyl)pyridine", XP093071304, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "5-methyl-2-phenyl-2,5-dihydro-1Himidazole", XP093071327, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "NoName_3149", XP093071296, retrieved from PUBCHEM *
DATABASE PUBCHEM COMPOUND ANONYMOUS : "Norcotinine", XP093071202, retrieved from PUBCHEM *

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