+

WO1996015100A1 - Composes heterocycliques, preparation et utilisation - Google Patents

Composes heterocycliques, preparation et utilisation Download PDF

Info

Publication number
WO1996015100A1
WO1996015100A1 PCT/DK1995/000444 DK9500444W WO9615100A1 WO 1996015100 A1 WO1996015100 A1 WO 1996015100A1 DK 9500444 W DK9500444 W DK 9500444W WO 9615100 A1 WO9615100 A1 WO 9615100A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
compound according
dicarboxylic acid
mmol
water
Prior art date
Application number
PCT/DK1995/000444
Other languages
English (en)
Inventor
Roberto Pellicciari
Roberto Luneia
Grazia Lombardi
Flavio Moroni
Original Assignee
Novo Nordisk A/S
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 A/S filed Critical Novo Nordisk A/S
Priority to AU38398/95A priority Critical patent/AU3839895A/en
Publication of WO1996015100A1 publication Critical patent/WO1996015100A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
    • C07C17/2637—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions between a compound containing only oxygen and possibly halogen as hetero-atoms and a halogenated hydrocarbon
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/50—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms being part of the same condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C61/16—Unsaturated compounds
    • C07C61/39—Unsaturated compounds containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/33—Polycyclic acids
    • C07C63/49—Polycyclic acids containing rings other than six-membered aromatic rings
    • 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
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to therapeutic active amino acids, a method for preparing the same, pharmaceutical compositions comprising the compounds and a method of treating therewith.
  • MGIuR 1 to MGIuR ⁇ different subtypes of the metabotropic glutamate receptors are described (MGIuR 1 to MGIuR ⁇ ) and in addition some spliced variants of the subtypes are reported.
  • Metabotropic glutamate receptor subtypes MGIuR, and MGIuR 5 are coupled to phosphoinositide hydrolysis (Johnson, G. and Bigge, C.F. (1991 ) Annu. Rep. Med. Chem. 26, 11-22, Hansen, J.J. and
  • trans-ACPD trans 1 S,3R-1-aminocyclopentane-1 ,3- dicarboxylic acid
  • L-AP3 L-2-amino-3-phosphono- propionic acid
  • Palmer E., Monaghan, D.T. and Cotman, C.W. (1989) Eur. J. Pharmacol. 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-(carbox ⁇ cyclopropyl)gi ⁇ cines) especially L-CCG-I and L-CCG-II (Hayashi, Y. et al. (1992), Br. J. Pharmacol. 107, 539- 543).
  • S-4-carboxyphenyl glycine S-4C3HPG (S-4-carboxy-3-hydroxy phenyl glycine) and S-MCPG ( S-alpha methyl-4-carboxyphenyl glycine) have been reported to antagonise trans ACPD stimulated phosphoinositide hydrolysis and thus possibly acting as antagonists at the metabotropic glutamate receptors at the subtypes MGIuR, and MGIuR s (Thomsen, C. and Suzdak, P, (1993) Eur. J. Pharmacol. 245, 299).
  • Literature evidence suggests that compounds selective for the meta ⁇ botropic glutamate receptors either as agonists or antagonists are useful in the treatment of different neurological diseases.
  • the use of compounds active at the metabotropic glutamate receptors for the treatment of epilepsy is corroborated by investigations of the influence of trans-ACPD in the formation of convulsions (Sacaan and Schoepp, (1992), Neurosci. lett. 139, 77) and that phosphoinositide hydrolysis mediated via MGIuR is increased after kindling experiments in rats (Akiyama et al. (1992), Brain Res. 569, 71 ).
  • 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 ). Also in the treatment of pain the 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. Neurosci. 5, 186).
  • the present invention relates to compounds of formula I
  • n 0, 1 or 2; and X is -O-, -S, -N(R 5 )- or -CH 2 -;
  • R 1 is H, NH 2 , NHR 5 or OH
  • R 2 and R 3 independently are H, COOH, COOR 5 , CONH 2 , CONHR 5 ,
  • R* is H, OH, NH 2 , NHR 5 , CF 3 , C ⁇ -alkyl, C 2 . 8 -alkenyl, C 2 . 8 -alkynyl, C 3 . ⁇ - cycloalkyl, phenyl or C ⁇ -alkoxy;
  • R 5 is H, C ⁇ -alkyl, C 2 . 8 -alkenyl, C 2 . 8 -alkynyl, phenyl or C 3 . ⁇ -cycloalkyl; and ring A can be partly or completely saturated or aromatic, or a salt thereof with a pharmaceutically acceptable acid or base.
  • salts include pharmaceutically acceptable acid addition salts, phar- maceutically acceptable metal salts or optionally alkylated ammonium salts, such as hydrochloric, h ⁇ drobromic, hydroiodic, phosphoric, sulfu- ric, trifluoroacetic, trichloroacetic, oxalic, maleic, p ⁇ ruvic, malonic, succinic, citric, mandelic, benzoic, cinnamic, methanesulfonic, ethane sulfonic, picric and the like, and include acids related to the pharmaceuti- cally acceptable salts listed in Journal of Pharmaceutical Science, 6J 2 (1977) and incorporated herein by reference, or lithium, sodium, potas ⁇ sium, magnesium and the like.
  • pharmaceutically acceptable acid addition salts such as hydrochloric, h ⁇ drobromic, hydroiodic, phosphoric, sulfu- ric, trifluoroacetic,
  • C 8 -alkyr refers to a straight or branched, saturated hydrocarbon chain having 1 to 8 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- methylpentyl, neopentyl, n-hexyl, 2,2-dimethylpropyl and the like.
  • C 2 . 8 -alkenyr refers to an unsaturated hydrocar ⁇ bon chain having from 2 to 8 carbon atoms and at least one double bond such as vinyl, 1-propenyl, allyl, isopropen ⁇ l, n-butenyl, n-pentenyl and n- hexenyl and the like.
  • C 2 - 8 -alkynyP refers to an unsaturated hydrocar ⁇ bon chain having from 2 to 8 carbon atoms and at least one triple bond such as -C_ ⁇ .CH, -C_ ⁇ .CCH 3 , -CH 2 C_ ⁇ .CH, -CH 2 -CH 2 -C_ ⁇ _CH, -CH(CH 3 )C_ ⁇ .CH and the like.
  • C j - ⁇ -cycloalkyP refers to a radical of a satu ⁇ rated cyclic hydrocarbon having from 3 to 6 carbon atoms such as c ⁇ clopropyl, cyclobutyl, cyclopentyl or c ⁇ clohexyl and the like.
  • 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 4 carbon atoms e.g. methoxy, ethoxy, propoxy, butoxy and the like.
  • the invention also relates to a method of preparing the above mentioned compounds. These methods comprise
  • X, n, R 3 , R 4 have the mean ⁇ ings defined above with reagents well known for converting oxo groups to amino acids or hydroxy acids either through hydantoin formation, through hydroxy nitrile or through aminonitrile formation, or
  • X, n, R ⁇ R 3 and R* have the meanings defined above with reagents known to transform a cyano group into a R 2 group wherein R 2 has the meaning defined above provided that R 2 must not be H.
  • the compounds of the invention were studied in an in vitro assay for measuring 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 hydroly- sis 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 glu ⁇ cose, 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 ⁇ 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.
  • Testprocedure 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 be stimulation by 10 ⁇ M glutamate and a dose response curve is generated.
  • test results obtained by testing some compounds of the present invention in the above mentioned assay appear from the follow ⁇ ing 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 administered, 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 trans- ports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intra ⁇ venous, intramuscular or intranasal, the oral route being preferred.
  • oral or parenteral e.g. rectal, transdermal, subcutaneous, intra ⁇ venous, intramuscular or intranasal, the oral route being preferred.
  • compositions include a compound of formula I or a pharmaceuti- cally acceptable acid addition salt thereof, associated with a pharma ⁇ ceutically acceptable carrier.
  • conventional techniques for the preparation of pharmaceutical compositions may be used.
  • 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 When 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, polyhydroxy- ethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaery ⁇ thritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • 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 deleteri- ously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated 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:
  • AICI 3 (1.706 g, 12.8 mmol) was added portionwise in 20 min to a solution of indan (1.50 g, 12.7 mmol) and AcCI (0.996 g, 12.7 mmol) in benzene (7.6 ml) kept under vigorous magnetic stirring at 0°C in an argon atmosphere. The resulting mixture was reacted at room tempera ⁇ ture for 2 h after which cold (0°C) water was added (30 ml). The reaction mixture was then acidified with 3N HCI and extracted with AcOEt (3x20 ml). The combined organic phases were washed with brine (20 ml) and dried over anhydrous Na 2 SO 4 .
  • AICI 3 (3.94 g, 29.5 mmol) was added portionwise in 20 min to a solution of 5-methoxyindane ( 2.04 g, 13.8 mmol) and AcCI (1.36 g, 17.3 mmol) in benzene (9 ml) kept under vigorous magnetic stirring at 0 "C in an argon atmosphere. The resulting mixture was reacted at room tempera ⁇ ture for 2 h after which cold (0 * C) water was added (30 ml). The reaction mixture was then acidified with 3N HCI and extracted with

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés hétérocycliques thérapeutiquement actifs, représentés par la formule (I). Dans cette formule, n est un entier valant de 0 à 2; X représente -O-, -S, -N(R5)- ou -CH¿2-; R?1 représente H, NH¿2?, NHR5 ou OH; R?2 et R3¿ représentent indépendamment H, COOH, COOR5, CONH¿2?, CONHR?5, CON(R5)¿2, CONHSO2R5 ou tétrazole; R4 représente H, OH, NH¿2?, NHR?5, CF¿3, C1-8-alkyle, C2-8-alcényle, C2-8 alcynyle, C3-6-cycloalkyle, phényle ou C1-4-alcoxy; R5 représente H, C¿1-8?-alkyle, C2-8-alcényle, C2-8 alcynyle, phényle ou C3-6-cycloalkyle; et le noyau A peut être entièrement ou en partie saturé ou aromatique. L'invention concerne également un sel de ces composés obtenu à partir d'un acide ou d'une base acceptable du point de vue pharmaceutique. L'invention concerne enfin un procédé de préparation de ces composés et des compositions pharmaceutiques à base de ces composés. Ces composés conviennent avantageusement au traitement des affections du système nerveux central liées au système récepteur du glutamate métabotrope.
PCT/DK1995/000444 1994-11-09 1995-11-08 Composes heterocycliques, preparation et utilisation WO1996015100A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU38398/95A AU3839895A (en) 1994-11-09 1995-11-08 Heterocyclic compounds, their preparation and use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ATPCT/DK94/00421 1994-11-09
PCT/DK1994/000421 WO1996015099A1 (fr) 1994-11-09 1994-11-09 Composes heterocycliques, preparation et utilisation de ces composes

Publications (1)

Publication Number Publication Date
WO1996015100A1 true WO1996015100A1 (fr) 1996-05-23

Family

ID=8154944

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/DK1994/000421 WO1996015099A1 (fr) 1994-11-09 1994-11-09 Composes heterocycliques, preparation et utilisation de ces composes
PCT/DK1995/000444 WO1996015100A1 (fr) 1994-11-09 1995-11-08 Composes heterocycliques, preparation et utilisation

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/DK1994/000421 WO1996015099A1 (fr) 1994-11-09 1994-11-09 Composes heterocycliques, preparation et utilisation de ces composes

Country Status (2)

Country Link
AU (2) AU1106195A (fr)
WO (2) WO1996015099A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US7034055B1 (en) 1999-06-30 2006-04-25 Prescient Neuropharma Inc. 2-aminoindane analogs
US7396857B2 (en) 2005-04-22 2008-07-08 Wyeth Therapeutic combinations for the treatment or prevention of depression
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
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
WO2011150380A1 (fr) 2010-05-28 2011-12-01 Xenoport, Inc. Méthodes de traitement du syndrome de l'x fragile, du syndrome de down, de l'autisme et des troubles associés
WO2012009646A1 (fr) 2010-07-15 2012-01-19 Xenoport, Inc. Méthodes de traitement du syndrome de l'x fragile, du syndrome de down, de l'autisme et de troubles associés
EP2567696A1 (fr) 2006-11-22 2013-03-13 Seaside Therapeutics, Inc. Procédés de traitement du retard mental, du syndrome de Down, du syndrome de l'X fragile et de l'autisme
WO2023042888A1 (fr) 2021-09-15 2023-03-23 国立大学法人 琉球大学 Composition pharmaceutique destinée à être mise en œuvre dans le traitement soit du déclin des fonctions cognitives, soit de la surcharge pondérale ou de l'obésité
WO2023042887A1 (fr) 2021-09-15 2023-03-23 国立大学法人 琉球大学 Composition pharmaceutique destinée à être mise en œuvre dans le traitement soit du déclin des fonctions cognitives, soit de la surcharge pondérale ou de l'obésité

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19801648A1 (de) * 1998-01-17 1999-07-22 Bayer Ag alpha-Substituierte Lactone
CA2356053A1 (fr) * 1998-12-30 2000-07-13 Bayer Aktiengesellschaft Utilisation de derives d'acides 4-biarylbutyrique et 5-biarylpentanoique substitues, en tant qu'inhibiteurs de la metalloprotease matricielle, pour le traitement des maladies respiratoires
US6699909B1 (en) * 1999-07-02 2004-03-02 Prescient Neuropharma Inc. Aminoindanes
GB0007193D0 (en) * 2000-03-25 2000-05-17 Univ Manchester Treatment of movrmrnt disorders
US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
AR037097A1 (es) 2001-10-05 2004-10-20 Novartis Ag Compuestos acilsulfonamidas, composiciones farmaceuticas y el uso de dichos compuestos para la preparacion de un medicamento
US8354427B2 (en) 2004-06-24 2013-01-15 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters
DK2502911T3 (en) 2004-06-24 2017-06-06 Vertex Pharma Modulators of ATP-binding cassette transporters
JP5409010B2 (ja) 2005-12-28 2014-02-05 バーテックス ファーマシューティカルズ インコーポレイテッド Ｎ−［２，４−ビス（１，１−ジメチルエチル）−５−ヒドロキシフェニル］−１，４−ジヒドロ−４−オキソキノリン−３−カルボキサミドの固体形態
WO2007134149A2 (fr) 2006-05-11 2007-11-22 Janssen Pharmaceutica N.V. Dérivés de 3,4-dihydro-2h-benzo[1,4]oxazine et thiazine en tant qu'inhibiteurs de cetp
JP2009536953A (ja) 2006-05-11 2009-10-22 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Ｃｅｔｐ阻害剤としての１，２，３，４−テトラヒドロ−キノリン誘導体
EP2408750B1 (fr) 2009-03-20 2015-08-26 Vertex Pharmaceuticals Incorporated Procédé pour préparer des modulateurs de régulateur de conductance transmembranaire de mucoviscidose
US8802700B2 (en) 2010-12-10 2014-08-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
AU2013226076B2 (en) 2012-02-27 2017-11-16 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administration thereof
CA2963945C (fr) 2014-10-07 2023-01-10 Vertex Pharmaceuticals Incorporated Co-cristaux de modulateurs du regulateur de conductance transmembranaire de la mucoviscidose

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4018817A (en) * 1972-12-07 1977-04-19 Takeda Chemical Industries, Ltd. 6-Halo-5-cyclohexylindan-1-carbohydroxamic acid
EP0077122A2 (fr) * 1981-09-15 1983-04-20 Imperial Chemical Industries Plc Tétralines substituées par des groupes amino et composés homocycliques apparentés
WO1990007490A1 (fr) * 1989-01-09 1990-07-12 The Upjohn Company Aminotetralines a substitution halo
EP0399982A1 (fr) * 1989-05-26 1990-11-28 Astra Aktiebolag 8-Substituées-2-aminotétralines
WO1990015047A1 (fr) * 1989-05-31 1990-12-13 The Upjohn Company Derives de 2-aminotetraline therapeutiquement utiles
WO1995004713A1 (fr) * 1993-08-06 1995-02-16 The Upjohn Company 2-aminoindanes utilises comme ligands selectifs de la dopamine d3

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1984000961A1 (fr) * 1982-09-07 1984-03-15 Yoshitomi Pharmaceutical Derives de 1,4-methano-2-benzazepine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4018817A (en) * 1972-12-07 1977-04-19 Takeda Chemical Industries, Ltd. 6-Halo-5-cyclohexylindan-1-carbohydroxamic acid
EP0077122A2 (fr) * 1981-09-15 1983-04-20 Imperial Chemical Industries Plc Tétralines substituées par des groupes amino et composés homocycliques apparentés
WO1990007490A1 (fr) * 1989-01-09 1990-07-12 The Upjohn Company Aminotetralines a substitution halo
EP0399982A1 (fr) * 1989-05-26 1990-11-28 Astra Aktiebolag 8-Substituées-2-aminotétralines
WO1990015047A1 (fr) * 1989-05-31 1990-12-13 The Upjohn Company Derives de 2-aminotetraline therapeutiquement utiles
WO1995004713A1 (fr) * 1993-08-06 1995-02-16 The Upjohn Company 2-aminoindanes utilises comme ligands selectifs de la dopamine d3

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHEM. PHARM. BULL., Volume 14, No. 4, 1966, SHUNSAKU SHIOTANI et al., "Studies on Diazabenzobicyclo 3.3.1 Nonane System. IV Synthesis of 1,2,3,4,5,6-Hexahydro-1, 5-Methanobenzo e 1,3 Diazocine Derivatives", pages 324-329. *
STN INTERNATIONAL, File CA, Volume 114, No. 19, 13 May 1991, (Columbus, Ohio, US), MA, SHENQXING et al., "Dopaminergic Structure-Activity Relationships of 2-Aminoindans and Cardiovascular Action and Dopaminergic Activity of 4-Hydroxy, 5-Metyl, 2-Di-N-Propylaminoindan (RD-211), Abstract No. 177884; & J. PHARMACOOL. EXP. *
STN INTERNATIONAL, File CA, Volume 80, No. 21, 27 May 1964, (Columbus, Ohio, US), EDLUND ULF, "Preparation of Some N-Substituted 2-Aminoindans", Abstract No. 120604; & ACTA CHEM. SCAND., (1973), 27(10), 4027-9. *
STN INTERNATIONAL, File CA, Volume 87, No. 21, 21 November 1977, (Columbus, Ohio, US), SUNDEEN, JOSEPH E. et al., "Selective Inhibition of the Monosynaptic Spinal Reflex by a Serier of Hydroxylated Alkylaminoindans", Abstract No. 161428; & J. MED. CHEM., (1977), 20(11), 1478-85. *
STN INTERNATIONAL, File Medline, STN Accession No. 87011614, CANNON J.G. et al., "Assessment of a Potential Dopaminergic Prodrug in Several Ring Systems"; & J. MED. CHEM., (Oct. 1986), 29(10), 2016-20. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US6723718B2 (en) 1998-01-17 2004-04-20 Bayer Aktiengesellschaft Substituted α, β-anellated butyrolactones
US7034055B1 (en) 1999-06-30 2006-04-25 Prescient Neuropharma Inc. 2-aminoindane analogs
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
US7396857B2 (en) 2005-04-22 2008-07-08 Wyeth Therapeutic combinations for the treatment or prevention of depression
EP2567696A1 (fr) 2006-11-22 2013-03-13 Seaside Therapeutics, Inc. Procédés de traitement du retard mental, du syndrome de Down, du syndrome de l'X fragile et de l'autisme
EP2578216A1 (fr) 2006-11-22 2013-04-10 Seaside Therapeutics, Inc. Procédés de traitement du syndrome de l'X fragile
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
WO2011150380A1 (fr) 2010-05-28 2011-12-01 Xenoport, Inc. Méthodes de traitement du syndrome de l'x fragile, du syndrome de down, de l'autisme et des troubles associés
WO2012009646A1 (fr) 2010-07-15 2012-01-19 Xenoport, Inc. Méthodes de traitement du syndrome de l'x fragile, du syndrome de down, de l'autisme et de troubles associés
WO2023042888A1 (fr) 2021-09-15 2023-03-23 国立大学法人 琉球大学 Composition pharmaceutique destinée à être mise en œuvre dans le traitement soit du déclin des fonctions cognitives, soit de la surcharge pondérale ou de l'obésité
WO2023042887A1 (fr) 2021-09-15 2023-03-23 国立大学法人 琉球大学 Composition pharmaceutique destinée à être mise en œuvre dans le traitement soit du déclin des fonctions cognitives, soit de la surcharge pondérale ou de l'obésité

Also Published As

Publication number Publication date
AU1106195A (en) 1996-06-06
AU3839895A (en) 1996-06-06
WO1996015099A1 (fr) 1996-05-23

Similar Documents

Publication Publication Date Title
WO1996015100A1 (fr) Composes heterocycliques, preparation et utilisation
US5945417A (en) Heterocyclic compounds, their preparation and use
EP0750621B1 (fr) Composes heterocycliques, leur preparation et leur utilisation
RU2063965C1 (ru) Производные декагидроизохинолина или их фармацевтически приемлемые соли
US3641127A (en) (3-benzoylphenyl) alkanoic acids
KR100372981B1 (ko) 비시클로[2.2.1]헵탄 및 관련 화합물
JP2001515839A (ja) 二環式向代謝性グルタミン酸受容体リガンド
JPS6323847A (ja) 置換アミノ−５，６，７，８−テトラヒドロナフチル−オキシ酢酸
JPH09501429A (ja) 選択的ドーパミンｄ３リガンドとしての２−アミノインダン類
JP2009167217A (ja) 置換フェニルアルカン酸誘導体及びその用途
EP0843660A1 (fr) Composes heterocycliques, leur preparation et utilisation
JP6653410B2 (ja) ＮａＰｉ−ＩＩｂ阻害剤として有用な縮合チオフェン誘導体
US5783575A (en) Antagonists, their preparation and use
US5696148A (en) Indole compounds and their use in treating diseases of the central nervous system
FI80014B (fi) Nya fenylalkansyraderivat, deras framstaellning och anvaendning.
JPH09500644A (ja) エンドセリン拮抗剤
JPH09502448A (ja) 心臓血管系に活性な２−アミノ−１，２，３，４−テトラヒドロナフタレン誘導体
US4134991A (en) Derivatives of 2-(3-phenyl-2-aminopropionyloxy)-acetic acid
JPH06211829A (ja) トリエン側鎖を有する新規クロメン化合物
EP1194400A1 (fr) Analogues de 2-aminoindane
US4999345A (en) Sulfonamide derivatives and drugs obtained therefrom
FI62531C (fi) Foerfarande foer framstaellning av terapeutiskt anvaendbart 3-yan-n-(n n-dimetylamino-propyl)-iminodibensyl och syraadd itonssalter daerav
US4695647A (en) Aromatic derivatives of 13-azaprostanoic acid
JP7593987B2 (ja) ネプリライシン（ｎｅｐ）阻害剤、特にアミノペプチダーゼｎ（ａｐｎ）及びネプリライシン（ｎｅｐ）の混合阻害剤としてのｎ－ホルミルヒドロキシルアミン
DK155280B (da) Analogifremgangsmaade til fremstilling af indolderivater

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KE KG KP KR KZ LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TT UA UG US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

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

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase
点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载