WO1996030372A1 - Derives diazabicyclo[3.3.1]nonane et leurs intermediaires, leur application therapeutique et procedes de production - Google Patents

Derives diazabicyclo[3.3.1]nonane et leurs intermediaires, leur application therapeutique et procedes de production Download PDF

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Publication number
WO1996030372A1
WO1996030372A1 PCT/JP1996/000742 JP9600742W WO9630372A1 WO 1996030372 A1 WO1996030372 A1 WO 1996030372A1 JP 9600742 W JP9600742 W JP 9600742W WO 9630372 A1 WO9630372 A1 WO 9630372A1
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diazabicyclo
nonane
oxo
group
carboxylic acid
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PCT/JP1996/000742
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English (en)
Japanese (ja)
Inventor
Koji Kobayashi
Kazuhiro Orita
Atsushi Hamada
Takashi Inaba
Hiroyuki Abe
Susumu Miyazaki
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Japan Tobacco Inc.
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Priority to AU50143/96A priority Critical patent/AU5014396A/en
Publication of WO1996030372A1 publication Critical patent/WO1996030372A1/fr

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    • 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

  • the present invention relates to a novel diazabicyclo [3.3.1] nonane derivative useful as a nicotinic cholinergic agent, which is used for treating dementia such as Alzheimer's disease, improving memory impairment, and treating central nervous degeneration. And cerebral dysfunction improver.
  • the present invention also relates to a novel intermediate for producing the diazavinclo [3.3.1] nonane derivative, a method for producing the intermediate, and a method for producing the diazabicyclo [3.3.1] nonane derivative.
  • Alzheimer's disease is said to be the most difficult to treat among dementias. According to reports from the United States National Institute of Aging, more than half of senile dementia patients in the United States have Alzheimer's disease, and 40% of the population over 85 years of age have Alzheimer's disease. It depends on
  • Drugs for treating dementia which have been studied based on this pathogenesis mechanism, are mainly acetylcholinesterase inhibitors (Japanese Patent Application Laid-Open No. Hei 5-194,872, Japanese Patent Application Laid-Open No. Hei 6-504,074, Japanese Patent Application Laid-Open (JP-A) No. 6-116637 and a cholinergic agonist (Japanese Patent Laid-Open No. 2-72179, Japanese Patent Laid-open No. 3-27377, Japanese Patent Laid-Open No. 3-68683) so is there.
  • cholinergic drugs have been studied mainly because musculin-like cholinergic drugs are present in most of the brain acetylcholine receptors.
  • Parkinson's disease is thought to be due to degeneration of the substantia nigra-striatal doha'min nervous system and abnormally reduced dobamine content. For this reason, treatment of Parkinson's disease has been to activate reduced dopamine action or to suppress the relatively dominant choline action.
  • Nicotine's excellent cognitive function improving and central nervous system degeneration-inhibitory effects are due to the fact that nicotine contained in tobacco sacrifice cognitive functions in animal models [Levin et.a., Behav. Neurol. Biol. , Vol. 53, 269. (1990)] that nicotine improves impaired cognitive function in a pilot study of Alzheimer's disease patients [Sahakian et. Al .. Brit. J. Psych .. Vol. 154. 797. (1989): Newhouse P. et. Al .. Psychopharmacol. Vol. 95. 171, (1988)], low incidence of Alzheimer's disease and Parkinson's disease in smokers [van Duijin et. al .. BMJ. Vol. 302. 1491-1494.
  • Nicotine is a rat substantia nigra dopaminergic neuropathy model. Vol. 79. 257, (1989): 0 recitation an et. A. Prog. Brain Res .. Vol. 79. 267. Uanson et. Al. Prog. Brain Res. (1989)] Kill. It is even more interesting that increasing the number of nicotine-like acetylcholine receptors in the brain when nicotine is administered to animals in a gunfire [Marks et. Al. J. Pharmacol. Exp. Terap .. Vol. 235. 619- 628. (1985)] has been reported.
  • nicotinic cholinergic drugs have been used as cerebral function improvers and central nervous system degenerative diseases [Japanese Translation of PCT Application No. 6-5088143, Arneric et. Al. J.
  • the present inventors have conducted intensive studies to search for a brain function improving drug that selectively acts on the central nervous system and has no side effect on peripheral nerves.
  • a diazabicyclo [3.3.1] nonane derivative having high nicotine-like choline receptor binding properties, less side effects on peripheral nerves, and a dopamine releasing action has been found, and the present invention has been completed.
  • the present invention also provides an intermediate useful for producing a diazabicyclo [3.3.1] nonane derivative.
  • the present invention provides a method for producing an intermediate, and a method for producing the diazabicyclo [3.3.1] nonane derivative of the present invention using the intermediate.
  • the compound having a diazabicyclo [3.3.1] nonane skeleton is, for example, an antiarrhythmic drug represented by the following formula:
  • the present invention relates to a novel diazabicyclo [3.3.1] nonane derivative and an intermediate thereof, a diazavinclo [3.3.1] nicotinic cholinergic drug containing a nonane derivative, a method for producing an intermediate, and a diazavinclo [3.3] .
  • the present invention relates to a method for producing a nonane derivative. Details are as shown in (1) to (28) below. (1) General formula [1]
  • R represents one C0NH— (CHR 1 ) B —R 2 (wherein, R ′ represents a hydrogen atom or an alkyl group, m represents 0, 1 or 2, and R 2 may be substituted. A good aryl group, an optionally substituted heterocyclic group, an optionally substituted cycloalkyl group, an alkyl group or an alkenyl group.) Or one CO—R 3 (where R 3 is an alkyl group, an aralkyl A carbonyl group or —NR 4 R 5 (wherein R * and R 5 are the same or different and represent an alkyl group, or R 4 and R 5 become- ⁇
  • a medicament comprising the diazabicyclo [3.3.1] nonane derivative or a pharmaceutically acceptable salt thereof described in any of the above (1) to (5).
  • a pharmaceutical composition comprising a nonane derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • a nicotine-like choline agonist comprising a nonane derivative or a pharmacologically acceptable salt thereof.
  • a pharmaceutical composition for treating central nervous system disorders due to reduced choline action in brain cells comprising a nonane derivative or a pharmaceutically acceptable salt thereof.
  • Treatment of central nervous system disorders due to reduced dobamine action containing the diazabicyclo [3.3.1] nonane derivative or a pharmaceutically acceptable salt thereof according to any of (1) to (5) above Pharmaceutical compositions for
  • a therapeutic agent for central nervous system degenerative disease comprising the diazavincro [3.3.1] nonane derivative or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (5).
  • a therapeutic agent for dementia comprising the diazabicyclo [3.3.1] nonane derivative or a pharmaceutically acceptable salt thereof according to any of (1) to (5).
  • a cerebral dysfunction improving agent comprising the diazabicyclo [3.3.1] nonane derivative or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (5).
  • a therapeutic agent for Parkinson's disease comprising the diazabicyclo [3.3.1] nonane derivative or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (5).
  • a memory disorder ameliorating agent comprising the diazabicyclo [3.3.1] nonane derivative or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (5).
  • a pharmaceutical composition for treating central nervous system disorders due to reduced dobamine action comprising a diazabicyclo [3.3.1] nonane derivative having a dopamine releasing action or a pharmaceutically acceptable salt thereof.
  • R 6 represents an alkyl group.
  • R e represents an alkyl group.
  • R 6 represents an alkyl group.
  • R 6 represents an alkyl group.
  • a nicotinic acid ester compound represented by the following formula is subjected to a catalytic hydrogenation reaction in the presence of an acid to give the following formula [30]
  • R s represents an alkyl group.
  • the nitrile reaction of copper (I) with an estyl compound represented by the formula: is followed by treatment with an aqueous solution of sodium hypochlorite to form a complex. After oxidation, the reaction solution is treated with an aqueous ammonia solution to remove copper ions and crystallized, thereby obtaining the following formula [29]
  • R 6 represents an alkyl group.
  • a catalytic hydrogenation reaction using platinum oxide or platinum carbon as a catalyst in a solvent selected from ethanol and isopropyl alcohol in the presence of hydrochloric acid in the presence of hydrochloric acid The following formula
  • R 6 represents an alkyl group.
  • R represents one CONH— (CHR 1 ) m- R 2 (wherein, R ′ represents a hydrogen atom or an alkyl group, m represents 0, 1 or 2, and R 2 may be substituted. good Ariru group, an optionally substituted heterocyclic group, an optionally substituted cycloalkyl group, an alkyl group or an alkenyl group.) or one C_ ⁇ one R 3 (wherein, R 3 is an alkyl group, Araru A carbonyl group or -NR 4 R 5 (wherein R 4 and R 5 are the same or different and represent an alkyl group, or R 4 and R 5 are taken together with an adjacent nitrogen atom to form
  • R 6 represents an alkyl group.
  • a nicotinic acid ester compound represented by the following formula is subjected to a catalytic hydrogenation reaction in the presence of an acid to give the following formula [30]
  • R represents in one C0NH- (CHR 1) "-R 2 (wherein, R 1 represents a hydrogen atom or a ⁇ alkyl group, m represents 0, 1 or 2, R 2 is substituted good Ariru group, an optionally substituted heterocyclic group, an optionally substituted cycloalkyl group, an alkyl group or an alkenyl group.) or one C_ ⁇ one R 3 (wherein, R 3 is an alkyl group, Araru A carbonyl group or one NR * R 5 (wherein R 4 and R 5 are the same or different and represent an alkyl group, or R 4 and R 5 together with an adjacent nitrogen atom form
  • Alkyl group means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group and an isobutyl group.
  • aryl group is specifically a phenyl group, a biphenyl group, or a naphthyl group, and is preferably a phenyl group.
  • Heterocyclic group means a 5- or 6-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms as ring-constituting atoms.
  • Group saturated heterocyclic group or unsaturated heterocyclic group, specifically, a phenyl group, a furyl group, a pyrrolyl group, an imidazolyl group, a bilabril group, a thiazolyl group, a dithiazolyl group, an oxazolyl group, an isoxazolyl group, and a morpholino group ,
  • they are a phenyl group, a pyridyl group or a piperidyl group.
  • the “cycloalkyl group” is a cyclic alkyl group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like. Represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group having 3 to 6 carbon atoms.
  • alkenyl group refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 2-methyl-1-butenyl group, 3-methyl-1-butenyl Group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2-methyl-1-pentenyl group, 3-methyl-11-pentenyl group, 4 —Methyl-1-pentenyl group, 2,2-dimethyl-1-butenyl group or 3,3-dimethyl-1-butenyl group.
  • alkenyl group having 2 to 4 carbon atoms which may be straightforward or capable of being separated, such as an ethenyl group, a 1-bromo group, a 2-probenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group.
  • 2-methyl-1-probenyl group, and particularly preferably an ethenyl group, a 1-bromo group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group or a 3-butenyl group. is there.
  • Diaralkyloxy refers to aryl (C, -C S ) alkyloxy-e.g. benzyloxy, phenethyloxy, 11-phenylethyloxy A 3-phenylpropyloxy group, a 4-phenylbutyloxy group, a 5-phenylpentyloxy group or a 6-phenylhexyloxy group, and preferably a benzyloxy group, a phenyloxy group, or a 1-phenyl group.
  • phenyl (d-C4) alkyloxy group such as a diphenylethyloxy group, a 3-phenylbroviroxy group, or a 4-phenylbutyloxy group, and particularly preferably a benzyloxy group.
  • substituent may be substituted with 1 to 4, preferably 1 to 3, substituents, which may be the same or different.
  • the position S of the substituent is arbitrary and is not particularly limited. Specifically, lower alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, butyl group and tert-butyl group: hydroxyl group; lower alkyl groups such as methoxy group, ethoxyquin group, propoxy group and butoxy group.
  • Alkoxy group halogen atom such as fluorine, chlorine, bromine, etc .; nitro group: cyano group: acyl group (for example, lower alkanoyl group such as formyl group, acetyl group, propionyl group); acyloxy group (for example, formyloxy group, acetylquinine group, propionyl) Lower alkanoyloxy group such as quinoline group): lower alkylthio group such as mercapto group methylthio group, ethylthio group, bromovirthio group, butylthio group, and isobutylthio group: amino group: methylamino group, ethylamino group, propylamino group, butylamino group Lower alkylamino groups such as: di Di-lower alkylamino groups such as methylamino group, cetylamino group, dibutylamino, dibutylamino group; carboxy
  • substituted aryl groups include 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 2 —Methoxyphenyl, 3-Methoxyphenyl, 4-Methoxyphenyl, 2-Ethoxyphenyl, 3-Ethoxyphenyl, 4-Ethoxyphenyl, 3,4-Dimethoxyphenyl, 3,4,5-Trimethoxyphenyl, 4-Hydroxyxy 3-Methoxyphenyl, 2-Chlorophenyl, 3-Chlorophenyl, 4-Chlorophenyl, 2-Fluorophenyl, 3-Fluorophenyl, 4-Fluorophenyl, 3,4-Dichloromouth Phenyl, 3-chloro-4-methoxyphenyl, 3-fluoro-4
  • “Amino protecting group” refers to a sulfonyl group (eg, toluenesulfonyl group, benzenesulfonyl group, methanesulfonyl group, benzylsulfonyl group, phenacylsulfonyl group); an aralkyl group (eg, benzyl group, 4-methoxybenzyl group, 3 , 4 dimethoxybenzyl group, 2-2 trobenzyl group, 412 trobenzyl group, benzylhydryl group, bis (4-methoxyphenyl) methyl group, trityl group); (For example, formyl, acetyl, propionyl, petyryl, oxaryl, succinyl, bivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2-bromoacetyl, 2,2-dichloro Acetyl group, 2,2,2-trichlor
  • Preferred amino protecting groups are toluenesulfonyl, benzyl, formyl, acetyl, 2-chloroacetyl, 2,2,2-trifluoroacetyl, benzoyl, isopropoxycarbonyl, tert-butoxy.
  • Halogen atom is chlorine, bromine, iodine or fluorine.
  • ⁇ Alkoxy group j is a straight or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy group, ethoxyquin group, n-propoquine group, isopropoxy group, n-butoxy group, Isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, neopentyloxy, 2-pentyloxy, 3-pentyloxy, n-hexyloxy And a lower alkoxy group having 1 to 4 carbon atoms which may be a straight chain or which may be separated, such as a methoxy group, an ethoxyquin group, and the like. Examples include n-broboxine group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group and tert-butoxy group.
  • the “pharmacologically acceptable salt” may be any salt that forms a nontoxic salt with the diazabicyclo [3.3.1] nonane derivative represented by the above general formula [1].
  • inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate and nitrate Addition salts; acetate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfone
  • Organic acid addition salts such as acid salts and ascorbate salts: salts with acidic amino acids such as aspartate and glutamate; aluminum salts such as sodium salts and potassium salts; magnesium salts and calcium Alkaline earth metal salts such as salts; ammonium salts; trimethylamine salts, triethylamine salts, pyridine salts, picolin salts, dicyclohexylamine salts, N, N'-dibenzy
  • Diazabicyclo [3.3.1] nonane derivative is a compound having a 2-oxo-13, a-diazabicyclo [3.3.1] nonane skeleton.
  • the “acid” in the step (c) is, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, etc .; acetic acid, propionic acid, oxalic acid, malonic acid, citric acid, lactic acid, malic acid, Organic acids such as succinic acid, tartaric acid, fumaric acid, maleic acid, glycolic acid, methanesulfonic acid, P-toluenesulfonic acid, gluconic acid, ascorbic acid, aspartic acid, and glutamic acid.
  • Preferred are hydrochloric acid, hydrobromic acid, sulfuric acid, and ⁇ acids, and particularly preferred is hydrochloric acid.
  • the “benzyl halide j” is benzyl chloride, benzyl bromide, benzyl chloride, or the like, preferably benzyl chloride.
  • the “optically active acid” in the above-mentioned processes (e) and (26) is, for example, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, camphorsulfonic acid or malic acid. Preferred are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and the like, and particularly preferred is dibenzoyltartaric acid.
  • the “alcohol” in the above-mentioned production method (22) includes methanol, ethanol-isopropyl alcohol and the like.
  • base J refers to an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or the like; an organic base such as triethylamine, pyridine, or the like; And inorganic bases such as sodium, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc., preferably sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc., and particularly preferably sodium methoxide or sodium methoxide.
  • the compound of the present invention can be produced, for example, by the following method, but the method of producing the compound of the present invention is not limited thereto.
  • X is a halogen atom (eg, chlorine, bromine, iodine),
  • R 6 is an alkyl group (eg, methyl group, ethyl group),
  • P represents an amino-protecting group (for example, benzyloxycarbonyl group, tert-butyne carbonyl group, 9-fluorenylmethyloxycarbonyl group).
  • Compound [3] is obtained by subjecting compound [2] to an esterification reaction.
  • an alcohol e.g. methanol, ethanol
  • R 'OH R 8 is an alkyl group
  • hydrochloric Bruno 1, 4 one Jiokisan an acid such as sulfuric acid
  • Compound [3] is dissolved in water, alcohol (eg, methanol, ethanol) or a mixture thereof at a temperature of from 20'C to 40, preferably from 0 to room temperature, or an acid such as hydrochloric acid, or lithium hydroxide or sodium hydroxide.
  • the compound [4] is obtained by hydrolysis in the presence of a base such as potassium hydroxide, barium hydroxide, or carbonated lithium.
  • the compound [4] is reacted with an acid halide (eg, thionyl chloride, oxalyl chloride) in a solvent-free or inert solvent at room temperature to reflux temperature to obtain a compound.
  • an acid halide eg, thionyl chloride, oxalyl chloride
  • Compound [5] from a 2 O'C 0'C preferably give compound [6] by treatment with an inert solvent containing ammonia ⁇ at 0 e C from a 1 O'C.
  • Compound [6] is used in a suitable solvent such as alcohol (eg, methanol, ethanol), acetic acid, 1,4-dioxane, etc., and is usually used for catalytic hydrogen reduction of Raney nickel, palladium monocarbon, platinum oxide, rhodium-alumina etc.
  • the compound [7] is obtained by reducing hydrogen or ammonium mothate or the like in the presence of the resulting catalyst at a reflux temperature from normal pressure to 200 atm.
  • compound [7] can be used in the next reaction (F) without isolation.
  • Compound [8] is obtained by introducing an amino-protecting group P into compound [7] by a conventional method.
  • the amino protecting group P include a benzyloxycarbonyl group, a tert-butoxycarbonyl group, and a 9-fluorenylmethyloxycarbonyl group, and any amino protecting group may be used as long as the reaction is not hindered. Is also good.
  • P is a tert-butoxycarbonyl group
  • the compound [7] is converted to sodium hydroxide, sodium bicarbonate, sodium bicarbonate, or triethylamine in a solvent such as 4-dioxane, water, N, N-dimethylformamide or a mixture thereof.
  • Compound [8] can be obtained by reacting with di-tert-butyl carbonate in the presence of a base such as
  • Compound [11] is added to an isocyanate [12] in an inert solvent such as toluene, dioxane, N, N-dimethylformamide, in the presence or absence of a base such as triethylamine, pyridine or potassium-tert-butoxide. Reaction with ⁇ at room temperature to reflux temperature gives compound [13].
  • Isocyanates other than commercially available products include (1) Curtius rearrangement reaction using the corresponding carboxylic acid with diphenylphosphoric acid azide, (2) reaction of the corresponding primary amine with phosgenes, or (3) ) It can be prepared and used by reacting the corresponding halide with sodium cyanate.
  • amino protecting group P is, for example, tert-butoxycarbonyl group, no solvent or in an inert solvent such as dichloromethane, chloroform, etc., hydrobromic acid / drunkic acid, 1,4-dioxane hydrochloride, nitroxic acid, hydrochloric acid Z acetate, Torifuruoro acetate, using an acid such as tri Furuoro acetate / acetic acid, at 70 from a 30 e C, preferably removing Amino protecting group P by ⁇ processed from 0 at 30 hand.
  • an inert solvent such as dichloromethane, chloroform, etc.
  • hydrobromic acid / drunkic acid 1,4-dioxane hydrochloride
  • nitroxic acid hydrochloric acid Z acetate
  • Torifuruoro acetate using an acid such as tri Furuoro acetate / acetic acid, at 70 from a 30 e C, preferably removing Amino
  • the amino protecting group P is, for example, a benzyl group
  • a suitable solvent such as alcohol (eg, methanol, ethanol, isopropyl alcohol), acetic acid, 1.4-dioxane, etc., palladium oxide, palladium black, Raney nickel, platinum oxide, rhodium -Reduction from O'C at reflux temperature, from normal pressure to 100 atm, using hydrogen or aluminum formate etc. as hydrogen source in the presence of a catalyst usually used for catalytic reduction such as alumina Removes the amino protecting group P.
  • alcohol eg, methanol, ethanol, isopropyl alcohol
  • acetic acid 1.4-dioxane, etc.
  • palladium oxide palladium black
  • Raney nickel Raney nickel
  • platinum oxide rhodium -Reduction from O'C at reflux temperature
  • the compound [14] is a basic compound having an amino group
  • a salt with an arbitrary acid can be formed as necessary.
  • compound [14] and fumaric acid are refluxed at 0 e C in an appropriate solvent such as alcohol (eg, methanol, ethanol, isopropyl alcohol), water, acetone, or ethyl acetate.
  • alcohol eg, methanol, ethanol, isopropyl alcohol
  • water acetone
  • ethyl acetate ethyl acetate
  • R 1 and m are the same as above,
  • P is an amino protecting group
  • R 2 a is substituted with S conversion has been Ariru group, substituted cycloalkyl group heterocyclic group, or Ararukiruokishi group that is conversion in Ararukiruokishi group
  • R 2 b is Ariru group substituted with a hydroxyl group, a hydroxyl group at Ararukiruokishi group Heterocyclic group or water Represents a cycloalkyl group substituted with an acid group.
  • R 4 and R 5 are the same as described above;
  • P is an amino protecting group
  • Y represents a halogen atom (for example, chlorine, bromine, iodine), or an unsubstituted group such as an alkoxy group (for example, methoxy group, ethoxy group). ]
  • R 3 is as defined above, and P represents an amino protecting group.
  • the compound [11] is reacted with an acid anhydride [20] (for example, acetic anhydride) in a solvent-free or inert solvent at a temperature of from 120 ° C to a reflux temperature, preferably from 4O'C to a reflux temperature.
  • an acid anhydride [20] for example, acetic anhydride
  • a solvent-free or inert solvent at a temperature of from 120 ° C to a reflux temperature, preferably from 4O'C to a reflux temperature.
  • This compound [21] can be led to compound [22] by reaction (K).
  • R 3 is the same as described above, X represents a halogen atom, and ⁇ represents an amino protecting group.
  • the compound [11] is treated with an acid halide [23] (e.g., Viva mouth Irkmouth, etc.) in an inert solvent such as dichloromethane, chloroform, dioxane or the like, in the presence of a base such as triethylamine, pyridine, potassium-tert-butoxide.
  • benzyl O carboxymethyl Cal Bonirukurorai de as one 4 0 e C from reflux temperature, preferably compounds by reacting at room temperature O e C obtaining [2 1].
  • This compound [21] can be converted to compound [22] by reaction (K).
  • (L) R 2 is an aralkyloxy group
  • (L) R 2 is an aralkyloxy group
  • Optically active substance of [21] Optically active substance of [22]
  • P is represents a Amino protecting group, 1 ⁇ , 13 ⁇ 4 2, 1 ? 2 1), 13 ⁇ 4 3, 1 ⁇ , 13 ⁇ 4 5 and m are as defined above. ]
  • Compound [24] can be obtained by deprotecting compound [11] in the same manner as in reaction (K).
  • This compound [24] uses an appropriate solvent (eg, alcohol such as methanol or ethanol, water) or a mixture thereof as a recrystallization solvent, and uses an optically active acid (eg, L-tartaric acid and D-tartaric acid).
  • an appropriate solvent eg, alcohol such as methanol or ethanol, water
  • an optically active acid eg, L-tartaric acid and D-tartaric acid.
  • optically active compounds of the compound [11] can be obtained by the reaction (F).
  • the corresponding optically active compound [14], [16 ⁇ ], [19] or [22] can be obtained from the optically active compound of the compound [11] in the same manner as in the above Production Methods 1 to 5. .
  • Compound [28] is obtained by subjecting compound [27] to an esterification reaction.
  • an alcohol represented compound [27] with R e OH (R * is as defined above) for example, methanol, Etasoru, isopropyl alcohol
  • R * is as defined above
  • acids such as sulfuric acid
  • Compound [28] can also be produced from nicotinic acid (compound [27 ']). Nicotinic acid, bromine and thionyl chloride can be prepared in a suitable solvent such as benzene, chlorobenzene, 1,2-dichlorobenzene, benzonitrile, nitrobenzene or the like, or without solvent, preferably under a nitrogen atmosphere at room temperature to 200 ° C. React to form 5-bromonicotinic acid chloride. To this is added an alcohol represented by R 6 OH (R 8 is the same as above) (eg, methanol, ethanol, isopropyl alcohol) and reacted at room temperature to reflux temperature to obtain compound [28] and bromide.
  • R 6 OH R 8 is the same as above
  • the reaction solution is made basic with a base such as potassium carbonate or sodium hydrogen carbonate, and then treated with a reducing agent such as sodium thiosulfate or sodium sulfite to obtain compound [28].
  • a base such as potassium carbonate or sodium hydrogen carbonate
  • a reducing agent such as sodium thiosulfate or sodium sulfite
  • the above method is a method described in J. Am. Chem. Soc., 70, 238 (1948), that is, converting 5-nicotinic acid (compound [27]) from nicotinic acid.
  • This is a simplified method of obtaining 5-bromonicotinic acid chloride (compound [28]) by reacting it with thionyl chloride to obtain 5-bromonicotinic acid chloride, and then reacting this with ethanol. .
  • compound [28] can be produced directly from nicotinic acid without passing through 5-bromonicotinic acid (compound [27]).
  • Compound [29] is obtained by crystallizing the obtained crude product from an appropriate solvent such as alcohol (eg, methanol, ethanol, isopropyl alcohol) or water, or a mixed solvent thereof.
  • an appropriate solvent such as alcohol (eg, methanol, ethanol, isopropyl alcohol) or water, or a mixed solvent thereof.
  • Compound [29] is converted to an appropriate solvent such as alcohol (eg, methanol, ethanol, isopropyl alcohol) in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, and platinum oxide, platinum-carbon,
  • an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, and platinum oxide, platinum-carbon
  • a catalyst usually used for catalytic hydrogenation such as Raney nickel, palladium-carbon, rhodium-alumina, etc.
  • the compound [30%] is obtained by carrying out a catalytic hydrogenation reaction under a pressure of 100 atm.
  • ethanol or pill alcohol is used as a solvent
  • hydrochloric acid is used as an acid
  • platinum oxide or platinum monocarbon is used as a catalyst.
  • Compound [30] is treated with sodium methoxide, sodium ethoxide, triethylamine, pyridine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate in an appropriate solvent such as alcohol (eg, methanol, ethanol, isopropyl alcohol).
  • alcohol eg, methanol, ethanol, isopropyl alcohol.
  • the compound is reacted by using a base such as thorium at room temperature to reflux temperature.
  • Compound [31] can be used without isolation in a suitable solvent such as alcohol (eg, methanol, ethanol, isopropyl alcohol), potassium carbonate, sodium carbonate, sodium hydrogencarbonate, triethylamine, diisoprovire.
  • a suitable solvent such as alcohol (eg, methanol, ethanol, isopropyl alcohol), potassium carbonate, sodium carbonate, sodium hydrogencarbonate, triethylamine, diisoprovire.
  • Compound [32] can also be obtained by reacting with aralkyl halides such as benzyl chloride, benzyl bromide and methoxybenzyl chloride in the presence of a base such as tilamine.
  • Compound [32] can be converted to an optically active acid (for example, tartaric acid, dibenbuyltartaric acid, ditoluoyltartaric acid, An optically active compound [33%] is obtained by optical resolution using a diastereomer crystallization method using camphorsulfonic acid, malic acid, and the like.
  • an optically active acid such as ditoluoyl monoL-tartaric acid and dibenzoyl L monotartaric acid can be used.
  • Compound [33] (wherein Bn is the same as described above) may be subjected to the above reaction (J) (reaction (J) to carry out reaction (L)), (M), (N) or (0) Compound [34] can be obtained by carrying out the reaction in the same manner as in. Subsequently, the target compound [35] can be obtained by carrying out a reaction in the same manner as in the reaction (K).
  • the production method 7 is characterized in that the intermediate [33] can be produced in a small number of steps and in good yield, and the starting material 5-bromonicotinic acid or nicotinic acid is inexpensive. Therefore, this is a method that can efficiently produce the desired diazabicyclo [3.3.1] nonane derivative at low cost.
  • Isolation and purification of the thus-obtained compound represented by the general formula [1] from the reaction mixture can be carried out by using any means commonly used in the field of synthetic organic chemistry. For example, column chromatography, solvent extraction, recrystallization and the like. Simplification and purification may be performed for each reaction, or may be performed after completion of some reactions.
  • the compound of the present invention represented by the general formula [1] may have a stereoisomer based on an asymmetric carbon, and such an isomer and a mixture thereof are all included in the scope of the present invention.
  • Diazabic ⁇ [3.3.1] nonane derivatives have nicotine-like choline action and dopamine release action, and are useful as nicotine-like cholinergic drugs or dopaminergic drugs. Therefore, the diazabicyclo [3.3.1] nonane derivative can be used as a medicament for treating central nervous disorder due to reduced choline action in brain cells or as a medicament for treating central nervous disorder due to decreased dopamine action. You. In detail, the diazavincro [3.3.1] nonane derivative can be used for treatment of central nervous system degenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Bick's disease, improvement of brain dysfunction, etc. In particular, it has a memory impairment improving effect and can be used as an agent for improving memory impairment represented by dementia.
  • central nervous system degenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Bick's disease, improvement of brain dysfunction, etc.
  • it has a memory impairment improving effect and can be used as an agent for improving memory impairment represented by dementia
  • the diazavinclo [3.3. 1] nonane derivative is not limited to the compound represented by the above-mentioned one-shot formula [1], but may be 2-oxo-1,3,7-diazabicyclo [3.3.1]. Includes compounds having a nonane skeleton.
  • the diazabicyclo [3.3.1] nonane derivative is a compound represented by the general formula [1].
  • diazabicyclo [3.3.1] nonane derivatives or pharmacologically acceptable salts thereof are used as pharmaceutical preparations, they are usually known per se as pharmacologically acceptable carriers, excipients, diluents, and bulking agents.
  • Disintegrants Disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, coloring agents, sweeteners, thickeners, corrigents, solubilizers, and other additives, specifically water, vegetable oils, Tablets, pills, powders mixed with alcohols such as ethanol or benzyl alcohol, carbohydrates such as polyethylene glycol, glycerol triacetate, gelatin, ratatose, starch, etc., magnesium stearate, talc, lanolin, petrolatum, etc.
  • Granules, suppositories, injections, eye drops, liquids, capsules, troches, aerosols, elixirs, suspensions, emulsions, emulsions Oral the form of such-up agent, can be administered by parenteral or external administration (topically).
  • the dosage may vary depending on the type and extent of the disease, the compound to be administered, the route of administration, the age, sex, and weight of the patient.
  • diazavincro [3.3.1] nonane per adult is usually used per day. It is preferable to administer the derivative (preferably a diazabicyclo [3.3.1] nonane derivative represented by the general formula [1]) in an amount of 0.1 mg to 1,000 mg, particularly 1 mg to 300 mg.
  • Example 6 from 7- (tert-butoxycarbonyl) -1,2-oxo-1,3,7-diazabisic mouth [3.3.1] nonan-1--3-carboxylic acid (4-cyclohexylbenzyl) amide (664 mg) -The title compound (343 mg) was obtained in the same manner as in b).
  • reaction solution was ice-cooled, N-N-dimethylcarbamoyl quenched lid (0.690 ml) was added, and the mixture was stirred as it was for 20 minutes.
  • the reaction mixture was poured into water, extracted with chloroform for drying, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (eluent: mixed solvent of chloroform and methanol). The title compound (549 mg) was obtained.
  • Example 11 7- (tert-Butkincarbonyl) -1,3,7-diazabicyclo [3.3.1] nonan-2-one (2.30 g) obtained in f) was treated with anhydrous acetic anhydride (lOral). In addition, the mixture was heated at 120 ° C for 2 hours. Methanol (15 ml) was added to the reaction solution, and the mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate.
  • lOral anhydrous acetic anhydride
  • Example 1 A solution of 7- (tert-butoxycarbonyl) -1,3,7-diazavinclo [3.3.1.1] nonane-2-one (6.40 g) obtained in 1 f) in 1,4-dioxane (50 ml) To the mixture was added 4N hydrogen chloride-1,4-dioxane (50 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was treated with potassium carbonate (5.51 g) aqueous solution and anhydrous sodium sulfate. To the mixture was added successively toluene, and the mixture was extracted with 5% ethanol in chloroform. The concentrate was concentrated to give the title compound (2.98 g).
  • the reaction solution was returned to room temperature, and ethyl acetate (100 ml), heptane (75 ml) and ethanol (5 ml) were sequentially added, and the mixture was stirred at room temperature for 12 hours.
  • the precipitate was collected, washed with ethyl acetate (300 ml), and air-dried.
  • the obtained target salt (221 g) was suspended in hebutane (750 ml) and water (750 ml), and potassium carbonate (95.5 g) and sodium thiosulfate (I07 g) were sequentially added with stirring. After confirming that the salt was completely dissolved, liquid separation was performed.
  • a suspension of copper (I) cyanide (98%, 45.68 g. 500 mL) and ethyl 5-bromonicotinate (100 g. 435 mmol) obtained in the above step a) in dimethylformamide (500 ml) was prepared.
  • the mixture was refluxed for 4 hours under a nitrogen atmosphere. After allowing the reaction solution to cool to an internal temperature of 50 ° C, ethyl acetate (500 ml) and an aqueous potassium carbonate solution (100 ml) were sequentially added.
  • An aqueous solution of 3.25N sodium hypochlorite (360 ml) was added dropwise over 25 minutes while maintaining the temperature at 30 to 40 ° C, and the mixture was stirred at the same temperature for 1 hour.
  • aqueous ammonia 45ral was slowly added to keep the temperature at 20 to 30 and then separated.
  • the water was re-extracted with ethyl acetate (lOOnil).
  • the organic layers were combined and washed sequentially with 103 ⁇ 4 saline (200 ml) and saturated saline (450 ml).
  • Activated carbon (6 g) was added to the organic layer, and the mixture was stirred at room temperature for 30 minutes. After removing insolubles, the filtrate was concentrated under reduced pressure. The residue was crystallized from methanol (200 ml) -water (500 ml) to give ethyl 5-cyanonicotinate (58.83 g, yield 77%) as pale yellow crystals.
  • acetonitrile (100 ml) of ethyl 5-bromonicotinate (100 g. 435 mol) obtained in the above step a) was added.
  • the solution was added, and the mixture was stirred at an internal temperature of 60 eC .
  • the reaction solution was allowed to cool, ethyl acetate (200 ml) and an aqueous solution of potassium pentacarbonate (100 ml) were added, and the mixture was stirred at room temperature for 30 minutes.
  • the mixture was further cooled on ice, a 10% aqueous sodium hypochlorite solution (150 ml) was added, the mixture was stirred for 30 minutes, and then separated.
  • the recruiter was re-extracted with ethyl acetate (100 ml).
  • the organic layers were combined, and washed successively with a mixture of saturated saline (50 ml) and water (50 ml), and 3N hydrochloric acid (a50 ml).
  • the aqueous layer separated by washing with 3N hydrochloric acid was re-extracted with ethyl acetate (100 ml).
  • the combined organic layers consist of saturated saline (50ml) and water (50ml)
  • the mixture was washed successively with a saturated saline solution (100 ml).
  • the organic layer was dried over anhydrous sodium sulfate.
  • the residue was crystallized from methanol (150 ml) -water (Oral) to give ethyl 5-cyanonicotinate (59.1 g, yield 77D) as white crystals.
  • EtOOC Methanol (300 ml) and 28% sodium methoxide methanol (66.0 g, 342 mmol) were added to the crude product (32.3 g) obtained in the above step c), and the mixture was refluxed for 2 hours.
  • Acetic acid (6.57 tnl. L mmol) was added dropwise to the reaction mixture, and then potassium carbonate (15.8 g. 114 mmol) and benzyl chloride (17.1 ml. 149 mmol) were added, and the mixture was refluxed again for 4 hours.
  • Acetic acid (13.lml, 228mraol) was added to the reaction solution, which was then reduced under reduced pressure.
  • the residue was separated with a 10% aqueous solution of citric acid (100 ml) -ethyl acetate (80 ml).
  • the organic layer was further extracted with a 10% aqueous solution of citric acid (60 ral., 40 ml once each).
  • the water was combined, and the mixture was adjusted to pH 9 to 10 while stirring at room temperature, and extracted with ethyl acetate (160 ml, 60 ml once each).
  • the organic layers were combined, washed with brine (50 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • Tables 1 to 26 show the structural formulas and physicochemical properties of the compounds of Examples 1 to 76.
  • Table 27 shows the results.
  • the IC 50 value is the concentration of the test compound that inhibited the specific [ 3 H] -cytisine binding by 50%.
  • the control compound ABT-418 in the table is 3-methyl-5- (1-methylbi-lidinyl-2-yl) isosoxazole.
  • the dopamine release effect was measured according to the method of Nagy et al. [Neurocem. Vol. 3, 1114-1123. (1984)].
  • Brain striatal regions from Sprague-Dawley rats were buffered with 5 mM N-2-hydroxyethylbiperazine-N'-2-ethanesulfonic acid (HE PES) (pH 7.5) at 0.3 mM.
  • the mixture was homogenized in a 2M show 2 ml using a glass-Teflon tissue grinder.
  • the homogenate was diluted to 5 ml with another homogenization solution and centrifuged at 1000 ⁇ g for 10 minutes. This procedure was repeated with respect to the obtained pellet, and the obtained supernatant and the above supernatant were combined, and further centrifuged at 1200 ⁇ g for 20 minutes.
  • the resulting pellets were dispersed in a HEPES buffered sucrose solution, and a separately prepared three-layer discontinuous Perc 0 1 having a Perc 0 11 concentration of 16% 10% and 7.5% was prepared. Laminated on one gradient. This was centrifuged at 1500 xg for 20 minutes, and the synabtosomes accumulated on the 16% layer were collected with a bathtool bit, and were mixed with a perfusion buffer (128 mM NaCl, 2.4 mM KC 1, 3. 2mM C a C 1 2.
  • the suspension obtained above was filtered through a glass fiber filter (Gelman type A / E) impregnated with 0.5% of polyethylene, and synabtosome was added to the filter.
  • the filter was washed by dropping the perfusion buffer onto the filter (0.2-0.3 ml / min) while aspirating with a peristaltic pump for at least 20 minutes before the dropping of the test substance. After 0.2 ml of a 10 ⁇ solution of the test substance was dropped onto the washed filter, the perfusate was collected in scintillation vials at 1 minute intervals. The amount of released dopamine was measured by scintillation counting.
  • the scobolamine-treated rat was used to measure the effect of improving disorders.
  • the rat was placed in a light room one hour before the acquisition trial, and the time from when the partition plate was opened until the rat entered the dark room (reaction latency) was measured.
  • reaction latency time from when the partition plate was opened until the rat entered the dark room.
  • the rat was placed in a bright room, the partition was opened, and 0.25 mA electrical stimulation (1 second) was applied to the grid on the floor when the rat entered the dark room. The reaction latency was recorded. Twenty-four hours later, a holding trial was performed, and the reaction latency was measured. Thirty minutes before the acquisition trial, scopolamine (0.5 mg / kg) dissolved in saline and a test compound (one of 0.1. 0.3. L. Orag / kg) were administered subcutaneously.
  • the reaction latency of the retention trial was recorded up to a maximum of 300 seconds, and longer than that was set to 300 seconds.
  • the retention trial response latencies of each group were tested using the Mann-Whitney U test, and the response latencies were significantly longer with a risk factor of 5% or less than that of the group administered saline and scobolamine containing no test compound.
  • a test compound group having a was determined to be effective.
  • Blood pressure changes were measured as indicators of peripheral effects.
  • Male Wistar rats (220-300 g) were anesthetized with sodium pentobarbital (25 mg / kg, ip) and sodium barbital (300 mg / kg. Ip), and a PE 10 Teflon tube was inserted into the crotch vein for drug administration.
  • a PE30 Teflon tube was inserted into the hip artery for blood pressure measurement, the change in blood pressure before and after drug administration was measured by connecting the hip arterial force to the pressure transducer.
  • the drug was dissolved in saline and administered continuously from the lowest dose (0.1 mg / kg) to the highest dose (10 mg / kg) at intervals of 20 minutes or more from the hip vein force neura.
  • Minimum effective dose is the dose at which blood pressure change before and after drug administration reaches 3 OmmHg (EC 30).
  • Table 29 shows the results. Table 29 shows the central effect Z peripheral effect ratio of each compound.
  • the compound of the present invention has a high binding property to a nicotine-like acetylcholine receptor, and also showed an excellent improvement effect in an in vivo memory impairment test using a scobolamine-treated rat.
  • the compound of the present invention is characterized by having high central selectivity and a low effect on peripheral nerves as compared with the control compounds cytisine, nicotine and ABT-418.
  • the diazavinclo [3.3.1] nonane derivative of the present invention has a high nicotine-like choline receptor binding property and also has a dopamine releasing action, and therefore is used as a nicotine-like cholinergic agonist or a dopamine agonist.
  • the compound of the present invention can be used for the treatment of central nervous system diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Pick's disease, and for improving brain dysfunction. It can be used as a remedy for memory disorders represented by dementia.
  • the compound of the present invention since the compound of the present invention has a low effect on peripheral nerves, it is characterized in that there are few side effects such as hypertension and diarrhea which are observed in conventional cholinergic agonists.
  • the compound of one-branch [11] is useful as an intermediate for producing a diazabicyclo [3.3.1] nonane derivative of one-branch [1].
  • the intermediate compound [33] can be produced in good yield from inexpensive starting material 5-bromonicotinic acid or nicotinic acid. Therefore, through these steps, the desired diazabicyclo [3.3.1] nonane derivative of the general formula [35] can be efficiently produced at low cost.

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Abstract

L'invention porte sur des dérivés diazabicyclo[3.3.1]nonane et leurs intermédiaires ainsi que sur un agent nicotinique cholinergique contenant ces dérivés. Ces derniers sont représentés par la formule générale suivante (1) dans laquelle R représente -CONH-(CHR1)m-R?2 (où R1¿ représente de l'hydrogène ou un alkyle, où m vaut 0, 1 ou bien 2 et où R2 représente un aryle éventuellement substitué, un hétérocycle éventuellement substitué, un cycloalkyle éventuellement substitué, un alkyle ou un alcényle) ou -CO-R?3 [où R3¿ représente un alkyle, un aralkyloxy ou bien -NR?4R5 {où R4 et R5¿ sont identiques ou différents et où chacun représente un alkyle, ou encore où R4 et R5, associés à l'atome d'azote auquel ils sont liés, constituent un groupe (a), (où n vaut 2 ou 3)}]. Un tel composé, qui a un effet nicotinique cholinergique ainsi qu'un effet de libération de dopamine, peut être utilisé comme remède contre la démence, telle que la maladie d'Alzheimer, comme médicament d'atténuation de troubles de la mémoire, comme remède contre les maladies de dégénérescence nerveuse et comme médicament pour soulager des troubles de la fonction cérébrale.
PCT/JP1996/000742 1995-03-24 1996-03-21 Derives diazabicyclo[3.3.1]nonane et leurs intermediaires, leur application therapeutique et procedes de production WO1996030372A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2786770A1 (fr) * 1998-12-04 2000-06-09 Synthelabo Derives de 1,4-diazabicyclo[3.2.2.]nonane, leur preparation et leur application en therapeutique
WO2003000261A1 (fr) * 2001-06-25 2003-01-03 Elan Pharmaceuticals, Inc. Utilisation de composes bicycliques dans le traitement de la maladie d'alzheimer
EP1415651A1 (fr) * 2001-08-06 2004-05-06 Mitsubishi Pharma Corporation Compositions prophylactiques/therapeutiques destinees a la neuropathie cholinergique
US6852721B2 (en) 2000-05-25 2005-02-08 Targacept, Inc. Pharmaceutical compositions and methods for use
US7214686B2 (en) 1997-06-30 2007-05-08 Targacept, Inc. Pharmaceutical compositions and methods for effecting dopamine release
US7402592B2 (en) 2003-10-15 2008-07-22 Targacept, Inc. Pharmaceutical compositions and methods for relieving pain and treating central nervous system disorders
EP2018874A2 (fr) 1998-08-07 2009-01-28 Targacept, Inc. compositions pharmaceutiques pour la prévention et le traitement de troubles du système nerveux central comprenant un analogue de la nicotine et un inhibiteur de l'acétylcholinestérase

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0588917A1 (fr) * 1991-05-29 1994-03-30 Abbott Laboratories Composes d'isoxazole et d'isothiazole ameliorant les fonctions cognitives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0588917A1 (fr) * 1991-05-29 1994-03-30 Abbott Laboratories Composes d'isoxazole et d'isothiazole ameliorant les fonctions cognitives

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7214686B2 (en) 1997-06-30 2007-05-08 Targacept, Inc. Pharmaceutical compositions and methods for effecting dopamine release
EP2018874A2 (fr) 1998-08-07 2009-01-28 Targacept, Inc. compositions pharmaceutiques pour la prévention et le traitement de troubles du système nerveux central comprenant un analogue de la nicotine et un inhibiteur de l'acétylcholinestérase
FR2786770A1 (fr) * 1998-12-04 2000-06-09 Synthelabo Derives de 1,4-diazabicyclo[3.2.2.]nonane, leur preparation et leur application en therapeutique
WO2000034279A1 (fr) * 1998-12-04 2000-06-15 Sanofi-Synthelabo Derives de 1,4-diazabicyclo[3.2.2]nonane, leur preparation et leur application en therapeutique
US6407095B1 (en) 1998-12-04 2002-06-18 Sanofi-Synthelabo 1,4-diazabicylo[3,2,2]nonane derivatives, their preparation and their therapeutic application
US6852721B2 (en) 2000-05-25 2005-02-08 Targacept, Inc. Pharmaceutical compositions and methods for use
USRE41439E1 (en) 2000-05-25 2010-07-13 Targacept, Inc. Pharmaceutical compositions and methods for use
WO2003000261A1 (fr) * 2001-06-25 2003-01-03 Elan Pharmaceuticals, Inc. Utilisation de composes bicycliques dans le traitement de la maladie d'alzheimer
EP1415651A1 (fr) * 2001-08-06 2004-05-06 Mitsubishi Pharma Corporation Compositions prophylactiques/therapeutiques destinees a la neuropathie cholinergique
EP1415651A4 (fr) * 2001-08-06 2005-11-09 Mitsubishi Pharma Corp Compositions prophylactiques/therapeutiques destinees a la neuropathie cholinergique
US7402592B2 (en) 2003-10-15 2008-07-22 Targacept, Inc. Pharmaceutical compositions and methods for relieving pain and treating central nervous system disorders
US7897611B2 (en) 2003-10-15 2011-03-01 Targacept, Inc. Pharmaceutical compositions and methods for relieving pain and treating central nervous system disorders

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