WO2003000269A2 - Nouvelle utilisation d'inhibiteurs de pde 10a - Google Patents

Nouvelle utilisation d'inhibiteurs de pde 10a Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
pde
parkinson
inhibitors
syndrome
ioa
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/EP2002/006309
Other languages
German (de)
English (en)
Other versions
WO2003000269A3 (fr
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
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.)
Bayer AG
Original Assignee
Bayer AG
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 Bayer AG filed Critical Bayer AG
Publication of WO2003000269A2 publication Critical patent/WO2003000269A2/fr
Publication of WO2003000269A3 publication Critical patent/WO2003000269A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic 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
    • C07D487/04—Ortho-condensed systems
    • 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
    • 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
    • A61K31/53—Heterocyclic 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17C—VESSELS 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
    • F17C2201/00—Vessel construction, in particular geometry, arrangement or size
    • F17C2201/01—Shape
    • F17C2201/0104—Shape cylindrical
    • F17C2201/0119—Shape cylindrical with flat end-piece
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17C—VESSELS 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
    • F17C2201/00—Vessel construction, in particular geometry, arrangement or size
    • F17C2201/05—Size
    • F17C2201/058—Size portable (<30 l)
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17C—VESSELS 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
    • F17C2203/00—Vessel construction, in particular walls or details thereof
    • F17C2203/06—Materials for walls or layers thereof; Properties or structures of walls or their materials
    • F17C2203/0602—Wall structures; Special features thereof
    • F17C2203/0612—Wall structures
    • F17C2203/0614—Single wall
    • F17C2203/0617—Single wall with one layer
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17C—VESSELS 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
    • F17C2203/00—Vessel construction, in particular walls or details thereof
    • F17C2203/06—Materials for walls or layers thereof; Properties or structures of walls or their materials
    • F17C2203/0634—Materials for walls or layers thereof
    • F17C2203/0636—Metals
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17C—VESSELS 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
    • F17C2205/00—Vessel construction, in particular mounting arrangements, attachments or identifications means
    • F17C2205/03—Fluid connections, filters, valves, closure means or other attachments
    • F17C2205/0302—Fittings, valves, filters, or components in connection with the gas storage device
    • F17C2205/0311—Closure means
    • F17C2205/0314—Closure means breakable, e.g. with burst discs
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17C—VESSELS 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
    • F17C2209/00—Vessel construction, in particular methods of manufacturing
    • F17C2209/22—Assembling processes
    • F17C2209/221—Welding
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17C—VESSELS 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
    • F17C2209/00—Vessel construction, in particular methods of manufacturing
    • F17C2209/22—Assembling processes
    • F17C2209/228—Assembling processes by screws, bolts or rivets
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17C—VESSELS 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
    • F17C2223/00—Handled fluid before transfer, i.e. state of fluid when stored in the vessel or before transfer from the vessel
    • F17C2223/01—Handled fluid before transfer, i.e. state of fluid when stored in the vessel or before transfer from the vessel characterised by the phase
    • F17C2223/0107—Single phase
    • F17C2223/0123—Single phase gaseous, e.g. CNG, GNC
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17C—VESSELS 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
    • F17C2260/00—Purposes of gas storage and gas handling
    • F17C2260/02—Improving properties related to fluid or fluid transfer
    • F17C2260/021—Avoiding over pressurising
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F17—STORING OR DISTRIBUTING GASES OR LIQUIDS
    • F17C—VESSELS 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
    • F17C2270/00—Applications
    • F17C2270/01—Applications for fluid transport or storage
    • F17C2270/0165—Applications for fluid transport or storage on the road
    • F17C2270/0181—Airbags

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).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne l'utilisation d'inhibiteurs de PDE 10A pour produire un médicament servant à traiter et/ou à prévenir des maladies neurodégénératives, telles que la maladie de Parkinson.
PCT/EP2002/006309 2001-06-22 2002-06-10 Nouvelle utilisation d'inhibiteurs de pde 10a Ceased WO2003000269A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10130151.0 2001-06-22
DE10130151A DE10130151A1 (de) 2001-06-22 2001-06-22 Neue Verwendung für PDE 10A-Inhibitoren

Publications (2)

Publication Number Publication Date
WO2003000269A2 true WO2003000269A2 (fr) 2003-01-03
WO2003000269A3 WO2003000269A3 (fr) 2003-04-03

Family

ID=7689081

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/006309 Ceased WO2003000269A2 (fr) 2001-06-22 2002-06-10 Nouvelle utilisation d'inhibiteurs de pde 10a

Country Status (2)

Country Link
DE (1) DE10130151A1 (fr)
WO (1) WO2003000269A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005290A1 (fr) * 2002-07-08 2004-01-15 Bayer Healthcare Ag Imidazotriazines substituees
WO2006072828A3 (fr) * 2005-01-07 2006-11-09 Pfizer Prod Inc Composes de quinoline heteroaromatiques
JP2009513494A (ja) * 2003-06-30 2009-04-02 ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｐｄｅ１０阻害剤としてのピロロジヒドロイソキノリン
US8338420B1 (en) 2002-12-04 2012-12-25 Mitsubishi Tanabe Pharma Corporation Treatment of Parkinson's disease and enhancement of dopamine signal using PDE 10 inhibitor

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10230604A1 (de) * 2002-07-08 2004-01-29 Bayer Ag Heterocyclisch substituierte Imidazotriazine

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1239064B (it) * 1990-05-14 1993-09-20 Fidia Spa Uso terapeutico del dipiridamolo
HUT71408A (en) * 1994-01-14 1995-11-28 Egyt Gyogyszervegyeszeti Gyar Pharmaceutical compositions containing papaverine for use to treatment of diseases related to glutamaterg neurotransmission
JP2003510349A (ja) * 1999-10-07 2003-03-18 ノヴァ−ニューロン インコーポレーテッド 線条体機能に必要な遺伝子、その使用、およびそれを調節するための化合物
IL149106A0 (en) * 2001-04-20 2002-11-10 Pfizer Prod Inc Therapeutic use of selective pde10 inhibitors

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005290A1 (fr) * 2002-07-08 2004-01-15 Bayer Healthcare Ag Imidazotriazines substituees
US7202243B2 (en) 2002-07-08 2007-04-10 Bayer Healthcare Ag Substituted imidazotriazines
US8338420B1 (en) 2002-12-04 2012-12-25 Mitsubishi Tanabe Pharma Corporation Treatment of Parkinson's disease and enhancement of dopamine signal using PDE 10 inhibitor
JP2009513494A (ja) * 2003-06-30 2009-04-02 ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｐｄｅ１０阻害剤としてのピロロジヒドロイソキノリン
WO2006072828A3 (fr) * 2005-01-07 2006-11-09 Pfizer Prod Inc Composes de quinoline heteroaromatiques
US7429665B2 (en) 2005-01-07 2008-09-30 Pfizer Inc Heteroaromatic quinoline compounds
KR100896380B1 (ko) * 2005-01-07 2009-05-08 화이자 프로덕츠 인코포레이티드 헤테로방향족 퀴놀린 화합물 및 ｐｄｅ10 저해제로서의그의 용도
EA012211B1 (ru) * 2005-01-07 2009-08-28 Пфайзер Продактс Инк. Гетероароматические соединения хинолинов и их применение в качестве ингибиторов pde10
AP2362A (en) * 2005-01-07 2012-02-08 Pfizer Prod Inc Heteroaromatic quinoline compounds and their use as PDE10 inhibitors.
AU2005323794B2 (en) * 2005-01-07 2012-07-19 Pfizer Products Inc. Heteroaromatic quinoline compounds and their use as PDE10 inhibitors
NO340476B1 (no) * 2005-01-07 2017-05-02 Pfizer Prod Inc Heteroaromatiske quinolinforbindelser, og anvendelse av disse som inhibitorer av PDE10

Also Published As

Publication number Publication date
DE10130151A1 (de) 2003-01-02
WO2003000269A3 (fr) 2003-04-03

Similar Documents

Publication Publication Date Title
EP1534711B1 (fr) Pyrazolopyrimidines substituees par phenyle
EP1534285B1 (fr) Inhibiteurs selectifs de la phosphodiesterase 9a en tant que medicaments pour ameliorer des processus cognitifs
DE60005493T2 (de) Pyrimido[6,1-a]isochinolinonderivate
CH692132A5 (de) Adenosin-A3-Rezeptor-Modulatoren
DE10238724A1 (de) Alkyl-substituierte Pyrazolpyrimidine
EP1363912B1 (fr) Imidazotriazinones substituees
EP1626971B1 (fr) Pyrazolopyrimidines substituees par 6-cyclylmethyle et 6-alkylmethyle
DE60001735T2 (de) 1-aminotriazolo 4,3-a chinazolin-5-one und/oder -thione inhibitoren von phosphodiesterasen iv
EP1307201A2 (fr) Inhibiteurs selectifs de pde 2 comme medicaments ameliorant la perception
EP1599479A1 (fr) Imidazotriazines substituees
DE10230604A1 (de) Heterocyclisch substituierte Imidazotriazine
EP1244673A2 (fr) Nouveaux imidazo 1,3,5]triazinones et leur utilisation
EP1442023B1 (fr) Sel de sodium cristallise de telmisartan et son utilisation comme antagoniste de l&#39;angiotensine
WO2004099210A1 (fr) Pyrazolopyrimidines substituees par 6-arylmethyle
EP2124955A2 (fr) Inhibition de la pde2a
DE60020556T2 (de) Ionenkanal modulierende mittel
DE10130151A1 (de) Neue Verwendung für PDE 10A-Inhibitoren
DE3888541T2 (de) Verbesserung der toxizitätskurven in der chemotherapie.
DE10201240A1 (de) Substituierte Alkyluracile und ihre Verwendung
WO2006125548A1 (fr) Utilisation de pyrazolopyrimidines contre des maladies cardiovasculaires
DE60106606T2 (de) Substituierte stilbenverbindungen als glucoseaufnahme inhibitoren
EP2298773B1 (fr) Pyrazolopyrimidines substituées par 6-cyclylméthyle et 6-alkylméthyle
EP0563733A1 (fr) Utilisation d&#39;acides carboxyliques-6-oxo-7-pyrido-7H benzoxacine(1,2,3-de)(1,4) ou d&#39;esters pour la fabrication d&#39;un médicament pour le traitement de maladies virales
DE10034801A1 (de) Substituierte Amidoalkyl-uracile und ihre Verwendung
WO2012052556A1 (fr) Nouvelle halogène-alkoxy-quinazoline, sa production et son utilisation

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG UZ VN YU ZA ZM ZW GH GM KE LS MW

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP