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WO1996015099A1 - Composes heterocycliques, preparation et utilisation de ces composes - Google Patents

Composes heterocycliques, preparation et utilisation de ces composes Download PDF

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Publication number
WO1996015099A1
WO1996015099A1 PCT/DK1994/000421 DK9400421W WO9615099A1 WO 1996015099 A1 WO1996015099 A1 WO 1996015099A1 DK 9400421 W DK9400421 W DK 9400421W WO 9615099 A1 WO9615099 A1 WO 9615099A1
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WO
WIPO (PCT)
Prior art keywords
compound according
metabotropic glutamate
mmol
dicarboxylic acid
pharmaceutical composition
Prior art date
Application number
PCT/DK1994/000421
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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 AU11061/95A priority Critical patent/AU1106195A/en
Priority to PCT/DK1994/000421 priority patent/WO1996015099A1/fr
Priority to AU38398/95A priority patent/AU3839895A/en
Priority to PCT/DK1995/000444 priority patent/WO1996015100A1/fr
Publication of WO1996015099A1 publication Critical patent/WO1996015099A1/fr

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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.
  • MGluR metabotropic glutamate receptor
  • the Metabotropic glutamate receptor subtypes MGluR, 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 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. 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-phos ⁇ honobutyrate 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. Neurosci. 5, 186).
  • the present invention relates to compounds of formula I
  • n 0, 1 or 2;
  • X is -0-, -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 , CON(R 5 ) 2> CONHSO 2 R 5 or tetrazole;
  • R 4 is H, OH, NH 2 , NHR 5 , CF 3 , C ⁇ -alkyl, C ⁇ -alkenyl, C ⁇ -alkynyl, C M - cycloalkyl, phenyl or C ⁇ -alkoxy;
  • R 5 is H, C ⁇ -alkyl, C M -alkenyl, C ⁇ -alkynyl, phenyl or C M -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, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluo- roacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, 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, magnesium and the like.
  • pharmaceutically acceptable acid addition salts such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluo- roacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic
  • Alkyl, alkenyl and alkynyl are intended to mean a straight or branched alkyl, alkenyl or alkynyl chain.
  • the invention also relates to a method of preparing the above mentioned compounds. These methods comprise
  • X, n, R 3 , R 4 have the meanings 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 1 , R 3 and R 4 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 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 rnGluRI ⁇ .
  • BHK570 cells expressing mGluRl ⁇ are cultured in DMEM (4.5 g/1 glucose, 2mM glutamin); 5% foetal calf serum; 0J0 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; 0J0; 0J7 and 0.25 M KHC0 3 , respectively. Usually IP1 and IP2 fractions are collected simultaneously. Scintillation liquid: use 12-15 ml Ultima Gold (Packard). Testorocedure
  • 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 following
  • 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 0J 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 transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.
  • oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, 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 pharmaceuti- cally acceptable carrier.
  • 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, alco ⁇ hols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monogly- cerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethyl- cellulose 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 deleteriously 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 temperature 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).
  • AICI 3 (15.3 g, 114.8 mmol) was added portionwise in 40 min. to a solution of 1 ,2,3,4-tetrahydronaphthalene (15.0 g, 113.5 mmol) and AcCI (8.9 g, 113.5 mmol) in benzene (45 ml) kept under vigorous magnetic stirring at 0°C in an argon atmosphere. The resulting mixture was reacted at room tempera ⁇ ture for 30 min. after which cold (0°C) water was added (100 ml). The reaction mixture was then acidified with 3N HCI and extracted with AcOEt (3x50 ml). The combined organic phases were washed with brine (60 ml) and dried over anhydrous Ne ⁇ SO ⁇ Evaporation of the solvent yielded 19 as a yellow oil (20 g) which was used in the next step without any further purification.

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

Abstract

La présente invention concerne des composés hétérocycliques thérapeutiquement actifs, ou un de leurs sels avec un acide ou une base pharmaceutiquement acceptable. Ces composés sont représentés par la formule générale (I) dans laquelle n est égal à 0, 1 ou 2; X est -O-, -S-, -N(R5)- ou -CH¿2-; R?1 est H, NH¿2, NHR?5 ou OH; R2 et R3 sont indépendamment H, COOH, COOR5, CONH¿2?, CONHR?5, CON(R5)¿2, CONHSO2R5 ou tétrazole; R4 est H, OH, NH¿2?, NHR?5, CF¿3, C1-8-alkyle, C2-8-alcényle, C2-8-alkynyle, C3-6-cycloalkyle, phényle ou C1-4-alcoxy; R5 est H, C¿1-8?-alkyle, C2-8-alcényle, C2-8-alkynyle, phényle ou C3-6-cycloalkyle; et le cycle A peut être partiellement ou complètement saturé ou aromatique. L'invention concerne également un procédé de préparation de ces composés et des compositions pharmaceutiques contenant lesdits composés. Les nouveaux composés sont utiles pour le traitement des maladies du système nerveux central liées au système récepteur du glutamate métabotrope.
PCT/DK1994/000421 1994-11-09 1994-11-09 Composes heterocycliques, preparation et utilisation de ces composes WO1996015099A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU11061/95A AU1106195A (en) 1994-11-09 1994-11-09 Heterocyclic compounds, their preparation and use
PCT/DK1994/000421 WO1996015099A1 (fr) 1994-11-09 1994-11-09 Composes heterocycliques, preparation et utilisation de ces composes
AU38398/95A AU3839895A (en) 1994-11-09 1995-11-08 Heterocyclic compounds, their preparation and use
PCT/DK1995/000444 WO1996015100A1 (fr) 1994-11-09 1995-11-08 Composes heterocycliques, preparation et utilisation

Applications Claiming Priority (1)

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

Publications (1)

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WO1996015099A1 true WO1996015099A1 (fr) 1996-05-23

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PCT/DK1995/000444 WO1996015100A1 (fr) 1994-11-09 1995-11-08 Composes heterocycliques, preparation et utilisation

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WO1999036419A1 (fr) * 1998-01-17 1999-07-22 Bayer Aktiengesellschaft Lactones substituees utilisees comme modulateurs de recepteurs metabotropes de glutamate
WO1999036417A1 (fr) * 1998-01-17 1999-07-22 Bayer Aktiengesellschaft β,η-LACTONES SUBSTITUEES
WO1999036416A1 (fr) * 1998-01-17 1999-07-22 Bayer Aktiengesellschaft α,β-BUTYROLACTONES ANNELEES SUBSTITUEES
WO1999036418A1 (fr) * 1998-01-17 1999-07-22 Bayer Aktiengesellschaft Lactones bicycliques substituees
WO2001002342A1 (fr) * 1999-06-30 2001-01-11 Igt Pharma Inc. Analogues de 2-aminoindane
WO2001002340A3 (fr) * 1999-07-02 2001-06-14 Igt Pharma Inc Nouveaux amino-indanes
WO2001072291A3 (fr) * 2000-03-25 2002-02-21 Univ Manchester Traitement de troubles des mouvements
US6900194B1 (en) * 1998-12-30 2005-05-31 Bayer Aktiengesellschaft Use of substituted 4-biarylbutyric and 5-biarylpentanoic acid derivatives as matrix metalloprotease inhibitors for the treatment of respiratory diseases
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
US7482462B2 (en) 2001-10-05 2009-01-27 Amarylla Horvath Acylsulfonamides as inhibitors of steroid sulfatase
US7495103B2 (en) 2004-06-24 2009-02-24 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US7749995B2 (en) 2006-05-11 2010-07-06 Janssen Pharmaceutica Nv 3,4-dihydro-2h-benzo[1,4]oxazine and thiazine derivatives as CETP inhibitors
US7928238B2 (en) 2006-05-11 2011-04-19 Janssen Pharmaceutica Nv 1,2,3,4-tetrahydro-quinoline derivatives as CETP inhibitors
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
US8354427B2 (en) 2004-06-24 2013-01-15 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters
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
US8410274B2 (en) 2005-12-28 2013-04-02 Vertex Pharmaceuticals Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US8802700B2 (en) 2010-12-10 2014-08-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
US9701639B2 (en) 2014-10-07 2017-07-11 Vertex Pharmaceuticals Incorporated Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator
US9751839B2 (en) 2009-03-20 2017-09-05 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
US10272046B2 (en) 2012-02-27 2019-04-30 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US10646481B2 (en) 2008-08-13 2020-05-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
WO2025168043A1 (fr) * 2024-02-08 2025-08-14 上海枢境生物科技有限公司 Dérivé cyclique fusionné, son procédé de préparation et son utilisation

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