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WO1997017326A1 - Enantiomers of cis-benz[e]indole compounds, their preparation and utility as dopamine-d3 receptor selective agents - Google Patents

Enantiomers of cis-benz[e]indole compounds, their preparation and utility as dopamine-d3 receptor selective agents Download PDF

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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
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compound according
pharmaceutically acceptable
dopamine
cis
benz
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PCT/DK1996/000464
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French (fr)
Inventor
Mark Scheideler
Rolf Hohlweg
Reinhardt Annemarie Varming
Michael Albert Crider
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Novo Nordisk A/S
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Priority to JP9517767A priority Critical patent/JPH11515030A/en
Priority to EP96937197A priority patent/EP0861234A1/en
Priority to AU74904/96A priority patent/AU7490496A/en
Publication of WO1997017326A1 publication Critical patent/WO1997017326A1/en

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    • 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

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Abstract

Enantiomers of cis-Benz[e]indole compounds of formula (I), wherein R1 is hydrogen, C¿1-6?-alkyl, cycloalkylmethyl, allyl or alkenyl; R?4¿ is hydroxy, C¿1-6?-alkoxy, O-acyl, triflate or carbamoyl; and R?2, R3, R5¿ are the same or different and independently are hydrogen, halogen, trifluoromethyl or C¿1-6?-alkyl, are useful as selective dopamine-D3 receptor ligands in the treatment of central nervous system ailments related to dysfunction of the central dopamine system.

Description

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-HT1A 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-HTιA receptor.
(+/-)cis-1,2,3al4,5,9b-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.
It has now been found that members of a novel group of benz[e]indoles have high affinity and selectivity for dopamine-D3 receptors. The present invention claims a utility for these compounds as specific dopamine-D3 receptor ligands which makes them useful in psychopharmaceutical preparations. Accordingly, the present invention relates to the enantiomers of cis-benz[e]indole com¬ pounds of the general formula (I)
Figure imgf000004_0001
and pharmaceutically acceptable acid addition salts and hydrates thereof, wherein R1 is hydrogen, Ci-e-alkyl, cycloalkylmethyl, allyl or alkenyl; R4 is hydroxy, d-β-alkoxy, O-acyl, triflate or carbamoyl; and R2, R3, R5 are the same or different and independently are hydrogen, halogen, trifluoromethyl or Ci-β-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.
The term "C1-6-alkyl" as used herein 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. The term "cycloalkylmethyl" as used herein 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
The term "alkenyl" as used herein 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
The term "Cι-6-alkoxy" as used herein refers to a substituent compnsing a C1-6-alkyl group linked through an ether oxygen Examples of such Cι-6-alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy, etc
The term O-acyl as used herein refers to groups R8-C(=0)- wherein R8 is Cι-6-alkyl Examples of such O-acyl groups are acetoxy, propionyloxy, butyryloxy, and the like
The term halogen as used herein refers to fluonne or chloπne
In a preferred embodiment of the invention, R1 represents propyl or allyl, R4 represents hydroxy and R2, R3, R5 represent hydrogen or halogen
Preferred compounds of the invention are
αs-(+)-8-hydroxy-3-(n-propyl)-1,2,3a,4,5,9b-hexahydro-3H-benz[e]ιndole,
cιs-(-)-8-hydroxy-3-(n-propyl)-1,2,3a,4,5,9b-hexahydro-3H-benz[e]ιndole,
cιs-(+)-8-hydroxy-3-(allyl)-1,2,3a,4,5,9b-hexahydro-3H-benz[e]ιndole,
cιs-(-)-8-hydroxy-3-(allyl)-1,2,3a,4,5,9b-hexahydro-3H-benz[e]ιndole,
and salts hereof Chemical Methods
The preparation of the 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:
a) reacting a compound of formula (II)
Figure imgf000006_0001
wherein R2,R3 and R5 are as defined above and R4 is methoxy, with an amine NH2R1, wherein R1 is as defined above to form a compound of formula (III)
Figure imgf000006_0002
wherein R1 is as defined above, R2,R3 and R5 are as defined above and R4 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)
Figure imgf000007_0001
wherein R1 R2,R3, R4 and R5 are the same as in formula (III).
Subsequently, the compound of formula (IV) may be reduced to form a compound of formula (I). The substituent R4 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. Further, a R4 being a hydroxy group in a compound of formula (I) may be converted to a Ci-β-alkoxy, O-acyl, triflate or carbamoyl . group by known methods.
b) Reacting a compound (II)
(II)
Figure imgf000007_0002
wherein R2,R3 and R5 are as defined above and R4 is methoxy, with a tertiary amine like pyrrolidine, in the same manner as described under method a), to form a compound (V)
Figure imgf000008_0001
wherein R2,R3 and R5 are as defined above and R4 is methoxy.
Subsequently reacting the compound of formula (V) with an alkyl bromoacetate and an acid to form a ketoester of formula (VI)
Figure imgf000008_0002
wherein R2to R5 are defined as in formula (V). Subsequently performing a reductive amination with the compound of formula (VI), as described by Borch, R.F. et al., J. Amer. Chem. Soc. (1971) 93, 2897-2904 to yield a compound of formula (VII)
Figure imgf000009_0001
wherein R1 , R2,R3 and R5 are as defined above and R4 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 R2,R3 and R5 are as defined above and R4 is methoxy. The substituent R4 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.
In another aspect 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.
Biological Methods
The pharmacological properties of the compounds of the invention can be illustrated by determining their ability to bind at Dopamine-D3 and -D2s receptors.
Detailed conditions for the In Vitro Assay of Dopamine-D3 Receptor Binding are described as follows:
By measuring radioligand binding to brain membranes Levesque, D. et al. (Proc. Natl. Acad.
Sci. (U.S.A.) (1992) 89, 8155-8159) have shown that the concentration of the Dopamine-D3 receptor in rodent striatum is high relative to its expression in many other brain areas.
Further, the 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.
Pharmacol. (1991) 199, 145-151). As these ligands are commercially available in a radiolabeled form the dopamine-D3 receptors present in this tissue can be identified by measuring the specific binding of [3H]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 [3H]R(+)7-OH-DPAT binding.
All membrane preparation steps are performed at 0-4°C. Freshly dissected rat striatum is homogenized with an Ultra-Torex homogenizer in Resuspension buffer (25mM Tris/HCl, pH 7.4, containing 0.32M Sucrose and 5mM EDTA), homogenized with a Ultra-Turrax homogenizer and centrifuged at 3000 φm (Beckman JA-20) for 10 min. The supernatant is saved and and the pellet homogenized a second time in the Resuspension buffer and centrifuged at 3000 φm (Beckman JA-20). This procedure is repeated 3 times, each time saving the supernatant. The 3 low-speed supernatants are then pooled and centrifuged at high speed 16,000 φm (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.
On the day of the assay, 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 MgCI2) with a teflon Dounce homogenizer.
To initiate the assay the tissue and test substance are mixed and [3H]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.
Detailed conditions for the In Vitro Assav of Dopamine-D2s Receptor Binding are described as follows:
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 [3H]Spiperone. Further, the expressed receptor is negatively coupled to adenylyl cyclase.
In order to stably transfect Ltk' cells 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 [3H]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.
On the day of the assay, 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 MgCI2) 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 [3H]Spiperone binding. To initiate the assay the tissue and test substance are mixed and [3H]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.
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. Pharmaceutical Formulation
The compounds of the invention, together with a conventional adjuvant, carrier or diluent, and if desired a pharmaceutically acceptable acid addition salt thereof, 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.
Examples of 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.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. Ampoules are convenient unit dosage forms.
For oral applications, particularly suitable are 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. Generally, as to broader ranges, 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:
Active compound 1.0 mg
Lactosum 67.9 mg ph. Eur Avicel® 31.4 mg
Amberlite® IRP 88 1.0 mg
Magnesii stearas 0.25 mg Ph. Eur.
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.
Due to their high degree of activity, 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.
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
The invention will now be described in further detail with reference to the following example, which may not be construed as limiting:
EXAMPLE 1
Enantiomeric separation of the compound of formula (I):
cis-8-hydroxy-3-(n-propyl)-1,2,3a,4,5,9b-hexahydro-3H-benz[e]indole was achieved via isocratic high pressure liquid chromatography (HPLC) on a chiral chromatography resin.
Briefly, 98 mg (0.37 mmol) of the HCI salt of the compound was dissolved in 14 ml of n- heptane:2-propanol:diethylamine (57:43:0.5) and fractionated by HPLC (13 runs) using a 20 X 250 mm Chiralcel-OD column (Daicel Chemical Industries, Inc.). The column was eluted isocratically with n-heptane:2-propanol:diethylamine (85:15:0.1) at a flowrate of 5 ml/min and fractions collected corresponding to 1 min/fraction. The eluting enantiomers were detected spectroscopically by measuring absorbance at a wavelength of 225 nm. Two eluting peaks were detected, corresponding to fractions 18-21 (Sample 1) and 23-26
(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).
Optical rotation measurements for the free base of each sample, using a Perkin Elmer Pola¬ rimeter (Model 241), gave a value for Sample 1 of [af° = +101.4° (c=0.5, MeOH), and a value for Sample 2 of [a]2° = -97.7° (c=0.5, MeOH).
The NMR spectra (300 MHz, CDCI3) for the free base form of both Sample 1 and Sample 2 were as follows, in ppm: d 0.95 (3H, t, propylCH3), 1.55-1.88 (5H, m), 2.29 (1 H, m), 2.40- 2.62 (3H, m), 2.66-2.83 (2H, m), 2.98 (1 H, m), 3.13 (1 H, t), 3.31 (1H, q), 6.58 (2H, m), 6.92 (1H, d). 2.62 (3H, m), 2.66-2.83 (2H, m), 2.98 (1 H, m), 3.13 (1H, t), 3.31 (1 H, q), 6.58 (2H, m), 6.92 (1H, d).
The absolute configuration of Sample 1 was further established by X-ray crystallography. 15 mg of Sample 1 was crystallized as a hydrochloride salt from acetone: methanol (3:1). M.p. 211-212°C. Orthorhombic crystals were formed comprising four molecules per unit cell. The unit cell dimensions were as follows: a=7.2790 + 0.003A, b=11.9720 + 0.003A, c=16.4550 + 0.005A. Using an Enraf Nonius X-ray diffractometer (Model CAD4) the enantiomeric configuration of Sample 1 was established as cis-1,2,3,aS,4,5,9bR-hexahydro-1 H- benz[e]indole.

Claims

A compound of the general formula (I)
Figure imgf000017_0001
wherein R1 is hydrogen, Ci-β-atkyi, cycloalkylmethyl, allyl or alkenyl; R4 is hydroxy, Cι.t alkoxy, O-acyl, triflate or carbamoyl; and R2, R3, R5 are the same or different and independently are hydrogen, halogen, trifluoromethyl or d-6-alkyl, and pharmaceutically acceptable acid addition salts and hydrates thereof.
2_. A compound according to claim 1 wherein the pyrrolidine ring is fused in a cis- manner to the tetrahydronaphthaline moiety.
3^ A compound according to claim 1 or 2 which represents the (+) enantiomer.
4. A compound according to claim 1 or 2 which represents the (-) enantiomer.
5^ A compound according to any one of the preceding claims wherein R1 represents propyl or allyl.
6^ A compound according to any one of the preceding claims wherein R2, R3 and Rs are hydrogen or halogen.
7. A compound according to any one of the preceding claims selected from the following:
cis-(+)-8-hydroxy-3-(n-propyl)-1 ,2,3a,4,5,9b-hexahydro-3H-benz[e]indole, cis-(-)-8-hydroxy-3-(n-propyl)-1 ,2,3a,4,5,9b-hexahydro-3H-benz[e]indole,
cis-(+)-8-hydroxy-3-(allyl)-1 ,2,3a,4,5,9b-hexahydro-3H-benz[e]indole and
cis-(-)-8-hydroxy-3-(allyl)-1 ,2,3a,4,5,9b-hexahydro-3H-benz[e]indole.
8^ A compound according to any of the claims 1-7 or a pharmaceutically acceptable salt thereof for use as a therapeutically acceptable substance.
9. A compound according to any of the claims 1-7 or a pharmaceutically acceptable salt thereof for use as a therapeutically acceptable substance in the treatment of central nervous system ailments related to dysfunction of the central dopamine system.
The use of a compound according to any of the claims 1-7 as a medicament.
11. The use of a compound according to any of the claims 1-7 or a pharmaceutically acceptable salt thereof as a selective ligand at the dopamine-D3 receptor.
V2^ A pharmaceutical composition comprising as active component a compound according to any of the claims 1-7 or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient, carrier or diluent.
13. A pharmaceutical composition for the treatment of central nervous system ailment related to dysfunction of the central dopamine system, which comprises a compound according to any of the claims 1-7 or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient, carrier or diluent.
14. Use of a compound according to any of the claims 1 - 7 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of a central nervous system ailment related to dysfunction of the central dopamine system. 15. A method of treating a central nervous system ailment related to dysfunction of the central dopamine system in a subject in need thereof, comprising administering an effective amount of a compound according to any of the claims 1 - 7.
.165^ A method of treating a central nervous system ailment related to dysfunction of the central dopamine system in a subject in need thereof comprising administering a pharmaceutical composition according to claim 12.
17. A process for the manufacture of a medicament, particular to be used in the treatment of a central nervous system ailment related to dysfunction of the central dopamine system, which process comprises bringing a compound according to any of the claims 1 - 7 or a pharmaceutically acceptable salt thereof into a galenic dosage form.
18. A method of separating a racemic mixture of a compound according to any of the claims 1 - 7 by a process employing a Chiracel-OD HPLC column
19. A method according to claim 18, wherein the eluent phase consists of 70-95% n- heptane, 5-28% 2-propanol and 0.1 to 2% diethylamine.
PCT/DK1996/000464 1995-11-10 1996-11-08 Enantiomers of cis-benz[e]indole compounds, their preparation and utility as dopamine-d3 receptor selective agents WO1997017326A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997047602A1 (en) * 1996-06-11 1997-12-18 Smithkline Beecham Plc Tricyclic amine derivatives
WO2000042038A1 (en) * 1999-01-12 2000-07-20 Basf Aktiengesellschaft Triazole compounds with dopamine-d3-receptor affinity
WO2009026935A1 (en) * 2007-08-31 2009-03-05 H. Lundbeck A/S Catecholamine derivatives and prodrugs thereof
WO2011087713A3 (en) * 2009-12-22 2011-10-27 Cephalon, Inc. Substituted hexahydrochromeno [3, 4 - b] pyrroles with affinity for the serotonin receptor (5-ht) family
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 (en) * 1969-09-08 1975-03-27 Laboratoires Jacques Logeais, Issy-Les-Moulineaux, Seine (Frankreich) Pyrrole derivatives, a process for their preparation and pharmaceuticals
WO1992020655A1 (en) * 1991-05-20 1992-11-26 The Upjohn Company Carboxamido-(1,2n)-carbocyclic-2-aminotetralin derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2044172B2 (en) * 1969-09-08 1975-03-27 Laboratoires Jacques Logeais, Issy-Les-Moulineaux, Seine (Frankreich) Pyrrole derivatives, a process for their preparation and pharmaceuticals
WO1992020655A1 (en) * 1991-05-20 1992-11-26 The Upjohn Company Carboxamido-(1,2n)-carbocyclic-2-aminotetralin derivatives

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. *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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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
WO2000042036A1 (en) * 1999-01-12 2000-07-20 Basf Aktiengesellschaft Triazole compounds with dopamine-d3-receptor affinity
WO2000042037A1 (en) * 1999-01-12 2000-07-20 Basf Aktiengesellschaft Triazole compounds with dopamine-d3-receptor affinity
JP2002534519A (en) * 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 Triazole compounds having dopamine-D3-receptor affinity
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
WO2000042038A1 (en) * 1999-01-12 2000-07-20 Basf Aktiengesellschaft Triazole compounds with dopamine-d3-receptor affinity
BG65086B1 (en) * 1999-01-12 2007-02-28 Basf Aktiengesellschaft Triazole compounds with dopamine-d3-receptor affinity
KR100730667B1 (en) * 1999-01-12 2007-06-21 애보트 게엠베하 운트 콤파니 카게 Triazole Compounds Having Dopamine-D3-Receptor Affinity
WO2009026935A1 (en) * 2007-08-31 2009-03-05 H. Lundbeck A/S Catecholamine derivatives and prodrugs thereof
CN101842354A (en) * 2007-08-31 2010-09-22 H.隆德贝克有限公司 Catecholamine derivatives and prodrugs thereof
US8129530B2 (en) 2007-08-31 2012-03-06 H. Lundbeck A/S Catecholamine derivatives and prodrugs thereof
EA018413B1 (en) * 2007-08-31 2013-07-30 Х. Лундбекк А/С Pharmaceutical compositions based on catecholamine derivatives and use thereof
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JP2014111635A (en) * 2007-08-31 2014-06-19 H Lundbeck As Catecholamine derivative and prodrug of the same
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