EP0712388A1 - Utilisation de phenols et de derives de phenols comme medicaments a effet reducteur du facteur i de coagulation - Google Patents

Utilisation de phenols et de derives de phenols comme medicaments a effet reducteur du facteur i de coagulation

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Publication number
EP0712388A1
EP0712388A1 EP94926836A EP94926836A EP0712388A1 EP 0712388 A1 EP0712388 A1 EP 0712388A1 EP 94926836 A EP94926836 A EP 94926836A EP 94926836 A EP94926836 A EP 94926836A EP 0712388 A1 EP0712388 A1 EP 0712388A1
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EP
European Patent Office
Prior art keywords
group
hydroxy
alkyloxy
substituted
omega
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Withdrawn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
EP94926836A
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German (de)
English (en)
Inventor
Ernst-Christian Witte
Karlheinz Stegmeier
Liesel Doerge
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.)
Roche Diagnostics GmbH
Original Assignee
Roche Diagnostics GmbH
Boehringer Mannheim GmbH
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Application filed by Roche Diagnostics GmbH, Boehringer Mannheim GmbH filed Critical Roche Diagnostics GmbH
Publication of EP0712388A1 publication Critical patent/EP0712388A1/fr
Withdrawn legal-status Critical Current

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    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/58—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
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    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
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    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
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    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/73—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C255/11—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton
    • C07C255/13—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
    • C07C39/15—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings with all hydroxy groups on non-condensed rings, e.g. phenylphenol
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    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
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    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl

Definitions

  • the present invention relates to the new use of phenols and phenol derivatives for the production of medicaments with a fibrinogen-lowering effect.
  • the invention also relates to new phenols and phenol derivatives, processes for their preparation and medicaments which contain these compounds.
  • the invention relates to the use of phenols and phenol derivatives of the general formula I.
  • R denotes hydrogen or one to three substituents which are selected independently of one another from the series halogen, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, cyano or trifluoromethyl,
  • X is in the meta or para position to B and means the following groups:
  • omega-hydroxy-C2-Cg-alkyloxy group substituted or unsubstituted phenyl urethane, phosphoric acid ester, aliphatic carboxylic acid ester group or, optionally substituted, benzoic acid ester grouping,
  • R denotes one to three substituents which are identical or different independently of one another and are located in any position on the benzene ring in relation to the substituent B.
  • halogen means fluorine, chlorine, bromine and iodine, with chlorine being preferred.
  • C ..- C 4 alkyl or alkoxy includes a straight chain or branched alkyl radical with 1-4 C atoms, methyl and isopropyl being preferred.
  • unbranched alkylene chains with 2-6 C atoms are preferred, it being possible for one of the saturated C atoms to be replaced by an oxygen atom or by one of the groups NH,> CO or> CH-OH.
  • two adjacent saturated C atoms can also be replaced together by a group CONH- or -NHCO-.
  • the oxygen atom is preferably para to the phenoxy oxygen of group X.
  • these groups are preferably in the alpha position to one of the two benzene rings.
  • the substituent X is in the meta or para position to the substituent B.
  • Ci-C ⁇ -alkyloxy for the substituent X means a straight-chain or branched alkyloxy chain, preferably methoxy, ethoxy and n-butyloxy.
  • the following alkoxy groups, which are substituted at the terminal C atom by a hydroxyl, halogen or cyano group, are particularly preferred: a) omega-hydroxy-C 2 -C 6 -alkyloxy, b) omega-halogen-C 2 - Cg-alkyloxy and c) omega-cyano-C "-Cg-alkyloxy or / and carry one or two methyl groups on the C atom adjacent to the ether oxygen.
  • Omega-hydroxy-C 2 -Cg-alkyloxy preferably means 2-hydroxy-ethoxy, 4-hydroxy-butoxy, 3-hydroxy-2-propoxy or 3-hydroxy-2-methyl-2-propoxy.
  • Omega-halogen-C 2 -Cg-alkyloxy preferably means omega-chloro-C 2 -Cg-alkyloxy, and here in particular 2-chloro-ethoxy- and 4-chloro-butoxy.
  • Omega-cyano-C ⁇ -C6-alkyloxy preferably means cyanomethyloxy and 5-cyano-pentyloxy. If the group X comprises a C. .. C 4 -alkyl urethane group, the alkyl group may be straight-chain or branched.
  • Methyl, ethyl and t-butyl urethane are preferred.
  • the phenyl radical in phenyl urethane can be unsubstituted or substituted by halogen, preferably chlorine, in the 3- or 4-position.
  • the substituent X comprises a benzoic acid ester radical
  • the phenyl radical is optionally substituted one or more times, preferably with halogen, methoxy or methyl.
  • Suitable aliphatic carboxylic ester residues are preferably those of acetic acid, propionic acid or n- or iso-butyric acid. If X is the benzoyloxy radical, this can optionally be substituted in the meta or para position, preferably by halogen.
  • radicals R are 4- or 3-chloro, 4-fluoro, 4 or 3-trifluoromethyl, 4-methyl, 4-methoxy, 4-cyano, 2,4di-chloro and 2-methoxy-5-chloro.
  • Preferred radicals X are in the para position to B and are hydroxy, carboxymethoxy, 1-carboxyethoxy, 1-carboxypropyloxy, 3-carboxypropyloxy, 2-hydroxyethoxy, 3-hydroxypropyl-2- oxy, 3-hydroxy-2-methyl-propyl-2-oxy, propyl-2-oxy and the rest -0-C (CH 3 ) 2 -CH 2 -0-C0- (CH 2 ) 2 -C00H.
  • R is 4-chloro, 4-trifluoromethyl or 4Cyano
  • X is in the para position to B.
  • Particularly preferred compounds of the general formula I are those in which R is 4-chlorine, X is in the para position to B and 1-carboxyethoxy and B represents trimethylene, trimethylene carbonyl or pentamethylene carbonyl.
  • the present invention also relates to new phenols and phenol derivatives falling under the formula.
  • B is the group -CONHCH 2 CH 2 -
  • R is the chlorine atom in the para position
  • X in the para position is the hydroxyl group, carboxymethoxy, 1-carboxypropyloxy or the p-chlorobenzoyloxy radical
  • R is hydrogen and X in the para position is the hydroxyl group, while B is the group CONHCH 2 CH 2 -,
  • R is the chlorine atom in the para position
  • B represents the trimethylene group
  • X represents the hydroxy group in the para position
  • X in the para position of the 1-carboxyethoxy radical and R in the para position is the chlorine atom, while B is the methylene, carbonyl or aminomethylene group,
  • X in the para position is the 3-hydroxypropyl-2-oxy radical
  • R in the para position is the chlorine atom
  • B is the group> CHOH.
  • Other works describe their use as a starting material or as a reaction component.
  • the compounds of the formula I are highly effective substances which reduce the fibrinogen concentration in the blood, which is particularly important for the treatment of cardiovascular diseases such as peripheral arterial occlusive disease, coronary heart disease and cerebral circulatory disorders Meaning is.
  • the most important rheological factors of the microcirculation are the fibrinogen-dependent parameters plasma viscosity and erythrocyte aggregation.
  • High concentrations of fibrinogen (and other protein fractions) lead to an enormous increase in plasma viscosity and erythrocyte aggregation.
  • a therapeutic reduction in plasma fibrinogen levels means a significant improvement in blood flow properties and thus an increase in microcirculation with improved oxygen release.
  • the compounds of the formula I have a pronounced fibrinogen-lowering action which is superior to that of the bezafibrate described as fibrinogen-lowering (Cook et al., TIPS Reviews 11 (1990), 450).
  • fibrinogen antagonists are substances which are able to prevent the binding of fibrinogen to a GP Ilb-Illa receptor located on the platelets, while the compounds of the general formula I the concentration of fibrinogen in the blood Reduce.
  • R 0 "
  • R has the meaning given above.
  • Suitable reactive derivatives are the acid halides, in particular the acid chlorides, or else acid imidazolides.
  • suitable acid-binding agents are alkali metal hydroxides (reaction under Schotten-Baumann conditions) or organic bases such as pyridine (see, for example, DE-AS 2 149 070) or triethylamine.
  • Such phenoxyalkyl carboxylic acids are described, for example, according to DE-AS 2 149 070 by reacting the phenols (Ia) with alpha-haloacetic acid esters or alpha-halogenopropionic acid esters in inert solvents such as butanone-2 and in the presence of acid acceptors such as powdered potassium carbonate.
  • the ethyl esters of bromo or chlorocarboxylic acids are preferably used as the halocarboxylic acid esters.
  • the resulting oxycarboxylic acid esters are then saponified to give the carboxylic acids by heating with an alcoholic alkali metal hydroxide solution.
  • condensation is preferably carried out in an aqueous alkaline medium, e.g. in the presence of aqueous sodium hydroxide solution.
  • condensation may also be preferred in the presence of mineral acid, e.g. aqueous-alcoholic hydrochloric acid.
  • the reduction of the chalcones Ib .. or Ib 2 to the trimethylene compounds Id according to the invention preferably takes place in two stages: First, the chalcones become the dihydrochalkones of the general formula Ic. or Ic 2 reduced,
  • Alk is the C ⁇ AIk Irest and Phe is unsubstituted or substituted phenyl.
  • the compounds of general formula I prepared if they are acidic or basic in nature, can be converted into physiologically tolerable salts, and in the case of carboxylic acids their conversion into esters with physiologically acceptable alcohols is possible.
  • Pharmacologically acceptable inorganic or organic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, methylglucamine, morpholine or ethanolamine are suitable for the formation of salts from carboxylic acids of the general formula I.
  • Suitable acids for forming salts on bases of the general formula I are, for example, hydrochloric acid, sulfuric acid, acetic acid, citric acid, maleic acid, fumaric acid and tartaric acid.
  • esters of these carboxylic acids with lower monohydric alcohols such as methanol or ethanol
  • polyhydric alcohols such as glycerol
  • alcohols are also included which carry other functional groups, such as e.g. Ethanolamine.
  • the pure enantiomers can be prepared from the racemates of the compounds of the general formula I obtained by racemate resolution (via salt formation with optically active bases). Pure enantiomers can also be obtained by using optically active starting materials in the synthesis.
  • the substances of the general formula I are mixed with suitable pharmaceutical carriers, flavoring, flavoring and coloring agents and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, e.g. in olive oil, suspended or dissolved.
  • the substances of the general formula I and their salts can be administered enterally or parenterally in liquid or solid form.
  • Water is preferably used as the injection medium, which contains the additives, such as stabilizers, solubilizers or buffers, which are customary for injection solutions.
  • additives are e.g. B. tartrate and citrate buffers, complexing agents (such as ethylenediaminetetraacetic acid and their non-toxic salts) and high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation.
  • Solid carriers are e.g. B.
  • Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
  • the dosage can depend on various factors such as the mode of administration, species, age or individual condition.
  • the compounds of the formula I are usually applied in amounts of 1.5 to 15 mg, preferably 5-10 mg per day and per kg of body weight. It is preferred to distribute the daily dose over two applications, two tablets with an active ingredient content of 85 to 200 mg each being administered for each application. The tablets can also be retarded, so that only one tablet with 100-1000 mg of active ingredient has to be given per day.
  • Sprague-Dawley rats (breeder: IFFA-CREDO, France) take 500 ⁇ l blood from the tail vein and use the CLAUSS method with a 2-channel coaguiometer (Biomatik 2000 Coagulometer, Sarstedt) the basal plasma fibrinogen concentration is determined. The animals then receive 50 mg / kg of the test substance p.o. (Standard dosage) in 1% tylose solution. Two hours after application of the test substance, an i.m. injection of 0.05 ml turpentine is placed in a hind limb. A further two hours after application of terpentine, the test substance is again p.o. administered, as well as after 24 and 48 hours.

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Abstract

L'invention concerne l'utilisation de phénols et de dérivés de phénols de la formule générale développée (I) pour préparer des médicaments à effet réducteur du facteur I de coagulation. L'invention concerne en outre de nouveaux phénols et dérivés de phénols, leurs procédés de préparation et des médicaments qui contiennent ce composé. Dans la formule (I), R désigne hydrogène ou un à trois substituants sélectionnés indépendamment les uns des autres dans la série halogène, alkyle C1-C4, alcoxy C1-C4, hydroxy, cyano ou trifluorométhyl, B symbolise une chaîne alkylène saturée ou non saturée, ayant jusqu'à six atomes de C, non substituée ou éventuellement substituée en position quelconque par un ou deux groupe(s) méthyle, un des atomes de C saturés pouvant être remplacé par un atome d'oxygène ou par un des groupes >NH, >C=O ou >CH-OH, et deux atomes de C saturés adjacents pouvant également être remplacés conjointement par un groupe -CONH- ou -NHCO, et X est en position méta ou para par rapport à B et désigne les groupes suivants: un groupe hydroxy ou un groupe alkyluréthane C1-C4 dérivé du précédent ou un groupe phényluréthane substitué ou non substitué, un groupe alkyloxy C1-C6, omega-hydroxy-alkyloxy C2-C6, omega-halogène-alcoxy C2-C6 ou omega-cyano-alkyloxy C1-C6 non ramifié ou substitué par un ou deux groupes méthyle en position quelconque, un groupement alkyluréthane C1-C4, un groupement phényluréthane, un groupement ester d'acide phosphorique, un groupement ester d'acide carboxylique aliphatique substitués ou non substitués, ou bien un groupement benzoate éventuellement substitué dérivés du groupe omega-hydroxy-alkyloxy C2-C6, un groupe aminocarbonyle-alkyloxy C1-C6 ou un groupe N-hydroxy-aminocarbonyle-alkyloxy C1-C6, carboxyméthoxy, 1-carboxy-éthoxy, 1-carboxy-propyloxy ou 3-carboxy-propyloxy, le reste -O-C-(CH3)2-CH2-O-CO-(CH2)2-COOH, le reste benzoyloxy qui est éventuellement substitué.
EP94926836A 1993-08-14 1994-08-13 Utilisation de phenols et de derives de phenols comme medicaments a effet reducteur du facteur i de coagulation Withdrawn EP0712388A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4327365A DE4327365A1 (de) 1993-08-14 1993-08-14 Verwendung von Phenolen und Phenolderivaten als Arzneimittel mit fibrinogensenkender Wirkung
DE4327365 1993-08-14
PCT/EP1994/002709 WO1995005358A1 (fr) 1993-08-14 1994-08-13 Utilisation de phenols et de derives de phenols comme medicaments a effet reducteur du facteur i de coagulation

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EP0712388A1 true EP0712388A1 (fr) 1996-05-22

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EP (1) EP0712388A1 (fr)
JP (1) JPH09501670A (fr)
AU (1) AU7653394A (fr)
CA (1) CA2169187A1 (fr)
DE (1) DE4327365A1 (fr)
WO (1) WO1995005358A1 (fr)

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR950704235A (ko) * 1993-08-30 1995-11-17 오오쓰까 아끼히꼬 벤질아민 유도체(benzylamine derivatives)
FR2713637B1 (fr) * 1993-12-15 1996-01-05 Cird Galderma Nouveaux composés bi-aromatiques dérivés d'amide, compositions pharmaceutiques et cosmétiques les contenant et utilisations.
US5883294A (en) * 1997-06-18 1999-03-16 The Regeants Of The University Of California Selective thyroid hormone analogs
EP0947511A1 (fr) * 1998-03-30 1999-10-06 F. Hoffmann-La Roche Ag Dérivés de l'acide phénoxyacétique et de phénoxyméthyltétrazole ayant une activité antitumorale
CA2384511A1 (fr) * 1999-08-24 2001-03-01 Virginia Commonwealth University Modificateurs allosteriques chiraux substitues d'hemoglobine
EP1246792B1 (fr) * 2000-01-13 2014-08-13 Emisphere Technologies, Inc. Composes et compositions permettant d'administrer des principes actifs
EP1598067B1 (fr) 2000-09-29 2009-05-06 TopoTarget UK Limited Derivées d'acide de carbamine contenant un group amide pour la traitement de malaria
GB0023983D0 (en) 2000-09-29 2000-11-15 Prolifix Ltd Therapeutic compounds
FR2841784B1 (fr) * 2002-07-08 2007-03-02 Composition a base de derives de 1,3-diphenylprop-2en-1-one substitues, preparation et utilisations
FR2841900B1 (fr) 2002-07-08 2007-03-02 Genfit S A Nouveaux derives de 1,3-diphenylprop-2-en-1-one substitues, preparation et utilisations
WO2004092115A2 (fr) 2003-04-07 2004-10-28 Axys Pharmaceuticals Inc. Nouveaux hydroxamates et leur utilisation comme agents therapeutiques
FR2864956B1 (fr) * 2004-01-08 2006-04-28 Genfit S A Compose derive de 1,3-diphenylprop-2-en-1-one, preparation et utilisations
CA2550576A1 (fr) 2004-01-08 2005-08-11 Genfit Composes derives de 1,3-diphenylprop-2-en-1-one, preparation et utilisations
FR2875805B1 (fr) * 2004-09-27 2006-12-29 Genfit S A Composes derives de n-(benzyl) phenylacetamide substitues, preparation et utilisations
WO2008016738A2 (fr) 2006-05-18 2008-02-07 Wisconsin Alumni Research Foundation Agents antibactériens et procédés de criblage apparentés utilisant des macroréseaux de petites molécules
FR2902789A1 (fr) * 2006-06-21 2007-12-28 Genfit Sa Derives de 1,3-diphenylpropane substitues, preparations et utilisations
DK2099442T3 (en) 2006-12-26 2015-02-16 Pharmacyclics Inc Method of using histone deacetylase inhibitors and monitoring biomarkers in combination therapy
NZ579048A (en) 2007-01-30 2012-05-25 Pharmacyclics Inc Methods for determining cancer resistance to histone deacetylase inhibitors
US8603521B2 (en) 2009-04-17 2013-12-10 Pharmacyclics, Inc. Formulations of histone deacetylase inhibitor and uses thereof
US9492423B2 (en) 2011-09-13 2016-11-15 Pharmacyclics Llc Formulations of histone deacetylase inhibitor in combination with bendamustine and uses thereof
EP3027192A4 (fr) 2013-08-02 2017-03-22 Pharmacyclics, LLC Méthodes permettant de traiter des tumeurs solides

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2149070C3 (de) * 1971-10-01 1978-03-23 Boehringer Mannheim Gmbh, 6800 Mannheim Phenoxyalkylcarbonsäurederivate und deren Salze, Verfahren zu deren Herstellung und Arzneimittel
DE2432560A1 (de) * 1974-07-06 1976-01-22 Boehringer Mannheim Gmbh Neue phenoxyalkylcarbonsaeurederivate und verfahren zur herstellung derselben
JPS518228A (ja) * 1974-07-10 1976-01-23 Takeda Chemical Industries Ltd Chikanfuenokishikarubonsanruino seizoho
GB1499508A (en) * 1974-12-06 1978-02-01 Ici Ltd 3,3,3-trifluoropropionic acid derivatives
GB1563195A (en) * 1975-08-20 1980-03-19 Sori Soc Rech Ind Derivating of phenoxy-alkylcarboxylic acids
DE2541342A1 (de) * 1975-09-17 1977-03-31 Boehringer Mannheim Gmbh Neue phenoxyalkylcarbonsaeuren und verfahren zur herstellung derselben
CH630879A5 (de) * 1977-08-29 1982-07-15 Siegfried Ag Verfahren zur herstellung lipidsenkender alkylenglykolderivate.
EP0002408A1 (fr) * 1977-11-26 1979-06-13 SOCIETE DE RECHERCHES INDUSTRIELLES S.O.R.I. Société anonyme dite: Nouveaux composés phénoxy-alcanols substitués, leur procédé de préparation et leur application en thérapeutique
CA2020888A1 (fr) * 1989-07-27 1991-01-28 Philippe Guerry Derives d'aminoalkoxybenzene substitues

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9505358A1 *

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DE4327365A1 (de) 1995-02-16
WO1995005358A1 (fr) 1995-02-23
AU7653394A (en) 1995-03-14
CA2169187A1 (fr) 1995-02-23
JPH09501670A (ja) 1997-02-18

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