WO2002008223A1 - Indole derivatives useful for the treatment of cns disorders - Google Patents

Indole derivatives useful for the treatment of cns disorders Download PDF

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Publication number
WO2002008223A1
WO2002008223A1 PCT/DK2001/000507 DK0100507W WO0208223A1 WO 2002008223 A1 WO2002008223 A1 WO 2002008223A1 DK 0100507 W DK0100507 W DK 0100507W WO 0208223 A1 WO0208223 A1 WO 0208223A1
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WO
WIPO (PCT)
Prior art keywords
indole
ethyl
piperidin
chloro
methylphenyl
Prior art date
Application number
PCT/DK2001/000507
Other languages
French (fr)
Inventor
Jakob Felding
Benny Bang-Andersen
Garrick Paul Smith
Kim Andersen
Original Assignee
H. Lundbeck A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to MXPA02012927A priority Critical patent/MXPA02012927A/en
Priority to JP2002514129A priority patent/JP2004504396A/en
Priority to UA2003010167A priority patent/UA73995C2/en
Priority to AU8173801A priority patent/AU8173801A/en
Priority to AT01960182T priority patent/ATE266024T1/en
Priority to EA200300179A priority patent/EA004749B1/en
Priority to SI200130124T priority patent/SI1305307T1/en
Priority to HU0302820A priority patent/HUP0302820A3/en
Priority to KR1020037000850A priority patent/KR100851793B1/en
Priority to AU2001281738A priority patent/AU2001281738B2/en
Priority to BR0112998-8A priority patent/BR0112998A/en
Priority to DE60103162T priority patent/DE60103162T2/en
Priority to DK01960182T priority patent/DK1305307T3/en
Priority to PL359157A priority patent/PL203538B1/en
Priority to SK203-2003A priority patent/SK286701B6/en
Priority to EP01960182A priority patent/EP1305307B1/en
Priority to NZ523436A priority patent/NZ523436A/en
Priority to IL15360501A priority patent/IL153605A0/en
Application filed by H. Lundbeck A/S filed Critical H. Lundbeck A/S
Priority to CA002416212A priority patent/CA2416212C/en
Publication of WO2002008223A1 publication Critical patent/WO2002008223A1/en
Priority to IS6663A priority patent/IS2172B/en
Priority to IL153605A priority patent/IL153605A/en
Priority to HR20030015A priority patent/HRP20030015A2/en
Priority to NO20030127A priority patent/NO323799B1/en
Priority to US10/347,574 priority patent/US6743809B2/en
Priority to BG107528A priority patent/BG107528A/en
Priority to HK04102653A priority patent/HK1059782A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel class of indole derivatives having affinity for the dopamine D 4 receptor.
  • the compounds have antagonistic effect at the dopamine D 4 receptor and are therefore useful in the treatment of certain psychiatric and neurologic disorders, in particular psychoses.
  • Some of the compounds also have affinity for the 5-HT A and/or the 5- HT 2 c receptor and some of the compounds are serotonin reuptake inhibitors.
  • AT 332401 discloses compounds of the general formula
  • R is hydrogen or alkyl
  • Ri and R are hydrogen or alkyl
  • p is 2 or 3
  • Xi is hydrogen, fluoro, chloro or bromo.
  • the compounds are said to be useful as neuroleptics.
  • the patent does not contain any experimental data.
  • WO 95/11680 relates to a broad class of compounds having antipsychotic activity.
  • One group of compounds claimed are compounds having the formula
  • Xi is O, S, NH or NR 2
  • Alk is alkylene
  • Wi is CH 2 , O, S or NH
  • R is hydrogen, alkyl, alkoxy, hydroxy, carboxyl, halogen, amino, alkylamino, dialkylamino, nitro, alkylthio, trifluoromethoxy, cyano, acylamino, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, etc.
  • the application does not explain any mechanism of action, but the compounds are said to have a reduced tendency to cause extrapyramidal side effects.
  • Dopamine D 4 receptors belong to the dopamine D subfamily of receptors which is considered to be responsible for the antipsychotic effect of neuroleptics.
  • the side effects of neuroleptic drugs which primarily exert their effect via antagonism of D 2 receptors are known to be due to D 2 receptor antagonism in the striatal regions of the brain.
  • dopamine D 4 receptors are primarily located in areas of the brain other than striatum, suggesting that selective antagonists of the dopamine D 4 receptor will be devoid of extrapyramidal side effects. This is illustrated by the antipsychotic clozapine, which exerts higher affinity for D 4 than D 2 receptors and is lacking extrapyramidal side effects (Van Tol et al. Nature 1991, 350, 610; Hadley Medicinal Research Reviews 1996, 16, 507-526, and SannerExj ⁇ Opin. Ther. Patents 1998, 8, 383-393).
  • D 4 ligands which were postulated to be selective D 4 receptor antagonists (L- 745,879 and U-101958), have been shown to posses antipsychotic potential (Mansbach et al. Psychopharmacology 1998, 135, 194-200).
  • these compounds are partial D 4 receptor agonists in various in vitro efficacy assays (Gazi et al. Br. J. Pharmacol. 1998, 124, 889-896 and Gazi et al. Br. J. Pharmacol. 1999, 128, 613- 620).
  • clozapine which is an effective antipsychotic, is a silent D 4 antagonists (Gazi et al. Br. J. Pharmacol. 1999, 128, 613-620).
  • D 4 ligands which are partial D receptor agonists or antagonists may have beneficial effects against psychoses.
  • Dopamine D antagonists may also be useful for the treatment of cognitive deficits (Jentsch et al. Psychopharmacology 1999, 142, 78-84). Furthermore, evidence for a genetic association between the "primarily inattentive" subtype of attention deficit hyperactivity disorder (ADHD) and a tandem duplication polymorphism in the gene encoding the dopamine D 4 receptor has been published (McCracken et al. Mol.
  • 5-HT reuptake inhibitors Compounds which are 5-HT reuptake inhibitors are well-known antidepressant drugs.
  • 5-HT 2 c ligands have been found to augment the effect of 5-HT reuptake inhibitors in microdialysis experiments and animal models, and compounds having 5-HT reuptake inhibiting effect combined with affinity for the 5-HT 2 c receptor may therefore be particularly useful for the treatment of depression and other disorders responsive to serotonin reuptake inhibitors (PCT application No. PCT/DKOO/00671).
  • dopamine D 4 receptor ligands are potential drugs for the treatment of schizophrenia and other psychoses, and compounds with combined effects at the 5-HT transporter may have the further benefit of improved effect on depressive and negative symptoms in schizophrenic patients.
  • Compounds with combined effect at the dopamine D 4 receptor and the 5-HT 2A receptor may have the benefit of improved effect on positive and negative symptoms of schizophrenia and the benefit of effect on depressive and anxiety symptoms.
  • the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia without inducing extrapyramidal side effects.
  • the object of the present invention is to provide compounds that are partial agonists or antagonists at the dopamine D 4 receptor and such compounds with combined effects at the dopamine D 4 receptor, the 5-HT 2 A receptor, the 5-HT 2 c and/or the 5-HT transporter.
  • R 1 is hydrogen or C 1-6 -alkyl, C 2-6 -alkenyl, C -6 -alkynyl, C 3-8 -cycloalkyl or C -8 - cycloalkyl-C 1-6 -alkyl, all of which may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, hydroxy, thiol, C 1-6 -alkoxy, C 1-6 -alkylthio trifluoromethyl, trifluoromethylsulfonyl and C 1-6 -alkylsulfonyl, or R 1 is aryl, aryl-C 1-6 -alkyl, heteroaryl, heteroaryl-C ⁇ - 6 -alkyl where the aryl and heteroaryl groups may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C ⁇ - 6 -alkyl, d- ⁇ -alkoxy,
  • W is a bond or W is an O, S, CO, CS, SO or SO 2 group;
  • n is 0-6, m is 0-6 and n+m is 0-6; provided that when W is O, or S, n > 2 and when W is CO, CS, SO or SO 2 , n > 1;
  • X is C, CH or N, and the dotted line emanating from X indicates a bond when X is C and no bond when X is N or CH;
  • R 2 is C 1-6 -alkyl
  • R 3 -R 7 are selected from hydrogen, halogen, cyano, nitro, amino, C 1-6 -alkyl, C 2-6 -alkenyl, C -6 -alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, C ⁇ _ 6 -alkoxy, C 1-6 -alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C 1-6 -alkylsulfonyl;
  • R 8 is hydrogen, Ci-e-alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 3 - 8 -cycloalkyl-C 1-6 - alkyl, aryl, aryl-C 1-6 -alkyl, acyl, thioacyl, C 1-6 -alkylsulf
  • the present invention relates to compounds wherein the indole is bound to X via position 3 of the indole.
  • the invention relates to such compounds wherein W is a bond.
  • the present invention relates to compounds wherein n + m is 2.
  • the present invention relates to such compounds wherem R is a methyl group.
  • the invention relates to compounds wherein the group -NH-CO-R 1 is attached to the phenyl group in a position para to the position of the R 2 group.
  • R 1 is C 1-6 -alkyl, C 3-8 - cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, phenyl, phenyl-C 1-6 -alkyl, furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, wherein the phenyl groups may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C ⁇ -6 -alkyl, C ⁇ _ 6 alkoxy, C ⁇ -6 - alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C 1-6 alkylsulfonyl, or R 1 is - NR'R" wherein one of R' and R" is selected from hydrogen and the other of R' and R" is selected from C 1-6 -alkyl, phenyl
  • the present invention relates to a compound selected from
  • the compounds of the invention are partial agonists or antagonist at the dopamine D 4 receptors. Many compounds have combined effect at dopamine D 4 receptors and the 5- ⁇ T A receptor, the 5- ⁇ T 2 c receptor and /or 5-HT reuptake inhibiting effect.
  • the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, aggression, side effects induced by conventional antipsychotic agents, migraine, cognitive disorders, ADHD and in the improvement of sleep.
  • anxiety disorders such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, aggression, side effects induced by conventional antipsychotic agents, migraine, cognitive disorders, ADHD and in the improvement of sleep.
  • the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia without inducing extrapyramidal side effects.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.
  • the present invention provides the use of a compound of formula I as defined above or an acid addition salt thereof for the manufacture of a pharmaceutical preparation for the treatment of the above mentioned disorders.
  • the compounds of general formula I may exist as optical isomers thereof and such optical isomers are also embraced by the invention.
  • C 1-6 -alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1 -butyl, 2-butyl, 2- methyl-2-propyl and 2-methyl- 1 -propyl.
  • C 2-6 -alkenyl and C 2-6 -alkynyl designate such groups having from two to six carbon atoms, including one double bond and one triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.
  • C 1-6 -alkoxy, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkylamino, C 1-6 - alkylcarbonyl, and the like designate such groups in which the alkyl group is C 1-6 alkyl as defined above.
  • C 3-8 -cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, etc.
  • Halogen means fluoro, chloro, bromo or iodo.
  • acyl refers to a formyl, C 1-6 -alkylcarbonyl, arylcarbonyl, aryl-C 1-6 -alkylcarbonyl, C 3-8 -cycloalkylcarbonyl or a C 3-8 -cycloalkyl-C 1-6 -alkyl-carbonyl group and the term thioacyl is the corresponding acyl group in which the carbonyl group is replaced with a thiocarbonyl group.
  • aryl refers to a carbocyclic aromatic group, such as phenyl, or naphthyl, in particular phenyl.
  • heteroaryl refers to 5 membered monocyclic rings such as lH-tetrazolyl, 3H- 1,2,3- oxathiazolyl, 3H-l,2,4-oxathiazolyl, 3H-l,2,5-oxathiazolyl, 1,3,2-oxathiazolyl, 1,3,4- oxathiazolyl, 1,4,2-oxathiazolyl, 3H-l,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,4,2-dioxazolyl, 3H-l,2,3-dithiazolyl, 3H-l,2,4-dithiazolyl, 1,3,2-dithiazolyl, 1,4,2-dithiazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxa iazolyl, 1,2,3-thiadiazoly
  • R 1 meaning a saturated or partially saturated 5- to 6-membered ring containing one or two hetero atoms selected from O, S or a group
  • N-R 9 includes groups wherein R 1 is a group - CR a R b and groups wherein R 1 is -NR a R wherein R and R together form a 5- to 6- membered saturated or partially saturated ring optionally containing an additional N-R group or an O or S atom, e.g groups such as piperidinyl, piperazinyl, N-(hydroxy-C 1-6 - alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyridyl, tetrahydropyranyl, tetrahydrofuranyl, etc.
  • the acid addition salts of the compounds of the invention are pharmaceutically acceptable salts formed with non-toxic acids.
  • organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p- aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8- halotheophyllines, for example 8-bromotheophylline.
  • inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
  • compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection.
  • suitable route for example orally in the form of tablets, capsules, powders, syrups, etc.
  • parenterally in the form of solutions for injection.
  • methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.
  • the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg.
  • the total daily dose is usually in the range of about 0.05 - 500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention.
  • the compounds of the invention may be prepared as follows:
  • R , 1 -R , X, W, n, m and the dotted line are as previously defined, and L is a leaving group such as e.g. halogen, mesylate or tosylate;
  • R .1 -R r.8 , W, n and m are as previously defined;
  • R ⁇ R 8 , XW, n, m and the dotted line are as previously defined by the use of a carboxylic acid and a coupling reagent, an activated ester, an acid chloride, an isocyaiiate, a carbamoyl chloride or a by a two-step procedure by treatment with phosgene followed by addition of an amine;
  • R ⁇ R 7 , X, W, n and m are as previously defined and R'OH is hydroxyethyl or hydroxymethyl polystyrene, Wang resin or analogous polyethylene glycol polystyrene resins; whereupon the compound of Formula I is isolated as the free base or a pharmaceutically acceptable acid addition salt thereof.
  • the alkylation according to method 1) is conveniently performed in an inert organic solvent such as a suitably boiling alcohol or ketone, preferably in the presence of an organic or inorganic base (potassium carbonate, diisopropylethylamine or triethylamine) at reflux temperature.
  • an organic or inorganic base potassium carbonate, diisopropylethylamine or triethylamine
  • the alkylation can be performed at a fixed temperature which is different from the boiling point, in one of the above-mentioned solvents or in dimethyl formamide (DMF), dimethylsulfoxide (DMSO) or N-methylpyrrolidin-2-one ( ⁇ MP), preferably in the presence of a base.
  • the alkylating derivatives of formula III are prepared by nitration of the alkyl-substituted phenylacetic acids followed by reduction of the nitro group, e.g. with tin(II) chloride and functionalization of the produced amino group.
  • the carboxylic acid is subsequently reduced to the corresponding alcohol, e.g. by treatment with borane followed by conversion of the alcohol to a leaving group, e.g. by treatment with methane sulfonyl chloride or thionyl bromide.
  • the reductive alkylation according to method 2) is performed by standard literature methods.
  • the reaction can be performed in two steps, e.g. coupling of amines of formula II with reagent of formula IV by standard methods via the carboxylic acid chloride, activated esters or by the use of carboxylic acids in combination with a coupling reagent such as e.g. dicyclohexyl carbodiimide, followed by reduction of the resulting amide with lithium aluminium hydride or alane.
  • the carboxylic acid of formula IV is prepared by nitration of the alkyl-substituted phenylacetic acid followed by reduction of the nitro group, e.g. with tin(II) chloride and finally functionalization of the resulting amino group.
  • the reaction can also be performed by a standard one-pot procedure, e.g. using a reductive animation of amines of formula II and aldehydes of formula IV.
  • the aldehydes of formula IV are prepared by reduction of the before mentioned functionalized (aminophenyl)acetic acid by treatment with a reducing agent such as e.g. borane.
  • a reducing agent such as e.g. borane.
  • the resulting alcohol is converted to the corresponding aldehyde by standard oxidation methods, e.g. pyridinium chlorochromate.
  • the reduction of the double bond according to method 3) is generally performed by catalytic hydrogenation at low pressure ( ⁇ 3 arm.) in a Parr apparatus, or by using reducing agents such as diborane or hydroboric derivatives as produced in situ from NaBH 4 in trifluoroacetic acid in inert solvents such as tetrahydrofuran (THF), dioxane or diethyl ether.
  • reducing agents such as diborane or hydroboric derivatives as produced in situ from NaBH 4 in trifluoroacetic acid in inert solvents such as tetrahydrofuran (THF), dioxane or diethyl ether.
  • the acylation according to method 4) is conveniently performed by standard methods via the carboxylic acid chloride, activated esters or by the use of carboxylic acids in combination with coupling reagents such as e.g. dicyclohexyl carbodiimide.
  • the acylating reagent is carbamoyl chlorides, isocyanates or a two-step procedure consisting of treatment with phosgene followed by addition of an amine.
  • the intermediate compounds of formula VI are prepared as described in methods 1) and 2).
  • the derivatives of structure VII are prepared by means of a solid phase synthesis sequence as outlined below.
  • the final product was cleaved from the resin according to method 5) using diluted sodium methoxide in a methanol/tetrahydrofuran mixture at ambient temperature.
  • the first building block, VIII prepared by tert-butoxycarbonyl protection of compounds of formula II, which is prepared by methods obvious to the chemist skilled in the art (see also EP-Al-465398), is generally attached to the resin (eg. polystyrene bound ethyl 4-nitrophenyl carbonate) using base e.g. NN-dimethylaminopyridine and N,N- diisopropylethylamine at elevated temperature (e.g.
  • the second diversifying building block is introduced by alkylation of compound X whereby compound XI is formed.
  • the alkylating reagent is prepared by nitration of alkylsubstituted phenylacetic acid by standard nitration procedures followed by reduction of the carboxylic acid, e.g. by treatment with borane in tetrahydrofurane and finally converting the produced alcohol to a leaving group, e.g. by treatment with methanesulfonyl chloride in dichloromethane and triethylamine.
  • the alkylation is performed at elevated temperature
  • the third diversifying building block is introduced by standard acylation procedures, e.g. addition of an acid chloride, isocyanate or carbamoyl chloride and base at low temperature in DMF, dichloromethane or acetonitrile.
  • Mass spectra were obtained by an alternating scan method to give molecular weight information.
  • the molecular ion, MH+ was obtained at low orifice voltage (5 -20V) and fragmentation at high orifice voltage ( 100-200 V).
  • Preparative LC-MS-separation was performed on the same instrument.
  • the LC conditions (C18 column 20 x 50 mm with a particle size of 5 ⁇ m) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (80:20:0.05) to water/acetonitrile/trifluoroacetic acid (5:95:0.03) in 7 min at 22.7 mL/min. Fraction collection was performed by split-flow MS detection.
  • NMR signals corresponding to acidic protons are generally omitted.
  • Content of water in crystalline compounds was determined by Karl Fischer titration. For column chromatography silica gel of type Kieselgel 60, 40-60 mesh ASTM was used. For ion-exchange chromatography (SCX, 1 g, Varian Mega Bond Elut®, Chrompack cat. no. 220776). Prior use of the SCX-columns was pre-conditioned with 10% solution of acetic acid in methanol (3 mL). Examples
  • the resin was filtered off and washed with dry dimethyl formamide (3 x 25 mL), dry acetonitrile (3 x 25 mL) and dry dichloromethane (3 x 25 mL).
  • the resin was transferred to a 250 mL glass cylinder with a fritte and a three way junction in the bottom.
  • the resin was then treated for 20 min with 80 mL of a 1 :1 mixture of dichloromethane and trifluoroacetic acid containing anisole (2%, w/w) and methionine (0.2
  • the reaction mixture was heated to 70 °C for 18 h. After cooling to room temperature, the resin was filtered off and washed with dry acetonitrile (3 x 25 mL) and dry dichloromethane (3 x 25 mL). The resin was transferred to a 250 mL round bottom flask and treated with tin(II) chloride dihydrate (60 mL of an 0.5 M solution in DMF). The reaction mixture was stirred for 18 h. at room temperature. The resin was filtered off and washed with dry dimethyl formamide (3 x 25 mL), dry acetonitrile (3 x 25 mL) and dry dichloromethane (3 x 25 mL). The resin was dried in vacuo (20 °C, 20 h) to yield the title resin (6.3 g).
  • Example 1 la 3-(l- ⁇ 2-[5-(Acetylamino)-2-methylphenyl]ethyl ⁇ piperidin-4-yl)-6-chloro-lH-indole, fumerate
  • a mixture of (2-methyl-5-nitrophenyl)acetic acid (47 g) and thionyl chloride (62 mL) in dichloromethane (400 mL) was boiled under reflux for 5 h and concentrated in vacuo.
  • the aqueous phase was extracted with an ethyl acetate/tetrahydrofuran mixture, and the combined organic phase was washed with brine, dried (MgSO 4 ), filtered and concentrated in vacuo.
  • the residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/ethanol/triethylamine 100:4:4) to give 3- ⁇ l-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl ⁇ -5-fluoro-lH-indole (1.0 g), which subsequently was dissolved in tetrahydrofuran (45 mL) and triethylamin (1.3 mL) at 5 °C followed by the addition of cyclobutancarbonyl chloride (0.3 g) in tetrahydrofuran (15 mL).
  • the compounds of the invention were tested in well-recognised and reliable tests. The tests were as follows:
  • the compounds have also been tested in a functional assay described by Gazi et al. in Br. J. Pharmacol. 1999, 128, 613-629. In this test, the compounds were shown to be partial agonists or antagonists at dopamine D receptors.
  • the compounds were tested with respect to affinity for the dopamine D 2 receptor by determining their ability to inhibit the binding of [ H] Spiperone to D receptors by the method of Hyttel et al. J. Neurochem. 1985, 44, 1615.
  • the compounds were tested with respect to their 5-HT reuptake inhibiting effect by measuring their ability to inhibit the uptake of [ H] Serotonin into whole rat brain synaptosomes in vitro.
  • the assay was performed as described by Hyttel Psychopharmacology 1978, 60, 13.
  • the compounds were tested with respect to their affinity for 5-HT A receptors by determining their ability to inhibit the binding of [ HJKetanserin (0.50 nM) to membranes from rat brain (cortex) in vitro. Method described in Sanchez et al. DrugDev. Res. 1991, 22, 239-250.
  • FLIPR fluorometric imaging plate reader
  • the compounds were found to have no substantial or only weak affinity for the dopamine D 2 receptor. Many of the compounds were also found to have affinity for 5-HT 2A receptors and serotonin reuptake inhibiting activity.
  • the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, side effects induced by conventional antipsychotic agents, migraine, and in the improvement of sleep.
  • the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia without inducing extrapyramidal side effects.
  • the pharmaceutical formulations of the invention may be prepared by conventional methods in the art.
  • Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine.
  • adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.
  • Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilising the solution and filling it in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
  • Typical examples of recipes for the formulation of the invention are as follows: 1) Tablets containing 5.0 mg of a compound of the invention calculated as the free base:

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Abstract

The present invention relates to dopamine and serotonin receptor ligands having the general formula (I) wherein the meanings of R1-R9, W, n and X are as given in the claims and the description. The compounds of the invention are useful in the treatment of certain psychiatric and neurological disorders, i.e. schizophrenia, other psychoses, anxiety disorders, depression, migraine, cognitive disorders, ADHD and sleep improvement.

Description

INDOLE DERIVATIVES USEFUL FOR THE TREATMENT OF CNS DISORDERS Field of the Invention
The present invention relates to a novel class of indole derivatives having affinity for the dopamine D4 receptor. The compounds have antagonistic effect at the dopamine D4 receptor and are therefore useful in the treatment of certain psychiatric and neurologic disorders, in particular psychoses. Some of the compounds also have affinity for the 5-HT A and/or the 5- HT2c receptor and some of the compounds are serotonin reuptake inhibitors.
Background of the Invention.
AT 332401 discloses compounds of the general formula
Figure imgf000002_0001
wherein R is hydrogen or alkyl, Ri and R are hydrogen or alkyl, p is 2 or 3 and Xi is hydrogen, fluoro, chloro or bromo. The compounds are said to be useful as neuroleptics. The patent does not contain any experimental data.
WO 95/11680 relates to a broad class of compounds having antipsychotic activity. One group of compounds claimed are compounds having the formula
Figure imgf000002_0002
wherein Xi is O, S, NH or NR2, Alk is alkylene, Wi is CH2, O, S or NH, and R is hydrogen, alkyl, alkoxy, hydroxy, carboxyl, halogen, amino, alkylamino, dialkylamino, nitro, alkylthio, trifluoromethoxy, cyano, acylamino, trifluoroacetyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, etc. The application does not explain any mechanism of action, but the compounds are said to have a reduced tendency to cause extrapyramidal side effects.
Dopamine D4 receptors belong to the dopamine D subfamily of receptors which is considered to be responsible for the antipsychotic effect of neuroleptics. The side effects of neuroleptic drugs which primarily exert their effect via antagonism of D2 receptors are known to be due to D2 receptor antagonism in the striatal regions of the brain. However, dopamine D4 receptors are primarily located in areas of the brain other than striatum, suggesting that selective antagonists of the dopamine D4 receptor will be devoid of extrapyramidal side effects. This is illustrated by the antipsychotic clozapine, which exerts higher affinity for D4 than D2 receptors and is lacking extrapyramidal side effects (Van Tol et al. Nature 1991, 350, 610; Hadley Medicinal Research Reviews 1996, 16, 507-526, and SannerExjλ Opin. Ther. Patents 1998, 8, 383-393).
A number of D4 ligands, which were postulated to be selective D4 receptor antagonists (L- 745,879 and U-101958), have been shown to posses antipsychotic potential (Mansbach et al. Psychopharmacology 1998, 135, 194-200). However, recently it has been reported that these compounds are partial D4 receptor agonists in various in vitro efficacy assays (Gazi et al. Br. J. Pharmacol. 1998, 124, 889-896 and Gazi et al. Br. J. Pharmacol. 1999, 128, 613- 620). Furthermore, it was shown that clozapine, which is an effective antipsychotic, is a silent D4 antagonists (Gazi et al. Br. J. Pharmacol. 1999, 128, 613-620).
Consequently, D4 ligands which are partial D receptor agonists or antagonists may have beneficial effects against psychoses.
Dopamine D antagonists may also be useful for the treatment of cognitive deficits (Jentsch et al. Psychopharmacology 1999, 142, 78-84). Furthermore, evidence for a genetic association between the "primarily inattentive" subtype of attention deficit hyperactivity disorder (ADHD) and a tandem duplication polymorphism in the gene encoding the dopamine D4 receptor has been published (McCracken et al. Mol.
Psychiatry 2000, 5, 531-536). This clearly indicates a link between the dopamine D4 receptor and ADHD, and ligands affecting this receptor may be useful for the treatment of this particular disorder.
Various effects are known with respect to compounds which are ligands at the different serotonin receptor subtypes. As regards the 5-HT A receptor, which was previously referred to as the 5-HT receptor, the following effects have been reported, e.g.:
Antidepressive effect and improvement of the sleep quality (Meert et al. Drug. Dev. Res. 1989, 18, 119), reduction of the negative symptoms of schizophrenia and of extrapyramidal side effects caused by treatment with classical neuroleptics in schizophrenic patients (Gelders British J. Psychiatry 1989, 155 (suppl. 5), 33). Furthermore, selective 5-HT2A antagonists could be effective in the prophylaxis and treatment of migraine (Scrip Report; "Migraine - Current trends in research and treatment"; PJB Publications Ltd.; May 1991) and in the treatment of anxiety (Colpart et al. Psychopharmacology 1985, 86, 303-305 and Perregaard et al. Current Opinion in Therapeutic Patents 1993, 1, 101-128).
Some clinical studies implicate the 5-HT2 receptor subtype in aggressive behaviour. Furthermore, atypical serotonin-dopamine antagonist neuroleptics have 5-HT2 receptor antagonistic effect in addition to their dopamine blocking properties and have been reported to possess anti-aggressive behaviour (Connor et al. Exp. Opin. Ther. Patents 1998, 8(4), 350-351).
Recently, evidence has also accumulated which support the rationale for selective 5-HT2A antagonists as drugs capable of treating positive symptoms of psychosis (Leysen et al. Current Pharmaceutical Design 1997, 3, 367-390 and Carlsson Current Opinion in CPNS Investigational Drugs 2000, 2(1), 22-24).
Compounds which are 5-HT reuptake inhibitors are well-known antidepressant drugs. 5-HT2c ligands have been found to augment the effect of 5-HT reuptake inhibitors in microdialysis experiments and animal models, and compounds having 5-HT reuptake inhibiting effect combined with affinity for the 5-HT2c receptor may therefore be particularly useful for the treatment of depression and other disorders responsive to serotonin reuptake inhibitors (PCT application No. PCT/DKOO/00671).
Accordingly, dopamine D4 receptor ligands are potential drugs for the treatment of schizophrenia and other psychoses, and compounds with combined effects at the 5-HT transporter may have the further benefit of improved effect on depressive and negative symptoms in schizophrenic patients. Compounds with combined effect at the dopamine D4 receptor and the 5-HT2A receptor may have the benefit of improved effect on positive and negative symptoms of schizophrenia and the benefit of effect on depressive and anxiety symptoms.
In particular, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia without inducing extrapyramidal side effects.
Summary of the Invention
The object of the present invention is to provide compounds that are partial agonists or antagonists at the dopamine D4 receptor and such compounds with combined effects at the dopamine D4 receptor, the 5-HT2A receptor, the 5-HT2c and/or the 5-HT transporter.
Accordingly, the present invention relates to novel compounds of the formula I
Figure imgf000005_0001
wherein R1 is hydrogen or C1-6-alkyl, C2-6-alkenyl, C -6-alkynyl, C3-8-cycloalkyl or C -8- cycloalkyl-C1-6-alkyl, all of which may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, hydroxy, thiol, C1-6-alkoxy, C1-6-alkylthio trifluoromethyl, trifluoromethylsulfonyl and C1-6-alkylsulfonyl, or R1 is aryl, aryl-C1-6-alkyl, heteroaryl, heteroaryl-Cι-6-alkyl where the aryl and heteroaryl groups may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, Cι-6-alkyl, d-ό-alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl, or R1 is -NR'R" wherein R' and R" are independently selected from hydrogen and C1-6-alkyl, aryl, aryl-C1-6-alkyl, heteroaryl and heteroaryl-C1-6-alkyl, all of which may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C1-6-alkyl, d_6 alkoxy, Cι-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl, and C1-6 alkylsulfonyl, or R1 is a saturated or partially saturated 5 to 6 membered ring containing one, two or three hetero atoms selected from O, S and a group N-R9 wherein R9 is hydrogen or C1-6-alkyl optionally substituted with substituents selected from halogen, cyano, nitro, amino, Cι-6-alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl;
W is a bond or W is an O, S, CO, CS, SO or SO2 group;
n is 0-6, m is 0-6 and n+m is 0-6; provided that when W is O, or S, n > 2 and when W is CO, CS, SO or SO2, n > 1;
X is C, CH or N, and the dotted line emanating from X indicates a bond when X is C and no bond when X is N or CH;
R2 is C1-6-alkyl;
R3-R7 are selected from hydrogen, halogen, cyano, nitro, amino, C1-6-alkyl, C2-6-alkenyl, C -6-alkynyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, Cι_6-alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C1-6-alkylsulfonyl; R8 is hydrogen, Ci-e-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6- alkyl, aryl, aryl-C1-6-alkyl, acyl, thioacyl, C1-6-alkylsulfonyl, trifluoromethylsulfonyl or arylsulfonyl, or a pharmaceutically acceptable acid addition salt thereof.
In one particular embodiment, the present invention relates to compounds wherein the indole is bound to X via position 3 of the indole.
In a further embodiment, the invention relates to such compounds wherein W is a bond. In particular, the present invention relates to compounds wherein n + m is 2.
In a further embodiment, the present invention relates to such compounds wherem R is a methyl group.
In another embodiment, the invention relates to compounds wherein the group -NH-CO-R1 is attached to the phenyl group in a position para to the position of the R2 group.
In particular, the present invention relates to such compounds, wherein R1 is C1-6-alkyl, C3-8- cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, wherein the phenyl groups may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, Cι-6-alkyl, Cι_6 alkoxy, Cι-6- alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl, or R1 is - NR'R" wherein one of R' and R" is selected from hydrogen and the other of R' and R" is selected from C1-6-alkyl, phenyl and phenyl-C1-6-alkyl, wherein the phenyl groups may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C1-6-alkyl, Cι_6 alkoxy, Cι-6-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and Ci-6 alkylsulfonyl, or R1 is a tetrahydropyranyl, morpholino, thiomo holino, piperidino, piperazino or a N-(hydroxy-C1-6-alkyl)piperazino group
In a specific embodiment, the present invention relates to a compound selected from
3-(l-{2-[5-(Acetylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-lH-indole;
3-(l-{2-[5-(Cyclobutylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro- lH-indole; 3-(l-{2-[5-(Acetylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-lH-indole;
3-(l-{2-[2-Methyl-5-(thiophen-2-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5- chloro-lH-indole;
3-(l-{2-[2-Methyl-5-(3-methoxybenzoylamino)phenyl]ethyl}piperidin-4-yl)-5-chloro-lH- indole;
3-(l-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro- lH-indole;
3-(l-{2- [2-Methyl-5 -(thiophen-2-ylmethanoylamino)phenyl] ethyl} piperidin-4-yl)-5 -fluoro- lH-indole; 3-(l-{2-[5-(Isobutanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-lH-indole;
3-(l-{2-[2-Methyl-5-(pivaloylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-lH-indole;
3-(l-{2-[5-(Hexanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-lH-indole;
3-(l - {2-[5-(4-Fluorobenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro- 1H- indole; 3-(l-{2-[5-(3-Methoxybenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-lH- indole;
3-(l-{2-[2-Methyl-5-(pyridin-3-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro- lH-indole;
3-(l-{2-[2-Methyl-5-(3-phenylpropanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-lH- indole;
3-(l-{2- [2-Methyl-5 -(4-methylbenzoylamino)phenyl] ethyl} piperidin-4-yl)-5 -fluoro- 1 H- indole;
3-(l-{2-[2-Methyl-5-(3-Methyl-3-phenylureido)phenyl]ethyl}piperidin-4-yl)-6-chloro-lH- indole; 3-(l-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro- lH-indole;
3-(l-{2-[2-Methyl-5-(thiophen-2-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-6-chloro- lH-indole;
3-(l-{2-[5-(Isobutanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-lH-indole; 3-(l-{2-[5-(3 -Methoxybenzoylamino)-2-methylphenyl] ethyl} piperidin-4-yl)-6-chloro- 1 H- indole;
3-(l-{2-[2-Methyl-5-(pyridin-3-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-6-chloro- lH-indole; 3-[l-(2-{5-[2-(4-Methoxyphenyl)ethanoylamino]-2-methylphenyl}ethyl)piperidin-4-yl]-6- chloro-lH-indole;
3-(l-{2- [2-Methyl-5-(4-methylbenzoylamino)phenyl] ethyl} piperidin-4-yl)-6-chloro- 1 H- indole; 3-[l-(2-{5-[(Cyclopentylmethanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-6-chloro- lH-indole;
3-(l-{2-[2-Methyl-5-(morfolin-4-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro- lH-indole;
3-[l-(2-{5-[3 -(4-Fluorophenyl)ureido]-2-methylphenyl} ethyl)piperidin-4-yl] -5 -fluoro- 1 H- indole;
3-(l-{2-[5-(Hexanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-lH-indole;
3-(l-{2-[2-Methyl-5-(tetrahydropyran-4-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5- fluoro- lH-indole;
3-(l-{2-[5-(4-Chlorobenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-lH- indole;
3-(l-{2-[5-(3-Cyclohexylpropanoylamino)-2-methylphenyl]ethyl}piperidm-4-yl)-5-fluoro- lH-indole;
3-[l-(2-{5-[(3-Phenylpropanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-7-chloro-lH- indole; 3 - [ 1 -(2- {5- [(2-Phenylethanoyl)amino] -2-methylphenyl} ethyl)pip eridin-4-yl] -7-chloro- 1 H- indole;
3-(l-{2-[2-Methyl-5-(4-methylbenzoylamino)phenyl]ethyl}piperidin-4-yl)-7-chloro-lH- indole;
3-(l-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro- lH-indole;
3-[l-(2-{5- [2-(4-Fluorophenyl)ethanoylamino] -2-methylphenyl} ethyl)piperidin-4-yl] -7- chloro-lH-indole;
3-[l-(2-{5-[2-(4-Methoxyphenyl)ethanoylamino]-2-methylphenyl}ethyl)piperidin-4-yl]-7- chloro-lH-indole; 3-[l-(2-{5-[(Cyclobutylmethanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-7-chloro- lH-indole;
3-(l-{2-[5-(benzoylamino)- 2-Methylphenyl]ethyl}piperidin-4-yl)-7-chloro-lH-indole; 3-(l-{2-[5-(4-Fluorobenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-lH- indole;
3-(l-{2-[5-(4-Methoxybenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-lH- indole; 3-[l-(2-{2-Methyl-5-[(pyridin-3-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7-chloro- lH-indole;
3-[l-(2-{2-Methyl-5-[(pyridin-4-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7-chloro- lH-indole;
3-[l-(2-{2-Methyl-5-[(thiophen-2-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7- chloro-lH-indole;
3-[l-(2-{2-Methyl-5-[(thiophen-3-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7- chloro-lH-indole;
3-[l-(2-{2-Methyl-5-[(l-[l,2,3]thiadiazol-5-ylmethanoyl)amino]phenyl}ethyl)-piperidin-4-yl]-
7-chloro- 1 H-indole; 3-{l-[2-(5-Acetylamino-2-methylphenyl)-ethyl]-3,6-dihydro-2H-pyridin-4-yl}-5-fluoro-iH- indole;
3-[ 1 -(2- {2-Methyl-5- [(pyridin-3 -ylmethanoyl)-amino] -phenyl} -ethyl)-3 ,6-dihydro-2H- pyridin-4-yl]- 5-fluoro-iH-indole;
3-[l-(2-{5-[(4-Fluorophenylmethanoyl)-amino]-2-methylphenyl}-ethyl)-3,6-dihydro-2H- pyridin-4-yl]- 5-fluoro-iH-indole;
3- { 1 -[2-(5-Acetylamino-2-methylphenyl)-ethyl]-3,6-dihydro-2H-pyridin-4-yl} -7-chloro- iH-indole;
3-[l-(2-{2-Methyl-5-[(pyridin-3-ylmethanoyl)-amino]-phenyl}-ethyl)-3,6-dihydro-2H- pyridin-4-yl]- 7-chloro-7H-indole and 3-[l-(2-{5-[(4-Fluorophenylmethanoyl)-amino]-2-methylphenyl}-ethyl)-3,6-dihydro-2H- pyridin-4-yl]- 7-chloro-7H-indole or a pharmaceutically acceptable salt thereof.
The compounds of the invention are partial agonists or antagonist at the dopamine D4 receptors. Many compounds have combined effect at dopamine D4 receptors and the 5-ΗT A receptor, the 5-ΗT2c receptor and /or 5-HT reuptake inhibiting effect.
Accordingly, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, aggression, side effects induced by conventional antipsychotic agents, migraine, cognitive disorders, ADHD and in the improvement of sleep.
In particular, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia without inducing extrapyramidal side effects.
In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula I as defined above or a pharmaceutically acceptable acid addition salt thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.
In a further aspect, the present invention provides the use of a compound of formula I as defined above or an acid addition salt thereof for the manufacture of a pharmaceutical preparation for the treatment of the above mentioned disorders.
Detailed Description of the Invention
The compounds of general formula I may exist as optical isomers thereof and such optical isomers are also embraced by the invention.
The term C1-6-alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1 -butyl, 2-butyl, 2- methyl-2-propyl and 2-methyl- 1 -propyl.
Similarly, C2-6-alkenyl and C2-6-alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and one triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.
The terms C1-6-alkoxy, C1-6-alkylthio, C1-6-alkylsulfonyl, C1-6-alkylamino, C1-6- alkylcarbonyl, and the like, designate such groups in which the alkyl group is C1-6 alkyl as defined above. The term C3-8-cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, etc.
Halogen means fluoro, chloro, bromo or iodo.
As used herein, the term acyl refers to a formyl, C1-6 -alkylcarbonyl, arylcarbonyl, aryl-C1-6-alkylcarbonyl, C3-8-cycloalkylcarbonyl or a C3-8-cycloalkyl-C1-6-alkyl-carbonyl group and the term thioacyl is the corresponding acyl group in which the carbonyl group is replaced with a thiocarbonyl group.
The term aryl refers to a carbocyclic aromatic group, such as phenyl, or naphthyl, in particular phenyl.
The term heteroaryl refers to 5 membered monocyclic rings such as lH-tetrazolyl, 3H- 1,2,3- oxathiazolyl, 3H-l,2,4-oxathiazolyl, 3H-l,2,5-oxathiazolyl, 1,3,2-oxathiazolyl, 1,3,4- oxathiazolyl, 1,4,2-oxathiazolyl, 3H-l,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,4,2-dioxazolyl, 3H-l,2,3-dithiazolyl, 3H-l,2,4-dithiazolyl, 1,3,2-dithiazolyl, 1,4,2-dithiazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxa iazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, lH-l,2,3-triazolyl, 1H-1,2,4- triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, IH-imidazolyl, IH-pyrazolyl, 1H- pyrrolyl, furanyl, thienyl, lH-pentazole, 6-membered monocyclic rings such as 1,2,3- oxathiazinyl, 1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, 4H-l,3,5-oxathiazinyl, 1,4,2- oxathiazinyl, 1,4,3-oxathiazinyl, 1,2,3-dioxazinyl, 1,2,4-dioxazinyl, 4H-l,3,2-dioxazinyl, 4H-l,3,5-dioxazinyl, 1,4,2-dioxazinyl, 2H-l,5,2-dioxazinyl, 1,2,3-dithiazinyl, 1,2,4- dithiazinyl, 4H-l,3,2-dithiazinyl, 4H-l,3,5-dithiazinyl, 1,4,2-dithiazinyl, 2H-1,5,2- dithiazinyl, 2H-l,2,3-oxadiazinyl, 2H-l,2,4-oxadiazinyl, 2H-l,2,5-oxadiazinyl, 2H-1,2,6- oxadiazinyl, 2H-l,3,4-oxadiazinyl, 2H-l,3,5-oxadiazinyl, 2H-l,2,3-thiadiazinyl, 2H-1,2,4- thiadiazinyl, 2H-l,2,5-thiadiazinyl, 2H-l,2,6-thiadiazinyl, 2H-l,3,4-thiadiazinyl, 2H-1,3,5- thiadiazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 2H-l,2-oxazinyl, 2H-1,3- oxazinyl, 2H-l,4-oxazinyl, 2H-l,2-thiazinyl, 2H-l,3-thiazinyl, 2H-l,4-thiazinyl, pyrazinyl, pyridazinyl, pyrimidyl, pyridyl, 2H-pyranyl, 2H-thiinyl, or bicyclic rings such as 3H- 1,2,3- benzoxathiazolyl, 1,3,2-benzodioxazolyl, 3H-l,2,3-benzodithiazolyl, 1,3,2- benzodithiazolyl, benzfurazanyl, 1,2,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3- benzothiadiazolyl, lH-benzotriazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzothiazolyl, 1H- benzimidazolyl, lH-indazolyl, 3H-l,2-benzoxathiolyl, 1,3-benzoxathiolyl, 3H-2,1- benzoxathiolyl, 3H-l,2-benzodioxolyl, 1,3-benzodioxolyl 3H- 1,2 -benzodithiolyl, 1,3- benzodithiolyl, IH-indolyl, 2H-isoindolyl, benzofuranyl, isobenzofuranyl, 1-benzothienyl,
2-benzothienyl, lH-2,l-benzoxazinyl, lH-2,3-benzoxazinyl, 2H-l,2-benzoxazinyl, 2H-1,3- benzoxazinyl, , 2H-l,4-benzoxazinyl, 2H-3,l-benzoxazinyl, lH-2,l-benzothiazinyl, lH-2,3- benzothiazinyl, 2H-l,2-benzothiazinyl, 2H-l,3-benzothiazinyl, 2H-l,4-benzothiazinyl, 2H-
3,1-benzothiazinyl, cinnolinyl, phtalazinyl, quinazolinyl, quinoxalinyl, isoquinolyl, quinolyl, lH-2-benzopyranyl, 2H-l-benzopyranyl, lH-2-benzothiopyranyl or 2H-1- benzothiopyranyl.
R1 meaning a saturated or partially saturated 5- to 6-membered ring containing one or two hetero atoms selected from O, S or a group N-R9 includes groups wherein R1 is a group - CRaRb and groups wherein R1 is -NRaR wherein R and R together form a 5- to 6- membered saturated or partially saturated ring optionally containing an additional N-R group or an O or S atom, e.g groups such as piperidinyl, piperazinyl, N-(hydroxy-C1-6- alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyridyl, tetrahydropyranyl, tetrahydrofuranyl, etc.
The acid addition salts of the compounds of the invention are pharmaceutically acceptable salts formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p- aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8- halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
The pharmaceutical compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used.
Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg.
The total daily dose is usually in the range of about 0.05 - 500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention.
The compounds of the invention may be prepared as follows:
1) Alkylating a piperazine, piperidine or tetrahydropyridine of formula II with an alkylating derivative of formula III:
Figure imgf000014_0001
wherein R , 1 -R , X, W, n, m and the dotted line are as previously defined, and L is a leaving group such as e.g. halogen, mesylate or tosylate;
2) Reductive alkylation of an amine of formula II with a reagent of formula IV:
Figure imgf000014_0002
(H) (IV) wherem R - R , X, W, n, m and the dotted line are as previously defined, and E is an aldehyde or an activated carboxylic acid; 3) Reducing the double bond in the tetrahydropyridinyl ring in derivatives of formula
V:
Figure imgf000015_0001
(V)
wherein R .1 -R r.8 , W, n and m are as previously defined;
4) Acylating an amine of formula VI
Figure imgf000015_0002
(VI)
wherein R^R8, XW, n, m and the dotted line are as previously defined by the use of a carboxylic acid and a coupling reagent, an activated ester, an acid chloride, an isocyaiiate, a carbamoyl chloride or a by a two-step procedure by treatment with phosgene followed by addition of an amine;
5) Cleaving a polymer bound derivative of formula VII
Figure imgf000015_0003
wherein R^R7, X, W, n and m are as previously defined and R'OH is hydroxyethyl or hydroxymethyl polystyrene, Wang resin or analogous polyethylene glycol polystyrene resins; whereupon the compound of Formula I is isolated as the free base or a pharmaceutically acceptable acid addition salt thereof.
The alkylation according to method 1) is conveniently performed in an inert organic solvent such as a suitably boiling alcohol or ketone, preferably in the presence of an organic or inorganic base (potassium carbonate, diisopropylethylamine or triethylamine) at reflux temperature. Alternatively, the alkylation can be performed at a fixed temperature which is different from the boiling point, in one of the above-mentioned solvents or in dimethyl formamide (DMF), dimethylsulfoxide (DMSO) or N-methylpyrrolidin-2-one (ΝMP), preferably in the presence of a base. The synthesis of the amines of formula II, 3-(piperidin- 4-yl)-lH-indoles and 3-(3,6-dihydro-2H-pyridin-4-yl)-lH-indoles, has been described in the literature (see EP-A1-465398).
The alkylating derivatives of formula III are prepared by nitration of the alkyl-substituted phenylacetic acids followed by reduction of the nitro group, e.g. with tin(II) chloride and functionalization of the produced amino group. The carboxylic acid is subsequently reduced to the corresponding alcohol, e.g. by treatment with borane followed by conversion of the alcohol to a leaving group, e.g. by treatment with methane sulfonyl chloride or thionyl bromide.
The reductive alkylation according to method 2) is performed by standard literature methods. The reaction can be performed in two steps, e.g. coupling of amines of formula II with reagent of formula IV by standard methods via the carboxylic acid chloride, activated esters or by the use of carboxylic acids in combination with a coupling reagent such as e.g. dicyclohexyl carbodiimide, followed by reduction of the resulting amide with lithium aluminium hydride or alane. The carboxylic acid of formula IV is prepared by nitration of the alkyl-substituted phenylacetic acid followed by reduction of the nitro group, e.g. with tin(II) chloride and finally functionalization of the resulting amino group.
The reaction can also be performed by a standard one-pot procedure, e.g. using a reductive animation of amines of formula II and aldehydes of formula IV. The aldehydes of formula IV are prepared by reduction of the before mentioned functionalized (aminophenyl)acetic acid by treatment with a reducing agent such as e.g. borane. The resulting alcohol is converted to the corresponding aldehyde by standard oxidation methods, e.g. pyridinium chlorochromate.
The reduction of the double bond according to method 3) is generally performed by catalytic hydrogenation at low pressure (< 3 arm.) in a Parr apparatus, or by using reducing agents such as diborane or hydroboric derivatives as produced in situ from NaBH4 in trifluoroacetic acid in inert solvents such as tetrahydrofuran (THF), dioxane or diethyl ether.
The acylation according to method 4) is conveniently performed by standard methods via the carboxylic acid chloride, activated esters or by the use of carboxylic acids in combination with coupling reagents such as e.g. dicyclohexyl carbodiimide. When the acylation produces urea derivatives, the acylating reagent is carbamoyl chlorides, isocyanates or a two-step procedure consisting of treatment with phosgene followed by addition of an amine.
The intermediate compounds of formula VI are prepared as described in methods 1) and 2).
The derivatives of structure VII are prepared by means of a solid phase synthesis sequence as outlined below. The final product was cleaved from the resin according to method 5) using diluted sodium methoxide in a methanol/tetrahydrofuran mixture at ambient temperature. The first building block, VIII, prepared by tert-butoxycarbonyl protection of compounds of formula II, which is prepared by methods obvious to the chemist skilled in the art (see also EP-Al-465398), is generally attached to the resin (eg. polystyrene bound ethyl 4-nitrophenyl carbonate) using base e.g. NN-dimethylaminopyridine and N,N- diisopropylethylamine at elevated temperature (e.g. 50-100 °C) in an aprotic solvent (e.g. DMF or DMSO). After deprotection of compound IX by trifluoroacetic acid, the second diversifying building block is introduced by alkylation of compound X whereby compound XI is formed. The alkylating reagent is prepared by nitration of alkylsubstituted phenylacetic acid by standard nitration procedures followed by reduction of the carboxylic acid, e.g. by treatment with borane in tetrahydrofurane and finally converting the produced alcohol to a leaving group, e.g. by treatment with methanesulfonyl chloride in dichloromethane and triethylamine. The alkylation is performed at elevated temperature
(50-100 °C) in an aprotic solvent such as DMF, acetone or acetonitrile leading to resin XI.
After reduction of the nitro group, e.g. by treatment with tin(II) chloride in DMF, the third diversifying building block is introduced by standard acylation procedures, e.g. addition of an acid chloride, isocyanate or carbamoyl chloride and base at low temperature in DMF, dichloromethane or acetonitrile.
Figure imgf000018_0001
Figure imgf000018_0002
R"=C(0)0(CH2)2(PS), PS = Wang resin, R 1, τ R> 7', X, W, n, and m is as defined above Experimental Section
Melting points were determined on a Bϋchi SMP-20 apparatus and are uncorrected. Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with IonSpray source and Shimadzu LC-8A/SLC-10A LC system. The LC conditions (C18 column 4.6 x 30 mm with a particle size of 3.5 μm) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (90:10:0.05) to water/acetonitrile/trifluoroacetic acid (10:90:0.03) in 4 min at 2 mL/min. Purity was determined by integration of the UV trace (254 nm). The retention times, Rt, are expressed in minutes.
Mass spectra were obtained by an alternating scan method to give molecular weight information. The molecular ion, MH+, was obtained at low orifice voltage (5 -20V) and fragmentation at high orifice voltage ( 100-200 V).
Preparative LC-MS-separation was performed on the same instrument. The LC conditions (C18 column 20 x 50 mm with a particle size of 5 μm) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (80:20:0.05) to water/acetonitrile/trifluoroacetic acid (5:95:0.03) in 7 min at 22.7 mL/min. Fraction collection was performed by split-flow MS detection.
1H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500 instrument or at 250.13 MHz on a Bruker AC 250 instrument. Deuterated chloroform (99.8%D) or dimethyl sulfoxide (99.9%D) were used as solvents. TMS was used as internal reference standard. Chemical shift values are expressed in ppm-values. The following abbreviations are used for multiplicity of NMR signals: s=singlet, d=doublet, t=triplet, q=quartet, qui=quintet, h=heptet, dd=double doublet, dt=double triplet, dq=double quartet, tt=triplet of triplets, m=nιuιtiplet. NMR signals corresponding to acidic protons are generally omitted. Content of water in crystalline compounds was determined by Karl Fischer titration. For column chromatography silica gel of type Kieselgel 60, 40-60 mesh ASTM was used. For ion-exchange chromatography (SCX, 1 g, Varian Mega Bond Elut®, Chrompack cat. no. 220776). Prior use of the SCX-columns was pre-conditioned with 10% solution of acetic acid in methanol (3 mL). Examples
Preparation of intermediates
A. Acylating reagent
(2-Methyl- 5 -nitrophenyl) acetic acid
A I L round bottom flask was charged with cone, sulfuric acid (500 mL) and cooled to -12 °C (ethyleneglycol-dry ice). (2-Methylphenyl)acetic acid (35.4 g, 0.24 mol) dissolved in dichloromethane (120 mL) was added during 10 minutes and the mixture was then treated dropwise during two hours with a pre-cooled (ethylene glycol-dry ice) solution of cone, sulfuric acid (100 mL) and 100% nitric acid (10 mL). The reaction mixture was stirred for one hour at -12 °C and then poured on ice. The aqueous phase was extracted with ethyl acetate (3 x 1 L). The combined organic phases were washed with brine (2 x IL) and water (2 x 1 L), dried (Na SO4) and concentrated in vacuo to give the 38. lg crude mixture (38 g). H NMR showed a 70:30 mixture of the title compound and (2-methyl-3-nitrophenyl)acetic acid, and the title compound was purified by trituation with diethyl ether.
B. Alkylating reagents
2-(2-Methanesulfonyloxyethyl)-l-methyl-4-nitrobenzene
A 500 mL round bottom flask was charged with (2-methyl-5-nitrophenyl)acetic acid (15 g, 77 mmol) and dry THF (300 mL). The mixture was cooled on ice-water and treated dropwise with borane-tefrahydrofurane complex (90 mL, IM in THF, 90 mmol) during one hour. The reaction mixture was stirred for two hours at room temperature and then poured on ice. The aqueous phase was extracted with ethyl acetate (3 x 600 mL). The combined organic phases were washed with brine (2 x IL) and water (2 x IL), dried (Na2SO4) and concentrated in vacuo. The residue was redissolved in dichloromethane (200 mL) and triethylamine (10.8 mL, 78 mmol). The mixture was cooled on ice-water and a mixture of methanesulfonyl chloride (6.05 mL, 78 mmol) dissolved in dichloromethane (100 mL) was added dropwise during 20 minutes. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 2:3) to give the title compound (7.8 g). !H NMR (CDCI3): 2.45 (s, 3H); 2.96 (s, 3H); 3.15 (t, 2H); 4.45 (t, 2H);
7.33 (d, 1H); 7.98-8.11 (m, 2H).
2-(2-Bromoethyl)-l-methyl-4-nitrobenzene
A mixture of 2-(2-methanesulfonyloxyethyl)-l-methyl-4-mtrobenzene (4.0 g) and lithium bromide (6.6 g) in acetone (250 mL) was boiled under reflux for 3Vi h. The resulting mixture was cooled and filtered. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:2) to give the title compound (3.7 g). 1H NMR (DMSO-d6): 2.45 (s, 3H); 3.25 (t, 2H); 3.80 (t, 2H); 7.50 (d, 1H); 8.05 (dd, 1H); 8.15 (d, 1H).
Preparation of solid supported intermediates
Preparation of4-nitrophenyloxycarbonyloxyethyl polystyren
A 2 L round bottom flask was charged with hydroxyethyl polystyren (62.9 g, 83 mmol, commercially available from Rapp Polymere, cat. no. HA 1 400 00), N-methyl-morpholine (20 mL, 183 mmol), and dry dichloromethane (900 mL). The suspension was cooled on an ice bath followed by the addition over a period of 5 min of 4-nitrophenyl chloroformiate, dissolved in dry dichloromethane (400 mL). The mixture was stirred at room temperature for 16 h. The resin was filtered off and washed with dry dichloromethane (5 x 200 mL). The resin was dried in vacuo (20 °C, 72 h) to yield the title resin (79.6 g).
Preparation of polymer bound 3-{l-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-5- fluoro-lH-indole :
A 100 mL round bottom flask was charged with 4-nitrophenyloxycarbonyloxyethyl polystyren (6.6 g, 7.1 mmol), 5-fluoro-3-(l-tert-butoxycarbonylpiperidin-4-yl)-lH-indole (2.7 g, 8.1 mmol), dusopropylethylamine (6.2 mL, 35.6 mmol), 4-dimethylaminopyridine (0.87 g, 7.1 mmol), and dry dimethyl formamide (85 mL). The mixture was stirred at 90 °C for 20 h. After cooling to room temperature, the resin was filtered off and washed with dry dimethyl formamide (3 x 25 mL), dry acetonitrile (3 x 25 mL) and dry dichloromethane (3 x 25 mL). The resin was transferred to a 250 mL glass cylinder with a fritte and a three way junction in the bottom. The resin was then treated for 20 min with 80 mL of a 1 :1 mixture of dichloromethane and trifluoroacetic acid containing anisole (2%, w/w) and methionine (0.2
%, w/w), using a flow of nitrogen to agitate the resin (Caution: Generation of carbon dioxide). The resin was filtered off and washed with dry dichloromethane (25 mL), a 1 : 1 mixture of dichloromethane:triethylamine (3 x 25 mL) and dry dichloromethane (3 x 25 mL). The resin was transferred to a 250 mL round bottom flask. Acetonitrile (70 mL), dusopropylethylamine (5.2 mL, 30 mmol) and 2-(2-methanesulfonyloxyethyl)-l-methyl-4- nitrobenzene (3.67 g, 14 mmol) was added. The reaction mixture was heated to 70 °C for 18 h. After cooling to room temperature, the resin was filtered off and washed with dry acetonitrile (3 x 25 mL) and dry dichloromethane (3 x 25 mL). The resin was transferred to a 250 mL round bottom flask and treated with tin(II) chloride dihydrate (60 mL of an 0.5 M solution in DMF). The reaction mixture was stirred for 18 h. at room temperature. The resin was filtered off and washed with dry dimethyl formamide (3 x 25 mL), dry acetonitrile (3 x 25 mL) and dry dichloromethane (3 x 25 mL). The resin was dried in vacuo (20 °C, 20 h) to yield the title resin (6.3 g).
The following polymer bound compounds were prepared in a similar manner:
3- { 1 -[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl} -5-chloro- lH-indole 3-{l-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-6-chloro-lH-indole 3-{l-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-7-chloro-lH-indole
Preparation of the compounds of the invention
Example 1 la, 3-(l-{2-[5-(Acetylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-lH-indole, fumerate A mixture of (2-methyl-5-nitrophenyl)acetic acid (47 g) and thionyl chloride (62 mL) in dichloromethane (400 mL) was boiled under reflux for 5 h and concentrated in vacuo. A small amount of the residue (5 g) was dissolved in tetrahydrofuran (100 mL) and added dropwise to a mixture of 6-chloro-3-(3,6-dihydro-2H-pyridin-4-yl)-lH-indole (6.0 g) and triethylamine (5 mL) in tetrahydrofuran (250 mL) at 0 °C over a period of 10 min. The mixture was concentrated in vacuo, aqueous 2 N sodium hydroxide (400 mL) and ethyl acetate (400 mL) was added, whereby 6-chloro-3-{l-[2-(2-methyl-5-nitrophenyl)-l- oxoethyl]-3,6-dihydro-2H-pyridin-4-yl}-lH-indole precipitated and was collected by filtration (3.7 g). The organic phases were isolated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane 2:1) to give another batch of 6-chloro-3-{l-[2-(2- methyl-5-nitrophenyl)-l-oxoethyl]-3,6-dihydro-2H-pyridin-4-yl}-lH-indole (2.2 g). A mixture of 6-chloro-3-{l-[2-(2-methyl-5-nitrophenyl)-l-oxoethyl]-3,6-dihydro-2H-pyridin- 4-yl}-lH-indole (5.3 g) in tetrahydrofuran (100 mL) and tin(ιι) chloride dihydrate (14.5 g) in ethanol (150 mL) was boiled under reflux for 2 h, and the solvent reduced to about 100 mL in vacuo. Aqueous ammonia was added and the organic phase was removed in vacuo. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried (Na SO4), filtered and concentrated in vacuo to give 6-chloro-3- { 1 - [2-(5 -amino-2-methylphenyl)- 1 -oxoethyl] -3 ,6-dihydro-2H-pyridin-4-yl} - lH-indole (5.1 g). This compound was dissolved in tetrahydrofuran (200 mL) and added dropwise to a suspension of lithium aluminium hydride (1.5 g) in tetrahydrofuran (100 mL) at 10 °C over a period of 15 min. The resulting mixture was stirred at room temperature for 16 h and subjected to a standard work up procedure to give crude 6-chloro-3-{l-[2-(5-amino-2- methylphenyl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-lH-indole (7.5 g, includes tetrahydrofuran). Crude compound (4.0 g) was dissolved in acetic acid (100 mL) followed by the addition of platinum oxide (400 mg), and the resulting mixture was shaken under 3 atmosphere hydrogen pressure for 6 h at room temperature. The mixture was filtered and added water (400 mL) followed by the addition of aqueous ammonia to basic pΗ. The aqueous phase was extracted with an ethyl acetate, and the combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give 6-chloro-3- {l-[2-(5-ammo-2-methylphenyl)ethyl]piperidin-4-yl}-lH-indole (2.4 g). The compound was dissolved in tetrahydrofuran (200 mL) and triethylamine (1 mL), and the mixture was cooled to 0 °C followed by dropwise addition of acetyl chloride (0.5 mL) in dichloromethane (30 mL). The resulting mixture was stirred at room temperature for 2 h, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/ethanol/triethylamine 80:20.4) to give crude title compound that was collected as the fumerate salt from ethanol (0.7 g). Mp 164-166 °C. 1H NMR (DMSO-d6): 1.85-2.10 (m, 4H); 2.25 (s, 3H); 2.65-3.00 (m, 7H); 3.30-3.45 (m, 2H); 6.60 (s,
3H (fumerate)); 7.00 (dd, 1H); 7.10 (d, 1H); 7.20 (d, 1H); 7.30-7.45 (m, 3H); 7.65 (d, 1H);
9.85 (s, 1H); 11.05 (s, 1H). MS m/z: 410 (MH+), 259, 247, 176.
Example 2
2a, 3-(l-{2-[5-(Cyclobutylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro- lH-indole, oxalate A mixture of 5-fluoro-3-(piperidin-4-yl)-lH-indole (2.7 g) in dimethyl formamide (75 mL), 2-(2-bromoethyl)-l-methyl-4-nitrobenzene (3.7 g) in butanone (200 mL) and triethylamine (9.3 mL) was boiled under reflux for 20 h, and the resulting mixture was concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/triethylamine 100:4) to give 5-fluoro-3-{l-[2-(2-methyl-5- nitrophenyl)ethyl]piperidin-4-yl}-lH-indole (3.6 g), which subsequently was dissolved in acetic acid (25 ml) followed by the addition of ethanol (75 mL) and platinum oxide (50 mg). The resulting mixture was shaken under 3 atmosphere hydrogen pressure for 3 h at room temperature. The mixture was reduced in vacuo (50 mL), poured onto an ice/water mixture followed by the addition of aqueous ammonia to basic pΗ. The aqueous phase was extracted with an ethyl acetate/tetrahydrofuran mixture, and the combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/ethanol/triethylamine 100:4:4) to give 3-{l-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-5-fluoro-lH-indole (1.0 g), which subsequently was dissolved in tetrahydrofuran (45 mL) and triethylamin (1.3 mL) at 5 °C followed by the addition of cyclobutancarbonyl chloride (0.3 g) in tetrahydrofuran (15 mL). The resulting mixture was stirred at 5 °C for 1 h, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/ethanol/triethylamine 100:4:4) to give the crude product that was isolated as the oxalate salt from ethyl acetate as a white crystalline compound (0.7 g). Mp 116-125 °C. 1H NMR (DMSO-d6): 1.75-1.85 (m, 1Η); 1.85-2.05 (m, 3Η); 2.05-2.25 (m, 6H); 2.30 (s, 3H); 2.90-3.25 (m, 8H); 3.65 (d, 2H); 6.85-6.95 (m, 1H); 7.10 (d, 1H); 7.25 (s, 1H); 7.30-7.40 (m, 2H); 7.40 (d, 1H); 7.55 (s, 1H); 9.65 (s, 1H); 11.00 (s, 1H). MS m/z: 434 (MH+). Example 3
3a, 3-(l-{2-[5-(Acetylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-lH-indole:
Polymer bound 3-[l-(2-{5-amino-2-methylphenyl}ethyl)piperidin-4-yl]-5-fluoro-lH-indole
(100 mg, 100 μmol), triethylamine (90 μL), and dimethylaminopyridine (0.50 mL of an 0.2 M solution in dry acetonitrile) were mixed in a reactor tube. The mixture was cooled to 0°C and treated with acetyl chloride (0.50 mL of an IM solution in dry acetonitrile). The reaction mixture was left at 0 °C for 2 h. The resin was filtered off and washed with dry acetonitrile (3 x 1 mL). The resin was treated for lh with 1 mL of a mixture of sodium methoxide (2 mL, 5 N sodium methoxide in methanol), methanol (50 mL) and tefrahydrofuran (50 mL). After filfration, the resin was washed with methanol (1 mL). The combined filtrates were loaded on a pre-conditioned ion exchange column (500 mg SCX column, commercially available from Analytical Instruments, part no. 1210-2040), washed with acetonitrile (1 mL) and methanol (1 mL). The product was eluted with 4 M ammonia in methanol. Evaporation of volatile solvents afforded the title compound as a yellow oil (6 mg, 15 μmol). LC/MS (m/z) 394 (MΗ+), RT = 1.98, purity: 88%.
The following compounds were prepared in similar manner. When ureas were prepared, the corresponding carbamoyl chloride was used in place of an acid chloride. The compounds were purified by preparative reversed phase HPLC chromatography if the UV trace (254 nm) showed less than 70% purity of the expected mass. The resulting solution was subsequently loaded on a pre-conditioned ion exchange column washed with acetonitrile (1 mL) and methanol (1 mL). The product was eluted with 4 M ammonia in methanol and the solution concentrated in vacuo to yield the final product.
3b, 3-(l-{2-[2-Methyl-5-(thiophen-2-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5- chloro-lH-indole : LC/MS (m/z) 478 (MH+), RT = 2.45, purity: 74%.
3c, 3-(l-{2-[2-Methyl-5-(3-methoxybenzoylamino)phenyl]ethyl}piperidin-4-yl)-5-chloro- lH-indole : LC/MS (m/z) 502 (MH+), RT = 2.51, purity: 86%.
3d, 3-(l-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5- fluoro-lH-indole: LC/MS (m/z) 420 (MH+), RT = 2.16, purity: 97%. 3e, 3-(l-{2-[2-Methyl-5-(thiophen-2-yhnethanoylamino)phenyl]ethyl}piperidin-4-yl)-5- fluoro-lH-indole : LC/MS (m/z) 462 (MH+), RT = 2.33, purity: 91%.
3f 3-(l-{2-[5-(Isobutanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-lH- indole: LC/MS (m/z) 422 (MH+), RT = 2.20, purity: 93%.
3g, 3-(l-{2-[2-Methyl~5-(pivaloylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-lH-indole : LC/MS (m/z) 436 (MH+), RT = 2.33, purity: 95%.
3h, 3-(l-{2-[5-(Hexanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-lH-indole: LC/MS (m/z) 450 (MH+), RT = 2.48, purity: 95%.
3i, 3-(l-{2-[5-(4-Fluorobenzoylamino)-2-7nethylphenyl]ethyl}piperidin-4-yl)-5-fluoro-lH- indole: LC/MS (m/z) 474 (MH+), RT = 4.02, purity: 95%.
3j, 3-(l-{2-[5-(3-Methoxybenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-lH- indole: LC/MS (m/z) 486 (MH+), RT = 2.41, purity: 91%.
3k, 3-(l-{2-[2-Methyl-5-(pyridin-3-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5- fluoro-lH-indole : LC/MS (m/z) 457 (MH+), RT = 1.90, purity: 80%.
31, 3-(l-{2-[2-Methyl-5-(3-phenylpropanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro- lH-indole : LC/MS (m/z) 484 (MH+), RT = 2.47, purity: 96%.
3m, 3-(l-{2-[2-Methyl-5-(4-methylbenzoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-lH- indole: LC/MS (m/z) 470 (MH+), RT = 2.47, purity: 90%.
3n, 3-(l-{2-[2-Methyl-5-(3-Methyl-3-phenylureido)phenyl]ethyl}piperidin-4-yl)-6-chloro- lH-indole: LC/MS (m/z) 501 (MH+), RT = 2.51, purity: 87%.
3o, 3-(l-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6- chloro-lH-indole: LC/MS (m/z) 436 (MH+), RT = 2.30, purity: 96%. 3p, 3-(l-{2-[2-Methyl-5-(thiophen-2-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-6- chloro-lH-indole: LC/MS (m/z) 478 (MH+), RT = 2.44, purity: 93%.
3q, 3-(l-f2-[5-(Isobutanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-lH- indole: LC/MS (m/z) 438 (MH+), RT = 2.33, purity: 96%.
3r, 3-(l-{2-[5-(3-Methoxybenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro- lH-indole: LC/MS (m/z) 502 (MH+), RT = 2.51, purity: 93%.
3s, 3-(l-{2-[2-Methyl-5-(pyridin-3-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-6- chloro-lH-indole: LC/MS (m/z) 473 (MH+), RT = 2.03, purity: 88%.
3t, 3-fl-(2-{5-[2-(4-Methoxyphenyl)ethanoylaminoJ-2-methylphenyl}ethyl)piperidin-4-ylJ- 6-chloro-lH-indole: LC/MS (m/z) 516 (MH+), RT = 2.52, purity: 94%.
3u, 3-(l-{2-[2-Methyl-5-(4-methylbenzoylamino)phenyl]ethyl}piperidin-4-yl)-6-chloro-lH- indole: LC/MS (m/z) 486 (MH+), RT = 2.58, purity: 93%.
3v, 3-[l-(2-{5-[(Cyclopentylmethanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-6- chloro-lH-indole: LC/MS (m/z) 465 (MH+), RT = 2.49, purity: 95%.
3x, 3-(l-{2-[2-Methyl-5-(morfolin-4-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5- fluoro-lH-indole: LC/MS (m/z) 465 (MH+), RT = 3.27, purity: 91%.
3y, 3-fl-(2-{5-[3-(4-Fluorophenyl)ureido]-2-methylphenyl}ethyl)piperidin-4-yl]-5-fluoro- lH-indole: LC/MS (m/z) 504 (MH+), RT = 2.52, purity: 92%.
3z, 3-(l-{2-[5-(Hexanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-lH-indole: LC/MS (m/z) 466 (MH+), RT = 2.55, purity: 88%.
3aa, 3-(l-{2-[2-Methyl-5-(tetrahydropyran-4-ylmethanoylamino)phenyl]ethyl}piperidin-4- yl)-5-fluoro-lH-indole: LC/MS (m/z) 464 (MH+), RT = 2.05, purity: 96%. 3ab, 3-(l-{2-[5-(4-Chlorobenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro- lH-indole: LC/MS (m/z) 506 (MH+), RT = 2.62, purity: 87%.
3ac, 3-(l-{2-[5-(3-Cyclohexylpropanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5- fluoro-lH-indole: LC/MS (m/z) 490 (MH+), RT = 2.76, purity: 95%.
3ad, 3-[l-(2-{5-f(3-Phenylpropanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-7- chloro-lH-indole: LC/MS (m/z) 500 (MH+), RT = 2.56, purity: 91%.
3ae, 3-[l-(2-{5-[(2-Phenylethanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-7-chloro- lH-indole: LC/MS (m z) 486 (MH+), RT = 2.48, purity: 92%.
3af, 3-(l-{2-[2-Methyl-5-(4-methylbenzoylamino)phenyl]ethyl}piperidin-4-yl)-7-chloro-lH- indole: LC/MS (m/z) 486 (MH+), RT = 2.54, purity: 89%.
3ag, 3-(l-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7- chloro-lH-indole: LC/MS (m/z) 436 (MH+), RT = 2.26, purity: 93%.
Example 4 4a, 3-[l-(2-{5-[2-(4-Fluorophenyl)ethanoylamino]-2-methylphenyl}ethyl)piperidin-4-yl]-7- chloro-lH-indole
A mixture of (2-methyl-5-nitrophenyl)acetic acid (2.5 g) and l,l'-carbonyldiimidazole (2.1 g) in dimethyl formamide (50 mL) was stirred at room temperature for 15 min and subsequently added a solution of 7-chloro-3-(piperidin-4-yl)-lH-indole (3.0 g) in dimethyl formamide (50 mL). The resulting mixture was stirred at room temperature for 1 h and poured onto an ice/water mixture. The compound was isolated by filtration and dissolved in tetrahydrofuran. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 7-chloro-3-{l-[2-(2-methyl-5-nitrophenyl)-l-oxoethyl]- piperidin-4-yl}-lH-indole (4.7 g). A mixture of 7-chloro-3-{l-[2-(2-methyl-5-nitrophenyl)- l-oxoethyl]-piperidin-4-yl}-lH-indole (16.6 g) and ethanol (500 mL) was heated to reflux temperature and subsequently added concentrated ΗC1 (22 mL) and iron powder (11.3 g) over a period of 30 min. The resulting mixture was boiled under reflux for an additional 90 min, filtered hot and concentrated in vacuo. The residue was dissolved in tetrahydrofuran, and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give give 7-chloro-3-{l-[2-(5-amino-2-methylphenyl)-l-oxoethyl]-piperidin-4-yl}- lH-indole (14.3 g). A suspension of lithium aluminium hydride (6.4 g) in tetrahydrofuran
(250 mL) was cooled (5 °C) and subsequently added a mixture of 7-chloro-3-{l-[2-(5- amino-2-methylphenyl)-l-oxoethyl]-piperidin-4-yl}-lH-indole (16.0 g) in tefrahydrofuran (250 mL). The resulting mixture was boiled under reflux for 90 min, cooled to 5 °C and quenched by the addition of water. The mixture was dried (MgSO4), stirred for 10 min, filtered and concenfrated in vacuo to give 7-chloro-3-{l-[2-(5-amino-2- methylphenyl)ethyl]piperidin-4-yl}-lH-indole (12.4 g). A solution of 7-chloro-3-{l-[2-(5- amino-2-methylphenyl)ethyl]piperidin-4-yl}-lH-indole (1.0 g) and N- ethyldiisopropylamine (0.7 g) in tetrahydrofuran (25 mL) was cooled (5 °C ) and subsequently added a solution of (4-fluorophenyl)acetyl chloride in tetrahydrofuran (25 mL). The resulting mixture was stirred at room temperature for 1 h and subsequently poured onto brine. The aqueous phase was extracted with tetrahydrofuran, and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/heptane/triethylamine 70:30:5) to give the product (0.81 g). LC/MS (m/z) 504 (MΗ+), RT = 2.45, purity: 62%.
The following compounds were prepared in a similar manner
4b, 3-[l-(2-{5-f2-(4-Methoxyphenyl)ethanoylamino]-2-methylphenyl}ethyl)piperidin-4-ylJ-
7-chloro-lH-indole from 7-chloro-3-{l-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-lH-indole and (4- methoxyphenyl)acetyl chloride. LC/MS (m/z) 516 (MΗ+), RT = 2.35, purity: 61%.
4c, 3-[l-(2-{5-[(Cyclobutylmethanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-7- chloro-lH-indole from 7-chloro-3- { 1 -[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl} - lH-indole and cyclobutanecarbonyl chloride. LC/MS (m/z) 450 (MΗ+), RT = 2.19, purity: 62%.
4d, 3-(l-{2-[5-(benzoylamino)- 2-Methylphenyl]ethyl}piperidin-4-yl)-7-clιloro-lH-indole from 7-chloro-3- { 1 -[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl} - lH-indole and benzoyl chloride. LC/MS (m/z) 472 (MH+), RT = 2.47, purity: 94%. 4e, 3-(l-{2-[5-(4-Fluorobenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-lH- indole from 7-chloro-3-{l-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-lH-indole and 4- fluorobenzoyl chloride. LC/MS (m/z) 490 (MΗ+), RT = 2.40, purity: 74%.
4f, 3-(l-{2-[5-(4-Methoxybenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-lH- indole from 7-chloro-3-{l-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-lH-indole and 4- methoxybenzoyl chloride. LC/MS (m/z) 502 (MH+), RT = 2.39, purity: 85%.
4g, 3-fl-(2-{2-Methyl-5-f(pyridin-3-ylmethanoyl)aminoJphenyl}ethyl)piperidin-4-ylJ-7- chloro-lH-indole from 7-chloro-3-{l-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-lH-indole and nicotinoyl chloride. LC/MS (m/z) 473 (MΗ+), RT = 1.85, purity: 75%.
4h, 3-fl-(2-{2-Methyl-5-[(pyridin-4-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7- chloro-lH-indole from 7-chloro-3- { 1 -[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl} - lH-indole and isonicotinoyl chloride. LC/MS (m/z) 473 (MH+), RT = 1.84, purity: 80%.
4i, 3-[l-(2-{2-Methyl-5-[(thiophen-2-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7- chloro-lH-indole from 7-chloro-3- { 1 -[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl} - lH-indole and thiophene-2-carbonyl chloride. LC/MS (m/z) 478 (MH+), RT = 2.34, purity: 95%.
4j, 3-[l-(2-{2-Methyl-5-[(tlιiophen-3-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7- chloro-lH-indole from 7-chloro-3- { 1 -[2-(5-amino-2-methylphenyl)ethyl]piρeridin-4-yl} - lH-indole and thioρhene-3-carbonyl chloride. LC/MS (m/z) 478 (MH+), RT = 2.31, purity: 77%.
4k, 3-fl-(2-{2-Methyl-5-f(l-fl,2,3Jthiadiazol-5-ybnethanoyl)aminoJphenyl}ethyl)piperidin-
4-ylJ- 7-chloro- lH-indole from 7-chloro-3-{l-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-lH-indole and [l,2,3]thiadiazole-5-carbonyl chloride. LC/MS (m/z) 480 (MΗ+), RT = 2.24, purity: 69%.
Pharmacological Testing
The compounds of the invention were tested in well-recognised and reliable tests. The tests were as follows:
Inhibition of the binding of [ H]YM-0915l-2 to human dopamine D4 receptors
By this method, the inhibition by drugs of the binding of [3H]YM-09151-2 (0.06 nM) to membranes of human cloned dopamine D4. receptors expressed in CHO-cells is determined in vitro. The method is modified from NEN Life Science Products, Inc., technical data certificate PC2533-10/96. In table 1 below, the test results are shown:
Figure imgf000031_0001
The compounds of the invention have been found potently to inhibit the binding of tritiated
YM-09151-2 to dopamine D4 receptors.
The compounds have also been tested in a functional assay described by Gazi et al. in Br. J. Pharmacol. 1999, 128, 613-629. In this test, the compounds were shown to be partial agonists or antagonists at dopamine D receptors.
The compounds of the invention have also been tested in the following tests:
Inhibition of the binding of [3H] Spiperone to D2 receptors
The compounds were tested with respect to affinity for the dopamine D2 receptor by determining their ability to inhibit the binding of [ H] Spiperone to D receptors by the method of Hyttel et al. J. Neurochem. 1985, 44, 1615.
Inhibition of the uptake of [3H] Serotonin into whole rat brain synaptosomes
The compounds were tested with respect to their 5-HT reuptake inhibiting effect by measuring their ability to inhibit the uptake of [ H] Serotonin into whole rat brain synaptosomes in vitro. The assay was performed as described by Hyttel Psychopharmacology 1978, 60, 13.
Inhibition of the binding of [3H]Ketanserin to 5-HT2A receptors
The compounds were tested with respect to their affinity for 5-HT A receptors by determining their ability to inhibit the binding of [ HJKetanserin (0.50 nM) to membranes from rat brain (cortex) in vitro. Method described in Sanchez et al. DrugDev. Res. 1991, 22, 239-250.
5-HT2c receptor efficacy as determined by fiuorometry
The compounds were tested with respect to their efficacy on 5-HT2c receptor-expressing CHO cells as determined by fluorometric imaging plate reader (FLIPR) analysis. This assay was carried out according to Molecular Devices Inc. instructions for their FLIPR Calcium
Assay Kit and as modified from Porter et al. Br. J. Pharmacol. 1999, 128, 13.
The compounds were found to have no substantial or only weak affinity for the dopamine D2 receptor. Many of the compounds were also found to have affinity for 5-HT2A receptors and serotonin reuptake inhibiting activity.
Thus, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, side effects induced by conventional antipsychotic agents, migraine, and in the improvement of sleep. In particular the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia without inducing extrapyramidal side effects.
Formulation Examples
The pharmaceutical formulations of the invention may be prepared by conventional methods in the art.
For example: Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients. Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilising the solution and filling it in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
Typical examples of recipes for the formulation of the invention are as follows: 1) Tablets containing 5.0 mg of a compound of the invention calculated as the free base:
Compound 5.0 mg Lactose 60 mg
Maize starch 30 mg
Hydroxypropylcellulose 2.4 mg
Microcrystalline cellulose 19.2 mg
Croscarmellose Sodium Type A 2.4 mg Magnesium stearate 0.84 mg
2) Tablets containing 0.5 mg of a compound of the invention calculated as the free base:
Compound 0.5 mg
Lactose 46.9 mg
Maize starch 23.5 mg
Povidone 1.8 mg
Microcrystalline cellulose 14.4 mg
Croscarmellose Sodium Type A 1.8 mg
Magnesium stearate 0.63 mg
3) Syrup containing per millilitre:
Compound 25 mg
Sorbitol 500 mg
Hydroxypropylcellulose 15 mg
Glycerol 50 mg
Methyl-paraben l mg
Propyl-paraben 0.1 mg
Ethanol 0.005 ml
Flavour 0.05 mg
Saccharin sodium 0.5 mg
Water ad 1 ml ) Solution for injection containing per millilifre:
Compound 0.5 mg
Sorbitol 5.1 mg
Acetic Acid 0.05 mg
Saccharin sodium 0.5 mg
Water ad 1 ml

Claims

Patent Claims
A substituted indole derivative of formula I
Figure imgf000036_0001
wherein R1 is hydrogen or C1-6-alkyl, C2-6-alkenyl, C -6-alkynyl, C3-8-cycloalkyl or C3-8- cycloalkyl-C1-6-alkyl, all of which may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, hydroxy, thiol, C1-6-alkoxy, C1-6-alkylthio, trifluoromethyl, trifluoromethylsulfonyl and C1-6-alkylsulfonyl, or R1 is aryl, aryl-Ci-6-alkyl, heteroaryl, heteroaryl-C1-6-alkyl where the aryl and heteroaryl groups may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C1-6-alkyl, Cι_6-alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl, or R1 is -NR'R" wherein R' and R" are independently selected from hydrogen and C1-6-alkyl, aryl, aryl-C1-6-alkyl, heteroaryl and heteroaryl-C1-6-alkyl, all of which may be substituted one or more times with substituents selected from halogen, cyano, nifro, amino, C1-6-alkyl, Cι_6 alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl, or R1 is a saturated or partially saturated 5- to 6-membered ring containing one, two or three hetero atoms selected from O or S, and a group N-R9 wherein R9 is hydrogen or C1-6-alkyl optionally substituted with substituents selected from halogen, cyano, nitro, amino, Cι_6-alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl;
W is a bond or an O, S, CO, CS, SO or SO2 group;
n is 0-6, m is 0-6 and n+m is 0-6; provided that when W is O or S, n > 2, and when W is CO, CS, SO or SO2, n > 1;
X is C, CH or N and the dotted line emanating from X indicates a bond when X is C and no bond when X is N or CH; R2 is Ci-β-alkyi;
R -R are selected from hydrogen, halogen, cyano, nitro, amino, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C -8-cycloalkyl-C1-6-alkyl, Cι_6-alkoxy, C1-6-alkylthio, hydroxy, thiol, trifluoromethyl, trifluoromethylsulfonyl and C1-6 alkylsulfonyl;
R is hydrogen, C1-6-alkyl, C -6-alkenyl, C2-6-alkynyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6- alkyl, aryl, aryl-C1-6-alkyl, acyl, thioacyl, C1-6-alkylsulfonyl, trifluoromethylsulfonyl, or arylsulfonyl or a pharmaceutically acceptable acid addition salt thereof.
2. The compound according to claim 1, wherein the indole is bound to X via position 3 of the indole.
3. The compound according to claims 1-2, wherein W is a bond.
4. The compound according to claim 3, wherein n + m is 2.
5. The compound according to claims 1-4, wherein R2 is a methyl group.
6. The compound according to claims 1 or 5, wherein the group -NH-CO-R1 is attached to the phenyl group in a position para to the position of the R group.
7. The compound according to claims 1 or 6, wherein R1 is C1-6-alkyl, C -8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, wherein the phenyl groups may be substituted one or more times with substituents selected from halogen, cyano, nitro, amino, C1-6-alkyl, Cι_6-alkoxy, C1-6- alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C1-6-alkylsulfonyl, or R1 is -NR'R" wherein one of R' and R" is hydrogen and the other of R' and R" is selected from Ci. 6-alkyl, phenyl and phenyl-C1-6-alkyl, wherein the phenyl groups may be substituted one or more times with substituents selected from halogen, cyano, nifro, amino, C1-6-alkyl, d_6- alkoxy, C1-6-alkylthio, hydroxy, trifluoromethyl, trifluoromethylsulfonyl and C1-6- alkylsulfonyl, or R1 is a tetrahydropyranyl or a morpholino, thiomorpholino, piperidino, piperazino or a N-(hydroxy-C1-6-alkyl)piperazinyl group.
8. The compound according to claim 1 selected from
3-(l-{2-[5-(Acetylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-lH-indole;
3-(l-{2-[5-(Cyclobutylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro- lH-indole; 3-(l-{2-[5-(Acetylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-lH-indole;
3-(l-{2-[2-Methyl-5-(thiophen-2-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5- chloro-lH-indole;
3-(l-{2- [2-Methyl-5 -(3 -methoxybenzoylamino)phenyl] ethyl} piperidin-4-yl)-5 -chloro- 1 H- indole; 3-(l-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro- lH-indole;
3-(l-{2-[2-Methyl-5-(thiophen-2-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro- lH-indole;
3-(l-{2-[5-(Isobutanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-lH-indole; 3-(l-{2-[2-Methyl-5-(pivaloylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-lH-indole;
3 -( 1 - {2- [5 -(Hexanoylamino)-2-methylphenyl] ethyl} piperidin-4-yl)-5 -fluoro- 1 H-indole;
3-(l-{2-[5-(4-Fluorobenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-lH- indole;
3-(l-{2-[5-(3-Methoxybenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro-lH- indole;
3-(l-{2-[2-Methyl-5-(pyridin-3-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro- lH-indole;
3-(l-{2-[2-Methyl-5-(3-phenylpropanoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-lH- indole; 3-(l-{2-[2-Methyl-5-(4-methylbenzoylamino)phenyl]ethyl}piperidin-4-yl)-5-fluoro-lH- indole;
3-(l-{2-[2-Methyl-5-(3-Methyl-3-phenylureido)phenyl]ethyl}ρiperidin-4-yl)-6-chloro-lH- indole;
3-(l-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro- lH-indole;
3-(l-{2-[2-Methyl-5-(tMophen-2-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-6-chloro- lH-indole;
3-(l-{2-[5-(Isobutanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-lH-indole; 3-(l-{2-[5-(3-Methoxybenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-6-chloro-lH- indole;
3-(l-{2-[2-Methyl-5-(jpyridin-3-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-6-chloro- lH-indole; 3-[l-(2-{5-[2-(4-Methoxyphenyl)ethanoylamino]-2-methylphenyl}ethyl)piperidin-4-yl]-6- chloro-lH-indole;
3-(l-{2-[2-Methyl-5-(4-methylbenzoylamino)phenyl]ethyl}piperidin-4-yl)-6-chloro-lH- indole;
3-[l-(2-{5-[(Cyclopentylmethanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-6-chloro- lH-indole;
3 -( 1 - {2- [2-Methyl-5 -(morfolin-4-ylmethanoylamino)phenyl] ethyl} piperidin-4-yl)-5 -fluoro- lH-indole;
3 - [ 1 -(2- { 5- [3 -(4-Fluorophenyl)ureido]-2-methylphenyl} ethyl)piperidin-4-yl] -5 -fluoro- 1 H- indole; 3-(l-{2-[5-(Hexanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-lH-indole;
3-(l-{2-[2-Methyl-5-(tefrahydropyran-4-ylmethanoylamino)phenyl]ethyl}piperidin-4-yl)-5- fluoro-lH-indole;
3-(l-{2-[5-(4-Chlorobenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-lH- indole; 3-(l-{2-[5-(3-Cyclohexylpropanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-5-fluoro- lH-indole;
3-[l-(2-{5-[(3-Phenylpropanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-7-chloro-lH- indole;
3-[l-(2-{5-[(2-Phenylethanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-7-chloro-lH- indole;
3-(l-{2-[2-Methyl-5-(4-methylbenzoylamino)phenyl]ethyl}piperidin-4-yl)-7-chloro-lH- indole;
3-(l-{2-[5-(Cyclopropylmethanoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro- lH-indole; 3-[l-(2-{5-[2-(4-Fluorophenyl)ethanoylamino]-2-methylphenyl}ethyl)piperidin-4-yl]-7- chloro- 1 H-indole;
3-[l-(2-{5-[2-(4-Methoxyphenyl)ethanoylamino]-2-methylphenyl}ethyl)piperidin-4-yl]-7- chloro- 1 H-indole; 3-[l-(2-{5-[(Cyclobutylmethanoyl)amino]-2-methylphenyl}ethyl)piperidin-4-yl]-7-chloro-
1 H-indole;
3 -( 1 - {2- [5 -(benzoylamino)- 2-Methylphenyl] ethyl} piperidin-4-yi)-7-chloro- 1 H-indole;
3-(l - {2-[5-(4-Fluorobenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro- 1H- indole;
3-(l-{2-[5-(4-Methoxybenzoylamino)-2-methylphenyl]ethyl}piperidin-4-yl)-7-chloro-lH- indole;
3-[l-(2-{2-Methyl-5-[(pyridin-3-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7-chloro-
1 H-indole; 3-[l-(2-{2-Methyl-5-[(pyridin-4-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7-chloro-
1 H-indole;
3-[l-(2-{2-Methyl-5-[(thiophen-2-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7- chloro-lH-indole;
3-[l-(2-{2-Methyl-5-[(thiophen-3-ylmethanoyl)amino]phenyl}ethyl)piperidin-4-yl]-7- chloro-1 H-indole;
3-[l-(2-{2-Methyl-5-[(l-[l,2,3]thiadiazol-5-ylmethanoyl)amino]phenyl}ethyl)- piperidin-4- yl]-7-chloro-lH-indole;
3-{l-[2-(5-Acetylamino-2-methylphenyl)-ethyl]-3,6-dihydro-2H-pyridin-4-yl}-5-fluoro-7H- indole; 3-[ 1 -(2- {2-Methyl-5-[(pyridin-3-ylmethanoyl)-amino]-phenyl} -ethyl)-3,6-dihydro-2H- pyridin-4-yl]- 5-fluoro-7H-indole;
3-[l-(2-{5-[(4-Fluorophenylmethanoyl)-amino]-2-methylphenyl}-ethyl)-3,6-dihydro-2H- pyridin-4-yl]- 5-fluoro-7H-indole;
3-{l-[2-(5-Acetylamino-2-methylphenyl)-ethyl]-3,6-dihydro-2H-pyridin-4-yl}-7-chloro- iH-indole;
3-[l-(2-{2-Methyl-5-[(pyridin-3-ylmethanoyl)-amino]-phenyl}-ethyl)-3,6-dihydro-2H- pyridin-4-yl]- 7-chloro-2H-indole and
3-[l-(2-{5-[(4-Fluorophenylmethanoyl)-amino]-2-methylphenyl}-ethyl)-3,6-dihydro-2H- pyridin-4-yl]- 7-chloro-7H-indole or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition characterised in that it comprises a compound of any of claims 1 to 8 in a therapeutically effective amount together with one or more pharmaceutically acceptable carriers or diluents.
10. Use of a compound of any of claims 1 to 8 for the manufacture of a medicament useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, aggression, side effects induced by conventional antipsychotic agents, migraine, cognitive disorders, ADHD and in the improvement of sleep.
11. A method of treating the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, aggression, side effects induced by conventional antipsychotic agents, migraine, cognitive disorders, ADHD and in the improvement of sleep comprising administration of a therapeutically acceptable amount of a compound according to ■ any of claims 1 to 8.
PCT/DK2001/000507 2000-07-21 2001-07-17 Indole derivatives useful for the treatment of cns disorders WO2002008223A1 (en)

Priority Applications (26)

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CA002416212A CA2416212C (en) 2000-07-21 2001-07-17 Indole derivatives useful for the treatment of cns disorders
UA2003010167A UA73995C2 (en) 2000-07-21 2001-07-17 Indole derivatives being useful for the treatment of cns disorders,, a pharmaceutical composition and a method for treatment
AU8173801A AU8173801A (en) 2000-07-21 2001-07-17 Indole derivatives useful for the treatment of cns disorders
AT01960182T ATE266024T1 (en) 2000-07-21 2001-07-17 INDOLE DERIVATIVES THAT CAN BE USED TO TREAT DISORDERS OF THE CNS
EA200300179A EA004749B1 (en) 2000-07-21 2001-07-17 Indole derivatives useful for the treatment of cns disorders
SI200130124T SI1305307T1 (en) 2000-07-21 2001-07-17 Indole derivatives useful for the treatment of cns disorders
HU0302820A HUP0302820A3 (en) 2000-07-21 2001-07-17 Indole derivatives useful for the treatment of cns disorders and pharmaceutical compositions containing them
KR1020037000850A KR100851793B1 (en) 2000-07-21 2001-07-17 Indole derivatives useful for the treatment of cns disorders
AU2001281738A AU2001281738B2 (en) 2000-07-21 2001-07-17 Indole derivatives useful for the treatment of cns disorders
BR0112998-8A BR0112998A (en) 2000-07-21 2001-07-17 Indole derivatives useful for the treatment of central nervous system (snc) disorders; compound; its use; pharmaceutical composition and treatment method
DE60103162T DE60103162T2 (en) 2000-07-21 2001-07-17 INDOLE DERIVATIVES WHICH CAN BE USED TO TREAT DISORDERS OF THE CNS
DK01960182T DK1305307T3 (en) 2000-07-21 2001-07-17 indole derivatives
PL359157A PL203538B1 (en) 2000-07-21 2001-07-17 Substituted indole derivative and its use and pharmaceutical composition
MXPA02012927A MXPA02012927A (en) 2000-07-21 2001-07-17 Indole derivatives useful for the treatment of cns disorders.
EP01960182A EP1305307B1 (en) 2000-07-21 2001-07-17 Indole derivatives useful for the treatment of cns disorders
NZ523436A NZ523436A (en) 2000-07-21 2001-07-17 Indole derivatives useful for the treatment of CNS discorders
IL15360501A IL153605A0 (en) 2000-07-21 2001-07-17 Indole derivatives useful for the treatment of cns disorders
SK203-2003A SK286701B6 (en) 2000-07-21 2001-07-17 Indole derivatives, pharmaceutical composition comprises a indole derivates and use there of
JP2002514129A JP2004504396A (en) 2000-07-21 2001-07-17 Indole derivatives useful for treating CNS disorders
IS6663A IS2172B (en) 2000-07-21 2002-12-23 Indole derivatives useful for the treatment of nervous system disorders
IL153605A IL153605A (en) 2000-07-21 2002-12-24 Indole derivative having affinity for the dopamine d4 receptor, a pharmaceutical composition and use thereof for the manufacture of a medicament for psychiatric and neurological disorders
HR20030015A HRP20030015A2 (en) 2000-07-21 2003-01-09 Indole derivatives useful for the treatment of cns disorders
NO20030127A NO323799B1 (en) 2000-07-21 2003-01-10 Indole derivatives, pharmaceutical compositions containing them and their use.
US10/347,574 US6743809B2 (en) 2000-07-21 2003-01-17 Indole Derivatives useful for the treatment of CNS disorders
BG107528A BG107528A (en) 2000-07-21 2003-02-05 Indole derivatives useful for the treatment of cns disorders
HK04102653A HK1059782A1 (en) 2000-07-21 2004-04-15 Indole derivatives useful for the treatment of cnsdisorders

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DKPA200001123 2000-07-21

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CN (1) CN1264838C (en)
AR (1) AR029858A1 (en)
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WO2006117314A2 (en) 2005-04-30 2006-11-09 Boehringer Ingelheim International Gmbh Novel piperidin- substituted indoles and their use as ccr-3 modulators
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CN110041318B (en) * 2018-01-17 2022-07-29 中国科学院上海药物研究所 Dopamine D5 receptor agonist and preparation and application thereof
CN110498789B (en) * 2018-05-17 2022-04-05 上海医药工业研究院 Aralkyl piperidine derivative and application thereof in multi-target anti-depression

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WO2005049559A2 (en) 2003-11-17 2005-06-02 Boehringer Ingelheim International Gmbh Novel piperidine-substituted indoles- or hetero-derivatives thereof and their use as modulators of chemokine receptor (ccr-3)
US7544806B2 (en) 2003-11-17 2009-06-09 Boehringer Ingelheim International Gmbh Piperidine-substituted indoles-or heteroderivatives thereof
EP1757599A1 (en) * 2004-05-12 2007-02-28 Eisai R&D Management Co., Ltd. Indole derivatives having piperidine rings
EP1757599A4 (en) * 2004-05-12 2010-07-14 Eisai R&D Man Co Ltd Indole derivatives having piperidine rings
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WO2008049874A1 (en) 2006-10-27 2008-05-02 Boehringer Ingelheim International Gmbh Piperidyl-propane-thiol ccr3 modulators

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DE60103162T2 (en) 2005-05-04
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