EP1157017A1 - N-substituted imide derivatives with serotonergic activity - Google Patents

N-substituted imide derivatives with serotonergic activity

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Publication number
EP1157017A1
EP1157017A1 EP00915928A EP00915928A EP1157017A1 EP 1157017 A1 EP1157017 A1 EP 1157017A1 EP 00915928 A EP00915928 A EP 00915928A EP 00915928 A EP00915928 A EP 00915928A EP 1157017 A1 EP1157017 A1 EP 1157017A1
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EP
European Patent Office
Prior art keywords
carbon atoms
alkyl
halogen
alkoxy
optionally substituted
Prior art date
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Application number
EP00915928A
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German (de)
French (fr)
Inventor
Wayne E. Childers
Michael G. Kelly
Gan Zhang
Yvette L. Palmer
Edward J. Podlesny
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Wyeth
Original Assignee
American Home Products Corp
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Publication of EP1157017A1 publication Critical patent/EP1157017A1/en
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    • 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
    • C07D295/16—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
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A61P25/12—Antiepileptics; Anticonvulsants for grand-mal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • C07D209/08—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

Compounds of Formula (I) wherein R2, Y, X and n are as defined in the specification which compounds are useful in the treatment of disorders associated with serotonergic neuron-related diseases.

Description

N-Substituted Imide Derivatives With Serotonergic Activity
Background of the Invention a) Field of the Invention
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. b) Description of the Prior Art
It is known that 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-HT1A 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. Boyer, Psychopathology, 22, 21 (1989); P.R. Saxena, CM. Nillalon, ΗPS, 11, 95 (1990); Ν. Matsuki, et al., Jpn. J. Pharmacol. Suppl., 58, 313 (1992).
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-HTι^ 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. Rocco, Recent Progress in Serotonin (5-HT1A Receptor Modulators, in Annual Reports in Medicinal Chemistry, Volume 30, J. A. Bristol, ed., pp. 1-9 (1995)). A series of naphylpiperazines useful as 5-HT1A receptor ligands having the generic structure:
are described in EPO 434561-A2 and U.S. Patent Nos 5,143,916; 5,162,321; 5,162,324; 5,166,156 and 5,166,157.
Reported in 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-HT1D receptor antagonists of the generic formula:
as inhibitors of cell growth in human small cell lung carcinoma, where R, is a moiety of formulae:
Reported in GB 2303303-A is a method of using 5HT, A or 5HT2 receptor antagonists of the formulae:
for preventing or reducing the side effects of serotonin re-uptake inhibitors
Reported in DE 19520499-A1, WO 9608480A1, and U.S. Patent Nos 5,696,123 and 5,708,006 is a series of aralkyl amines, amides and ureas as neurokinin antagonists.
The 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. Summary of the Invention Accordingly, the present invention discloses compounds represented by Formula (I):
R /(CH2)n ^ χ
Y
(I)
wherein: n is an integer of 0 to 5;
X is a moiety selected from the group consisting of:
R -Nf N-ξ- ? R1~ N and R — < N~ξ- .
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, -Nθ2, 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 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, -Nθ2, and halogen; R2 is independently 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, -(CH2)z-O-alkyl of 1 to 6 carbon atoms , -(CH2)z-S-alkyl of 1 to 6 carbon atoms, -(CH2)zOH, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms , -CN, -NO2, and halogen; 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; 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 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; z is an integer of 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 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;
with the proviso that X is not the radical
when R5is H, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and hydroxyl; n is 0; Rj is H; Y is the radical
and R4 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.
Among the preferred compounds of Formula (I) of this invention are those in the subgroups, and pharmaceutically acceptable salts thereof:
a) compounds having the general formula:
wherein: Rj, R3, X and n are hereinbefore defined; b)compounds having the general formula:
wherein: Rj, R4, X and n are hereinbefore defined;
c)compounds having the general formula:
wherein:
Rj, R3, R4, X and n are hereinbefore defined; d)compounds of the general Formula (I) wherein:
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, benzothiadiazolyl, benzooxazolyl and 2,3-dihydro-benzo[l,4]dioxin; and
R2, R3, R4, X and n are hereinbefore defined;
e)compounds of the general Formula (I) wherein:
R2 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, -(CH2)z-O-alkyl of 1 to 6 carbon atoms, -(CH2)z-S-alkyl of 1 to 6 carbon atoms, -(CH2)zOH, 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, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, and 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, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzopyranyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, benzothiazolyl, benzothiadiazolyl, benzooxazolyl and 2,3-dihydro-benzo[l,4]dioxin; and R,, R3, R4, Y, X, z and n are hereinbefore defined;
Among the more preferred compounds of Formula (I) of this invention are those in the subgroups, and pharmaceutically acceptable salts thereof:
a) compounds having the general formula:
wherein:
R,, R^, R3, and n are hereinbefore defined;
b)compounds having the general formula:
wherein:
R,, R^, R4and n are hereinbefore defined; c)compounds having the general formula:
wherein:
Rj, Rj, R3, R4, and n are hereinbefore defined;
d) compounds having the general formula:
wherein:
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, -Nθ2, and halogen; indolyl and 2,3-dihydro-benzo[l,4]dioxin; and Rj and n are hereinbefore defined;
e)compounds having the general formula:
wherein:
Rj 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
R2 and n are hereinbefore defined;
f)compounds having the general formula:
wherein:
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
R2 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
Alzheimer's Disease and additionally prostate cancer:
Cyclohexanecarboxylic acid cyclohexanecarbonyl- { 2-[4-(2-methoxyphenyl)-piperazin-
1 -yl] -ethyl } -amide; Cyclohexanecarboxylic acid cyclohexanecarbonyl- { 2- [4- ( 1 H-indol-4-yl)-piperazin- l-yl]-ethyl}-amide;
Cyclohexanecarboxylic acid cyclohexanecarbonyl-{2-[4~(2,3-dihydro-benzo[l,4]- dioxin)-5-yl } -piperazin- 1 -yl] -ethyl } -amide;
(R)-Cyclohexanecarboxylic acid cyclohexanecarbonyl-! l-methyl-2-[4-(2- methoxyphenyl)-piperazin- 1 -yl]-ethyl } -amide;
(R)-Cyclohexanecarboxylic acid cyclohexanecarbonyl-! l-(4-benzyl)-2-[4-(2-methoxy- phenyl)-piperazin- 1 -yl] -ethyl } -amide;
(R)-Cyclohexanecarboxylic acid cyclohexanecarbonyl-! l-(4-methoxybenzyl)-2-[4-(2- methoxyphenyl)-piperazin- 1 -yl] -ethyl } -amide; (R)-Cyclohexanecarboxylic acid cyclohexanecarbonyl- { 1 - [4- (2-methoxyphenyl)- piperazin- 1 -ylmethyl]-2-( 1-methyl- lH-indol-3-yl)ethyl } -amide;
Cyclohexanecarboxylic acid { 2-[4-(2,3-dihydro-benzo[ 1 ,4]dioxin-5-yl)-piperazin-
1-yl-] ethyl}- amide;
Cyclohexanecarboxylic acid benzoyl-{2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)- piperazin- 1-ylethyl]- amide;
N-Benzoyl-N-{ -2-[4-(2-methoxyphenyl)-piperazin-l-yl]-ethyl}-benzamide and
(R)-N-Benzoyl-N- { 1 -methyl- 2- [4-(2-methoxyphenyl)-piperazin- 1 -yl] -ethyl } - benzamide.
In particular, 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.
For the compounds defined above and referred to herein, unless otherwise noted, the following terms are explained.
The term halogen may be selected from fluorine, chlorine, bromine and iodine, unless otherwise specified.
The term alkyl includes a branched or unbranched, saturated aliphatic hydrocarbon radical. Examples of 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.
The term 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.
The term alkynyl includes a branched or unbranched hydrocarbon radical containing at least one carbon-carbon triple bond.
The term 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.
The term 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.
The term 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. The term cycloalkyl includes a saturated monocyclic ring which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The term 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.
The term 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.
The term heteroaryl includes an optionally substituted monocychc heteroaromatic ring. Preferred include 2- or 3-furyl, 2- or 3-thienyl, or 2-,3- or 4-pyridyl.
The term 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.
When R3 and R4 are used multiple times in a moiety such as
each R3 or R4 may be the same or different.
It is understood by those practicing the art that the definition of compounds of Formula (I) when R,, R2, R3 and R4 contain asymmetric carbons, encompass all possible stereoisomers, mixtures and regioisomers thereof which possess the activity discussed below. Such regioisomers may be obtained pure by standard separation methods known to those skilled in the art. In particular, the definition encompasses any optical isomers and diastereomers as well as the racemic and resolved enantiomerically pure R and S stereoisomers as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof, which possess the activity discussed below. Optical isomers may be obtained in pure form by standard separation techniques or enantiomer specific synthesis. It is understood that this invention encompasses all crystalline forms of compounds of Formula (I). 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. In particular, 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
R2(CH2)n-CH(CH2X)-NH-COR3 (A) or
R2(CH2)n-CH(CH2X)-NH-COR4(B) or
R2-(CH2)n-CH(CH2X)-NH2 (C) or a salt thereof with a reactive derivative of a carboxylic acid having the formula HO-CO-R3 or HO-CO-R4 wherein R^R^R^n and X are as defined in claim 1; or
(b) N-alkylation of an imide having the formula
R3CO-NH-COR4 or a salt thereof with an alkylating agent for introducing a substituted alkyl group having the formula R2-(CH2)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 R2-(CH2)n-CH(CH2X)-NH2 (C) or an activated derivative thereof with a carboxylic acid having the formula HO-CO-R3 or HO-CO-R4 or an acylating derivative thereof wherein R2,R3,R4, n and X are as defined above; or
(b) N-alkylation of an amide having the formula R3CO-NH2 or R4CO-NH2 or a salt thereof with an alkylating agent for introducing a substituted alkyl group having the formula R2-(CH2)U-CH(CH2X)- wherein R^R^R^ n and X are as defined above; and, if desired, converting a resultant compound having formula (A or B) into a salt thereof.
The compounds of formula I may be prepared by methods known to be useful for the preparation of imides. In particular 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 R3CO2H or R4CO2H, for instance, the acyl chloride, preferably in the present of a base, for example, a tertiary amine, for instance, triethylamine. In the case of the amine having formula C, sufficient acylating agent is used to convert the amine into a imide. If desired, 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 RjCOjH or R4CO2H 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 R3CONH2 or R^ONFL,. As alkylating agent there may be used a compound having the formula R2-(CH2)n-CHZ-CH2X 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. The compounds of formula I may be prepared in a similar manner by using an appropriate imide as the substance to be N-alkylated.
DESCRIPTION OF THE INVENTION
Compounds of Formula I may be synthesized as described in Scheme I from amine intermediate 1 where n, R2 and X are hereinbefore defined by acylation with two equivalents of acid chloride 2 where R3 is hereinbefore defined to give imide 3, where n, RT,, R3 and X are hereinbefore defined, and which may be isolated as a pharmaceutically acceptable salt.
Amine intermediate 1 can be further acylated with acid chloride 4 where R4 is hereinbefore defined to give imide 5, where n, R2, R4 and X are hereinbefore defined, and which may be isolated as a pharmaceutically acceptable salt. Scheme I
As shown in Scheme II, 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 R3 is hereinbefore defined gives amide 6_ where n, Rj, R3 and X are hereinbefore defined and which is further acylated with acid chloride 4 to give imide 7, where n, R2, R3, R4 and X are hereinbefore defined and which may be isolated as a pharmaceutically acceptable salt.
Scheme TJ
Alternatively, as described in Scheme HI, imide 7 may be prepared by introducing the first acyl group using an appropriate carboxylic acid 8 where R3 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 give amide 6 where n, Rj, R3 and X are hereinbefore defined. Acylation of amide 6 with acid chloride 4 yields imide 9 where n, R^, R3, R4 and X are hereinbefore defined.
Scheme HI
1 ≤ 2
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.
Scheme JN χ_H BrCH2CΝ χ_^N reduction i
10 base ϋ R2 is H and n is O
Using the second general method, amine intermediate 1 where Rj 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. Removal of the t-butylcarbamate (BOC) protecting group under acid catalysis gives 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 Rj, X and n are hereinbefore defined.
Scheme V
R /(CH2 >)n ^A .0H NH2
12
13 14
15
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. According to a further aspect of the present invention there is provided 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-HT1A 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-HT1A receptor in place of 5-HT1D receptor; the use of [3H]-8-OH-DPAT (1.5mM) as radioligand in place of [3H]-LSD; nonspecific binding determined with 10 μM 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.
Table 1
Example 5-HT1A Affinity (IC50)
Example 6 3.10 nM
Example 7 4.55 nM
Example 8 4.77 nM
Example 9 2.69 nM
Example 10 61.01 nM
Example 11 0.38 nM
Example 12 0.78 nM
Example 14 5.13 nM
Example 15 23.45 nM
Example 16 79.60 nM
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
[35S]-GTPγS to the 5-HT A receptor-G protein complex in CHO cells stably transfected with the human 5-HT receptor following a variation of the procedure described by Lazareno and Birdsall (Br. J. Pharmacol., 109, 1120 (1993). The variation includes: the use of cells containing clonal human 5-HT1A receptor rather than muscarinic receptors; the pH of the medium was 8 rather than 7.4; the use of 10 μM 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 ICjo 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.
Based on the activity in the standard pharmacological test procedures, 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. Thus according to this aspect of this invention there is provided the use of compounds of the Formula (I) or the pharmaceutically acceptable salts thereof in the manufacturing of medicament for use in the production of agonists and antagonists useful as pharmaceutical compositions for preventing and treating 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 in a warm-blooded animal such as a human.
The compounds of this invention may be formulated neat or may be combined with one or more pharmaceutically acceptable carriers for administration. 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. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. 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.
The preferred pharmaceutical 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. In all cases, 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.
The following examples are presented to illustrate rather than limit the methods for the production of representative compounds of the invention. 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). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration on a rotary evaporator gave the desired compound as a light yellow oil which solidified on standing (5.1 g, 99% yield). The compound was isolated as its hydrochloride salt by treatment in ethyl acetate with ethereal HCl to yield a hght yellow solid, mp = 193- 194°C; MS (+)
ESI m/z = 260 (M+H)+.
Analysis for C14H17N3O2 • HCl ♦ 0.75 H2O
Calculated: C: 54.37; H: 6.36; N: 13.59 Found: C: 54.55; H: 6.36; N: 15.50.
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. The reaction was quenched by dropwise addition of saturated aqueous ammonium chloride just until foaming ceased. The resulting mixture was filtered through a pad of diatomaceous earth , which was washed throughly with ethyl acetate. The combined organic solution was washed with water (25 mL) and brine (25 mL) and dried over anhydrous sodium sulfate. Filtration and concentration gave the title compound as a white solid, mp = 68-69°C; MS (+) ESI m/z = 264 (M+H)+.
Analysis for C14H12N3O2 Calculated: C: 63.85; H: 8.04; N: 15.96 Found: C: 63.64; H: 8.13; N: 15.36.
Example 3 (R> { 1 -methyl-2-r4-(2-methoxyphenyl)-piperazin- 1 -yl] -2-oxo-ethyl ) -carbamic acid- tert-butyl ester
To a solution of D-N-(tert-butoxycarbonyl)-alanine (4.0 g, 21.1 mmol) and l-(2-methyxophenyl)-piperazine (4.47 g, 23.3 mmol) in dimethylformamide (40 mL) at 0°C was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.05 g, 21.1 mmol), 1 -hydroxy benzotriazole hydrate (3.71 g, 27.5 mmol) and 1-methyl morpholine (3.4 mL, 31.7 mmol). The resulting mixture was stirred overnight, during which time it came up to room temperature. The 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. Filtration and concentration on a rotary evaporator yielded the crude product which was purified by flash chromatography on silica gel (ethyl acetate/hexane) to afford the desired (R)- { 1 -methyl-2-[4-(2-methoxyphenyl)-piperazin- 1 -yl]-2-oxo-ethyl } -carbamic acid- tert-butyl ester (7.24 g, 95%) as a yellow oil.
Example 4
(R)-π-methyl-2-r4-(2-methox\φhenyl)-piperazin-l-yl1-2-amino-propan-2-l-one The (R)-{ l-methyl-2-[4-(2-methoxyphenyl)-piperazin-l-yl]-2-oxo-ethyl}- carbamic acid-tert-butyl ester (7.24 g, 19.9 mmol) was dissolved in a 1: 1 mixture of 4N aqueous HCl/dioxane (100 mL) and stirred overnight at room temperature. Concentration of the mixture on a rotary evaporator yielded the required (R)-{ 1-methyl- 2-[4-(2-methoxyphenyl)-piperazin-l-yl]-2-amino-propan-2-l-one (5.90 g, 99%) as a hydrochloride salt. Example 5 (R)- { 2-r4-(2-methoxyphenyl)-piperazin- 1 -yll - 1 -methyl-ethyl ) -amine The above mentioned (R)-{ l-methyl-2-[4-(2-methoxyphenyl)-piperazin-l-yl]-2- amino-propan-2-l-one hydrochloride (5.90 g, 19.7 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) at room temperature. Triethylamine (6.3 mL, 45 mmol) was added, followed by dropwise addition of a 1M solution of borane in tetrahydrofuran (77.5 mL, 45 mmol). 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. Filtration and concentration on a rotary evaporator yielded 4.62 g (94%) of the desired of 2-[4-(2-methoxyphenyl)-piperazin-l- yl]-ethylamine as a colorless oil which was used without further purification.
Example 6 Cyclohexanecarboxylic acid cvclohexanecarbonyl-(2-F4-(2-methoxyphenylVpiperazin- l-yil-ethyll-amide dihydrochloride
To a solution of 2-[4-(2-methoxyphenyl)-piperazin-l-yl]-ethylamine (0.40 g, 1.7 mmol) and triethylamine (0.95. mL, 6.8 mmol) in dichloromethane (20 mL) at 0°C was added cyclohexanecarboxylic acid chloride (0.56 g, 3.8 mmol). The 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 (dichloromethane/methanol) and then converted to its dihydrochloride salt with ethanolic HCl to yield 0.77 g (86%) of the title compound as a white solid; mp = 159-160°C; MS (+) ESI m/z = 456 (M+H)+.
Analysis for C27H41N3θ2 • 2HC1 Calculated: C: 61.35; H: 8.20; N: 7.95 Found: C: 61.16; H: 8.29; N: 8.04. Example 7 Cyclohexanecarboxylic acid cyclohexanecarbonyl-! 2-!4-(lH-indol-4-yl)-piperazin-
1-yll-ethyll-amide dihydrochloride To a solution of 2-[4-(lH-indol-4-yl)-piperazin-l-yl]-ethylamine (0.16 g, 0.66 mmol) and triemylamine (0.137 mL, 2.64 mmol) in dichloromethane (10 mL) at 0°C was added cyclohexanecarboxylic acid (0.22 g, 1.49 mmol). The 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 (dichloromethane/methanol) and then converted to its dihydrochloride salt with ethanolic HCl to yield 0.22 g (81%) of the title compound as an off-white solid; mp = 144-146°C; MS (+) ESI m/z = 465 (M+H)+
Analysis for C28H40N4O2 • 2HC1 Calculated: C: 62.56; H: 7.88; N: 10.42 Found: C: 62.32; H: 8.01; N: 10.27.
Example 8
Cvclohexanecarboxylic acid cyclohexanecarbonyl- 12-!4— (2.3-dihvdro-benzo! 1.41- dioxin)-5-yl 1 -piperazin- 1 -yll-ethyl i-amide sesquihvdrochloride monohydrate To a solution of 2-[4-(2,3-dihydro-benzo[l,4]-dioxin)-5-yl}-piperazin-l-yl]- ethylamine (0.20 g, 0.76 mmol) and triethylamine (0.31 mL, 2.28 mmol) in dichloromethane (10 mL) at 0°C was added cyclohexanecarboxylic acid chloride (0..33 g, 2.28 mmol). The 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. g (67%) of the title compound as a white solid; mp = 148 - 149°C; MS (+) ESI m/z = 484 (M+H)+.
Analysis for C28H41N3O4 • 1.5 HCl • H2O Calculated: C: 60.45; H: 8.06; N: 7.55 Found: C: 60.45; H: 7.92; N: 7.56. Example 9 (R)-Cyclohexanecarboxylic acid cyclohexanecarbonyl- 1 l-methyl-2-!4-("2- methoxyphenyD-piperazin- 1 -yl]-ethyl I -amide fumarate To a solution of (R)-l-methyl-2-[4-(2-methoxyphenyl)-piperazin-l-yl]-ethylarnine (0.48 g, 1.9 mmol) and triethylamine (2.0 mL, 14.4 mmol) in dichloromethane (20 mL) at 0°C was added cyclohexanecarboxylic acid chloride (1.04 g, 7.2 mmol). The 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 monofumarate salt in ethanol to yield 0.87 g (78%) of the title compound as an off-white solid; mp = 127-130 °C; MS (+) ESI m/z = 470 (M+H)+.
Analysis for 02 ^3^03 • C4H4O4 Calculated: C: 65.62; H: 8.09; N: 7.17 Found: C: 65.54; H: 8.12; N: 7.07.
Example 10
(RV Cyclohexanecarboxylic acid cvclohexanecarbonyl-! l-benzyl)-2-!4-(2-methoxy- phenvD-piperazin- 1 -yll-ethyl 1 -amide fumarate To a solution of (R)-l-(4-benzyl)-2-[4-(2-methoxyphenyl)-piperazin-l-yl]-ethyl- amine (0.49 g, 1.5 mmol) and triethylamine (0.84 mL, 6.0 mmol) in dichloromethane (10 mL) at 0°C was added of cyclohexanecarboxylic acid chloride (0.66 g, 4.5 mmol). The 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 fumarate salt in ethyl acetate to yield 0.79 g (80%) of the title compound as an off- white solid; mp = 146-147°C; MS (+) ESI m/z = 546 (M+H)+.
Analysis for C34H47N3O3 • C4H4O4
Calculated: C: 68.96; H: 7.77; N: 6.35 Found: C: 68.62; H: 7.80; N: 6.29. Example 11 (R)-Cyclohexanecarboxylic acid cyclohexanecarbonyl-! l-(4-methoxybenzyl)-2-r4-(2- methoxyphenyD-piperazin- 1 -yll-ethyl I -amide hydrochloride To a solution of (R)-l-(4-methoxybenzyl)-2-[4-(2-methoxyyphenyl)-piperazin- l-yl]-ethylamine (0.21 g, 0.59 mmol) and triethylamine (0.33 mL, 2.36 mmol) in dichloromethane (10 mL) at 0°C was added cyclohexanecarboxylic acid chloride (0.19 g, 1.33 mmol). The 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 (dichloromethane/methanol) and then converted to its dihydrochloride salt with ethanolic HCl to yield 0.30 g (84%) of the title compound as an off-white solid; mp=106-108°C; MS (+) ESI m/z = 576 (M+H)+.
Analysis for C35H49N3O4 ♦ HCl Calculated: C: 68.66; H: 8.23; N: 6.86 Found: C: 68.57; H: 7.87; N: 6.95.
Example 12
(R)-Cvclohexanecarboxylic acid cvclohexanecarbonyl-! l-r4-(2-methoxyphenyl)- piperazin- 1 - ylmethyl] -2-( 1 -methyl- lH-indol-3-yl)ethyl I -amide hydrochloride monohydrate To a solution of (R)-l-[4-(2-methoxyphenyl)-piperazin-l-ylmethyl]-2-(l- methyl-lH-indol-3-yl)ethylamine (0.21 g, 0.56 mmol) and triethylamine (0.31 mL,
2.24 mmol) in dichloromethane (10 mL) at 0°C was added cyclohexanecarboxylic acid chloride (0.18 g, 1.26 mmol). The 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. 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 (dichloromethane/methanol) and converted to its hydrochloride • monohydrate salt with ethanolic HCl yield 0.28 g (77%) of the title compound as a white solid; mp = 136-138°C; MS (+) ESI m/z = 599 (M+H)+. Analysis for C37H50N4θ3 • HCl • H2O Calculated: C: 68.02; H: 8.17; N: 8.57 Found: C: 67.29; H: 7.77; N: 8.31.
Example 13
Cyclohexanecarboxylic acid ! 2-!4-(2.3-dihydro-benzo! 1.41dioxin-5-yl)-piperazin- l-yl-1ethyll- amide A solution of 2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin- l-yl-]ethylamine (0.20 g, 0.76 mmol) in dichloromethane (5 mL) was treated with cyclohexanecarbonyl chloride (0.11 g, 0.76 mmol) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred overnight, during which time it came up to room temperature. The product was precipitated by the addition of hexane to yield the hydrochloride semihydrate salt of the titled compound (0.25 g, 80%) as a white solid; mp = 165-166°C; MS (+) ESI m/z = 374 (M+H)+.
Analysis for C2iH31N3O3 • HCl • 0.5 H2O
Calculated: C: 60.20; H: 7.94; N: 10.03 Found: C: 60.19; H: 7.88; N: 9.83.
Example 14 Cyclohexanecarboxylic acid benzoyl- 12-!4-(2.3-dihydro-benzo! 1 ,41dioxin-5-yl)- piperazin-l-ylethyll- amide hydrochloride sesquihydrate To a solution of cyclohexanecarboxylic acid {2-[4-(2,3-dihydro- benzo[ 1 ,4]dioxin-5-yl)-piperazin- 1 -yl-]ethyl }-amide hydrochloride semihydrate (0.14 g, 0.34 mmol) and triethylamine (0.14 mL, 1.02 mmol) in dichloromethane (5 mL) at 0°C was added benzoyl chloride (0.096 g, 0.68 mmol). The 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. 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 converted to its hydrochloride ♦ sesquihydrate salt with ethereal HCl to yield 0.08 g (45%) of the title compound as a white solid; mp = 169-171°C; MS (+) ESI m/z = 478 (M+H)+.
Analysis for C28H35N3O4 • HCl • 1.25 H2O Calculated: C: 62.68; H: 7.23; N: 7.83 Found: C: 62.27; H: 6.82; N: 7.54. Example 15 N-Benzoyl-N- 1 -2-!4-(2-methoxyphenyl)-piperazin- 1 -yll-ethyl I -benzamide hydrochloride hemihydrate To a solution of 2-[4-(2-methoxyphenyl)-piperazin-l-yl]-ethylamine (0.50 g, 2.12 mmol) and triethylamine (1.2 mL, 8.48 mmol) in dichloromethane (20 mL) at 0°C was added benzoyl chloride (0.75 g, 6.36 mmol). The 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 hydrochloride hemihydrate salt with ethereal HCl to yield 0.38 g (37%) of the title compound as a white solid mp = 208-209 °C; MS (+) ESI m/z = 444 (M+H)+
Analysis for C27H29N3O3 • HCl • 0.25 H2O Calculated: C: 66.93; H: 6.35; N: 8.67 Found: C: 66.59; H: 6.45; N: 8.61.
Example 16
(R)-N-Benzoyl-N- ! 1 -methyl-2- !4- (2-methoxyphenyl)-piperazin- 1 - yll -ethyl ) - benzamide semifumarate-hemihvdrate To a solution of (R)-l-methyl-2-[4-(2-methoxyphenyl)-piperazin-l-yl]-ethyl- arnine (0.57 g, 2.3 mmol) and triethylamine (1.3 mL, 9.1 mmol) in dichloromethane (20 mL) at 0°C was added benzoyl chloride (0.45 mL, 3.9 mmol). The 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. 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 semifumarate salt in ethanol to yield 0.29 g (24%) of the title compound as a tan solid; mp = 115-120 °C; MS (+) ESI m/z = 458 (M+H)+.
Analysis for C28H31N3O3 • 0.5 C4H4O4 • 0.70 H2O Calculated: C: 68.21; H: 6.57; N: 7.95 Found: C: 68.29; H: 6.29; N: 7.62.

Claims

What is claimed is:
1. A compound having the Formula (I)
(I) wherein: 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, -NO2, 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 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; R2 is independently 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, -(CH2)z-O-alkyl of 1 to 6 carbon atoms , -(CH2)z-S-alkyl of 1 to 6 carbon atoms, -(CH2)zOH, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms , -CN, -NO2, and halogen; 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; 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 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; z is an integer of 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; 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 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; with the proviso that X is not the radical
when R5 is H, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and hydroxyl; n is 0; R2 is H; Y is the radical
and R4 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.
2. A compound according to claim 1 wherein Y is the moiety
or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 wherein Y is the moiety vΛ/VΛ
R4 R4
or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1 wherein Y is the moiety or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1 wherein
Rj 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; 2 or 3-furyl, 2 or 3-thienyl, 2- ,3- or 4-pyridyl; indolyl, azaindolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzopyranyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, benzothiazolyl, benzothiadiazolyl, benzooxazolyl and 2,3-dihydro-benzo[l,4]dioxin; or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 1 wherein: R2 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, -(CH2)z-O-alkyl of 1 to 6 carbon atoms, -(CH2)z-S-alkyl of 1 to 6 carbon atoms, -(CH2)zOH, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, -CN, -Nθ2, 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, alkoxy of 1 to 10 carbon atoms, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms, -CN, -Nθ2, and halogen; 2 or 3-furyl, 2 or 3-thienyl, 2-,3- or 4-pyridyl; indolyl, azaindolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzopyranyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl, benzothiazolyl, benzothiadiazolyl, benzooxazolyl and 2,3-dihydro-benzo[l,4]dioxin; or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1 wherein X is the moiety
Y is the moiety
or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1 wherein X is the moiety
Y is the moiety
or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 1 wherein X is the moiety
Y is the moiety
or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 1 wherein X is the moiety
Y is the moiety
Rj is phenyl optionally substituted wit 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; or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 1 wherein X is the moiety
Y is the moiety
Rj 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, -Nθ2, 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; or a pharmaceutically acceptable salt thereof.
12. A compound according to claim 1 wherein X is the moiety
Rj 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;
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, -Nθ2, and halogen;
Y is the moiety
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 which is selected from the group consisting of cyclohexanecarboxylic acid cyclohexanecarbonyl-! 2- [4- (2-methoxyphenyi)-piperazin- l-yl]-ethyl} -amide cyclohexanecarboxylic acid cyclohexanecarbonyl-{2-[4-(lH-indol- 4-yl)-piperazin-l-yl]-ethyl}-amide , cyclohexanecarboxylic acid cyclohexanecarbonyl- { 2-[4~(2,3-dihydrobenzo[ 1 ,4]-dioxin)-5-yl } -piperazin- 1 -yl]-ethyl } -amide, (R)-cyclo- hexanecarboxylic acid cyclohexanecarbonyl- { 1 -methyl- 2-[4-(2-methoxyphenyl)- piperazin- 1 -yl]-ethyl } -amide ,(R)-cyclohexanecarboxylic acid cyclohexanecarbonyl- { l-(4-benzyl)-2-[4-(2-methoxyphenyl)-piperazin- 1 -yl] -ethyl } -amide, (R)-cyclohexanecarboxylic acid cyclohexanecarbonyl-! l-(4-methoxybenzyl)-2-[4-(2- methoxyphenyl)-piperazin-l-yl]-ethyl}-amide, (R)-cyclohexanecarboxylic acid cyclohexanecarbonyl-! l-[4-(2-methoxyphenyl)- piperazin- l-ylmethyl]-2-( 1 -methyl- lH-indol-3-yl)ethyl }-amide, cyclohexanecarboxyhc acid {2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl-ethyl}-amide, cyclohexanecarboxyhc acid benzoyl-{2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)- piperazin- 1-yl-ethyl]- amide, N-benzoyl-N- { -2-[4-(2-methoxyphenyl)-piperazin-l-yl]- ethyl } -benzamide, (R)-N-benzoyl-N- { 1 -methyl- 2- [4-(2-methoxyphenyl)-piperazin- 1 - yl]-ethyl} -benzamide; and the pharmaceutically acceptable salts thereof.
14. A pharmaceutical composition for treating disorders associated with serotonergic neuron-related diseases, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I)
(I)
wherein: n is an integer of 0 to 5;
X is a moiety selected from the group consisting of:
R -K JM- - i — ( /N" and RΓΛ /H
Y is a moiety selected from the group consisting of:
RMs 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; 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 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, -Nθ2, and halogen;
R2 is independently 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, -(CH2)z-O-alkyl of 1 to 6 carbon atoms , -(CH2)z-S-alkyl of 1 to 6 carbon atoms, -(CH2)zOH, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms , -CN, -NO2, and halogen; 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; 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 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; z is an integer of 1 to 3;
R3 is independently cycloalkyl or cycloalkenyl of 3 to 10 carbon atoms;
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, -NO2, 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 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;
with the proviso that X is not the radical
when R5is H, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and hydroxyl; n is 0; R2 is H; Y is the radical
and R4 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 together with one or more pharmaceutically acceptable carriers.
15. A method of treating serotonergic neuron-related diseases 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)
(I)
wherein: 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:
aanndd
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, -Nθ2, 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, -Nθ2, and halogen; bicyclic heteroaryl having 8 to 20 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; R2 is independently 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, -(CH2)z-O-alkyl of 1 to 6 carbon atoms , -(CH2)z-S-alkyl of 1 to 6 carbon atoms, -(CH2)zOH, perhaloalkyl of 1 to 10 carbon atoms, perhaloalkoxy of 1 to 10 carbon atoms , -CN, -NO2, and halogen; 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; heteroaryl is a 5- or 6-membered monocyclic heteroaromatic ring which contains 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 is a bicyclic saturated, unsaturated or aromatic ring system having 8 to 20 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; z is an integer of 1 to 3;
R is independently cycloalkyl or cycloalkenyl of 3 to 10 carbon atoms;
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, -NO2, 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 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;
with the proviso that X is not the radical
when R5 is H, halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and hydroxyl; n is 0; R^ is H; Y is the radical
and R4 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.
16. The method of Claim 15 wherein the serotonergic neuron-related disease in warm-blooded animals is selected from the group consisting of anxiety, depression, eating disorders, high blood pressure, emesis, schizophrenia, the cognitive deficits resulting from neurodegenerative diseases of Alzheimer's Disease and prostate cancer.
17. The method of Claim 16 wherein the serotonergic neuron-related disease in warm-blooded animals is depression.
18. The method of Claim 16 wherein the serotonergic neuron-related disease in warm-blooded animals is anxiety.
19. The method of Claim 16 wherein the serotonergic neuron-related disease in warm-blooded animals is the neurodegenerative diseases of Alzheimer's Disease.
20. Use of a compound as claimed in claim 1 to prepare a medicament for the treatment of a disorder associated with a serotonergic disease.
21. A process of preparation of a compound claimed in claim 1, which process comprises
(a) reaction of a compound having the formula R2-(CH2)n-CH(CH2X)-NH-COR3 (A) or R2-(CH2)n-CH(CH2X)-NH-COR4 (B) or R2-(CH2)n-CH(CH2X)-NH2 (C) or a salt thereof with a reactive derivative of a carboxylic acid having the formula HO-CO-R3 or HO-CO-R4 wherein R2, R3, R4, n and X are as defined in claim 1; or (b) N-alkylation of an imide having the formula R3CO-NH-COR4 or a salt thereof with an alkylating agent for introducing a substituted alkyl group having the formula R2-(CH2)n-CH(CH2X)- wherein R2, R3, R4, n and X are as defined above; and, if desired, converting a resultant compound having formula (I) as shown and defined in claim 1 into a pharmaceutically acceptable salt thereof.
22. A compound having the formula R2-(CH2)n-CH(CH2X)-NH-COR3 (A) or R2-(CH2)n-CH(CH2X)-NH-COR4 (B) wherein R2, R3, R4, n and X are as defined in claim 1 or a salt thereof.
23. A process for the preparation of a compound claimed in claim 22, which process comprises (a) reaction of a compound having the formula R2-(CH2 n-CH(CH2X)-NH2 (C) or an activated derivative thereof with a carboxyhc acid having the formula HO-CO-R3 or HO-CO-R4 or an acylating derivative thereof wherein R2, R3, R4, n and X are as defined in claim 22; or (b) N-alkylation of an amide having the formula R3CO-NH2 or a salt thereof with an alkylating agent for introducing a substituted alkyl group having the formula R2-(CH2)n-CH(CH2X)- wherein R2, R3, R4, n and X are as defined above; and, if desired, converting a resultant compound having formula (A or B) as shown and defined in claim 22 into a salt thereof.
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