WO1995005358A1 - 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 Download PDF

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WO1995005358A1
WO1995005358A1 PCT/EP1994/002709 EP9402709W WO9505358A1 WO 1995005358 A1 WO1995005358 A1 WO 1995005358A1 EP 9402709 W EP9402709 W EP 9402709W WO 9505358 A1 WO9505358 A1 WO 9505358A1
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group
hydroxy
alkyloxy
substituted
omega
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English (en)
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Ernst-Christian Witte
Karlheinz Stegmeier
Liesel Doerge
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Roche Diagnostics GmbH
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Boehringer Mannheim GmbH
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Priority to EP94926836A priority Critical patent/EP0712388A1/fr
Priority to AU76533/94A priority patent/AU7653394A/en
Priority to JP7506754A priority patent/JPH09501670A/ja
Publication of WO1995005358A1 publication Critical patent/WO1995005358A1/fr
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    • 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
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    • 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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    • C07C235/44—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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    • C07C255/13—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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    • 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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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.
PCT/EP1994/002709 1993-08-14 1994-08-13 Utilisation de phenols et de derives de phenols comme medicaments a effet reducteur du facteur i de coagulation Ceased WO1995005358A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP94926836A EP0712388A1 (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
AU76533/94A AU7653394A (en) 1993-08-14 1994-08-13 Use of phenols and phenol derivates as medicaments with fibrinogen-reducing effect
JP7506754A JPH09501670A (ja) 1993-08-14 1994-08-13 フィブリノーゲンを下げる作用を有する医薬剤としてのフェノール及びフェノール誘導体の使用

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DE4327365A DE4327365A1 (de) 1993-08-14 1993-08-14 Verwendung von Phenolen und Phenolderivaten als Arzneimittel mit fibrinogensenkender Wirkung
DEP4327365.3 1993-08-14

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WO1995005358A1 true WO1995005358A1 (fr) 1995-02-23

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WO (1) WO1995005358A1 (fr)

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US5883294A (en) * 1997-06-18 1999-03-16 The Regeants Of The University Of California Selective thyroid hormone analogs
WO2002026703A1 (fr) * 2000-09-29 2002-04-04 Prolifix Limited Composes d'acide carbamique comprenant une liaison ether et utiles en tant qu'inhibiteurs de hdac
FR2875805A1 (fr) * 2004-09-27 2006-03-31 Genfit S A Composes derives de n-(benzyl) phenylacetamide substitues, preparation et utilisations
US7276612B2 (en) 2003-04-07 2007-10-02 Pharmacyclics, Inc. Hydroxamates as therapeutic agents
US7880020B2 (en) 2000-09-29 2011-02-01 Topotarget Uk Limited Carbamic acid compounds comprising an amide linkage as HDAC inhibitors
US7943661B2 (en) 2002-07-08 2011-05-17 Genfit Substituted 1,3-diphenylprop-2-en-1-one derivatives and preparation and uses thereof
US8618327B2 (en) 2006-05-18 2013-12-31 Wisconsin Alumni Research Foundation Antibacterial agents and methods of use thereof
US9128096B2 (en) 2007-01-30 2015-09-08 Pharmacyclics, Inc. Methods for determining cancer resistance to histone deacetylase inhibitors
US9403032B2 (en) 2009-04-17 2016-08-02 Pharmacyclics Llc Formulations of histone deacetylase inhibitor and uses therof
US9408816B2 (en) 2006-12-26 2016-08-09 Pharmacyclics Llc Method of using histone deacetylase inhibitors and monitoring biomarkers in combination therapy
US9421208B2 (en) 2013-08-02 2016-08-23 Pharmacyclics Llc Methods for the treatment of solid tumors
US9492423B2 (en) 2011-09-13 2016-11-15 Pharmacyclics Llc Formulations of histone deacetylase inhibitor in combination with bendamustine and uses thereof

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EP0666840A1 (fr) * 1993-08-30 1995-08-16 Otsuka Pharmaceutical Co., Ltd. Derives de benzylamine
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.
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
JP2003529543A (ja) * 1999-08-24 2003-10-07 ヴァージニア コモンウェルス ユニバーシティ 置換キラル・アロステリック・ヘモグロビン調節剤
US7151191B2 (en) * 2000-01-13 2006-12-19 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
FR2841784B1 (fr) * 2002-07-08 2007-03-02 Composition a base de derives de 1,3-diphenylprop-2en-1-one substitues, preparation et utilisations
FR2864956B1 (fr) * 2004-01-08 2006-04-28 Genfit S A Compose derive de 1,3-diphenylprop-2-en-1-one, preparation et utilisations
EA011305B1 (ru) * 2004-01-08 2009-02-27 Жанфит Производные 1,3-дифенилпроп-2-ен-1-она, способ их получения и применение
FR2902789A1 (fr) * 2006-06-21 2007-12-28 Genfit Sa Derives de 1,3-diphenylpropane substitues, preparations et utilisations

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US5883294A (en) * 1997-06-18 1999-03-16 The Regeants Of The University Of California Selective thyroid hormone analogs
US7880020B2 (en) 2000-09-29 2011-02-01 Topotarget Uk Limited Carbamic acid compounds comprising an amide linkage as HDAC inhibitors
WO2002026703A1 (fr) * 2000-09-29 2002-04-04 Prolifix Limited Composes d'acide carbamique comprenant une liaison ether et utiles en tant qu'inhibiteurs de hdac
US6960685B2 (en) 2000-09-29 2005-11-01 Topotarget Uk Limited Carbamic acid compounds comprising an ether linkage as HDAC inhibitors
US8058308B2 (en) 2002-07-08 2011-11-15 Genfit Substituted 1,3-diphenylprop-2-en-1-one derivatives, preparation and uses thereof
US7943661B2 (en) 2002-07-08 2011-05-17 Genfit Substituted 1,3-diphenylprop-2-en-1-one derivatives and preparation and uses thereof
US8026371B2 (en) 2003-04-07 2011-09-27 Pharmacyclics, Inc. Hydroxamates as therapeutic agents
US9186347B1 (en) 2003-04-07 2015-11-17 Pharmacyclics Llc Hydroxamates as therapeutic agents
US7517988B2 (en) 2003-04-07 2009-04-14 Pharmacyclics, Inc. Hydroxamates as therapeutic agents
US7834054B2 (en) 2003-04-07 2010-11-16 Pharmacyclics, Inc. Hydroxamates as therapeutic agents
US7420089B2 (en) 2003-04-07 2008-09-02 Pharmacyclics, Inc. Hydroxamates as therapeutic agents
US7276612B2 (en) 2003-04-07 2007-10-02 Pharmacyclics, Inc. Hydroxamates as therapeutic agents
US8389570B2 (en) 2003-04-07 2013-03-05 Pharmacyclics, Inc. Hydroxamates as therapeutic agents
US7482466B2 (en) 2003-04-07 2009-01-27 Pharmacyclics, Inc. Hydroxamates as therapeutic agents
US8779171B2 (en) 2003-04-07 2014-07-15 Pharmacyclics, Inc. Hydroxamates as therapeutic agents
WO2006035157A3 (fr) * 2004-09-27 2006-06-29 Genfit Composes derives de n- (benzyl) phenylacetamide substitues , preparation et utilisations comme ligands des ppar dans le traitement des dereglements lipidiques et/ou glucidiques
FR2875805A1 (fr) * 2004-09-27 2006-03-31 Genfit S A Composes derives de n-(benzyl) phenylacetamide substitues, preparation et utilisations
US8618327B2 (en) 2006-05-18 2013-12-31 Wisconsin Alumni Research Foundation Antibacterial agents and methods of use thereof
US9408816B2 (en) 2006-12-26 2016-08-09 Pharmacyclics Llc Method of using histone deacetylase inhibitors and monitoring biomarkers in combination therapy
US9128096B2 (en) 2007-01-30 2015-09-08 Pharmacyclics, Inc. Methods for determining cancer resistance to histone deacetylase inhibitors
US9403032B2 (en) 2009-04-17 2016-08-02 Pharmacyclics Llc Formulations of histone deacetylase inhibitor and uses therof
US10105552B2 (en) 2009-04-17 2018-10-23 Pharmacyclics Llc 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
US9421208B2 (en) 2013-08-02 2016-08-23 Pharmacyclics Llc Methods for the treatment of solid tumors

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CA2169187A1 (fr) 1995-02-23
DE4327365A1 (de) 1995-02-16
JPH09501670A (ja) 1997-02-18
AU7653394A (en) 1995-03-14
EP0712388A1 (fr) 1996-05-22

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