WO2003002543A1 - Pyrimidinoxyalkylpiperazines et leur usage therapeutique - Google Patents

Pyrimidinoxyalkylpiperazines et leur usage therapeutique Download PDF

Info

Publication number
WO2003002543A1
WO2003002543A1 PCT/EP2002/007183 EP0207183W WO03002543A1 WO 2003002543 A1 WO2003002543 A1 WO 2003002543A1 EP 0207183 W EP0207183 W EP 0207183W WO 03002543 A1 WO03002543 A1 WO 03002543A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
alkyl
pyrimidinoxyalkylpiperazines
phenyl
alkoxy
Prior art date
Application number
PCT/EP2002/007183
Other languages
English (en)
Inventor
Dorothea Starck
Kai Blumbach
Ernst Buschmann
Original Assignee
Abbott Laboratories
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
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of WO2003002543A1 publication Critical patent/WO2003002543A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • 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
    • A61P25/24—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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • the present invention relates to pyrimidinoxyalkylpiperazines and their therapeutic use.
  • the compounds possess valuable therapeutic properties and can be used, in particular for treating diseases which respond to modulation of the dopamine D 3 receptor.
  • Neurones obtain their information by way of G protein- coupled receptors, inter alia. There are a large number of substances which exert their effect by way of these receptors . One of these substances is dopamine .
  • D 3 receptors are principally expressed in the limbic system, it is assumed that, while a selective D 3 ligand should probably have the properties of known antipsychotic agents, it should not have their dopamine D 2 receptor-mediated neurological secondary effects (P. Sokoloff et al . , Localization and Function of the D 3 Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1), 224 (1992); P. Sokoloff et al . , Molecular Cloning and Characterization of a Novel Dopamine Receptor (D 3 ) as a Target for Neuroleptics, Nature, 347, 146 (1990)).
  • WO 96/02519 discloses substituted pyrimidine compounds of the Formula
  • R x , R 2 , R 3 , A, B and Ar have defined meanings.
  • the compounds of WO 96/02519 are selective dopamine D 3 receptor ligands and are effective, inter alia, for treating schizophrenia, depression and psychoses.
  • the invention is therefore based on the object of making available selective dopamine D 3 receptor ligands which exhibit a high degree of bioavailability.
  • n an integer from 2 to 6
  • Ri represents H, C ⁇ -C 6 -alkyl or phenyl- (C ⁇ -C 6 ) -alkyl in which the phenyl radical can be substituted by one or more substituents selected from d-C 6 -alkyl and C ⁇ -C 6 - alkoxy,
  • R represents H, C 1 -C 4 -alkyl, OH, C x -C 3 -alkoxy, NH 2 or C ⁇ -C 6 -halogenoalkyl,
  • R 3 and R 4 independently of each other, represent H, C - Cg-alkyl, C ⁇ -C 6 -hydroxyalkyl, C ⁇ -C 3 -halogenoalkyl, pyrrolyl or phenyl, which latter can be substituted by one or more substituents selected from Ci-Cg-alkyl, Ci- C 6 -hydroxyalkyl, C ⁇ -C 6 -alkoxy, OH, halogen or C ⁇ -C 3 - halogenoalkyl , phenyl, cyano or nitro,
  • radicals R 3 and R 4 on the pyrimidine ring are in each case arranged in the m position (metaposition) in relation to each other and to the piperazine substituent on the pyrimidine ring, and at least one of the radicals R 3 and R 4 represents C 3 -C 6 -alkyl or C 3 -C 6 -hydroxyalkyl, which in each case possesses a branched alkyl chain or is bonded to the pyrimidine ring by way of a secondary carbon atom, or trifluoromethyl ,
  • Halogen denotes: fluorine, chlorine, bromine or iodine
  • C ⁇ -C 6 -alkyl denotes: methyl, ethyl, propyl, 1- methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methyl- butyl, 3 -methylbutyl , 2, 2-dimethylpropyl, 1- ethyl - propyl, hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,
  • C x -C 6 -alkoxy denotes; C ⁇ -C 3 -alkyloxy containing a C ⁇ -C 6 -alkyl radical as mentioned above;
  • Ci-Ce-halogenoalkyl denotes: a C ⁇ -C 6 -alkyl radical, as mentioned above, in which one or more hydrogen atoms is/are substituted by fluorine, chlorine, bromine and/or iodine;
  • Ci-Cg-hydroxyalkyl denotes: a C ⁇ -C 6 -alkyl radical, as mentioned above, in which one or more hydrogen atoms is/are replaced with hydroxyl groups;
  • (hydroxy) alkyl radical is linked to the basic molecule, is linked to 2 or 3 further carbon atoms in the
  • (hydroxy) alkyl radical such as 1-methylethyl, 1-methylpropyl, 1, 1-dimethylethyl, 1-methylbutyl, 1-ethylpropyl, 1, 1-dimethylpropyl, 1-methylpentyl, 1,1- dimethylbutyl , 1-ethylbutyl, 1, 1, 2-trime hylpropyl, 1- ethyl-1-methylpropyl and l-ethyl-3-methylpropyl; or the said radicals in which one or more hydrogen atoms is/are replaced with hydroxyl groups.
  • At least one of the radicals R 3 and R 4 preferably represents C 3 -C 6 -alkyl which is bonded to the pyrimidine ring by way of a secondary or tertiary carbon atom, preferably 1-methylethyl or 1, 1-dimethylethyl, or C 3 -C 6 - hydroxyalkyl which is bonded to the pyrimidine ring by way of a secondary or tertiary carbon atom, preferably 2-hydroxy-1-methylethyl or 2-hydroxy-l, 1-dimethylethyl .
  • Ri preferably represents H or benzyl whose phenyl radical can be substituted by one or more, preferably 1, 2 or 3, C ⁇ -C 6 -alkoxy radicals, for example 3, 4-dimethyloxybenzyl, 4-methoxybenzyl, 2, 3 , 4-trimethoxy- benzyl, 3,4, 5-trimethoxybenzyl or 2, 5-dimethoxybenzyl .
  • Ri represents, in particular, H.
  • R 2 preferably represents H, methyl, ethyl, OH, C ⁇ -C 6 - alkoxy, trifluoromethyl or difluoromethyl; and in particular represents H or OH.
  • R 3 and R 4 preferably represent, independently of each other, H, Ci-C 3 -alkyl, C ⁇ -C 6 -hydroxyalkyl, C ⁇ -C 3 -halo- genoalkyl or phenyl, which latter can be substituted by one or more substituents selected from C ⁇ -C 6 -alkyl, C x - C 6 -alkoxy, halogen or phenyl.
  • n preferably represents 3 or 4.
  • Preferred embodiments of the pyrimidinoxyalkyl- piperazines according to the invention are those of the Formula la
  • R lf R 2 , R 3 , R and n have the abovementioned meanings and preferred meanings .
  • More strongly preferred embodiments of the pyrimidinoxyalkylpiperazines of the Formula la are those in which R 3 represents C 3 -C 6 -alkyl which is bonded to the pyrimidine ring by way of a tertiary carbon atom, and
  • R 4 represents C ⁇ -C 6 -alkyl, C ⁇ -C 6 -halogenoalkyl or phenyl, which latter can be substituted by one or more substituents selected from C ⁇ -C 6 -alkyl, C ⁇ -C 6 -alkoxy, halogen or phenyl .
  • pyrimidinoxyalkylpiperazines of the Formula la are those in which R 3 represents trifluoromethyl and R 4 represents C ⁇ -C 6 - alkyl, C ⁇ -C 6 -halogenoalkyl or phenyl.
  • the invention also encompasses the acid addition salts of the pyrimidinoxyalkylpiperazines of the Formula I with physiologically tolerated acids.
  • physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid and benzoic acid.
  • Other acids which can be used are described in Fort Whitneye der Arzneistoff- utz [Advances in Drug Research] , Volume 10, p. 224 ff., Birkhauser-Verlag, Basel and Stuttgart, 1966.
  • the invention also relates to the piperazine-N-oxides of compounds of the Formula I which can be depicted by the following formula
  • oxidizing agent in particular an inorganic or organic peroxide or hydroperoxide, such as hydrogen peroxide, or percarboxylic acids, such as peracetic acid, perbenzoic acid or m-chloroperbenzoic acid.
  • the pyrimidinoxyalkylpiperazines of the Formula I can be prepared in a variety of ways . They are preferably obtained using one of the following processes A or B.
  • the compounds according to the invention can be obtained by reacting a compound of the Formula II
  • Yi represents a leaving group which can be displaced nucleophilically, such as halogen, C ⁇ -C 6 - alkylthio, C ⁇ -C 6 -alkylsulphonyl, C ⁇ -C 3 -alkylsulphinyl or the like, and Ri, R 2 R3 R and n have the meaning which have already been indicated.
  • the reaction is preferably carried out in the presence of a diluent.
  • a diluent All the solvents which are inert towards the reagents employed can be used for this purpose.
  • these diluents are water and aliphatic, alicyclic and aromatic hydrocarbons which can in each case be chlorinated, where appropriate, such as hexane, cyclohexane, petroleum ether, ligroin, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers, such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, dioxane and tetrahydrofuran, ketones, such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl
  • the reaction is preferably carried out in a temperature range of between 0°C and the boiling point of the diluent.
  • the reaction preferably takes place in the added presence of a suitable base.
  • An alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate, such as alkali metal carbonate, e.g. sodium carbonate or potassium carbonate, an alkali metal hydroxide or alkaline earth metal hydroxide, such as sodium hydroxide or potassium hydroxide, an organometallic compound, such as butyllithium, or an alkali metal amide, such as lithium diisopropylamide, can serve as the base .
  • the compounds of the Formula II are known or can be prepared in a customary manner.
  • Suitable oxidizing agents are halogens, such as chlorine or bromine, peroxides or peracids, such as hydrogen peroxide or perbenzoic acid, perhalogenates, such as sodium periodate, transition metal oxidizing agents, such as disodium tungstate or potassium permanganate, and the like.
  • the radical R ia can, if desired, be converted into hydrogen using customary methods for removing the protecting group. However, this conversion is preferably effected after the compound of the Formula Ila has reacted with the compound of the Formula III.
  • the compounds of the Formula III can be prepared in accordance with customary methods, for example in a manner analogous to that described in WO 97/25324.
  • the compounds according to the invention can also be prepared by reacting a compound of the Formula IV
  • Y 2 represents a leaving group which can be displaced nucleophilically, for example halogen, in particular chlorine, bromine or iodine, C ⁇ -C 6 - alkylsulphonyloxy or C 6 -C ⁇ 0 -arylsulphonyloxy, and R x , R 2 , R 3 , R 4 and n have the meaning which have already been indicated.
  • the reaction preferably takes place in a diluent and in the presence of a base.
  • Suitable diluents and bases are those mentioned above.
  • the compounds of the Formula V are known or can be prepared in a customary manner, for example in accordance with methods which are analogous to those described in WO 97/25324.
  • the compounds of the Formula IV can be prepared in a customary manner, for example by reacting a compound of the Formula II with an ⁇ , ⁇ - C 2 -C 6 -alkanediol, and converting the aliphatic OH group in the resulting intermediate into a leaving group which can be displaced nucleophilically.
  • the pyrimidinoxyalkylpiperazines according to the invention are selective dopamine D 3 receptor ligands which act regioselectively in the limbic system and, because of their low affinity for the D 2 receptor, have fewer secondary effects than do the classic neuroleptic agents, which are D 2 receptor antagonists.
  • the compounds can therefore be used for treating diseases which respond to dopamine D 3 ligands, i.e. they are effective for treating those diseases in which modulation of the dopamine D 3 receptors leads to an improvement of the disease picture or to the disease being cured.
  • diseases of this nature are diseases of the central nervous system, in particular schizophrenia, emotional disturbances, neurotic, stress and somatoform disturbances, psychoses, attention deficit disorders, amnestic and cognitive disturbances, such as impaired learning and memory (impaired cognitive function), depression and addiction diseases.
  • the addiction diseases include the psychic disturbances and behavioural disturbances caused by the abuse of psychotropic substances, such as pharmaceuticals or drugs, and also other addiction diseases, such as compulsive gambling (impulse control disorders not elsewhere classified) .
  • addication- generating substances are: opioids (e.g.
  • morphine, heroin and codeine cocaine; nicotine; alcohol; substances which interact with the GABA-chloride channel complex, sedatives, hypnotics or tranquilizers , for example benzodiazepines; LSD; cannabinoids ; psychomotor stimulants, such as 3 , 4-methylenedioxy-N- methylamphetamine (ecstasy) ; amphetamine and amphetamine-like substances, such as methyl phenidate, or other stimulants, including caffeine.
  • Addition- generating substances which particularly come into consideration are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol.
  • the compounds according to the invention are preferably employed for treating emotional disturbances; neurotic, stress and somatoform disturbances and psychoses, schizophrenia, depression or addiction diseases.
  • the compounds according to the invention are administered orally or parenterally (subcutaneously, intravenously, intramuscularly or intraperitoneally) , in a customary manner.
  • the compounds can also be administered through the nasopharynx using vapours or sprays. However, administration preferably takes place orally.
  • the dosage depends on the age, condition and weight of the patient and on the mode of administration.
  • the daily dose of active compound is from about 10 to 1 000 mg per patient and day when administered orally.
  • the invention also relates to pharmaceutical compositions which comprise the pyrimidinoxyalkylpiperazines according to the invention and/or their salts .
  • These compositions are present in the customary galenic administration forms in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions or sprays.
  • the active compounds can be processed together with the customary galenic auxiliary substances, such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and/or propellant gases (cf. H. Sucker et al . , Pharmazeutician Technologie [Pharmaceutical technology] , Thieme-Verlag, Stuttgart, 1978) .
  • the resulting administration forms customarily comprise the active compound in a quantity of from 1 to 99% by weight.
  • the above pyrimidine was synthesized, in a manner known per se, by condensing 2, 2-dimethylpropionamidine with ethyl trifluoroacetoacetate and sodium methoxide in ethanol, see Heterocyclic Compounds, Vol. 52, The Pyrimidines, p. 189 ff., D.J. Brown et al . (Eds.) John Wiley and Sons, 1994. m.p. 169°C
  • Phosphorus oxychloride or thionyl chloride was used, in a manner known per se, to convert the hydroxypyrimidine from step B 1) into the chloro compound, see Heterocyclic Compounds, Vol. 52, The Pyrimidines, p. 329 ff., John Wiley and Sons, 1994. The compound is present as a yellowish oil.
  • Tablets of the following composition are pressed on a tablet press in the customary manner:
  • Example 2 120 mg of maize starch 13.5 mg of gelatin 45 mg of lactose 2.25 mg of Aerosil (chemically pure salicic acid in submicroscopically fine dispersion) 6.75 mg of potato starch (as a 6% paste)
  • the core substance consists of 9 parts of maize starch
  • the saccharification substance consists of 5 parts of cane sugar, 2 parts of maize starch, 2 parts of calcium carbonate and 1 part of talc.
  • the sugar-coated tablets which are prepared in this way are subsequently provided with a gastric juice-resistant coating.
  • the D 3 -expressing cells were multiplied in RPMI-1640 containing 10% fetal calf serum (GIBCO No. 041-32400 N) ; 100 U of penicillin/ml and 0.2% streptomycin (GIBCO BRL, Gaithersburg, MD, USA) . After 48 h, the cells were washed with PBS and incubated for 5 min with PBS containing 0.05% trypsin. After that, the cell suspension was neutralized with medium and cells were collected by centrifuging at 300 g.
  • the pellet was briefly washed with lysis buffer (5 mM Tris-HCl, pH 7.4, containing 10% glycerol) and, after that, incubated at 4°C for 30 min at a concentration of 10 7 cells/ml of lysis buffer.
  • the cells were centrifuged at 200 g for 10 min and the pellet was stored in liquid nitrogen.
  • the membranes were suspended in incubation buffer (50 mM Tris-HCl, pH 7.4, containing 120 mM NaCl, 5 mM KC1 , 2 mM CaCl 2 , 2 mM MgCl 2 , 10 mM quinolinol, 0.1% ascorbic acid and 0.1% BSA) at a concentration of approx. 10 s cells/250 ml of test mixture and incubated with 0.1 nM 125 iodine sulpiride at 30°C in the presence and absence of test substance. Nonspecific binding was determined using 10 "6 M spiperone.
  • the free radioligand and the bound radioligand were separated by filtration through GF/B glass fibre filters (Whatman, England) on a Skatron cell collector (Skatron, Lier, Norway) , and the filters were washed with ice-cold Tris-HCl buffer, pH 7.4. The radioactivity which had collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.
  • the Ki values were determined by means of nonlinear regression analysis using the LIGAND program.
  • HEK-293 cells possessing stably expressed human dopamine D 2 A receptors were cultured in RPMI 1640 containing Glutamax ITM and 25 mM HEPES containing 10% fetal calf serum. All the media contained 100 units of penicillin per ml and 100 ⁇ g of streptomycin/ml. The cells were kept at 37°C in a moist atmosphere containing 5% C0 2 .
  • the cells were prepared for binding studies by trypsinizing (0.05% trypsin solution) for 3-5 minutes at room temperature. After that, the cells were centrifuged at 250 g for 10 minutes and treated at 4°C for 30 minutes with lysis buffer (5 mM Tris-HCl, 10% glycerol, pH 7.4). After centrifuging at 250 g for 10 minutes, the residue was stored at -20°C until used.
  • trypsinizing 0.05% trypsin solution
  • lysis buffer 5 mM Tris-HCl, 10% glycerol, pH 7.4
  • the assay mixtures (1 ml) consisted of 1 x io 5 cells in incubation buffer (50 mM Tris, 120 mM NaCl, 5 mM KC1, 2 mM MgCl 2 and 2 mM CaCl 2 , pH 7.4 with HC1) and 0.1 nM
  • the assay mixtures were filtered through GF/B glass fibre filters (Whatman, England) on a Skatron cell collector
  • the Ki values were determined by nonlinear regression analysis using the LIGAND program or by converting the IC 50 values using the Cheng and Prusoff Formula.
  • the compounds according to the invention exhibit very good affinities at the D 3 receptor ( ⁇ 1 ⁇ molar, in particular ⁇ 100 nmolar) and bind selectively to the D 3 receptor.
  • test substances were administered to male Wistar rats in parallel experiments, in one case intravenously (tail vein, 2 mg/kg of body weight) and in the other case orally (by gavage, 10 mg/kg of body weight) .
  • the test compound was dissolved in physiological sodium chloride solution containing 1 vol% dimethyl sulphoxide while, for the oral administration, it was dissolved in water containing 0.5% hydroxymethylpropyl cellulose.
  • intravenously 0.083; 0.25; 0.5; 2; 8 and 24 h; orally: 0.5; 1; 3; 8 and 24 h
  • two rats were anaesthetized with dinitrogen oxide and a blood sample was withdrawn.
  • the area under the plasma concentration time curve was calculated from the results which were obtained using the trapezium method [ ( (t n -t n . ⁇ ) x (c n +c n - ⁇ ) /2) , in which t n is the time of the determination and t n - ⁇ is the time of the preceding determination, and c n and c n - ⁇ are the plasma concentrations at times t n and t n _ ⁇ , respectively] .
  • the bioavailability was determined in accordance with the Formula

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Addiction (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Pyrimidinoxyalkylpipérazines correspondant à la formule (I) dans laquelle n représente un entier entre 2 et 6, R1 représente H, alkyle C1-C6 ou phényle alkyle (C1-C6) dans laquelle le radical phényle peut être substitué par un ou plusieurs substitutifs sélectionnés parmi alkyle C1-C6 et alcoxy C1-C6, R2 représente H, alkyle C1-C4, OH, alcoxy C1-C6, NH2 ou halogène-alkyle C1-C6, R3 et R4, indépendamment les uns des autres, représentent H, alkyle C1-C6, hydroxyalkyle C1-C6, halogène-alkyle C1-C6, pyrrolyle ou phényle, dans laquelle ce dernier peut être substitué par un ou plusieurs substitutifs sélectionnés parmi alkyle C1-C6, hydroxyalkyle C1-C6, C1-C6-alcoxy, OH, halogène ou halogène-alkyle C1-C6, phényle, cyano ou nitro. Les composés peuvent être utilisés pour traiter les maladies qui réagissent à la modulation du récepteur de dopamine D3; ils sont caractérisés par un degré élevé de biodisponibilité.
PCT/EP2002/007183 2001-06-29 2002-06-28 Pyrimidinoxyalkylpiperazines et leur usage therapeutique WO2003002543A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10131543.0 2001-06-29
DE10131543A DE10131543A1 (de) 2001-06-29 2001-06-29 Pyrimidinoxyalkylpiperazine und ihre therapeutische Verwendung

Publications (1)

Publication Number Publication Date
WO2003002543A1 true WO2003002543A1 (fr) 2003-01-09

Family

ID=7690013

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/007183 WO2003002543A1 (fr) 2001-06-29 2002-06-28 Pyrimidinoxyalkylpiperazines et leur usage therapeutique

Country Status (2)

Country Link
DE (1) DE10131543A1 (fr)
WO (1) WO2003002543A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080981A1 (fr) * 2003-03-13 2004-09-23 Abbott Gmbh & Co. Kg Composes de pyrimidin-2-one et leur utilisation en tant que ligands du recepteur de la dopamine d3
JP2005520821A (ja) * 2002-03-15 2005-07-14 チバ　スペシャルティ　ケミカルズ　ホールディング　インコーポレーテッド ４−アミノピリミジン及び表面の抗菌処理のためのその使用
WO2005118571A1 (fr) * 2004-06-04 2005-12-15 Abbott Gmbh & Co. Kg Composes pyridin-2-one et leur utilisation en tant que modulateurs du recepteur d3 de la dopamine
WO2006066885A1 (fr) 2004-12-21 2006-06-29 Abbott Gmbh & Co. Kg Composes n-heterocycliques substitues et leur utilisation comme ligands du recepteur de la dopamine d3
US7320979B2 (en) 2003-04-14 2008-01-22 Abbott Gmbh & Co. Kg. N-[(piperazinyl)hetaryl]arylsulfonamide compounds
US8476275B2 (en) 2003-04-14 2013-07-02 Abbott Gmbh & Co. Kg N-[piperazinyl hetaryl]arylsufonamide compounds with affinity for the dopamine D3 receptor
WO2014064038A1 (fr) 2012-10-22 2014-05-01 AbbVie Deutschland GmbH & Co. KG Composés d'acylaminocycloalkyle appropriés pour le traitement de troubles répondant à la modulation du récepteur d3 de la dopamine
WO2017181004A1 (fr) * 2016-04-14 2017-10-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Agonistes sélectifs du récepteur de la dopamine d3 et leurs procédés d'utilisation

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10358004A1 (de) 2003-12-11 2005-07-14 Abbott Gmbh & Co. Kg Ketolactam-Verbindungen und ihre Verwendung
US20050137186A1 (en) 2003-12-18 2005-06-23 Abbott Gmbh & Co. Kg. Tetrahydrobenzazepines and their use
WO2005058328A1 (fr) 2003-12-18 2005-06-30 Abbott Gmbh & Co. Kg Tetrahydrobenzazepines et leur utilisation dans la modulation du recepteur dopaminergique d3

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996002519A1 (fr) * 1994-07-15 1996-02-01 Basf Aktiengesellschaft Composes substitues de pyrimidine et leur utilisation
WO1997025324A1 (fr) * 1996-01-12 1997-07-17 Basf Aktiengesellschaft Composes aza- et diazacycloheptane et -cyclo-octane substitues et leur utilisation
WO2000067847A2 (fr) * 1999-05-07 2000-11-16 Basf Aktiengesellschaft Utilisation de ligands du recepteur de la dopamine d3 pour la production de medicaments servant au traitement de dysfonctionnements renaux

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996002519A1 (fr) * 1994-07-15 1996-02-01 Basf Aktiengesellschaft Composes substitues de pyrimidine et leur utilisation
WO1997025324A1 (fr) * 1996-01-12 1997-07-17 Basf Aktiengesellschaft Composes aza- et diazacycloheptane et -cyclo-octane substitues et leur utilisation
WO2000067847A2 (fr) * 1999-05-07 2000-11-16 Basf Aktiengesellschaft Utilisation de ligands du recepteur de la dopamine d3 pour la production de medicaments servant au traitement de dysfonctionnements renaux

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005520821A (ja) * 2002-03-15 2005-07-14 チバ　スペシャルティ　ケミカルズ　ホールディング　インコーポレーテッド ４−アミノピリミジン及び表面の抗菌処理のためのその使用
WO2004080981A1 (fr) * 2003-03-13 2004-09-23 Abbott Gmbh & Co. Kg Composes de pyrimidin-2-one et leur utilisation en tant que ligands du recepteur de la dopamine d3
US8008488B2 (en) 2003-03-13 2011-08-30 Abbott Gmbh & Co. Kg Pyrimidin-2-one compounds and their use as dopamine D3 receptor ligands
US7320979B2 (en) 2003-04-14 2008-01-22 Abbott Gmbh & Co. Kg. N-[(piperazinyl)hetaryl]arylsulfonamide compounds
US8476275B2 (en) 2003-04-14 2013-07-02 Abbott Gmbh & Co. Kg N-[piperazinyl hetaryl]arylsufonamide compounds with affinity for the dopamine D3 receptor
WO2005118571A1 (fr) * 2004-06-04 2005-12-15 Abbott Gmbh & Co. Kg Composes pyridin-2-one et leur utilisation en tant que modulateurs du recepteur d3 de la dopamine
US7960386B2 (en) 2004-06-04 2011-06-14 Abbott Gmbh & Co. Kg Pyridin-2-one compounds and their use as modulators of the dopamine D3 receptor
US8334289B2 (en) 2004-06-04 2012-12-18 Abbott Gmbh & Co. Kg Pyridin-2-one compounds and their use as modulators of the dopamine D3 receptor
WO2006066885A1 (fr) 2004-12-21 2006-06-29 Abbott Gmbh & Co. Kg Composes n-heterocycliques substitues et leur utilisation comme ligands du recepteur de la dopamine d3
WO2014064038A1 (fr) 2012-10-22 2014-05-01 AbbVie Deutschland GmbH & Co. KG Composés d'acylaminocycloalkyle appropriés pour le traitement de troubles répondant à la modulation du récepteur d3 de la dopamine
WO2017181004A1 (fr) * 2016-04-14 2017-10-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Agonistes sélectifs du récepteur de la dopamine d3 et leurs procédés d'utilisation
US11634404B2 (en) 2016-04-14 2023-04-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Selective D3 dopamine receptor agonists and methods of their use

Also Published As

Publication number Publication date
DE10131543A1 (de) 2003-01-16

Similar Documents

Publication Publication Date Title
DE69615085T2 (de) Sulfonamide Derivate und Verfahren zu deren Herstellung
NO312030B1 (no) Substituerte pyrimidinforbindelser, anvendelse og fremstilling derav, samt farmasöytisk middel
CA2567489C (fr) Composes pyridin-2-one et leur utilisation en tant que modulateurs du recepteur d3 de la dopamine
KR100379196B1 (ko) 트리아졸화합물및도파민-d₃리간드로서의그의용도
JP4904267B2 (ja) ドーパミンｄ３受容体の調節に応答する障害の治療に好適な４−ピペラジニル−ピリミジン化合物
NO316753B1 (no) Substituerte aza- og diazacykloheptan og -cyklooktan-forbindelser og deres anvendelser, samt farmasoytiske blandinger inneholdende slike forbindelser
WO2004080981A1 (fr) Composes de pyrimidin-2-one et leur utilisation en tant que ligands du recepteur de la dopamine d3
WO2003002543A1 (fr) Pyrimidinoxyalkylpiperazines et leur usage therapeutique
US20120095015A1 (en) Triazole compounds suitable for treating disorders that respond to modulation of the dopamine d3 receptor
US6919342B2 (en) Triazole compounds suitable for treating disorders that respond to modulation of the dopamine D3 receptor
AU2008320814B2 (en) 1,2,4,-triazin-3,5-dione compounds for treating disorders that respond to modulation of the dopamine D3 receptor
EP1484330B1 (fr) Composés de triazol pour le traitement de troubles liés à la modulation du récepteur 3 de la dopamine
US5401762A (en) Aminoalkyl-substituted thiazolin-2-ones, the preparation and use thereof
JP3013752B2 (ja) スルホンアミド誘導体
EP2203426B9 (fr) Composés de benzènesulfonamide appropriés pour le traitement de troubles qui répondent à une modulation du récepteur d<sb>3</sb>de la dopamine

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP