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WO1996031512A1 - Composes de benzopyranopyrrole, leur fabrication et leur utilisation - Google Patents

Composes de benzopyranopyrrole, leur fabrication et leur utilisation Download PDF

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Publication number
WO1996031512A1
WO1996031512A1 PCT/DK1996/000157 DK9600157W WO9631512A1 WO 1996031512 A1 WO1996031512 A1 WO 1996031512A1 DK 9600157 W DK9600157 W DK 9600157W WO 9631512 A1 WO9631512 A1 WO 9631512A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
hydrogen
defined above
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/DK1996/000157
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English (en)
Inventor
Marit Kristiansen
Mark Scheideler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
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Novo Nordisk AS
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 AS filed Critical Novo Nordisk AS
Priority to AU52722/96A priority Critical patent/AU5272296A/en
Publication of WO1996031512A1 publication Critical patent/WO1996031512A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to the therapeutically active benzopyrano ⁇ pyrrole 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, for example Parkinson's disease, psychoses, depression, drug abuse, pain, neurode- generative diseases, schizophrenia, appetite regulation and obesity control.
  • diseases related to dysfunction of the central dopamine system for example Parkinson's disease, psychoses, depression, drug abuse, pain, neurode- generative diseases, schizophrenia, appetite regulation and obesity control.
  • Dopamine receptors may be divided into D1 -dopamine and D2-dopamine receptor families.
  • the D2s and D3 dopamine receptors are subtypes of the D2-dopamine receptor family.
  • Compounds capable of binding selec ⁇ tively to D3 receptors are well known in the art (see, e.g. Sokoloff et al. , ature 347 ( 1 990) 146).
  • the present invention relates to benzopyranopyrrole com ⁇ pounds of the general formula I
  • R 1 is hydrogen, C ⁇ -alkyl optionally substituted with phenyl, thiophene or naphthalene, or R 1 is cycloalkyl, alkenyl or ally! optionally substituted with halogen; and R 2 , R 3 are the same or different and independently are hydrogen, C, ⁇ - alkyl, aralkyl or phenyl; and
  • R 4 is hydrogen, halogen, trifluoromethyl, C-,. ⁇ -alkyl or cyano; and R 5 , R 6 , R 7 are the same or different and independently are hydrogen, hydroxy, C-.g-alkoxy, O-acyl, halogen, trifluoromethyl, C,. e -alkyl, triflate, cyano, carbamoyl or amine optionally substituted with C-.g-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 this invention have asymmetric carbon atoms as well as cis and trans-isomers.
  • the present invention includes within its scope all such e ⁇ antiomers, stereoisomers, and mixtures, including racemic mixtures.
  • the term 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.
  • cycloalkyl refers to a saturated carbocyclic ring having from 3 to 7 carbon atoms such as cyclopropane, cyclobu- tane, cyclopentane, cyclohexane or cycloheptane, 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.
  • aralkyl refers to an alkyl chain of 1 to 6 carbon atoms substituted with phenyl or naphthyl. Examples of such aralkyl groups are benzyl, phenethyl, 1 -naphtylmethyl, etc.
  • alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy, etc.
  • O-acyl groups are acetoxy, propionyloxy, butyryloxy, and the like.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • R 1 represents propyl or allyl
  • ' ⁇ 2 and R 3 represent hydrogen
  • R 4 represents hydrogen or halogen
  • At least one of R 5 , R ⁇ or R 7 is hydroxy and the others or R 5 , R 6 and R 7 are selected from halogen or hydrogen.
  • Preferred compounds of the invention are:
  • the invention also relates to methods of preparing the above-mentioned compounds. These methods comprise:
  • R 4 , R 5 , R 6 and R 7 are as defined above, with an amine NH 2 R ⁇ wherein R 1 is as defined above to form a compound of formula III
  • R ⁇ R 4 , R 5 , R ⁇ and R 7 are as defined above.
  • the reaction is generally carried out in a non-protic solvent e.g. dichloromethane in the presence of a dehydrating agent such as molecular sieve or a Lewis' acid such as titanium(IV) chloride, and reacting the compound of formula III with a compound of formula IV:
  • a dehydrating agent such as molecular sieve or a Lewis' acid such as titanium(IV) chloride
  • R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above.
  • Each of the leaving groups X and Y may be any suitable leaving group, for example halogen.
  • the reaction is preferably carried out under alkaline conditions, i.e. , in the presence of a base, and among bases magnesium halogen alkyles are preferred.
  • the compound of formula V may be reduced to form a compound of the general formula I.
  • the reduction is generally carried out using a reducing catalyst such as Platinum(IV) oxide in a hydrogen atmosphere.
  • Halogen-substituted compounds of formula I can be made by substitu- tion of one or more hydrogen atoms by action of a halogenating agent, such as bromine, chlorine or iodine in acetic acid, or such as sulphuryl chloride, to give the compounds of formula I, wherein one or more of the substituents R 4 , R 5 , R 6 and R 7 are chlorine, bromine or iodine.
  • a halogenating agent such as bromine, chlorine or iodine in acetic acid, or such as sulphuryl chloride
  • R 2 , R 3 , R ⁇ R 5 , R 6 and R 7 are as defined above, with R 1 Y, where ⁇ in R 1 is as defined above and Y is a leaving group, to form a compound of formula I.
  • the leaving group Y may be any suitable leaving group as for example halogen.
  • reaction is generally carried out in a non-protic solvent, e.g. toluene in the presence of a dehydrating agent, such as p-toluenesulphonic acid, and reacting the compound of formula VII with a compound of formula VIM
  • R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above.
  • the leaving group Y may be any suitable leaving group as for example halogen.
  • the compound of formula IX may be reduced to form a compound of the formula VI, wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above.
  • the reduction is generally carried out using Lithium aluminum hydride and a reducing catalyst such as Platinum(IV) oxide in a hydrogen atmosphere.
  • the formed compound of formula VI is hereafter treated as described in method c) .
  • reaction products contain protective groups, these may be removed by catalytic reduction (e.g. catalytic hydrogenation) or by treatment with lithium diphenylphosphide, boron tribromide, hydrobromic acid, trimethylsilyl iodide or hydroiodic acid.
  • catalytic reduction e.g. catalytic hydrogenation
  • lithium diphenylphosphide boron tribromide
  • hydrobromic acid trimethylsilyl iodide or hydroiodic acid.
  • the starting materials employed in the syntheses of the compounds of formula I are either known or may be prepared in conventional manner from commercially available materials, e.g. according to Wise et al.,
  • the invention in another aspect 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. Furthermore, the invention also relates to the use of the inventive com ⁇ pounds of formula I as medicaments useful in the treatment of central nervous system ailments, especially related to dysfunctions of the central dopamine system, such as Parkinson's disease, psychoses, depression, drug abuse, pain, neurodegenerative diseases and schizo ⁇ phrenia.
  • the pharmacological properties of the compounds of the invention can be illustrated by determining their ability to bind at Dopamine D3- and D2s-receptors.
  • the structural gene for the human Dopamine-D2s receptor has previously been cloned and stably expressed in a mammalian Ltk " cell line (Bunzow,
  • the dopamine-D2s receptor is stably expressed to high levels as a single binding site for the dopamine-D2 ligand [ 3 H]Spipe- rone. 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.
  • the antibiotic G-418 is used to maintain selection for the Neomycin resistance gene 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 ( 1 990) J. Biol. Chem. 265. 1 5176-1 5182. Cells are harvested cells 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 resuspen- sion 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 resus- pended 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 Resuspen- sion buffer (25 mM K-Phosphate, pH 7.5, containing 0.32 M Sucrose and 5 mM EDTA) and stored at -80°C.
  • Resuspen- sion buffer 25 mM K-Phosphate, pH 7.5, containing 0.32 M Sucrose and 5 mM EDTA
  • the needed amount of protein is thawed at room temperature and diluted into 20-30 ml of Assay buffer (20mM Hepes, pH 7.4, containing 2 mM MgCI 2 ) in order to wash the cell membranes. After centrifugation for 10 min at 1 6,000 rpm (Beckman JA-20) the cell membrane pellet is re-homogenized in Assay buffer with a teflon Dounce homogenizer to yield a typical concentration in the assay of 0.1 mg/ml.
  • Assay buffer 20mM Hepes, pH 7.4, containing 2 mM MgCI 2
  • the affinity of a test substance for the dopamine-D2s receptor is deter ⁇ mined by measuring its ability to compete for specific [ 3 H]Spiperone binding.
  • tissue and test substance are preincubated at 25°C for 1 5 min. Then [ 3 H]Spiperone (New England Nuclear) is added to yield a final concentration in the assay of 0.3 nM and the incubation continued at 25°C for 40 min. The samples are then passed through Whatman GF/B filters under vacuum and immediately washed twice with
  • Non-specific binding is evaluated by including D-Butaclamol (3 ⁇ M) in the assay instead of test substance. Data were fit to competititon curves and analyzed using non-linear least squares fitting procedures. Results are reported as I , values.
  • Dopamine-D3 receptor binding is performed essentially as described by D. Levesque et al. ( 1 992) Proc. Natl. Acad. Sci (USA) 89 , 81 55-81 59.
  • the concentration of Dopamine-D3 receptors in striatum is high relative to Dopamine-D2 receptor expression.
  • the two receptor subtypes can be distinguished in a radioreceptor binding assay which employs striatal membranes by measuring the specific binding of the selective dopamine- D3 ligand [ 3 H]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 specific [ 3 H]7-OH-DPAT binding.
  • tissue and test substance are preincubated at 25°C for 1 5 min. Then [ 3 H]7-OH-DPAT (Amersham) is added to yield a final concentration in the assay of 2 nM and the incubation continued at
  • Non-specific binding is evaluated by including quinpirole (5 ⁇ W ⁇ ) in the assay instead of test substance. Data were fit to competititon curves and analyzed using non-linear least squares fitting procedures. Results are reported as K, values.
  • the compounds of the present invention had K, values lower than 1 ⁇ M at the human Dopamine D3 receptors.
  • the compounds of the invention may be placed into the form of pharmaceutical compo ⁇ sitions and unit disages 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 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 1 -50 mg per tablet are accordingly suitable representative unit dosage forms.
  • the compounds of this invention can thus be used for the formulation of pharmaceutical preparations e.g. for oral and parenteral administration to mammals including humans in accordance with conventional methods of galenic pharmacy.
  • 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, hydroxymethylcellu- lose 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 cap ⁇ sules 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 inven- tion 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 tech ⁇ niques contains:
  • the reaction mixture was heated at reflux temperature for 1 h after which an additional solution of Grignard reagent (30 ml) was added.
  • the reaction mixture was heated at reflux temperature for addi ⁇ tionally 1 h.
  • the cooled mixture was diluted with 10 % aqueous ammo- nium chloride (100 ml) and extracted twice with toluene (75 ml).
  • the combined organic phases was washed twice with water and evaporated to dryness to give 8-methoxy-3-propyl-1 ,2,3,4-tetrahydro-[1 ]benzopyra- no[3,4-b]pyrrole (23.4 g, yield 88 %) as a red oil. Because of the insta ⁇ bility of this material, subsequent reactions were carried out with the crude enamine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention décrit des composés de benzopyranopyrrole de formule (I), dans laquelle R1 représente hydrogène, alkyle facultativement substitué, cycloalkyle, alcényle ou allyle facultativement substitué; et R2, R3 sont identiques ou différents et représentent indépendamment hydrogène, alkyle, aralkyle ou phényle; et R4 représente hydrogène, halogène, trifluorométhyle, alkyle ou cyano; et R?5, R6, R7¿ sont identiques ou différents et représentent indépendamment hydrogène, hydroxy, alcoxy, O-acyle, halogène, trifluorométhyle, alkyle, triflate, cyano, carbamoyle ou amine facultativement substitué; ces composés étant utiles dans le traitement de malaises du système nerveux central relatif au dysfonctionnement du système central de dopamine.
PCT/DK1996/000157 1995-04-06 1996-04-01 Composes de benzopyranopyrrole, leur fabrication et leur utilisation Ceased WO1996031512A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU52722/96A AU5272296A (en) 1995-04-06 1996-04-01 Benzopyranopyrrole compounds, their preparation and use

Applications Claiming Priority (2)

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DK39395 1995-04-06
DK0393/95 1995-04-19

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000042038A1 (fr) * 1999-01-12 2000-07-20 Basf Aktiengesellschaft Composes de triazol presentant une affinite pour le recepteur 3 de la dopamine
CN101962384A (zh) * 2009-07-21 2011-02-02 瑟维尔实验室 色烯类化合物、其制备方法和包含其的药物组合物
WO2011087713A2 (fr) 2009-12-22 2011-07-21 Cephalon, Inc. Dérivés tricycliques et leur utilisation pharmaceutique et compositions
US20190367527A1 (en) * 2018-05-31 2019-12-05 Regents Of The University Of Minnesota Substituted phenethylamine derivatives

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3888946A (en) * 1971-03-17 1975-06-10 Little Inc A Pyrano benzopyrans
EP0224332A1 (fr) * 1985-10-23 1987-06-03 Glaxo Group Limited Composés hétérocycliques de groupe amine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3888946A (en) * 1971-03-17 1975-06-10 Little Inc A Pyrano benzopyrans
EP0224332A1 (fr) * 1985-10-23 1987-06-03 Glaxo Group Limited Composés hétérocycliques de groupe amine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
INDIAN JOURNAL OF CHEMISTRY, Volume 30B, March 1991, RAMESH CHANDRA GUPTA et al., "Novel Syntheses of Substituted (I)Benzopyrano(3,4-b)Pyrroles and Tetrahydropyrroles", pages 297-298. *
TETRAHEDRON LETTERS, Volume 49, 1970, WOLFGANG OPPOLZER et al., "Intramolekulare Cycloadditionen von N-Alkyl-C-Phenoxymethyl-Nitronen an Ortho-Staendige C=C-Doppelbindungen", pages 4313-4314. *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2000042036A1 (fr) * 1999-01-12 2000-07-20 Basf Aktiengesellschaft Composes de triazol presentant une affinite pour le recepteur 3 de la dopamine
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
US6602867B1 (en) 1999-01-12 2003-08-05 Abbott Laboratories Triazole compounds with dopamine-D3-receptor affinity
CN101962384A (zh) * 2009-07-21 2011-02-02 瑟维尔实验室 色烯类化合物、其制备方法和包含其的药物组合物
CN101962384B (zh) * 2009-07-21 2013-04-10 瑟维尔实验室 色烯类化合物、其制备方法和包含其的药物组合物
WO2011087713A2 (fr) 2009-12-22 2011-07-21 Cephalon, Inc. Dérivés tricycliques et leur utilisation pharmaceutique et compositions
EP2516446B1 (fr) * 2009-12-22 2014-08-13 Cephalon, Inc. Dérivés tricycliques et leur utilisation pharmaceutique et compositions
EP2792678A1 (fr) 2009-12-22 2014-10-22 Cephalon, Inc. Dérivés tricycliques et leur utilisation pharmaceutique et compositions
US20190367527A1 (en) * 2018-05-31 2019-12-05 Regents Of The University Of Minnesota Substituted phenethylamine derivatives
US10941153B2 (en) * 2018-05-31 2021-03-09 Regents Of The University Of Minnesota Substituted phenethylamine derivatives

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