WO2001068097A1 - VERWENDUNG VON PYRIDO[3,2-e]-PYRAZINONEN ALS INHIBITOREN DER PHOSPHODIESTERASE 5 ZUR THERAPIE VON EREKTILER DYSFUNKTION - Google Patents

VERWENDUNG VON PYRIDO[3,2-e]-PYRAZINONEN ALS INHIBITOREN DER PHOSPHODIESTERASE 5 ZUR THERAPIE VON EREKTILER DYSFUNKTION Download PDF

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Publication number
WO2001068097A1
WO2001068097A1 PCT/EP2001/002485 EP0102485W WO0168097A1 WO 2001068097 A1 WO2001068097 A1 WO 2001068097A1 EP 0102485 W EP0102485 W EP 0102485W WO 0168097 A1 WO0168097 A1 WO 0168097A1
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WO
WIPO (PCT)
Prior art keywords
methyl
methoxy
ethyl
pyπdo
ιmιdazo
Prior art date
Application number
PCT/EP2001/002485
Other languages
German (de)
English (en)
French (fr)
Inventor
Degenhard Marx
Norbert Höfgen
Ute Egerland
Stefan Szelenyi
Thomas Kronbach
Original Assignee
Elbion 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 Elbion Ag filed Critical Elbion Ag
Priority to BR0109163-8A priority Critical patent/BR0109163A/pt
Priority to IL15164601A priority patent/IL151646A0/xx
Priority to HU0300551A priority patent/HUP0300551A2/hu
Priority to AU2001244192A priority patent/AU2001244192A1/en
Priority to SK1323-2002A priority patent/SK13232002A3/sk
Priority to EP01917067A priority patent/EP1267877A1/de
Priority to JP2001566661A priority patent/JP2003528056A/ja
Publication of WO2001068097A1 publication Critical patent/WO2001068097A1/de
Priority to BG107077A priority patent/BG107077A/bg
Priority to NO20024364A priority patent/NO20024364L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • This invention relates to the use of pyrido [3,2-e] -pyrazinones of the formula as active ingredients for the treatment of erectile dysfunction (impotence) and pharmaceutical preparations which contain these compounds.
  • Male impotence can be defined as his inability to have sexual intercourse due to lack of erection and / or lack of ejaculation.
  • Erectile dysfunction affects approximately 10% of the male population. Men between the ages of 40 and 70 are particularly affected with about 52%. Worldwide, several million men suffer from this disease (approx. 7.5 million in Germany alone), which in most cases is organic, less often psychological. Erectile dysfunction is a common problem among older men, especially when there are other chronic conditions such as high blood pressure, atherosclerosis and diabetes.
  • Silde ⁇ afil is an orally active phosphodiesterase 5 (PDE5) inhibitor, which does not directly cause an erection, but the effect of the sexual Stimulation of nitric oxide (NO) released in the penis increases NO, like its 'second messenger' cGMP, causes a vasodilation in the corpus cavemosum (swelling body) so that blood can flow in more, which causes the erection
  • Phosphodiesterases are an isoenzyme family to which 10 different isoenzymes have so far been assigned. PDE enzymes cleave by hydrolysis of cyclic guanos ⁇ n-3 ' , 5-monophosphate (cGMP) or cyclic adenos ⁇ n-3 ' , 5 ' -monophosphate ( cAMP), which occur as 'second messengers' in a large number of cells.
  • Phosphodiesterase 5 PDE 5
  • PDE 5 is cGMP-specific and dominates in the tissue of the human corpus cavernosum
  • the inhibition of PDE 5 in the human cavernous body leads to an increase in the intracellular cGMP level induced by NO. This is associated with relaxation of the smooth muscles of the cavernous body and, as a result, an erection
  • Inhibitors of PDE 5 are therefore suitable as therapeutic agents for the indication of erectile dysfunction
  • European patent 0 400 583 relates to imidazoquinoxane of the general formula
  • A represents a nitrogen atom or CH
  • B and D represent a nitrogen atom or CH or a substituted carbon atom for positions 7 or 8
  • the radicals R, R ⁇ , R2 represent hydrogen or various organic substituents
  • Patent application WO 93/20 077 relates to imidazoquinoxahnones of the general formula
  • R 1 can be NO2 or CF3 and X for various nitrogen-containing ones
  • the invention relates to Py ⁇ do [3,2-e] -pyraz ⁇ none of formula 1
  • R, R 2 , R 4 may be the same or different and represent -C ⁇ - alkyl groups, which may be straight-chain or branched-chain, and R 3 for -CH 2 -A stands for A can
  • the invention also relates to the physiologically acceptable salts of the compounds of the formula 1, which can be obtained by neutralizing the bases with inorganic or organic acids or by neutralizing the acids with inorganic or organic bases or by quaternizing tertiary amines to form quaternary ammonium salts
  • Formulas are known per se from patent DE 195 10 965, to which reference has already been made in the prior art, where pyrido [3,2-e] pyrazionones were identified as dual inhibitors of PDE 4 and PDE 5, which also means that described application as anti-asthmatics or anti-allergies
  • Those compounds of the formula ⁇ according to the invention in which A is a cyclohexyl group and R 1 , R 2 and R 4 have the meaning described are new
  • the compounds of the formula according to the invention are distinguished by the fact that their inhibitory action on PDE 5 is particularly pronounced. It is the essence of this invention that the compounds according to the formula ⁇ according to the invention are particularly suitable for use as therapeutic agents for the treatment of erectile dysfunction by this active principle are
  • a particular advantage of the compounds according to the invention is that they affect the cGMP level in human tissue with a high selectivity, but not the cAMP level. This has been shown for both human tissue of the heart and of the penis. With this selectivity, the risk of heart Circulatory side effects are minimized With regard to cGMP selectivity, the compounds according to the invention are superior to the standard therapeutic agent sildenafil
  • the compounds of the formula ⁇ according to the invention can be administered systemically, for example intravenously, intramuscularly, subcutaneously, orally, buccally or sub ngually.
  • Topical application for example by inhalation or intranasally, is also possible.
  • Oral application of 5-200 mg of the compound before sexual intercourse is a preferred therapy regimen
  • Medicaments which contain one or more of the compounds of the formula according to the invention in addition to conventional physiologically acceptable carriers and / or diluents or auxiliaries, and also processes for the preparation of these medicaments are also part of this invention
  • the compounds of formula 1 according to the invention and the medicaments which contain the compounds of formula 1 according to the invention can be used both individually and in combination with one another
  • the compounds according to the invention can be used as veterinary therapeutic agents for the prophylaxis and therapy of erectile dysfunction in male mammals.
  • the dosage, the application scheme and the galenical formulation of the compound are carried out taking into account species differences and the requirements of veterinary practice
  • the compounds according to the invention are strong inhibitors of phosphodiesterase 5. Their therapeutic potential is demonstrated in vitro, for example, by increasing the effect of NO on the intracellular cGMP levels in fibroblasts in the rat, the selectivity of influencing the cAMP and cGMP levels in human tissues and the Relaxation of human corpus cavernosum demonstrated
  • the PDE 5 actinate is determined in enzyme preparations from human platelets. Human blood was anticoagulated with citrate. By centrifugation at 700 xg for 20 minutes at room temperature, the platelet-rich plasma in the supernatant is separated from the erythrocytes and leukocytes.
  • the platelets are lysed by ultrasound and in the PDE 5-assay used
  • the phosphodiesterase activity is determined with some modifications according to the method described by Thompson et al (Thompson, WJ, Appleman, MM, Assay of cyclic nucleotide phosphodiesterase and resolution of multiple molecular forms of the enzyme Adv Cycl Nucl Res 1979, 10, 69-92)
  • the reaction mixtures contain 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, the inhibitors in variable concentrations, the enzyme preparation and the further components necessary for the detection of the individual isoenzyme PDE 5 (see below) the addition of the substrate 0.5 ⁇ M [ 3 H] -cGMP (approx.
  • the samples are stopped on ice, 400 ⁇ l each of a mixture of Dowex-water-ethanol (1 +1 +1) are added , well mixed and incubated again on ice for 15 minutes.
  • the reaction vessels are centrifuged for 20 minutes at 3000 xg. 200 ⁇ l aliquots of the supernatant are transferred directly into scintillation vials. After the addition of 3 ml scintillator, the samples are measured in a beta counter 100 ⁇ M IBMX determined in the determination of PDE 5 and subtracted from the test values
  • Rat fetal lung fibroblast cells are a suitable medium for examining the influence of NO on intracellular cGMP levels (Ishn et al 1991).
  • the basic mechanism is based on the smooth vascular muscles transferable in the corpus cavernosum
  • the compounds according to the invention intensify the concentration-dependent increase in the intracellular cGMP levels induced by the NO donor S-nitroso-N-acetyl-D, l_-pen ⁇ c ⁇ llam ⁇ n
  • compound 13 induces a significant increase in cGMP level at a concentration of 0.10 ⁇ mol / l.
  • the effectiveness of compound 13 is 1000 times stronger than that which is achieved by using the non-specific PDE inhibitor 3-isobutyl-1 - methylxanth ⁇ n (IBMX) reached
  • the compounds according to the invention are superior to the standard therapeutic agent sildenafil.
  • Sildenafil increases the cGMP level in human atrium tissue by 147%, and the cAMP level at the same time by 240%.
  • the cGMP is increased by sildenafil.
  • the compounds according to the invention have a relaxing effect on the corpus cavernosum strips pre-contracted with Noradrenahn. For example, an EC50 value of 0 15 ⁇ mol / l was determined for compound 13

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Reproductive Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gynecology & Obstetrics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
PCT/EP2001/002485 2000-03-14 2001-03-06 VERWENDUNG VON PYRIDO[3,2-e]-PYRAZINONEN ALS INHIBITOREN DER PHOSPHODIESTERASE 5 ZUR THERAPIE VON EREKTILER DYSFUNKTION WO2001068097A1 (de)

Priority Applications (9)

Application Number Priority Date Filing Date Title
BR0109163-8A BR0109163A (pt) 2000-03-14 2001-03-06 Uso de pirido[3,2-e]-pirazinonas como inibidores da fosfodieterase 5, para terapia de disfunção erétil
IL15164601A IL151646A0 (en) 2000-03-14 2001-03-06 Use of pyrido[3,2-e]-pyrazinones as inhibitors of phosphodicesterase 5 for treating erectile dysfunction
HU0300551A HUP0300551A2 (hu) 2000-03-14 2001-03-06 Pirido[3,2-e]-pirazinon-származékok alkalmazása merevedési zavar terápiája foszfodiészteráz 5 enzim gátlása útján és ezeket tartalmazó gyógyszerkészítmények
AU2001244192A AU2001244192A1 (en) 2000-03-14 2001-03-06 Use of pyrido(3,2-E)-pyrazinones as inhibitors of phosphodiesterase 5 for treating erectile dysfunction
SK1323-2002A SK13232002A3 (sk) 2000-03-14 2001-03-06 Použitie pyrido[3,2-e]-pyrazinónov ako inhibítorov fosfodiesterázy 5 na liečbu erektilnej dysfunkcie
EP01917067A EP1267877A1 (de) 2000-03-14 2001-03-06 VERWENDUNG VON PYRIDO 3,2-e]-PYRAZINONEN ALS INHIBITOREN DER PHOSPHODIESTERASE 5 ZUR THERAPIE VON EREKTILER DYSFUNKTION
JP2001566661A JP2003528056A (ja) 2000-03-14 2001-03-06 勃起性機能障害の治療のためのホスホジエステラーゼ５の阻害物質としてのピリド［３，２−ｅ］−ピラジノンの使用
BG107077A BG107077A (bg) 2000-03-14 2002-09-10 Използуване на пиридо /3,2-е/ - пиразинони като инхибитори на фосфодиестераза 5 за лечение на еректилна дисфункция
NO20024364A NO20024364L (no) 2000-03-14 2002-09-12 Anvendelse av pyrido [3,2-E]-pyrazinoner som inhibitorer av fosfodiesterase 5 for behandling av erektil dysfunksjon

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10012373A DE10012373A1 (de) 2000-03-14 2000-03-14 Verwendung von Pyrido[3,2-e]-pyrazinonen als Inhibitoren der Phosphodiesterase 5 zur Therapie von erektiler Dysfunktion
DE10012373.2 2000-03-14

Publications (1)

Publication Number Publication Date
WO2001068097A1 true WO2001068097A1 (de) 2001-09-20

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PCT/EP2001/002485 WO2001068097A1 (de) 2000-03-14 2001-03-06 VERWENDUNG VON PYRIDO[3,2-e]-PYRAZINONEN ALS INHIBITOREN DER PHOSPHODIESTERASE 5 ZUR THERAPIE VON EREKTILER DYSFUNKTION

Country Status (14)

Country Link
EP (1) EP1267877A1 (ja)
JP (1) JP2003528056A (ja)
AR (1) AR028250A1 (ja)
AU (1) AU2001244192A1 (ja)
BG (1) BG107077A (ja)
BR (1) BR0109163A (ja)
CZ (1) CZ20023078A3 (ja)
DE (1) DE10012373A1 (ja)
HU (1) HUP0300551A2 (ja)
IL (1) IL151646A0 (ja)
NO (1) NO20024364L (ja)
RU (1) RU2002127413A (ja)
SK (1) SK13232002A3 (ja)
WO (1) WO2001068097A1 (ja)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7875618B2 (en) 2007-11-30 2011-01-25 Wyeth Substituted imidazo[1,5-a]quinoxalines useful as inhibitors of phosphodiesterase 10 for the treatment of neurological and other disorders
US8252937B2 (en) 2007-09-14 2012-08-28 Janssen Pharmaceuticals, Inc. 1,3-disubstituted 4-(aryl-X-phenyl)-1H-pyridin-2-ones
US8299101B2 (en) 2007-03-07 2012-10-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive mGluR2-receptor modulators
US8399493B2 (en) 2004-09-17 2013-03-19 Janssen Pharmaceuticals, Inc. Pyridinone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

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MX357320B (es) 2012-06-18 2018-07-04 Dart Neuroscience Cayman Ltd Compuestos de la azolopirimidina-5-(6h)-ona de piridina sustituida.
JP6420400B2 (ja) * 2017-04-12 2018-11-07 ダート・ニューロサイエンス・（ケイマン）・リミテッド 置換ピリジンアゾロピリミジン−５−（６ｈ）−オン化合物

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8399493B2 (en) 2004-09-17 2013-03-19 Janssen Pharmaceuticals, Inc. Pyridinone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US9266834B2 (en) 2006-03-15 2016-02-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US8299101B2 (en) 2007-03-07 2012-10-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive mGluR2-receptor modulators
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US11071729B2 (en) 2007-09-14 2021-07-27 Addex Pharmaceuticals S.A. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US8252937B2 (en) 2007-09-14 2012-08-28 Janssen Pharmaceuticals, Inc. 1,3-disubstituted 4-(aryl-X-phenyl)-1H-pyridin-2-ones
US9132122B2 (en) 2007-09-14 2015-09-15 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US7875618B2 (en) 2007-11-30 2011-01-25 Wyeth Substituted imidazo[1,5-a]quinoxalines useful as inhibitors of phosphodiesterase 10 for the treatment of neurological and other disorders
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9226930B2 (en) 2009-05-12 2016-01-05 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-a] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US9737533B2 (en) 2009-05-12 2017-08-22 Janssen Pharmaceuticals. Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US10071095B2 (en) 2009-05-12 2018-09-11 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of neurological and psychiatric disorders
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
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BG107077A (bg) 2003-05-30
NO20024364L (no) 2002-09-27
CZ20023078A3 (cs) 2003-03-12
EP1267877A1 (de) 2003-01-02
NO20024364D0 (no) 2002-09-12
DE10012373A1 (de) 2001-09-20
IL151646A0 (en) 2003-04-10
HUP0300551A2 (hu) 2003-07-28
AR028250A1 (es) 2003-04-30
AU2001244192A1 (en) 2001-09-24
BR0109163A (pt) 2002-11-26
SK13232002A3 (sk) 2003-05-02
RU2002127413A (ru) 2004-02-27

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