WO2000052002A1 - Derives imide n-substitues a activite serotonergique - Google Patents

Derives imide n-substitues a activite serotonergique Download PDF

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WO2000052002A1
WO2000052002A1 PCT/US2000/005182 US0005182W WO0052002A1 WO 2000052002 A1 WO2000052002 A1 WO 2000052002A1 US 0005182 W US0005182 W US 0005182W WO 0052002 A1 WO0052002 A1 WO 0052002A1
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carbon atoms
alkyl
halogen
alkoxy
optionally substituted
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Wayne E. Childers
Michael G. Kelly
Gan Zhang
Yvette L. Palmer
Edward J. Podlesny
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Wyeth LLC
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American Home Products Corp
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Priority to CA002361182A priority Critical patent/CA2361182A1/fr
Priority to HK02103923.4A priority patent/HK1042090A1/zh
Priority to EP00915928A priority patent/EP1157017A1/fr
Priority to JP2000602229A priority patent/JP2002538154A/ja
Priority to AU37115/00A priority patent/AU3711500A/en
Publication of WO2000052002A1 publication Critical patent/WO2000052002A1/fr
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a series of novel N- substituted imide derivatives and non-toxic salts thereof, which have a high affinity for the serotonin 5-HT, A receptor, acting as partial agonists and antagonists and are useful for preventing and treating serotonergic neuron-related diseases.
  • serotonin [5-hydroxytryptamine (5-HT)] as a neurotransmitter has correlations with various physiological phenomena, such as appetite, memory, thermoregulation, sleep, sexual behavior, anxiety, depression and stress [Glennon, R.A., J. Med. Chem., 30, 1 (1987)]. It is also known that compounds acting on a 5-HT 1A receptor which is one of the serotonin-susceptive receptors are useful for preventing and treating anxiety, depression, eating disorders, high blood pressure and emesis. Results of studies on various compounds have been reported [see "Nippon Rinsho (Japanese Journal of Clinical Medicine)" vol. 47, special edition, pp. 1241-1248 (1989); J.P. Feighnev, W.F.
  • 5-HTJ receptor Compounds having selective partial agonist activity at the 5-HTJ receptor have established a presence in the marketplace as effective anxiolytic agents (buspirone HC1, 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione monohydrochloride , U.S. Patent No. 3,717,634).
  • 5-HT ⁇ agonists and antagonists are being evaluated in the laboratory and in the clinic for use in the treatment of several diseases such as anxiety, depression, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases like Alzheimer's Disease, and additionally prostate cancer ( K. Rasmussen and V. P.
  • WO 9640136- A 1 is a series of N-(piperidinyl or piperazinyl alkyl)phenyl acetamide derivatives as alpha la adrenergic receptor antagonists having the generic formula:
  • EP 795328- A 1 discloses a new use for naphthalene serotonin 5-HT 1D receptor antagonists of the generic formula:
  • R is a moiety of formulae:
  • Reported in GB 2303303-A is a method of using 5HT, A or 5HT 2 receptor antagonists of the formulae:
  • N-substituted imide derivatives or pharmaceutically acceptable salts thereof of the present invention and described herein are useful in the treatment of disorders associated with serotonergic neuron-related diseases such as anxiety, depression, eating disorders, high blood pressure, emesis, schizophrenia, the cognitive deficits resulting from neurodegeneratrve diseases of Alzheimer's Disease and additionally prostate cancer.
  • serotonergic neuron-related diseases such as anxiety, depression, eating disorders, high blood pressure, emesis, schizophrenia, the cognitive deficits resulting from neurodegeneratrve diseases of Alzheimer's Disease and additionally prostate cancer.
  • n is an integer of 0 to 5;
  • X is a moiety selected from the group consisting of:
  • Y is a moiety selected from the group consisting of:
  • R! is aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, -CN, -N ⁇ 2, and halogen; heteroaryl having 5 or 6 ring atoms containing 1 to 3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -NO2, and halogen; bicyclic heteroaryl having 8 to 20 ring atoms containing 1 to 3
  • R3 is independently cycloalkyl or cycloalkenyl of 3 to 10 carbon atoms
  • R4 is aryl of 6 to 12 carbon atoms optionally substituted with one or more substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, -CN, -NO2, and halogen; having 5 or 6 ring atoms containing 1 to 3 heteroatoms which may be the same or different, selected from nitrogen, oxygen and sulfur, optionally substituted with 1 to 3 substituents which may be the same or different selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, -CN, -NO2, and halogen; bicyclic heteroaryl having 8 to 20 ring atoms containing 1 to 3 heteroatoms which may
  • R 4 is phenyl substituted with three substituents which are the same or different selected from H, halogen, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.
  • R j , R 4 , X and n are hereinbefore defined;
  • R is selected from phenyl optionally substituted with 1 or 2 substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, -CN, -NO2, and halogen; 2 or 3-furyl, 2 or 3-thienyl, 2-,3- or 4-pyridyl, indolyl, azaindolyl, benzi idazolyl, indazolyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzopyranyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, benzothiazolyl, benzothiadiazol
  • R 2 , R 3 , R 4 , X and n are hereinbefore defined;
  • R 2 is selected from H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydroxy, -(CH 2 ) z -O-alkyl of 1 to 6 carbon atoms, -(CH 2 ) z -S-alkyl of 1 to 6 carbon atoms, -(CH 2 ) z OH, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, -CN, -NO2, and halogen; phenyl optionally substituted with 1 or 2 substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy
  • R,, R ⁇ , R 3 , and n are hereinbefore defined;
  • R j , R j , R 3 , R 4 , and n are hereinbefore defined;
  • R is phenyl optionally substituted with one or two substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, -CN, -N ⁇ 2, and halogen; indolyl and 2,3-dihydro-benzo[l,4]dioxin; and R j and n are hereinbefore defined;
  • R j is phenyl optionally substituted with one or two substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, -CN, -NO2, and halogen; indolyl and 2,3-dihydro-benzo[l,4]dioxin;
  • R is phenyl, optionally substituted with one, two or three substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, -CN, -NO2, and halogen; and
  • R 2 and n are hereinbefore defined;
  • R is phenyl optionally substituted with one or two substituents selected alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, -CN, -NO2, and halogen; indolyl and 2,3-dihydro-benzo[l,4]dioxin;
  • R4 is phenyl, optionally substituted with one, two or three substituents selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, -CN, -NO2, and halogen; and
  • R 2 and n are hereinbefore defined.
  • Among the most particularly preferred compounds of this invention according to general Formula (I) are the following compounds or pharmaceutically acceptable salts thereof for the method of treating disorders associated with serotonergic neuron-related diseases such as anxiety, depression, eating disorders, high blood pressure, emesis, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases of
  • the present invention also provides a method of treatment of disorders associated with serotonergic neuron-related diseases such as anxiety, depression, eating disorders, high blood pressure, emesis, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases of Alzheimer's Disease and additionally prostate cancer by acting on a 5-HT, A receptor in warm-blooded animals in need thereof, which comprises administering to said warm-blooded animals, preferably mammals, most preferably humans, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • disorders associated with serotonergic neuron-related diseases such as anxiety, depression, eating disorders, high blood pressure, emesis, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases of Alzheimer's Disease and additionally prostate cancer by acting on a 5-HT, A receptor in warm-blooded animals in need thereof, which comprises administering to said warm-blooded animals, preferably mammals, most preferably humans, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • halogen may be selected from fluorine, chlorine, bromine and iodine, unless otherwise specified.
  • alkyl includes a branched or unbranched, saturated aliphatic hydrocarbon radical.
  • alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-heptyl, 2-methylhexyl, and the like unless otherwise specified.
  • alkenyl includes a branched or unbranched hydrocarbon radical containing at least one carbon-carbon double bond, each double bond being independently cis, trans or a nongeometric isomer.
  • alkynyl includes a branched or unbranched hydrocarbon radical containing at least one carbon-carbon triple bond.
  • alkoxy includes a branched or unbranched hydrocarbon radical attached through an oxygen bridge and including for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and the like.
  • perhaloalkyl includes a branched or unbranched hydrocarbon radical in which three of more hydrogens are replaced with halogen and encompass groups such as trifluoromethyl, perfluoroethyl and the like.
  • perhaloalkoxy includes a branched or unbranched hydrocarbon radical attached through an oxygen bridge in which three or more hydrogens are replaced with halogen and encompass groups such as trifluorornethoxy, perfluoroethoxy and the like.
  • cycloalkyl includes a saturated monocyclic ring which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • cycloalkenyl includes a unsaturated monocychc ring containing at least one carbon-carbon double bond, examples which include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like.
  • Phenyl as used herein refers to a 6-membered aromatic ring.
  • aryl when used alone includes a homocyclic aromatic radical, whether or not fused.
  • Preferred aryl groups include phenyl, alpha-naphthyl and beta-naphthyl and the like optionally substituted with one, two or three substituents.
  • heteroaryl includes an optionally substituted monocychc heteroaromatic ring.
  • Preferred include 2- or 3-furyl, 2- or 3-thienyl, or 2-,3- or 4-pyridyl.
  • bicyclic heteroaryl includes an optionally substituted bicyclic saturated, unsaturated or aromatic ring system.
  • Preferred are: indolyl, azaindolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzopyranyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, benzothiazolyl, benzothiadiazolyl, benzooxazolyl and 2,3-dihydro-benzo[l,4]dioxin.
  • each R 3 or R 4 may be the same or different.
  • the pharmaceutically acceptable salts of the basic compounds of this invention are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, fumaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic and similarly known acceptable acids.
  • the present invention accordingly provides a pharmaceutical composition which comprises a compound of Formula (I) of this invention in combination or association with a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
  • the invention also provides a process of preparation of a compound having formula 1 or a pharmaceutically acceptable salt thereof, which process comprises (a) reaction of a compound having the formula
  • R 3 CO-NH-COR 4 or a salt thereof with an alkylating agent for introducing a substituted alkyl group having the formula R 2 -(CH 2 ) n -CH(CH,X)- wherein R ⁇ R ⁇ R ⁇ n and X are as defined above: and, if desired, converting a resultant compound having formula (I) into a pharmaceutically acceptable salt thereof.
  • the compound having formula (A) or (B) or a salt thereof may be prepared by a process that comprises (a) reaction of a compound having the formula R 2 -(CH 2 ) n -CH(CH 2 X)-NH 2 (C) or an activated derivative thereof with a carboxylic acid having the formula HO-CO-R 3 or HO-CO-R 4 or an acylating derivative thereof wherein R 2 ,R 3 ,R 4 , n and X are as defined above; or
  • the compounds of formula I may be prepared by methods known to be useful for the preparation of imides.
  • an amide having the formula A or B or an amine having the formula C may be acylated with a reactive derivative of a carboxylic acid R 3 CO 2 H or R 4 CO 2 H, for instance, the acyl chloride, preferably in the present of a base, for example, a tertiary amine, for instance, triethylamine.
  • a base for example, a tertiary amine, for instance, triethylamine.
  • sufficient acylating agent is used to convert the amine into a imide.
  • the conversion of the amine into an imide may be carried out in a single process step or by means of two steps, a first step to prepare an amide and a second step to convert the amide into the imide.
  • the formation of the amide of formula A or B may also be carried out by reaction of the carboxylic acid R j CO j H or R 4 CO 2 H with the amine of formula in C in the presence of a condensing agent or with an activated derivative of the amine.
  • the amide of formula A or B may also be prepared by N- alkylation of an amide R 3 CONH 2 or R ⁇ ONFL,.
  • alkylating agent there may be used a compound having the formula R 2 -(CH 2 ) n -CHZ-CH 2 X where Z is a leaving group, for example , chloro, bromo or tosyloxy, preferably in the presence of a base, for instance, a tertiary amine, for instance, triethylamine.
  • Z is a leaving group, for example , chloro, bromo or tosyloxy, preferably in the presence of a base, for instance, a tertiary amine, for instance, triethylamine.
  • the compounds of formula I may be prepared in a similar manner by using an appropriate imide as the substance to be N-alkylated.
  • Amine intermediate 1 can be further acylated with acid chloride 4 where R 4 is hereinbefore defined to give imide 5, where n, R 2 , R 4 and X are hereinbefore defined, and which may be isolated as a pharmaceutically acceptable salt.
  • compounds of Formula I may be prepared from amine intermediate 1 where n, R ⁇ and X are hereinbefore defined by sequential acylation using acid chlorides 2 and 4.
  • Acylation of amine intermediate 1 with acid chloride 2 where R 3 is hereinbefore defined gives amide 6_ where n, R j , R 3 and X are hereinbefore defined and which is further acylated with acid chloride 4 to give imide 7, where n, R 2 , R 3 , R 4 and X are hereinbefore defined and which may be isolated as a pharmaceutically acceptable salt.
  • imide 7 may be prepared by introducing the first acyl group using an appropriate carboxylic acid 8 where R 3 is hereinbefore defined in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC) or alternatively using appropriate coupling reagents which include: 1) N,N'-dicyclohexylcarbodiimide plus 1-hydroxybenzotriazole 2)benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP-reagent) 3) N,N'bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride (BOP-Cl) 4) diphenylphosphinyl chloride (DPP-Cl) 5) diethoxyphosphoryl cyanide 6) 2-chloro-l-methylpyridinium iodide 7) phenyldichlorophosphate plus imidazole to
  • Amine intermediate 1 can be prepared using two general methods. Using the first general method, as shown in Scheme IV, unsubstituted compounds where R2 is H and n is 0 are synthesized from appropriate aryl piperazines, piperidines, or tetrahydropyridines JO, where X is hereinbefore defined by condensation with bromoacetonitrile in the presence of a base which include but are not limited to triethylamine, N,N-diisopropylethylamine or pyridine to give nitrile JJ, followed by reduction in the presence of palladium-on-carbon and hydrogen or by methods known to those versed in the art to give amine 1 where R ⁇ is H and n is 0.
  • a base include but are not limited to triethylamine, N,N-diisopropylethylamine or pyridine to give nitrile JJ, followed by reduction in the presence of palladium-on-carbon and hydrogen or by methods known to those versed in
  • amine intermediate 1 where R j and n are hereinbefore defined can be synthesized in three steps as shown in Scheme V.
  • An amino acid 12 where R ⁇ and n are hereinbefore defined may be converted to the protected t-butylcarbamate intermediate 13 which may be condensed with an appropriate aryl piperazine, piperidine, or tetrahydropyridine 10 in the presence of a coupling reagent (DCC) or alternatively with coupling reagents hereinbefore defined to give protected amine 14.
  • DCC coupling reagent
  • BOC t-butylcarbamate
  • amine . 15 which may be converted, using an appropriate reducing agent such as Uthium aluminum hydride or borane to the desired amine intermediate 1 where R j , X and n are hereinbefore defined.
  • Reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the various functionalities present on the molecule must be consistent with the chemical transformations proposed. This may necessitate judgement as to the order of synthetic steps, protecting groups, if required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions. Such restrictions to the substituents which are compatible with the reaction conditions will be apparent to one skilled in the art. Some of the compounds of the hereinbefore described schemes have centers of asymmetry. The compounds may, therefore, exist in at least two and often more stereoisomeric forms.
  • the present invention encompasses all stereoisomers of the compounds whether free from other stereoisomers or admixed with other stereoisomers in any proportion and thus includes, for instance, racemic mixture of enantiomers as well as the diastereomeric mixture of isomers.
  • the absolute configuration of any compound may be determined by conventional X-ray crystallography.
  • a series of compounds of Formula (I) or the pharmaceutically acceptable salts thereof as defined hereinbefore for use in a method of treatment of human or animal disease The compounds of this invention have high affinity for the 5-HT receptor and this activity was established using standard pharmacological test procedures with representative compounds of this invention as follows.
  • Affinity for the serotonin 5-HT receptor was established by assaying the test compound's ability to displace [3H] 8-OHDPAT (dipropylaminotetralin) from its binding site on the receptor complex in CHO cells stably transfected with the human 5-HT 1A receptor following a variation of a procedure of J. Zgombick et al., Naunyn- Schmiedeberg's Arch. Pharmacol., 354, 226-236 (1996), as described by J. Dunlop, Y. Zhang, D. L. Smith and L. E. Schechter, Journal of Pharmacological and Toxicological Methods 40, 47-55 (1998).
  • the variation includes: the use of cells containing clonal human 5-HT 1A receptor in place of 5-HT 1D receptor; the use of [3H]-8-OH-DPAT (1.5mM) as radioligand in place of [3H]-LSD; nonspecific binding determined with 10 ⁇ M 5-HT; and the test procedure was run at room temperature rather than 37° C.
  • the compounds of this invention displayed high affinity for the 5-HT receptor, as described in Table 1.
  • Some of the compounds of this invention displayed 5-HT partial agonist activity, as assessed by the test compound' s ability to stimulate the binding of
  • the variation includes: the use of cells containing clonal human 5-HT 1A receptor rather than muscarinic receptors; the pH of the medium was 8 rather than 7.4; the use of 10 ⁇ M GDP; and the test procedure was run at 37° C rather than 30°C.
  • the compounds of this invention which demonstrated agonist activity in this assay possessed IC jo values between 1 and 100 nM.
  • Some of the compounds of this invention demonstrated 5-HT antagonist activity, as measured by the test compound's ability to inhibit forskolin-stimulated cAMP turnover in CHO cells stably transfected with the human 5-HT receptor using a variation of a procedure of J. Zgombick et al, Naunyn-Schmiedeberg's Arch. Pharmacol., 354, 226-236 (1996), as described by J. Dunlop, Y. Zhang, D. L. Smith and L. E. Schechter, Journal of Pharmacological and Toxicological Methods 40, 47-55 (1998).
  • the compounds of this invention which demonstrated 5-HT antagonist activity in this assay possessed IC values between 1 and 100 nM.
  • the compounds of this invention modulate serotonergic activity and therefore are useful in the treatment of disorders associated with serotonergic neuron-related diseases such as anxiety, depression, eating disorders, high blood pressure, emesis, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases of Alzheimer's Disease and additionally prostate cancer.
  • the compounds of this invention may be formulated neat or may be combined with one or more pharmaceutically acceptable carriers for administration.
  • pharmaceutically acceptable carriers for example, solvents, diluents and the like; and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspension containing from about 0.05 to 5% suspending agent in an isotonic medium.
  • Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 1000 mg/kg of animal body weight, optionally given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 1 to 1000 mg, preferably from about 2 to 500 mg.
  • Dosage forms suitable for internal use comprise from about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of this invention may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes.
  • Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.
  • Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
  • compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred. In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol.
  • the compounds of this invention may also be administered parenterally or intraperitoneally.
  • Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Example 1 r4-(23-Dihydro-benzori.41dioxin-5-yl)-piperazin-l-yll-acetonitrile
  • a solution of bromoacetonitrile (2.38 g, 19.86 mmol), benzodioxin- 5-ylpiperazine (5.1 g, 19.86 mmol) and triethylamine (11.05 mL, 79.4 mmol) in dimethylformamide (50 mL) was stirred under a nitrogen atmosphere at 70°C for 3 days. Water (300 mL) was added and the product extracted into ethyl acetate (6 x 50 mL).
  • Example 2 2-F4-f 2.3-Dihvdro-benzor 1.41dioxinyl-5-ylVpiperazin- 1 -yll-ethylamine
  • a solution of [4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-acetonitrile (1.55 g, 5.97 mmol) in anhydrous tetrahydrofuran (10 mL) at 0°C under an atmosphere of nitrogen was treated dropwise with a 1M solution of lithium aluminum hydride in tetrahydrofuran (6.0 mL, 6.0 mmol). The resulting solution was stirred overnight during which time it came up to room temperature.
  • reaction mixture was then diluted with water (100 mL) and ethyl acetate (150 mL) and the layers separated. The aqueous layer was extracted with three additional 30 mL portions of ethyl acetate. The combined organic layers were washed with IN aqueous HCl (50 mL) and saturated aqueous NaHCO and then dried over anhydrous sodium sulfate.
  • the resulting mixture was refluxed for 18 hours. After cooling the reaction mixture to room temperature, ethyl acetate (60 mL) and 2N aqueous HCl were added and the resulting mixture was stirred at room temperature for one hour. The layers were separated and the aqueous layer was made basic by careful addition of 50% aqueous NaOH. The resulting basic mixture was extracted with three 50 mL portions of ethyl acetate. The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate.
  • reaction mixture was allowed to stir under nitrogen for eighteen hours, during which time the reaction came up to room temperature.
  • the reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with sat. aq. NaHCO3 and brine.
  • the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (ethyl acetate/hexane) and then converted to its 1.5 hydrochloride monohydrate salt in ethyl acetate to yield 0.28.
  • reaction mixture was allowed to stir under nitrogen for eighteen hours, during which time the reaction came up to room temperature.
  • the reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with sat. aq. NaHCO3 and brine.
  • reaction mixture was allowed to stir under nitrogen for eighteen hours, during which time the reaction came up to room temperature.
  • the reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with sat. aq. NaHCO3 and brine.
  • reaction mixture was allowed to stir under nitrogen for eighteen hours, during which time the reaction came up to room temperature.
  • the reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with sat. aq. NaHCO3 and brine.
  • reaction mixture was allowed to stir under nitrogen for 18 hours, during which time it came up to room temperature.
  • the reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine.
  • reaction mixture was allowed to stir under nitrogen for eighteen hours, during which time the reaction came up to room temperature.
  • the reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with sat. aq. NaHCO3 and brine.
  • reaction mixture was allowed to stir under nitrogen for eighteen hours, during which time it came to room temperature.
  • the reaction mixture was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with sat. aq. NaHCO3 and brine.

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Abstract

La présente invention concerne des composés représentés par la formule générale (I). Dans cette formule, R2, Y, X et n sont tels que définis par les spécifications. Ces composés conviennent au traitement de troubles survenant dans le cas d'affections en relation avec les neurones de la sérotonergie.
PCT/US2000/005182 1999-03-02 2000-03-01 Derives imide n-substitues a activite serotonergique Ceased WO2000052002A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA002361182A CA2361182A1 (fr) 1999-03-02 2000-03-01 Derives imide n-substitues a activite serotonergique
HK02103923.4A HK1042090A1 (zh) 1999-03-02 2000-03-01 N-取代的具有5-羟色胺能活性的酰亚胺衍生物
EP00915928A EP1157017A1 (fr) 1999-03-02 2000-03-01 Derives imide n-substitues a activite serotonergique
JP2000602229A JP2002538154A (ja) 1999-03-02 2000-03-01 セロトニン作動活性を有するｎ−置換イミド誘導体
AU37115/00A AU3711500A (en) 1999-03-02 2000-03-01 N-substituted imide derivatives with serotonergic activity

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US09/261,298 1999-03-02

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001034586A3 (fr) * 1999-11-12 2002-11-07 Wyeth Corp Adamantyle, noradamantyle aryl- et aralkylpiperazines ramifies a activite de type serotonine 5-ht1a
WO2002085871A3 (fr) * 2001-04-04 2003-02-20 Wyeth Corp Agents serotonergiques presentant des effets in vivo a action prolongee
US7067518B2 (en) 2002-09-05 2006-06-27 Wyeth Pyridinyl-methyl-ethyl cyclohexanecarboxamides as serotonergic agents
US7491821B2 (en) 2005-08-15 2009-02-17 Roche Palo Alto Llc Inhibitors of P2X3

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106795160B (zh) * 2015-07-23 2019-04-19 广东东阳光药业有限公司 取代的吲哚化合物及其使用方法和用途

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Publication number Priority date Publication date Assignee Title
EP0343961A2 (fr) * 1988-05-24 1989-11-29 American Home Products Corporation Aryl- et hétéroaryl pipérazinyl carboxamides avec activité sur le système nerveux central
EP0395312A2 (fr) * 1989-04-22 1990-10-31 JOHN WYETH & BROTHER LIMITED Dérivés de pipérazine
EP0434561A2 (fr) * 1989-12-20 1991-06-26 Adir Et Compagnie Dérivés de la napht-1-yl pipérazine, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
EP0496692A1 (fr) * 1991-01-24 1992-07-29 Fabrica Espanola De Productos Quimicos Y Farmaceuticos, S.A. (Faes) Dérivés de 2-méthoxyphénylpipérazine
US5250544A (en) * 1990-07-10 1993-10-05 Adir Et Compagnie New piperidine tetrahydropyridine and pyrrolidine compounds
US5486518A (en) * 1995-04-10 1996-01-23 American Home Products Corporation 4-indolylpiperazinyl derivatives

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0343961A2 (fr) * 1988-05-24 1989-11-29 American Home Products Corporation Aryl- et hétéroaryl pipérazinyl carboxamides avec activité sur le système nerveux central
EP0395312A2 (fr) * 1989-04-22 1990-10-31 JOHN WYETH & BROTHER LIMITED Dérivés de pipérazine
EP0434561A2 (fr) * 1989-12-20 1991-06-26 Adir Et Compagnie Dérivés de la napht-1-yl pipérazine, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
US5250544A (en) * 1990-07-10 1993-10-05 Adir Et Compagnie New piperidine tetrahydropyridine and pyrrolidine compounds
EP0496692A1 (fr) * 1991-01-24 1992-07-29 Fabrica Espanola De Productos Quimicos Y Farmaceuticos, S.A. (Faes) Dérivés de 2-méthoxyphénylpipérazine
US5486518A (en) * 1995-04-10 1996-01-23 American Home Products Corporation 4-indolylpiperazinyl derivatives

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001034586A3 (fr) * 1999-11-12 2002-11-07 Wyeth Corp Adamantyle, noradamantyle aryl- et aralkylpiperazines ramifies a activite de type serotonine 5-ht1a
WO2002085871A3 (fr) * 2001-04-04 2003-02-20 Wyeth Corp Agents serotonergiques presentant des effets in vivo a action prolongee
US6696450B2 (en) 2001-04-04 2004-02-24 Wyeth Serotonergic agents with long-acting in vivo effects
US6894053B2 (en) 2001-04-04 2005-05-17 Wyeth Serotonergic agents with long-acting in vivo effects
US7067518B2 (en) 2002-09-05 2006-06-27 Wyeth Pyridinyl-methyl-ethyl cyclohexanecarboxamides as serotonergic agents
US7491821B2 (en) 2005-08-15 2009-02-17 Roche Palo Alto Llc Inhibitors of P2X3

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CA2361182A1 (fr) 2000-09-08
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EP1157017A1 (fr) 2001-11-28
AU3711500A (en) 2000-09-21
CN1342152A (zh) 2002-03-27

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