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WO2003000269A2 - Novel use for pde 10a inhibitors - Google Patents

Novel use for pde 10a inhibitors Download PDF

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Publication number
WO2003000269A2
WO2003000269A2 PCT/EP2002/006309 EP0206309W WO03000269A2 WO 2003000269 A2 WO2003000269 A2 WO 2003000269A2 EP 0206309 W EP0206309 W EP 0206309W WO 03000269 A2 WO03000269 A2 WO 03000269A2
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WO
WIPO (PCT)
Prior art keywords
pde
parkinson
inhibitors
syndrome
ioa
Prior art date
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PCT/EP2002/006309
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German (de)
French (fr)
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WO2003000269A3 (en
Inventor
Ulrich Niewöhner
Jens-Kerim ERGÜDEN
Marcus Bauser
Nils Burkhardt
Dietmar Flubacher
Arno Friedl
Irene Gerlach
Volker Hinz
Reinhard Jork
Paul Naab
Thorsten-Oliver Repp
Karl-Heinz Schlemmer
Jürgen Stoltefuss
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Bayer Aktiengesellschaft
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Publication of WO2003000269A2 publication Critical patent/WO2003000269A2/en
Publication of WO2003000269A3 publication Critical patent/WO2003000269A3/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs
    • FMECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17CVESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
    • F17C2201/00Vessel construction, in particular geometry, arrangement or size
    • F17C2201/01Shape
    • F17C2201/0104Shape cylindrical
    • F17C2201/0119Shape cylindrical with flat end-piece
    • FMECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17CVESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
    • F17C2201/00Vessel construction, in particular geometry, arrangement or size
    • F17C2201/05Size
    • F17C2201/058Size portable (<30 l)
    • FMECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17CVESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
    • F17C2203/00Vessel construction, in particular walls or details thereof
    • F17C2203/06Materials for walls or layers thereof; Properties or structures of walls or their materials
    • F17C2203/0602Wall structures; Special features thereof
    • F17C2203/0612Wall structures
    • F17C2203/0614Single wall
    • F17C2203/0617Single wall with one layer
    • FMECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17CVESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
    • F17C2203/00Vessel construction, in particular walls or details thereof
    • F17C2203/06Materials for walls or layers thereof; Properties or structures of walls or their materials
    • F17C2203/0634Materials for walls or layers thereof
    • F17C2203/0636Metals
    • FMECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17CVESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
    • F17C2205/00Vessel construction, in particular mounting arrangements, attachments or identifications means
    • F17C2205/03Fluid connections, filters, valves, closure means or other attachments
    • F17C2205/0302Fittings, valves, filters, or components in connection with the gas storage device
    • F17C2205/0311Closure means
    • F17C2205/0314Closure means breakable, e.g. with burst discs
    • FMECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17CVESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
    • F17C2209/00Vessel construction, in particular methods of manufacturing
    • F17C2209/22Assembling processes
    • F17C2209/221Welding
    • FMECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17CVESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
    • F17C2209/00Vessel construction, in particular methods of manufacturing
    • F17C2209/22Assembling processes
    • F17C2209/228Assembling processes by screws, bolts or rivets
    • FMECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17CVESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
    • F17C2223/00Handled fluid before transfer, i.e. state of fluid when stored in the vessel or before transfer from the vessel
    • F17C2223/01Handled fluid before transfer, i.e. state of fluid when stored in the vessel or before transfer from the vessel characterised by the phase
    • F17C2223/0107Single phase
    • F17C2223/0123Single phase gaseous, e.g. CNG, GNC
    • FMECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17CVESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
    • F17C2260/00Purposes of gas storage and gas handling
    • F17C2260/02Improving properties related to fluid or fluid transfer
    • F17C2260/021Avoiding over pressurising
    • FMECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17CVESSELS FOR CONTAINING OR STORING COMPRESSED, LIQUEFIED OR SOLIDIFIED GASES; FIXED-CAPACITY GAS-HOLDERS; FILLING VESSELS WITH, OR DISCHARGING FROM VESSELS, COMPRESSED, LIQUEFIED, OR SOLIDIFIED GASES
    • F17C2270/00Applications
    • F17C2270/01Applications for fluid transport or storage
    • F17C2270/0165Applications for fluid transport or storage on the road
    • F17C2270/0181Airbags

Definitions

  • the invention relates to the use of PDE IOA inhibitors for the manufacture of a medicament for the treatment and / or prophylaxis of neurodegenerative disorders
  • Phosphodiesterases play an important role in regulating the concentrations of cGMP and cAMP. So far, 11 phosphodiesterase isoenzyme groups are known (PDE 1-7: Beavo et al. Mol. Pharmacol. 1994, 399-405; PDE 8-10: Soderling and Beavo Curr. Opin. Cell Biol. 2000, 12, 174- 179; PDE 11: Fawcett et al. Proc. Natl. Acad. Sci. USA 2000, 97, 3702-3707).
  • the PDE 10A hydrolyzes both cAMP and cGMP. Transcribed PDE 10A was identified primarily in the putamen and caudate nucleus regions of the brain, as well as in thyroid and testicular tissues. Compared to normal tissue, the PDE IOA mRNA is also increasingly expressed in certain tumor tissues, such as tissues of breast, liver, colon and lung tumors.
  • Parkinson's syndrome is a chronic, progressive disease of the central nervous system. It is caused by the degeneration of dopaminergic neurons in the substantia nigra, which produce and release the neurotransmitter dopamine. The resulting reduction in dopaminergic neurotransmission leads to massive dysfunctions in the extrapyramidal system of motion control. These disorders affect not only the basal ganglia but also other closely linked brain areas.
  • Parkinson's syndrome idiopathic or primary Parkinson's syndrome, symptomatic or secondary Parkinson's syndrome as well as special forms of Parkinson's syndrome such as Parkinson's dementia-ALS complex or Parkinson's plus syndrome (Pschyrembel Klinisches Dictionary, 257th edition, de Gruyter; Berlin, 1994; p.1153, keyword
  • WO 01/29199 discloses a cyclic nucleotide phosphodiesterase, designated 22045 and homologous to PDE 10A. According to WO 01/29199, modulators can be used to determine the concentration or activity of this PDE Diseases are examined. Brain diseases, including Parkinsonism, are listed under a variety of diseases (p.19, Z.32).
  • WO 01/24781 suggests the treatment of neuronal dysfunctions, such as, for example, Huntington's disease, by upregulating PDE
  • PDE 10A activity before Another treatable neuronal disease is called Parkinson's disease.
  • Another treatable neuronal disease is called Parkinson's disease.
  • the upregulation of PDE 10A activity corresponds to the opposite of PDE 10A inhibition.
  • the present invention therefore relates to the use of PDE IOA inhibitors for the production of a medicament for the treatment and / or neurodegenerative diseases, in particular of Parkinson's syndrome, in particular of idiopathic Parkinson's syndrome.
  • Preferred PDE 10A inhibitors are those which inhibit PDE 10A with an IC 50 of less than 1 ⁇ M, preferably less than 0.1 ⁇ M, in the test given below.
  • the PDE IOA inhibitors according to the invention are preferably also selective towards other PDEs, particularly preferably towards PDE IC, 2A, 3B, 4B, 5A and 7B.
  • Very particularly preferred compounds of the invention inhibit PDE 10A at least stronger than the other PDEs by a factor of 10, ie the IC 50 - value is for PDE 10A by at least a factor of 10 lower than the value recorded for the other PDEs IC 5 o value.
  • the IC 50 values for the PDEs are measured according to the conditions specified below. PDE IOA inhibitors with the property profile described above can be identified with these assays.
  • PDE 10A (WO 01/29199, Fig. 1A) is recombinantly expressed in full length in Sf9 insect cells (Invitrogen, Carlsbad, CA) using the Bac-to-Bac TM baculovirus expression system from Life Technologies (Gaithersburg, MD). 48 hours after
  • the cells are harvested and in 20 mL (per IL culture) lysis buffer (50 mM Tris-HCl, pH 7.4, 50 mM NaCl, 1 raM MgCl 2 , 1.5 raM EDTA, 10% glycerol plus 20 ⁇ L protease inhibitor cocktail set III [ CalBiochem, La Jolla, CA USA]) suspended.
  • the cells are treated with ultrasound at 4 ° C. for 1 minute and then centrifuged for 30 minutes at 4 ° C. at 10,000 rpm.
  • test substances are dissolved in 100% DMSO and serially diluted. Typically, dilution series from 200 ⁇ M to 1.6 ⁇ M are prepared (resulting final concentrations in
  • Test 4 ⁇ M to 0.032 ⁇ M). 2 ⁇ L of the diluted substance solutions are placed in the wells of microtiter plates (Isoplate; Wallac Inc., Atlanta, GA). Then 50 ⁇ L of a dilution of the PDE10A preparation described above are added. The dilution of the PDE IO preparation is chosen such that less than 70% of the substrate is converted during the later incubation (typical dilution: 1: 10000; dilution buffer: 50 mM Tris / HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA , 0.2% BSA). The substrate, [5 ', 8- 3 H] -cAMP (.
  • the enzyme reaction is finally started.
  • the test batches are incubated for 60 min at room temperature and the reaction is stopped by adding 25 ⁇ L of a suspension with 18 mg / ml Yttrium ScintiUation Proximity Beads (Amersham Pharmacia Biotech., Piscataway, NJ.).
  • the microtiter plates are sealed with a film and left to stand for 60 min at room temperature.
  • the plates are then measured in a Microbeta scintillation counter (Wallac Inc., Atlanta, GA) for 30 s per well.
  • IC 50 values are determined on the basis of the graphical plot of the substance concentration against the percentage inhibition.
  • Example 1 inhibited under these conditions PDE 10A with an IC 5 o value of
  • the in vitro effect of test substances on recombinant PDE 3B, PDE 4B, and PDE 7B is determined according to the test protocol described above for PDE 10A.
  • the protocol is adapted as follows: With PDE IC, additional Calmodulin 10 "7 M and CaCl 2 3mM are added to the reaction mixture.
  • PDE 2A is added by adding cGMP 1 ⁇ M stimulated and tested with a BSA concentration of 0.01%.
  • PDE 5A is used as a substrate [8- 3 H] -cGMP (Amersham Pharmacia Biotech., Piscataway, NJ).
  • Example 1 inhibits the PDE IC, 2A, 3B, 4B, 5A and 7B with IC 50 values of 2 ⁇ M,>10 ⁇ M,> 4 ⁇ M, 2.5 ⁇ M, 10 ⁇ M and 3.8 ⁇ M.
  • 6-Hydroxydopamine (6-OH-DA) lesion in the rat
  • the clinical picture of Parkinson's syndrome can be simulated to a large extent by injecting the neurotoxin 6-OH-DA intracerebrally into rats.
  • Pargyline 50 mg / kg ip
  • Desmethylimipramine HC1 25 mg / kg ip
  • the lesion of the nigrostriatal neurotransmission is then performed under anesthesia by giving the test animals a single stereotactic injection of 8 ⁇ g 6-OH-DA.
  • the coordinates of the injection according to König and Klippel are: 2.4 mm anterior, 1.49 mm lateral, -2.7 mm ventral.
  • the animals were treated with test substance one day after the operation until the end of the experiment 28 days after the operation.
  • Staircase test (motor skills test of the front extremity): Barneoud et al: Effects of complete and partial lesions of the dopaminergic mesotelencephalic system on skilled forelimb use in the rat. Neuroscience 1995, 67, 837-848.
  • Example 1 improved the motor skills of the front extremities in the staircase test in a dose range of 0.3 to 3.0 mg / kg bid p.o.
  • the other test parameters namely balance test and tensile force measurement, were also positively influenced.
  • MPTP l-methyl-4-phenyl-l, 2,3,6-tetrahydropyridine
  • MPTP is a neurotoxin that causes the degeneration of dopaminergic neurons in the substantia nigra characteristic of Parkinson syndrome in humans and animals and the motor symptoms typical of Parkinsonism.
  • mice were given 3 mg / kg MPTP i.p. on 3 consecutive days. applied (method modified according to Bezard E. et al., Kinetics of nigral degeneration in a chronic model of MPTP-treated mice, Neurosci. Lett. 1997, 234, 47-50).
  • the experimental animals then show a reduced number of dopaminergic neurons in the substantia nigra pars compacta.
  • dopaminergic neurons are made immunohistochemically visible as cells that contain the enzyme tyrosine hydroxylase, which is essential in dopamine metabolism, and finally quantified using a computer program (Nelson EL et al., Midbrain dopaminergic neurons in the mouse: Computer assisted mapping, J. Comp. Neurol. 1996, 369, 361-371).
  • the active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of the use of water as a diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously. However, it can also be done by inhalation through the mouth or nose, for example with the aid of a spray, or topically via the
  • N-acetyl-alanine (4.92 g, 37.5 mmol), 9.10 ml pyridine and 150 mg DMAP are dissolved in 200 ml THF and the solution is brought to a boil.
  • 8.6 ml (10.5 g, 75 mmol) of ethyl oxalyl chloride are added dropwise at the boiling point, and after the addition has ended, the mixture is stirred at the boiling point for a further 3 h.
  • the reaction mixture is poured onto 600 ml of ice water, extracted with ethyl acetate (4 x 150 ml), the combined organic phases are saturated with 200 ml. Washed NaCl solution, dried over sodium sulfate and concentrated. The material obtained is further reacted without delay in ethanol.
  • 3,4-Dimethoxybenzenecarboximidamide hydrochloride (5.42 g, 25 mmol) is placed in 100 ml of ethanol. 1.34 ml of hydrazine hydrate (1.34 g, 27.5 mmol) are added and the mixture is stirred at 45 ° C. for 3 h. After this time, ethyl 3- (acetylamino) -2-oxobutanoate in 50 ml of ethanol is added and the reaction mixture is stirred for 6 hours at 80 ° C. bath temperature and then for 12 hours at room temperature. The mixture is concentrated and the residue is purified by flash chromatography (mobile phase gradient dichloromethane / methanol 40: 1 to 20: 1).

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Abstract

The invention relates to the use of PDE 10A inhibitors for producing a medicament for the treatment and/or prophylaxis of neurodegenerative diseases, especially Parkinson's disease.

Description

Neue Verwendung für PDE lOA-InhibitorenNew use for PDE IOA inhibitors
Die Erfindung betrifft die Verwendung von PDE lOA-Inhibitoren zur Herstellung eines Arzneimittels zur Behandlung und/oder Prophylaxe von neurodegenerativenThe invention relates to the use of PDE IOA inhibitors for the manufacture of a medicament for the treatment and / or prophylaxis of neurodegenerative
Erkrankungen, insbesondere des Parkinson-Syndroms.Diseases, especially Parkinson's syndrome.
Die cyclischen Nucleotide cGMP und cAMP gehören zu den wichtigsten intrazellulären Botenstoffen. Bei der Regulation der Konzentrationen von cGMP und cAMP spielen Phosphodiesterasen (PDEs) eine wesentliche Rolle. Bisher sind 11 Phospho- diesterase-Isoenzymgruppen bekannt (PDE 1 - 7: Beavo et al. Mol. Pharmacol. 1994, 399-405; PDE 8- 10: Soderling und Beavo Curr. Opin. Cell Biol. 2000, 12, 174-179; PDE 11 : Fawcett et al. Proc. Natl. Acad. Sei. U. S. A. 2000, 97, 3702- 3707).The cyclic nucleotides cGMP and cAMP are among the most important intracellular messengers. Phosphodiesterases (PDEs) play an important role in regulating the concentrations of cGMP and cAMP. So far, 11 phosphodiesterase isoenzyme groups are known (PDE 1-7: Beavo et al. Mol. Pharmacol. 1994, 399-405; PDE 8-10: Soderling and Beavo Curr. Opin. Cell Biol. 2000, 12, 174- 179; PDE 11: Fawcett et al. Proc. Natl. Acad. Sci. USA 2000, 97, 3702-3707).
Die PDE 10A hydrolysiert sowohl cAMP als auch cGMP. Transkribierte PDE 10A wurde vor allem in den Putamen- und Caudate Nucleus-Regionen des Gehirns sowie in Schilddrüsen- und Hodengewebe identifiziert. Im Vergleich zu normalem Gewebe wird die PDE lOA-mRNA außerdem verstärkt in bestimmten Tumorgeweben, wie beispielsweise in Geweben von Brust-, Leber-, Colon- und Lungentumoren expri- miert.The PDE 10A hydrolyzes both cAMP and cGMP. Transcribed PDE 10A was identified primarily in the putamen and caudate nucleus regions of the brain, as well as in thyroid and testicular tissues. Compared to normal tissue, the PDE IOA mRNA is also increasingly expressed in certain tumor tissues, such as tissues of breast, liver, colon and lung tumors.
Das Parkinson-Syndrom ist eine chronische, progressive Erkrankung des zentralen Nervensystems. Sie wird verursacht durch die Degeneration dopaminerger Neurone in der Substantia nigra, welche den Neurotransmitter Dopamin produzieren und freisetzen. Die daraus resultierende Verringerung der dopaminergen Neurotrans- mission fuhrt zu massiven Dysfunktionen des extrapyramidalen Systems der Bewegungskontrolle. Diese Störungen betreffen nicht nur die Basalganglien sondern auch andere eng verknüpfte Gehirnareale. Mehrere Formen des Parkinson-Syndroms werden unterschieden: das idiopathische oder primäre Parkinson-Syndrom, das symptomatische oder sekundäre Parkinson- Syndrom sowie Sonderformen des Parkinson-Syndroms wie beispielsweise der Parkinson-Demenz-ALS-Komplex oder das Parkinson-plus-Syndrom (Pschyrembel Klinisches Wörterbuch, 257.Aufl., de Gruyter; Berlin, 1994; S.1153, StichwortParkinson's syndrome is a chronic, progressive disease of the central nervous system. It is caused by the degeneration of dopaminergic neurons in the substantia nigra, which produce and release the neurotransmitter dopamine. The resulting reduction in dopaminergic neurotransmission leads to massive dysfunctions in the extrapyramidal system of motion control. These disorders affect not only the basal ganglia but also other closely linked brain areas. A distinction is made between several forms of Parkinson's syndrome: idiopathic or primary Parkinson's syndrome, symptomatic or secondary Parkinson's syndrome as well as special forms of Parkinson's syndrome such as Parkinson's dementia-ALS complex or Parkinson's plus syndrome (Pschyrembel Klinisches Dictionary, 257th edition, de Gruyter; Berlin, 1994; p.1153, keyword
, Parkinson-Syndrom').'Parkinson's syndrome').
Die Ätiologie des idiopathischen Parkinson-Syndroms ist immer noch weitgehend unbekannt. Zunehmende Evidenzen deuten jedoch darauf hin, dass der Zelltod dopaminerger Neurone der Substantia nigra durch Apoptose in Folge mitochondrialerThe aetiology of idiopathic Parkinson's syndrome is still largely unknown. However, increasing evidence indicates that the cell death of dopaminergic neurons in the substantia nigra due to apoptosis is more mitochondrial
Fehlfunktionen zustande kommt. Neben genetischen Störungen, werden auch erhöhte Glutamatspiegel und/oder eine defiziente Versorgung mit neurotrophen Faktoren als Ursache für die mitochondrialen Fehlfunktionen diskutiert.Malfunction occurs. In addition to genetic disorders, increased glutamate levels and / or a deficient supply of neurotrophic factors are also discussed as the cause of the mitochondrial malfunction.
Die derzeit klinisch verwendeten Therapeutika für das Parkinson-Syndrom verfolgen in der Mehrzahl einen rein symptomatischen Ansatz. Ziel dieser Therapien ist entweder die direkte Substitution des fehlenden Dopamins durch ein Dopaminvor- läufermolekül (L-DOPA), das im Körper zu Dopamin metabolisiert wird, oder aber die Stimulation defizitärer dopaminerger Neurotransmissionsprozesse mittels Ago- nisten an Dopaminrezeptoren oder durch Verminderung des Dopaminabbaus (MAO-The majority of the currently used therapeutics for Parkinson's syndrome follow a purely symptomatic approach. The goal of these therapies is either the direct substitution of the missing dopamine by a dopamine precursor molecule (L-DOPA), which is metabolized to dopamine in the body, or the stimulation of deficient dopaminergic neurotransmission processes by means of agonists at dopamine receptors or by reducing the dopamine breakdown (MAO -
Inhibitoren, COMT-Inhibitoren). Alle derzeitigen Therapien sind jedoch durch starke Nebenwirkungen (z.B. Dyskinesien, Psychosen, Schlafstörungen) oder langfristigen Wirkungsverlust gekennzeichnet.Inhibitors, COMT inhibitors). However, all current therapies are characterized by strong side effects (e.g. dyskinesias, psychoses, sleep disorders) or long-term loss of effectiveness.
Über einen nicht näher spezifizierten Zusammenhang zwischen PDE 10A und juvenilem Parkinsonismus hat bereits Fujishige (J. Biol. Chem. 1999, 274, 18438- 18445) spekuliert.Fujishige (J. Biol. Chem. 1999, 274, 18438-18445) has already speculated about an unspecified connection between PDE 10A and juvenile Parkinsonism.
Aus der WO 01/29199 ist eine als 22045 bezeichnete, zu PDE 10A homologe, cyclische Nucleotid-Phosphodiesterase bekannt. Gemäß der WO 01/29199 können mit Modulatoren der Konzentration oder Aktivität dieser PDE bestimmte Erkrankungen untersucht werden. Unter einer Vielzahl von Krankheiten sind Gehirnerkrankungen, u.a. auch Parkinsonismus, aufgelistet (S.19, Z.32).WO 01/29199 discloses a cyclic nucleotide phosphodiesterase, designated 22045 and homologous to PDE 10A. According to WO 01/29199, modulators can be used to determine the concentration or activity of this PDE Diseases are examined. Brain diseases, including Parkinsonism, are listed under a variety of diseases (p.19, Z.32).
Die WO 01/24781 (S.33) schlägt die Behandlung von neuronalen Dysfunktionen, wie beispielsweise der Huntingtonschen Krankheit, durch Hochregulierung der PDEWO 01/24781 (p.33) suggests the treatment of neuronal dysfunctions, such as, for example, Huntington's disease, by upregulating PDE
10A- Aktivität vor. Als weitere behandelbare, neuronale Erkrankung wird u.a. die Parkinsonsche Krankheit genannt. Pharmakologisch entspricht jedoch die Hochregulierung der PDE 10A- Aktivität dem Gegenteil einer PDE lOA-Inhibition.10A activity before. Another treatable neuronal disease is called Parkinson's disease. However, pharmacologically, the upregulation of PDE 10A activity corresponds to the opposite of PDE 10A inhibition.
Unerwarteterweise wirken aber gerade selektive PDE lOA-Inhibitoren in Tiermodellen für neurodegenerative Erkrankungen, insbesondere das Parkinson- Syndrom.Unexpectedly, however, selective PDE IOA inhibitors work in animal models for neurodegenerative diseases, in particular Parkinson's syndrome.
Außerdem wird zum ersten Mal gezeigt, dass selektive PDE lOA-Inhibitoren in Tier- modellen für das Parkinson-Syndrom wirken.It is also shown for the first time that selective PDE IOA inhibitors work in animal models for Parkinson's syndrome.
Die vorliegende Erfindung betrifft daher die Verwendung von PDE lOA-Inhibitoren zur Herstellung eines Arzneimittels zur Behandlung und/oder von neurodegenerativen Erkrankungen, insbesondere des Parkinson-Syndroms, insbesondere des idiopathischen Parkinson-Syndroms.The present invention therefore relates to the use of PDE IOA inhibitors for the production of a medicament for the treatment and / or neurodegenerative diseases, in particular of Parkinson's syndrome, in particular of idiopathic Parkinson's syndrome.
Dabei werden solche PDE lOA-Inhibitoren bevorzugt, welche im unten angegebenen Test PDE 10A mit einem IC50 von weniger als 1 μM, bevorzugt weniger als 0,1 μM inhibieren.Preferred PDE 10A inhibitors are those which inhibit PDE 10A with an IC 50 of less than 1 μM, preferably less than 0.1 μM, in the test given below.
Vorzugsweise sind die erfindungsgemäßen PDE lOA-Inhibitoren auch selektiv gegenüber anderen PDEs, besonders bevorzugt gegenüber PDE IC, 2A, 3B, 4B, 5A und 7B. Ganz besonders bevorzugt hemmen die erfindungsgemäßen Verbindungen PDE 10A mindestens um den Faktor 10 stärker als die anderen PDEs, d.h. der IC50- Wert liegt für PDE 10A um mindestens den Faktor 10 niedriger als der für die anderen PDEs gemessene IC5o-Wert. Die Messungen der IC50- Werte für die PDEs erfolgt nach den unten angegebenen Bedingungen. PDE lOA-Inhibitoren mit dem oben beschriebenen Eigenschaftsprofil können mit diesen Assays identifiziert werden.The PDE IOA inhibitors according to the invention are preferably also selective towards other PDEs, particularly preferably towards PDE IC, 2A, 3B, 4B, 5A and 7B. Very particularly preferred compounds of the invention inhibit PDE 10A at least stronger than the other PDEs by a factor of 10, ie the IC 50 - value is for PDE 10A by at least a factor of 10 lower than the value recorded for the other PDEs IC 5 o value. The IC 50 values for the PDEs are measured according to the conditions specified below. PDE IOA inhibitors with the property profile described above can be identified with these assays.
Inhibition der PDE 10AInhibition of PDE 10A
PDE 10A (WO 01/29199, Fig.lA) wird in Sf9 Insektenzellen (Invitrogen, Carlsbad, CA) mit Hilfe des Bac-to-Bac™ Baculovirus Expressionssystems von Life Tech- nologies (Gaithersburg, MD) rekombinant in voller Länge exprimiert. 48 h nach derPDE 10A (WO 01/29199, Fig. 1A) is recombinantly expressed in full length in Sf9 insect cells (Invitrogen, Carlsbad, CA) using the Bac-to-Bac ™ baculovirus expression system from Life Technologies (Gaithersburg, MD). 48 hours after
Infektion werden die Zellen geerntet und in 20 mL (pro IL Kultur) Lysispuffer (50 mM Tris-HCl, pH 7.4, 50 mM NaCl, 1 raM MgCl2, 1.5 raM EDTA, 10 % Glycerin plus 20 μL Protease Inhibitor Cocktail Set III [CalBiochem, La Jolla, CA USA]) suspendiert. Die Zellen werden bei 4°C für 1 Minute mit Ultraschall be- handelt und anschließend für 30 Minuten bei 4°C mit 10000 Upm zentrifugiert. DerInfection, the cells are harvested and in 20 mL (per IL culture) lysis buffer (50 mM Tris-HCl, pH 7.4, 50 mM NaCl, 1 raM MgCl 2 , 1.5 raM EDTA, 10% glycerol plus 20 μL protease inhibitor cocktail set III [ CalBiochem, La Jolla, CA USA]) suspended. The cells are treated with ultrasound at 4 ° C. for 1 minute and then centrifuged for 30 minutes at 4 ° C. at 10,000 rpm. The
Überstand (PDE lOA-Präparat) wird gesammelt und bei -20°C aufbewahrt.Supernatant (PDE IO preparation) is collected and stored at -20 ° C.
Die Testsubstanzen werden zur Bestimmung ihrer in vitro Wirkung an PDE 10A in 100 % DMSO aufgelöst und seriell verdünnt. Typischerweise werden Verdünnungs- reihen von 200 μM bis 1.6 μM hergestellt (resultierende Endkonzentrationen imTo determine their in vitro effect on PDE 10A, the test substances are dissolved in 100% DMSO and serially diluted. Typically, dilution series from 200 μM to 1.6 μM are prepared (resulting final concentrations in
Test: 4 μM bis 0.032 μM). Jeweils 2 μL der verdünnten Substanzlösungen werden in die Vertiefungen von Mikrotiterplatten (Isoplate; Wallac Inc., Atlanta, GA) vorgelegt. Anschließend werden 50 μL einer Verdünnung des oben beschriebenen PDE10A Präparates hinzugefugt. Die Verdünnung des PDE lOA-Präparates wird so gewählt, dass während der späteren Inkubation weniger als 70 % des Substrates umgesetzt wird (typische Verdünnung: 1: 10000; Verdünnungspuffer: 50 mM Tris/HCl pH 7.5, 8.3 mM MgCl2, 1.7 mM EDTA, 0.2 % BSA). Das Substrat, [5',8-3H]-cAMP (1 μCi/μL; Amersham Pharmacia Biotech., Piscataway, NJ) wird 1 :2000 mit Assaypuffer (50 mM Tris/HCl pH 7.5, 8.3 mM MgCl2, 1.7 mM EDTA) auf eine Konzentration von 0.0005 μCi/μL verdünnt. Durch Zugabe von 50 μLTest: 4 μM to 0.032 μM). 2 μL of the diluted substance solutions are placed in the wells of microtiter plates (Isoplate; Wallac Inc., Atlanta, GA). Then 50 μL of a dilution of the PDE10A preparation described above are added. The dilution of the PDE IO preparation is chosen such that less than 70% of the substrate is converted during the later incubation (typical dilution: 1: 10000; dilution buffer: 50 mM Tris / HCl pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EDTA , 0.2% BSA). The substrate, [5 ', 8- 3 H] -cAMP (. 1 uCi / ul; Amersham Pharmacia Biotech, Piscataway, NJ) is 1: 2000 with assay buffer (50 mM Tris / HCl pH 7.5, 8.3 mM MgCl 2, 1.7 mM EDTA) diluted to a concentration of 0.0005 μCi / μL. By adding 50 μL
(0.025 μCi) des verdünnten Substrates wird die Enzymreaktion schließlich gestartet. Die Testansätze werden für 60 min bei Raumtemperatur inkubiert und die Reaktion durch Zugabe von 25 μL einer Suspension mit 18 mg/mL Yttrium ScintiUation Proximity Beads (Amersham Pharmacia Biotech., Piscataway, NJ.) gestoppt. Die Mikrotiterplatten werden mit einer Folie versiegelt und für 60 min bei Raum- temperatur stehengelassen. Anschließend werden die Platten für 30 s pro Vertiefung in einem Microbeta Szintillationzähler (Wallac Inc., Atlanta, GA) vermessen. IC50- Werte werden anhand der graphischen Auftragung der Substanzkonzentration gegen die prozentuale Inhibition bestimmt.(0.025 μCi) of the diluted substrate, the enzyme reaction is finally started. The test batches are incubated for 60 min at room temperature and the reaction is stopped by adding 25 μL of a suspension with 18 mg / ml Yttrium ScintiUation Proximity Beads (Amersham Pharmacia Biotech., Piscataway, NJ.). The microtiter plates are sealed with a film and left to stand for 60 min at room temperature. The plates are then measured in a Microbeta scintillation counter (Wallac Inc., Atlanta, GA) for 30 s per well. IC 50 values are determined on the basis of the graphical plot of the substance concentration against the percentage inhibition.
Beispiel 1 inhibiert unter diesen Bedingungen PDE 10A mit einem IC5o-Wert vonExample 1 inhibited under these conditions PDE 10A with an IC 5 o value of
35nM.35nm.
Inhibition der PDEs 1 - 5 und 7Inhibition of PDEs 1-5 and 7
Rekombinante PDE IC (GenBank/EMBL Accession Number: NM_005020), PDERecombinant PDE IC (GenBank / EMBL Accession Number: NM_005020), PDE
2A (Rosman et al. Gene 1997 191, 89-95), PDE 3B (Miki et al. Genomics 1996 36, 476-485), PDE 4B (Böiger et al. Mol. Cell. Biol. 1993 13, 6558-6571), PDE 5A (GenBank/EMBL Accession Number: AJ004865) und PDE 7B (Hetman et al. Proc. Natl. Acad. Sei. U.S.A. 2000 97, 472-476) werden mit Hilfe des pFASTBAC Baculovirus Expressionssystems (GibcoBRL) in Sf9 Zellen exprimiert.2A (Rosman et al. Gene 1997 191, 89-95), PDE 3B (Miki et al. Genomics 1996 36, 476-485), PDE 4B (Böiger et al. Mol. Cell. Biol. 1993 13, 6558-6571 ), PDE 5A (GenBank / EMBL Accession Number: AJ004865) and PDE 7B (Hetman et al. Proc. Natl. Acad. Sei. USA 2000 97, 472-476) are converted into Sf9 cells with the aid of the pFASTBAC baculovirus expression system (GibcoBRL) expressed.
Die in vitro Wirkung von Testsubstanzen an rekombinanter PDE 3B, PDE 4B, und PDE 7B wird nach dem oben für PDE 10A beschriebenen Testprotokoll bestimmt. Für die Bestimmung einer entsprechenden Wirkung an rekombinanter PDE IC, PDE2A und PDE5A wird das Protokoll wie folgt angepasst: Bei PDE IC werden zusätzlich Calmodulin 10"7 M und CaCl2 3mM zum Reaktionsansatz gegeben. PDE 2A wird im Test durch Zugabe von cGMP 1 μM stimuliert und mit einer BSA Konzentration von 0,01 % getestet. Für PDE 5A wird als Substrat [8-3H]-cGMP (Amersham Pharmacia Biotech., Piscataway, NJ) eingesetzt. Beispiel 1 inhibiert die PDE IC, 2A, 3B, 4B, 5A und 7B mit IC50- Werten von 2μM, >10μM, >4μM, 2,5μM, lOμM bzw. 3,8μM.The in vitro effect of test substances on recombinant PDE 3B, PDE 4B, and PDE 7B is determined according to the test protocol described above for PDE 10A. To determine a corresponding effect on recombinant PDE IC, PDE2A and PDE5A, the protocol is adapted as follows: With PDE IC, additional Calmodulin 10 "7 M and CaCl 2 3mM are added to the reaction mixture. In the test, PDE 2A is added by adding cGMP 1 μM stimulated and tested with a BSA concentration of 0.01%. For PDE 5A is used as a substrate [8- 3 H] -cGMP (Amersham Pharmacia Biotech., Piscataway, NJ). Example 1 inhibits the PDE IC, 2A, 3B, 4B, 5A and 7B with IC 50 values of 2μM,>10μM,> 4μM, 2.5μM, 10μM and 3.8μM.
Die Eignung der erfindungsgemäßen Verbindungen zur Behandlung des Parkinson- Syndroms kann in folgenden Tiermodellen gezeigt werden:The suitability of the compounds according to the invention for the treatment of Parkinson's syndrome can be shown in the following animal models:
6-Hydroxydopamine (6-OH-DA)-Läsion an der Ratte6-Hydroxydopamine (6-OH-DA) lesion in the rat
Das Krankheitsbild des Parkinson-Syndroms kann zu großen Teilen simuliert werden, indem Ratten das Neurotoxin 6-OH-DA intracerebral injiziert wird.The clinical picture of Parkinson's syndrome can be simulated to a large extent by injecting the neurotoxin 6-OH-DA intracerebrally into rats.
30 Minuten vor der Läsion wird den Tieren Pargyline (50 mg/kg i.p.) und Desmethylimipramine HC1 (25 mg/kg i.p.) verabreicht, um den Metabolismus von 6- Hydroxydopamin zu unterbinden, bzw. um die Aufnahme von 6-Hydroxydopamin in noradrenerge Strukturen zu verhindern. Unter Narkose erfolgt dann die Läsion der nigrostriatalen Neurotransmission indem die Versuchstieren eine einmalige stereotaktische Injektion von 8 μg 6-OH-DA erhalten. Die Koordinaten der Injektion lauten nach König und Klippel: 2.4 mm anterior, 1.49 mm lateral, -2.7 mm ventral. In der Verum-Gruppe wurden die Tiere einen Tag nach der Operation bis zum Versuchsende 28 Tage nach der Operation mit Testsubstanz behandelt.30 minutes before the lesion, Pargyline (50 mg / kg ip) and Desmethylimipramine HC1 (25 mg / kg ip) were administered to the animals to prevent the metabolism of 6-hydroxydopamine or to absorb 6-hydroxydopamine in noradrenergic structures to prevent. The lesion of the nigrostriatal neurotransmission is then performed under anesthesia by giving the test animals a single stereotactic injection of 8 μg 6-OH-DA. The coordinates of the injection according to König and Klippel are: 2.4 mm anterior, 1.49 mm lateral, -2.7 mm ventral. In the verum group, the animals were treated with test substance one day after the operation until the end of the experiment 28 days after the operation.
Die motorischen Ausfälle der läsionierten Ratten wurden mit den folgenden Tests wie in der jeweiligen Literatur beschrieben quantifiziert:The motor failures of the lesionized rats were quantified using the following tests as described in the relevant literature:
a) Staircase Test (Motorik-Test der Vorderextremität): Barneoud et al: Effects of complete and partial lesions of the dopaminergic mesotelencephalic system on skilled forelimb use in the rat. Neuroscience 1995, 67, 837 - 848.a) Staircase test (motor skills test of the front extremity): Barneoud et al: Effects of complete and partial lesions of the dopaminergic mesotelencephalic system on skilled forelimb use in the rat. Neuroscience 1995, 67, 837-848.
b) Accelerating Rotarod Test (Balancier-Test): Spooren et al.: Effects of the prototypical mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine on rotarod, locomotor activity and rotational responses in unilateral 6-OHDA- lesioned rats. Eur. J. Pharmacol. 2000, 406, 403 - 410. c) Zugkraftmessung der Vorderextremitäten: Dunnet et al.: A laterised grip strength test to evaluate unilateral nigrostriatal lesions in rats. Neurosci. Leu. 1998, 246", 1 - 4.b) Accelerating Rotarod Test: Spooren et al .: Effects of the prototypical mGlu 5 receptor antagonist 2-methyl-6- (phenylethynyl) -pyridine on rotarod, locomotor activity and rotational responses in unilateral 6-OHDA-lesioned Board. Eur. J. Pharmacol. 2000, 406, 403-410. c) Tensile force measurement of the forelimbs: Dunnet et al .: A laterised grip strength test to evaluate unilateral nigrostriatal lesions in rats. Neurosci. Leu. 1998, 246 " , 1-4.
Beispiel 1 verbesserte die Motorik der Vorderextremitäten im Staircase-Test in einem Dosisbereich von 0,3 bis 3,0 mg/kg bid p.o. In einem vergleichbaren Dosisbereich wurden auch die anderen Versuchparameter, nämlich Balanciertest und Zugkraftmessung, positiv beeinflusst.Example 1 improved the motor skills of the front extremities in the staircase test in a dose range of 0.3 to 3.0 mg / kg bid p.o. In a comparable dose range, the other test parameters, namely balance test and tensile force measurement, were also positively influenced.
MPTP-Maus - ModellMPTP mouse - model
Die neuroprotektive in vivo- Wirkung der erfindungsgemäßen Verbindungen wurde in einem Mausmodell für das Parkinson-Syndrom, dem sogenannten MPTP-Modell gezeigt. MPTP (=l-Methyl-4-phenyl-l,2,3,6-tetrahydropyridin) ist ein Neurotoxin, das bei Menschen und Tieren die für das Parkinson-Syndrom charakteristische Degeneration dopaminerger Neurone in der Substantia nigra und die Parkinsonismustypischen Motorsymptome verursacht.The neuroprotective in vivo effect of the compounds according to the invention was shown in a mouse model for Parkinson's syndrome, the so-called MPTP model. MPTP (= l-methyl-4-phenyl-l, 2,3,6-tetrahydropyridine) is a neurotoxin that causes the degeneration of dopaminergic neurons in the substantia nigra characteristic of Parkinson syndrome in humans and animals and the motor symptoms typical of Parkinsonism.
Den Mäusen wurde an 3 aufeinanderfolgenden Tagen, je 4mg/kg MPTP i.p. appli- ziert (Methode modifiziert nach Bezard E. et al., Kinetics of nigral degeneration in a chronic model of MPTP-treated mice, Neurosci. Lett. 1997, 234, 47-50). Die Versuchstiere zeigen danach eine verringerte Anzahl dopaminerger Neurone in der Substantia nigra pars compacta.The mice were given 3 mg / kg MPTP i.p. on 3 consecutive days. applied (method modified according to Bezard E. et al., Kinetics of nigral degeneration in a chronic model of MPTP-treated mice, Neurosci. Lett. 1997, 234, 47-50). The experimental animals then show a reduced number of dopaminergic neurons in the substantia nigra pars compacta.
Durch eine histologische Untersuchung am zehnten Tag nach MPTP-Injektion wird das Ausmaß der Zellschädigung quantifiziert. Dopaminerge Neurone werden dazu immunhistochemisch sichtbar gemacht als Zellen, die das im Dopamin-Stoffwechsel essentielle Enzym Tyrosinhydroxylase enthalten und schliesslich mit Hilfe eines Computerprogrammes quantitativ erfasst (Nelson E.L. et al., Midbrain dopaminergic neurons in the mouse: Computer assisted mapping, J. Comp. Neurol. 1996, 369, 361-371).The extent of cell damage is quantified by a histological examination on the tenth day after MPTP injection. For this purpose, dopaminergic neurons are made immunohistochemically visible as cells that contain the enzyme tyrosine hydroxylase, which is essential in dopamine metabolism, and finally quantified using a computer program (Nelson EL et al., Midbrain dopaminergic neurons in the mouse: Computer assisted mapping, J. Comp. Neurol. 1996, 369, 361-371).
Mäuse, die ab dem ersten Tag der MPTP-Intoxikation über 10 Tage hinweg Beispiel 1 in einer Dosis von 3 mg/kg bid p.o. erhielten, besaßen signifikant mehr dopaminerge Neurone in der Substantia nigra pars compacta als Kontrolltiere, die nur MPTP erhalten hatten.Mice that used Example 1 in a dose of 3 mg / kg bid po for 10 days from the first day of MPTP intoxication. had significantly more dopaminergic neurons in the substantia nigra pars compacta than control animals that only received MPTP.
Die Wirkstoffe können in bekannter Weise in die üblichen Formulierungen überfuhrt werden, wie Tabletten, Dragees, Pillen, Granulate, Aerosole, Sirupe, Emulsionen, Suspensionen und Lösungen, unter Verwendung inerter, nicht toxischer, pharmazeutisch geeigneter Trägerstoffe oder Lösungsmittel. Hierbei soll die therapeutisch wirksame Verbindung jeweils in einer Konzentration von etwa 0,5 bis 90 Gew.-% der Gesamtmischung vorhanden sein, d.h. in Mengen, die ausreichend sind, um den angegebenen Dosierungsspielraum zu erreichen.The active compounds can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents. Here, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
Die Formulierungen werden beispielsweise hergestellt durch Verstrecken der Wirkstoffe mit Lösungsmitteln und/oder Trägerstoffen, gegebenenfalls unter Verwendung von Emulgiermitteln und/oder Dispergiermitteln, wobei z.B. im Fall der Benutzung von Wasser als Verdünnungsmittel gegebenenfalls organische Lösungsmittel als Hilfslösungsmittel verwendet werden können.The formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of the use of water as a diluent, organic solvents can optionally be used as auxiliary solvents.
Die Applikation erfolgt in üblicher Weise, vorzugsweise oral, transdermal oder paren- teral, insbesondere perlingual oder intravenös. Sie kann aber auch durch Inhalation über Mund oder Nase, beispielsweise mit Hilfe eines Sprays erfolgen, oder topisch über dieThe application is carried out in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously. However, it can also be done by inhalation through the mouth or nose, for example with the aid of a spray, or topically via the
Haut.Skin.
Im Allgemeinen hat es sich als vorteilhaft erwiesen, Mengen von etwa 0,001 bis 10 mg/kg, bei oraler Anwendung vorzugsweise etwa 0,005 bis 3 mg/kg Körpergewicht zur Erzielung wirksamer Ergebnisse zu verabreichen. Trotzdem kann es gegebenenfalls erforderlich sein, von den genannten Mengen abzuweichen, und zwar in Abhängigkeit vom Körpergewicht bzw. der Art des Applikationsweges, vom individuellen Verhalten gegenüber dem Medikament, der Art von dessen Formulierung und dem Zeitpunkt bzw. Intervall, zu welchen die Verabreichung erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der vorgenannten Mindestmenge auszukommen, während in anderen Fällen die genannte obere Grenze überschritten werden muss. Im Falle der Applikation größerer Mengen kann es empfehlenswert sein, diese in mehreren Einzelgaben über den Tag zu verteilen. In general, it has proven to be advantageous to administer amounts of approximately 0.001 to 10 mg / kg, preferably approximately 0.005 to 3 mg / kg of body weight in the case of oral use in order to achieve effective results. Nevertheless, it may be necessary to deviate from the amounts mentioned, depending on the body weight or the type of application route, on the individual behavior towards the medication, the type of its formulation and the time or interval at which the administration takes place , In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.
2-(3 ,4-Dimethoxyphenyl)-5 ,7-dimethyl-4-(3 ,4,5-trimethoxyphenoxy)imidazo [5 , 1 -fj- [l,2,4]triazin (Beispiel 1) wurde wie folgt hergestellt:2- (3, 4-Dimethoxyphenyl) -5, 7-dimethyl-4- (3, 4,5-trimethoxyphenoxy) imidazo [5, 1-fj- [1,2,4] triazine (Example 1) was as follows manufactured:
a) 3, 4-Dimethoxybenzolcarboximidamid-Hydrochlorida) 3, 4-Dimethoxybenzenecarboximidamide hydrochloride
Figure imgf000011_0001
Figure imgf000011_0001
21,4 g (400 mmol) Ammoniumchlorid werden in einem Dreihalskolben mit Thermometer, Kühler, Tropftrichter und mechanischen Rührer unter Argonatmosphäre in 200 ml wasserfreiem Toluol suspendiert und auf 0°C gekühlt. 400 mmol Trimethyl- aluminium (200 ml 2 M Lösung in Hexan) werden zugetropft, und der Ansatz wird bei Raumtemperatur gerührt, bis keine Gasentwicklung mehr beobachtet wird (ca. 1,5 h). Eine Lösung von 33,6 g (200 mmol) 3,4-Dimethoxybenzonitril in 100 ml trockenem Toluol wird zugetropft und die Reaktionsmischung 18 h bei 80°C gerührt.21.4 g (400 mmol) of ammonium chloride are suspended in 200 ml of anhydrous toluene in a three-necked flask equipped with a thermometer, condenser, dropping funnel and mechanical stirrer under an argon atmosphere and cooled to 0 ° C. 400 mmol of trimethyl aluminum (200 ml of 2 M solution in hexane) are added dropwise, and the mixture is stirred at room temperature until no more gas evolution is observed (approx. 1.5 h). A solution of 33.6 g (200 mmol) of 3,4-dimethoxybenzonitrile in 100 ml of dry toluene is added dropwise and the reaction mixture is stirred at 80 ° C. for 18 h.
Nach dem Abkühlen wird die Mischung bei -10°C tropfenweise mit 60 ml Methanol versetzt und im Anschluss 90 min bei RT kräftig gerührt. Der Ansatz wird abgesaugt und der Rückstand mit Methanol (5 x 200 ml) gewaschen. Das Filtrat wird eingeengt, der Rückstand mit Methanol/Diethylethergemisch und Diethylether gewaschen und der erhaltene Feststoff (Ausbeute: 28,2 g) getrocknet. Die Waschphasen werden eingeengt, in Ethanol aufgenommen und mit Aktiv-Kohle entfärbt. Die Aktiv-Kohle wird abfiltriert und das Filtrat eingeengt. Der erhaltene Rückstand wird mit Diethylether versetzt und abgesaugt. Man erhält weitere 11,2 g Produkt.After cooling, the mixture is added dropwise at -10 ° C with 60 ml of methanol and then stirred vigorously at RT for 90 min. The mixture is filtered off with suction and the residue is washed with methanol (5 × 200 ml). The filtrate is concentrated, the residue is washed with methanol / diethyl ether mixture and diethyl ether and the solid obtained (yield: 28.2 g) is dried. The washing phases are concentrated, taken up in ethanol and decolorized with activated carbon. The activated carbon is filtered off and the filtrate is concentrated. The residue obtained is mixed with diethyl ether and suction filtered. Another 11.2 g of product are obtained.
Gesamtausbeute 92 % d. Th.Total yield 92% of theory Th.
Η-NMR (200 MHz, DMSO-d6): δ = 3.85 (s, 3H), 3.86 (s, 3H), 7.17 (d, 1H), 7.45 (d, 1H), 7.47-7.53 (m, 1H). b) Ethyl 3-(acetylamino)-2-oxobutanoatΗ NMR (200 MHz, DMSO-d 6 ): δ = 3.85 (s, 3H), 3.86 (s, 3H), 7.17 (d, 1H), 7.45 (d, 1H), 7.47-7.53 (m, 1H ). b) Ethyl 3- (acetylamino) -2-oxobutanoate
Figure imgf000012_0001
Figure imgf000012_0001
N-Acetyl- Alanin (4,92 g, 37, 5 mmol), 9,10 ml Pyridin und 150 mg DMAP werden in 200 ml THF gelöst und die Lösung zum Sieden gebracht. In der Siedehitze werden 8,6 ml (10,5 g, 75 mmol) Ethyloxalylchlorid zugetropft, nach beendeter Zugabe wird für weitere 3 h in der Siedehitze gerührt. Nach dem Abkühlen wird die Reaktions- mischung auf 600 ml Eiswasser gegeben, mit Essigsäureethylester (4 x 150 ml) extrahiert, die vereinigten organischen Phasen mit 200 ml ges. NaCl-Lösung gewaschen, über Natriumsulfat getrocknet und eingeengt. Das erhaltene Material wird ohne Verzögerung in Ethanol gelöst weiter umgesetzt.N-acetyl-alanine (4.92 g, 37.5 mmol), 9.10 ml pyridine and 150 mg DMAP are dissolved in 200 ml THF and the solution is brought to a boil. 8.6 ml (10.5 g, 75 mmol) of ethyl oxalyl chloride are added dropwise at the boiling point, and after the addition has ended, the mixture is stirred at the boiling point for a further 3 h. After cooling, the reaction mixture is poured onto 600 ml of ice water, extracted with ethyl acetate (4 x 150 ml), the combined organic phases are saturated with 200 ml. Washed NaCl solution, dried over sodium sulfate and concentrated. The material obtained is further reacted without delay in ethanol.
c) N-{l-[3-(3, 4-Dimethoxyphenyl)-5-oxo-4, 5-dihydro-l, 2, 4-triazin-6-yl] ethyl} - acetamidc) N- {1- [3- (3,4-Dimethoxyphenyl) -5-oxo-4,5-dihydro-1,2,4-triazin-6-yl] ethyl} acetamide
Figure imgf000012_0002
3,4-Dimethoxybenzolcarboximidamid-Hydrochlorid (5,42 g, 25 mmol) wird in 100 ml Ethanol vorgelegt. 1,34 ml Hydrazinhydrat (1,34 g, 27,5 mmol) werden zugegeben und der Ansatz 3 h bei 45°C gerührt. Nach dieser Zeit wird Ethyl 3-(acetyl- amino)-2-oxobutanoat in 50 ml Ethanol zugegeben und die Reaktionsmischung 6 h bei 80°C Badtemperatur, anschließend 12 h bei Raumtemperatur gerührt. Der Ansatz wird eingeengt und der Rückstand fiash-chromatographisch (Laufmittelgradient Dichlormethan/Methanol 40:1 bis 20:1) gereinigt.
Figure imgf000012_0002
3,4-Dimethoxybenzenecarboximidamide hydrochloride (5.42 g, 25 mmol) is placed in 100 ml of ethanol. 1.34 ml of hydrazine hydrate (1.34 g, 27.5 mmol) are added and the mixture is stirred at 45 ° C. for 3 h. After this time, ethyl 3- (acetylamino) -2-oxobutanoate in 50 ml of ethanol is added and the reaction mixture is stirred for 6 hours at 80 ° C. bath temperature and then for 12 hours at room temperature. The mixture is concentrated and the residue is purified by flash chromatography (mobile phase gradient dichloromethane / methanol 40: 1 to 20: 1).
Ausbeute: 2,85 g (35 % d. Th.), amorpher Feststoff. Fp.: 218°CYield: 2.85 g (35% of theory), amorphous solid. Mp .: 218 ° C
1H-NMR (300 MHz, DMSO-d6): δ = 1.35 (d, 3H), 1.84 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 5.00 (quint, 1H), 7.16 (d, 1H), 7.59-7.77 (m, 2H), 8.24 (d, 1H), 13.93 (s, 1H).1H-NMR (300 MHz, DMSO-d 6 ): δ = 1.35 (d, 3H), 1.84 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 5.00 (quint, 1H), 7.16 (d, 1H), 7.59-7.77 (m, 2H), 8.24 (d, 1H), 13.93 (s, 1H).
d) 2-(3, 4-Dimethoxyphenyl)-5, 7-dimethylimidazo[5, 1 -f][l, 2, 4]triazin-4(3H)-ond) 2- (3, 4-Dimethoxyphenyl) -5, 7-dimethylimidazo [5, 1 -f] [1,2,4] triazin-4 (3H) -one
Figure imgf000013_0001
Figure imgf000013_0001
N-{l-[3-(3,4-Dimethoxyphenyl)-5-oxo-4,5-dihydro-l,2,4-triazin-6-yl]ethyl}acetamid (2,60 g, 8,13 mmol) wird in 100 ml 1,2-Dichlorethan vorgelegt und die Lösung mitN- {l- [3- (3,4-Dimethoxyphenyl) -5-oxo-4,5-dihydro-l, 2,4-triazin-6-yl] ethyl} acetamide (2.60 g, 8.13 mmol) is placed in 100 ml of 1,2-dichloroethane and the solution with
0,19 ml (2,04 mmol) Phosphorylchlorid versetzt. Der Ansatz wird 24 h in der Siedehitze gerührt. Nach dem Abkühlen wird der Niederschlag abgesaugt der Rückstand mit Wasser (2 x 50 ml) und Diethylether (50 ml) gewaschen und getrocknet.0.19 ml (2.04 mmol) of phosphoryl chloride were added. The mixture is stirred at the boil for 24 h. After cooling, the precipitate is filtered off with suction, the residue is washed with water (2 × 50 ml) and diethyl ether (50 ml) and dried.
Ausbeute: 1 ,90 g (77 % d. Th.) 1H-NMR (300 MHz, DMSO-ds): δ = 2.55 (s, 3H), 2.64 (s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), 7.13 (d, 1H), 7.58-7.62 (m, 1H), 7.64-7.71 (m, 1H).Yield: 1.90 g (77% of theory) 1H-NMR (300 MHz, DMSO-ds): δ = 2.55 (s, 3H), 2.64 (s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), 7.13 (d, 1H), 7.58 -7.62 (m, 1H), 7.64-7.71 (m, 1H).
e) 2-(3, 4-Dimethoxyphenyl)-5, 7-dimethyl-4-(lH-l, 2, 4-triazol-l -yl)imidazo[5, 1- f][l,2,4]triazine) 2- (3, 4-dimethoxyphenyl) -5, 7-dimethyl-4- (lH-l, 2,4-triazol-l -yl) imidazo [5, 1- f] [l, 2,4] triazine
Figure imgf000014_0001
Figure imgf000014_0001
0,53 ml (879 mg, 5,67 mmol) Phosphorylchlorid werden unter Argon zu einer Lösung von 568 mg (1,89 mmol) N-{l-[3-(3,4-Dimethoxyphenyl)-5-oxo-4,5-di- hydro-l,2,4-triazin-6-yl]ethyl}acetamid in 80 ml trockenem Pyridin bei 0°C zugetropft und der Ansatz für 20 min gerührt. Anschließend wird bei 0°C eine Lösung von 3,33 g (47 mmol) 1,2,4-Triazol in 80 ml trockenem Pyridin zugegeben und der Ansatz nach beendeter Zugabe bei RT für 16 h gerührt. Die dunkelrote Reaktions- mischung wird eingeengt, der Rückstand mit 150 ml Eiswasser versetzt, und die0.53 ml (879 mg, 5.67 mmol) of phosphoryl chloride become under argon a solution of 568 mg (1.89 mmol) of N- {l- [3- (3,4-dimethoxyphenyl) -5-oxo-4 , 5-di-hydro-l, 2,4-triazin-6-yl] ethyl} acetamide was added dropwise in 80 ml of dry pyridine at 0 ° C. and the mixture was stirred for 20 min. A solution of 3.33 g (47 mmol) of 1,2,4-triazole in 80 ml of dry pyridine is then added at 0 ° C. and the mixture is stirred at RT for 16 h after the addition has ended. The dark red reaction mixture is concentrated, the residue is mixed with 150 ml of ice water, and the
Mischung mit Dichlormethan extrahiert (3 x 100 ml). Die vereinigten organischen Phasen werden getrocknet (Natriumsulfat) und das Lösungsmittel im Vakuum entfernt. Der Rückstand wird fiash-chromatographisch gereinigt (Laufmittel Dichlor- methan/Methanol 40:1). Man erhält 238 mg (36 % d. Th.) an Produkt.Mixture extracted with dichloromethane (3 x 100 ml). The combined organic phases are dried (sodium sulfate) and the solvent is removed in vacuo. The residue is purified by flash chromatography (mobile phase dichloromethane / methanol 40: 1). 238 mg (36% of theory) of product are obtained.
MS (ESI): 352 [M+H]+ MS (ESI): 352 [M + H] +
1H-NMR (400 MHz, CDC13): δ = 2.81 (s, 3H), 2.87 (s, 3H), 3.98 (s, 3H), 4.02 (s, 3H), 6.99 (d, 1H), 7.88 (d, 1H), 8.00 (q, 1H), 8.26 (s, 1H), 9.36 (s, 1H). Fp.: 220°C f) 2-(3, 4-Dimethoxyphenyl)-5, 7-dimethyl-4-(3, 4, 5-trimethoxyphenoxy)imidazo[5, 1- f]-[l, 2, 4]triazin1H-NMR (400 MHz, CDC1 3 ): δ = 2.81 (s, 3H), 2.87 (s, 3H), 3.98 (s, 3H), 4.02 (s, 3H), 6.99 (d, 1H), 7.88 ( d, 1H), 8.00 (q, 1H), 8.26 (s, 1H), 9.36 (s, 1H). Mp .: 220 ° C f) 2- (3, 4-Dimethoxyphenyl) -5, 7-dimethyl-4- (3, 4, 5-trimethoxyphenoxy) imidazo [5, 1- f] - [1,2,4] triazine
Figure imgf000015_0001
Figure imgf000015_0001
Eine Lösung von 208 mg (1,85 mmol) Kalium tert.-Butylat, 682 mg (3,70 mmol) 3,4,5-Trimethoxyphenol und 650 mg (1,85 mmol) 2-(3,4-Dimethoxyphenyl)-5,7- dimethyl-4-(lH-l,2,4-triazol-l-yl)imidazo[5,l-fJ[l,2,4]triazin in 120 ml Pyridin werden für 16 h in der Siedehitze gerührt. Nach dem Abkühlen wird das Lösungsmittel entfernt und der Rückstand in 200 ml Dichlormethan aufgenommen. Man wäscht mit 2 N Salzsäure (3 x 50 ml) und ges. Natriumchlorid-Lsg. (50 ml), trocknet über Natriumsulfat und entfernt das Lösungsmittel im Vakuum. Man reinigt zunächst fiash-chromatographisch (Laufmittelgradient Dichlormethan-Dichlormethan / Metha- nol 20: 1), anschließend durch HPLC, und trocknet in Hochvakuum.A solution of 208 mg (1.85 mmol) of potassium tert-butoxide, 682 mg (3.70 mmol) of 3,4,5-trimethoxyphenol and 650 mg (1.85 mmol) of 2- (3,4-dimethoxyphenyl) -5,7-dimethyl-4- (lH-l, 2,4-triazol-l-yl) imidazo [5, l-fJ [l, 2,4] triazine in 120 ml pyridine are at boiling for 16 h touched. After cooling, the solvent is removed and the residue is taken up in 200 ml of dichloromethane. It is washed with 2N hydrochloric acid (3 x 50 ml) and sat. Sodium chloride soln. (50 ml), dries over sodium sulfate and removes the solvent in vacuo. It is first cleaned by flash chromatography (mobile phase gradient dichloromethane-dichloromethane / methanol 20: 1), then by HPLC, and dried in a high vacuum.
Ausbeute: 525 mg (61 % d. Th.)Yield: 525 mg (61% of theory)
Fp.: 184°C;Mp: 184 ° C;
MS (DCI): 467 [M+H]+;MS (DCI): 467 [M + H] + ;
1H-NMR (200 MHz, DMSO-d6): δ = 2.61 (s, 3H), 2.66 (s, 3H), 3.69 (s, 3H), 3.71 (s, 3H), 3.78 (s, 9H), 6.84 (s, 2H), 7.06 (d, 1H), 7.59-7.68 (m, 2H). 1H-NMR (200 MHz, DMSO-d 6 ): δ = 2.61 (s, 3H), 2.66 (s, 3H), 3.69 (s, 3H), 3.71 (s, 3H), 3.78 (s, 9H), 6.84 (s, 2H), 7.06 (d, 1H), 7.59-7.68 (m, 2H).

Claims

Patentansprüche claims
1. Verwendung von PDE lOA-Inhibitoren zur Herstellung eines Arzneimittels zur Behandlung und/oder Prophylaxe von neurodegenerativen Erkrankungen.1. Use of PDE IOA inhibitors for the manufacture of a medicament for the treatment and / or prophylaxis of neurodegenerative diseases.
2. Verwendung nach Anspruch 1, wobei die neurodegenerative Erkrankung das Parkinson-Syndrom ist.2. Use according to claim 1, wherein the neurodegenerative disease is Parkinson's syndrome.
3. Verwendung nach Anspruch 1 oder 2, wobei der PDE lOA-Inhibitor einen IC5o-Wert von weniger als 1 μM hat.3. Use according to claim 1 or 2, wherein the PDE IOA inhibitor has an IC 5 o value of less than 1 micron.
4. Verwendung nach Anspruch 1 oder 2, wobei der PDE lOA-Inhibitor einen IC50- Wert von weniger als 1 OOnM hat.4. Use according to claim 1 or 2, wherein the PDE IOA inhibitor has an IC 50 value of less than 1 OOnM.
5. Verwendung nach einem der Ansprüche 1 bis 4, wobei der PDE 10A-5. Use according to one of claims 1 to 4, wherein the PDE 10A-
Inhibitor selektiv gegenüber anderen Phosphodiesterasen ist.Inhibitor is selective for other phosphodiesterases.
6. Verwendung nach einem der Ansprüche 1 bis 4, wobei der PDE 10A- Inhibitor selektiv gegenüber PDE IC, 2A, 3B, 4B, 5A und 7B ist.6. Use according to any one of claims 1 to 4, wherein the PDE 10A inhibitor is selective for PDE IC, 2A, 3B, 4B, 5A and 7B.
7. Verwendung nach Anspruch 5 oder 6, wobei der PDE lOA-Inhibitor um mindestens den Faktor 10 potenter die PDE 10A als die anderen Phosphodiesterasen inhibiert.7. Use according to claim 5 or 6, wherein the PDE 10A inhibitor inhibits the PDE 10A more potent than the other phosphodiesterases by at least a factor of 10.
8. Verwendung von PDE lOA-Inhibitoren nach einem der Ansprüche 1 bis 7 zur8. Use of PDE IOA inhibitors according to one of claims 1 to 7 for
Herstellung eines Arzneimittels zur Behandlung und/oder Prophylaxe des idiopathischen Parkinson-Syndroms. Manufacture of a medicament for the treatment and / or prophylaxis of idiopathic Parkinson's syndrome.
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