WO1997017326A1 - Enantiomeres de composes de cis-benz[e]indole, leur preparation et utilite en tant qu'agents selectifs du recepteur de la dopamine-d3 - Google Patents

Enantiomeres de composes de cis-benz[e]indole, leur preparation et utilite en tant qu'agents selectifs du recepteur de la dopamine-d3 Download PDF

Info

Publication number
WO1997017326A1
WO1997017326A1 PCT/DK1996/000464 DK9600464W WO9717326A1 WO 1997017326 A1 WO1997017326 A1 WO 1997017326A1 DK 9600464 W DK9600464 W DK 9600464W WO 9717326 A1 WO9717326 A1 WO 9717326A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound according
pharmaceutically acceptable
dopamine
cis
benz
Prior art date
Application number
PCT/DK1996/000464
Other languages
English (en)
Inventor
Mark Scheideler
Rolf Hohlweg
Reinhardt Annemarie Varming
Michael Albert Crider
Original Assignee
Novo Nordisk 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
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU74904/96A priority Critical patent/AU7490496A/en
Priority to JP9517767A priority patent/JPH11515030A/ja
Priority to EP96937197A priority patent/EP0861234A1/fr
Publication of WO1997017326A1 publication Critical patent/WO1997017326A1/fr

Links

Classifications

    • 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
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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

Definitions

  • Enantiomers of cis-benz[e]indole compounds their preparation and utility as dopamine-D3 receptor selective agents.
  • the present invention relates to the therapeutically active cis-benz[e]indole compounds, a method of preparing the same, pharmaceutical compositions comprising the compounds, and their use in therapy, e.g. in treatment of central nervous system ailments, more precisely diseases related to dysfunction of the central dopamine system, ie; Parkinson's disease, psychoses including schizophrenia, depression, drug abuse, pain, neurode ⁇ generative diseases, and appetite regulation.
  • Dopamine receptors may be divided into dopamine-D1 and dopamine-D2 receptor families.
  • the dopamine-D2s and dopamine-D3 receptors are subtypes of the dopamine-D2 receptor family.
  • Compounds capable of binding selectively to dopamine-D3 receptors are well known in the art (see, e.g. Sokoloff, P. et al., Nature (1990) 347, 146-151).
  • WO 91/11435 describes 6,7,8,9-tetrahydro-N,N-dialkyl-3H-benz[e]indole-8-amine compounds claiming to possess selective 5-HT 1A pharmacological properties.
  • WO 92/20655 describes carboxamido-(1,2N)-carbocyclic-2-amino-1,2,3,4-tetrahydro-2- naphthylene derivatives. These compounds are described as having effects at the 5-HT ⁇ A receptor.
  • (+/-)cis-1,2,3a l 4,5,9b-hexahydro-3H-benz[e]indoles their synthesis and in vitro binding affinity at dopamine D1 and D2 receptors were described by Cruse et al. in J. Pharm. Sci., 82, 1993, pp 334-339.
  • the present invention relates to the enantiomers of cis-benz[e]indole com ⁇ pounds of the general formula (I)
  • R 1 is hydrogen, Ci-e-alkyl, cycloalkylmethyl, allyl or alkenyl;
  • R 4 is hydroxy, d- ⁇ -alkoxy, O-acyl, triflate or carbamoyl;
  • R 2 , R 3 , R 5 are the same or different and independently are hydrogen, halogen, trifluoromethyl or Ci- ⁇ -alkyl.
  • Pharmaceutically acceptable acid addition salts include inorganic salts such as hydrochloride, hydrobromide, sulphate, phosphate and nitrate, and organic salts such as maleate, fumarate, benzoate, and tartrate. If desirable, selected salts may be subjected to further purification by recrystallization.
  • the compounds of formula (I) have asymmetric carbon atoms as well as cis and trans- isomers.
  • the scope of the present invention specifically pertains to both enantiomers of the cis-stereoisomers.
  • C 1-6 -alkyl refers to a straight or branched, saturated hydrocarbon chain having 1-6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.butyl, n-pentyl, sec-pentyl, n-hexyl, 2,2-dimethylpropyl, and the like.
  • cycloalkylmethyl refers to a methyl group substituted with a saturated carbocyclic ring having from 3 to 7 carbon atoms such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl and the like
  • alkenyl refers to straight or branched carbon chains having at least one carbon-carbon double bond and containing from 2 to 6 carbon atoms such as ethenyl, 1-propenyl, 2-butenyl, etc
  • C ⁇ -6 -alkoxy refers to a substituent compnsing a C 1-6 -alkyl group linked through an ether oxygen Examples of such C ⁇ -6 -alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy, etc
  • O-acyl groups are acetoxy, propionyloxy, butyryloxy, and the like
  • halogen refers to fluonne or chlo ⁇ ne
  • R 1 represents propyl or allyl
  • R 4 represents hydroxy
  • R 2 , R 3 , R 5 represent hydrogen or halogen
  • racemic compounds of formula (I) may be carried out using known procedures, as described by Cruse, S.F. et al., J. Pharmacol. Sci. (1990) 347, 146-151 ; Lin, C-H. et al., J. Med. Chem. (1993) 36, 1053-1068; and, Song, X. et al., J. Amer. Chem. Soc.-Ann. Meeting Abstracts (1995) 210, Medi135. These methods comprise:
  • R 2 ,R 3 and R 5 are as defined above and R 4 is methoxy, with an amine NH 2 R 1 , wherein R 1 is as defined above to form a compound of formula (III)
  • R 1 is as defined above, R 2 ,R 3 and R 5 are as defined above and R 4 is methoxy.
  • the reaction is generally carried out in a non-protic solvent in the presence of a dehydrating agent such as molecular sieves or a Lewis acid such as titanium (IV) chloride; and reacting the compound of formula (III) with a base as sodium hydride or isopropyl magnesium chloride and subsequently a 1,2-dihaloethane to form a compound of the formula (IV)
  • a dehydrating agent such as molecular sieves or a Lewis acid such as titanium (IV) chloride
  • R 1 R 2 ,R 3 , R 4 and R 5 are the same as in formula (III).
  • the compound of formula (IV) may be reduced to form a compound of formula (I).
  • the substituent R 4 in formula (I) being a methoxy may subsequently be converted to a hydroxy group by means of an acid like hydrobromic acid or a Lewis acid like boron tribromide.
  • a R 4 being a hydroxy group in a compound of formula (I) may be converted to a Ci- ⁇ -alkoxy, O-acyl, triflate or carbamoyl . group by known methods.
  • R 2 ,R 3 and R 5 are as defined above and R 4 is methoxy.
  • R 1 , R 2 ,R 3 and R 5 are as defined above and R 4 is methoxy.
  • the compound of formula (VII) may be reacted with a reducing agent like lithium aluminium hydride to form a compound of formula (I), wherein R 2 ,R 3 and R 5 are as defined above and R 4 is methoxy.
  • the substituent R 4 may be further modified as described in method a).
  • the compounds of formula (II), which are starting materials for the above described synthetic routes a) and b), are commercially available or may be synthesized according to methods known to a person skilled in the art, e.g. as described by Craig, J.C. et al., J. Med. Chem. (1989) 32, 961-968.
  • the invention further relates to methods to separate the mentioned compounds into the claimed enantiomeric structures. These separations can be performed via isocratic high pressure liquid chromatography on a chiral chromatography resin.
  • the employed eluent mixtures may consist of 70-95% n-heptane, 5-28% 2-propanol and 0.1 to 2% dietbylamine.
  • the invention relates to a compound of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof for use as a therapeutically acceptable substance, preferably for use as a therapeutically acceptable substance in the treatment of central nervous system ailments.
  • This invention also relates to pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent. Furthermore, the invention also relates to the use of the inventive compounds of formula (I) for preparing a medicament useful in the treatment of central nervous system ailments, especially related to dysfunctions of the central dopamine system, ie; Parkinson's disease, psychoses including schizophrenia, depression, drug abuse, pain, neurodegenerative diseases and appetite control.
  • the pharmacological properties of the compounds of the invention can be illustrated by determining their ability to bind at Dopamine-D3 and -D2s receptors.
  • dopaminergic ligand 7-OH-DPAT and its active enantiomer R(+)7-OH-DPAT were shown to have high affinity and selectivity for the dopamine-D3 receptor (Levesque, D. et al., Proc. Natl. Acad. Sci. (U.S.A.) (1992) 89, 8155-8159; Timmerman, W. et al., Eur. J.
  • the dopamine-D3 receptors present in this tissue can be identified by measuring the specific binding of [ 3 H]R(+)7-OH-DPAT.
  • the affinity of a test substance for the dopamine-D3 receptor can then be determined by measuring its ability to compete for the specific [ 3 H]R(+)7-OH-DPAT binding.
  • the 3 low-speed supernatants are then pooled and centrifuged at high speed 16,000 ⁇ m (Beckman JA-20) for 10 min.
  • the final pellet is homogenized with a teflon Dounce homogenizer in Resuspension buffer and frozen at -80°C in 1 ml aliquots.
  • membranes are thawed at room temperature, diluted 1 :10 (v/v) in assay buffer and washed by centrifuging for 10 min. at 16,000 rpm (Beckman JA-20). The pellet is then re-homogenized in Assay buffer (20 mM Hepes, pH 7.4, containing 2 mM MgCI 2 ) with a teflon Dounce homogenizer.
  • tissue and test substance are mixed and [ 3 H]R(+)-7-OH-DPAT (Amersham) is added; this mixture is then incubated at 25°C for 45 min.
  • the samples are then passed through Whatman GF/B filters under vacuum and rapidly washed with ice-cold Assay buffer containing 0.1M NaCl. Filters are placed in counting vials, 4ml of Ultima Gold (Packard) is added, and total dpm estimated by scintillation counting.
  • Non-specific binding is evaluated by including quinpirole (5 mM) in the assay instead of test substance. Data were fit to competition curves and analyzed using non-linear least squares fitting procedures. Results are reported as K, values.
  • the compounds of the present invention had Kj values lower than 0.1 mM at the human Dopamine-D3 receptor.
  • the structural .gene for the human Dopamine-D2s receptor has previously been cloned and stably expressed in a mammalian Ltk ' cell line, as described by Bunzow, J.R. et al. (Nature (1988) 336, 783-787).
  • the dopamine-D2s receptor is stably expressed to high levels as a single binding site for the dopamine-D2 ligand [ 3 H]Spiperone. Further, the expressed receptor is negatively coupled to adenylyl cyclase.
  • the dopamine-D2s structural gene was cloned into the pZEM3 plasmid and co-transfected into Ltk ' cells with the plasmid pRSVneo, as described by Neve, K.A. et al. (Mol. Pharmacol. (1989) 36, 446-451).
  • the antibiotic G-418 is used to maintain selection for the Neomycin resistance gene located on the pRSVneo plasmid and is normally included (0.5 mg/ml) in the cell growth media (Dulbeccos Modified Eagles Media containing 10% fetal bovine serum (v/v) and 1% Pencillin/Streptomycin (w/v)).
  • Cell membranes used in measurements of specific [ 3 H]Spiperone binding are prepared from confluent plates of cells at 0-4°C by hypotonic lysis as previously described by Scheideler, M.A. and R.S. Zukin (J. Biol. Chem. (1990) 265, 15176-15182). Cells are harvested by scraping in physiologic saline and then collected by centrifugation at low speed (600-800 X g for 5 min).
  • the cell pellets are washed by gentle resuspension in low ionic strength buffer (10 mM K-phosphate, pH 7.5), collected by high-speed centrifugation (30,000 X g for 10 min) and then resuspended in 30 vol of the low ionic strength buffer for 20 min to initiate hypo-osmotic swelling and breakage. Unbroken cells are removed by centrifugation at low speed and cell membranes collected by high-speed centrifugation. The resulting cell pellets are homogenized in Resuspension buffer (25 mM K-Phosphate, pH 7.5, containing 0.32 M Sucrose and 5 mM EDTA) and stored at -80°C.
  • Resuspension buffer 25 mM K-Phosphate, pH 7.5, containing 0.32 M Sucrose and 5 mM EDTA
  • membranes are thawed at room temperature, diluted 1 :10 (v/v) in Assay buffer and washed by centrifuging for 10 min. at 16,000 rpm (Beckman JA-20). The pellet is then re-homogenized in Assay buffer (20 mM Hepes, pH 7.4, containing 2 mM MgCI 2 ) with a teflon Dounce homogenizer.
  • the affinity of a test substance for the dopamine-D2s receptor is determined by measuring its ability to compete for specific [ 3 H]Spiperone binding.
  • tissue and test substance are mixed and [ 3 H]Spiperone (New England Nuclear) is added. This mixture is then incubated at 25°C for 40 min.
  • the samples are then passed through Whatman GF/B filters under vacumn and rapidly washed with ice-cold Assay Buffer containing 0.1 M NaCl. Filters are placed in counting vials, 4ml of Ultima Gold (Packard) is added, and total dpm estimated by scintillation counting.
  • Ultima Gold Packard
  • Non-specific binding is evaluated by including D-Butaclamol (3 mM) in the assay instead of test substance. Data were fit to competition curves and analyzed using non-linear least squares fitting procedures. Results are reported as K, values.
  • the compounds in the present invention had Kj values in the dopamine-D2s assay which were at least 10-fold higher than the values established for binding to the Dopamine-D3 receptor.
  • the compounds of the invention may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may be prepared by conventional techniques and may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective central nervous system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing 0.05-100 mg of active ingredient, or more specified 0.1-50 mg are accordingly suitable representative unit dosage forms.
  • Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.
  • Such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compound.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compound.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Ampoules are convenient unit dosage forms.
  • tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or like can be used when a sweetened vehicle can be employed.
  • the compound of the invention is dispensed in unit dosage form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.
  • a typical tablet which may be prepared by conventional tabletting techniques contains:
  • the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • oral or parenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • the compounds of the invention may be administered to a subject, e.g..a living animal body, in need of such treatment, elimination, alleviation or amelioration of an indication such as Parkinson's disease, psychoses including schizophrenia, depression, drug abuse, pain, neurodegenerative diseases and appetite control, concurrently, simultaneously or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal or parenteral (including subcutaneous) route, in an effective amount.
  • a pharmaceutically acceptable carrier or diluent especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal or parenteral (including subcutaneous) route, in an effective amount.
  • Suitable dosage ranges varies as indicated above depending as usual upon the exact mode of administration, form in which administered, the indication towards which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge. Examples
  • Sample 2 Fractions from the different runs corresponding to these peaks were separately pooled to yield 43 mg of Sample 1 (100% ee: Determined by HPLC using a 4.6 X 250 mm chiral cell OD column eluted with n-heptane:2-propanol;diethylamine (90:10:0.1). The flowrate was 0.5 ml/min, eluting sample was monitored spectroscopically at 225 and 280 nm. The peak .retention time was 9.2 min.) and 43 mg of Sample 2 (>99.6 ee: Conditions as described for Sample 1. The peak retention time was 10.6 min).
  • Model CAD4 Enraf Nonius X-ray diffractometer

Landscapes

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

Abstract

Cette invention concerne des énantiomères de composés de cis-Benz[e]indole, représentés par la formule générale (I), dans laquelle R1 est hydrogène, alkyle-C¿1-6?, cycloalkylméthyle, allyle ou alcényle, R?4¿ est hydroxy, alkoxy-C¿1-6?, O-acyle, triflate ou carbamyle, et R?2, R3, et R5¿ sont identiques ou différents et représentent indépendamment hydrogène, halogène trifluorométhyle ou alkyle-C¿1-6?. Lesdits énantiomères s'avèrent utiles en tant que ligands sélectifs du récepteur de la dopamine-D3 dans le traitement des troubles du système nerveux central liés à un dysfonctionnement du système central de la dopamine.
PCT/DK1996/000464 1995-11-10 1996-11-08 Enantiomeres de composes de cis-benz[e]indole, leur preparation et utilite en tant qu'agents selectifs du recepteur de la dopamine-d3 WO1997017326A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU74904/96A AU7490496A (en) 1995-11-10 1996-11-08 Enantiomers of cis-benz{e}indole compounds, their preparation and utility as dopamine-d3 receptor selective agents
JP9517767A JPH11515030A (ja) 1995-11-10 1996-11-08 シス−ベンズ［ｅ］インドール化合物のエナンチオマー、これらの製造、及びドーパミン−Ｄ３受容体選択的医薬としての利用
EP96937197A EP0861234A1 (fr) 1995-11-10 1996-11-08 Enantiomeres de composes de cis-benz e]indole, leur preparation et utilite en tant qu'agents selectifs du recepteur de la dopamine-d3

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK126195 1995-11-10
DK1261/95 1995-11-10

Publications (1)

Publication Number Publication Date
WO1997017326A1 true WO1997017326A1 (fr) 1997-05-15

Family

ID=8102865

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1996/000464 WO1997017326A1 (fr) 1995-11-10 1996-11-08 Enantiomeres de composes de cis-benz[e]indole, leur preparation et utilite en tant qu'agents selectifs du recepteur de la dopamine-d3

Country Status (4)

Country Link
EP (1) EP0861234A1 (fr)
JP (1) JPH11515030A (fr)
AU (1) AU7490496A (fr)
WO (1) WO1997017326A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997047602A1 (fr) * 1996-06-11 1997-12-18 Smithkline Beecham Plc Derives d'amine tricycliques
WO2000042036A1 (fr) * 1999-01-12 2000-07-20 Basf Aktiengesellschaft Composes de triazol presentant une affinite pour le recepteur 3 de la dopamine
WO2009026935A1 (fr) * 2007-08-31 2009-03-05 H. Lundbeck A/S Dérivés de catécholamine et promédicaments associés
WO2011087713A3 (fr) * 2009-12-22 2011-10-27 Cephalon, Inc. Dérivés tricycliques et leur utilisation pharmaceutique et compositions
US8129530B2 (en) 2007-08-31 2012-03-06 H. Lundbeck A/S Catecholamine derivatives and prodrugs thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2044172B2 (de) * 1969-09-08 1975-03-27 Laboratoires Jacques Logeais, Issy-Les-Moulineaux, Seine (Frankreich) Pyrrolderivate, ein Verfahren zu ihrer Herstellung und Arzneimittel
WO1992020655A1 (fr) * 1991-05-20 1992-11-26 The Upjohn Company Derives de carboxamido-(1,2n)-carbocyclique-2-aminotetraline

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2044172B2 (de) * 1969-09-08 1975-03-27 Laboratoires Jacques Logeais, Issy-Les-Moulineaux, Seine (Frankreich) Pyrrolderivate, ein Verfahren zu ihrer Herstellung und Arzneimittel
WO1992020655A1 (fr) * 1991-05-20 1992-11-26 The Upjohn Company Derives de carboxamido-(1,2n)-carbocyclique-2-aminotetraline

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHIM. THER., Volume 7, 1972, MICHEL LANGLOIS et al., "Recherches Dans la Serie des Ary1-3 Pyrrolidines III. Preparation de Derives du Benzo(e)indole et de L'Indano(1,2b) Pyrrole", pages 450-458. *
J. MED. CHEM., Volume 37, 1994, CLAS SONESSON et al., "Substituted (S)-Phenylpiperidines and Rigid Congeners as Preferential Dopamine Autoreceptor Antagonists: Synthesis and Structure-Activity Relationships", pages 2735-2753. *
JOURNAL OF PHARMACEUTICAL SCIENCES, Volume 82, No. 3, March 1993, SHARON F. CRUISE et al, "Cis-1,2,3a,4,5,9b-Hexahydro-3H-benz(e)indo les: Synthesis and in Vitro Binding Affinity at Dopamine D1 and D2 Receptors", pages 334-339. *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997047602A1 (fr) * 1996-06-11 1997-12-18 Smithkline Beecham Plc Derives d'amine tricycliques
US6080752A (en) * 1996-06-11 2000-06-27 Smithkline Beecham Plc Tricyclic amine derivatives
US6602867B1 (en) 1999-01-12 2003-08-05 Abbott Laboratories Triazole compounds with dopamine-D3-receptor affinity
WO2000042038A1 (fr) * 1999-01-12 2000-07-20 Basf Aktiengesellschaft Composes de triazol presentant une affinite pour le recepteur 3 de la dopamine
WO2000042037A1 (fr) * 1999-01-12 2000-07-20 Basf Aktiengesellschaft Composes de triazol presentant une affinite pour le recepteur 3 de la dopamine
JP2002534519A (ja) * 1999-01-12 2002-10-15 ビーエーエスエフ アクチェンゲゼルシャフト ドーパミン−ｄ３−レセプター親和性を有するトリアゾール化合物
US6579892B1 (en) 1999-01-12 2003-06-17 Abbott Laboratories Triazole compounds with dopamine-D3-receptor affinity
US6583166B1 (en) 1999-01-12 2003-06-24 Abbott Laboratories Triazole compounds with dopamine-D3-receptor affinity
WO2000042036A1 (fr) * 1999-01-12 2000-07-20 Basf Aktiengesellschaft Composes de triazol presentant une affinite pour le recepteur 3 de la dopamine
BG65086B1 (bg) * 1999-01-12 2007-02-28 Basf Aktiengesellschaft Триазоли с допамин-d3 рецепторен афинитет
KR100730667B1 (ko) * 1999-01-12 2007-06-21 애보트 게엠베하 운트 콤파니 카게 도파민-ｄ3-수용체 친화성을 갖는 트리아졸 화합물
WO2009026935A1 (fr) * 2007-08-31 2009-03-05 H. Lundbeck A/S Dérivés de catécholamine et promédicaments associés
CN101842354A (zh) * 2007-08-31 2010-09-22 H.隆德贝克有限公司 儿茶酚胺衍生物及其前药
US8129530B2 (en) 2007-08-31 2012-03-06 H. Lundbeck A/S Catecholamine derivatives and prodrugs thereof
EA018413B1 (ru) * 2007-08-31 2013-07-30 Х. Лундбекк А/С Фармацевтические композиции на основе катехоламиновых производных и их применение
TWI404702B (zh) * 2007-08-31 2013-08-11 Lundbeck & Co As H 兒茶酚胺衍生物和其前藥
JP2014111635A (ja) * 2007-08-31 2014-06-19 H Lundbeck As カテコールアミン誘導体およびそのプロドラッグ
CN107253956A (zh) * 2007-08-31 2017-10-17 H.隆德贝克有限公司 用于治疗帕金森症的儿茶酚胺衍生物及其制备方法
WO2011087713A3 (fr) * 2009-12-22 2011-10-27 Cephalon, Inc. Dérivés tricycliques et leur utilisation pharmaceutique et compositions

Also Published As

Publication number Publication date
AU7490496A (en) 1997-05-29
JPH11515030A (ja) 1999-12-21
EP0861234A1 (fr) 1998-09-02

Similar Documents

Publication Publication Date Title
CA1252793A (fr) 1,2,3,9-tetrahydro-3-¬(imidazol-1-yl)-methyl| -4hcarbazol-4-ones
JP3708962B2 (ja) 治療に有用なスピロ−アザ二環式化合物
EP0319429B1 (fr) Dérivés de la 9-(acylamino)tétrahydroacridine et agents pour l'amélioration de la mémoire les contenant comme ingrédient
US5391549A (en) Cinnoline-3-carboxylic acid derivatives
JP3453394B2 (ja) ジヒドロベンゾフランカルボキサミド及びその製造方法
US5968949A (en) Substituted hydroisoquinoline derivatives and their use as pharmaceuticals
US6194423B1 (en) Fused isoquinolines as dopamine receptor ligands
EP0861234A1 (fr) Enantiomeres de composes de cis-benz e]indole, leur preparation et utilite en tant qu'agents selectifs du recepteur de la dopamine-d3
Khan et al. Isoquinuclidines: a review of chemical and pharmacological properties
US5637596A (en) Azabicycloalkyl derivatives of imidazo[1,5-a]indol-3-one and process for their preparation
JP4505135B2 (ja) Ｄ２及びｄ３ドーパミンならびに５ｈｔ１ａ及び５ｈｔ２セロトニンのレセプターのリガンドとしての８−アザビシクロ［３．２．１］オクタン−３−メタンアミン誘導体
TWI244485B (en) Tricyclic Delta3-piperidines as pharmaceuticals
JPH09501954A (ja) イミダゾ［５，１−ｃ］［１，４］ベンゾキサジン−１−オンのイミダゾリルアルキル誘導体およびそれらの製造法
JPH09512025A (ja) ５ｈｔ▲下２ｃ▼および５ｈｔ▲下２ｂ▼アンタゴニストとしての三環式誘導体
EP1192161B1 (fr) Chromeno [4,3,2- de ]isoquinolines en tant que ligands puissants de recepteurs de la dopamine
WO1997041101A1 (fr) Enantiomeres de composes trans-benz(e)indole, leur preparation et leur utilisation en tant qu'agents selectifs du recepteur dopaminergique d3
US5364854A (en) Derivatives of substituted imidazo benzoxazin-1-one and process for their preparation
WO1996031512A1 (fr) Composes de benzopyranopyrrole, leur fabrication et leur utilisation
JPS62425A (ja) 医薬組成物
Ishizuka et al. (R)-and (S)-4-methylaminomethyl-2, 3, 4, 9-tetrahydrothiopyrano [2, 3-b] indole: synthesis, absolute configuration, conformation, and analgesic activity
US4233449A (en) 1-(8-Methyl-2-phenyl(or thienyl)-8-azabicyclo[3.2.1]octan-3-yl) ethanone
US4281130A (en) Lower-alkyl 4,6,7,8,8a-9-hexahydro-6,9-ethanothieno[3,2-f]indolizine-10-carboxylate
JPH0517441A (ja) スピロイソインドリン化合物、その製造方法、それを含有する神経症を治療するための医薬およびそれを製造するための中間体
JPH01228969A (ja) ベンゾ〔６，７〕シクロヘプタ〔１，２−ｃ〕ピリダジン化合物およびその医薬用途

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI

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

Ref country code: JP

Ref document number: 1997 517767

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1996937197

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1996937197

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

WWW Wipo information: withdrawn in national office

Ref document number: 1996937197

Country of ref document: EP