WO1997005109A1 - Heterocyclic compounds, their preparation and use - Google Patents
Heterocyclic compounds, their preparation and use Download PDFInfo
- Publication number
- WO1997005109A1 WO1997005109A1 PCT/DK1996/000332 DK9600332W WO9705109A1 WO 1997005109 A1 WO1997005109 A1 WO 1997005109A1 DK 9600332 W DK9600332 W DK 9600332W WO 9705109 A1 WO9705109 A1 WO 9705109A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- indolyl
- alkyl
- chloro
- compound
- defined above
- Prior art date
Links
- 0 **1c2c(*)c(*)c(*)c(*)c2CC1=O Chemical compound **1c2c(*)c(*)c(*)c(*)c2CC1=O 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- Heterocyclic compounds their preparation and use .
- the present invention relates to therapeutic active indolderivatives, a method for preparing the same, pharmaceutical compositions comprising the com- pounds and a method of treating diseases in the central nervous system therewith.
- MGIuR 1 to MGIuR 8 different subtypes of the metabotropic glutamate receptors are described (MGIuR 1 to MGIuR 8 ) and in addition some spliced variants of the subtypes are reported.
- the Metabotropic glutamate receptor subtypes MGIuR., and MGIuR 5 are coupled to phosphoinositide hydrolysis (Johnson, G. and Bigge, CF. (1991) Annu. Rep. Med. Chem. 26, 11-22, Hansen, J.J. and Krogsgaard Larsen, P. Med. Res. Rev. 10,55-94, Thomsen, C. and Suzdak, P. (1993) Eur. J. Pharmacol. 245 ,299), while the others are coupled to cyclic AMP formation (Schoepp, D.D., Johnson, B.G. and Monn, J.A. (1992) J. Neurochem. 58, 1184-1186, Cartmell et al. (1992) J. Neurochem. 58, 1964-1966, Manzoni, O. et al. (1992) Eur. J. Pharmacol. 225, 357-358).
- trans-ACPD trans 1S,3R-1-aminocyclopentane-1,3-dicar- boxylic acid
- L-AP3 L-2-amino-3-phosphonopropionic acid
- Palmer E., Monaghan, D.T. and Cotman, C.W. (1989) Eur. J. Phar ⁇ macol. 166, 585-587, Desai, M.A. and Conn, P.J. (1990) Neurosci. Lett. 109, 157-162, Schoepp, D.D. et al. (1991), J. Neurochem. 56, 1789-1796, Schoepp D.D. and Johnson B.G. (1989), J. Neurochem.
- L-AP4 L-2-amino-4-phosphonobutyrate which is an agonist at the MGIuR 4 receptor (Thomsen C. et al. (1992), Eur. J. Pharmacol. 227, 361-362) and some of the isomers of CCG (2-(carboxycyclopropyl)glycines) especially L-CCG-I and L-CCG-II (Hayashi, Y. et al. (1992), Br. J. Pharmacol. 107, 539- 543).
- Literature evidence suggests that compounds selective for the metabotropic glutamate receptors either as agonists or antagonists are useful in the treatment of different neurological diseases.
- Trans-ACPD has been shown to increase release of dopamine in the rat brain which indicates that compounds acting on the metabotropic glutamate receptors might be usable for the treatment of Parkinson's disease and Huntington's Chorea (Sacaan et al. (1992), J. Neurochem. 59, 245).
- Trans-ACPD has been shown to be a neuroprotective agent in an MCAO model in mice (Chiamulera et al. (1992), Eur. J. Pharmacol. 215, 353), and it has been shown to inhibit NMDA induced neurotoxicity in nerve cell cultures (Koh et al., (1991), Proc. Natl. Acad. Sci. USA 88, 9431).
- metabotropic glutamate receptor active compounds seem of interest, proved by the fact that antagonists at the metabotropic glutamate receptors antagonises sensory synaptic response to noxious stimuli of thalamic neurons (Eaton, S.A. et al. (1993), Eur. J. Neuro ⁇ sci. 5, 186).
- the present invention relates to compounds of formula la
- R 1a is C ⁇ -alkyl optionally substituted with halogen; C 2 . 6 -alkenyi;
- -COR 10a -COOR 10a ; C ⁇ -alkyl substituted with dimethylamino; -R 10a -O-R a ; -R 10a -O-R 11a -O-R 2a ; phenylsulfonyl; benzoyl; benzyl; or phenyl; each of which aromatic group is optionally substituted with C ⁇ -alkyl, C ⁇ -alkoxy, halogen, carboxy or nitro; wherein R 10a , R 11a , and R 12a are independently C ⁇ -alkyl;
- R 2a is halogen; C ⁇ -alky! substituted with C 3 . 6 -cycloalkyl; C 3 . 6 -cycloalkyl; C 2 . 6 -alkenyl; C 2 . 6 -alkynyl; benzyl; C ⁇ -alkyl substituted with dimethylamino; -R 10a -O-R 11a ; -R 10a -O-R 11a -O-R 12a ; wherein R 10a , R 11a and R 12a are independ- ently C 14 -alkyl; -O optionally substituted with C 3 . 6 -cycloalkyl, C 2 . 6 -alkenyl, C 2 .
- R 3a and R 4a are independently H; -CN; -COR 13a ; -COOR 13a ; -SOR 3a ; or -SO 2 R 13a ; wherein R 13a is C,. 6 -alkyl optionally substituted with C 3 . 6 -cycloalkyl, C 3 . 6 -cycloalkyl, C 2 . 6 -alkenyl, C 2 .
- R 5a is H or C ⁇ -alkyl; provided that R 5a is not H when either R 3a or R 4a is H;
- R 6a , R 7a , R 8a and R 9a are independently H; nitro; amino; halogen; tri- fluoromethyl; trifluoroacetyl; sulfo; carboxy; carbamoyl; sulfamoyl;
- R 10a is as defined above; C ⁇ -alkoxy; or C ⁇ -alkyl optionally substituted with halogen; or a salt thereof with a pharma ⁇ ceutically acceptable acid or base.
- salts include pharmaceutically acceptable acid addition salts, phar ⁇ maceutically acceptable metal salts or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluo ⁇ roacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, methanesulfonic, ethane sulfonic, picric and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference, or lithium, sodium, potassium, magne ⁇ sium and the like.
- pharmaceutically acceptable acid addition salts such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluo ⁇ roacetic, trichloroacetic, oxalic, male
- C ⁇ -alkyl refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methyl- pentyl, neopentyl, n-hexyl and 2,2-dimethylpropyl.
- C ⁇ -alkoxy refers to a monovalent substituent comprising a lower alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy.
- C 2 . 6 -alkenyl refers to an unsaturated hydrocarbon chain having 2-6 carbon atoms and one double bond such as e.g. vinyl, 1 -propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl and n-hexenyl.
- C 3 . 6 -cycloalkyl refers to a radical of a saturated cyclic hydrocarbon with the indicated number of carbons such as cyclopro ⁇ pyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
- halogen means fluorine, chlorine, bromine and iodine.
- R 1a is benzyl optionally substituted with C ⁇ -alkyl.
- C ⁇ -alkoxy, halogen, carboxy or nitro, and/or R 3a and R a are independently -CN; -COR 13a or -COOR 13a ; wherein R 13a is C ⁇ -alky! optionally substituted with C 3 . 6 -cycloalkyl, C 3.6 - cycloalkyl, C 2 . 6 -alkenyl, C 2 .
- the invention also relates to methods of preparing the above mentioned compounds. These methods comprise
- R 1a , R 6a , R 7a , R 8a , and R 9a have the meanings defined above, with a N,N-dimethyl amide, preferably dimethylfor ⁇ mamide or dimethylacetamide, and POX 3 , wherein X is chlorine or bromine, using Vilsmeyer-Hack conditions, to form a compound of formula Ilia
- R 1a , R 5a , R 6a , R 7a , R 8a , and R 9a have the meanings defined above; and subsequently
- R 1a , R 5a , R 6a , R 7a , R 8a , R 9a , R 14a and R 15a have the meanings defined above, or
- R 1a , R 6a , R 7a , R 8a , and R 9a have the meanings defined above and R 16a is C,. 6 -alkyl optionally substituted with C 3 . 6 -cycloalklyl; C 3 . 6 -cycloalkyl; C 2 . 6 -alkenyl; C 2 .
- R 10a , R 11a and R 12a are independently C ⁇ -alkyl; with a N,N-dimethyl amide, preferably dimethylformamide or dimethylacetamide, and POX 3 , wherein X is chlorine or bromine, using Vilsmeyer-Hack condi ⁇ tions, to form a compound of formula Via,
- R 1a , R 5a , R 6a , R 7a , R 8a ,R 9a and R 16a have the meanings defined above, and subsequently
- R 13a have the meanings defined above, either in the presence or absence of an added base, preferable triethylamine, piperidine or potassium carbonate to form a compound of for ⁇ mula Vila,
- R 1a , R 5a , R 6a , R 7a , R 8a ,R 9a , R 14a , R 15a and R 16a have the meanings defined above, or
- R 1a , R 5a , R 6a , R 7a , R 8a ,R 9a , R 14a and R 16a have the meanings defined above, or
- R 1a , R 4a , R 5a , R 6a , R 7a , R 8a ,R 9a , R 14a , and R 16a have the meanings defined above, or
- R 10a -O-R 11a , -R 10a -O-R 11a -O-R 12a substituted with dimethylamino, R 10a -O-R 11a , -R 10a -O-R 11a -O-R 12a ; wherein R 10a , R 11a and R 12a are independently C 1-6 -alkyl, to form a compound of formula Xa,
- Y a is -O- or -S-
- R 1a , R 5a , R 6a , R 7a , R 8a ,R 9a , and R 18a have the meanings defined above, and subsequently
- Y a , R 1a , R 3a ,R 4a , R 5a , R 6a , R 7a , R 8a ,R 9a , and R 18a have the meanings defined above, or
- Ethyl 2-cyano-3-(1 -benzyl-2-chloro-3-indolyl)acrylate Ethyl 2-cyano-3-(1 -methyl-2-chloro-3-indolyl)acrylate, 3-(1-Methyl-2-chloro-3-indolyl)-2-methylsulfonyl-acrylonitrile, 3-(1-Benzyl-2-chloro-3-indolyl)-2-methylsulfonylacrylonitrile,
- the pharmacological properties of the compounds of the invention can be illustrated by determining their effects in different conventional radioligand binding assays or in functional in vitro assays.
- the compounds of the invention were studied in an in vitro assay for meas ⁇ uring inhibition of Pl-hydrolysis in BHK 570 cells expressing mGluR ⁇ receptors.
- the metabotropic glutamate receptor (mGluR) is selectively activated by trans-aminocyclopentane dicarboxylic acid and is coupled to the hydrolysis of inositol phosphates via a GTP-binding protein.
- mGluRl ⁇ The first subtype isolated (Houamed et al., 1991 , Science 252, 1318), termed the mGluRl ⁇ , has been shown to be coupled to Pl-hydrolysis when expressed in baby hamster kidney cells (BHK) (Thomsen et al., Brain Res. (in press)). In these cells no stimulation by 1 mM quisqualate or glutamate was observed with control BHK cells whereas a 6-8 fold increase over basal Pl-hydrolysis was seen with BHK cells expressing mGluRl ⁇ .
- BHK570 cells expressing mGluRl ⁇ are cultured in DMEM (4.5 g/l glucose, 2mM glutamin); 5% foetal calf serum; 0.10 mg/ml neomycin; 0.5 mg/ml G418; 1 ⁇ M methotrexate; 50 ⁇ g/ml gentamycin. Cells are subcultured every 5 days using 0.05% trypsin/EDTA in PBS.
- the protocol for Pl-hydrolysis was measured using a modification of a method previously described (Berridge et al., 1982, Biochem. J. 206,587).
- Cells were plated in 16 mm wells (24 well multidish, Costar) with 1 confluent 100 mm dish per multidish.
- Replace the medium 24 h before the experiment with 500 ⁇ l fresh growth medium containing 4 ⁇ Ci/ml myo-[2- 3 H]inositol (specific activity 18 Ci/mmol, Amersham).
- the cells were washed twice with Krebs-Henseleit buffer (Sigma cat.
- IP1 to IP4 fractions may be collected with 5 ml 0.05; 0.10; 0.17 and 0.25 M KHCO 3 , respectively. Usually IP1 and IP2 fractions are collected simultaneously. Scintillation liquid: use 12-15 ml Ultima Gold (Packard).
- Testcompounds are dissolved in DMSO, DMSO and Pluronic F-127 or ethanol and diluted in assay buffer. Glutamate (10 ⁇ M and 1000 ⁇ M) and buffer alone are included as a control.
- the stimulation by 10 ⁇ M shall represent a submaximal stimulation.
- the response by 10 ⁇ M glutamate should exceed 3-fold the basal level and should be below maximal stimulation (glutamate at 1 mM).
- the results are calculated relative to the stimulation by 10 ⁇ M glutamate and a dose re ⁇ sponse curve is generated.
- test results obtained by testing a compound of the present invention in the above mentioned assay appear from the following Table 1.
- the compounds according to the invention are effective over a wide dosage range.
- dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used.
- a most preferable dosage is about 10 mg to about 70 mg per day.
- the exact dosage will depend upon the mode of administration, form in which admin ⁇ istered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
- the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramus ⁇ cular or intranasal, the oral route being preferred.
- oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramus ⁇ cular or intranasal, the oral route being preferred.
- compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier for example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
- the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
- the active compound can be adsorbed on a granular solid container for example in a sachet.
- suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, mag ⁇ nesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinyl- pyrrolidone.
- the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
- injectable solutions or suspensions preferably aqueous solutions with the active compound dis ⁇ solved in polyhydroxy lated castor oil.
- Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
- Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
- a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
- the compounds are dispensed in unit form comprising from about 1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.
- a typical tablet appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9507124A JPH11509847A (en) | 1995-07-31 | 1996-07-31 | Heterocyclic compounds, their preparation and use |
EP96924801A EP0843660A1 (en) | 1995-07-31 | 1996-07-31 | Heterocyclic compounds, their preparation and use |
AU65142/96A AU6514296A (en) | 1995-07-31 | 1996-07-31 | Heterocyclic compounds, their preparation and use |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK87095 | 1995-07-31 | ||
DK0870/95 | 1995-07-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997005109A1 true WO1997005109A1 (en) | 1997-02-13 |
Family
ID=8098461
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/DK1996/000332 WO1997005109A1 (en) | 1995-07-31 | 1996-07-31 | Heterocyclic compounds, their preparation and use |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0843660A1 (en) |
JP (1) | JPH11509847A (en) |
AU (1) | AU6514296A (en) |
WO (1) | WO1997005109A1 (en) |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999002497A2 (en) * | 1997-07-11 | 1999-01-21 | Novartis Ag | Pyridine derivatives |
WO2001029011A2 (en) * | 1999-10-15 | 2001-04-26 | F. Hoffmann-La Roche Ag | Benzodiazepine derivatives as metabotropic glutamate receptor antagonists |
WO2001029012A2 (en) * | 1999-10-15 | 2001-04-26 | F. Hoffmann-La Roche Ag | Benzodiazepine derivatives as metabotropic glutamate receptor antagonists |
US6376539B1 (en) | 1998-01-17 | 2002-04-23 | Bayer Aktiengesellschaft | Substituted bicyclic lactones |
US6433004B1 (en) | 1998-01-17 | 2002-08-13 | Bayer Aktiengesellschaft | Substituted β,γ-anellated lactones |
US6462074B1 (en) | 1998-01-17 | 2002-10-08 | Bayer Aktiengesellschaft | Substituted α, β-anellated butyrolactones |
US6642264B1 (en) | 1999-04-06 | 2003-11-04 | Yamanouchi Pharmaceutical Co., Ltd. | Thiazolobenzoimidazole derivatives |
WO2006037996A1 (en) * | 2004-10-05 | 2006-04-13 | Merz Pharma Gmbh & Co. Kgaa | Novel cyclic and acyclic propenones for treating cns disorders |
US7511033B2 (en) | 2007-04-19 | 2009-03-31 | Hoffmann-La Roche Inc. | Dihydro-benzo[B][1,4]diazepin-2-one sulfonamide derivatives |
WO2011109398A2 (en) | 2010-03-02 | 2011-09-09 | President And Fellows Of Harvard College | Methods and compositions for treatment of angelman syndrome and autism spectrum disorders |
WO2011150380A1 (en) | 2010-05-28 | 2011-12-01 | Xenoport, Inc. | Methods of treatment of fragile x syndrome, down's syndrome, autism and related disorders |
WO2012009646A1 (en) | 2010-07-15 | 2012-01-19 | Xenoport, Inc. | Methods of treating fragile x syndrome, down's syndrome, autism and related disorders |
EP2567696A1 (en) | 2006-11-22 | 2013-03-13 | Seaside Therapeutics, Inc. | Compositions for treating autism spectrum disorder |
US8969347B2 (en) | 2008-06-03 | 2015-03-03 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
US9359379B2 (en) | 2012-10-02 | 2016-06-07 | Intermune, Inc. | Anti-fibrotic pyridinones |
US9527816B2 (en) | 2005-05-10 | 2016-12-27 | Intermune, Inc. | Method of modulating stress-activated protein kinase system |
WO2017196936A1 (en) * | 2016-05-12 | 2017-11-16 | Regents Of The University Of Minnesota | Indole and indazole cyanocinnamate compounds and therapeutic uses thereof |
US10233195B2 (en) | 2014-04-02 | 2019-03-19 | Intermune, Inc. | Anti-fibrotic pyridinones |
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1996
- 1996-07-31 AU AU65142/96A patent/AU6514296A/en not_active Abandoned
- 1996-07-31 JP JP9507124A patent/JPH11509847A/en active Pending
- 1996-07-31 EP EP96924801A patent/EP0843660A1/en not_active Withdrawn
- 1996-07-31 WO PCT/DK1996/000332 patent/WO1997005109A1/en not_active Application Discontinuation
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Cited By (36)
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US6656957B1 (en) | 1997-07-11 | 2003-12-02 | Novartis Ag | Pyridine derivatives |
US6433004B1 (en) | 1998-01-17 | 2002-08-13 | Bayer Aktiengesellschaft | Substituted β,γ-anellated lactones |
US6462074B1 (en) | 1998-01-17 | 2002-10-08 | Bayer Aktiengesellschaft | Substituted α, β-anellated butyrolactones |
US6723718B2 (en) | 1998-01-17 | 2004-04-20 | Bayer Aktiengesellschaft | Substituted α, β-anellated butyrolactones |
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US6407094B1 (en) | 1999-10-15 | 2002-06-18 | Hoffmann-La Roche Inc. | Glutamate receptor antagonists |
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WO2001029012A3 (en) * | 1999-10-15 | 2001-11-08 | Hoffmann La Roche | Benzodiazepine derivatives as metabotropic glutamate receptor antagonists |
US6960578B2 (en) | 1999-10-15 | 2005-11-01 | Hoffmann-La Roche Inc. | Glutamate receptor antagonists |
US7018998B2 (en) | 1999-10-15 | 2006-03-28 | Hoffmann-La Roche Inc. | Glutamate receptor antagonists |
US7151098B2 (en) | 1999-10-15 | 2006-12-19 | Hoffmann-La Roche Inc. | Glutamate receptor antagonists |
WO2006037996A1 (en) * | 2004-10-05 | 2006-04-13 | Merz Pharma Gmbh & Co. Kgaa | Novel cyclic and acyclic propenones for treating cns disorders |
US9527816B2 (en) | 2005-05-10 | 2016-12-27 | Intermune, Inc. | Method of modulating stress-activated protein kinase system |
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Also Published As
Publication number | Publication date |
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JPH11509847A (en) | 1999-08-31 |
AU6514296A (en) | 1997-02-26 |
EP0843660A1 (en) | 1998-05-27 |
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