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WO1999065896A1 - Preparation de composes heteroaryle - Google Patents

Preparation de composes heteroaryle Download PDF

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Publication number
WO1999065896A1
WO1999065896A1 PCT/US1999/013521 US9913521W WO9965896A1 WO 1999065896 A1 WO1999065896 A1 WO 1999065896A1 US 9913521 W US9913521 W US 9913521W WO 9965896 A1 WO9965896 A1 WO 9965896A1
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WO
WIPO (PCT)
Prior art keywords
mmol
tert
tetrahydropyridine
butoxycarbonyl
heteroaryl
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Ceased
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PCT/US1999/013521
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English (en)
Inventor
Vincent Patrick Rocco
Daniel James Koch
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Eli Lilly and Co
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Eli Lilly and Co
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Priority to CA002334677A priority Critical patent/CA2334677A1/fr
Priority to AU46856/99A priority patent/AU4685699A/en
Priority to EP99930289A priority patent/EP1087962A4/fr
Priority to JP2000554721A priority patent/JP2002518386A/ja
Publication of WO1999065896A1 publication Critical patent/WO1999065896A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems

Definitions

  • 4-Arylpiperidines and 4-aryl-l, 2 , 3 , 6- tetrahydropyri- dines as a class are known to exhibit diverse pharmacological activity.
  • Piperidinylindoles and tetrahydropiperidinylindoles are known to be agonists at the serotonin 5-HT ⁇ _-like receptor (Baker et al . , U.S. Patent
  • 5-HT 1A 5-HT 1A
  • 5-HT 2 receptors 5-HT 1A
  • 5-HT 2 receptors 5-HT 2 receptors
  • This class of molecules is generally accessed through coupling of an appropriate aryl substrate with a 4- piperidone or piperidone enolate derivative.
  • Such coupling pairs include an aryl anion with a 4-piperidone; or an arylboronic acid with an enol triflate in the presence of a palladium catalyst . While these methods have provided access to a number of derivatives, those compounds where the point of connectivity to the heteroaryl moiety is adjacent to a nitrogen atom have been difficult or impossible to prepare.
  • the present invention provides a process for the preparation of these heteroaryl- 1, 2 , 3 , 6-tetrahydropyridines and heteroarylpiperidines .
  • the present invention provides a process for the preparation of heteroaryl- 1, 2 , 3 , 6-tetrahydropyridines of Formula I :
  • R 1 - is C 1 -C 4 alkyl or a nitrogen protecting group
  • R 2 is hydrogen or C ⁇ _-Cg alkyl, comprising reacting a heteroaryl halide of Formula II:
  • the present invention also provides a process for the preparation of heteroarylpiperidines of Formula IV:
  • R 1 is C 1 -C4 alkyl or a nitrogen protecting group
  • R 2 is hydrogen or C ⁇ -Cg alkyl.
  • the present invention also provides processes further comprising deprotecting those compounds of Formula I and
  • R 1 is a nitrogen protecting group to provide the corresponding secondary amine.
  • halide is chloro, bromo, or iodo
  • R 1 is C1-C4 alkyl or a nitrogen protecting group
  • R 2 is hydrogen or C ⁇ _-Cg alkyl .
  • the process of the invention is performed by reacting an appropriate heteroaryl halide (II) with an appropriate triflate (III) in the presence of a palladium catalyst, a hexa(C ⁇ -C4 alkyl) ditin, and lithium chloride in a suitable solvent.
  • the resultant tetrahydropyridine (I) is isolated by standard extractions and filtrations. If desired, the tetrahydropyridine product may be further purified by chromatography or crystallization as appropriate. While the order and manner of combining the reactants are not critical, and may be varied as a matter of convenience, it is preferred that the palladium catalyst is added last to the reaction mixture .
  • Reactions employing the process of the present invention are preferably performed at the reflux temperature of the chosen reaction medium.
  • the reactions may be performed at temperatures below reflux if convenient or desired. The skilled artisan will appreciate that reaction rates typically decrease as the temperature is lowered.
  • the heteroaryl portion of the heteroaryl halides (II) useful for the process of the present invention are characterized as a heterocyclic ring containing at least one sp 2 -hybridized nitrogen atom which is adjacent to an sp 2 - hybridized carbon atom bearing the halide atom.
  • An sp 2 - hybridized carbon atom is one that uses sp 2 -hybridized orbitals to form bonds with the three atoms to which it is attached.
  • an sp 2 -hybridized nitrogen atom is one that uses sp 2 -hybridized orbitals to form bonds with the two atoms to which it is attached.
  • heterocyclic ring may be an isolated ring or it may be fused to other ring systems.
  • the heterocyclic ring may also be substituted so long as the requisite functionality exists and the substituents do not interfere with the reaction.
  • Heteroaryl moieties which are useful substrates for the process of the present invention include pyrazol-3- yl, imidazol-2-yl, imidazol-4-yl , pyridin-2-yl , pyrimidin-2- yl, pyrimidin-4-yl, pyrimidin- 6-yl , pyridazin-3-yl , pyrazin- 2-yl, indazol-3-yl, benzimidazol-2-yl, benzothiazol-2-yl, benzoxazol-2-yl, benzoisothiazol-3-yl, benzoisoxazol-3-yl, quinolin-2-yl, isoquinolin- 1-yl , isoquino
  • the halide portion of the heteroaryl halide (II) is selected from chloro, bromo and iodo. Heteroaryl halides (II) where the halide is chloro are preferred.
  • the heteroaryl halides (II) are either commercially available or may be prepared by techniques well known to one of ordinary skill in the art.
  • the triflate reagent is a compound of formula III:
  • R 1 is C ⁇ _-C alkyl or a nitrogen protecting group
  • R 2 is hydrogen or C ⁇ _-Cg alkyl.
  • Nitrogen protecting groups are those moieties which allow the reactions of the process to proceed without interference by the secondary nitrogen atom, and then are subsequently removed to regenerate the secondary amine .
  • Nitrogen protecting groups useful for the process of the invention are well known to the skilled artisan (Greene, Protective Groups in Organic Chemistry, Second Edition, Wiley Interscience, New York (1991) ) .
  • Preferred protecting groups are phenoxycarbonyl and the C ⁇ _-
  • the requisite triflates are prepared by reacting the enolate of the corresponding piperidin-4-one with an appropriate triflating reagent, preferably N-phenyltrifluoromethanesul- fonimide.
  • the enolates may be prepared by treatment of the corresponding piperidin-4-one with a suitable base, or by conjugate addition of a nucleophilic reagent, such as a hydride reducing agent or a C 1 -C 4 alkyl Grignard reagent, to the corresponding 1, 2 , 3 , 4- tetrahydropyridin-4-one.
  • a nucleophilic reagent such as a hydride reducing agent or a C 1 -C 4 alkyl Grignard reagent
  • the heteroaryl halide (II) and triflate (III) are typically added in about equimolar amounts, and this molar ratio is preferred. The skilled artisan will appreciate that a molar excess of either reagent relative to the other may be used if necessary or desired.
  • the palladium catalyst for the process of the present invention must be a palladium(O) catalyst such as tris(di- benzylideneacetone) dipalladium(O) , tetrakis (triphenylphos- phine) palladium (0) , and tetrakis (methyldiphenylphosphine) - palladium (0) .
  • the palladium (0) catalyst is complexed to ligands
  • at least one or the ligands may be bound to an insoluble solid support if desired.
  • the palladium catalyst is tetrakis (triphenylphosphine) palladium (0) .
  • the palladium catalyst may be present in from about 2 to about 25 mole percent based on the amount of substrate. The amount of palladium catalyst ranging from about 5 to about 10 mole percent is preferred, and about 5 mole percent is most preferred for the process of the present invention.
  • the hexa(C]_-Cg alkyl) ditin employed for the process of the present invention is not critical so long as at least about one molar equivalent of the reagent based on substrate is present.
  • the preferred amount or ditin reagent is about an equimolar amount with substrate, and the preferred ditin reagent is hexamethylditin.
  • the ditin reagents are either commercially available or may be conveniently prepared by methods well known to the skilled artisan.
  • the lithium chloride employed in the process of the present invention is used in excess relative to the substrates. From about a 2 to about a 10 fold molar excess of lithium chloride relative to substrate may be used. A molar excess of from about 2 to about five is preferred, with about a 3 fold molar excess being most preferred.
  • the lithium chloride employed in the process of the present invention should be anhydrous. Anhydrous, as used here, is taken to mean that the lithium chloride is sufficiently free of water to facilitate the process of the present invention.
  • Reaction media useful for the process of the invention must be capable of dissolving a sufficient amount of the substrates for the process to proceed.
  • Organic solvents useful as reaction media for the process of this invention include ethers such as tetrahydrofuran, tetrahydropyran, dioxane, diethyl ether, diisopropyl ether, and methyl tert- butyl ether.
  • the preferred solvent is dioxane. It is also preferred that the dioxane is anhydrous where anhydrous is taken to mean that the dioxane is sufficiently free of water to allow the process of the invention to proceed.
  • the reaction medium be deoxygenated prior to use in the process of the invention. Deoxygenation may be accomplished by bubbling an inert gas, such as nitrogen or argon, through the reaction medium. It is preferred that the reaction medium is deoxygenated with nitrogen.
  • the process may be carried out over a large range of concentrations, from about 0.05 molar to about 1 molar of he substrate, dependant upon the solubility of the particular substrate in the chosen reaction medium.
  • the reaction may also be performed on slurries of the substrates so long as a sufficient amount of the substrate is soluble in the reaction medium for the reaction to proceed.
  • the process is performed at a concentration from about 0.4 molar to about 1 molar. A concentration of about 0.4 molar to about 0.8 molar is most preferred.
  • the 1, 2 , 3 , 6- etrahydropyridines of Formula I where R 1 is a nitrogen protecting group are useful intermediates for the preparation of the corresponding secondary amines.
  • the deprotection step may be accomplished by methods well known to the skilled artisan.
  • the tert-butoxycarbonyl group for example, may be removed by treatment with trifluoroacetic acid.
  • the process of the present invention therefore, further comprises deprotection of a compound of Formula I where R 1 is a nitrogen protecting group to provide the corresponding secondary amine.
  • the intermediate 1, 2 , 3 , 6-tetrahydropyridines of Formula I may also be used to prepare the corresponding piperidines of Formula IV by hydrogenation over a precious metal catalyst, such as palladium on carbon.
  • a precious metal catalyst such as palladium on carbon.
  • a hydrogenation catalyst such as sulfided platinum on carbon, platinum oxide, or a mixed catalyst system of sulfided platinum on carbon with platinum oxide is used to prevent hydrogenolysis of the bromo substituent during reduction of the tetrahydropyridinyl double bond.
  • the hydrogenation solvent may consist of a lower alkanol, such as methanol or ethanol, tetrahydrofuran, or a mixed solvent system of tetrahydrofuran and ethyl acetate.
  • the hydrogenation may be performed at an initial hydrogen pressure of 20-80 p.s.i., preferably from 50-60 p.s.i., at 0-60°C, preferably at ambient temperature to 40°C, for 1 hour to 3 days. Additional charges of hydrogen may be required to drive the reaction to completion depending on the specific substrate.
  • the piperidines prepared in this manner are isolated by removal of the catalyst by filtration followed by concentration of the reaction solvent under reduced pressure. The product recovered may be used directly in a subsequent step or further purified by chromatography, or by recrystallization from a suitable solvent.
  • 1, 2 , 3 , 6-tetrahydropyridines may be converted to the corresponding piperidines by treatment with triethylsilane if desired.
  • the 1,2,3,6- tetrahydropyridine is dissolved in trifluoroacetic acid to which is added an excess, 1.1-10.0 equivalents, of triethylsilane.
  • the reaction mixture is stirred at about ambient temperature for from about 1 to about 48 hours at which time the reaction mixture is concentrated under reduced pressure.
  • the residue is then treated with 2N sodium or potassium hydroxide and the mixture extracted with a water immiscible solvent such as dichloromethane or diethyl ether.
  • the resultant piperidine may be purified by standard methods if necessary or desired.
  • the resultant piperidine where R 1 is a nitrogen protecting group may then be removed as previously discussed to provide the corresponding secondary amine.
  • the skilled artisan will appreciate that the deprotection may occur prior or subsequent to the reduction of the double bond as necessary or desired.
  • the present invention therefore, also provides a process which further comprises the reduction of the 1, 2, 3, 6-tetrahydropyridine double bond to prepare the corresponding piperidine and, where R 1 is a nitrogen protecting group, deprotecting the nitrogen.
  • the phases were separated and the organic phase extracted with 3 x 100 mL 5N hydrochloric acid.
  • the combined aqueous phases were allowed to stand at room temperature for 18 hours and were then heated to reflux for 4 hours .
  • the reaction mixture was cooled to 0°C and basified (pH ⁇ 14) with 50% aqueous NaOH.
  • the mixture was extracted with 4 x 200 mL dichloromethane .
  • the combined organic extracts were dried over sodium sulfate and then concentrated under reduced pressure to provide 22.2 gm of a brown oil. This residual oil was subjected to silica gel chromatography, eluting with 5% methanol in dichloromethane containing a trace of ammonium hydroxide.
  • reaction mixture was then concentrated under reduced pressure and the residue dissolved in diethyl ether.
  • ether extracts were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was subjected to flash silica gel chromatography, eluting with 9:1 hexane: ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 9.46 gm (52%) of the title compound as a yellow oil.
  • reaction mixture was cooled to room temperature and then poured into saturated aqueous potassium fluoride.
  • the mixture was then diluted with ethyl acetate and stirred for about 2 hours.
  • the phases were separated and the organic phase washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure.
  • the residue was subjected to flash silica gel chromatography, eluting with hexane containing about 6% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.632 gm of the desired compound as a light yellow oil.
  • EXAMPLE 2 1 - tert -butoxycarbonyl - 4 - (pyridin-2-yl) -1,2,3,6- tetrahydropyridine Beginning with 0.52 gm (4.6 mMol) 2 - chloropyridine and 1.53 gm (4.6 mMol) 1 - tert -butoxy- 4 - trifluoromethanesulfonyl - oxy-1,2, 3 , 6- tetrahydropyridine, 0.59 gm (49%) of the title compound were prepared substantially by the procedure described in EXAMPLE 1.
  • EA Calculated for C20H23N3O2: Theory: C, 71.19; H, 6.87; N, 12.45. Found: C, 71.27; H, 6.65; N, 12.39.
  • EXAMPLE 13 1 - tert-butoxycarbonyl - 4 - (4-methylbenzothiazol-2-yl) -1,2,3,6 tetrahydropyridine Beginning with 0.227 gm (1.2 mMol) 2 -chloro- 4 -methyl - benzothiazole and 0.409 gm (1.3 mMol) 1- tert-butoxy-4- trifluoromethanesulfonyloxy- 1 ,2,3,6- tetrahydropyridine , 0.254 gm (64%) of the title compound were prepared as an off-white waxy solid substantially by the procedure described in EXAMPLE 1.
  • EA Calculated for C18H22N2O2S: Theory: C, 65.43; H,
  • EXAMPLE 14 1 - tert-butoxycarbonyl - 4 - (4-methoxybenzothiazol-2-yl) - 1,2,3,6- tetrahydropyridine Beginning with 0.231 gm (1.2 mMol) 2-chloro-4-methoxy- benzothiazole and 0.403 gm (1.2 mMol) 1 - tert -butoxy- 4 - trifluoromethanesulfonyloxy- 1,2, 3, 6 -tetrahydropyridine, 0.191 gm (48%) of the title compound were prepared as an off-white solid substantially by the procedure described in
  • EXAMPLE 15 l-tert-butoxycarbonyl-4- (5-nitrobenzothiazol-2-yl) -1,2,3,6- tetrahydropyridine hemihydrate Beginning with 0.130 gm (0.6 mMol) 2 -chloro- 5-nitro- benzothiazole and 0.211 gm (0.64 mMol) 1- tert-butoxy-4- trifluoromethanesulfonyloxy- 1,2,3,6- tetrahydropyridine , 0.031 gm (14%) of the title compound were prepared as a light yellow waxy solid substantially by the procedure described in EXAMPLE 1.
  • EA Calculated for C17H19N3O4S- 0.5 H 2 0: Theory: C, 55.12;
  • EXAMPLE 17 4 - ( 6 - chlorobenzothiazol - 2 -yl) piperidine 1 - tert-butoxycarbonyl - 4 - ( 6 - chlorobenzothiazol -2 - yl) iperidine
  • the reaction mixture was concentrated under reduced pressure and the residue dissolved in a minimal volume of ethyl acetate. This mixture was passed through a bed of silica gel, eluting with a 1:1 mixture of ethyl acetate and hexane . The filtrate was concentrated underreduced pressure to provide 0.663 gm (70%) of the desired compound as a light tan oil.
  • EXAMPLE 18 l-tert-butoxycarbonyl-2-methyl-4- (4, 5-dimethylbenzothiazol- 2-yl) -1,2,3, 6-tetrahydropyridine Beginning with 1.30 gm (6.58 mMol) 2-chloro-4, 5- dimethylbenzothiazole and 2.28 gm (6.58 mMol) 1-tert-butoxy- 4-trifluoromethanesulfonyloxy-l, 2, 3, ⁇ -tetrahydropyridine, 1.0 gm (43%) of the title compound were prepared as an oily semi-solid, substantially by the procedure described in EXAMPLE 1.
  • EXAMPLE 20 l-tert-butoxycarbonyl-2-methyl-4- (4, 6-difluorobenzothiazol- 2-yl) -1,2,3, 6-tetrahydropyridine Beginning with 1.50 gm (7.30 mMol) 2-chloro-4, 6- difluorobenzothiazole and 2.52 gm (7.30 mMol) 1-tert-butoxy- 4-trifluoromethanesulfonyloxy-1, 2, 3, 6-tetrahydropyridine, 1.49 gm (56%) of the title compound were prepared as an oily semi-solid, substantially by the procedure described in EXAMPLE 1.
  • Compounds available by the process of the present invention are useful intermediates for the preparation of pharmacologically active compounds.
  • Certain of the compounds available by the process of the present invention are inhibitors of serotonin reuptake.
  • the efficacy of compounds to inhibit the reuptake of serotonin has been determined by a paroxetine binding essay, the usefulness of which is set out by Wong, et al . , Neuropsychopharmacology . 8 . , 23-33 (1993) .
  • Synaptosomal preparations from rat cerebral cortex were made from the brains of 100-150 g Sprague-Dawley rats which were killed by decapitation.
  • the cerebral cortex was homogenized in 9 volumes of a medium containing 0.32 M sucrose and 20 ⁇ M glucose.
  • the preparations were resuspended after centrifugation by homogenizing in 50 volumes of cold reaction medium (50 ⁇ M sodium chloride, 50 ⁇ M potassium chloride, pH 7.4) and centrifuging at 50,000 g for 10 minutes. The process was repeated two times with a 10 -minute incubation at 37°C between the second and third washes. The resulting pellet was stored at -70°C until use.
  • Binding of 3 H-paroxetine to 5-HT uptake sites was carried out in 2 ml reaction medium containing the appropriate drug concentration, 0.1 nM 3 H- paroxetine, and the cerebral cortical membrane (50 ⁇ g protein/tube) . Samples were incubated at 37°C for 30 minutes; those containing 1 ⁇ M fluoxetine were used to determine nonspecific binding of 3 H-paroxetine . After incubation, the tubes were filtered through Whatman GF/B filters, which were soaked in 0.05% polyethylenimine for 1 hour before use, using a cell harvester by adding about 4 ml cold Tris buffer (pH 7.4), aspirating, and rinsing the tubes three additional times. Filters were then placed in scintillation vials containing 10 ml scintillation fluid, and the radioactivity was measured by liquid scintillation spectrophotometry.
  • Certain compounds available by the method of the present invention have been tested in this assay and have been found to be inhibitors of serotonin reuptake.
  • the compound of Example 12 was found to have a K- of 20.9 nMol .
  • fluoxetine is in clinical trials for the treatment of depression and is likely to become a marketed drug for the purpose .
  • Depression is often associated with other diseases and conditions, or caused by such other conditions. For example, it is associated with Parkinson's disease; with HIV; with Alzheimer's disease; and with abuse of anabolic steroids. Depression may also be associated with abuse of any substance, or may be associated with behavioral problems resulting from or occurring in combination with head injuries, mental retardation or stroke. Depression in all its variations is a preferred target of treatment with the present adjunctive therapy method and compositions.
  • Obsessive- compulsive disease appears in a great variety of degrees and symptoms, generally linked by the victim's uncontrollable urge to perform needless, ritualistic acts. Acts of acquiring, ordering, cleansing and the like, beyond any rational need or rationale, are the outward characteristic of the disease. A badly afflicted subject may be unable to do anything but carry out the rituals required by the disease. Fluoxetine is approved in the United States and other countries for the treatment of obsessive- compulsive disease and has been found to be effective.
  • Obesity is a frequent condition in the American population. It has been found that fluoxetine will enable an obese subject to lose weight, with the resulting benefit to the circulation and heart condition, as well as general well being and energy.
  • ICD International Classification of Diseases
  • DSM Diagnostic and Statistical Manual of Mental Disorders, 3rd Version Revised, published by the American Psychiatric Association (DSM) .
  • ICD or DSM code numbers are supplied below for the convenience of the reader. depression, ICD 296.2 & 296.3, DSM 296, 294.80, 293.81,
  • DSM 307.90 alcoholism ICD 305.0, DSM 305.00 & 303.90 tobacco abuse, ICD 305.1, DSM 305.10 & 292.00 panic disorder, ICD 300.01, DSM 300.01 & 300.21 anxiety, ICD 300.02, DSM 300.00 post- traumatic syndrome, DSM 309.89 memory loss, DSM 294.00 dementia of aging, ICD 290 social phobia, ICD 300.23, DSM 300.23 attention deficit hyperactivity disorder, ICD 314.0 disruptive behavior disorders, ICD 312 impulse control disorders, ICD 312, DSM 312.39 & 312.34 borderline personality disorder, ICD 301.83, DSM 301.83 chronic fatigue syndrome premature ejaculation, DSM 302.75 erectile difficulty, DSM 302.72 anorexia nervosa, ICD 307.1, DSM 307.10 disorders of sleep, ICD 307.4 autism mutism trichotillomania

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des procédés de préparation de 4-hétéroaryl-1,2,3,6-tétrahydropyridines et de 4-hétéroarylpipéridines.
PCT/US1999/013521 1998-06-19 1999-06-16 Preparation de composes heteroaryle Ceased WO1999065896A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002334677A CA2334677A1 (fr) 1998-06-19 1999-06-16 Preparation de composes heteroaryle
AU46856/99A AU4685699A (en) 1998-06-19 1999-06-16 Preparation of heteroaryl compounds
EP99930289A EP1087962A4 (fr) 1998-06-19 1999-06-16 Preparation de composes heteroaryle
JP2000554721A JP2002518386A (ja) 1998-06-19 1999-06-16 ヘテロアリール化合物の製造

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US8984698P 1998-06-19 1998-06-19
US60/089,846 1998-06-19

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Cited By (16)

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JP2002518386A (ja) 2002-06-25
EP1087962A1 (fr) 2001-04-04
CA2334677A1 (fr) 1999-12-23
AU4685699A (en) 2000-01-05

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