EP0843660A1 - Composes heterocycliques, leur preparation et utilisation - Google Patents

Composes heterocycliques, leur preparation et utilisation

Info

Publication number
EP0843660A1
EP0843660A1 EP96924801A EP96924801A EP0843660A1 EP 0843660 A1 EP0843660 A1 EP 0843660A1 EP 96924801 A EP96924801 A EP 96924801A EP 96924801 A EP96924801 A EP 96924801A EP 0843660 A1 EP0843660 A1 EP 0843660A1
Authority
EP
European Patent Office
Prior art keywords
indolyl
alkyl
chloro
compound
defined above
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.)
Withdrawn
Application number
EP96924801A
Other languages
German (de)
English (en)
Inventor
Jane Marie Lundbeck
Anders Kanstrup
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.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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 Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP0843660A1 publication Critical patent/EP0843660A1/fr
Withdrawn legal-status Critical Current

Links

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

La présente invention se rapporte à des composés hétérocycliques (Ia) thérapeutiquement actifs, à un procédé pour les préparer et à des compositions pharmaceutiques les contenant. Les nouveaux composés sont utiles pour le traitement de maladies du système nerveux central en relation avec le système récepteur du glutamate métabotropique.
EP96924801A 1995-07-31 1996-07-31 Composes heterocycliques, leur preparation et utilisation Withdrawn EP0843660A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DK87095 1995-07-31
DK87095 1995-07-31
PCT/DK1996/000332 WO1997005109A1 (fr) 1995-07-31 1996-07-31 Composes heterocycliques, leur preparation et utilisation

Publications (1)

Publication Number Publication Date
EP0843660A1 true EP0843660A1 (fr) 1998-05-27

Family

ID=8098461

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96924801A Withdrawn EP0843660A1 (fr) 1995-07-31 1996-07-31 Composes heterocycliques, leur preparation et utilisation

Country Status (4)

Country Link
EP (1) EP0843660A1 (fr)
JP (1) JPH11509847A (fr)
AU (1) AU6514296A (fr)
WO (1) WO1997005109A1 (fr)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW544448B (en) 1997-07-11 2003-08-01 Novartis Ag Pyridine derivatives
DE19801647A1 (de) 1998-01-17 1999-07-22 Bayer Ag Substituierte beta,gamma-annellierte Lactone
DE19801646A1 (de) 1998-01-17 1999-07-22 Bayer Ag Substituierte alpha,beta-annellierte Butyrolactone
DE19801636A1 (de) 1998-01-17 1999-07-22 Bayer Ag Substituierte bicyclische Lactone
AU2241400A (en) 1999-04-06 2000-10-12 Yamanouchi Pharmaceutical Co., Ltd. Novel thiazolobenzoimidazole derivative
CZ20021663A3 (cs) 1999-10-15 2002-09-11 F. Hoffmann-La Roche Ag Nové deriváty benzodiazepinu
BR0014859A (pt) * 1999-10-15 2002-07-16 Hoffmann La Roche Derivados de benzodiazepina
MX2007003922A (es) * 2004-10-05 2007-06-07 Merz Pharma Gmbh & Co Kgaa Nuevas propenonas ciclicas y aciclicas para tratar trastornos del sistema nervioso central.
ES2600460T3 (es) 2005-05-10 2017-02-09 Intermune, Inc. Derivados de piridona-2-ona como moduladores del sistema de proteína cinasa activada por estrés
CA2670116C (fr) 2006-11-22 2015-03-10 Seaside Therapeutics, Llc Procedes de traitement du retard mental, du syndrome de down, du syndrome de l'x fragile et de l'autisme
CN101657432B (zh) 2007-04-19 2013-04-10 弗·哈夫曼-拉罗切有限公司 二氢-苯并[b][1,4]二氮杂*-2-酮磺酰胺衍生物
CA2726588C (fr) 2008-06-03 2019-04-16 Karl Kossen Composes et procedes de traitement des troubles inflammatoires et fibrotiques
WO2011109398A2 (fr) 2010-03-02 2011-09-09 President And Fellows Of Harvard College Procédés et compositions pour le traitement du syndrome d'angelman et des troubles du spectre autistique
US20110294879A1 (en) 2010-05-28 2011-12-01 Xenoport, Inc. Method of treatment of fragile x syndrome, down's syndrome, autism and related disorders
US20120016021A1 (en) 2010-07-15 2012-01-19 Xenoport, Inc. Methods of treating fragile x syndrome, down's syndrome, autism and related disorders
AR092742A1 (es) 2012-10-02 2015-04-29 Intermune Inc Piridinonas antifibroticas
WO2015153683A1 (fr) 2014-04-02 2015-10-08 Intermune, Inc. Pyridinones anti-fibrotiques
WO2017196936A1 (fr) * 2016-05-12 2017-11-16 Regents Of The University Of Minnesota Composés indole et indazole cyanocinnamate et leurs utilisations thérapeutiques

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3931230A (en) * 1974-04-12 1976-01-06 Warner-Lambert Company 3-Substituted isotryptamine derivatives and process for their production
ES2088011T3 (es) * 1990-07-16 1996-08-01 Merrell Pharma Inc Antagonistas de aminoacidos excitadores.
US5284862A (en) * 1991-03-18 1994-02-08 Warner-Lambert Company Derivatives of 2-carboxyindoles having pharmaceutical activity

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9705109A1 *

Also Published As

Publication number Publication date
JPH11509847A (ja) 1999-08-31
AU6514296A (en) 1997-02-26
WO1997005109A1 (fr) 1997-02-13

Similar Documents

Publication Publication Date Title
US5945417A (en) Heterocyclic compounds, their preparation and use
EP0750621B1 (fr) Composes heterocycliques, leur preparation et leur utilisation
WO1997005109A1 (fr) Composes heterocycliques, leur preparation et utilisation
WO1996015099A1 (fr) Composes heterocycliques, preparation et utilisation de ces composes
US5696148A (en) Indole compounds and their use in treating diseases of the central nervous system
US5783575A (en) Antagonists, their preparation and use
US20120015966A1 (en) Ppar active compounds
CN101304992A (zh) 用作ppar调节剂的1,3-二取代吲哚衍生物
WO2007030574A2 (fr) Composes actifs sur les ppar
DE19719621A1 (de) Sulfonylaminocarbonsäuren
KR102232744B1 (ko) Ｐ２ｘ７ 수용체 길항제로서의 인돌 카르복사미드 유도체
EP0866059A1 (fr) Nouveaux derives heterocycliques et leur utilisation medicinale
KR20090101307A (ko) 스핑고신-1-포스페이트(ｓ1ｐ) 수용체 길항제 생물학적 활성을 갖는 6-치환된 인돌-3-카르복실산 아미드 화합물
JP6653410B2 (ja) ＮａＰｉ−ＩＩｂ阻害剤として有用な縮合チオフェン誘導体
AU2008320718B2 (en) Indol-2-one derivatives disubstituted in the 3-position, preparation thereof and therapeutic use thereof
HUE031453T2 (en) Substituted benzamides having activity against EP4 receptors
FR2824827A1 (fr) Nouveaux derives de 5-phenyl-1h-indole antagoniste des recepteurs de l'interleukine-8
WO2015139619A1 (fr) Composé servant de modulateur rorγ
JP2012522796A (ja) プロスタグランジンｅレセプター拮抗薬
JP2001506243A (ja) 複素環式カルボン酸誘導体、その製造およびエンドセリン受容体拮抗物質としての使用
EP3983387B1 (fr) Dérivés de sulfonylurée et leurs utilisations
CZ20032260A3 (cs) Nové deriváty 5-kyano-1H-indolových antagonistů receptorů interleukinu-8
KR101183553B1 (ko) 퀴녹살린 유도체 또는 이의 염을 유효성분으로 포함하는 암 예방 또는 치료용 약학 조성물
JPS6040420B2 (ja) ３−アミノ−２−（５−フルオル−及び５−メトキシ−１ｈ−インド−ル−３−イル）プロパン酸誘導体類、その製法及び利用
MXPA96004023A (es) Compuestos heterociclicos, su preparacion y su

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19980302

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

17Q First examination report despatched

Effective date: 20000201

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20000614