WO1994026274A1 - Therapie faisant appel a des derives biologiquement actifs du tropane - Google Patents

Therapie faisant appel a des derives biologiquement actifs du tropane Download PDF

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Publication number
WO1994026274A1
WO1994026274A1 PCT/US1994/003661 US9403661W WO9426274A1 WO 1994026274 A1 WO1994026274 A1 WO 1994026274A1 US 9403661 W US9403661 W US 9403661W WO 9426274 A1 WO9426274 A1 WO 9426274A1
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WO
WIPO (PCT)
Prior art keywords
group
uptake
coch
naphthyl
binding
Prior art date
Application number
PCT/US1994/003661
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English (en)
Inventor
Huw M. L. Davies
Stevens R. Childers
Barbara Bennett
Original Assignee
Wake Forest University
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
Priority claimed from US08/063,431 external-priority patent/US6008227A/en
Application filed by Wake Forest University filed Critical Wake Forest University
Priority to AU67671/94A priority Critical patent/AU673265B2/en
Priority to EP94915779A priority patent/EP0697871A4/fr
Priority to JP6525413A priority patent/JP2906085B2/ja
Publication of WO1994026274A1 publication Critical patent/WO1994026274A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the tropane skeleton is a basic structural unit that can lead to compounds with diverse Central
  • neurotransmitters and thus have the potential for the treatment of major depression, Parkinson's disease and attention-deficit hyperactivity disorder (ADD).
  • ADD attention-deficit hyperactivity disorder
  • neurotransmitters are serotonin (5-HT) and dopamine (DA). Together with norepinephrine and epinephrine, these neurotransmitters comprise the group of agents known as the monoamines. Either 5-HT or DA have been implicated in a variety of disorders, including depression, Parkinsons disease, ADD, obesity and cocaine addiction.
  • Major depression represents one of the most common mental illness, affecting between 5-10% of the population.
  • the disease is characterized by extreme changes in mood which may also be associated with psychoses. It has generally been found that most antidepressant agents exert significant effects on the regulation of monoamine neurotransmitters, including DA, 5-HT and norepinephrine.
  • monoamine neurotransmitters including DA, 5-HT and norepinephrine.
  • antidepressants such as imipramine
  • imipramine are the most commonly used drugs for the treatment of depression. Their ability to inhibit the neuronal uptake of norepinephrine is believed to be a major factor behind their efficacy.
  • Parkinson's disease effects about 1% of the population over the age of 65 and leads to serious neurological disorders.
  • the main clinical features of the disease are centered around disruption of motor function, such as walking, speech, eating and other skilled acts. It has been recognized that the disease is the result of dopamine deficiency in the basal ganglia. Thus, drugs that can increase the levels of dopamine have the potential to be effective
  • levodopa which acts as a biogenic precursor to
  • antidepressants have been used as medications to control the disorder. Many of these drugs interact with the monoamine uptake transporters.
  • monoamine transport are useful therapeutic agents.
  • sympathomimetic drugs i.e., those which increase synaptic levels of monoamines
  • Drugs like mazindol, which act as sympathomimetic agents by blocking monoamine uptake, have been useful in the treatment of obesity.
  • the basic ring structure of cocaine is a tropane ring system.
  • Boja et al. European Journal of Pharmacology, 1990, 183,329; Boja et al., European Journal of
  • tropane analogs can be synthesized which selectively block DA transporters and selectively increase synaptic levels of DA.
  • the tropane skeleton is ideally suited to prepare highly selective compounds because it is a rigid structure and tropane derivatives will have rather limited conformational flexibility. Such derivatives may be altered by appropriate structural changes so that analogs favoring binding to either the 5-HT or DA reuptake site could be prepared.
  • the novel chemistry that has been developed, as referred to in our parent application, has enabled preparation of a much wider range of tropane analogs than was
  • invention is to prepare a range of tropane analogs which can be investigated as drugs for the treatment of chronic depression.
  • invention is to provide a wide range of tropane derivatives which can be systematically used and tested to determine structure-activity relationships for binding at dopamine, 5-HT and norepinephrine transporters.
  • a further objective is to provide a treatment system for diseases whose course can be altered by patient treatment with compounds that selectively bind to either the 5-HT or DA reuptake site and therefore prevent neurotransmissions at this site.
  • Biologically active derivatives of the tropane ring system are provided which selectively bind either to the 5-HT or DA reuptake site, leading to compounds which have use for treatment of clinical depression, Parkinson's Disease, ADD and obesity.
  • Figures 1, 2, 3, & 4 show the potencies of various analogs of the present invention 5-HT and DA in binding to transporters. These results demonstrate analogs with three different categories of
  • R 1 is an aromatic moeity and may be any 1-naphthyl, 2-naphthyl, phenyl, C 1 to C 8 alkylaryl or indole moiety. Preferred are isopropylphenyl and naphthyl.
  • R 2 and R 3 may be as follows: Only one of R 2 and R 3 can be hydrogen at the same time and each of R 2 and R 3 can be a ketone moxety, an ester moiety, a phosponate, a sulfone moiety, a cyan o, an oxazole, or a imidazole.
  • R 2 and R 3 be selected from ketone moieties or ester moieties, preferably C 1 to C 8 alkyl or alkoxy. If desired the M e group may be more generally described as R 4 which may be hydrogen or lower (C 1 to C 8 ) alkyl.
  • R is C 1 to C 8 and Ar is an aryl moiety as earlier defined.
  • 3-aryltropane derivatives are prepared by reacting 8-azabicyclo[3.2.1]oct-2-ene with an aryl Grignard reagent in the presence of catalytically effective amounts of copper (I) and/or copper (II) salts.
  • the 3-aryl-tropane derivative starting material can be conveniently prepared by decomposing functionalized vinyldiazomethanes in the presence of certain
  • pyrroles preferably in substantial excess of the stoichiometric amount, using a decomposition catalyst, preferably a rhodium catalyst.
  • the catalyst may also be a copper, palladium or silver salt catalyst.
  • the starting material of the process is, namely the 8-azabicyclo[3.2.1]oct-2-ene, and has the
  • R is selected from the group consisting of C 1 to C 8 alkyl and C 1 to C 8 oxyalkyl.
  • the two position moiety may be
  • Z is a functional group protector, and also in the presence of a small but effective amount of a decomposition catalyst selected from the group
  • R as shown above represents a C 1 to C 8 alkyl or C 1 to C 8 oxyalkyl.
  • R is an alkyl and
  • Z represents a functional group protector such as trimethylsilylethyl, although it is understood that other classic protecting groups such as tertiarybutyl group may also be employed.
  • the amount of the pyrrole for this first reaction scheme needs to be at least a stoichiometric amount in comparison with the vinyldiazomethane and preferably is in excess of the stoichiometric amount, perhaps within the range of a two-fold to a five-fold excess.
  • An excess is preferred in terms of achieving the desired high yields of the bicyclic intermediate because the vinyldiazomethane is decomposed to a very reactive intermediate, namely a vinylcarbenoid which will, unless it is trapped by use of stoichiometric excesses of the pyrrole, rapidly decompose.
  • the pyrroles above described can be conventionally prepared using well known chemistry as described in the Journal of Organic Chemistry, 1991, vol. 56 article, of the author earlier cited.
  • the reaction is preferably run at a temperature of within the range of from 25°C to about 100°C, preferably at about 80°C.
  • the reaction can be run at 25°C if there is slow addition of the vinyldiazomethane to the pyrrole.
  • the pressure is not critical in this reaction step.
  • the reaction is conducted in the presence of a decomposition catalyst selected from the group consisting of rhodium, copper, palladium and silver salts.
  • a decomposition catalyst selected from the group consisting of rhodium, copper, palladium and silver salts.
  • the catalyst is a rhodium salt catalyst and may be a rhodium (II) acetate, mandelate, trifluoroacetate, hexanoate, pivalate or octanoate.
  • the presently most preferred catalyst is rhodium octanoate which seems to allow higher yields of desired product.
  • the amount of catalyst may vary from 0.25 mole per cent to about 2.0 mole per cent of the vinyldiazomethane, and is preferably about 1.0 mole per cent of the amount of the vinyldiazomethane reactant.
  • the other carbon atoms of the 8-azabicyclo[3.2.1]oct-2-ene can include substituents other than hydrogen (e.g. one or more of the other carbon atoms of the bicyclic system can include a lower alkyl substituent group) because a more highly substituted pyrrole or
  • vinyldiazomethane may be used as starting material.
  • This first step reaction produces an intermediate bicyclic compound which upon hydrogenating, removal of the deprotective group and reductive methylation is converted to the earlier described 8-azabicyclo
  • This reaction is preferably conducted in the presence of a solvent and the solvent is preferably a non-polar solvent.
  • Suitable non-polar solvents for conducting this reaction may be pentane, hexane, and benzene.
  • Other suitable non-polar solvents, capable of dissolving the basic reactants may also be
  • catalytic hydrogenation is a process employing a Wilkinson's catalyst and that deprotection occurs with, for example, tertiarybutyl ammonium flouride to give the desired 8-azabicyclo
  • composition is purified by silica gel column
  • the 8-azabicyclo[3.2.1]oct-2-ene is then used as a starting material for the process of the present invention. It has been found that the 8-azabicyclo [3.2.1]oct-2-ene formula earlier described, can be converted to biologically active cocaine analogs having a wide variety of active analog structures by reacting with a aryl Grignard reagent in the presence of a catalytically effective amount of a copper salt catalyst.
  • the copper salt catalyst may be a copper (I) or copper (II) catalyst.
  • the R group of the 8-azabicyclo[3.2.1]oct-2-ene be C 1 to C 8 alkyl, rather than an oxyalkyl since it is preferred that the two substituent be a ketone substitution rather than an ester substitution.
  • the ketones behave better in the copper catalysed reaction, and as explained later in the biological activity section of the specification, should have higher metabolic stability and have equivalent binding site activity.
  • the Grignard addition reaction is run in a suitable non-polar organic solvent, preferably ether or
  • the Grignard reagent may be any suitable aryl magnesium halide.
  • the aryl group may be phenyl, substituted phenyl, C 1 to C 8 alkylaryl, polyaryl such as naphthyl, anthracyl or alkylpolyaryl.
  • Alkyl magnesium halides (C 1 to C 8 ) may also be used.
  • the "X" moiety represents a halide group and is preferably bromide.
  • the copper salt may be a copper (I) or (II) salt and can be, for example, copper bromide dimethyl sulfide.
  • the amount of the Grignard reagent is preferably an excess of the stoichiometric amount in order to assure completion of the reaction.
  • the amount of the copper salt catalyst can be from 5% (molar) to 20% (molar) of the Grignard reagent, and is preferably 15 mole percent of the amount of the Grignard reagent.
  • reaction product is a mixture of two structural isomers, one with the 2-moiety position upwardly (a) and the second with the 2-moiety position downwardly, (b)
  • Those analogs that are most preferred are the analogs wherein R is alkyl and therefore the two position moiety is a ketone moiety, and that the structural isomer is with the ketone groups in an up position.
  • the reaction is not temperature critical and may be run at anything from 0oC or lower up to room temperature, or even higher.
  • the reaction is not temperature critical and may be run at anything from 0oC or lower up to room temperature, or even higher.
  • reaction preferably run under an inert gas atmosphere.
  • the reaction is substantially immediate and therefore may be run from a few minutes to as much as twelve hours.
  • the reaction occurs under stirring in order to assure completeness.
  • the reaction can be quenched with for example HCl/ice, with the desired compound extracted with ether. It may be purified as illustrated in the examples by
  • the compounds may be administered orally, parenterally or intravenously.
  • the preferred route of administration is oral.
  • the dose levels may be from 4 micrograms per kilogram of body weight up to 50 milligrams/kg of body weight and more typically from 20 micrograms/kg up to 15 mg/kg.
  • Figure 1 compares the displacement of [ 125 I]RTI-55 binding by cocaine with four tropane analogs, PTT, PIT, WF-23, and WF-33. This leads to information on how these compounds bind to the dopamine transporter. These data showed that the two 2-naphthyl analogs, WF-23 and WF-33, were the most potent of these compounds, followed by PTT. PIT, in contrast, was less potent in displacing [ 125 I]RTI-55 than cocaine. Comparison of IC 50 values (Table 1) showed that WF-23 and WF-33 were 900 to 1300 times, while PTT was 20 times, more potent than cocaine in binding to dopamine transporters. In contrast, PIT was 2.5 times less potent than cocaine at dopamine transporters.
  • Figure 2 shows how the selectivities of these analogs were determined in [ 3 H]paroxetine binding experiments. This leads to information on how these compounds bind to the 5-HT transporter. Again, the 2-naphthyl analogs, WF-23 and WF-33, were the most potent compounds in displacing [ 3 H]paroxetine binding, as they were vs. [ 125 I]RTI-55 binding (Fig. 1).
  • [ 3 H]5-HT uptake in cortical cells also supported the results of the binding assays, showing that WF-23 and WF-31 were both significantly more potent than cocaine in blocking [ 3 H]5-HT uptake.
  • the uptake assays confirmed the selectivities of these tropane analogs as determined in binding assays.
  • WF-11 was 140 times more potent in inhibiting dopamine uptake than 5-HT uptake
  • WF-31 was 120 times more potent in inhibiting 5-HT uptake than dopamine uptake, both somewhat greater than the ratios determined by binding studies (Table 1).
  • WF-23 whether assayed as a racemic mixture or as its active stereoisomer, provided a dopamine: 5-HT ratio of only 3-4 regardless of the assay used.
  • Parkinson's Disease Treatment of other diseases associated with monoamine imbalances such as Parkinson's Disease, attention-deficit hyperactivity disorder, and obesity.

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  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
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  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On réalise le blocage sélectif de sites de fixation de la dopamine (DA) et de la sérotonine (5-HT) à l'aide de dérivés 3-aryltropane.
PCT/US1994/003661 1993-05-18 1994-04-04 Therapie faisant appel a des derives biologiquement actifs du tropane WO1994026274A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU67671/94A AU673265B2 (en) 1993-05-18 1994-04-04 Treatment process with biologically active tropane derivatives
EP94915779A EP0697871A4 (fr) 1993-05-18 1994-04-04 Therapie faisant appel a des derives biologiquement actifs du tropane
JP6525413A JP2906085B2 (ja) 1993-05-18 1994-04-04 生物学的活性トロパン誘導体による治療方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/063,431 1993-05-18
US08/063,431 US6008227A (en) 1992-03-13 1993-05-18 Process for blocking 5-HT and dopamine uptake with biologically active tropane derivatives

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WO1994026274A1 true WO1994026274A1 (fr) 1994-11-24

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EP (1) EP0697871A4 (fr)
JP (1) JP2906085B2 (fr)
AU (1) AU673265B2 (fr)
CA (1) CA2163095A1 (fr)
WO (1) WO1994026274A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6100275A (en) * 1995-10-13 2000-08-08 Neurosearch A/S 8-azabicyclo[3.2.1.]oct-2-ene derivatives, their preparation and use
WO2001013715A2 (fr) * 1999-08-24 2001-03-01 The Babraham Institute Modele animal et ses utilisations
EP1238978A3 (fr) * 1999-05-12 2005-03-02 President And Fellows Of Harvard College Produits intermédiaires pour la synthèse de tropanes radiomarqués
US7105678B2 (en) 1995-11-03 2006-09-12 Organix, Inc. Boat tropanes
WO2007028770A1 (fr) * 2005-09-05 2007-03-15 Neurosearch A/S Inhibiteurs du recaptage du neurotransmetteur monoamine pour une neuroprotection chez des patients souffrant d'une maladie mentale avancée

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003227520B9 (en) * 2002-05-30 2008-06-26 Neurosearch A/S Triple monoamine reuptake inhibitors for the treatment of chronic pain

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3813404A (en) * 1972-11-15 1974-05-28 Sterling Drug Inc Tropane-2-carboxylates and derivatives

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5262428A (en) * 1992-03-13 1993-11-16 Wake Forest University Biologically active tropane derivatives
US5288872A (en) * 1992-03-13 1994-02-22 Wake Forest University Compounds for treatment of neurodegenerative diseases
AU672052B2 (en) * 1992-12-23 1996-09-19 Neurosearch A/S Antidepressant and antiparkinsonian compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3813404A (en) * 1972-11-15 1974-05-28 Sterling Drug Inc Tropane-2-carboxylates and derivatives

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
European Journal of Pharmacology-Mol. Pharm. Sect., Vol. 244, issued 1993, H.M.L. DAVIES et al., "Novel 2-Substituted Cocaine Analogs: Binding Properties at Dopamine Transport Sites in Rat Striatum", pages 93-97. *
Life Sciences, Volume 46, No. 9, issued 1990, M.C. RITZ et al., "Cocaine Inhibition of Ligand Binding at Dopamine, Norepinephrine and Serotonin Transporters: A Structure-Activity Study", pages 635-645, see especially the Abstract and pages 638-9. *
See also references of EP0697871A4 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6100275A (en) * 1995-10-13 2000-08-08 Neurosearch A/S 8-azabicyclo[3.2.1.]oct-2-ene derivatives, their preparation and use
US7105678B2 (en) 1995-11-03 2006-09-12 Organix, Inc. Boat tropanes
EP1238978A3 (fr) * 1999-05-12 2005-03-02 President And Fellows Of Harvard College Produits intermédiaires pour la synthèse de tropanes radiomarqués
WO2001013715A2 (fr) * 1999-08-24 2001-03-01 The Babraham Institute Modele animal et ses utilisations
WO2001013715A3 (fr) * 1999-08-24 2001-09-20 Babraham Inst Modele animal et ses utilisations
WO2007028770A1 (fr) * 2005-09-05 2007-03-15 Neurosearch A/S Inhibiteurs du recaptage du neurotransmetteur monoamine pour une neuroprotection chez des patients souffrant d'une maladie mentale avancée

Also Published As

Publication number Publication date
AU673265B2 (en) 1996-10-31
EP0697871A1 (fr) 1996-02-28
CA2163095A1 (fr) 1994-11-24
AU6767194A (en) 1994-12-12
JPH08510238A (ja) 1996-10-29
EP0697871A4 (fr) 1998-04-22
JP2906085B2 (ja) 1999-06-14

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