WO1999011625A1 - Derives de l'huperzine a - Google Patents

Derives de l'huperzine a Download PDF

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Publication number
WO1999011625A1
WO1999011625A1 PCT/US1998/018260 US9818260W WO9911625A1 WO 1999011625 A1 WO1999011625 A1 WO 1999011625A1 US 9818260 W US9818260 W US 9818260W WO 9911625 A1 WO9911625 A1 WO 9911625A1
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Prior art keywords
huperzine
alkyl
alkenyl
alkynyl
formula
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PCT/US1998/018260
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English (en)
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Alan P. Kozikowski
Werner TÜCKMANTEL
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Macro Hi-Tech Jv, Ltd.
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Priority to AU89259/98A priority Critical patent/AU8925998A/en
Publication of WO1999011625A1 publication Critical patent/WO1999011625A1/fr

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    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to huperzine A derivatives, methods for their synthesis, pharmaceutical compositions comprising the huperzine A derivatives and methods for their use.
  • AD Alzheimer's disease
  • NGF nerve growth factors
  • muscarinic and nicotinic agonists include the use of acetylcholinesterase (AChE) inhibitors, GABA-inverse agonists, NMDA modulators, and others. It is, however, unlikely that any single drug will restore cognition, especially in view of the involvement of a number of different neurotransmitter systems in memory processing, and the fact that dead neurons cannot be replaced.
  • a number of possible therapeutic interventions include the use of nerve growth factors (NGF) , muscarinic and nicotinic agonists, acetylcholinesterase (AChE) inhibitors, GABA-inverse agonists, NMDA modulators, and others. It is, however, unlikely that any single drug will restore cognition, especially in view of the involvement of a number of different neurotransmitter systems in memory processing, and the fact that dead neurons cannot be replaced.
  • (-) -huperzine A has been studied by workers at Hoffman LaRoche in mice and squirrel monkeys, and the compound has been found to be an effective cognition enhancer.
  • the duration of action of a single dose (2 mg/kg i.m.) of (-) -huperzine A is over 6 hr, a remarkable result in relation to the AChE inhibitory action of physostigmine (0.65 mg/kg i.m.), which has a maximal duration of action of 60 min and which causes considerable side effects.
  • A. P. Kozikowski et al. U.S. Pat. No. 4,929,731 disclose the analog of huperzine A, wherein the amino group has been replaced by -CH 2 NH 2 .
  • A. P. Kozikowski U.S. Pat. No. 5,104,880 discloses analogs of huperzine A wherein the C8-C15 double bond and the C15-methyl group are absent.
  • A. P. Kozikowski et al. U.S. Pat. No. 5,547,960 discloses C10-substituted analogs of huperzine A.
  • BBB blood-brain barrier
  • prodrugs An approach taken to enhance the lipophilicity of pharmacological agents has been to convert the pharmacological agents into lipophilic "prodrugs." Such prodrugs , by virtue of their being more lipophilic than the particular pharmacological agents themselves, can more easily penetrate the BBB. Once within the brain parenchyma, the prodrugs are converted, generally enzymatically, back to the original pharmacological agent.
  • prodrugs that bear hydroxyl, amino or carboxylic acid groups can be esterified or amidated with reactive species that contain hydrophobic moieties ⁇ Id . at 436).
  • prodrugs offer the patient or subject the benefit of a sustained release of the pharmacological agent, generally resulting in a longer duration of action.
  • prodrugs that contain certain easily cleavable groups are susceptible to hydrolysis during formulation and storage as well.
  • prodrugs that were hydrophobically modified with groups that resist cleavage may be stable to intracellular esterases, precluding their conversion to therapeutically effective amounts of the active pharmacological agents.
  • the present invention provides huperzine A derivatives having the formula (I) , methods for their synthesis, pharmaceutical compositions comprising the huperzine A derivatives, as well as methods for their use. Particularly, the present invention provides huperzine A derivatives having the formula (I) :
  • X is selected from the group consisting of 0 and S;
  • p is 0 or 1; and each R is independently selected from the group consisting of phenyl, C 2 -C 24 alkyl, C 2 -C 2 alkenyl, C 2 -C 24 alkynyl, C-,-C 24 cycloalkyl, C-,-C 24 cycloalkenyl, adamantyl, bicyclo (m.n.o.
  • the compound of formula (I) is selected from the group consisting of:
  • compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier or vehicle.
  • Such compositions are useful for inhibiting AChE, and treating Alzheimer's dementia, myasthenia gravis, an age-related memory impairment, Down's syndrome and glaucoma.
  • the invention still further provides a method for inhibiting AChE in a mammal comprising administering to the mammal in need of said AChE inhibition, a therapeutically effective amount of a composition comprising a compound of formula (I) .
  • the invention still further provides a method for treating a disorder in a mammal, the disorder selected from the group consisting of Alzheimer's dementia, myasthenia gravis, an age-related memory impairment, Down's syndrome and glaucoma, comprising administering to the mammal in need of such treatment, a therapeutically effective amount of the composition comprising a therapeutically effective amount of a compound of the formula (I) .
  • the invention still further provides a method for the synthesis of a compound of formula (I) comprising the step of contacting huperzine A with a compound selected from the group consisting of formula (Ila) and formula (lib) :
  • Z is -OH or a leaving group.
  • the huperzine A derivatives (the "compounds of formula (I)") useful for inhibiting AChE and treating Alzheimer's dementia, myasthenia gravis, an age-related memory impairment, Down's syndrome and glaucoma are represented by formula (I) :
  • X is selected from the group consisting of O and S; Y is selected from the group consisting of -0-,
  • each R is independently selected from the group consisting of phenyl, C 2 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 3 -C 2 cycloalkyl, C 3 -C 24 cycloalkenyl, adamantyl, bicyclo(m.n.o.
  • Any pharmaceutically acceptable salt known, or to be developed, can be utilized and include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, carbonic, nitric and the like; and those prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic, gluconic and the like.
  • Such salts can be prepared, for example, according to Examples 7 and 8 of U.S. Patent No. 4,383,114 to Vince, or by other methods commonly
  • the counter ion associated with the -NH, + or -N + (C,-C 8 alkyl) (C,-C 8 alkyl) (C,-C 8 alkyl) group is a conjugate base of an acid described above.
  • C 2 -C 24 alkyl is meant to include straight- and branched-chain saturated aliphatic hydrocarbon groups having 2-24 carbon atoms including, but not limited to, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n- pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl and the like.
  • C 2 -C 2 alkenyl is meant to include straight- and branch chain hydrocarbon groups having at least one double bond and including, but not limited to, vinyl, allyl, isoprenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, pentenyl, hexenyl, heptenyl, farnesyl, geranyl, geranylgeranyl and the like.
  • C 2 -C 24 alkynyl is meant to include straight- and branch chain hydrocarbon groups having at least one triple bond and including, but not limited to, propargyl.
  • C 3 -C 24 cycloalkyl is meant to include non-aromatic, cyclic hydrocarbon groups including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclodecyl, cyclododecyl and the like.
  • C 3 -C 24 cycloalkenyl is meant to include non- aromatic, cyclic hydrocarbon groups having at least one double bond and including, but not limited to, cyclopropenyl, cyclobutenyl , cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl and the like.
  • amino acid is meant the L-, D- or racemic form of an ⁇ - or ⁇ -amino acid.
  • Amino acids useful in this regard include, but are not limited to glycine, alanine, valine, leucine, isoleucine, proline, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartic acid, glutamic acid, asparagine, glutamine, cysteine, methionine and -alanine.
  • peptide is meant a linear sequence of 2 or more amino acids joined via a peptide bond.
  • the number of amino acids in such a peptide ranges from 2 to about 20.
  • -C ( X) - (Y) -R taken together form a radical selected from the group consisting of pivaloyl, 1- adamantoyl, n-caproyl, n-capryloyl, n-capryl, n-Lauryl, n- myristyl, n-palmityl, n-stearyl, linoleyl, linolenyl, acetylsalicylyl, o-toluoyl, 2 , 4 , 6-trimethoxybenzoyl , nicotinoyl, O-acetylmandelyl, 2 , 2-dimethyl-3-phenylpropionyl, 1-methyl-l-cyclohexanecarbonyl, isobutyryl, endo-norbornane- 2-carbonyl, -C (0) OC (CHJ and -C (0) OCH 2 CH 2 N (CH 3 ) 3 +
  • the compounds of formula (I) are better able than huperzine A to transverse the BBB.
  • the compounds of formula (I) accumulate within "depots,” i.e., fatty domains of the brain, in particular within cell membranes. In such depots, the compounds of formula (I) act to inhibit AChE, and treat Alzheimer's dementia, myasthenia gravis, an age-related memory impairment, Down's syndrome and glaucoma.
  • the compounds of formula (I) slowly hydrolyze in the presence of brain esterases or other enzymes to provide huperzine A, which is capable of inhibiting AChE and treating Alzheimer's dementia, myasthenia gravis, an age-related memory impairment, Down's syndrome and glaucoma.
  • the compounds of formula (I) behave as prodrugs of huperzine A.
  • prodrug is meant a derivative of huperzine A which, when administered to a mammal, especially a human, is hydrolyzed by esterases or other hydrolytic enzymes endemic to brain or other tissue, so as to make huperzine A available at its target site(s).
  • esterases or other hydrolytic enzymes endemic to brain or other tissue.
  • the slow hydrolysis of the compounds of formula (I) is believed to offer a desirable "slow release" of huperzine A from the compounds of formula (I) .
  • the compounds of formula (I) are believed to remain in circulation in the body and reside in brain depots for relatively longer periods of time, until they are hydrolyzed by the enzymes described above, releasing huperzine A.
  • the compounds of formula (Ila) and formula (lib) are useful as intermediates for obtaining the compounds of formula (I) which are capable of inhibiting AChE, and treating Alzheimer's dementia, myasthenia gravis, an age-related memory impairment, Down's syndrome and glaucoma.
  • preferable leaving groups are -Cl (such compounds are alkyl chloroformate ⁇ , obtained by reaction between an alcohol and phosgene employing conditions known to those of ordinary skill in the art), -F (V.A. Dang et al., J. Org. Chem.
  • a preferable leaving group is -Cl (M.S. Newman et al. J . Org . Chem . 21:3980 (1966); H.J. Kurth, Chem . Ber . 106:2419 (1973); B. Blank et al., J. Med . Chem . 12:1065 (1974); A. Kaji et al.. Bull . Chem . Soc . Jpn . 4_4:1393 (1971); C.F. Reinecke et al., J. Org . Chem .
  • a preferable leaving group is -Cl (D.L. Garmaise et al., J. Org . Chem . 22:4509 (1962) and S. Wakamori et al., Agric . Biol . Chem . (Tokyo) 33 . : 1700 (1969)).
  • carboxylic acids can be obtained from oxidation of corresponding alcohols and aldehydes (Carruthers, Some Modern Methods of Organic Synthesis 338-55 (1978) ; and Chinn, Selection of Oxidants in Synthesis 63-70 (2d ed. 1971)); oxidation of aromatic and heteroaromatic alkyl groups (Lee, The Oxidation of Organic Compounds by Permanganate Ion and Hexavalent Chromium 43-64 (1980)); carboxylation of Grignard and organolithium reagents (H.W. Gschwend et al., Chem . Rev . 2_6: 1-360 (1979); R.D. Clark et al., Chem . Rev .
  • Activating agents useful in this regard include methanesulfonyl chloride (S. Chandrasekaran et al., Syn . Commun . 12:727 (1982)), trifluoromethanesulfonic anhydride (L. Brown et al., J. Org . Chem . 1£:3875 (1984)), a carbodiimide such as dicyclohexylcarbodiimide, preferably in the presence of 4-dimethylaminopyridine (B. Neises et al., Angew . Chem . , Int . Ed . Engl . 12:522 (1978); A. Hassner et al., Tetrahedron Lett.
  • azole derivatives such as oxalyldiimidazole, oxalylditriazole and oxalylditetrazole (S. Murata, Bull . Chem . Soc . Jpn . 27:3597 (1984)) and carbonylditetrazole (J. Strawinsky et al., J . Chem . Soc , Chem . Commun . 243 (1976)).
  • the reaction of the amino acid or peptide with huperzine A will take place in the presence of an activating agent described above.
  • the amino acid or peptide will have a protecting group at its N- terminus and at other nucleophilic sites if present, which are optionally removed subsequent to the reaction of the amino acid or peptide with huperzine A. Examples of useful protecting groups are found in Theodora W.
  • the reaction of the compounds of formula (Ila) with huperzine A can take place in the presence of an acylation catalyst such as 4-dimethylaminopyridine, tributylphosphine (E. Vedejs et al., J . Am . Chem . Soc . 115:3358 (1993) and E. Vedejs et al., J. Org . Chem . 58:7268 (1993)), scandium trifluoromethanesulfonate (K. Ishihara et al., J . Am . Chem . Soc . 112:4413 (1995)) and P (NMeCH,CH 2 ) 3 N (B.A. d'Sa et al., J . Org . Chem . 21:2963 (1996).
  • an acylation catalyst such as 4-dimethylaminopyridine, tributylphosphine (E. Vedejs et al.
  • reaction of ( ⁇ ) -huperzine A with the compounds of formula (Ila) or formula (lib) will result in compounds of formula (I) that are racemic.
  • reaction of (+) -huperzine A with the compounds of formula (Ha) or formula (lib) will result in compounds of formula (I) that possess the same absolute configuration as (+)- huperzine A
  • reaction of (-) -huperzine A with the compounds of formula (Ila) or formula (lib) will result in compounds of formula (I) that possess the same absolute configuration as (-) -huperzine A.
  • reaction of a mixture of (+) - and (-) -huperzine having an enantiomeric excess of the (-) -enantiomer with the compounds of formula (Ila) or formula (lib) will result in compounds of formula (I) that have an enantiomeric excess of the compound of formula (I) that is derived from the (-)- enantiomer.
  • (+) -Huperzine A can be synthesized according to methods disclosed in F. Yamada et al., J . Am . Chem . Soc 113 : 4695-96 (1991), or obtained via an enantiomeric resolution using chiral high-performance liquid chromatography according to the method of McKinney et al., Eur . J . Pharmacol . 203 : 303 (1991).
  • huperzine A when not preceded by "( ⁇ )-,” “(+)-” or “(-)-,” encompasses ( ⁇ )-, (+)- and (-) -huperzine A.
  • the compounds of formula (I) can be obtained by reacting from about 1 to about 2 equivalents, preferably from about 1 to about 1.5 equivalents and more preferably from about 1 to about 1.2 equivalents of a compound of formula (Ila) or formula (lib) with about 1 equivalent of huperzine A, preferably in the presence of about 1 to about 10 equivalents of an organic base such as pyridine, 4- (dimethylamino) pyridine, DBU, triethylamine, imidazole, lutidine, collidine, methylamine, diisopropylethylamine, di- tert-butylamine and the like, and mixtures thereof; or an inorganic base such as an alkali metal alkoxide, an alkyllithium reagent, lithium diisopropylamide, an alkali metal hexamethyldisilazide, an alkali metal hydride and the like.
  • an organic base such as pyridine, 4- (dimethylamino) pyr
  • the organic base scavenges acids liberated in the reaction between the compound of formula (Ila) or formula (lib) and huperzine A, and the inorganic base deprotonates the amide nitrogen atom of huperzine A, converting its C-l carbonyl group to an enolate and a relatively stronger nucleophile.
  • the reaction between huperzine A and the compound of formula (Ila) or formula (lib) takes place in the presence of an organic solvent.
  • organic solvents useful in this regard include, but are not limited to, dichloro ethane, chloroform, diethyl ether, tetrahydrofuran, dimethylformamide, benzene, toluene and the like.
  • the organic solvent is dichloromethane or, if an alkali metal base is used, tetrahydrofuran.
  • the mixture of huperzine A, compound of formula (Ila) or formula (lib) , and optionally organic base form a mixture that is about 10 to about 70 weight percent, relative to the organic solvent.
  • "reagent” is meant to encompass huperzine A, a compound of formula (Ila) , a compound of formula (lib) , organic base and organic solvent. While the particular sequence of reagent addition is not critical to the synthesis of the compounds of formula (I), preferably, the compound of formula (Ila) or formula (lib) is added to a huperzine A which is optionally in the presence of organic base and organic solvent. Reagent addition can occur at a temperature from about -78 °C to about 50°C, preferably from about -25 °C to about room temperature, and most preferably at about room temperature.
  • the reaction mixture is allowed to stir at the temperature of reagent addition or preferably, at a higher temperature, until the formation of a compound of formula (I) is complete.
  • the addition of reagents takes place at about 0°C, and the reaction mixture is allowed to stir at about room temperature.
  • the progress of the reaction between huperzine A and the compound of formula (Ila) or formula (lib) can be monitored using thin layer chromatography, high performance liquid chromatography, or other means known to those skilled in the art.
  • the reaction mixture which contains the compound of formula (I) can be purified via recrystallization, silica gel chromatography, high performance liquid chromatography, or other means known to those skilled in the art.
  • the reaction mixture is concentrated, i . e . , volatiles such as organic solvent and organic base are removed therefrom, prior to purification.
  • adsorbent such as CELITE® (silicon dioxide) or silica gel can be added to the reaction mixture just prior to concentration, and the resulting mixture concentrated such that the compound of formula (I) is adsorbed onto the surface of the adsorbent.
  • huperzine A contains three nucleophilic groups, namely a primary amino group at C- 13, a pyridone nitrogen atom and a pyridone carbonyl oxygen atom at C-1. Prior to the present invention, it would have been predicted by one of skill in the art that the three nucleophilic groups of huperzine A would compete with one another for reaction with the compounds of formula (Ila) and formula (lib) .
  • the compounds of formula (Ila) and formula (lib) react predominantly with the C-1 pyridone carbonyl oxygen atom of huperzine A, with little competition from side reactions, and with only minor reaction with either the C-13 amino group or the pyridone nitrogen atom. Accordingly, the compounds of formula (I) can be obtained directly from huperzine A and compounds of formula (Ila) or formula (lib) without the need for using protecting groups for the C-13 amino group and the pyridone nitrogen atom, providing highly desirable time- and cost-saving benefits, as well as increased yield of product as a result of requiring fewer synthetic steps.
  • the compounds of formula (I) are useful for inhibiting AChE.
  • Compounds that inhibit AChE are useful as pharmaceutical agents for treating mammals, especially humans, for the treatment of disorders wherein AChE is involved, e.g., in clinical settings, for the treatment of memory and learning disorders.
  • Such conditions include Alzheimer's dementia (AD), myasthenia gravis, and other age-related memory impairments.
  • the compounds of formula (I) can be used to treat Down's syndrome and glaucoma .
  • the compounds of formula (I) are useful for the treatment of any disorder known or to be discovered wherein inhibition of AChE results in treatment of the disorder.
  • disorders include memory and learning disorders, including AD, myasthenia gravis, and other age-related memory impairments.
  • the compounds of formula (I) are believed to offer the added advantage of being more readily capable of traversing the BBB, and being capable of residing in brain depots for longer periods of time, relative to huperzine A.
  • the compounds of formula (I) When administered to a mammal for veterinary use or to a human for clinical use, the compounds of formula (I) , or mixtures thereof, can be used alone, or in combination with any physiologically acceptable carrier or excipient suitable for enteral or parenteral administration.
  • suitable mammals include, for example, dogs, particularly those used as guides for the sight-impaired, and humans.
  • the physiologically acceptable carrier When used for parenteral administration, the physiologically acceptable carrier must be sterile and suitable for in vivo use in a human, or for use in a veterinary clinical situation.
  • the compounds of formula (I) can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains at least one of the compounds of formula (I) , including their therapeutically active salts, as a bioactive component, alone or in combination with another AChE inhibiting compound such as physostigmine, clonidine, deprenyl or desipra ine, in admixture with a carrier or an excipient suitable for enteral or parental administration.
  • the compounds of formula (I) may be compounded, for example with a pharmaceutically acceptable carrier for solid compositions such as tablets, pellets or capsules; capsules containing liquids; suppositories; solutions; emulsions; suspensions or any other form suitable for use.
  • Suitable carriers include, for example, sterile water, sterile physiological saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like.
  • auxiliary, stabilizing, thickening, lubricating and coloring agents may be used.
  • the compounds of formula (I) are present in the compositions in an amount sufficient to inhibit AChE, and produce a desired effect upon Alzheimer's dementia, myasthenia gravis, an age-related memory impairment, Down's syndrome and glaucoma.
  • compositions of this invention may be administered in a therapeutically effective amount by a variety of methods including orally, intramuscularly, intravenously, subcutaneously , transder ally , rectally or by inhalation. While the preferred mode of administration is through the oral mode, the precise mode of administration is left to the discretion of the practitioner. They are advantageously effective when administered orally.
  • compositions for oral administration may be in the form of tablets, troches, lozenges, aqueous or oily suspensions, granules or powders, emulsions, capsules, syrups or elixirs.
  • Orally administered compositions may contain one or more agents, such as, sweetening agents such as fructose, aspartame or saccharin, flavoring agents such as peppermint, oil of wintergreen, or cherry, coloring agents and preserving agents, to provide a pharmaceutically palatable preparation.
  • agents such as, sweetening agents such as fructose, aspartame or saccharin, flavoring agents such as peppermint, oil of wintergreen, or cherry, coloring agents and preserving agents, to provide a pharmaceutically palatable preparation.
  • carriers which are commonly used include lactose, mannitol and corn starch; and lubricating agents, such as magnesium stearate, are commonly added.
  • compositions in tablet form may be coated to delay disintegration and absorption in the
  • the compound of formula (I) can be administered in dry form in a hard gelatin capsule or in a suitable gelled or liquid vehicle, such as a liquid polyethylene glycol or a carrageenan gel, in a soft gelatin capsule.
  • a suitable gelled or liquid vehicle such as a liquid polyethylene glycol or a carrageenan gel
  • Selectively permeable membranes surrounding an osmotically active driving compound are also suitable orally administered compositions.
  • fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
  • a time delay material such as glycerol monostearate or glycerol stearate may also be used.
  • Aqueous suspensions containing the compounds of formula (I) can be combined with emulsifying and suspending agents.
  • Aqueous suspensions may also contain one or more preservatives, such as, for example, ethyl or n-propyl-p- hydroxybenzoate, one or more coloring agents, flavoring agents or sweetening agents.
  • preservatives such as, for example, ethyl or n-propyl-p- hydroxybenzoate, one or more coloring agents, flavoring agents or sweetening agents.
  • sterile solutions of the compound of formula (I) preferably a pharmaceutically acceptable salt thereof, are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled in order to render the preparations isotonic.
  • a compound of formula (I) When a compound of formula (I) is used as in a mammal, preferably a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms. However, in most instances, an effective daily dosage of the compound of formula (I) will be in the range of from about 0.05 mg/kg to about 1 mg/kg of body weight, and preferably, of from about 0.1 mg/kg to about 0.5 mg/kg of body weight, administered in single or divided doses. In a preferred embodiment, a 50 mg tablet comprising about 100 ⁇ g of a compound of formula (I) is administered about 4 to about 8 times per day. In some cases, however, it may be necessary to use dosages outside these limits, depending, e . g . , on the route and frequency of administration. Treatment can be repeated as needed, depending upon the dosage and need.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof can be used for research purposes, for example, to investigate the mechanism and activity of AChE inhibitors.
  • Example 1 O-Pivaloylhuperzine A. To 247 mg (1.02 mmol) of (-) -huperzine A, 0.71 mL (5.1 mmol) of triethylamine and 11.5 mg (0.1 mmol) of 4- (dimethylamino) pyridine in 8 mL of CH 2 C1 2 was added, with ice cooling, 126 ⁇ L (1.02 mmol) pivaloyl chloride. The resulting mixture was allowed to stir for 5h, during which time the temperature of the reaction mixture was allowed to rise to room temperature. The reaction mixture was admixed with 1 g of CELITE®, and the volatiles were evaporated therefrom.
  • Example 2 O- (1-Adamantoyl) huperzine A.
  • the crude acid chloride product was diluted with 0.3 mL of CH 2 C1 2 , and the resulting solution was added, with ice cooling, to a solution of 15.0 mg (62 ⁇ mol) of (-) -huperzine A, 42 ⁇ L (300 ⁇ mol) of triethylamine, and 0.8 mg (6 ⁇ mol) of 4- (dimethylamino) pyridine in 0.3 mL of CH,C1 2 .
  • the resulting mixture was allowed to stir at room temperature for 26h, and evaporated.
  • Toluoyl) huperzine A, O- (2 , 4 , 6-trimethoxybenzoyl) huperzine A; O- (nicotinoyl) huperzine A; O- (O-acetylmandelyl) huperzine A and O- (isobutyryl) huperzine A are prepared according to the procedure of Example 1, above, except that o-toluoyl chloride, 2 , 4 , 6-trimethoxybenzoyl chloride, nicotinoyl chloride hydrochloride, O-acetylmandelic chloride and isobutyryl chloride respectively, are used in place of pivaloyl chloride.
  • Example 4 O-Acyl Derivatives of Huperzine A. 0-(n- Caproyl) huperzine A, O- (n-Capryloyl) huperzine A, 0-(n- Capryl) huperzine A, O- (n-Lauryl) huperzine A, 0-(n-)
  • Example 5 O- (tert-Butoxycarbonyl) uperzine A. To a mixture of 9.8 mg (40.4 ⁇ m) of (-) -huperzine A and 15 mg (0.12 mmol) of 4- (dimethylaminopyridine) was added a solution of 35 mg (0.16 mmol) of di-tert-butyl dicarbonate in 0.1 mL of anhydrous dichloromethane. Vigorous gas evolution instantaneously took place. The resulting mixture was allowed to stir at room temperature for 70 minutes, and then was filtered over silica gel using 1:6 ethyl acetate: hexane as a solvent. The fractions containing the above-titled product (R- approx.
  • Example 6 O- (Cholinecarbonyl) Huperzine A. To 1 eq. of choline chloride and 1-2 eq. of poly (4-vinylpyridine) in dichloromethane is added between 1-2 eq. of phosgene at 0°C. The resulting mixture is allowed to stir at 0°C for 20 min., whereupon 1 eq. of additional poly (4-vinylpyridine) , followed by 1 eq. of huperzine A, are added. The resulting mixture is allowed to stir at 0°C for 2h, and then at room temperature for 20 min. The reaction mixture is filtered, concentrated in vivo, and crystallized from a polar solvent such as methanol, or from a non-polar solvent such as benzene or hexane, to afford the above-titled product.
  • a polar solvent such as methanol
  • non-polar solvent such as benzene or hexane
  • a compound of formula (I) is incubated with excess AChE-free human plasma obtained according to the method of D. De La Hoz et al.. Life Sci . 3_9_: 195-99 (1986).
  • the human plasma contains an esterase that converts the compound of formula (I) to huperzine A.
  • An aliquot of the resulting incubation mixture is removed, and its ability to inhibit AChE is measured in 50 mM sodium phosphate containing 1 mM dithionitrobenzoic acid (pH 8.0) at 22 ° C , according to the procedure of Ellman et al., Biochem . Pharmacol . 1:88-95 (1961) , using 1 mM acetylthiocholine as the substrate.
  • Inhibition of AChE is achieved by diluting an appropriate volume of a stock solution of a compound of formula (I) (2-5 mM) into an enzyme solution (15-20 units of AChE/mL in 50 M sodium phosphate (pH 8.0), containing 0.01% bovine serum albumen) , and measuring residual enzyme activity at various times. Plots of percent residual activity vs. time at each concentration are used to calculate the rate of inhibition (k n ) . Direct measurement of the rate constant of regeneration of enzyme activity (k oN ) is initiated by a
  • the K, values for the inhibition of fetal bovine serum AChE with huperzine A derived from the compound of formula (I) is determined by analysis of kinetic data described according to Scheme II, below:
  • K (the competitive inhibition constant) and ⁇ -K, (the uncompetitive inhibition constant) reflect the interaction of huperzine A with free AChE and the enzyme-substrate complex, respectively.
  • S is the acetyl thiocholine substrate
  • P is acetate and thiocholine product.
  • Data for this analysis is obtained by measuring inhibition of enzyme activity over an acetylthiocholine concentration range of 0.025-0.4 mM and at a series of huperzine A concentrations.
  • Plots of reciprocal velocities vs. reciprocal substrate concentrations yield a family of slopes. Replots of slopes and intercepts vs. inhibitor concentrations are used for the determination of K, and ⁇ K, values, respectively.
  • BChE activity is measured in 50 mM sodium phosphate containing ImM dithionitrobenzoic acid (pH 8.0) at 22 °C as described in Ell an et al . , Biochem . Pharmacol . 1:88-95 (1961), using butyrylthiocholine as the substrate, and according to the protocol of Example 6, above.

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Abstract

L'invention concerne des dérivés de l'huperzine A, des procédés d'obtention de ces composés, des compositions pharmaceutiques les comprenant, ainsi que des méthodes d'utilisation de ces dérivés en tant qu'agents d'inhibition de l'acétylcholinestérase, par exemple, dans le traitement de la maladie d'Alzheimer, de la myasthénie grave, des troubles mnésiques en rapport avec l'âge, du syndrome de Down et du glaucome. Ces dérivés de l'huperzine A sont plus aptes à traverser la barrière hémato-encéphalique que l'huperzine A, et ils sont relativement plus efficaces pour inhiber l'acétylcholinestérase, et en conséquence pour traiter la maladie d'Alzheimer, la myasthénie grave, les troubles mnésiques en rapport avec l'âge, le syndrome de Down et le glaucome.
PCT/US1998/018260 1997-09-03 1998-09-02 Derives de l'huperzine a WO1999011625A1 (fr)

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US08/922,734 1997-09-03

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1050303A2 (fr) * 1999-04-27 2000-11-08 Pfizer Products Inc. Methodes et compositions pour le traitement des troubles du comportement liées à l'age des animaux de compagnie
US6271379B1 (en) 2000-03-08 2001-08-07 Georgetown University Intermediates useful for the synthesis of huperzine A
KR100390777B1 (ko) * 2000-12-19 2003-07-10 한국화학연구원 피리돈 유도체의 제조방법
EP1891954A2 (fr) 1998-09-30 2008-02-27 Takeda Pharmaceutical Company Limited Agents pour améliorer le pouvoir de vidange de la vessie
EP2070519A1 (fr) 2000-05-08 2009-06-17 N.V. Nutricia Préparation pour la prévention et/ou le traitement des troubles vasculaires
US8097726B2 (en) 2006-05-17 2012-01-17 Industrial Technology Research Institute Huperzine a compound for treatment of alzheimer's disease
WO2012121863A1 (fr) * 2011-03-04 2012-09-13 Yale University Procédés de fabrication de (-) huperzine a, compositions associées, et méthodes de traitement
TWI404531B (zh) * 2007-05-17 2013-08-11 Ind Tech Res Inst 石杉鹼甲化合物及包含此化合物之醫藥組合物
EP3215492A4 (fr) * 2014-10-03 2018-04-25 Amphastar Nanjing Pharmaceuticals Inc. Procédés de résolution d'un mélange racémique pour obtenir de la (-)-huperzine a
CN114848689A (zh) * 2022-05-12 2022-08-05 暨南大学 一种千层塔有效部位及其制备方法与在制备具有预防或治疗老年痴呆作用的药物中的应用

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US5604294A (en) * 1991-09-05 1997-02-18 Luly; Jay R. Macrocyclic immunomodulators
US5750534A (en) * 1994-03-16 1998-05-12 National Science Council Nalbuphine esters having long acting analgesic action and method of use
US5547960A (en) * 1994-09-07 1996-08-20 Mayo Foundation For Medical Education And Research C-10 analogs of huperzine a

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1891954A2 (fr) 1998-09-30 2008-02-27 Takeda Pharmaceutical Company Limited Agents pour améliorer le pouvoir de vidange de la vessie
EP1050303A3 (fr) * 1999-04-27 2003-01-15 Pfizer Products Inc. Methodes et compositions pour le traitement des troubles du comportement liées à l'age des animaux de compagnie
EP1050303A2 (fr) * 1999-04-27 2000-11-08 Pfizer Products Inc. Methodes et compositions pour le traitement des troubles du comportement liées à l'age des animaux de compagnie
US6271379B1 (en) 2000-03-08 2001-08-07 Georgetown University Intermediates useful for the synthesis of huperzine A
EP2316426A1 (fr) 2000-05-08 2011-05-04 N.V. Nutricia Préparation pour la prévention et/ou le traitement des troubles vasculaires
EP2070519A1 (fr) 2000-05-08 2009-06-17 N.V. Nutricia Préparation pour la prévention et/ou le traitement des troubles vasculaires
US7560447B2 (en) 2000-05-08 2009-07-14 N.V. Nutricia Preparation for the prevention and/or treatment of vascular disorders
US7772217B2 (en) 2000-05-08 2010-08-10 N.V. Nutricia Preparation for the prevention and/or treatment of vascular disorders
EP2292210A1 (fr) 2000-05-08 2011-03-09 N.V. Nutricia Préparation pour la prévention et/ou le traitement des troubles vasculaires
US8865687B2 (en) 2000-05-08 2014-10-21 N.V. Nutricia Preparation for the prevention and/or treatment of vascular disorders
US8377912B2 (en) 2000-05-08 2013-02-19 N. V. Nutricia Preparation for the prevention and/or treatment of vascular disorders
KR100390777B1 (ko) * 2000-12-19 2003-07-10 한국화학연구원 피리돈 유도체의 제조방법
US8097726B2 (en) 2006-05-17 2012-01-17 Industrial Technology Research Institute Huperzine a compound for treatment of alzheimer's disease
TWI404531B (zh) * 2007-05-17 2013-08-11 Ind Tech Res Inst 石杉鹼甲化合物及包含此化合物之醫藥組合物
KR20140009444A (ko) * 2011-03-04 2014-01-22 예일 유니버시티 (-)-후페리진 제조 및 관련 조성물 및 치료방법
EP3434669A1 (fr) * 2011-03-04 2019-01-30 Yale University Composés intermédiaires utilisables dans la synthèse de (-) l'huperzine et procédé pour obtenir un de ces composés intermédiaires
JP2014508777A (ja) * 2011-03-04 2014-04-10 エール ユニヴァーシティ （−）−フペルジンａの工程及び関連組成物並びに治療法
WO2012121863A1 (fr) * 2011-03-04 2012-09-13 Yale University Procédés de fabrication de (-) huperzine a, compositions associées, et méthodes de traitement
CN103687849B (zh) * 2011-03-04 2016-08-17 耶鲁大学 (-)-石杉碱甲方法及相关组合物和治疗方法
US11142503B2 (en) 2011-03-04 2021-10-12 Yale University (−)-huperzine A processes and related compositions and methods of treatment
US10059672B2 (en) 2011-03-04 2018-08-28 Yale University (−)-Huperzine A processes and related compositions and methods of treatment
CN103687849A (zh) * 2011-03-04 2014-03-26 耶鲁大学 (-)-石杉碱甲方法及相关组合物和治疗方法
KR102017123B1 (ko) 2011-03-04 2019-09-02 예일 유니버시티 (-)-후페리진 제조 및 관련 조성물 및 치료방법
US10457643B2 (en) 2011-03-04 2019-10-29 Yale University (−)-huperzine A processes and related compositions and methods of treatment
US10781179B2 (en) 2011-03-04 2020-09-22 Yale University (−)-huperzine A processes and related compositions and methods of treatment
EP3215492A4 (fr) * 2014-10-03 2018-04-25 Amphastar Nanjing Pharmaceuticals Inc. Procédés de résolution d'un mélange racémique pour obtenir de la (-)-huperzine a
CN114848689A (zh) * 2022-05-12 2022-08-05 暨南大学 一种千层塔有效部位及其制备方法与在制备具有预防或治疗老年痴呆作用的药物中的应用
CN114848689B (zh) * 2022-05-12 2023-04-07 暨南大学 一种千层塔有效部位及其制备方法与在制备具有预防或治疗老年痴呆作用的药物中的应用

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