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WO2013166468A1 - Compositions and methods for treating neurodegenerative diseases - Google Patents

Compositions and methods for treating neurodegenerative diseases Download PDF

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Publication number
WO2013166468A1
WO2013166468A1 PCT/US2013/039584 US2013039584W WO2013166468A1 WO 2013166468 A1 WO2013166468 A1 WO 2013166468A1 US 2013039584 W US2013039584 W US 2013039584W WO 2013166468 A1 WO2013166468 A1 WO 2013166468A1
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compound
alkyl
amino
trideca
azatricyclo
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French (fr)
Inventor
David KOLB
Seth HERZON
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Insero Health Inc
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Insero Health Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • a composition may include a therapeutically effective amount of an acetylcholinesterase inhibitor that is not a huperzine.
  • the acetylcholinesterase inhibitor may have specificity for the G4 isoform of acetylcholinesterase enzyme.
  • a method of treating a neurodegenerative disease may include administering a therapeutically effective amount of an acetylcholinesterase inhibitor that is not a huperzine wherein the neurodegenerative disease is treated.
  • the acetylcholinesterase inhibitor may have selective activity for the G4 isoform of acetylcholinesterase enzyme.
  • a composition may include a therapeutically effective amount of an acetylcholinesterase inhibitor, an NMDA receptor (a specific type of ionotropic glutamate receptor that has N-methyl-D-aspartate as an agonist)) antagonist, and either or both of a mitochondrial protectant and an anti-inflammatory agent.
  • an acetylcholinesterase inhibitor an NMDA receptor (a specific type of ionotropic glutamate receptor that has N-methyl-D-aspartate as an agonist)) antagonist, and either or both of a mitochondrial protectant and an anti-inflammatory agent.
  • NMDA receptor a specific type of ionotropic glutamate receptor that has N-methyl-D-aspartate as an agonist
  • a method of treating a neurodegenerative disease may include administering a therapeutically effective amount of an acetylcholinesterase inhibitor, an NMDA receptor antagonist, and either or both of a mitochondrial protectant and an antiinflammatory agent wherein the neurodegenerative disease is treated.
  • Optical isomers - diastereomers - geometric isomers - tautomers Compounds described herein may contain an asymmetric center and may thus exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereomers.
  • the present invention includes all possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers.
  • the formulas are show without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of such formulas and pharmaceutically acceptable salts and solvates thereof.
  • Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example, by use of an optically active acid or base or a resolving agent or on a chiral HPLC column. Further, any enantiomer or diastereomer of a compound of the general formula may be obtained by stereospecific using optically pure starting materials or reagents of known configuration.
  • the term "about” means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%.
  • administering when used in conjunction with a therapeutic means to administer a therapeutic agent into or onto a target tissue or to administer a therapeutic to a patient whereby the therapeutic agent positively impacts the tissue to which it is targeted.
  • Administering may be done by the actual subject being treated or a health care professional.
  • huperzine means huperzine A, huperzine B, or huperzine C, or salts thereof, unless otherwise defined in a particular embodiment.
  • Huperzine A is ( 1R,95", 13£ 1 -amino- 13 -ethylidene- 11 -methyl-6-azatricyclo [7.3.1.0 2 ' 7 ]trideca- 2(7),3 , 10- trien- 5-one.
  • Huperzine B is (4aR,5R, 10bR)-2,3,4,4a,5,6-hexahydro-12-methyl-lH-5, 10b- propeno-l,7-phenanthrolin-8(7H)-one
  • Huperzine C is (lR,9S,13R)-l-amino-13-ethenyl-l 1- methyl-6-azatricyclo[7.3.1.0 2 ' 7 ]trideca- 2(7),3, 10- trien- 5-one.
  • the terms "individual”, “host”, “subject”, “patient”, and “animal” as used interchangeably herein include, but are not limited to, humans and non-human vertebrates such as wild, domestic and farm animals.
  • inhibiting includes the administration of a compound of the present invention to prevent the onset of the symptoms, alleviating the symptoms, or eliminating or ameliorating the disease, condition or disorder.
  • pharmaceutically acceptable it is meant the carrier, diluent, excipient, or counter ion must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • salts as anionic counter ions include, but are not limited to, acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, tosylate, adipate, caprate, caproate, caprylate, dodecylsulfate, glutarate, laurate, oleate, palmitate, sebacate, stearate, undecylenate, and combinations thereof.
  • Pharmaceutically acceptable salts as cationic counter ions include, but are not limited to, ammonium, arginine, diethylamine, ethylenediamine, piperazine, and combinations thereof.
  • Pharmaceutically acceptable salts include, but are not limited to, chloride, bromide, nitrate, sulfate, tosylate, phosphate, tartrate, or maleate.
  • Pharmaceutically acceptable compounds include hydrates thereof.
  • terapéutica means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient.
  • embodiments of the present invention are directed to the treatment of neurodegenerative disease or decrease the symptoms thereof.
  • a "therapeutically effective amount” or “effective amount” of a composition is a predetermined amount calculated to achieve the desired effect such as to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient.
  • the activity contemplated by the present methods includes both medical therapeutic and/or prophylactic treatment, as appropriate.
  • the specific dose of a compound administered according to this invention to obtain therapeutic and/or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated.
  • the compounds are effective over a wide dosage range and, for example, dosages per day will normally fall within the range of from 0.001 to 10 mg/kg, more usually in the range of from 0.01 mg/kg to 1 mg/kg.
  • a therapeutically effective amount of compound of this invention is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • carrier may be used interchangeably and refer to a composition with which the therapeutic agent is administered.
  • Such carriers may be sterile liquids such as, for example, water and oils, including those of petroleum, animal, vegetable or synthetic origin. Saline solution, aqueous dextrose and glycerol solution may also be employed as liquid carriers.
  • Suitable pharmaceutical excipients include, but are not limited to, glucose, starch, lactose, sucrose, gelatin, malt, rice, flour, chalk, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, and ethanol.
  • the composition if desired, may contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions may take a form of solutions, suspensions, emulsions, powders, sustained-release formulations, and the like.
  • alkyl refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl and the like.
  • Preferred alkyl groups herein contain 1 to 6 carbon atoms.
  • Alkyl groups may be optionally substituted with one to three groups chosen from halo, amino, methoxy, ethoxy, hydroxyl, methylthio, methylsulfonyl, nitro, aryl, heterocyclyl and heteroaryl.
  • alkenyl refers to a branched or unbranched hydrocarbon group of 2 to 24 carbon atoms containing at least one unsaturated bond, such as, without limitation, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, decenyl, and the like.
  • Preferred alkenyl groups herein contain 2 to 6 carbon atoms.
  • Alkenyl groups may be optionally substituted with one to three groups chosen from halo, amino, methoxy, ethoxy, hydroxyl, methylthio, methylsulfonyl, nitro, aryl, heterocyclyl and heteroaryl.
  • cycloalkyl refers to ring-containing alkyl radicals of 3 to 14 carbon atoms. Examples include cyclohexyl, cyclopentyl, cyclopropyl, cyclopropylmethyl and norbornyl. Cycloalkyl groups may be optionally substituted with one to three groups chosen from halo, amino, methoxy, ethoxy, hydroxyl, methylthio, methylsulfonyl, nitro, aryl, heterocyclyl and heteroaryl.
  • aryl or “Ar” employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic group containing one or more rings (typically one, two or three rings). Multiple rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include, but are not limited to, phenyl, anthracyl and naphthyl. Preferred are phenyl (Ph) and naphthyl, most preferred is phenyl.
  • Aryl groups may be optionally substituted with one to three groups chosen from halo, amino, methoxy, ethoxy, hydroxyl, methylthio, methylsulfonyl, nitro, aryl, heterocyclyl and heteroaryl.
  • heterocycle by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, stable, mono- or multicyclic heterocyclic ring system consisting of carbon atoms and at least one heteroatom including, but not limited to, N, O, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized.
  • the heterocycle may be attached to the compound of which it is a component, unless otherwise stated, at any heteroatom or carbon atom in the heterocycle that affords a stable structure.
  • Heterocyclic groups may be optionally substituted with one to three groups chosen from halo, amino, methoxy, ethoxy, hydroxyl, methylthio, methylsulfonyl, nitro, aryl, heterocyclyl and heteroaryl.
  • non-aromatic heterocycles include monocyclic groups such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolinyl, pyrazolidinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, 1,3-dioxanyl, homopiperaz
  • heteroaryl refers to a heterocycle having aromatic character.
  • a monocyclic heteroaryl group is preferably a 5-, 6-, or 7-membered ring, examples of which are pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl and pyrazinyl.
  • a polycyclic heteroaryl may comprise multiple aromatic rings or may include one or more partially saturated rings.
  • Heteroaryl groups may be optionally substituted with one to three groups chosen from halo, amino, methoxy, ethoxy, hydroxyl, methylthio, methylsulfonyl, nitro, aryl, heterocyclyl and heteroaryl.
  • Examples of monocyclic heteroaryl groups include, for example, six- membered monocyclic aromatic rings such as, for example, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; and five-membered monocyclic aromatic rings such as, for example, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3 -triazolyl, 1,2,4- triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
  • six- membered monocyclic aromatic rings such as, for example, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl
  • polycyclic heteroaryl groups containing a partially saturated ring examples include tetrahydroquinolyl and 2,3 -dihydrobenzo furyl.
  • polycyclic heteroaryls examples include indolyl, indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl, 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1 ,4-benzodioxanyl, chromene-2-one-yl (coumarinyl), dihydrocoumarin, chromene-4-one-yl, benzofuryl, 1,5-naphthyridinyl, 2,3- dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, purinyl, benzimidazolyl, benzotriazolyl, thioxanthinyl, benzazepinyl, benzodiazepin
  • substituted refers to a molecular group that replaces a hydrogen in a compound and may include, but are not limited to, trifluoromethyl, nitro, cyano, C1-C2 0 alkyl, aromatic or aryl, halide (F, CI, Br, I), C1-C2 0 alkyl ether, benzyl halide, benzyl ether, aromatic or aryl ether, hydroxy, alkoxy, amino, alkylamino (-NHR'), dialkylamino (-NR'R”) or other groups which do not interfere with the formation of the diaryl alkylphosphonate.
  • neurodegenerative disease refers to conditions or symptoms resulting from progressive loss of structure or function of neurons, including neuronal death.
  • Conditions or diseases that can be classified as neurodegenerative include, but are not limited to, Alzheimer's disease, epilepsy, Parkinson's disease, Huntington's disease, neuropathic pain, multiple sclerosis, ataxia, amyotrophic lateral sclerosis, AIDS- related dementia, neurotoxic poisoning, muscular dystrophy, myasthenia gravis, vascular dementia, glaucoma, orthostatic hypotension, mitochondrial diseases, and infantile spasms.
  • Acetylcholinesterase is an enzyme that degrades, through hydrolytic activity, acetylcholine to produce choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate synaptic transmission.
  • the AChE enzyme has a very high catalytic activity, wherein each molecule being capable of degrading up to about 25,000 acetylcholine molecules per second.
  • the term "acetylcholinesterase” encompasses all known and unknown isoforms of AChE and other enzymes with analogous activity including, but not limited to, butyrylcholinesterase unless the context clearly dictates otherwise.
  • AChE is a highly polymorphic enzyme, isoforms of which can be distinguished by their subunit associations and hydrodynamic properties. Differing sedimentation coefficients of different isoforms allow for their separation by ultracentrifugation on sucrose density gradients. In mammalian brain, the bulk of AChE occurs as a tetrameric, G4 form together with much smaller amounts of a monomeric, Gl . There is strong evidence that not all acetylcholinesterase inhibitors inhibit all forms of AChE equally.
  • the G4 form of AChE is the major isoform in most regions within the brain. Approximately 60%-90% of this enzymatic form is ectocellular. Ectocellular G4 AChE is the major form for metabolizing acetylcholine (ACh) and this form is selectively depleted in Alzheimer's disease suggesting that G4 is the physiologically relevant isoform at cholinergic synapses and its inhibition would be expected to prolong the action of AChE. By contrast, Gl occurs primarily in the neural cytoplasm where its inhibition would be unlikely to affect synaptic physiology, making G4 selective AChE inhibitors much more effective and potent. AChE inhibitors may or may not have equal efficacy in different parts of the brain. In some methods, the AChE inhibitor may be substantially equally effective in all regions of the brain.
  • AChE inhibitors inhibit AChE with similar mechanisms and to a similar degree. Yet, different AChE inhibitors effect on other cholinesterases such as, for example, butyrylcholinesterase (BuChE), is specific to the particular compound being used. BuChE is a non-specific cholinesterase enzyme that hydrolyses many different choline esters and in human plasma exists at 160-fold higher concentration than AChE.
  • BuChE butyrylcholinesterase
  • Huperzine A is an acetylcholinesterase inhibitor with ring numbering shown:
  • the present disclosure is directed to compounds and compositions for treating neurodegenerative diseases and symptoms thereof, by targeting various mechanisms for neuronal death or loss of function in neurons.
  • aspects of the present invention are directed to compositions comprising an acetylcholinesterase inhibitor exhibiting selective inhibition of the G4 isoform of AChE.
  • the AChE inhibitor may exhibit selective inhibition of the G4 isoform of AChE compared to the Gl and G2 isoforms of AChE.
  • the selectivity in inhibition may be by at least a factor of about 2. In other embodiments the selectivity may be by a factor of at least about 5, and in yet other embodiments, the selectivity may be by a factor of at least about 10.
  • the AChE inhibitor may not be one or more of the following:
  • Huperzine A IR,9S, 13E)- 1 -Amino- 13-ethylidene- 1 1 - methyl-6-azatricyclo[7.3.1.0 2 ' 7 ]trideca-
  • An aspect is an AChE inhibitor compound selective for the G4 isoform.
  • the selective AChE inhibitor compound has a proviso that the G4 isoform selective AChE inhibitor compound is not a huperzine.
  • the compound has a proviso that the compound is not huperzine A; huperzine B; huperzine C; (lR ⁇ lS ⁇ -l-amino-lS-trifluoroethylidene-l 1-methyl- 6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; (lR,95', 13£)-l-amino-13-ethylidene-l l-trifluoromethyl-6- azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; (lR,95,13£)-l-amino-13- trifluoroethylidene-1 l-trifluoromethyl-6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5- one; or (lR,9S,13is)-l-amino
  • the AChE inhibitor is selective for the G4 isoform and has no inhibitory effect on BuChE. In other embodiments, the G4 selective AChE inhibitor and has a lesser inhibitory effect on BuChE. In still other embodiments, the G4 selective AChE inhibitor has higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2. In some embodiments, the selective AChE inhibitor compound has a higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2 and has a proviso the compound is not a huperzine.
  • the compound has a proviso that the compound is not huperzine A; huperzine B; huperzine C; (IR,9S, 13E -1- amino-13-trifluoroethylidene-l l-methyl- 6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5- one; (lR,9S, 13is)-l-amino-13-ethylidene-l l-trifluoromethyl-6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; (lR,95 , ,13£)-l-amino-13-trifluoroethylidene-l l-trifluoromethyl-6- azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; or (lR,9S, 13is)-l-a
  • the acetylcholinesterase inhibitor has the general formula
  • Ri is selected from CH 3 , CF 3 , CF 2 CF 3 , CF 2 CF 2 CF 3 , S0 2 CH 3 , S0 2 Ph, S0 2 Ar, S0 3 H, and S0 3 Ar;
  • R 2 is selected from an (Ci-C 2 4)alkyl, an aryl, a cycloalkyl, a (C 2 -C 2 4)alkenyl, a heterocycle, and a heteroaryl;
  • R P1 , R P2 , R V i, Rv2 are independently selected from hydrogen and fluorine;
  • RNI and RN 2 are independently selected from H, (Ci-C 2 4)alkyl, CF 3 , CF 2 CF 3 , CC1 3 , CBr 3 , and CHO;
  • RN 3 is selected from absent and (Ci-C 2 4)alkyl; and
  • n is an integer selected from 1, 2, 3, and 4; with the proviso the compound is
  • Some embodiments of the general formula I have the 1 -amino group as a quaternary amine.
  • RNI and RN 2 are independently selected from (Ci- C 24 )alkyl, CF 3 , CF 2 CF 3 , CC1 3 , CBr 3 , and CHO; and R N3 is (Ci-C 24 )alkyl.
  • the quaternary amine can have three independent alkyl groups.
  • the quaternary amine may have three methyl groups.
  • the anionic counter ion of the quaternary amine can be any pharmaceutically acceptable salt.
  • anionic counter ions include, but are not limited to, acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, tosylate, adipate, caprate, caproate, caprylate, dodecylsulfate, glutarate, laurate, oleate, palmitate, sebacate, stearate, undecylenate, and combinations thereof.
  • Preferable anionic counterions are acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, and tosylate.
  • RN 3 is absent and the 1 -amino group is not a quaternary amine.
  • n as an integer selected from 2, 3, and 4.
  • n is 2.
  • R 2 is phenyl and n is an integer selected from 2, 3, and 4.
  • n is 2.
  • R 2 is phenyl
  • Ri is methyl
  • RNI and RN 2 are H
  • RN 3 is absent.
  • the compound has a formula II,
  • n is an integer selected from 2, 3, and 4. In some of these embodiments, n is 2.
  • Ri is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl, with a proviso the compound is not
  • Ri is a substituted phenyl group. In other embodiments, Ri is (C 2 - C 20 )alkyl. Preferably, Ri is (C 2 -C 4 )alkyl. More preferably, Ri is (C 2 -C 3 )alkyl. The alkyl may be substituted.
  • R N i is selected from (Ci-C24)alkyl, CF 3 , CF 2 CF 3 , CCI 3 , CBr 3 , and CHO.
  • RNI is (Ci-C2o)alkyl.
  • RNI is (Ci-C4)alkyl.
  • R N i may be (Ci)alkyl. More preferably, RNI is be (C2-C4)alkyl.
  • the alkyl may be substituted.
  • R 2 is selected from CF 2 CF 3 , CF 2 CF 2 CF 3 , S0 2 CH 3 , S0 2 Ph, S0 2 Ar, S0 3 H, and S0 3 Ar with the proviso the compound is not
  • Ar is phenyl
  • an AChE inhibitor may be of general formula:
  • Ri is selected from an (C2-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl.
  • an AChE inhibitor may be of general formula:
  • Ri is selected from CH 3 , CF 3 , CF 2 CF 3 , CF 2 CF 2 CF 3 , S0 2 CH 3 , S0 2 Ph, S0 2 Ar, S0 3 H, and S0 3 Ar;
  • R 2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl;
  • R P i is H or F;
  • R P2 is H or F;
  • R V i is H or F;
  • R V 2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Rv2 is fluorine;
  • RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF 3 , CF 2 CF 3 , CC1 3 , CBr 3 , and CHO; and n is an integer selected from 1, 2, 3, and 4.
  • an AChE inhibitor may be of general formula:
  • compositions comprising an AChE inhibitor, an NMDA receptor antagonist, and a third agent selected from an anti-inflammatory agent, a mitochondrial protectant and a combination thereof.
  • the AChE inhibitor, the NMDA receptor antagonist and the third agent may be administered together as a single composition. In other embodiments, the AChE inhibitor, the NMDA receptor antagonist and the third agent may be administered separately.
  • the administration of the AChE inhibitor, the NMDA receptor antagonist and the third agent may be separated in time.
  • the AChE inhibitor may be, but is not limited to, huperzine, tacrine, galanthamine, donepezil, rivastagmine, neostigmine, physotigmine, or a combination thereof.
  • the AChE inhibitors may be natural, or synthetic compounds that exhibit reversible or quasi-irreversible inhibition of acetylcholinesterase.
  • Such compounds include, but are not limited to, carbamates, organophosphates, cannabinoids, phenantherene derivatives, piperidines, phyostigmine, neostigmine, rivastigmine, pyridostigmine, ambenonium, demarcarium, tacrine, donepezil, distigmine, phenserine, galantamine, edrophonium, huperzine A, ladostigil, ungeremine, lactucopicrin, and their pharmaceutically accepted salts and solvates.
  • carbamates may include, but are not limited to, aldicarb, bendiocarb, bufencarb, carbaryl, carbendazim, carbetamide, carbofuran, carbosulfan, chlorbufam, choloropropham, ethiofencarb, formetanate, methiocarb, methomyl, oxamyl, phenmedipham, pinmicarb, pirimicarb, propamocarb, propham, and propoxur.
  • organophosphates include, but are not limited to, ecothiophate, diisopropyl fluorophosphate, cadusafos, cyclosarin, dichlorvos, dimethoate, metrifonate, parathion, malathion, diazinon or their pharmaceutically accepted salt or solvate.
  • cannabinoids include, but are not limited to, ⁇ 9 - tetrahydrocannabinol, a synthetic cannabinoid, a semisynthetic cannabinoid, or their combination.
  • the AChE inhibitors may further act as mitochondrial protectants, such as, for example, membrane penetrating antioxidants or pyruvates.
  • the AChE inhibitors may exhibit anti-inflammatory activity by lowering factors including, but not limited to, TNF-a, 11-6, and COX -2. Examples include, without limitation, galantamine, donepezil, and so forth.
  • the AChE inhibitors may additionally exhibit NMDA receptor antagonism, more preferably at the MK-801 binding site, for example, donepezil, galanthamine, tacrine, rivastigmine, neostigmine, memantine, and the like.
  • the AChE inhibitor is a compound selective for the G4 isoform.
  • the selective AChE inhibitor has a proviso the compound is not a huperzine.
  • the compound selective for the G4 isoform has a proviso that the compound is not huperzine A; huperzine B; huperzine C; (IR,9S, 13E -1- amino-13-trifluoroethylidene-l l-methyl- 6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5- one; ( 1R,9«S, 13 is)- 1 -amino- 13 -ethylidene- 11 -trifluoromethyl-6-azatricyclo [7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; (lR,95 , ,13£)-l-amino-13
  • the compositions comprises an AChE inhibitor, an NMDA receptor antagonist, and a third agent selected from an anti-inflammatory agent, a mitochondrial protectant and a combination thereof, wherein the AChE inhibitor has no inhibitory effect on BuChE.
  • the G4 selective AChE inhibitor and has a lesser inhibitory effect on BuChE.
  • the G4 selective AChE inhibitor has higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2.
  • the selective AChE inhibitor compound has a higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2 and has a proviso the compound is not a huperzine.
  • the compound has a proviso that the compound is not huperzine A; huperzine B; huperzine C; (lR,9S, 13is)-l-amino-13- trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; ( ⁇ R,9S, 13E)- 1 -amino- 13-ethylidene- 1 l-trifluoromethyl-6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; (lR,95 , ,13£)-l-amino-13-trifluor
  • compositions comprising an AChE inhibitor, and an NMDA receptor antagonist, and optionally a third agent selected from an antiinflammatory agent, a mitochondrial protectant and a combination thereof, wherein the acetylcholinesterase inhibitor has the general formula I:
  • Rj is selected from CH 3 , CF 3 , CF 2 CF 3 , CF 2 CF 2 CF 3 , S0 2 CH 3 , S0 2 Ph, S0 2 Ar, S0 3 H, and S0 3 Ar;
  • R 2 is selected from an (Ci-C 2 4)alkyl, an aryl, a cycloalkyl, a (C 2 -C 2 4)alkenyl, a heterocycle, and a heteroaryl;
  • R N i and RN2 are independently selected from H, (Ci-C24)alkyl, CF 3 , CF 2 CF 3 , CCI 3 , CBr 3 , and CHO;
  • RN3 is selected from absent and (Ci-C24)alkyl; and
  • n is an integer selected from 1, 2, 3, and 4, or pharmaceutically acceptable salt thereof.
  • the acetylcholinesterase inhibitor has a proviso the inhibitor compound is not
  • the 1 -amino group is a quaternary amine.
  • RNI and RN2 are independently selected from (Ci-C 24 )alkyl, CF 3 , CF 2 CF 3 , CC1 3 , CBr 3 , and CHO; and R N3 is (Ci-C 24 )alkyl.
  • the quaternary amine can have three independent alkyl groups.
  • the quaternary amine may have three methyl groups.
  • the anionic counter ion of the quaternary amine can be any pharmaceutically acceptable salt.
  • anionic counter ions include, but are not limited to, acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, tosylate, adipate, caprate, caproate, caprylate, dodecylsulfate, glutarate, laurate, oleate, palmitate, sebacate, stearate, undecylenate, and combinations thereof.
  • Preferable anionic counterions are acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, and tosylate.
  • RN3 is absent and the 1 -amino group is not a quaternary amine.
  • n as an integer selected from 2, 3, and 4. In certain embodiments, n is 2. In other embodiments, R2 is phenyl and n is an integer selected from 2, 3, and 4. In certain embodiments, n is 2. In select embodiments, R2 is phenyl, Ri is methyl, RNI and RN2 are H, and RN3 is absent.
  • compositions comprise an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent, wherein the AChE inhibitor compound is of formula II,
  • n is an integer selected from 2, 3, and 4. In some of these embodiments, n is 2.
  • compositions comprise an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent, wherein the AChE inhibitor may be of general formula:
  • Ri is selected from an (C2-C24)alkyl , an aryl, a cycloalkyl, an (C2-C24)alkenyl, a heterocycle, and a heteroaryl.
  • compositions comprising an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent, wherein the AChE inhibitors are of general formula IV:
  • Ri is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C2 4 )alkenyl, a heterocycle, and a heteroaryl.
  • the AChE inhibitor has a proviso the AChE inhibitor compound is not
  • Ri is a substituted phenyl group. In other embodiments, Ri is (C 2 - C 20 )alkyl. Preferably, Ri is (C 2 -C 4 )alkyl. More preferably, Ri is (C 3 -C 4 )alkyl. The alkyl may be substituted.
  • compositions comprising an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent, wherein the AChE inhibitor is of the general formula V:
  • R N i is selected from (Ci-C2 4 )alkyl, CF 3 , CF 2 CF 3 , CCI 3 , CBr 3 , and CHO.
  • RNI is (Ci-C2o)alkyl.
  • RNI is (Ci-C2o)alkyl.
  • RNI may be (Ci)alkyl. More preferably, RNI is (C2-C 4 )alkyl. The alkyl may be substituted.
  • compositions comprising an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent, wherein the AChE inhibitor is of the general formula VI:
  • R 2 is selected from CF 2 CF 3 , CF 2 CF 2 CF 3 , S0 2 CH 3 , S0 2 Ph, S0 2 Ar, S0 3 H, and S0 3 Ar, or pharmaceutically acceptable salt thereof.
  • the AChE inhibitor compound has a proviso that the inhibitor compound is not
  • Ar is phenyl
  • compositions comprising an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent, wherein the AChE inhibitor is of the general formula VII:
  • Rj is selected from CH 3 , CF 3 , CF 2 CF 3 , CF 2 CF 2 CF 3 , S0 2 CH 3 , S0 2 Ph, S0 2 Ar, S0 3 H, and S0 3 Ar;
  • R 2 is selected from an (Ci-C 2 4)alkyl, an aryl, a cycloalkyl, a (C 2 -C 2 4)alkenyl, a heterocycle, and a heteroaryl;
  • R P i is H or F;
  • R P2 is H or F;
  • R V i is H or F;
  • R V 2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Rv2 is fluorine;
  • RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF 3 , CF 2 CF 3 , CCI 3 , CBr 3 , and CHO; and
  • n is an integer selected from 1,
  • compositions comprising an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent, wherein the AChE inhibitor is of the general formula VIII:
  • R P i is H or F
  • R P2 is H or F
  • R V i is H or F
  • R V 2 is H or F
  • at least one of Rpi, Rp2, Rvi, and Rv2 is fluorine.
  • the present disclosure is directed to methods of treating a neurodegenerative disease by administering an acetylcholinesterase inhibitor with a selectivity for the G4 isoform of AChE compared to Gl and G2 isoforms of AChE, wherein the AChE inhibitor is not huperzine wherein the neurodegenerative disease is treated.
  • the method of treating a neurodegenerative disease comprises administering a therapeutically effective amount of an AChE inhibitor having specificity for the G4 isoform of acetylcholinesterase enzyme (AChE) with the proviso the compound is not a huperzine.
  • AChE inhibitor having specificity for the G4 isoform of acetylcholinesterase enzyme (AChE) with the proviso the compound is not a huperzine.
  • the AChE inhibitor has a proviso that the compound is not huperzine A; huperzine B; huperzine C; (lR,9S,13is)-l-amino-13- trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; (IR,9S, 13E)- 1 -amino- 13-ethylidene- 1 l-trifluoromethyl-6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; (lR,95 , ,13£)-l-amino-13-trifluoroethylidene-l l-trifluoromethyl-6- azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; or (lR,9S,
  • the method of treating a neurodegenerative disease comprises administering an AChE inhibitor selective for the G4 isoform with no inhibitory effect on BuChE wherein the neurodegenerative disease is treated.
  • the G4 selective AChE inhibitor has a lesser inhibitory effect on BuChE than for inhibition of AChE.
  • the G4 selective AChE inhibitor has higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2.
  • the selective AChE inhibitor compound has a higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2 and has a proviso the compound is not a huperzine.
  • the compound has a proviso that the compound is not huperzine A; huperzine B; huperzine C; (l ?,95, 13£ -l-amino-13-trifluoroethylidene-l l- methyl- 6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; (lR,95,13£)-l-amino-13- ethylidene-1 l-trifluoromethyl-6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; ( 1R,9,S, 13E)- 1 -amino- 13 -trifluoroethylidene- 1 1 -trifluoromethyl-6-azatricyclo [7.3.1.0 2 ' 7 ] trideca- 2(7),3,10- trien- 5-one; or (lR,9S, 13
  • the method of treating a neurodegenerative disease comprises administering a therapeutically effective amount of an AChE inhibitor wherein the acetylcholinesterase inhibitor has the general formula I:
  • Ri is selected from CH 3 , CF 3 , CF 2 CF 3 , CF 2 CF 2 CF 3 , S0 2 CH 3 , S0 2 Ph, S0 2 Ar, S0 3 H, and S0 3 Ar;
  • R 2 is selected from an (Ci-C 2 4)alkyl, an aryl, a cycloalkyl, a (C 2 -C 2 4)alkenyl, a heterocycle, and a heteroaryl;
  • R N i and RN 2 are independently selected from H, (Ci-C 2 4)alkyl, CF 3 , CF 2 CF 3 , CC1 3 , CBr 3 , and CHO;
  • RN 3 is selected from absent and (Ci-C 2 4)alkyl; and
  • n is an integer selected from 1, 2, 3, and 4, with a proviso the inhibitor compound is not
  • the 1 -amino group is a quaternary amine.
  • RNI and RN 2 are independently selected from (Ci-C 24 )alkyl, CF 3 , CF 2 CF 3 , CC1 3 , CBr 3 , and CHO; and R N3 is (Ci-C 24 )alkyl.
  • the quaternary amine can have three independent alkyl groups.
  • the quaternary amine may have three methyl groups.
  • the anionic counter ion of the quaternary amine can be any pharmaceutically acceptable salt.
  • anionic counter ions include, but are not limited to, acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, tosylate, adipate, caprate, caproate, caprylate, dodecylsulfate, glutarate, laurate, oleate, palmitate, sebacate, stearate, undecylenate, and combinations thereof.
  • Preferable anionic counterions are acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, and tosylate.
  • RN3 is absent and the 1 -amino group is not a quaternary amine.
  • n as an integer selected from 2, 3, and 4. In certain embodiments, n is 2. In other embodiments, R2 is phenyl and n is an integer selected from 2, 3, and 4. In certain embodiments, n is 2. In select embodiments, R2 is phenyl, Ri is methyl, RNI and RN2 are H, and RN3 is absent.
  • the method of treating a neurodegenerative disease comprises administering a therapeutically effective amount an AChE inhibitor of formula II,
  • the method of treating a neurodegenerative disease comprises administering a therapeutically effective amount of an AChE inhibitor of general formula:
  • Ri is selected from an (C2-C24)alkyl , an aryl, a cycloalkyl, an (C2-C24)alkenyl, a heterocycle, and a heteroaryl wherein the neurodegenerative disease is treated.
  • FIG. 1 AChE inhibitor of general formula IV:
  • Ri is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C2 4 )alkenyl, a heterocycle, and a heteroaryl, wherein the AChE inhibitor has a proviso the AChE inhibitor compound is not
  • Ri is a substituted phenyl group. In other embodiments, Ri is (C 2 - C 20 )alkyl. Preferably, Ri is (C 2 -C 4 )alkyl. More preferably, Ri is (C 3 -C 4 )alkyl. The alkyl may be substituted.
  • Various embodiments of the method of treating a neurodegenerative disease comprises administering a therapeutically effective amount an AChE inhibitor of the general formula V:
  • R N i is selected from (Ci-C2 4 )alkyl, CF 3 , CF 2 CF 3 , CCI 3 , CBr 3 , and CHO wherein the neurodegenerative disease is treated.
  • RNI is (Ci-C2o)alkyl.
  • RNI is (Ci-C 4 )alkyl.
  • R N i is (Ci)alkyl. More preferably, RNI is (C2-C 4 )alkyl.
  • the alkyl may be substituted.
  • Various embodiments are methods of treating a neurodegenerative disease comprising administering a therapeutically effective amount an AChE inhibitor of the general formula VI:
  • R 2 is selected from CF 2 CF 3 , CF 2 CF 2 CF 3 , S0 2 CH 3 , S0 2 Ph, S0 2 Ar, S0 3 H, and S0 3 Ar, wherein the AChE inhibitor compound has a proviso that the inhibitor compound is not
  • Ar is phenyl
  • Various embodiments are methods of treating a neurodegenerative disease comprising administering a therapeutically effective amount an AChE inhibitor of the general formula VII:
  • Rj is selected from CH 3 , CF 3 , CF 2 CF 3 , CF 2 CF 2 CF 3 , S0 2 CH 3 , S0 2 Ph, S0 2 Ar, S0 3 H, and S0 3 Ar;
  • R 2 is selected from an (Ci-C 2 4)alkyl, an aryl, a cycloalkyl, a (C 2 -C 2 4)alkenyl, a heterocycle, and a heteroaryl;
  • R P i is H or F;
  • R P2 is H or F;
  • R V i is H or F;
  • R V2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Rv2 is fluorine;
  • RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF 3 , CF 2 CF 3 , CCI 3 , CBr 3 , and CHO; and
  • n is an integer selected from 1,
  • R P i is H or F
  • R P2 is H or F
  • R V i is H or F
  • R V 2 is H or F
  • at least one of Rpi, Rp2, Rvi, and Rv2 is fluorine.
  • the present disclosure is directed to method of treating a neurodegenerative disease comprising administering a an AChE inhibitor, an NMDA receptor antagonist, and a third agent selected from an anti-inflammatory agent, a mitochondrial protectant and a combination thereof wherein the neurodegenerative disease is treated.
  • a third agent selected from an anti-inflammatory agent, a mitochondrial protectant and a combination thereof wherein the neurodegenerative disease is treated.
  • the AChE inhibitor, the NMDA receptor antagonist and the third agent may be administered together as a single composition.
  • the third agent selected from an anti-inflammatory agent, a mitochondrial protectant and a combination thereof
  • AChE inhibitor, the NMDA receptor antagonist and the third agent may be administered separately.
  • the administration of the AChE inhibitor, the NMDA receptor antagonist and the third agent may be separated in time.
  • the administration of the AChE inhibitor, the NMDA receptor antagonist and the third agent may be separated in time.
  • AChE inhibitor may be, but is not limited to, huperzine, tacrine, galanthamine, donepezil, rivastagmine, neostigmine, physotigmine, or a combination thereof.
  • the AChE inhibitors may be natural, or synthetic compounds that exhibit reversible or quasi-irreversible inhibition of acetylcholinesterase.
  • Such compounds include, but are not limited to, carbamates, organophosphates, cannabinoids, phenantherene derivatives, piperidines, phyostigmine, neostigmine, rivastigmine, pyridostigmine, ambenonium, demarcarium, tacrine, donepezil, distigmine, phenserine, galantamine, edrophonium, huperzine A, ladostigil, ungeremine, lactucopicrin, and their pharmaceutically accepted salts and solvates.
  • carbamates may include, but are not limited to, aldicarb, bendiocarb, bufencarb, carbaryl, carbendazim, carbetamide, carbofuran, carbosulfan, chlorbufam, choloropropham, ethiofencarb, formetanate, methiocarb, methomyl, oxamyl, phenmedipham, pinmicarb, pirimicarb, propamocarb, propham, and propoxur.
  • organophosphates include, but are not limited to, ecothiophate, diisopropyl fluorophosphate, cadusafos, cyclosarin, dichlorvos, dimethoate, metrifonate, parathion, malathion, diazinon or their pharmaceutically accepted salt or solvate.
  • cannabinoids include, but are not limited to, ⁇ 9 - tetrahydrocannabinol, a synthetic cannabinoid, a semisynthetic cannabinoid, or their combination.
  • the AChE inhibitors may further act as mitochondrial protectants, such as, for example, membrane penetrating antioxidants or pyruvates.
  • the AChE inhibitors may exhibit anti-inflammatory activity by lowering factors including, but not limited to, TNF-a, 11-6, and COX -2. Examples include, without limitation, galantamine, donepezil, and so forth.
  • the AChE inhibitors may additionally exhibit NMDA receptor antagonism, more preferably at the MK-801 binding site, for example, donepezil, galanthamine, tacrine, rivastigmine, neostigmine, memantine, and the like.
  • a method of treating a neurodegenerative disease comprising administering a an AChE inhibitor, an NMDA receptor antagonist, and a third agent selected from an anti-inflammatory agent, a mitochondrial protectant, and combinations thereof, wherein the neurodegenerative disease is treated.
  • the AChE inhibitor compound has a proviso the compound is not a huperzine.
  • the compound selective for the G4 isoform has a proviso the compound is not huperzine A; huperzine B; huperzine C; (l ?,95, 13£ -l-amino-13-trifluoroethylidene-l l- methyl- 6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; (lR,95,13£)-l-amino-13- ethylidene-1 l-trifluoromethyl-6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; ( 1R,9,S, 13E)- 1 -amino- 13 -trifluoroethylidene- 1 1 -trifluoromethyl-6-azatricyclo [7.3.1.0 2 ' 7 ] trideca- 2(7),3,10- trien- 5-one; or (
  • the method of treating a neurodegenerative disease comprises administering an AChE inhibitor, an NMDA receptor antagonist, and the third agent, wherein the AChE inhibitor has no inhibitory effect on BuChE, and wherein the neurodegenerative disease is treated.
  • the AChE inhibitor has a lesser inhibitory effect on BuChE than for inhibition of AChE.
  • the AChE inhibitor has higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2.
  • the selective AChE inhibitor compound has a higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2 and has a proviso the compound is not a huperzine.
  • the compound has a proviso that the compound is not huperzine A; huperzine B; huperzine C; (lR,9S, 13is)-l-amino-13- trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; ( ⁇ R,9S, 13E)- 1 -amino- 13-ethylidene- 1 l-trifluoromethyl-6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; (lR,95 , ,13£)-l-amino-13-trifluoroethylidene-l l-trifluoromethyl-6- azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3, 10- trien- 5-one; or (lR,9S, 13is
  • Some embodiments comprise method of treating a neurodegenerative disease comprising administering an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent wherein the acetylcholinesterase inhibitor has the general formula I:
  • Ri is selected from CH 3 , CF 3 , CF 2 CF 3 , CF 2 CF 2 CF 3 , S0 2 CH 3 , S0 2 Ph, S0 2 Ar, S0 3 H, and S0 3 Ar;
  • R 2 is selected from an (Ci-C 2 4)alkyl, an aryl, a cycloalkyl, a (C 2 -C 2 4)alkenyl, a heterocycle, and a heteroaryl;
  • R P i is H or F;
  • R P2 is H or F;
  • R V i is H or F;
  • R V2 is H or F;
  • R N i and RN 2 are independently selected from H, (Ci-C 2 4)alkyl, CF 3 , CF 2 CF 3 , CC1 3 , CBr 3 , and CHO;
  • RN 3 is selected from absent and (Ci-C 2 4)alkyl; and
  • n is an integer selected from 1,
  • the selective compound has a proviso the compound is not ( 1R,9 «S, 13E)- 1 -amino- 13-ethylidene- 11 -methyl-6-azatricyclo [7.3.1.0 2 ' 7 ]trideca- 2(7),3, 10- trien- 5-one, (IR,9S, 13E)- ⁇ -amino- 13-trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.0 2 ' 7 ] trideca- 2(7),3,10- trien- 5-one,
  • the 1 -amino group is a quaternary amine.
  • RNI and RN2 are independently selected from (Ci-C 24 )alkyl, CF 3 , CF 2 CF 3 , CC1 3 , CBr 3 , and CHO; and R N3 is (Ci-C 24 )alkyl.
  • the quaternary amine can have three independent alkyl groups.
  • the quaternary amine may have three methyl groups.
  • the anionic counter ion of the quaternary amine can be any pharmaceutically acceptable salt.
  • anionic counter ions include, but are not limited to, acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, tosylate, adipate, caprate, caproate, caprylate, dodecylsulfate, glutarate, laurate, oleate, palmitate, sebacate, stearate, undecylenate, and combinations thereof.
  • Preferable anionic counterions are acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, and tosylate.
  • RN 3 is absent and the 1 -amino group is not a quaternary amine.
  • n as an integer selected from 2, 3, and 4.
  • n is 2.
  • R 2 is phenyl and n is an integer selected from 2, 3, and 4.
  • n is 2.
  • R 2 is phenyl
  • Ri is methyl
  • RNI and RN 2 are H
  • RN 3 is absent.
  • the method of treating a neurodegenerative disease comprising administering a an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent wherein the AChE inhibitor compound is of formula II,
  • n is an integer selected from 2, 3, and 4, wherein the neurodegenerative disease is treated. In some of these embodiments, n is 2.
  • the method of treating a neurodegenerative disease comprising administering a combination of an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent wherein the AChE inhibitor may be of general formula:
  • Ri is selected from an (C2-C2 4 )alkyl, an aryl, a cycloalkyl, a (C2-C2 4 )alkenyl, a heterocycle, and a heteroaryl, wherein the neurodegenerative disease is treated.
  • Other embodiments are method of treating a neurodegenerative disease comprising administering an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent wherein the AChE inhibitors are of general formula IV:
  • Ri is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl, wherein the neurodegenerative disease is treated.
  • the AChE inhibitor compound has a proviso the compound is not
  • Ri is a substituted phenyl group. In other embodiments, Ri is (C 2 - C2o)alkyl. Preferably, (C2-C4)alkyl. More preferably, (C3-C4)alkyl. The alkyl may be substituted.
  • R N i is selected from (Ci-C24)alkyl, CF 3 , CF 2 CF 3 , CCI 3 , CBr 3 , and CHO, wherein the neurodegenerative disease is treated.
  • RNI is (Ci-C2o)alkyl.
  • RNI is (Ci-C4)alkyl.
  • RNI may be (Ci)alkyl. More preferably, RNI is (C2-C4)alkyl.
  • the alkyl may be substituted.
  • Various embodiments are methods of treating a neurodegenerative disease comprising administering a combination of an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent wherein the AChE inhibitor is of the general formula VI:
  • R 2 is selected from CF 2 CF 3 , CF 2 CF 2 CF 3 , S0 2 CH 3 , S0 2 Ph, S0 2 Ar, S0 3 H, and S0 3 Ar, , wherein the neurodegenerative disease is treated.
  • the selective AChE inhibitor compound has a proviso the compound is not (IR,9S, 13E)- 1 -amino- 13-ethylidene- 11 -methyl-6-azatricyclo[7.3.1.0 2 ' 7 ]trideca-
  • Ar is phenyl
  • Various embodiments are methods of treating a neurodegenerative disease comprising administering a combination of an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent wherein the AChE inhibitor is of the general formula VII:
  • Ri is selected from CH 3 , CF 3 , CF 2 CF 3 , CF 2 CF 2 CF 3 , S0 2 CH 3 , S0 2 Ph, S0 2 Ar, S0 3 H, and S0 3 Ar;
  • R 2 is selected from an (Ci-C 2 4)alkyl, an aryl, a cycloalkyl, a (C 2 -C 2 4)alkenyl, a heterocycle, and a heteroaryl;
  • R P i is H or F;
  • R P2 is H or F;
  • R V i is H or F;
  • R V2 is H or F; wherein at least one of Rpi, Rp 2 , Rvi, and Rv2 is fluorine;
  • RNI and RN2 are independently selected from H, (Ci-C 2 4)alkyl, CF 3 , CF 2 CF 3 , CC1 3 , CBr 3 , and CHO; and n is an integer selected from
  • AChE inhibitor is of the general formula VIII:
  • Rpi is H or F
  • Rp2 is H or F
  • Rvi is H or F
  • Rv2 is H or F
  • at least one of Rpi, Rp2, Rvi, and Rv2 is fluorine.
  • the AChE inhibitor may exhibit selective inhibition for the G4 isoform of the AChE compared to the Gl and G2 isoforms of AChE.
  • the selectivity in inhibition may be by a factor of at least about 2.
  • the selectivity may be by a factor of at least about 5, and in yet other embodiments, the selectivity may be by a factor of at least about 10.
  • the AChE inhibitor has at least about 2 times as much affinity as for BuChE as compared to affinity for AChE.
  • the mitochondrial protectants may be, for example, membrane penetrating anti-oxidants or pyruvates.
  • the anti-inflammatory effect of the agent may be via lowering factors including, but not limited to, TNF-a, 11-6, and COX-2, such as, for example, infliximab, adalimumab, certolizumab pegol, golimumab, tocilizumab, celecoxib and rofecoxib.
  • NMDA receptor antagonism may be via action at the MK-801 binding site such as, for example, donepezil, galanthamine, tacrine, rivastigmine, neostigmine, memantine, and the like.
  • any of the huperzine or huperzine analog compounds described above is co-administered with an anti-inflammatory agent, a pro-drug of the antiinflammatory agent, a precursor of the anti-inflammatory agent, any combination thereof, and/or the like.
  • the huperzine or huperzine analog compound is coadministered with an anti-inflammatory agent, a pro-drug of the anti-inflammatory agent, a precursor of the anti-inflammatory agent, any combination thereof, and/or the like, wherein the acetylcholinesterase inhibitor has the general formula I:
  • Rj is selected from CH 3 , CF 3 , CF 2 CF 3 , CF 2 CF 2 CF 3 , S0 2 CH 3 , S0 2 Ph, S0 2 Ar, S0 3 H, and S0 3 Ar;
  • R 2 is selected from an (Ci-C 2 4)alkyl, an aryl, a cycloalkyl, a (C 2 -C 2 4)alkenyl, a heterocycle, and a heteroaryl;
  • R P1 , R P2 , R V1 , Rv2 are independently selected from hydrogen and fluorine;
  • RNI and RN 2 are independently selected from H, (Ci-C 2 4)alkyl, CF 3 , CF 2 CF 3 , CC1 3 , CBr 3 , and CHO;
  • RN3 is selected from absent and (Ci-C 2 4)alkyl; and
  • n is an integer selected from 1, 2, 3, and 4; with the proviso the compound
  • anti-inflammatory agents which may be co-administered with huperzine or an analog thereof include, but are not limited to, non-steroidal anti-inflammatory drugs, immune-selective anti-inflammatory derivatives, anti-inflammatory herbal extracts, NF-Kappa B inhibitors, IL-inhibitors, any combinations thereof, and/or the like.
  • anti-inflammatory agents include, but are not limited to, tanshinone, cryptotanshinone, ferulic acid, cycloartenol, cycloartyl ferulate, hydroxytyrosol, homovanillyl alcohol, extracts of salix purpurea, extracts of piper longum, 4-O-methylgallic acid, extracts of boswellia serrata and extracts of prunella vulgaris, and any combination thereof.
  • any of the huperzine or huperzine analog compounds described above is co-administered with an antioxidant agent.
  • the huperzine or huperzine analog compound is co-administered with an anti-oxidant agent, a pro-drug of the anti-oxidant agent, a precursor of the anti-oxidant agent, any combination thereof, and/or the like, wherein the acetylcholinesterase inhibitor has the general formula I:
  • Ri is selected from CH 3 , CF 3 , CF 2 CF 3 , CF 2 CF 2 CF 3 , S0 2 CH 3 , S0 2 Ph, S0 2 Ar, S0 3 H, and S0 3 Ar;
  • R 2 is selected from an (Ci-C 2 4)alkyl, an aryl, a cycloalkyl, a (C 2 -C 2 4)alkenyl, a heterocycle, and a heteroaryl;
  • R P1 , R P2 , R V1 , Rv2 are independently selected from hydrogen and fluorine;
  • RNI and RN 2 are independently selected from H, (Ci-C 2 4)alkyl, CF 3 , CF 2 CF 3 , CC1 3 , CBr 3 , and CHO;
  • RN 3 is selected from absent and (Ci-C 2 4)alkyl; and
  • n is an integer selected from 1, 2, 3, and 4; with the proviso the compound is
  • anti-oxidant agents which may be co-administered with huperzine or an analog thereof include, but are not limited to, ascorbic acid, glutathione, lipoic acid, uric acid, beta-carotene, vitamin A, vitamin E, co-enzyme Q; a pro-drug of the anti-oxidants, a precursor of the anti-oxidants; and any combination thereof, and/or the like.
  • antioxidant agents include, but are not limited to, uric acid, ascorbic acid, glutathione, melatonin, tocopherols and tocotrienols (vitamin E), salubrious polyphenols, in particular catechins, the most abundant of which are epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCG), epigallocatechin and gallic acid, methyl gallate, and any combination thereof.
  • uric acid ascorbic acid
  • glutathione glutathione
  • melatonin tocopherols and tocotrienols
  • vitamin E salubrious polyphenols
  • catechins the most abundant of which are epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCG), epigallocatechin and gallic acid, methyl gallate, and any combination thereof.
  • a huperzine or huperzine analog is co-administered with mitochondrial agent.
  • mitochondrial protectants which may be co-administered with huperzine or an analog thereof include, but are not limited to, muscarinic receptor agonists that activate M2 subtype to prevent ACh release which in turn can activate mitochondrial protection.
  • Muscarinic receptor agonists include, but are not limited to, compounds such as bethanechol and (2S,2'R,3'S,5'R)-l-methyl-2-(2-methyl-l,3- oxathiolan-5-yl)pyrrol-idine 3-sulfoxide methyl iodide, any combinations thereof, and/or the like.
  • a huperzine or huperzine analog, described above is co-administered with an NMDA receptor antagonist.
  • NMDA receptor antagonists which may be co-administered with huperzine or an analog thereof include, but are not limited to, R-2-amino-5-phosphonopentanoate, 2-amino-7-phosphonoheptanoic acid, 3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-l-phosphonic acid, selfotel, amantadine, dextrallorphan, dextromethorphan, dextrorphan, dizocilpine , ethanol, eticyclidine, gacyclidine, ibogaine, magnesium, memantine, methoxetamine, nitrous oxide, phencyclidine, rolicyclidine, tenocyclidine, methoxydine, tiletamine, xenon
  • co-administration when used herein the compounds may be combined in one pharmaceutically-acceptable carrier, or they may be placed in separate carriers and administered to the patient at different times.
  • formulations and/or routes of administration of the various agents/therapies used may vary.
  • the appropriate dosage for co-administration can be readily determined by one skilled in the art. The important consideration being that the compounds should be administered sufficiently close in time that there is at least some temporal overlap in the biological effects generated by the compounds into the mammal being tested.
  • the present disclosure is directed to methods for treating neurodegenerative diseases by administering a composition comprising an AChE inhibitor and a pharmaceutically acceptable carrier, excipient, or combination thereof.
  • Methods may be directed toward treating neurodegenerative diseases by administering a composition comprising an AChE inhibitor and a pharmaceutically acceptable excipient.
  • the composition may be administered orally, nasally, rectally, intravenously, intrathecally, intramuscularly, transdermally, opthalmically, and the like.
  • the composition may be administered via a combination of these various routes.
  • Methods may be directed to compounds and compositions administered by any route where they are active.
  • Administration can be systemic, topical, or oral.
  • administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, or ocular routes, or intravaginally, by inhalation, by depot injections, or by implants.
  • modes of administration for the compounds of the present invention can be, but are not limited to, sublingual, injectable (including short-acting, depot, implant and pellet forms injected subcutaneously or intramuscularly), or by use of vaginal creams, suppositories, pessaries, vaginal rings, rectal suppositories, intrauterine devices, and transdermal forms such as patches and creams.
  • the composition may be administered in the form of a tablet, a capsule, an aqueous solution, an aqueous mixture, an aqueous colloid, a milk, an emulsion, a sponge, an ointment, a paste, a spray, a patch, a cream, a gel, a foam, a pump, a biodegradable implantable device, a sustained release vehicle, and the like.
  • the composition may be administered as a combination of these various forms.
  • Specific modes of administration will depend on the indication.
  • the selection of the specific route of administration and the dose regimen is to be adjusted or titrated by the clinician according to methods known to the clinician in order to obtain the optimal clinical response.
  • the amount of compound to be administered is that amount which is therapeutically effective.
  • the dosage to be administered will depend on the characteristics of the subject being treated, e.g., the particular animal treated, age, weight, health, types of concurrent treatment, if any, and frequency of treatments, and can be easily determined by one of skill in the art (e.g., by the clinician).
  • huperzine may be administered at about 1 mcg/kg, about 2 mcg/kg, about 5 mcg/kg, about 10 mcg kg, about 20 mcg/kg, about 30 mcg/kg, about 60 mcg/kg, about 120 mcg/kg, about 240 mcg/kg, about 500 mcg/kg, about 1 mg/kg, or at a range between or including any two of the doses.
  • the huperzine analog may be administered at about 1 mcg/kg, about 2 mcg/kg, about 5 mcg/kg, about 10 mcg/kg, about 20 mcg/kg, about 30 mcg/kg, about 60 mcg/kg, about 120 mcg/kg, about 240 mcg/kg, about 500 mcg/kg, about 1 mg/kg, or at a range between or including any two of the doses.
  • An embodiment includes a composition of an acetylcholinesterase inhibitor compound and an antioxidant.
  • the acetylcholinesterase inhibitor is huperzine A
  • the antioxidant agent is selected from uric acid, ascorbic acid, glutathione, melatonin, a tocopherol, a tocotrienol, epicatechin, epigallocatechin, epicatechin gallate, epigallocatechin gallate, epigallocatechin, gallic acid, methyl gallate, and combinations thereof.
  • the huperzine A is dosed over a 24 hour period at about 1 mcg/kg, about 2 mcg/kg, about 5 mcg/kg, about 10 mcg/kg, about 20 mcg/kg, about 30 mcg/kg, about 60 mcg/kg, about 120 mcg/kg, about 240 mcg/kg, about 500 mcg/kg, about 1 mg/kg, or at a range between or including any two of the doses.
  • the antioxidant agent is dosed over a 24 hour period at about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 60 mg/kg, about 120 mg/kg, about 2240 mg/kg, about 500 mg/kg, about 1 gram/kg, or at a range between or including any two of the doses.
  • the weight ratio of antioxidant agent to huperzine A is about 100,000: 1, about 50:000: 1, about 20:000: 1, 10,000: 1, about 5000: 1, 2000: 1, 1000: 1, about 500: 1, about 200: 1, about 100: 1, about 10: 1, or at a range between or including any two of the ratios.
  • the acetylcholinesterase inhibitor is huperzine A and the antioxidant agent epigallocatechin gallate.
  • the dosage of huperzine A is about 10 meg and the dosage of epigallocatechin gallate is about 100 mg/kg.
  • the dosage of huperzine A is about 5 meg and the dosage of epigallocatechin gallate is about 100 mg/kg.
  • compositions containing the compounds of the present invention and a suitable carrier can be solid dosage forms which include, but are not limited to, tablets, capsules, cachets, pellets, pills, powders and granules; topical dosage forms which include, but are not limited to, solutions, powders, fluid emulsions, fluid suspensions, semisolids, ointments, pastes, creams, gels and jellies, and foams; and parenteral dosage forms which include, but are not limited to, solutions, suspensions, emulsions, and dry powder; comprising an effective amount of a polymer or copolymer of the present invention.
  • the active ingredients can be contained in such formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • pharmaceutically acceptable diluents fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • the means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman & Gilman 's The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980) can be
  • the compounds of the present invention can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • the compounds can be administered by continuous infusion subcutaneous ly over a period of about 15 minutes to about 24 hours.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the compounds can be formulated readily by combining these compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP).
  • disintegrating agents can be added, such as, but not limited to, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores can be provided with suitable coatings.
  • suitable coatings can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include, but are not limited to, push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as, e.g., lactose, binders such as, e.g., starches, and/or lubricants such as, e.g., talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions can take the form of, e.g., tablets or lozenges formulated in a conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
  • the compounds of the present invention can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds of the present invention can also be formulated as a depot preparation.
  • Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the compounds of the present invention for example, can be applied to a plaster, or can be applied by transdermal, therapeutic systems that are consequently supplied to the organism.
  • compositions of the compounds also can comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as, e.g., polyethylene glycols.
  • the compounds of the present invention can also be administered in combination with other active ingredients, such as, for example, adjuvants, protease inhibitors, or other compatible drugs or compounds where such combination is seen to be desirable or advantageous in achieving the desired effects of the methods described herein.
  • active ingredients such as, for example, adjuvants, protease inhibitors, or other compatible drugs or compounds where such combination is seen to be desirable or advantageous in achieving the desired effects of the methods described herein.
  • the disintegrant component comprises one or more of croscarmellose sodium, carmellose calcium, crospovidone, alginic acid, sodium alginate, potassium alginate, calcium alginate, an ion exchange resin, an effervescent system based on food acids and an alkaline carbonate component, clay, talc, starch, pregelatinized starch, sodium starch glycolate, cellulose floe, carboxymethylcellulose, hydroxypropylcellulose, calcium silicate, a metal carbonate, sodium bicarbonate, calcium citrate, or calcium phosphate.
  • the diluent component comprises one or more of mannitol, lactose, sucrose, maltodextrin, sorbitol, xylitol, powdered cellulose, microcrystalline cellulose, carboxymethylcellulose, carboxyethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, starch, sodium starch glycolate, pregelatinized starch, a calcium phosphate, a metal carbonate, a metal oxide, or a metal aluminosilicate.
  • the optional lubricant component when present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, silica, silicic acid, talc, propylene glycol fatty acid ester, polyethoxylated castor oil, polyethylene glycol, polypropylene glycol, polyalkylene glycol, polyoxyethylene-glycerol fatty ester, polyoxyethylene fatty alcohol ether, polyethoxylated sterol, polyethoxylated castor oil, polyethoxylated vegetable oil, or sodium chloride.
  • a compound of formula (I) is prepared according to the following Scheme 1 :
  • Huperzine A Control Mice (a group of eight) were tested with huperzine A by intraperitoneal injection. The mice were given doses of 0.2, 0.3, 0.415, 0.85 mg/kg of huperzine A. The mice were then shocked at 1 hour, using 32 mA of electricity at 6 Hz for 0.2 seconds. The mice were observed for an anticonvulsant biological response, e.g. tremors or minimal motor impairment. At 0.2 mg/kg, a biological response was not observed in the eight mice tested. At 0.3 mg/kg, two of eight mice showed biological response. At 0.415 mg/kg, seven of eight mice were affected. At a dose of 0.83 mg/kg, all eight mice tested showed a biological response.
  • the effective dose (ED50) of huperzine A at one hour was 0.339 mg/kg, with a 95% confidence interval of 0.28-0.404 mg/kg, slope 13.17, and standard error of 4.91. Peak biological effect was observed for the 0.83 mg/kg dose at 1.0 hours.
  • EGCG Epigallocatechin Gallate
  • Huperzine A with EGCG Four mice were tested with 100 mg/kg of EGCG and 0.01 mg/kg huperzine A. The mice were shocked as above at 0.25 hours, 0.5 hours, 1.0 hours, 2.0 hours, and 4.0 hours. No biological effect was seen at 0.25 hours, one mouse affected at 0.5 hours, two mice at 1 hours, two mice at 2 hours, and no mice at 4 hours. No toxicity was observed at the various time points.
  • the effective dose, ED50, of the huperzine when dosed in the presence of the EGCG was about 0.01 mg/kg, about a 36 fold increase in activity in comparison to the huperzine A control.

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Description

COMPOSITION AND METHODS FOR TREATING NEURODEGENERATIVE
DISEASES
Cross-Reference to Related Applications:
[0001] This application claims priority to U.S. Provisional Application No. 61/642,661 entitled "Composition and Methods for Treating Neurodegenerative Diseases" filed May 4, 2012, and U.S. Provisional Application No. 61/723,240 entitled "Composition and Methods for Treating Neurodegenerative Diseases" filed November 6, 2012, which are herein incorporated by reference in their entirety.
Brief summary of the invention:
[0002] In an embodiment, a composition may include a therapeutically effective amount of an acetylcholinesterase inhibitor that is not a huperzine. The acetylcholinesterase inhibitor may have specificity for the G4 isoform of acetylcholinesterase enzyme.
[0003] In an embodiment, a method of treating a neurodegenerative disease may include administering a therapeutically effective amount of an acetylcholinesterase inhibitor that is not a huperzine wherein the neurodegenerative disease is treated. The acetylcholinesterase inhibitor may have selective activity for the G4 isoform of acetylcholinesterase enzyme.
[0004] In an embodiment, a composition may include a therapeutically effective amount of an acetylcholinesterase inhibitor, an NMDA receptor (a specific type of ionotropic glutamate receptor that has N-methyl-D-aspartate as an agonist)) antagonist, and either or both of a mitochondrial protectant and an anti-inflammatory agent.
[0005] In an embodiment, a method of treating a neurodegenerative disease may include administering a therapeutically effective amount of an acetylcholinesterase inhibitor, an NMDA receptor antagonist, and either or both of a mitochondrial protectant and an antiinflammatory agent wherein the neurodegenerative disease is treated. [0006] Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, compositions, or methodologies described, as these may vary. It is to be also understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
[0007] Optical isomers - diastereomers - geometric isomers - tautomers. Compounds described herein may contain an asymmetric center and may thus exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereomers. The present invention includes all possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers. The formulas are show without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of such formulas and pharmaceutically acceptable salts and solvates thereof. Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example, by use of an optically active acid or base or a resolving agent or on a chiral HPLC column. Further, any enantiomer or diastereomer of a compound of the general formula may be obtained by stereospecific using optically pure starting materials or reagents of known configuration.
[0008] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to a "cell" is a reference to one or more cells and equivalents thereof known to those skilled in the art, and so forth.
[0009] As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%.
[0010] "Administering" when used in conjunction with a therapeutic means to administer a therapeutic agent into or onto a target tissue or to administer a therapeutic to a patient whereby the therapeutic agent positively impacts the tissue to which it is targeted. Administering may be done by the actual subject being treated or a health care professional.
[0011] The term "huperzine" means huperzine A, huperzine B, or huperzine C, or salts thereof, unless otherwise defined in a particular embodiment. Huperzine A is ( 1R,95", 13£ 1 -amino- 13 -ethylidene- 11 -methyl-6-azatricyclo [7.3.1.02'7]trideca- 2(7),3 , 10- trien- 5-one. Huperzine B is (4aR,5R, 10bR)-2,3,4,4a,5,6-hexahydro-12-methyl-lH-5, 10b- propeno-l,7-phenanthrolin-8(7H)-one, Huperzine C is (lR,9S,13R)-l-amino-13-ethenyl-l 1- methyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one.
[0012] The terms "individual", "host", "subject", "patient", and "animal" as used interchangeably herein include, but are not limited to, humans and non-human vertebrates such as wild, domestic and farm animals.
[0013] The term "improves" as used herein, is used to convey that the present invention changes either the appearance, form, characteristics, physiological, and/or the physical attributes of the tissue and/or organ to which it is being provided, applied or administered.
[0014] The term "inhibiting" includes the administration of a compound of the present invention to prevent the onset of the symptoms, alleviating the symptoms, or eliminating or ameliorating the disease, condition or disorder.
[0015] By "pharmaceutically acceptable", it is meant the carrier, diluent, excipient, or counter ion must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
[0016] Pharmaceutically acceptable salts as anionic counter ions include, but are not limited to, acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, tosylate, adipate, caprate, caproate, caprylate, dodecylsulfate, glutarate, laurate, oleate, palmitate, sebacate, stearate, undecylenate, and combinations thereof. Pharmaceutically acceptable salts as cationic counter ions include, but are not limited to, ammonium, arginine, diethylamine, ethylenediamine, piperazine, and combinations thereof. Pharmaceutically acceptable salts include, but are not limited to, chloride, bromide, nitrate, sulfate, tosylate, phosphate, tartrate, or maleate. Pharmaceutically acceptable compounds include hydrates thereof.
[0017] As used herein, the term "therapeutic" means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient. In part, embodiments of the present invention are directed to the treatment of neurodegenerative disease or decrease the symptoms thereof.
[0018] A "therapeutically effective amount" or "effective amount" of a composition is a predetermined amount calculated to achieve the desired effect such as to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient. The activity contemplated by the present methods includes both medical therapeutic and/or prophylactic treatment, as appropriate. The specific dose of a compound administered according to this invention to obtain therapeutic and/or prophylactic effects, will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated. The compounds are effective over a wide dosage range and, for example, dosages per day will normally fall within the range of from 0.001 to 10 mg/kg, more usually in the range of from 0.01 mg/kg to 1 mg/kg. However, it will be understood that the effective amount administered will be determined by the physician in the light of the relevant circumstances including the conditions to be treated, the choice of compound to be administered, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. A therapeutically effective amount of compound of this invention is typically an amount such that when it is administered in a physiologically tolerable excipient composition, it is sufficient to achieve an effective systemic concentration or local concentration in the tissue.
[0019] The terms "treat", "treated", or "treating" as used herein refer to both therapeutic treatment and preventative measures, wherein the object is to prevent or slow down an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
[0020] The terms "carrier", "excipient", "diluent", and "adjuvant" may be used interchangeably and refer to a composition with which the therapeutic agent is administered. Such carriers may be sterile liquids such as, for example, water and oils, including those of petroleum, animal, vegetable or synthetic origin. Saline solution, aqueous dextrose and glycerol solution may also be employed as liquid carriers. Suitable pharmaceutical excipients include, but are not limited to, glucose, starch, lactose, sucrose, gelatin, malt, rice, flour, chalk, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, and ethanol. The composition, if desired, may contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions may take a form of solutions, suspensions, emulsions, powders, sustained-release formulations, and the like.
[0021] The term "alkyl," as used herein, refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl and the like. Preferred alkyl groups herein contain 1 to 6 carbon atoms. Alkyl groups may be optionally substituted with one to three groups chosen from halo, amino, methoxy, ethoxy, hydroxyl, methylthio, methylsulfonyl, nitro, aryl, heterocyclyl and heteroaryl.
[0022] The term "alkenyl," as used herein, refers to a branched or unbranched hydrocarbon group of 2 to 24 carbon atoms containing at least one unsaturated bond, such as, without limitation, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, decenyl, and the like. Preferred alkenyl groups herein contain 2 to 6 carbon atoms. Alkenyl groups may be optionally substituted with one to three groups chosen from halo, amino, methoxy, ethoxy, hydroxyl, methylthio, methylsulfonyl, nitro, aryl, heterocyclyl and heteroaryl. [0023] The term "cycloalkyl" refers to ring-containing alkyl radicals of 3 to 14 carbon atoms. Examples include cyclohexyl, cyclopentyl, cyclopropyl, cyclopropylmethyl and norbornyl. Cycloalkyl groups may be optionally substituted with one to three groups chosen from halo, amino, methoxy, ethoxy, hydroxyl, methylthio, methylsulfonyl, nitro, aryl, heterocyclyl and heteroaryl.
[0024] The term "aryl" or "Ar" employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic group containing one or more rings (typically one, two or three rings). Multiple rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include, but are not limited to, phenyl, anthracyl and naphthyl. Preferred are phenyl (Ph) and naphthyl, most preferred is phenyl. Aryl groups may be optionally substituted with one to three groups chosen from halo, amino, methoxy, ethoxy, hydroxyl, methylthio, methylsulfonyl, nitro, aryl, heterocyclyl and heteroaryl.
[0025] The term "heterocycle", "heterocyclyl" or "heterocyclic" by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, stable, mono- or multicyclic heterocyclic ring system consisting of carbon atoms and at least one heteroatom including, but not limited to, N, O, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heterocycle may be attached to the compound of which it is a component, unless otherwise stated, at any heteroatom or carbon atom in the heterocycle that affords a stable structure. Heterocyclic groups may be optionally substituted with one to three groups chosen from halo, amino, methoxy, ethoxy, hydroxyl, methylthio, methylsulfonyl, nitro, aryl, heterocyclyl and heteroaryl.
[0026] Examples of non-aromatic heterocycles include monocyclic groups such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolinyl, pyrazolidinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1,4-dioxanyl, 1,3-dioxanyl, homopiperazinyl, homopiperidinyl, 1,3-dioxepinyl, 4,7-dihydro- 1,3-dioxepinyl and hexamethyleneoxide.
[0027] The term "heteroaryl" or "heteroaromatic" refers to a heterocycle having aromatic character. A monocyclic heteroaryl group is preferably a 5-, 6-, or 7-membered ring, examples of which are pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl and pyrazinyl. A polycyclic heteroaryl may comprise multiple aromatic rings or may include one or more partially saturated rings. Heteroaryl groups may be optionally substituted with one to three groups chosen from halo, amino, methoxy, ethoxy, hydroxyl, methylthio, methylsulfonyl, nitro, aryl, heterocyclyl and heteroaryl.
[0028] Examples of monocyclic heteroaryl groups include, for example, six- membered monocyclic aromatic rings such as, for example, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; and five-membered monocyclic aromatic rings such as, for example, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3 -triazolyl, 1,2,4- triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
[0029] Examples of polycyclic heteroaryl groups containing a partially saturated ring include tetrahydroquinolyl and 2,3 -dihydrobenzo furyl.
[0030] Examples of polycyclic heteroaryls include indolyl, indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl, 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1 ,4-benzodioxanyl, chromene-2-one-yl (coumarinyl), dihydrocoumarin, chromene-4-one-yl, benzofuryl, 1,5-naphthyridinyl, 2,3- dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, purinyl, benzimidazolyl, benzotriazolyl, thioxanthinyl, benzazepinyl, benzodiazepinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl and quinolizidinyl.
[0031] The term "substituted" refers to a molecular group that replaces a hydrogen in a compound and may include, but are not limited to, trifluoromethyl, nitro, cyano, C1-C20 alkyl, aromatic or aryl, halide (F, CI, Br, I), C1-C20 alkyl ether, benzyl halide, benzyl ether, aromatic or aryl ether, hydroxy, alkoxy, amino, alkylamino (-NHR'), dialkylamino (-NR'R") or other groups which do not interfere with the formation of the diaryl alkylphosphonate.
[0032] As used herein, the term "neurodegenerative disease" refers to conditions or symptoms resulting from progressive loss of structure or function of neurons, including neuronal death. Conditions or diseases that can be classified as neurodegenerative include, but are not limited to, Alzheimer's disease, epilepsy, Parkinson's disease, Huntington's disease, neuropathic pain, multiple sclerosis, ataxia, amyotrophic lateral sclerosis, AIDS- related dementia, neurotoxic poisoning, muscular dystrophy, myasthenia gravis, vascular dementia, glaucoma, orthostatic hypotension, mitochondrial diseases, and infantile spasms.
[0033] Acetylcholinesterase (AChE) is an enzyme that degrades, through hydrolytic activity, acetylcholine to produce choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate synaptic transmission. The AChE enzyme has a very high catalytic activity, wherein each molecule being capable of degrading up to about 25,000 acetylcholine molecules per second. As used herein, the term "acetylcholinesterase" encompasses all known and unknown isoforms of AChE and other enzymes with analogous activity including, but not limited to, butyrylcholinesterase unless the context clearly dictates otherwise.
[0034] AChE is a highly polymorphic enzyme, isoforms of which can be distinguished by their subunit associations and hydrodynamic properties. Differing sedimentation coefficients of different isoforms allow for their separation by ultracentrifugation on sucrose density gradients. In mammalian brain, the bulk of AChE occurs as a tetrameric, G4 form together with much smaller amounts of a monomeric, Gl . There is strong evidence that not all acetylcholinesterase inhibitors inhibit all forms of AChE equally.
[0035] The G4 form of AChE is the major isoform in most regions within the brain. Approximately 60%-90% of this enzymatic form is ectocellular. Ectocellular G4 AChE is the major form for metabolizing acetylcholine (ACh) and this form is selectively depleted in Alzheimer's disease suggesting that G4 is the physiologically relevant isoform at cholinergic synapses and its inhibition would be expected to prolong the action of AChE. By contrast, Gl occurs primarily in the neural cytoplasm where its inhibition would be unlikely to affect synaptic physiology, making G4 selective AChE inhibitors much more effective and potent. AChE inhibitors may or may not have equal efficacy in different parts of the brain. In some methods, the AChE inhibitor may be substantially equally effective in all regions of the brain.
[0036] In some instances, AChE inhibitors inhibit AChE with similar mechanisms and to a similar degree. Yet, different AChE inhibitors effect on other cholinesterases such as, for example, butyrylcholinesterase (BuChE), is specific to the particular compound being used. BuChE is a non-specific cholinesterase enzyme that hydrolyses many different choline esters and in human plasma exists at 160-fold higher concentration than AChE.
[0037] Huperzine A is an acetylcholinesterase inhibitor with ring numbering shown:
Figure imgf000011_0001
Huperzine A [0038] In some aspects, the present disclosure is directed to compounds and compositions for treating neurodegenerative diseases and symptoms thereof, by targeting various mechanisms for neuronal death or loss of function in neurons. Aspects of the present invention are directed to compositions comprising an acetylcholinesterase inhibitor exhibiting selective inhibition of the G4 isoform of AChE. In some embodiments, the AChE inhibitor may exhibit selective inhibition of the G4 isoform of AChE compared to the Gl and G2 isoforms of AChE. In some embodiments, the selectivity in inhibition may be by at least a factor of about 2. In other embodiments the selectivity may be by a factor of at least about 5, and in yet other embodiments, the selectivity may be by a factor of at least about 10.
[0039] In particular embodiments, the AChE inhibitor may not be one or more of the following:
Huperzine A: IR,9S, 13E)- 1 -Amino- 13-ethylidene- 1 1 - methyl-6-azatricyclo[7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one;
Huperzine B;
(4aR,5R,10bR)-2,3,4,4a,5,6-hexahydro-
12-methyi-lH-5,10b-propeno-l ,7- phenanthroHn~8(7H)~one;
Huperzine C:
(1 R,9S, 13R)- 1 -Amino- 13-ethenyl- 1 1 - methyl-6-azatricyclo[7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one;
Figure imgf000012_0001
IR,9S, 13E)- 1 -Amino- 13-ethylidene- 1 1 - trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one;
(lR,9S, 13£)-l-Amino-13- trifluoroethylidene- 11 -methyl- 6- azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one;
(lR,9S, 13£)-l-Amino-13- trifluoroethylidene- 1 1 -trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one; or
(IR,9S, 13E - 1 -Amino- 13-ethylidene- 1 1 - phenyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one, or
pharmaceutically acceptable salt thereof.
Figure imgf000013_0001
[0040] An aspect is an AChE inhibitor compound selective for the G4 isoform. In some embodiments, the selective AChE inhibitor compound has a proviso that the G4 isoform selective AChE inhibitor compound is not a huperzine. In other embodiments, the compound has a proviso that the compound is not huperzine A; huperzine B; huperzine C; (lR^^ lS^-l-amino-lS-trifluoroethylidene-l 1-methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; (lR,95', 13£)-l-amino-13-ethylidene-l l-trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; (lR,95,13£)-l-amino-13- trifluoroethylidene-1 l-trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5- one; or (lR,9S,13is)-l-amino-13-ethylidene-l l-phenyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one, or pharmaceutically acceptable salt thereof.
[0041] In some embodiments, the AChE inhibitor is selective for the G4 isoform and has no inhibitory effect on BuChE. In other embodiments, the G4 selective AChE inhibitor and has a lesser inhibitory effect on BuChE. In still other embodiments, the G4 selective AChE inhibitor has higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2. In some embodiments, the selective AChE inhibitor compound has a higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2 and has a proviso the compound is not a huperzine. In other embodiments, the compound has a proviso that the compound is not huperzine A; huperzine B; huperzine C; (IR,9S, 13E -1- amino-13-trifluoroethylidene-l l-methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5- one; (lR,9S, 13is)-l-amino-13-ethylidene-l l-trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; (lR,95,,13£)-l-amino-13-trifluoroethylidene-l l-trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; or (lR,9S, 13is)-l-amino-13-ethylidene- l l-phenyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one, or pharmaceutically acceptable salt thereof.
[0042] In an embodiment, the acetylcholinesterase inhibitor has the general formula
I:
Figure imgf000015_0001
(I), or pharmaceutically acceptable salt thereof, wherein Ri is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar; R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl; RP1, RP2, RVi, Rv2 are independently selected from hydrogen and fluorine; RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; RN3 is selected from absent and (Ci-C24)alkyl; and n is an integer selected from 1, 2, 3, and 4; with the proviso the compound is not
( 1R,9«S, 13E)- 1 -amino- 13 -ethylidene- 11 -methyl-6-azatricyclo [7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one;
(IR,9S, 13E)-\ -amino- 13-trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one;
(\R,9S, 13E)- 1 -amino- 13 -ethylidene- 1 1 -trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one;
( 1R,9«S, 13E)- 1 -amino- 13 -trifluoroethylidene- 11 -trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one; or
(\R,9S, 13E)- 1 -amino- 13 -ethylidene- 11 -phenyl-6-azatricyclo[7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one.
[0043] Some embodiments of the general formula I have the 1 -amino group as a quaternary amine. In some embodiments, RNI and RN2 are independently selected from (Ci- C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; and RN3 is (Ci-C24)alkyl. The quaternary amine can have three independent alkyl groups. The quaternary amine may have three methyl groups. The anionic counter ion of the quaternary amine can be any pharmaceutically acceptable salt. Pharmaceutically acceptable anionic counter ions include, but are not limited to, acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, tosylate, adipate, caprate, caproate, caprylate, dodecylsulfate, glutarate, laurate, oleate, palmitate, sebacate, stearate, undecylenate, and combinations thereof. Preferable anionic counterions are acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, and tosylate. In other embodiments, RN3 is absent and the 1 -amino group is not a quaternary amine.
[0044] Other embodiments have n as an integer selected from 2, 3, and 4. In certain embodiments, n is 2. In other embodiments, R2 is phenyl and n is an integer selected from 2, 3, and 4. In certain embodiments, n is 2. In select embodiments, R2 is phenyl, Ri is methyl, RNI and RN2 are H, and RN3 is absent. In select embodiments, the compound has a formula II,
Figure imgf000016_0001
(II), or pharmaceutically acceptable salt thereof wherein n is an integer selected from 2, 3, and 4. In some of these embodiments, n is 2.
[0045] Various embodiments of the first aspect have the general formula IV:
Figure imgf000017_0001
(IV), or pharmaceutically acceptable salt thereof wherein Ri is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl, with a proviso the compound is not
( 1R,9«S, 13E)- 1 -amino- 13 -ethylidene- 11 -methyl-6-azatricyclo [7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one;
(\R,9S, 13E)-\ -amino- 13-trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one; or
( 1R,9«S, 13E)- 1 -amino- 13 -ethylidene- 11 -phenyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one.
In some embodiments, Ri is a substituted phenyl group. In other embodiments, Ri is (C2- C20)alkyl. Preferably, Ri is (C2-C4)alkyl. More preferably, Ri is (C2-C3)alkyl. The alkyl may be substituted.
[0046] Various embodiments of the first aspect have the general formula V:
Figure imgf000017_0002
(V), or pharmaceutically acceptable salt thereof wherein RNi is selected from (Ci-C24)alkyl, CF3, CF2CF3, CCI3, CBr3, and CHO. In some embodiments, RNI is (Ci-C2o)alkyl. Preferably, RNI is (Ci-C4)alkyl. RNi may be (Ci)alkyl. More preferably, RNI is be (C2-C4)alkyl. The alkyl may be substituted.
[0047] Various embodiments of the first aspect have the general formula VI:
Figure imgf000018_0001
(VI) or pharmaceutically acceptable salt thereof wherein R2 is selected from CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar with the proviso the compound is not
( 1R,9«S, 13E)- 1 -amino- 13 -ethylidene- 11 -methyl-6-azatricyclo [7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one; or
(IR,9S, 13E)- 1 -amino- 13 -ethylidene- 1 1 -phenyl-6-azatricyclo [7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one, or pharmaceutically acceptable salt thereof.
. In some embodiments, Ar is phenyl.
[0048] In other embodiments, an AChE inhibitor may be of general formula:
Figure imgf000018_0002
harmaceutically acceptable salt thereof wherein Ri is selected from an (C2-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl.
[0049] In other embodiments, an AChE inhibitor may be of general formula:
Figure imgf000019_0001
(VII), or pharmaceutically acceptable salt thereof wherein Ri is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar; R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl; RPi is H or F; RP2 is H or F; RVi is H or F; RV2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Rv2 is fluorine; RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; and n is an integer selected from 1, 2, 3, and 4.
[0050] In other embodiments, an AChE inhibitor may be of general formula:
Figure imgf000019_0002
(VIII), or pharmaceutically acceptable salt thereof wherein RPi is H or F; RP2 is H or F; RVi is H or F; RV2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Rv2 is fluorine. [0051] In another aspect, the present disclosure is directed to compositions comprising an AChE inhibitor, an NMDA receptor antagonist, and a third agent selected from an anti-inflammatory agent, a mitochondrial protectant and a combination thereof. In some embodiments, the AChE inhibitor, the NMDA receptor antagonist and the third agent may be administered together as a single composition. In other embodiments, the AChE inhibitor, the NMDA receptor antagonist and the third agent may be administered separately. In particular embodiments, the administration of the AChE inhibitor, the NMDA receptor antagonist and the third agent may be separated in time. In certain embodiments, the AChE inhibitor may be, but is not limited to, huperzine, tacrine, galanthamine, donepezil, rivastagmine, neostigmine, physotigmine, or a combination thereof.
[0052] In other embodiments, the AChE inhibitors may be natural, or synthetic compounds that exhibit reversible or quasi-irreversible inhibition of acetylcholinesterase. Such compounds include, but are not limited to, carbamates, organophosphates, cannabinoids, phenantherene derivatives, piperidines, phyostigmine, neostigmine, rivastigmine, pyridostigmine, ambenonium, demarcarium, tacrine, donepezil, distigmine, phenserine, galantamine, edrophonium, huperzine A, ladostigil, ungeremine, lactucopicrin, and their pharmaceutically accepted salts and solvates.
[0053] In some embodiments, carbamates may include, but are not limited to, aldicarb, bendiocarb, bufencarb, carbaryl, carbendazim, carbetamide, carbofuran, carbosulfan, chlorbufam, choloropropham, ethiofencarb, formetanate, methiocarb, methomyl, oxamyl, phenmedipham, pinmicarb, pirimicarb, propamocarb, propham, and propoxur.
[0054] Examples of organophosphates include, but are not limited to, ecothiophate, diisopropyl fluorophosphate, cadusafos, cyclosarin, dichlorvos, dimethoate, metrifonate, parathion, malathion, diazinon or their pharmaceutically accepted salt or solvate. [0055] As used herein, cannabinoids include, but are not limited to, Δ9- tetrahydrocannabinol, a synthetic cannabinoid, a semisynthetic cannabinoid, or their combination.
[0056] In some embodiments, the AChE inhibitors may further act as mitochondrial protectants, such as, for example, membrane penetrating antioxidants or pyruvates.
[0057] In other embodiments, the AChE inhibitors may exhibit anti-inflammatory activity by lowering factors including, but not limited to, TNF-a, 11-6, and COX -2. Examples include, without limitation, galantamine, donepezil, and so forth.
[0058] In yet other embodiments, the AChE inhibitors may additionally exhibit NMDA receptor antagonism, more preferably at the MK-801 binding site, for example, donepezil, galanthamine, tacrine, rivastigmine, neostigmine, memantine, and the like.
[0059] In some embodiments, the AChE inhibitor is a compound selective for the G4 isoform. In other embodiments, the selective AChE inhibitor has a proviso the compound is not a huperzine. In other embodiments, the compound selective for the G4 isoform has a proviso that the compound is not huperzine A; huperzine B; huperzine C; (IR,9S, 13E -1- amino-13-trifluoroethylidene-l l-methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5- one; ( 1R,9«S, 13 is)- 1 -amino- 13 -ethylidene- 11 -trifluoromethyl-6-azatricyclo [7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; (lR,95,,13£)-l-amino-13-trifluoroethylidene-l l-trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; or (lR,9S, 13is)-l-amino-13-ethylidene- l l-phenyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one, or pharmaceutically acceptable salt thereof.
[0060] In some other embodiments, the compositions comprises an AChE inhibitor, an NMDA receptor antagonist, and a third agent selected from an anti-inflammatory agent, a mitochondrial protectant and a combination thereof, wherein the AChE inhibitor has no inhibitory effect on BuChE. In other embodiments, the G4 selective AChE inhibitor and has a lesser inhibitory effect on BuChE. In still other embodiments, the G4 selective AChE inhibitor has higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2. In some embodiments, the selective AChE inhibitor compound has a higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2 and has a proviso the compound is not a huperzine. In other embodiments, the compound has a proviso that the compound is not huperzine A; huperzine B; huperzine C; (lR,9S, 13is)-l-amino-13- trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; (\R,9S, 13E)- 1 -amino- 13-ethylidene- 1 l-trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; (lR,95,,13£)-l-amino-13-trifluoroethylidene-l l-trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; or (lR,9S, 13is)-l-amino-13-ethylidene- l l-phenyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one, or pharmaceutically acceptable salt thereof.
[0061] Some embodiments comprise compositions comprising an AChE inhibitor, and an NMDA receptor antagonist, and optionally a third agent selected from an antiinflammatory agent, a mitochondrial protectant and a combination thereof, wherein the acetylcholinesterase inhibitor has the general formula I:
Figure imgf000022_0001
(I), or pharmaceutically acceptable salt thereof, wherein Rj is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar; R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl; RNi and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CCI3, CBr3, and CHO; RN3 is selected from absent and (Ci-C24)alkyl; and n is an integer selected from 1, 2, 3, and 4, or pharmaceutically acceptable salt thereof. In some embodiments, the acetylcholinesterase inhibitor has a proviso the inhibitor compound is not
( 1R,9«S, 13E)- 1 -amino- 13 -ethylidene- 11 -methyl-6-azatricyclo [7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one;
(\R,9S, 13E)-l -amino- 13-trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one;
(IR,9S, 13E)- 1 -amino- 13 -ethylidene- 1 1 -trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one;
( 1R,9«S, 13E)- 1 -amino- 13 -trifluoroethylidene- 11 -trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one; or
(\R,9S, 13E)- 1 -amino- 13 -ethylidene- 11 -phenyl-6-azatricyclo[7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one.
[0062] Some embodiments wherein the AChE inhibitor is of formula 1 , the 1 -amino group is a quaternary amine. In various embodiments, RNI and RN2 are independently selected from (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; and RN3 is (Ci-C24)alkyl. The quaternary amine can have three independent alkyl groups. The quaternary amine may have three methyl groups. The anionic counter ion of the quaternary amine can be any pharmaceutically acceptable salt. Pharmaceutically acceptable anionic counter ions include, but are not limited to, acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, tosylate, adipate, caprate, caproate, caprylate, dodecylsulfate, glutarate, laurate, oleate, palmitate, sebacate, stearate, undecylenate, and combinations thereof. Preferable anionic counterions are acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, and tosylate. In other embodiments, RN3 is absent and the 1 -amino group is not a quaternary amine.
[0063] Other embodiments have n as an integer selected from 2, 3, and 4. In certain embodiments, n is 2. In other embodiments, R2 is phenyl and n is an integer selected from 2, 3, and 4. In certain embodiments, n is 2. In select embodiments, R2 is phenyl, Ri is methyl, RNI and RN2 are H, and RN3 is absent.
[0064] In select embodiments, the compositions comprise an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent, wherein the AChE inhibitor compound is of formula II,
Figure imgf000024_0001
(II) or pharmaceutically acceptable salt thereof wherein n is an integer selected from 2, 3, and 4. In some of these embodiments, n is 2.
[0065] In other embodiments, the compositions comprise an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent, wherein the AChE inhibitor may be of general formula:
Figure imgf000025_0001
(III) or pharmaceutically acceptable salt thereof wherein Ri is selected from an (C2-C24)alkyl , an aryl, a cycloalkyl, an (C2-C24)alkenyl, a heterocycle, and a heteroaryl.
[0066] Other embodiments are compositions comprising an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent, wherein the AChE inhibitors are of general formula IV:
Figure imgf000025_0002
(IV) or pharmaceutically acceptable salt thereof wherein Ri is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl. In some embodiments, the AChE inhibitor has a proviso the AChE inhibitor compound is not
( 1R,9«S, 13E)- 1 -amino- 13 -ethylidene- 11 -methyl-6-azatricyclo [7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one;
(1R,9«S, 13E)-l -amino- 13-trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one; or (IR,9S, 13E)- 1 -amino- 13-ethylidene- 1 1 -phenyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one.
In some embodiments, Ri is a substituted phenyl group. In other embodiments, Ri is (C2- C20)alkyl. Preferably, Ri is (C2-C4)alkyl. More preferably, Ri is (C3-C4)alkyl. The alkyl may be substituted.
[0067] Various embodiments are compositions comprising an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent, wherein the AChE inhibitor is of the general formula V:
Figure imgf000026_0001
(V) or pharmaceutically acceptable salt thereof wherein RNi is selected from (Ci-C24)alkyl, CF3, CF2CF3, CCI3, CBr3, and CHO. In some embodiments, RNI is (Ci-C2o)alkyl. Preferably, RNI is (Ci-C2o)alkyl. RNI may be (Ci)alkyl. More preferably, RNI is (C2-C4)alkyl. The alkyl may be substituted.
[0068] Various embodiments are compositions comprising an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent, wherein the AChE inhibitor is of the general formula VI:
Figure imgf000027_0001
R2 is selected from CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar, or pharmaceutically acceptable salt thereof. In some embodiments, the AChE inhibitor compound has a proviso that the inhibitor compound is not
( 1R,9«S, 13E)- 1 -amino- 13 -ethylidene- 11 -methyl-6-azatricyclo [7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one; or
(\R,9S, 13E)- 1 -amino- 13 -ethylidene- 1 1 -phenyl-6-azatricyclo [7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one.
In some embodiments, Ar is phenyl.
[0069] Various embodiments are compositions comprising an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent, wherein the AChE inhibitor is of the general formula VII:
Figure imgf000027_0002
(VII), or pharmaceutically acceptable salt thereof wherein Rj is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar; R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl; RPi is H or F; RP2 is H or F; RVi is H or F; RV2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Rv2 is fluorine; RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CCI3, CBr3, and CHO; and n is an integer selected from 1, 2, 3, and 4.
[0070] Other embodiments are compositions comprising an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent, wherein the AChE inhibitor is of the general formula VIII:
Figure imgf000028_0001
(VIII), or pharmaceutically acceptable salt thereof wherein RPi is H or F; RP2 is H or F; RVi is H or F; RV2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Rv2 is fluorine.
[0071] In some aspects, the present disclosure is directed to methods of treating a neurodegenerative disease by administering an acetylcholinesterase inhibitor with a selectivity for the G4 isoform of AChE compared to Gl and G2 isoforms of AChE, wherein the AChE inhibitor is not huperzine wherein the neurodegenerative disease is treated.
[0072] In some embodiments, the method of treating a neurodegenerative disease comprises administering a therapeutically effective amount of an AChE inhibitor having specificity for the G4 isoform of acetylcholinesterase enzyme (AChE) with the proviso the compound is not a huperzine. In other embodiments, the AChE inhibitor has a proviso that the compound is not huperzine A; huperzine B; huperzine C; (lR,9S,13is)-l-amino-13- trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; (IR,9S, 13E)- 1 -amino- 13-ethylidene- 1 l-trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; (lR,95,,13£)-l-amino-13-trifluoroethylidene-l l-trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; or (lR,9S, 13is)-l-amino-13-ethylidene- l l-phenyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one, or pharmaceutically acceptable salt thereof wherein the neurodegenerative disease is treated.
[0073] In some embodiments, the method of treating a neurodegenerative disease comprises administering an AChE inhibitor selective for the G4 isoform with no inhibitory effect on BuChE wherein the neurodegenerative disease is treated. In other embodiments, the G4 selective AChE inhibitor has a lesser inhibitory effect on BuChE than for inhibition of AChE. In still other embodiments, the G4 selective AChE inhibitor has higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2. In some embodiments, the selective AChE inhibitor compound has a higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2 and has a proviso the compound is not a huperzine. In other embodiments, the compound has a proviso that the compound is not huperzine A; huperzine B; huperzine C; (l ?,95, 13£ -l-amino-13-trifluoroethylidene-l l- methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; (lR,95,13£)-l-amino-13- ethylidene-1 l-trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; ( 1R,9,S, 13E)- 1 -amino- 13 -trifluoroethylidene- 1 1 -trifluoromethyl-6-azatricyclo [7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one; or (lR,9S, 13is)-l-amino-13-ethylidene-l l-phenyl-6- azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one, or pharmaceutically acceptable salt thereof.
[0074] In some embodiments, the method of treating a neurodegenerative disease comprises administering a therapeutically effective amount of an AChE inhibitor wherein the acetylcholinesterase inhibitor has the general formula I:
Figure imgf000030_0001
(I), or pharmaceutically acceptable salt thereof, wherein Ri is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar; R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl; RNi and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; RN3 is selected from absent and (Ci-C24)alkyl; and n is an integer selected from 1, 2, 3, and 4, with a proviso the inhibitor compound is not
( 1R,9«S, 13E)- 1 -amino- 13 -ethylidene- 11 -methyl-6-azatricyclo [7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one,
(IR,9S, 13E)-\ -amino- 13-trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one,
(\R,9S, 13E)- 1 -amino- 13 -ethylidene- 1 1 -trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one,
( 1R,9«S, 13E)- 1 -amino- 13 -trifluoroethylidene- 11 -trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one, or
(\R,9S, 13E)- 1 -amino- 13 -ethylidene- 11 -phenyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one, wherein the neurodegenerative disease is treated.
[0075] Some embodiments wherein the AChE inhibitor is of formula 1 , the 1 -amino group is a quaternary amine. In various embodiments, RNI and RN2 are independently selected from (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; and RN3 is (Ci-C24)alkyl. The quaternary amine can have three independent alkyl groups. The quaternary amine may have three methyl groups. The anionic counter ion of the quaternary amine can be any pharmaceutically acceptable salt. Pharmaceutically acceptable anionic counter ions include, but are not limited to, acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, tosylate, adipate, caprate, caproate, caprylate, dodecylsulfate, glutarate, laurate, oleate, palmitate, sebacate, stearate, undecylenate, and combinations thereof. Preferable anionic counterions are acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, and tosylate. In other embodiments, RN3 is absent and the 1 -amino group is not a quaternary amine.
[0076] Other embodiments have n as an integer selected from 2, 3, and 4. In certain embodiments, n is 2. In other embodiments, R2 is phenyl and n is an integer selected from 2, 3, and 4. In certain embodiments, n is 2. In select embodiments, R2 is phenyl, Ri is methyl, RNI and RN2 are H, and RN3 is absent.
[0077] In select embodiments, the method of treating a neurodegenerative disease comprises administering a therapeutically effective amount an AChE inhibitor of formula II,
Figure imgf000031_0001
(II) or pharmaceutically acceptable salt thereof wherein n is an integer selected from 2, 3, and 4 wherein the neurodegenerative disease is treated. In some of these embodiments, n is 2. [0078] In other embodiments, the method of treating a neurodegenerative disease comprises administering a therapeutically effective amount of an AChE inhibitor of general formula:
Figure imgf000032_0001
(III) or pharmaceutically acceptable salt thereof wherein Ri is selected from an (C2-C24)alkyl , an aryl, a cycloalkyl, an (C2-C24)alkenyl, a heterocycle, and a heteroaryl wherein the neurodegenerative disease is treated.
[0079] Other embodiments are methods of treating a neurodegenerative disease comprising administering a therapeutically effective amount of an AChE inhibitor of general formula IV:
Figure imgf000032_0002
(IV) or pharmaceutically acceptable salt thereof wherein Ri is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl, wherein the AChE inhibitor has a proviso the AChE inhibitor compound is not
( 1R,9«S, 13E)- 1 -amino- 13 -ethylidene- 11 -methyl-6-azatricyclo [7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one, (IR,9S, 13E)-l -amino- 13-trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one, or
( 1R,9«S, 13E)- 1 -amino- 13-ethylidene- 11 -phenyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one wherein the neurodegenerative disease is treated.
In some embodiments, Ri is a substituted phenyl group. In other embodiments, Ri is (C2- C20)alkyl. Preferably, Ri is (C2-C4)alkyl. More preferably, Ri is (C3-C4)alkyl. The alkyl may be substituted.
[0080] Various embodiments of the method of treating a neurodegenerative disease comprises administering a therapeutically effective amount an AChE inhibitor of the general formula V:
Figure imgf000033_0001
(V) or pharmaceutically acceptable salt thereof wherein RNi is selected from (Ci-C24)alkyl, CF3, CF2CF3, CCI3, CBr3, and CHO wherein the neurodegenerative disease is treated. In some embodiments, RNI is (Ci-C2o)alkyl. Preferably, RNI is (Ci-C4)alkyl. RNi is (Ci)alkyl. More preferably, RNI is (C2-C4)alkyl. The alkyl may be substituted.
[0081] Various embodiments are methods of treating a neurodegenerative disease comprising administering a therapeutically effective amount an AChE inhibitor of the general formula VI:
Figure imgf000034_0001
(VI) or pharmaceutically acceptable salt thereof
R2 is selected from CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar, wherein the AChE inhibitor compound has a proviso that the inhibitor compound is not
( 1R,9«S, 13E)- 1 -amino- 13 -ethylidene- 11 -methyl-6-azatricyclo [7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one, or
(\R,9S, 13E)- 1 -amino- 13 -ethylidene- 1 1 -phenyl-6-azatricyclo [7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one wherein the neurodegenerative disease is treated.
In some embodiments, Ar is phenyl.
[0082] Various embodiments are methods of treating a neurodegenerative disease comprising administering a therapeutically effective amount an AChE inhibitor of the general formula VII:
Figure imgf000034_0002
(VII), or pharmaceutically acceptable salt thereof wherein Rj is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar; R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl; RPi is H or F; RP2 is H or F; RVi is H or F; RV2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Rv2 is fluorine; RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CCI3, CBr3, and CHO; and n is an integer selected from 1, 2, 3, and 4.
[0083] Other embodiments are methods of treating a neurodegenerative disease comprising administering a therapeutically effective amount an AChE inhibitor of the general formula VIII:
Figure imgf000035_0001
(VIII), or pharmaceutically acceptable salt thereof
[0084] wherein RPi is H or F; RP2 is H or F; RVi is H or F; RV2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Rv2 is fluorine.
[0085] In other embodiments, the present disclosure is directed to method of treating a neurodegenerative disease comprising administering a an AChE inhibitor, an NMDA receptor antagonist, and a third agent selected from an anti-inflammatory agent, a mitochondrial protectant and a combination thereof wherein the neurodegenerative disease is treated. In some embodiments, the AChE inhibitor, the NMDA receptor antagonist and the third agent may be administered together as a single composition. In other embodiments, the
AChE inhibitor, the NMDA receptor antagonist and the third agent may be administered separately. In particular embodiments, the administration of the AChE inhibitor, the NMDA receptor antagonist and the third agent may be separated in time. In certain embodiments, the
AChE inhibitor may be, but is not limited to, huperzine, tacrine, galanthamine, donepezil, rivastagmine, neostigmine, physotigmine, or a combination thereof. [0086] In embodiments of neurodegenerative disease by administering a combination of an AChE inhibitor, an NMDA receptor antagonist, and a third agent selected from an anti-inflammatory agent, a mitochondrial protectant, wherein the neurodegenerative disease is treated, the AChE inhibitors may be natural, or synthetic compounds that exhibit reversible or quasi-irreversible inhibition of acetylcholinesterase. Such compounds include, but are not limited to, carbamates, organophosphates, cannabinoids, phenantherene derivatives, piperidines, phyostigmine, neostigmine, rivastigmine, pyridostigmine, ambenonium, demarcarium, tacrine, donepezil, distigmine, phenserine, galantamine, edrophonium, huperzine A, ladostigil, ungeremine, lactucopicrin, and their pharmaceutically accepted salts and solvates.
[0087] In some embodiments, carbamates may include, but are not limited to, aldicarb, bendiocarb, bufencarb, carbaryl, carbendazim, carbetamide, carbofuran, carbosulfan, chlorbufam, choloropropham, ethiofencarb, formetanate, methiocarb, methomyl, oxamyl, phenmedipham, pinmicarb, pirimicarb, propamocarb, propham, and propoxur.
[0088] Examples of organophosphates include, but are not limited to, ecothiophate, diisopropyl fluorophosphate, cadusafos, cyclosarin, dichlorvos, dimethoate, metrifonate, parathion, malathion, diazinon or their pharmaceutically accepted salt or solvate.
[0089] As used herein, cannabinoids include, but are not limited to, Δ9- tetrahydrocannabinol, a synthetic cannabinoid, a semisynthetic cannabinoid, or their combination.
[0090] In some embodiments, the AChE inhibitors may further act as mitochondrial protectants, such as, for example, membrane penetrating antioxidants or pyruvates.
[0091] In other embodiments, the AChE inhibitors may exhibit anti-inflammatory activity by lowering factors including, but not limited to, TNF-a, 11-6, and COX -2. Examples include, without limitation, galantamine, donepezil, and so forth. [0092] In yet other embodiments, the AChE inhibitors may additionally exhibit NMDA receptor antagonism, more preferably at the MK-801 binding site, for example, donepezil, galanthamine, tacrine, rivastigmine, neostigmine, memantine, and the like.
[0093] In some embodiments directed to a method of treating a neurodegenerative disease comprising administering a an AChE inhibitor, an NMDA receptor antagonist, and a third agent selected from an anti-inflammatory agent, a mitochondrial protectant, and combinations thereof, wherein the neurodegenerative disease is treated. In embodiments, the AChE inhibitor compound has a proviso the compound is not a huperzine. In other embodiments, the compound selective for the G4 isoform has a proviso the compound is not huperzine A; huperzine B; huperzine C; (l ?,95, 13£ -l-amino-13-trifluoroethylidene-l l- methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; (lR,95,13£)-l-amino-13- ethylidene-1 l-trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; ( 1R,9,S, 13E)- 1 -amino- 13 -trifluoroethylidene- 1 1 -trifluoromethyl-6-azatricyclo [7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one; or (lR,9S, 13is)-l-amino-13-ethylidene-l l-phenyl-6- azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one, or pharmaceutically acceptable salt thereof.
[0094] In some embodiments, the method of treating a neurodegenerative disease comprises administering an AChE inhibitor, an NMDA receptor antagonist, and the third agent, wherein the AChE inhibitor has no inhibitory effect on BuChE, and wherein the neurodegenerative disease is treated. In other embodiments, the AChE inhibitor has a lesser inhibitory effect on BuChE than for inhibition of AChE. In still other embodiments, the AChE inhibitor has higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2. In some embodiments, the selective AChE inhibitor compound has a higher selectivity for inhibiting AChE compared to BuChE by a factor of at least about 2 and has a proviso the compound is not a huperzine. In other embodiments, the compound has a proviso that the compound is not huperzine A; huperzine B; huperzine C; (lR,9S, 13is)-l-amino-13- trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; (\R,9S, 13E)- 1 -amino- 13-ethylidene- 1 l-trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; (lR,95,,13£)-l-amino-13-trifluoroethylidene-l l-trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; or (lR,9S, 13is)-l-amino-13-ethylidene- l l-phenyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one, or pharmaceutically acceptable salt thereof.
[0095] Some embodiments comprise method of treating a neurodegenerative disease comprising administering an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent wherein the acetylcholinesterase inhibitor has the general formula I:
Figure imgf000038_0001
(I), or pharmaceutically acceptable salt thereof, wherein Ri is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar; R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl; RPi is H or F; RP2 is H or F; RVi is H or F; RV2 is H or F; RNi and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; RN3 is selected from absent and (Ci-C24)alkyl; and n is an integer selected from 1, 2, 3, and 4, or pharmaceutically acceptable salt thereof, wherein the neurodegenerative disease is treated. In some embodiments, the selective compound has a proviso the compound is not ( 1R,9«S, 13E)- 1 -amino- 13-ethylidene- 11 -methyl-6-azatricyclo [7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one, (IR,9S, 13E)-\ -amino- 13-trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one,
(\R,9S, 13E)- 1 -amino- 13 -ethylidene- 1 1 -trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one,
( 1R,9«S, 13E)- 1 -amino- 13 -trifluoroethylidene- 11 -trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one, or
(IR,9S, 13E)- 1 -amino- 13 -ethylidene- 11 -phenyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one.
[0096] Some embodiments wherein the AChE inhibitor is of formula 1 , the 1 -amino group is a quaternary amine. In various embodiments, RNI and RN2 are independently selected from (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; and RN3 is (Ci-C24)alkyl. The quaternary amine can have three independent alkyl groups. The quaternary amine may have three methyl groups. The anionic counter ion of the quaternary amine can be any pharmaceutically acceptable salt. Pharmaceutically acceptable anionic counter ions include, but are not limited to, acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, tosylate, adipate, caprate, caproate, caprylate, dodecylsulfate, glutarate, laurate, oleate, palmitate, sebacate, stearate, undecylenate, and combinations thereof. Preferable anionic counterions are acetate, bromide, camsylate, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate, thiocyanate, and tosylate. In other embodiments, RN3 is absent and the 1 -amino group is not a quaternary amine.
[0097] Other embodiments have n as an integer selected from 2, 3, and 4. In certain embodiments, n is 2. In other embodiments, R2 is phenyl and n is an integer selected from 2, 3, and 4. In certain embodiments, n is 2. In select embodiments, R2 is phenyl, Ri is methyl, RNI and RN2 are H, and RN3 is absent. [0098] In select embodiments, the method of treating a neurodegenerative disease comprising administering a an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent wherein the AChE inhibitor compound is of formula II,
Figure imgf000040_0001
(II) or pharmaceutically acceptable salt thereof wherein n is an integer selected from 2, 3, and 4, wherein the neurodegenerative disease is treated. In some of these embodiments, n is 2.
[0099] In other embodiments, the method of treating a neurodegenerative disease comprising administering a combination of an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent wherein the AChE inhibitor may be of general formula:
Figure imgf000040_0002
(III) or pharmaceutically acceptable salt thereof wherein Ri is selected from an (C2-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl, wherein the neurodegenerative disease is treated. [00100] Other embodiments are method of treating a neurodegenerative disease comprising administering an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent wherein the AChE inhibitors are of general formula IV:
Figure imgf000041_0001
(IV) or pharmaceutically acceptable salt thereof wherein Ri is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl, wherein the neurodegenerative disease is treated. In some embodiments, the AChE inhibitor compound has a proviso the compound is not
( 1R,9«S, 13E)- 1 -amino- 13 -ethylidene- 11 -methyl-6-azatricyclo [7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one;
(\R,9S, 13E)-l -amino- 13-trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one; or
( 1R,9«S, 13E)- 1 -amino- 13 -ethylidene- 11 -phenyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one.
In some embodiments, Ri is a substituted phenyl group. In other embodiments, Ri is (C2- C2o)alkyl. Preferably, (C2-C4)alkyl. More preferably, (C3-C4)alkyl. The alkyl may be substituted.
[00101] Various embodiments are methods of treating a neurodegenerative disease comprises administering a combination of an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent wherein the AChE inhibitor is of the general formula V:
Figure imgf000042_0001
(V) or pharmaceutically acceptable salt thereof wherein RNi is selected from (Ci-C24)alkyl, CF3, CF2CF3, CCI3, CBr3, and CHO, wherein the neurodegenerative disease is treated. In some embodiments, RNI is (Ci-C2o)alkyl. Preferably, RNI is (Ci-C4)alkyl. RNI may be (Ci)alkyl. More preferably, RNI is (C2-C4)alkyl. The alkyl may be substituted.
[00102] Various embodiments are methods of treating a neurodegenerative disease comprising administering a combination of an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent wherein the AChE inhibitor is of the general formula VI:
Figure imgf000042_0002
(VI) or pharmaceutically acceptable salt thereof
R2 is selected from CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar, , wherein the neurodegenerative disease is treated. In some embodiments, the selective AChE inhibitor compound has a proviso the compound is not (IR,9S, 13E)- 1 -amino- 13-ethylidene- 11 -methyl-6-azatricyclo[7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one; or
(\R,9S, 13E)- 1 -amino- 13 -ethylidene- 1 1 -phenyl-6-azatricyclo [7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one. In some embodiments, Ar is phenyl.
[00103] Various embodiments are methods of treating a neurodegenerative disease comprising administering a combination of an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent wherein the AChE inhibitor is of the general formula VII:
Figure imgf000043_0001
(VII), or pharmaceutically acceptable salt thereof wherein Ri is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar; R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl; RPi is H or F; RP2 is H or F; RVi is H or F; RV2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Rv2 is fluorine; RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; and n is an integer selected from 1, 2, 3, and 4.
[00104] Other embodiments are methods of treating a neurodegenerative disease comprising administering a combination of an AChE inhibitor, an NMDA receptor antagonist, and optionally the third agent wherein the AChE inhibitor is of the general formula VIII:
Figure imgf000044_0001
(VIII), or pharmaceutically acceptable salt thereof wherein Rpi is H or F; Rp2 is H or F; Rvi is H or F; Rv2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Rv2 is fluorine.
[00105] In some embodiments, the AChE inhibitor may exhibit selective inhibition for the G4 isoform of the AChE compared to the Gl and G2 isoforms of AChE. In particular embodiments, the selectivity in inhibition may be by a factor of at least about 2. In other embodiments the selectivity may be by a factor of at least about 5, and in yet other embodiments, the selectivity may be by a factor of at least about 10. In some embodiments, the AChE inhibitor has at least about 2 times as much affinity as for BuChE as compared to affinity for AChE.
[00106] In some embodiments, the mitochondrial protectants, may be, for example, membrane penetrating anti-oxidants or pyruvates.
[00107] In certain embodiments, the anti-inflammatory effect of the agent may be via lowering factors including, but not limited to, TNF-a, 11-6, and COX-2, such as, for example, infliximab, adalimumab, certolizumab pegol, golimumab, tocilizumab, celecoxib and rofecoxib.
[00108] In certain embodiments, NMDA receptor antagonism may be via action at the MK-801 binding site such as, for example, donepezil, galanthamine, tacrine, rivastigmine, neostigmine, memantine, and the like. [00109] In some embodiments, any of the huperzine or huperzine analog compounds described above is co-administered with an anti-inflammatory agent, a pro-drug of the antiinflammatory agent, a precursor of the anti-inflammatory agent, any combination thereof, and/or the like. In some embodiments, the huperzine or huperzine analog compound is coadministered with an anti-inflammatory agent, a pro-drug of the anti-inflammatory agent, a precursor of the anti-inflammatory agent, any combination thereof, and/or the like, wherein the acetylcholinesterase inhibitor has the general formula I:
Figure imgf000045_0001
(I), or pharmaceutically acceptable salt thereof, wherein Rj is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar; R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl; RP1, RP2, RV1, Rv2 are independently selected from hydrogen and fluorine; RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; RN3 is selected from absent and (Ci-C24)alkyl; and n is an integer selected from 1, 2, 3, and 4; with the proviso the compound is not
( 1R,9«S, 13E)- 1 -amino- 13 -ethylidene- 11 -methyl-6-azatricyclo [7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one;
(\R,9S, 13E)-l -amino- 13-trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; (IR,9S, 13E)- 1 -amino- 13 -ethylidene- 1 1 -trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one;
( IR,9S, 13E)- 1 -amino- 13 -trifluoroethylidene- 1 1 -trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; or
(IR,9S, 13E)- 1 -amino- 13 -ethylidene- 1 1 -phenyl-6-azatricyclo[7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one.
[00110] Examples of anti-inflammatory agents which may be co-administered with huperzine or an analog thereof include, but are not limited to, non-steroidal anti-inflammatory drugs, immune-selective anti-inflammatory derivatives, anti-inflammatory herbal extracts, NF-Kappa B inhibitors, IL-inhibitors, any combinations thereof, and/or the like. Additional examples of anti-inflammatory agents include, but are not limited to, tanshinone, cryptotanshinone, ferulic acid, cycloartenol, cycloartenyl ferulate, hydroxytyrosol, homovanillyl alcohol, extracts of salix purpurea, extracts of piper longum, 4-O-methylgallic acid, extracts of boswellia serrata and extracts of prunella vulgaris, and any combination thereof.
[00111] In some embodiments, any of the huperzine or huperzine analog compounds described above is co-administered with an antioxidant agent. In some embodiments, the huperzine or huperzine analog compound is co-administered with an anti-oxidant agent, a pro-drug of the anti-oxidant agent, a precursor of the anti-oxidant agent, any combination thereof, and/or the like, wherein the acetylcholinesterase inhibitor has the general formula I:
Figure imgf000047_0001
(I), or pharmaceutically acceptable salt thereof, wherein Ri is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar; R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl; RP1, RP2, RV1, Rv2 are independently selected from hydrogen and fluorine; RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; RN3 is selected from absent and (Ci-C24)alkyl; and n is an integer selected from 1, 2, 3, and 4; with the proviso the compound is not
( 1R,9«S, 13E)- 1 -amino- 13 -ethylidene- 11 -methyl-6-azatricyclo [7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one;
(IR,9S, 13E)-\ -amino- 13-trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one;
(\R,9S, 13E)- 1 -amino- 13 -ethylidene- 1 1 -trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one;
( 1R,9«S, 13E)- 1 -amino- 13 -trifluoroethylidene- 11 -trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one; or
(IR,9S, 13E)- 1 -amino- 13 -ethylidene- 11 -phenyl-6-azatricyclo[7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one.
[00112] Examples of anti-oxidant agents which may be co-administered with huperzine or an analog thereof include, but are not limited to, ascorbic acid, glutathione, lipoic acid, uric acid, beta-carotene, vitamin A, vitamin E, co-enzyme Q; a pro-drug of the anti-oxidants, a precursor of the anti-oxidants; and any combination thereof, and/or the like. Additional examples of antioxidant agents include, but are not limited to, uric acid, ascorbic acid, glutathione, melatonin, tocopherols and tocotrienols (vitamin E), salubrious polyphenols, in particular catechins, the most abundant of which are epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCG), epigallocatechin and gallic acid, methyl gallate, and any combination thereof.
[00113] In some embodiments, a huperzine or huperzine analog, described above, is co-administered with mitochondrial agent. Examples of mitochondrial protectants which may be co-administered with huperzine or an analog thereof include, but are not limited to, muscarinic receptor agonists that activate M2 subtype to prevent ACh release which in turn can activate mitochondrial protection. Muscarinic receptor agonists include, but are not limited to, compounds such as bethanechol and (2S,2'R,3'S,5'R)-l-methyl-2-(2-methyl-l,3- oxathiolan-5-yl)pyrrol-idine 3-sulfoxide methyl iodide, any combinations thereof, and/or the like.
[00114] In some embodiments, a huperzine or huperzine analog, described above, is co-administered with an NMDA receptor antagonist. Examples of NMDA receptor antagonists which may be co-administered with huperzine or an analog thereof include, but are not limited to, R-2-amino-5-phosphonopentanoate, 2-amino-7-phosphonoheptanoic acid, 3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-l-phosphonic acid, selfotel, amantadine, dextrallorphan, dextromethorphan, dextrorphan, dizocilpine , ethanol, eticyclidine, gacyclidine, ibogaine, magnesium, memantine, methoxetamine, nitrous oxide, phencyclidine, rolicyclidine, tenocyclidine, methoxydine, tiletamine, xenon, neramexane, eliprodil, etoxadrol, dexoxadrol, remacemide, delucemine, 8a-phenyldecahydroquinoline, aptiganel, remacemide, rhynchophylline, ketamine, 1 -aminocyclopropanecarboxylic acid, 7- chlorokynurenate, 5,7-dichlorokynurenic acid, kynurenic acid, lacosamide; a pro-drug of the NMDA receptor antagonist, a precursor of the NMDA receptor antagonist; and any combination thereof, and/or the like.
[00115] The term "co-administration," when used herein the compounds may be combined in one pharmaceutically-acceptable carrier, or they may be placed in separate carriers and administered to the patient at different times. Those of skill in the art understand that the formulations and/or routes of administration of the various agents/therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art. The important consideration being that the compounds should be administered sufficiently close in time that there is at least some temporal overlap in the biological effects generated by the compounds into the mammal being tested.
[00116] In some aspects, the present disclosure is directed to methods for treating neurodegenerative diseases by administering a composition comprising an AChE inhibitor and a pharmaceutically acceptable carrier, excipient, or combination thereof. Methods may be directed toward treating neurodegenerative diseases by administering a composition comprising an AChE inhibitor and a pharmaceutically acceptable excipient. In some embodiments, the composition may be administered orally, nasally, rectally, intravenously, intrathecally, intramuscularly, transdermally, opthalmically, and the like. In some embodiments the composition may be administered via a combination of these various routes.
[00117] Methods may be directed to compounds and compositions administered by any route where they are active. Administration can be systemic, topical, or oral. For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, or ocular routes, or intravaginally, by inhalation, by depot injections, or by implants. Thus, modes of administration for the compounds of the present invention (either alone or in combination with other pharmaceuticals) can be, but are not limited to, sublingual, injectable (including short-acting, depot, implant and pellet forms injected subcutaneously or intramuscularly), or by use of vaginal creams, suppositories, pessaries, vaginal rings, rectal suppositories, intrauterine devices, and transdermal forms such as patches and creams.
[00118] In each of the composition aspects, the composition may be administered in the form of a tablet, a capsule, an aqueous solution, an aqueous mixture, an aqueous colloid, a milk, an emulsion, a sponge, an ointment, a paste, a spray, a patch, a cream, a gel, a foam, a pump, a biodegradable implantable device, a sustained release vehicle, and the like. In other embodiments of the various aspects, the composition may be administered as a combination of these various forms.
[00119] Specific modes of administration will depend on the indication. The selection of the specific route of administration and the dose regimen is to be adjusted or titrated by the clinician according to methods known to the clinician in order to obtain the optimal clinical response. The amount of compound to be administered is that amount which is therapeutically effective. The dosage to be administered will depend on the characteristics of the subject being treated, e.g., the particular animal treated, age, weight, health, types of concurrent treatment, if any, and frequency of treatments, and can be easily determined by one of skill in the art (e.g., by the clinician). In various embodiments of the invention, huperzine may be administered at about 1 mcg/kg, about 2 mcg/kg, about 5 mcg/kg, about 10 mcg kg, about 20 mcg/kg, about 30 mcg/kg, about 60 mcg/kg, about 120 mcg/kg, about 240 mcg/kg, about 500 mcg/kg, about 1 mg/kg, or at a range between or including any two of the doses. In other embodiments, the huperzine analog may be administered at about 1 mcg/kg, about 2 mcg/kg, about 5 mcg/kg, about 10 mcg/kg, about 20 mcg/kg, about 30 mcg/kg, about 60 mcg/kg, about 120 mcg/kg, about 240 mcg/kg, about 500 mcg/kg, about 1 mg/kg, or at a range between or including any two of the doses. [00120] An embodiment includes a composition of an acetylcholinesterase inhibitor compound and an antioxidant. In some embodiments the acetylcholinesterase inhibitor is huperzine A, the antioxidant agent is selected from uric acid, ascorbic acid, glutathione, melatonin, a tocopherol, a tocotrienol, epicatechin, epigallocatechin, epicatechin gallate, epigallocatechin gallate, epigallocatechin, gallic acid, methyl gallate, and combinations thereof. In embodiments, the huperzine A is dosed over a 24 hour period at about 1 mcg/kg, about 2 mcg/kg, about 5 mcg/kg, about 10 mcg/kg, about 20 mcg/kg, about 30 mcg/kg, about 60 mcg/kg, about 120 mcg/kg, about 240 mcg/kg, about 500 mcg/kg, about 1 mg/kg, or at a range between or including any two of the doses. In embodiments, the antioxidant agent is dosed over a 24 hour period at about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 60 mg/kg, about 120 mg/kg, about 2240 mg/kg, about 500 mg/kg, about 1 gram/kg, or at a range between or including any two of the doses. In embodiments, the weight ratio of antioxidant agent to huperzine A is about 100,000: 1, about 50:000: 1, about 20:000: 1, 10,000: 1, about 5000: 1, 2000: 1, 1000: 1, about 500: 1, about 200: 1, about 100: 1, about 10: 1, or at a range between or including any two of the ratios. In certain embodiments the acetylcholinesterase inhibitor is huperzine A and the antioxidant agent epigallocatechin gallate. In an embodiment, the dosage of huperzine A is about 10 meg and the dosage of epigallocatechin gallate is about 100 mg/kg. In another embodiment, the dosage of huperzine A is about 5 meg and the dosage of epigallocatechin gallate is about 100 mg/kg.
[00121] Pharmaceutical formulations containing the compounds of the present invention and a suitable carrier can be solid dosage forms which include, but are not limited to, tablets, capsules, cachets, pellets, pills, powders and granules; topical dosage forms which include, but are not limited to, solutions, powders, fluid emulsions, fluid suspensions, semisolids, ointments, pastes, creams, gels and jellies, and foams; and parenteral dosage forms which include, but are not limited to, solutions, suspensions, emulsions, and dry powder; comprising an effective amount of a polymer or copolymer of the present invention. It is also known in the art that the active ingredients can be contained in such formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like. The means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman & Gilman 's The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co., New York (1980) can be consulted.
[00122] The compounds of the present invention can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. The compounds can be administered by continuous infusion subcutaneous ly over a period of about 15 minutes to about 24 hours. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
[00123] For oral administration, the compounds can be formulated readily by combining these compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as, but not limited to, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
[00124] Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
[00125] Pharmaceutical preparations which can be used orally include, but are not limited to, push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as, e.g., lactose, binders such as, e.g., starches, and/or lubricants such as, e.g., talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.
[00126] For buccal administration, the compositions can take the form of, e.g., tablets or lozenges formulated in a conventional manner.
[00127] For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[00128] The compounds of the present invention can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
[00129] In addition to the formulations described previously, the compounds of the present invention can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
[00130] Depot injections can be administered at about 1 to about 6 months or longer intervals. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[00131] In transdermal administration, the compounds of the present invention, for example, can be applied to a plaster, or can be applied by transdermal, therapeutic systems that are consequently supplied to the organism.
[00132] Pharmaceutical compositions of the compounds also can comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as, e.g., polyethylene glycols.
[00133] The compounds of the present invention can also be administered in combination with other active ingredients, such as, for example, adjuvants, protease inhibitors, or other compatible drugs or compounds where such combination is seen to be desirable or advantageous in achieving the desired effects of the methods described herein.
[00134] In some embodiments, the disintegrant component comprises one or more of croscarmellose sodium, carmellose calcium, crospovidone, alginic acid, sodium alginate, potassium alginate, calcium alginate, an ion exchange resin, an effervescent system based on food acids and an alkaline carbonate component, clay, talc, starch, pregelatinized starch, sodium starch glycolate, cellulose floe, carboxymethylcellulose, hydroxypropylcellulose, calcium silicate, a metal carbonate, sodium bicarbonate, calcium citrate, or calcium phosphate.
[00135] In some embodiments, the diluent component comprises one or more of mannitol, lactose, sucrose, maltodextrin, sorbitol, xylitol, powdered cellulose, microcrystalline cellulose, carboxymethylcellulose, carboxyethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, starch, sodium starch glycolate, pregelatinized starch, a calcium phosphate, a metal carbonate, a metal oxide, or a metal aluminosilicate.
[00136] In some embodiments, the optional lubricant component, when present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, silica, silicic acid, talc, propylene glycol fatty acid ester, polyethoxylated castor oil, polyethylene glycol, polypropylene glycol, polyalkylene glycol, polyoxyethylene-glycerol fatty ester, polyoxyethylene fatty alcohol ether, polyethoxylated sterol, polyethoxylated castor oil, polyethoxylated vegetable oil, or sodium chloride.
[00137] The present disclosure should not be considered limited to the particular embodiments described above, but rather should be understood to cover all aspects of the disclosure as fairly set out in the attached claims. Various modifications as well as numerous structures to which the present disclosure may be applicable, will be readily apparent to those skilled in the art to which the present disclosure is directed upon review of the present specification. The claims are intended to cover such modifications and devices.
[00138] The invention and embodiments thereof illustrating the method and materials used may be further understood by reference to the following non-limiting examples. This invention and embodiments illustrating the method and materials used may be further understood by reference to the following non-limiting examples.
Examples
Example 1;
[00139] A compound of formula (I) is prepared according to the following Scheme 1 :
Scheme 1
Figure imgf000056_0001
Figure imgf000057_0001
1 : Chiral Lithium Amide Base (Koga base), TMSC1; Iodoxybenzoic acid
2. Ph(CH3)2SiLi, Cul, THF, -78 °C, then 3-bromo-2-(bromomethyl)-6-methoxypyridine
3. LiHMDS, TsCN, toluene, -78 °C.
4. Pd(P ?-Bu3)2 (5mol %), NaO t- u, toluene, 1 10 °C;
5. RiCH2PPh3Br, LiHMDS, Et20, 24 °C;
6. TfOH, then TBAF, H202, K2C03, DMF, 40 °C
7. Methyl Ν,Ν-diethylsulfamoylcarbamate; toluene, 110 °C, then EtOH-H20, 95 °C;
8. PIFA, CH3OH, then TMSI
[00140] Similarly, compounds having n=2, 3, or 4, may be prepared from stepwise Tiffeneau-Demjanof or diazomethane ring expansion of an appropriate substituted ketone intermediate.
[00141] Huperzine A Control: Mice (a group of eight) were tested with huperzine A by intraperitoneal injection. The mice were given doses of 0.2, 0.3, 0.415, 0.85 mg/kg of huperzine A. The mice were then shocked at 1 hour, using 32 mA of electricity at 6 Hz for 0.2 seconds. The mice were observed for an anticonvulsant biological response, e.g. tremors or minimal motor impairment. At 0.2 mg/kg, a biological response was not observed in the eight mice tested. At 0.3 mg/kg, two of eight mice showed biological response. At 0.415 mg/kg, seven of eight mice were affected. At a dose of 0.83 mg/kg, all eight mice tested showed a biological response. Based on the biological response, the effective dose (ED50) of huperzine A at one hour was 0.339 mg/kg, with a 95% confidence interval of 0.28-0.404 mg/kg, slope 13.17, and standard error of 4.91. Peak biological effect was observed for the 0.83 mg/kg dose at 1.0 hours.
[00142] Epigallocatechin Gallate (EGCG) Control: Four mice were dosed with 100 mg/kg EGCG by intraperitoneal injection. The mice were then shocked with 32 mA of electricity at 6 Hz or 0.2 seconds. No biological effect or toxicity was observed in any mouse at 0.25 hours, 0.5 hours, 1.0 hours, 2.0 hours and 4.0 hours.
[00143] Huperzine A with EGCG: Four mice were tested with 100 mg/kg of EGCG and 0.01 mg/kg huperzine A. The mice were shocked as above at 0.25 hours, 0.5 hours, 1.0 hours, 2.0 hours, and 4.0 hours. No biological effect was seen at 0.25 hours, one mouse affected at 0.5 hours, two mice at 1 hours, two mice at 2 hours, and no mice at 4 hours. No toxicity was observed at the various time points. The effective dose, ED50, of the huperzine when dosed in the presence of the EGCG was about 0.01 mg/kg, about a 36 fold increase in activity in comparison to the huperzine A control.
[00144] Although the present invention has been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description and the preferred versions contained within this specification.

Claims

Claims
What is claimed is:
1. A compound comprising formula I:
Figure imgf000059_0001
pharmaceutically acceptable salt thereof,
wherein Ri is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar;
R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl;
Rpi, Rp2, Rvi, Rv2 are independently selected from hydrogen and fluorine;
RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO;
RN3 is selected from absent and (Ci-C24)alkyl; and
n is an integer selected from 1, 2, 3, and 4; with the proviso the compound is not
(\R,9S, 13E)- 1 -amino- 13-ethylidene- 11 -methyl-6-azatricyclo[7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one;
(IR,9S, 13E)-l -amino- 13-trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one;
(IR,9S, 13E)- 1 -amino- 13 -ethylidene- 1 1 -trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; (\R,9S, 13E)-l -amino- 13-trifluoroethylidene- 11 -trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one; or
( 1R,9«S, 13E)- 1 -amino- 13-ethylidene- 11 -phenyl-6-azatricyclo[7.3.1.02'7]trideca- 2(7),3, 10- trien- 5-one.
2. The compound of claim I, wherein RNi and RN2 are independently selected from (Ci-
C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; and RN3 is (d-C24)alkyl.
3. The compound of claim 1, wherein RN3 is absent.
4. The compound of claim 1, wherein the compound comprises formula II:
Figure imgf000060_0001
(II) or pharmaceutically acceptable salt thereof wherein n is an integer selected from 2, 3, and 4.
5. The compound of claim 4, wherein n is 2.
6. The compound of claim 1, wherein the compound comprises formula III:
Figure imgf000060_0002
(III) or pharmaceutically acceptable salt thereof.
7. The compound of claim I, wherein the compound comprises formula IV:
Figure imgf000061_0001
(IV) or pharmaceutically acceptable salt thereof wherein Ri is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl.
The compound of claim 1, wherein the compound comprises formula V:
Figure imgf000061_0002
(V) or pharmaceutically acceptable salt thereof wherein RN1 is selected from (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO.
9. The compound of claim 1, wherein the compound comprises formula VI:
Figure imgf000061_0003
(VI) or pharmaceutically acceptable salt thereof wherein R2 is selected from CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar.
10. The compound of claim 1, wherein compound comprises formula VII:
Figure imgf000062_0001
(VII), or pharmaceutically acceptable salt thereof wherein ¾ is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar; R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2- C24)alkenyl, a heterocycle, and a heteroaryl; RPi is H or F; RP2 is H or F; RVi is H or F; RV2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Ry2 is fluorine; RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; and n is an integer selected from 1, 2, 3, and 4.
11. The compound of claim 1, wherein the compound comprises formula VIII:
Figure imgf000062_0002
(VIII), or pharmaceutically acceptable salt thereof wherein RPi is H or F; RP2 is H or F; RVi is H or F; RV2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Ry2 is fluorine.
2. A method for treating a neurodegenerative disease comprising administering to a subject an effective amount of a compound of formula I:
Figure imgf000063_0001
(I), or pharmaceutically acceptable salt thereof, wherein Ri is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar; R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2- C24)alkenyl, a heterocycle, and a heteroaryl; RP1, RP2, RVi, Rv2 are independently selected from hydrogen and fluorine; RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; RN3 is selected from absent and (Ci-C24)alkyl; and
n is an integer selected from 1, 2, 3, and 4; with the proviso the compound is not (IR,9S, 13E)- 1 -amino- 13-ethylidene- 11 -methyl-6-azatricyclo[7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one;
(\R,9S, 13E)-\ -amino- 13-trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one;
(IR,9S, 13E)- 1 -amino- 13 -ethylidene- 1 1 -trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one;
( 1R,9«S, 13E)- 1 -amino- 13 -trifluoroethylidene- 11 -trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one; or (IR,9S, 13E)- 1 -amino- 13-ethylidene- 1 1 -phenyl-6-azatricyclo[7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one, wherein the neurodegenerative disease is treated in the subject.
13. The method of claim 12, wherein the compound has RNI and RN2 independently selected from (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; and RN3 is (d- C24)alkyl.
14. The method of claim 12, wherein the compound has RN3 as absent.
15. The method of claim 12, wherein the compound is of formula II:
Figure imgf000064_0001
harmaceutically acceptable salt thereof
wherein n is an integer selected from 2, 3, and 4.
16. The method of claim 12, wherein the compound is of formula III:
Figure imgf000064_0002
harmaceutically acceptable salt thereof
17. The method of claim 12, wherein the compound is of formula IV:
Figure imgf000065_0001
(IV) or pharmaceutically acceptable salt thereof wherein Ri is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2-C24)alkenyl, a heterocycle, and a heteroaryl.
18. The method of claim 12, wherein the compound is of formula V:
Figure imgf000065_0002
(V) or pharmaceutically acceptable salt thereof wherein R3 is selected from (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, CH2OH, and CHO.
19. The method of claim 12, wherein the compound is of formula VI:
Figure imgf000065_0003
harmaceutically acceptable salt thereof wherein R2 is selected from CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar.
20. The method of claim 12, wherein the compound is of formula VII:
Figure imgf000066_0001
(VII), or pharmaceutically acceptable salt thereof wherein Rj is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar; R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2- C24)alkenyl, a heterocycle, and a heteroaryl; RPi is H or F; RP2 is H or F; RVi is H or F; RV2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Ry2 is fluorine; RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; and n is an integer selected from 1, 2, 3, and 4.
21. The method of claim 12, wherein the compound is of formula VIII:
Figure imgf000066_0002
(VIII), or pharmaceutically acceptable salt thereof wherein RPi is H or F; RP2 is H or F; RVi is H or F; RV2 is H or F; wherein at least one of Rpi, Rp2, Rvi, and Ry2 is fluorine.
22. The method of claim 12, wherein the neurodegenerative disease is selected from the group of Alzheimer's disease, epilepsy, neuropathic pain, multiple sclerosis,
Parkinson's disease, ataxia, Huntington's disease, amyotrophic lateral sclerosis, AIDS-related dementia, neurotoxic poisoning, and infantile spasms; and combinations thereof.
23. A method for treating a neurodegenerative disease comprising administering to a subject an effective amount of a compound of formula I:
Figure imgf000067_0001
(I), or pharmaceutically acceptable salt thereof, wherein ¾ is selected from CH3, CF3, CF2CF3, CF2CF2CF3, S02CH3, S02Ph, S02Ar, S03H, and S03Ar; R2 is selected from an (Ci-C24)alkyl, an aryl, a cycloalkyl, a (C2- C24)alkenyl, a heterocycle, and a heteroaryl; RP1, RP2, RVi, Rv2 are independently selected from hydrogen and fluorine; RNI and RN2 are independently selected from H, (Ci-C24)alkyl, CF3, CF2CF3, CC13, CBr3, and CHO; RN3 is selected from absent and (Ci-C24)alkyl; and n is an integer selected from 1, 2, 3, and 4; and
co-administering an agent selected from an NMDA antagonist, a mitochondrial protectant, an antioxidant agent, an anti-inflammatory agent and combinations thereof, wherein the neurodegenerative disease is treated.
The method of claim 23, with the proviso the compound is not (IR,9S, 13E)- 1 -amino- 13-ethylidene- 11 -methyl-6-azatricyclo[7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one;
(\R,9S, 13E)-l -amino- 13-trifluoroethylidene- 11 -methyl- 6-azatricyclo[7.3.1.02 trideca- 2(7),3, 10- trien- 5-one;
(IR,9S, 13E)- 1 -amino- 13 -ethylidene- 1 1 -trifluoromethyl-6-azatricyclo[7.3.1.02'7] trideca- 2(7),3, 10- trien- 5-one;
( 1R,9«S, 13E)- 1 -amino- 13 -trifluoroethylidene- 11 -trifluoromethyl-6- azatricyclo[7.3.1.02'7] trideca- 2(7),3,10- trien- 5-one; or
(\R,9S, 13E)- 1 -amino- 13-ethylidene- 11 -phenyl-6-azatricyclo[7.3.1.02'7]trideca-
2(7),3, 10- trien- 5-one.
The method of claim 23, wherein the compound has the following structure:
Figure imgf000068_0001
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CN108653290A (en) * 2018-08-01 2018-10-16 浙江省医学科学院 Application of the huperzine in preparing the percutaneous drug administration preparation for treating or preventing epileptics
CN116925039A (en) * 2023-07-18 2023-10-24 陕西中药研究所(陕西医药信息中心) A kind of N-(3,5,6-trimethylpyrazine-2-methylene)-huperzine A and its synthesis method and application

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CN108653290A (en) * 2018-08-01 2018-10-16 浙江省医学科学院 Application of the huperzine in preparing the percutaneous drug administration preparation for treating or preventing epileptics
CN108653290B (en) * 2018-08-01 2021-04-13 浙江省医学科学院 Application of huperzine A in preparing transdermal drug delivery preparation for treating or preventing epilepsy
CN116925039A (en) * 2023-07-18 2023-10-24 陕西中药研究所(陕西医药信息中心) A kind of N-(3,5,6-trimethylpyrazine-2-methylene)-huperzine A and its synthesis method and application

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