EP1003739A2 - 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1h-indole derivatives - Google Patents

2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1h-indole derivatives

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Publication number
EP1003739A2
EP1003739A2 EP98935229A EP98935229A EP1003739A2 EP 1003739 A2 EP1003739 A2 EP 1003739A2 EP 98935229 A EP98935229 A EP 98935229A EP 98935229 A EP98935229 A EP 98935229A EP 1003739 A2 EP1003739 A2 EP 1003739A2
Authority
EP
European Patent Office
Prior art keywords
fluoro
disorders
piperazin
hydrogen
ylmethyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP98935229A
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German (de)
English (en)
French (fr)
Inventor
Anton Franz Josef Fliri
Mark Jerome Majchrzak
Patricia Ann Seymour
Stevin Howard Zorn
Hans Rollema
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Products Inc
Original Assignee
Pfizer Products Inc
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Filing date
Publication date
Application filed by Pfizer Products Inc filed Critical Pfizer Products Inc
Publication of EP1003739A2 publication Critical patent/EP1003739A2/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61P25/18—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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1 H- indole derivatives possessing central dopaminergic activity. Such compounds are useful in the treatment of Central Nervous Systems (CNS) disorders.
  • CNS Central Nervous Systems
  • This invention also relates to a method of using such compounds in the treatment of the above disorders in mammals, especially humans, and the pharmaceutical compositions useful therefor.
  • dopamine receptors seem to be important for many functions in the animal body. For example, altered functions of these receptors participate in the genesis of psychosis, drug addiction, compulsive disorders, bipolar disorders, vision, emesis, sleep, feeding, learning, memory, sexual behavior, regulation of immunological responses and blood pressure. Since these receptors control a great number of pharmacological events, not all of them are presently known, there is a possibility that compounds acting preferentially on D4 dopamine receptor may exert a wide range of therapeutic effects in humans.
  • the 2-(4-aryl or heteroaryi-piperazin-1-ylmethyl)-1H-indole derivatives of the present invention are centrally acting D4-dopamine receptor agonists and thus are useful as cognition enhancers and treatment of CNS diseases, such as Parkinsons disease, Alzheimer's disease, learning and memory abnormalities.
  • Another feature of this invention provides for the use of combinations " of compounds of the present invention in conjunction with D1 , D2, D3 or D5 dopamine receptor agonists, such as L- dopa and D2 agonists, in treatment of CNS diseases, such as Parkinson's disease, Alzheimer's disease, attention deficit disorder and learning and memory abnormalities.
  • a is 0 or 1 , wherein when a is 0, X may form an optional double bond with the carbon adjacent to V;
  • V is CHR 10 wherein R 10 is hydrogen or (d-C ⁇ alkyl; T is nitrogen or CH;
  • X is nitrogen or CR 11 wherein R 11 is hydrogen, (Ci-C ⁇ Jalkyl, (CrCeJalkoxy, hydroxy or cyano;
  • Y and Z are each independently nitrogen or CR 12 wherein R 12 is hydrogen, chloro, bromo, trifluoromethyi, trifluoromethoxy, cyano, (C-
  • R 1 is hydrogen, fluoro, chloro, bromo, trifluoromethyi, trifluoromethoxy, cyano or (C C 6 )alkyl; .
  • R 2 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, fluoro, chloro, bromo, trifluoromethyi, trifluoromethoxy, cyano, (C ⁇ C ⁇ Jalkoxy and (C C 6 )alkyl;
  • R 3 and R 4 are each independently hydrogen or (d-CeJalkyl
  • R 5 is hydrogen, (d-C ⁇ alkoxy, trifluoromethyi, cyano, (C C 6 )alkyl or R 13 CO- wherein R 13 is amino, ((C 1 -C 6 )alkyl) 2 amino, (C 1 -C 6 )alkyl, (C 6 - C 10 )aryl; or when a is 1 , R 1 and R 10 may be taken together with the carbons to which they are attached to form a compound of the formula wherein the broken lines represent optional bonds;
  • T, X, Y, Z, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are defined as above; b is 0 or 1 ;
  • a and B are each independently CH, CH 2 , oxygen, sulfur, NH or nitrogen; with the proviso that when X is nitrogen, the optional double bond between X and V does not exist; with the proviso that when b is 0, the optional double bond between A and B does not exist; and with the proviso that when b is 1 , A and B cannot both be oxygen or sulfur.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovending hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
  • alkoxy includes O-alkyl groups wherein "alky! is defined above.
  • treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorders or condition.
  • treatment refers to the act of treating, as “treating” is defined immediately above.
  • disorders of the dopamine system refers to disorders the treatment of which can be effected or facilitated by altering (i.e., increasing or decreasing) dopamine mediated neurotransmission.
  • the compounds in accordance with the present invention being ligands for dopamine receptor subtypes, especially the dopamine D receptor, within the body, are accordingly of use in the treatment of disorders of the dopamine system.
  • the compound of formula I may have chiral centers and therefore exist in different enantiomeric forms.
  • This invention relates to all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof.
  • Preferred compounds of formula I include those wherein X is nitrogen.
  • R 2 is hydrogen, fluoro or chloro.
  • R 3 , R 4 and R 5 are hydrogen.
  • More preferred compounds of formula I include those wherein X is nitrogen; Y and Z are each CR 13 wherein R 3 is hydrogen or fluoro; R 2 is hydrogen fluoro or chloro; R 3 , R 4 and R 5 are hydrogen; R 7 is fluoro or chloro; and R 9 is fluoro, chloro, bromo or alkoxy.
  • Specific preferred compounds of formula I include the following:
  • the present invention also relates to a method for treating disorders of the dopamine system including psychotic disorders (affective psychosis, schizophrenia, and schizoaffective disorders), movement disorders (extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, Gilles De La Tourette's syndrome, Parkinson's disease or Huntington's disease), gastrointestinal disorders (gastric acid secretion or emesis), chemical abuse, chemical dependencies, substance abuse, vascular and cardiovascular disorders (congestive heart failure and hypertension), ocular disorders and sleep disorders in a mammal, comprising administering to said mammal an amount of a D4 dopamine receptor selective compound according to formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.
  • psychotic disorders adjective psychosis, schizophrenia, and schizoaffective disorders
  • movement disorders extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, Gilles De La Tourette'
  • the present invention also relates to a method for treating disorders of the dopamine system including psychotic disorders (affective psychosis, schizophrenia, and schizoaffective disorders), movement disorders (extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, Gilles De La Tourette's syndrome, Parkinson's disease or Huntington's disease), gastrointestinal disorders (gastric acid secretion or emesis), chemical abuse, chemical dependencies, substance abuse, vascular and cardiovascular disorders (congestive heart failure and hypertension), ocular disorders and sleep disorders in a mammal, comprising administering to said mammal an amount of a D4 dopamine receptor selective compound according to formula I, or a pharmaceutically acceptable salt thereof, in conjunction with one or more D1, D2, D3 or D5 dopamine receptor agonists, that is effective in treating such disorder.
  • psychotic disorders adjective psychosis, schizophrenia, and schizoaffective disorders
  • movement disorders extrapyramidal side effects from neuroleptic agents
  • the present invention also relates to a pharmaceutical composition for treating disorders of the dopamine system including psychotic disorders (affective psychosis, schizophrenia, and schizoaffective disorders), movement disorders (extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, Gilles De La Tourette's syndrome, Parkinson's disease or Huntington's disease), gastrointestinal disorders (gastric acid secretion or emesis), chemical abuse, chemical dependencies, substance abuse, vascular and cardiovascular disorders (congestive heart failure and hypertension), ocular disorders and sleep disorders in a mammal, comprising administering to said mammal an amount of a D4 dopamine receptor selective compound according to formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.
  • psychotic disorders adjective psychosis, schizophrenia, and schizoaffective disorders
  • movement disorders extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, Gilles De La Tourette
  • the present invention also relates to a pharmaceutical composition for treating disorders of the dopamine system including psychotic disorders (affective psychosis, schizophrenia, and schizoaffective disorders), movement disorders (extrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, Gilles De La Tourette's syndrome, Parkinson's disease or Huntington's disease), gastrointestinal disorders (gastric acid secretion or emesis), chemical abuse, chemical dependencies, substance abuse, vascular and cardiovascular disorders (congestive heart failure and hypertension), ocular disorders and sleep disorders in a mammal, comprising administering to said mammal an amount of a D4 dopamine receptor selective compound according to formula I, or a pharmaceutically acceptable salt thereof, in conjunction with one or more D1, D2, D3 or D5 dopamine receptor agonists, that is effective in treating such disorder.
  • psychotic disorders adjective psychosis, schizophrenia, and schizoaffective disorders
  • movement disorders extrapyramidal side effects from neuroleptic
  • reaction 1 of Scheme 1 the compounds of formula III and IV are coupled to form the corresponding compound of formula I by first treating III with O-, N- dimethyl hydroxylamine hydrochloride, dicyciohexylcarbodiimide and a base, such as triethylamine, in a polar aprotic solvent, such as methylene chloride.
  • a polar aprotic solvent such as methylene chloride.
  • the hydroxamide intermediate so formed is reduced, using a reducing agent such as lithium aluminum hydride, in a polar aprotic solvent, such as tetrahydrofuran.
  • the reductive amination of the aldehyde intermediate so formed is accomplished by reacting the aldehyde with the compound of the formula IV in the presence of sodium triacetoxyborohydride and a polar aprotic solvent, such as dichloroethane.
  • the reaction mixture is stirred, under inert atmosphere, at room temperature for a time period between about 40 hours to about 56 hours, preferably about 48 hours.
  • the methanone compound of formula V is converted to the corresponding compound of formula I, wherein R 3 and R 4 are hydrogen, by reducing V with a reducing agent, such as lithium aluminum hydride or a borane derivative, in the presence of a polar aprotic solvent, such as tetrahydrofuran, for a time period between about 10 hours to about 14 hours, preferably about 12 hours.
  • a reducing agent such as lithium aluminum hydride or a borane derivative
  • a polar aprotic solvent such as tetrahydrofuran
  • pressure is not critical. Pressures in th range of about 0.5 atmospheres to 3 atmospheres are suitable, and ambient pressure (generally, about one atmosphere) is preferred as a matter of convenience. Also, for those reactions where the preferred temperature varies with the particular compounds reacted, no preferred temperature is stated. For such reactions, preferred temperatures for particular reactants may be determined by monitoring the reaction using thin layer chromatography.
  • novel compounds of the formula I and the pharmaceutically acceptable salts thereof are useful as dopaminergic agents, i.e., they possess the ability to alter dopamine mediated neurotransmission in mammals, including humans. They are therefore able to function as therapeutic agents in the treatment of a variety of conditions in mammals, the treatment or prevention of which can be effected or facilitated by an increase or decrease in dopamine mediated neurotransmission.
  • the compounds of the formula I that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
  • the therapeutic compounds of this invention can be administered orally, transdermally (e.g. through the use of a patch), parenterally or topically. Oral administration is preferred. In general, these compounds are most desirably administered in dosages ranging from about 0.1 mg up to about 1000 mg per day, or 1 mg to 1000 mg per day in some cases, although variations may occur depending on the weight and condition of the person being treated and the particular route of administration chosen. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • the therapeutic compounds of the invention may be administered alone or in combination with pharmaceutically acceptable earners or diluents by either of the two routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the novel therapeutic compounds of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, for example. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intra-articuiar, intramuscular and subcutaneous injection purposes.
  • the preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
  • D Receptor Binding Ability The determination of D 4 receptor binding ability has been described by Van Tol, et al. (Nature, 1991, 350, 610). Clonal cell lines expressing the human dopamine D 4 receptor are harvested and homogenized (polytron) in a 50 mM Tris:HCI (pH 7.4 at 4 °C) buffer containing 5 mM EDTA, 1.5 mM calcium chloride (CaCI 2 ), 5 mM magnesium chloride (MgCI 2 ), 5 mM potassium chloride (KCI) and 120 mM sodium chloride (NaCI). The homogenates are centrifugated for 10-15 min.
  • tissue homogenate is incubated in triplicate with increasing concentrations of (70.3 Ci/mmol; 10-3000 pM final concentration) for 30- 120 minutes at 22 °C in a total volume of 1 ml.
  • assays are initiated by the addition of 0.75 ml of membrane and incubated in duplicate with the indicated concentrations of competing ligands (10 "14 -10 "3 M) and/or [ 3 H]- spiperone (100-300 pM) for 60-120 min at 22°C.
  • CHO cells expressing the human D4.4 dopamine receptor were obtained from Dr. H. Van Tol (Clarke Institute of Psychiatry, Toronto), and were grown to confluence in Minimal Essential Alpha Media (Gibco) supplemented with 2.5% Fetal Bovine Serum (not heat inactivated), 2.5% Equine Serum (heat inactivated), and 500 ⁇ g/ml Geneticin.
  • Monolayers were disrupted and cells disloged with 5 mM ethylenediaminetetraacetic acid (EDTA) and resuspended in phosphate buffered saline buffer containing 5 mM magnesium chloride, 30 mM hydroxyethylpiperazine-N-ethanesulfonic acid (HEPES), 300 ⁇ M 3-isobutyl-1-methyl- xanthine (IBMX, a phosphodiesterase inhibitor), and 5.6 mM dextrose.
  • EDTA ethylenediaminetetraacetic acid
  • HEPES hydroxyethylpiperazine-N-ethanesulfonic acid
  • IBMX 3-isobutyl-1-methyl- xanthine
  • EXAMPLE 2 5-Fluoro-1 H-indol-2-yl)-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl1-methanone A mixture of 1.0 mmol of 5-fluoro, 2-indole carboxylicacidchloride and 230 mg of meta-trifiuoromethylphenylpiperazine and 129 mg of diisopropylethylamine in 10 ml methylenchloride is kept at ambient temperature for 12 hours. Water is added, the organic layers separated, washed with wate, dried over sodium sulfate and concentrated to yield 296 mg of the title compound. MP: 198°C. EXAMPLE 3
  • -1 H-indole hydrochloride A solution of 275 mg of 5-Fluoro-1 H-indol-2-yl)-[4-(3-trifluoromethyl-phenyl)- piperazin-1-yl]methanone in 5 ml anhydrous tetrahydrofurane is kept under an inert gas atmosphere and is treated at ambient temperature with 2.11 ml of a 1M solution of Lithiumaluminumhydride in tetrahydrofurane.
  • EXAMPLE 42 (2' ⁇ . 3'a ⁇ . 5' ⁇ . 6'a ⁇ V2-Fluoro-4-r4-(3. 3'. 3'a. 4. 4'. 5'. 6'. a-hexahydrospiropH- 1 -benzopyran-2.2'(1 'W-oentalen]- 5'-yh-1 -piperazinyl]-benzonitrile maleate
  • EXAMPLE 52 (2' ⁇ . 3'a ⁇ . 5' ⁇ . 6'a ⁇ -Phenyl-4-(3. 3'. 3'a. 4. 4'. 5'. 6'. 6'a-hexahvdrospiro[2H-1- benzopyran-2.2'(1 ⁇ pentaleny5'-vl -5'-vlVpiperazine maleate
  • EXAMPLE 53 (2' ⁇ . 3'a ⁇ . 5' ⁇ . 6'a ⁇ 1-Phenyl-4-(3. 3'. 3'a. 4. 4'. 5'. 6'. 6'a-hexahvdrospiro H-1- benzopyran-2.2'(1 ⁇ Vpentalen]-5'-yl]-5'-yl)-piperazine maleate
  • EXAMPLE 54 (2' ⁇ . 3'a ⁇ . 5' ⁇ . 6'a ⁇ 3-f5'-(4-Phenvl-piperazin-1-vn- octahvdro-pentalen-2'-yl]- 1 H-indole maleate
  • EXAMPLE 56 (2' ⁇ . 3'a ⁇ . 5' ⁇ . 6'a ⁇ V1-Phenyl-4-(5'-phenyl-octahvdro-pentalen-2'-vn-piperazine maleate
  • EXAMPLE 77 (2' ⁇ . 3'a ⁇ . 5' ⁇ . 6'aB)-5-Fluoro-2-r4-(3'. 3'a. 4'. 5'. 6'. 6'a-hexahvdro-3'a fi'a- dimethylspiropsobenzofuran-1 (3H 2'(1 'H)-pentalen -5'-vh-1 -piperazinyl]-pyrimidine maleate MP: 222-223°C. NMR DMSO d 6 ⁇ 8.58 (s, 2H), 7.34-7.30 (m, 1H), 7.28-7.25 (m,

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EP98935229A 1997-08-15 1998-08-05 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1h-indole derivatives Withdrawn EP1003739A2 (en)

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US5576497P 1997-08-15 1997-08-15
US55764P 1997-08-15
PCT/IB1998/001198 WO1999009025A2 (en) 1997-08-15 1998-08-05 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1h-indole derivatives interacting with the dopamine d4 receptor

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PL338947A1 (en) 2000-12-04
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NO20000722D0 (no) 2000-02-14
WO1999009025A3 (en) 1999-04-15
AU8457298A (en) 1999-03-08
WO1999009025A2 (en) 1999-02-25
HRP980441A2 (en) 1999-04-30
EA200000023A1 (ru) 2000-08-28
AR017019A1 (es) 2001-08-22
CA2297486A1 (en) 1999-02-25
BR9811557A (pt) 2000-08-22
TNSN98151A1 (fr) 2005-03-15
CN1265660A (zh) 2000-09-06
DZ2583A1 (fr) 2003-02-22
AP9801321A0 (en) 2000-02-14
TR200000414T2 (tr) 2000-08-21
SK1352000A3 (en) 2000-08-14
PA8457001A1 (es) 2000-09-29
KR20010022507A (ko) 2001-03-15
ZA987304B (en) 2000-02-14
PE106299A1 (es) 1999-11-02
ID23803A (id) 2000-05-11
CO4960656A1 (es) 2000-09-25
HUP0003425A2 (hu) 2001-10-28
CA2297486C (en) 2005-05-03
MA24632A1 (fr) 1999-04-01
HUP0003425A3 (en) 2002-02-28
BG104069A (en) 2001-05-31
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OA11286A (en) 2003-10-22
NO20000722L (no) 2000-02-14

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