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WO1998001427A1 - Procede de preparation de derives de pyrazolone - Google Patents

Procede de preparation de derives de pyrazolone Download PDF

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Publication number
WO1998001427A1
WO1998001427A1 PCT/EP1997/003377 EP9703377W WO9801427A1 WO 1998001427 A1 WO1998001427 A1 WO 1998001427A1 EP 9703377 W EP9703377 W EP 9703377W WO 9801427 A1 WO9801427 A1 WO 9801427A1
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Prior art keywords
aryl
hetaryl
alkyl
formula
compounds
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PCT/EP1997/003377
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German (de)
English (en)
Inventor
Lutz F. Tietze
Adrian Steinmetz
Original Assignee
Basf Aktiengesellschaft
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Application filed by Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Priority to AU34383/97A priority Critical patent/AU3438397A/en
Publication of WO1998001427A1 publication Critical patent/WO1998001427A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms

Definitions

  • the invention relates to a process for the preparation of pyrazolone derivatives and the use thereof.
  • the invention further relates to a process for the ⁇ -alkylation of ⁇ -keto esters on a solid phase, alkylated ⁇ -keto esters on a solid phase and the use of the method.
  • a large number of molecular test systems such as receptor binding assays, enzyme assays and Zeil cell interaction assays, have been and are currently being developed for modern drug discovery research.
  • the automation and miniaturization of these test systems enables high sample throughput. Due to this development, an ever increasing number of chemicals can be tested for their biological effects in random screening and thus for a possible use as a lead structure for an active ingredient in medicine, veterinary medicine or in plant protection.
  • a modern automated test system enables the screening of 100,000 and more chemicals per year for their biological effects in a mass screening.
  • Combinatorial chemistry can make a contribution to this required increase in efficiency, especially if it uses automated solid-phase synthesis methods (see review article J. Med. Chem. 1994, 37, 1233 and 1994, 37, 1385).
  • Combinatorial chemistry enables the synthesis of a wide range Diversity of different chemical compounds, so-called substance libraries.
  • the synthesis on the solid phase has the advantage that by-products and excess reactants can be easily removed, so that no complex cleaning of the products is necessary.
  • the finished synthesis products can be mass-screened directly, ie carrier-bound, or after cleavage from the solid phase. Intermediate products can also be tested in mass screening.
  • No. 5,288,514 reports on one of the first combinatorial solid-phase syntheses in organic chemistry outside of peptide and nucleotide chemistry.
  • US 5 288 514 describes the sequential synthesis of 1,4-benzodiazepines on a solid phase.
  • WO 95/16712 WO 95/30642 and WO 96/00148 describe further solid-phase syntheses of potential active substances in combinatorial chemistry.
  • Heterocycles are a component of many pharmaceutical and agrochemical active ingredients, for example pyrazolone derivatives are found in analgesics, anti-inflammatory drugs, anti-rheumatic drugs or anti-pyretic drugs. Heterocycles are therefore sought compounds for the synthesis of active substances. It is therefore important to provide efficient methods for their manufacture, especially on a solid phase.
  • Fields ER et al. (Tetrahedron Lett., Vol 37, No. 7, pp 1003-1006, 1996) describes a first solid phase synthesis of pyrazolone derivatives. The disadvantage of this method is that no acid-labile groups may be present in the synthesized molecule, since they would be destroyed by the resin when they are split off. The monoalkylation described on the ⁇ -C atom also hinders the subsequent cyclization to the pyrazolone. After the synthesized products have been split off, the resin cannot be recycled.
  • R 1 , R 2 equal or different
  • Ci -Cio alkyl - C 2 -C 8 alkenyl, C 2 -C 6 alkynyl -, C 3 -C 8 cycloalkyl, aryl, C j -Cio alkylaryl, Aryl (-C-C ⁇ o-alkyl) -, hetaryl, C -.- C K - alkyl - hetaryl-, hetaryl (C ⁇ -C ⁇ 0 alkyl) -,
  • R 1 and R 2 in the formulas I, II and IV denote hydrogen, substituted or unsubstituted Ci-Cio-alkyl -, C 3 -C 8 alkenyl, C 3 -C 6 alkynyl -, C 3 -C 8 - Cycloalkyl -, aryl, aryl (C ⁇ -C ⁇ o-alkyl) -, aryl (C 3 -C 8 alkenyl) -, aryl (C 3 -C 6 alkynyl) -, aryl (C 3 -C 8 cycloalkyl) -, hetaryl, hetaryl (Ci -C 10 alkyl) -, hetaryl (C 3 -C 8 alkenyl) -, hetaryl (C 3 -C 6 alkynyl) -, hetaryl (C 3 -C 8 - cycloalkyl) -,
  • R 1 and R 2 may be the same or different.
  • R 1 and R 2 have the following meanings, for example:
  • Alkyl branched or unbranched C ⁇ -C ⁇ o-alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1-methylbutyl , 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4 -Methylpentyl, 1, 1 -Di ethylbutyl, 1, 2 -Dimethylbutyl, 1, 3 -Dimethylbutyl, 2, 2 -Dimethylbutyl,
  • Alkenyl branched or unbranched C 3 -C 8 alkenyl chains such as, for example, propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylpropenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- Methyl -1-butenyl, 2-methyl-1-butenyl, 3-methyl -1-butenyl, 1-methyl-2-butenyl, 2-methyl -2-butenyl, 3-methyl -2-butenyl, 1-methyl - 3-butenyl, 2-methyl-3-butenyl, 3-methyl -3-butenyl, 1, 1-dimethyl -2-propenyl, 1, 2-dimethyl - 1 - propenyl, 1,2-dimethyl -2-propenyl, 1-ethyl -1-propenyl,
  • Alkynyl branched or unbranched C 3 -CG - alkynyl such as prop-1 - in-1-yl, prop-2 - in-1-yl, n-but-1-in-1-yl, n-but-l -in-3-yl, n-but-1- in-4 -yl, n-but-2 - in-1 -yl, n-pent-1 - in-l-yl, n-pent-1 - in -3 -yl, n- Pen - 1 - in 4 -yl, n-Pen -1 - in-5-yl, n-Pent-2 - in-1 -yl, n- Pen - 2 - in- 4 -yl, n-Pent-2-in-5-yl, 3-methyl-but-1 - in 3 -yl, 3-methyl-but-1- in-4-yl, n-hex-1 - in - 1 -yl, n-Hex
  • Hetaryl simple or condensed aromatic ring systems with one or more heteroaromatic 3- to 7-membered rings which may contain one or more heteroatoms such as N, 0 or S, and which may contain one or more residues such as halogen such as fluorine, chlorine or bromine, Cyano, nitro, amino, hydroxy, thio, alkyl, alkoxy or further aromatic or further saturated or unsaturated non-aromatic rings or ring systems can be substituted and optionally via a Ci -C ⁇ 0 alkyl, C 3 -C 8 alkenyl - , C 3 -C 6 alkynyl - or C 3 -C 8 cycloalkyl chain with the abovementioned meaning are bound to the basic structure.
  • substituents such as halogen, such as fluorine, chlorine, bromine, cyano, nitro, amino, hydroxy, thio, alkyl, aryl, hetaryl, alkoxy, carboxy, benzyloxy, phenyl, may be used as substituents of the radicals mentioned for R 1 and R 2 or benzyl in question.
  • halogen such as fluorine, chlorine, bromine, cyano, nitro, amino, hydroxy, thio, alkyl, aryl, hetaryl, alkoxy, carboxy, benzyloxy, phenyl
  • R 3 in the formulas I, III or IV denotes hydrogen, substituted or unsubstituted Ci-Cio-alkyl-, C 2 -C 8 -alkenyl-, C 2 -C 6 -alkynyl -, C 3 -C 8 -cycloalkyl -, Aryl, C 1 -C 8 alkylaryl, aryl (C 1 -C 8 alkyl), hetaryl, C 1 -C 10 alkyl hetaryl, hetaryl (C 1 -C 8 alkyl) -, the said radicals have the following meaning:
  • Ci -Cirj alkyl chains such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, n-pentyl, 1-methylbutyl , 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1 -methylpentyl, 2 -methylpentyl, 3 -methylpentyl, - Methylpentyl, 1, 1 -dimethylbutyl,
  • Alkynyl branched or unbranched C 2 -C 6 alkynyl chains such as, for example, acetylene, prop-1-in-1-yl, prop-2-in-1-yl, n-but-1-in-1-yl, n - But-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-l-yl, n-pent - 1- in-1-yl, n-pent- 1-in-3 -yl, n-pent-1-in-4-yl, n-pent-1-in-5-yl, n-pent-2-in-1-yl, n-pent-2 - in -yl, n-pent-2-yn-5-yl, 3-methyl-but-1-yn-3-yl, 3-methyl-but-1-yn-4-yl, n-hex-1 -in-l-yl, n-Hex-1 -in-3-
  • Aryl simple or condensed aromatic ring systems which may optionally be substituted by one or more radicals such as halogen, such as fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, thio, alkoxy or other saturated or unsaturated non-aromatic rings or ring systems, or can optionally be substituted with at least one further Ci -C ⁇ 0 alkyl chain or via a Cx-Cio-alkyl chain, where Ci -Cio "alkyl in both cases has the meaning given above, are bound to the basic structure, are preferred as aryl radical Phenyl and naphthyl,
  • Hetaryl simple or fused aromatic ring systems with one or more heteroaromatic 3- to 7-membered rings which can contain one or more heteroatoms such as N, O or S and optionally with one or more residues such as halogen such as fluorine, chlorine or bromine, cyano, nitro , Amino, hydroxyl, thio, alkoxy or further aromatic or further saturated or unsaturated non-aromatic rings or ring systems may be substituted or may optionally be substituted by at least one further Ci-Cio-alkyl chain or via a Cj -C ⁇ 0 -alkyl chain, where
  • Ci-Cio-alkyl in both cases has the meaning given above, to which the basic structure is bound.
  • radicals mentioned for R 3 are alkyl, alkenyl, alkynyl or cycloalkyl
  • halogen such as fluorine, chlorine, bromine, cyano, nitro, amino, hydroxy, thio, alkyl, aryl, ester, hetaryl, alkoxy, carboxy, benzyloxy, phenyl or benzyl in question.
  • C ⁇ -C 4 R 8 alkyl such as branched or unbranched C ⁇ -C B alkyl chains, such as methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1 -methylpropyl -, 2-methyl - propyl, 1, 1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methyl-butyl, 3-methylbutyl, 2, 2 -dimethylpropyl, 1-ethylpropyl, n-hexyl, 1, 1-dimethylpropyl, 1, 2 -Dimethylpropyl, 1 -methylpentyl, 2-methylpentyl, 3 -methylpentyl, -Methylpentyl, 1, 1 -dimethylbutyl, 1, 2 -dimethylbutyl, 1, 3 -dimethylbutyl, 2, 2 -dimethylbutyl, 2, 3 -dimethylbutyl
  • -Butyl, or aryl such as simple or condensed aromatic ring systems, which can be substituted with another saturated or unsaturated non-aromatic ring or ring system.
  • Both radicals mentioned for R 4 can optionally be substituted with one or more radicals such as halogen, such as fluorine, chlorine or bromine, cyano, nitro, amino, hydroxy, thio, alkoxy, alkyl, cycloalkyl, aryl, hetaryl or other radicals.
  • halogen such as fluorine, chlorine or bromine
  • cyano nitro, amino, hydroxy, thio, alkoxy, alkyl, cycloalkyl, aryl, hetaryl or other radicals.
  • variable (P) in formulas II, IV or V means a fixed phase.
  • the solid phase (P) used in the process according to the invention can be carriers which are known from solid phase peptide synthesis. As far as they are compatible with the synthetic chemistry used, usable supports can consist of a large number of materials. The size of the straps can be varied widely depending on the material. Particles in the range from 1 ⁇ m to 1.5 cm are preferably used as carriers, particularly preferably in the case of polymeric carriers, particles in the range between 1 ⁇ m and 500 ⁇ m, very particularly preferably 50 ⁇ m to 300 ⁇ m.
  • the shape of the carrier is arbitrary, spherical particles are preferred.
  • the size distribution of the carriers can be homogeneous or heterogeneous; homogeneous particle sizes are preferred. Mixtures of carriers can also be used.
  • Suitable solid phases (P) are, for example, ceramics, glass, latex, crosslinked polystyrenes, crosslinked polyacrylamides, resins, silica gels, natural polymers, gold or colloidal metal particles.
  • the support In order to enable the reactants to be attached or to be split off after the synthesis, the support must be suitably functionalized or provided with a linker which has a corresponding functional group.
  • Suitable carriers or carrier-linker conjugates are, for example, chlorobenzyl resin (Merrifield resin), Rink resin (Novabiochem), Sieber resin (Novabiochem), Wang resin (Bachern), tentagel resins (Rapp polymers) or Pega- Resin (Polymer Laboratories). Chlorobenzyl resins or tentagel resins are particularly preferred as carriers.
  • a solid phase can be suitably functionalized, for example, via a linker that a free hydroxyl group for connecting compounds of the
  • the linker can be branched or unbranched, chiral or achiral.
  • diols examples are ethylene glycol, 1,3-propanediol, 1,2-propanediol, 1,2-butanediol, 1,3-butanediol, 1,2-butanediol, 2,3-butanediol, 1,2-pentanediol, 1,3 Pentanediol, 1,4-pentanediol, 1,5-pentanediol, 2,4-pentanediol, 2-methyl-1,4-butanediol, 1,2-hexanediol, 1,3-hexanediol, 1,4-hexanediol, 1 , 5-hexanediol, 1, 6-hexanediol, 2, 3-hexanediol, 2, 4-hexanediol, 2, 5-hexanediol, 2-methyl-1, 5-pentanediol or 3-methyl-1
  • the coupling of the preferred linker to Merrif ield resin can, for example, directly in the double-deprotonated form of the linker (Scheme I) in the presence of aprotic, non-polar or polar solvents such as, for example, diethylformamide (DMF), methylene chloride (CH 2 C1 2 ), dimethyl sulfoxide (DMSO) or tetrahydrofuran (THF).
  • aprotic, non-polar or polar solvents such as, for example, diethylformamide (DMF), methylene chloride (CH 2 C1 2 ), dimethyl sulfoxide (DMSO) or tetrahydrofuran (THF).
  • connection of the preferred linker to the carrier is carried out between 30 and 150 ° C., preferably between 60 and 100 ° C.
  • the process according to the invention for the preparation of the pyrazolone derivatives can be carried out in four separate steps in accordance with Scheme II; or all four steps can be carried out together in a successive sequence.
  • the method according to the invention can be carried out in a series of parallel automated synthesis approaches. Mixtures of reactants can also be used in a synthesis approach or parallel synthesis approaches. The method can also be used in a split synthesis (Balkenhohl et al. Angew. Chemie 1996, in press).
  • the synthesis can be terminated after each synthesis step (a) to (d) and the products of the synthesis stages can be isolated directly or after cleavage from supports and used in mass screening.
  • reaction a The acetoacetic acid from the ⁇ -keto esters (VII) is bound to the solid phase (reaction a) at an elevated temperature in the presence of a solvent.
  • a solvent in principle, all solvents are suitable, expediently high-boiling solvents such as toluene or xylene are used, in which these are swellable when using resins as carriers.
  • Reaction (a) is carried out in a temperature range between 80 to 5 150 ° C., preferably between 100 to 120 ° C. If resins are used as the solid phase, temperatures which are just below the temperature at which the resin is destroyed can be selected as the maximum reaction temperature.
  • ⁇ -keto esters are preferably used for the attachment to the support, in which the radical R 4 is a secondary or tertiary alcohol, preferably tert. -Butanol. These alcohols have a low nucleophilicity and therefore have only a slight tendency to react back to the ß-ketoester after cleavage and thus favor reaction (a). Reaction (a) can advantageously be further favored by using an excess of ⁇ -keto esters.
  • the dianion of the solid-phase-bound ⁇ -ketoester is formed.
  • the dianion formed can in principle be alkylated with all alkylating agents known to the person skilled in the art [reaction (b)].
  • LDA lithium diisopropylamine
  • LiHMDS lithium hexamethyldisilazide
  • LiTMP lithium tetraethylpiperidide
  • the dianion can also be added by adding another strong base such as n-butyllithium (n-BuLi), sec. -Butyllithium (sec -BuLi) or sodium hydride (NaH) are formed and then alkylated.
  • n-BuLi n-butyllithium
  • sec. -Butyllithium sec. -Butyllithium
  • NaH sodium hydride
  • a dianion can then be formed again, which can be alkylated again, so that two radicals R 1 and R 2 , which may be the same or different, are introduced.
  • the two substeps described for mono- or dialkylation can also be carried out in one step by adding a multiple excess of base, and the dialkylation product can thus be formed immediately.
  • A can Alkylating agents or a mixture of alkylating agents can be used. When the dianion is formed on the support, the color changes from pale yellow to deep red. The red color disappears again due to the alkylation. This color change can be used as a reaction indicator.
  • Suitable solvents for reaction (b) are advantageously solvents which are inert to the bases used, for example non-deprotonable solvents such as benzene, THF or petroleum ether.
  • alkylating agents are suitable as alkylating agents VI for the alkylation of the ⁇ -keto esters, such as, for example, alkyl halides of chlorine, bromine or iodine, sulfonic acid esters such as nosylates, brosylates, mesylates, tosylates, triflates, tresylates or nonaflates or sulfuric acid esters such as dimethyl sulfate.
  • alkyl halides are preferred for cost reasons.
  • alkenyl or alkynyl radicals are to be transferred in the alkylation reaction - for the introduction of the radicals R 1 and / or K 2 - the carbon atom adjacent to the leaving group, for example to the halide, may advantageously not be part of an aromatic or heteroaromatic ring or part of a double or Be triple bond.
  • the reaction can be driven up to 100% conversion by adding an excess of alkylating agent.
  • the alkylation is carried out at a temperature of -40 ° C to + 40 ° C, preferably between -10 ° C to + 30 ° C.
  • the reaction is expediently carried out on ice.
  • the temperature is allowed to rise up to 25 ° C. during the reaction.
  • reaction (c) is then carried out.
  • Reaction (c) introduces a further R J radical into the alkylated ⁇ -keto esters via hydrazines. Solid phase bound hydrazones are formed.
  • all aprotic or protic solvents are suitable as solvents; preference is given to protic solvents such as methanol, ethanol, particularly preferably in mixtures with solvents such as THF, which cause the resins to swell well.
  • the reaction 5 is carried out in a temperature range between 0 ° C. to 50 ° C., preferably from 10 ° C. to 35 ° C. In order to achieve complete conversion in reaction (c), it is advantageous to work with a large excess of hydrazines.
  • reaction (d) the hydrazones are finally cleaved from the solid phase with cyclization to give the corresponding pyrazolone derivatives.
  • the cleavage with cyclization takes place at elevated temperature 15 in a range from 80 to 150 ° C., preferably between 100 to
  • aprotic and protic solvents are suitable as solvents; preference is given to solvents with a high boiling point such as toluene, xylene or dioxane, particularly preferred solvents which have a high boiling point and can be easily separated from the product such as toluene.
  • An advantage of the process according to the invention is that the ⁇ -alkylation of the ⁇ -keto esters can be stopped selectively at the level of the mono- or dialkylated products.
  • the yields over 25 the entire reaction sequence are between 40 and 76%, depending on the reaction sequence, reactants and product.
  • the products can be used directly in mass screening without any further cleaning steps.
  • the product purity is over 30 90%. Only the products with structures according to formula IV are split off from the carrier with cyclization. Impurities remain bound to the carrier.
  • the carriers can be reused after the products have been split off.
  • the process is also particularly suitable for the preparation of 5 defined mixtures of pyrazolone derivatives of the formula I, for example in the context of a split synthesis.
  • the solid-phase-bound reaction partner is then reacted with the other reaction partner in accordance with the process described and then, if appropriate, split off from the solid phase with cyclization.
  • the substance mixtures can either be separated beforehand or used directly in the form of a mixture.
  • a potential active ingredient is identified after testing.
  • Another object of the invention is the use of the production method according to the invention for bound or free substance of the formulas I, II or IV for the generation of substance libraries.
  • the substance libraries that can be generated in this way can be quickly checked for a certain effectiveness in what is known as mass screening. This greatly speeds up the search for potent active ingredients.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de dérivés de pyrazolone et son utilisation, ainsi qu'un procédé de η-alkylation de β-céto-esters en phase solide, des β-céto-esters alkylés en phase solide et l'utilisation dudit procédé.
PCT/EP1997/003377 1996-07-05 1997-06-27 Procede de preparation de derives de pyrazolone WO1998001427A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU34383/97A AU3438397A (en) 1996-07-05 1997-06-27 Process for preparing pyrazolone derivatives

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Application Number Priority Date Filing Date Title
DE1996127002 DE19627002A1 (de) 1996-07-05 1996-07-05 Verfahren zur Herstellung von Pyrazolonderivaten
DE19627002.2 1996-07-05

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WO2001064605A3 (fr) * 2000-03-01 2001-12-27 Therascope Ag Synthese et criblage d'une banque combinatoire dynamique
WO2010059241A2 (fr) 2008-11-20 2010-05-27 Cambria Pharmaceuticals, Inc. Traitement de la sclérose latérale amyotrophique
US9145424B2 (en) 2008-11-20 2015-09-29 Northwestern University Treatment of amyotrophic lateral sclerosis

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WO1996033972A1 (fr) * 1995-04-28 1996-10-31 Glaxo Group Limited Procedes de synthese de divers ensembles de pyridines, pyrimidines, derives 1,4-dihydro de ces composes et derives de piperidine

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WO1996033972A1 (fr) * 1995-04-28 1996-10-31 Glaxo Group Limited Procedes de synthese de divers ensembles de pyridines, pyrimidines, derives 1,4-dihydro de ces composes et derives de piperidine

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001064605A3 (fr) * 2000-03-01 2001-12-27 Therascope Ag Synthese et criblage d'une banque combinatoire dynamique
WO2010059241A2 (fr) 2008-11-20 2010-05-27 Cambria Pharmaceuticals, Inc. Traitement de la sclérose latérale amyotrophique
EP2367798A4 (fr) * 2008-11-20 2013-03-13 Cambria Pharmaceuticals Inc Traitement de la sclérose latérale amyotrophique
AU2009318098B2 (en) * 2008-11-20 2015-07-16 Northwestern University Treatment of amyotrophic lateral sclerosis
US9145424B2 (en) 2008-11-20 2015-09-29 Northwestern University Treatment of amyotrophic lateral sclerosis
US9809556B2 (en) 2008-11-20 2017-11-07 Northwestern University Treatment of amyotrophic lateral sclerosis
US10167263B2 (en) 2008-11-20 2019-01-01 Northwestern University Treatment of amyotrophic lateral sclerosis
US10526289B2 (en) 2008-11-20 2020-01-07 Northwestern University Substituted pyrazolone compounds for use in treatment of amyotrophic lateral sclerosis

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DE19627002A1 (de) 1998-01-08

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