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

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  • 1996-11-08 WO PCT/DK1996/000464 patent/WO1997017326A1/en not_active Application Discontinuation
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