EP0712388A1 - Use of phenols and phenol derivates as medicaments with fibrinogen-reducing effect - Google Patents

Use of phenols and phenol derivates as medicaments with fibrinogen-reducing effect

Info

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
Authority
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Withdrawn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
Other languages
German (de)
French (fr)
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
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 Roche Diagnostics GmbH, Boehringer Mannheim GmbH filed Critical Roche Diagnostics GmbH
Publication of EP0712388A1 publication Critical patent/EP0712388A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—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
    • 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
    • C07C217/58—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 with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—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
    • 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
    • C07C217/82—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 of the same non-condensed six-membered aromatic ring
    • C07C217/84—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 of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—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
    • 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
    • C07C235/38—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 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • 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
    • C07C235/46—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/56—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—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
    • C07C259/04—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/88—Unsaturated compounds containing keto groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Phenols and phenol derivatives having the general structural formula (I) are used to produce medicaments with fibrinogen-reducing effect. Also disclosed are new phenols and phenol derivatives, a process for producing the same and medicaments containing these compounds. In the formula, R stands for hydrogen or one to three substituents selected independently from each other from the halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxy, cyano oder trifluoromethyl series; B stands for a saturated or unsaturated alkylene chain with up to 6 C atoms substituted or not by one or two methyl groups in any desired position. One of the saturated C atoms may be substituted by an oxygen atom or by one of the groups >NH, >C=O oder >CH-OH, and two adjacent saturated C atoms may also be substituted together by a group -CONH- or -NHCO-. X is in a meta- or para-position in relation to B and stands for the following groups: a hydroxy group or a C1-C4-alkylurethane or substituted or non-substituted phenylurethane group derived from the hydroxy group; an unbranched or a C1-C6-alkyloxy, omega-hydroxy-C2-C6-alkyloxy, omega-halogen-C2-C6-alkyloxy or omega-cyano-C1-C6-alkyloxy group substituted by one or two methyl groups in any desired position; a C1-C4-alkyl urethane, a substituted or non-substituted phenyl urethane, phosphoric acid ester, aliphatic carboxylic acid ester grouping or a possibly substituted benzoic acid ester grouping derived from the omega-hydroxy-C2-C6-alkoxy group; an aminocarbonyl-C1-C6-alkoxy or a N-hydroxy-aminocarbonyl-C1-C6-alkoxy group; carboxymethoxy, 1-carboxy-ethoxy, 1-carboxy-propyloxy or 3-carboxy-propyloxy; the residue -O-C-(CH3)2-CH2-O-CO-(CH2)2-COOH; the possibly substituted benzoyloxy residue.

Description

Verwendung von Phenolen und Phenolderivaten als Arzneimittel mit fibrinogensenkender WirkungUse of phenols and phenol derivatives as drugs with a fibrinogen-lowering effect
Die vorliegende Erfindung betrifft die neue Verwendung von Phenolen und Phenol¬ derivaten zur Herstellung von Arzneimitteln mit fibrinogensenkender Wirkung. Ge¬ genstand der Erfindung sind außerdem neue Phenole und Phenolderivate, Verfah¬ ren zu deren Herstellung und Arzneimittel, die diese Verbindungen enthalten.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.
Die Erfindung betrifft die Verwendung von Phenolen und Phenolderivaten der allgemeinen Formel IThe invention relates to the use of phenols and phenol derivatives of the general formula I.
zur Herstellung von Arzneimitteln mit fibrinogensenkender Wirkung,for the production of drugs with a fibrinogen-lowering effect,
in welcherin which
R Wasserstoff oder ein bis drei Substituenten bedeutet, die unabhängig von¬ einander aus der Reihe Halogen, C^-C^Alkyl, C^C^-Alkoxy, Hydroxy, Cyano oder Trifluormethyl ausgewählt sind,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,
B eine unsubstituierte oder gegebenenfalls durch ein oder zwei Methylgruppen in beliebiger Stellung substituierte, gesättigte oder ungesättigte Alkylenkette mit bis zu sechs C-Atomen symbolisiert, wobei eines der gesättigten C-Atome ersetzt sein kann durch ein Sauerstoffatom oder durch eine der Gruppen >NH, >C=O oder >CH-OH, und zwei benachbarte gesättigte C-Atome auch gemeinsam durch eine Gruppe -CONH- oder -NHCO- ersetzt sein können, undB symbolizes an unsubstituted or optionally substituted by one or two methyl groups in any position, saturated or unsaturated alkylene chain with up to six carbon atoms, whereby one of the saturated carbon atoms can be replaced by an oxygen atom or by one of the groups>NH,> C = O or> CH-OH, and two neighboring saturated C atoms too can be replaced together by a group -CONH- or -NHCO-, and
X in meta- oder para-Stellung zu B steht und folgende Gruppen bedeutet:X is in the meta or para position to B and means the following groups:
eine Hydroxygruppe oder eine von dieser abgeleitete C1-C4- Alkylurethan- oder substituierte oder unsubstituierte Phenyl¬ urethangruppe,a hydroxyl group or a C1-C4-alkyl urethane or substituted or unsubstituted phenyl urethane group derived therefrom,
eine unverzweigte oder eine durch eine oder zwei Methylgruppen in beliebiger Stellung substituierte C..-Cg-Alkyloxy-, omega-Hydroxy- C2Cg- alkyloxy-, omega-Halogen-C2-Cg-alkyloxy oder omega- Cyano-C .. -Cg-alkyloxygruppe,a straight-chain or a C ..- Cg-alkyloxy-, omega-hydroxy- C 2 Cg-alkyloxy-, omega-halogen-C2-Cg-alkyloxy or omega-cyano-C .. substituted by one or two methyl groups in any position -Cg alkyloxy group,
eine von der omega-Hydroxy-C2-Cg-alkyloxygruppe abgeleitete substituierte oder unsubstituierte Phenyl- urethan-, Phosphorsäureester-, aliphatische Carbonsäureester¬ oder, gegebenenfalls substituierte, Benzoesäureestergruppierung,one derived from the 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,
eine Aminocarbonly-C^Cg-alkyloxy- oder eine N-Hydroxy-amino- carbonyl-C. -Cg-alkyloxygruppean aminocarbonly-C ^ Cg-alkyloxy or an N-hydroxyamino-carbonyl-C. -Cg alkyloxy group
Carboxymethoxy, 1-Carboxy-ethoxy, 1 -Carboxy-propyloxy oder 3-Carboxy-propyloxyCarboxymethoxy, 1-carboxy-ethoxy, 1-carboxypropyloxy or 3-carboxypropyloxy
den Rest -0-C(CH3)2-CH2-0-C0-(CH2)2-C00Hthe balance -0-C (CH 3 ) 2 -CH 2 -0-C0- (CH 2 ) 2 -C00H
den Benzoyloxyrest, der gegebenenfalls substituiert ist,the benzoyloxy radical, which is optionally substituted,
sowie deren Enantiomere, Diastereomere, Z- oder E-Isomere und gegebe¬ nenfalls deren physiologisch verträgliche Salze oder Ester.and their enantiomers, diastereomers, Z or E isomers and, where appropriate, their physiologically tolerable salts or esters.
R bedeutet ein bis drei Substituenten, die unabhängig voneinander gleich oder ver¬ schieden sind und sich zum Substituenten B in beliebiger Stellung am Benzolring befinden. In der Definition von R bedeutet Halogen Fluor, Chlor, Brom und Jod, wo¬ bei Chlor bevorzugt ist. C..-C4-Alkyl oder -Alkoxy beinhaltet einen geradkettigen oder verzweigten Alkylrest mit 1-4 C-Atomen, wobei Methyl und Isopropyl bevorzugt sind.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. In the definition of R, 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.
Für B sind unverzweigte Alkylenketten mit 2-6 C-Atomen bevorzugt, wobei eines der gesättigten C-Atome ersetzt sein kann durch ein Sauerstoffatom oder durch eine der Gruppen NH, >CO oder >CH-OH. Es können aber auch zwei benachbarte gesättigte C- Atome gemeinsam ersetzt sein durch eine Gruppe CONH- bzw. -NHCO-. Für den Fall, daß ein C-Atom durch ein Sauerstoffatom ersetzt ist, steht das Sauerstoffatom bevorzugt in para-Stellung zu dem Phenoxy-Sauerstoff der Gruppe X. Gleiches gilt für die bevorzugte Position einer einzelnen Carbonylgruppe >C=0 bzw. für eine sek. Alkoholgruppe >CH-OH. Für den Fall jedoch, daß >C=O bzw. >CH-OH Teil einer Kette B aus drei Kohlenstoffatomen ist, stehen diese Gruppen bevorzugt in alpha- Stellung zu einem der beiden Benzolringe.For B, 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. However, two adjacent saturated C atoms can also be replaced together by a group CONH- or -NHCO-. In the event that a carbon atom is replaced by an oxygen atom, the oxygen atom is preferably para to the phenoxy oxygen of group X. The same applies to the preferred position of a single carbonyl group> C = 0 or for one sec . Alcohol group> CH-OH. However, in the event that> C = O or> CH-OH is part of a chain B of three carbon atoms, these groups are preferably in the alpha position to one of the two benzene rings.
Keine Bevorzugungen gibt es für die Stellung von Amino- oder Carbonylamino- Gruppen. Unter den Verbindungen mit ungesättigter Gruppe B sind insbesondere die Gruppen -CO-CH=CH- und CH=CHCO- bevorzugt ("Chalkone").There are no preferences for the position of amino or carbonylamino groups. Among the compounds with unsaturated group B, the groups -CO-CH = CH- and CH = CHCO- are particularly preferred ("chalcones").
Als Verbindungen, die als Bestandteil der Gruppe B neben einer Doppelbindung eine Carbonyiaminogruppe tragen, sind die Zimtsäureamide mit den Resten -CH=CH-CONH- und -NHCO-CH=CH- bevorzugt.As compounds which, as a component of group B, carry a carbonyiamino group in addition to a double bond, the cinnamic acid amides with the radicals -CH = CH-CONH- and -NHCO-CH = CH- are preferred.
Der Substituent X steht in meta- oder para-Stellung zum Substituenten B. C-i-Cβ- Alkyloxy für den Substituenten X bedeutet eine geradkettige oder verzweigte Alkyl- oxykette, vorzugsweise Methoxy, Ethoxy und n-Butyloxy. Besonders bevorzugt sind folgende Alkoxy-Gruppen, die am endständigen C-Atom durch eine Hydroxy-, Halo¬ gen- oder Cyangruppe substituiert sind: a) omega-Hydroxy-C2-Cg-alkyloxy, b) omega-Halogen-C2-Cg-alkyloxy und c) omega-Cyano-C«-Cg-alkyloxy oder/und an dem dem Ethersauerstoff benachbarten C-Atom eine oder zwei Methylgruppen tragen. Omega-Hydroxy-C2-Cg-alkyloxy bedeutet vorzugsweise 2-Hydroxy-ethoxy, 4-Hydroxy-butoxy, 3-Hydroxy-2-propoxy oder 3-Hydroxy-2-methyl-2-propoxy. Omega-Halogen-C2-Cg-alkyloxy bedeutet bevorzugt omega-Chlor-C2- Cg-alkyloxy, und hier insbesondere 2-Chlor-ethoxy- und 4-Chlor- butoxy. Omega-Cyano-Cη-C6- alkyloxy bedeutet bevorzugt Cyanmethyloxy- und 5-Cyano-pentyloxy. Umfaßt die Gruppe X eine C..-C4-Alkyiurethangruppe, so kann die Alkylgruppe ge- radkettig oder verzweigt sein. Bevorzugt sind Methyl, Ethyl und t-Butylurethan. Der Phenylrest im Phenylurethan kann sowohl unsubsituiert als auch durch Halogen, vorzugsweise Chlor, in 3- oder 4-Stellung subsituiert sein.The substituent X is in the meta or para position to the substituent B. Ci-Cβ-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-Cη-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.
Umfaßt der Substituent X einen Benzoesäureesterrest, so ist der Phenylrest gege¬ benenfalls ein- oder mehrfach substituiert, vorzugsweise mit Halogen, Methoxy oder Methyl. Als aliphatische Carbonsäureesterreste kommen vorzugsweise die der Essigsäure, Propionsäure oder n- oder iso-Buttersäure in Frage. Bedeutet X den Benzoyloxyrest, so kann dieser gegebenenfalls in meta- oder para-Stellung substitu¬ iert sein, vorzugsweise durch Halogen.If 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.
Besonders bevorzugte Reste R sind 4- oder 3-Chlor, 4-Fluor, 4 oder 3-Trifluor- methyl, 4-Methyl, 4-Methoxy, 4-Cyano, 2,4di-Chlor und 2-Methoxy-5-Chlor.Particularly preferred 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.
Besonders bevorzugte Reste B sind -CONHCH2CH2-, -CH=CH-CO-, COCH=CH-, -NHCH2-, -CH2NH-, -CH2NHCH2-, >CHOH, -NHCO-, -CONH- , NHCOCH2-, -CH2NHCO-, Carbonyl, unverzweigtes Cj-Cg-Alkylen oder unverzweigtes C2-Cc-Alkylencarbonyl, insbesondere Ethylencarbonyl, Trimethylencarbonyl und Pentamethylencarbonyl.Particularly preferred radicals B are -CONHCH 2 CH 2 -, -CH = CH-CO-, COCH = CH-, -NHCH 2 -, -CH 2 NH-, -CH 2 NHCH 2 -,> CHOH, -NHCO-, -CONH-, NHCOCH 2 -, -CH 2 NHCO-, carbonyl, unbranched C j -Cg alkylene or unbranched C 2 -Cc alkylene carbonyl, especially ethylene carbonyl, trimethylene carbonyl and pentamethylene carbonyl.
Bevorzugte Reste X stehen in para-Stellung zu B und sind Hydroxy, Carboxy- methoxy, 1-Carboxy-ethoxy, 1 -Carboxy-propyloxy, 3-Carboxy-propyloxy, 2-Hydroxy-ethoxy, 3-Hydroxy-propyl-2-oxy, 3-Hydroxy-2-methyl-propyl-2-oxy, Propyl-2-oxy und der Rest -0-C(CH3)2-CH2-0-C0-(CH2)2-C00H.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.
Insbesondere bevorzugt sind Verbindungen der allgemeinen Formell, in denen R 4-Chlor, 4-Trifluormethyl oder 4Cyano bedeutet, B >CHOH, -CONHCH2CH2-, Tri- methylen, Trimethylencarbonyl oder Pentamethylencarbonyl ist, X in para-Stellung zu B steht und 1-Carboxy-ethoxy, Propyl-2-oxy, 3-Hydroxy-propyl-2- oxy oder den Rest -0-C(CH3)2-CH2-0-C0-(CH2)2-C00H darstellt.Particularly preferred are compounds of the general formula in which R is 4-chloro, 4-trifluoromethyl or 4Cyano, B> CHOH, -CONHCH 2 CH 2 -, trimethylene, trimethylene carbonyl or pentamethylene carbonyl, X is in the para position to B. and 1-carboxy-ethoxy, propyl-2-oxy, 3-hydroxypropyl-2-oxy or the radical -0-C (CH 3 ) 2 -CH 2 -0-CO- (CH 2 ) 2 -C00H .
Besonders bevorzugte Verbindungen der allgemeinen Formel I sind solche, in denen R 4-Chlor bedeutet, X in para-Stellung zu B steht und 1 -Carboxy-ethoxy bedeutet und B Trimethylen, Trimethylencarbonyl oder Pentamethylencarbonyl darstellt.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.
Gegenstand der vorliegenden Erfindung sind auch neue unter die Formell fallende Phenole und Phenolderivate.The present invention also relates to new phenols and phenol derivatives falling under the formula.
In der Literatur sind bereits unter die Formel I fallende Verbindungen beschrieben,Compounds falling under formula I have already been described in the literature,
in denenin which
a) B die Gruppe -CONHCH2CH2- bedeutet, R das Chloratom in para-Stellung ist, X in para-Stellung die Hydroxygruppe, Carboxymethoxy, 1-Carboxy- propyloxy oder der p-Chlorbenzoyloxyrest ist,a) 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,
b) R Wasserstoff und X in para-Stellung die Hydroxygruppe ist, während B die Gruppe CONHCH2CH2- bedeutet,b) R is hydrogen and X in the para position is the hydroxyl group, while B is the group CONHCH 2 CH 2 -,
c) R das Chloratom in para-Stellung ist, B die Trimethylengruppe bedeutet und X in para-Stellung die Hydroxygruppe darstellt,c) R is the chlorine atom in the para position, B represents the trimethylene group and X represents the hydroxy group in the para position,
d) X in para-Stellung der 1 -Carboxy-ethoxy-Rest und R in para-Stellung das Chloratom ist, während B die Methylen-, Carbonyl- oder Aminomethylen- gruppe ist,d) 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,
e) X in para-Stellung den 3-Hydroxy-propyl-2-oxy-rest bedeutet, R in para-Stellung das Chloratom ist und B die Gruppe >CHOH bedeutet.e) X in the para position is the 3-hydroxypropyl-2-oxy radical, R in the para position is the chlorine atom and B is the group> CHOH.
So wird die Verbindung mit R = H, B = -CONHCH2CH2- und X = 4-OH im Zusam¬ menhang mit Phosphomonoesterase-Hemmung von Aso und Murakoshi in den Symposia on Enzyme Chem. 8, 64-65 (1953) (Jap.) genannt. Andere Arbeiten be¬ schreiben ihre Verwendung als Ausgangsmaterial oder als Reaktionskomponente. Sie wird ebenso wie die Verbindung mit R = Cl, B = -CONHCH2CH2- und X = 4-OH z.B. in der DE-OS 2149070 als Vorstufe für die Herstellung lipidsenkender Substan¬ zen beschrieben. Die Verbindung mit R = 4-CI, B = -CONHCH2CH2- und X = 4-OCH2-COOH ist ebenfalls Gegenstand der DE-OS 2149070. Sie gehört zu einer Reihe sowohl die Serumlipide als auch die Cholesterinspiegei senkender Substanzen, die z. B. gegen Atheroscierosis wirksam sind.Thus, the compound with R = H, B = -CONHCH 2 CH 2 - and X = 4-OH in connection with phosphomonoesterase inhibition by Aso and Murakoshi in the Symposia on Enzyme Chem. 8, 64-65 (1953) Called (Jap.). Other works describe their use as a starting material or as a reaction component. Like the compound with R = Cl, B = -CONHCH 2 CH 2 - and X = 4-OH, it is described, for example, in DE-OS 2149070 as a precursor for the preparation of lipid-lowering substances. The compound with R = 4-CI, B = -CONHCH 2 CH 2 - and X = 4-OCH 2 -COOH is also the subject of DE-OS 2149070. It belongs to a series of substances which lower both serum lipids and cholesterol levels, the z. B. are effective against atheroscierosis.
Die Verbindung mit R = H, B = -(CH2)3- und X = 4-OH diente als Ausgangsmaterial für die Synthese lipidsenkender Verbindungen vom "Fibrat"-Typ (Kyushin Pharm. , Ltd., J.Med.Chem. 3_1, 1205-9 (1988)). Sie erwies sich als Hemmstoff für Pilzwachs¬ tum (Bultman et al., CA 89:85632), als aπtimikrobielles Agens (Jurd et al., US 3915889, CA 84:39706; Jurd et al., US 3867548, CA 83:23435: Jurd et al., US 3775541 , CA 81 :22227d; King et al., Antimicrob. Agents Chemother. 1, 263-7 (1972); Jurd et al., J.Pharm.Sci. 60, 1753-5 (1971);, als den Algenwuchs hemmende Substanz (Chan und Jurd, Experientia 29, 1196-7 (1973)), und als Sporostaticum (Lewis und Jurd, Spores 5, 384-9 (1972)).The compound with R = H, B = - (CH 2 ) 3 - and X = 4-OH served as the starting material for the synthesis of lipid-lowering compounds of the "fibrate" type (Kyushin Pharm., Ltd., J.Med.Chem. 3_1, 1205-9 (1988)). It turned out to be an inhibitor of fungal growth (Bultman et al., CA 89: 85632), as an antimicrobial agent (Jurd et al., US 3915889, CA 84: 39706; Jurd et al., US 3867548, CA 83: 23435 : Jurd et al., US 3775541, CA 81: 22227d; King et al., Antimicrob. Agents Chemother. 1, 263-7 (1972); Jurd et al., J.Pharm. Sci. 60, 1753-5 ( 1971); as an inhibitor of algae growth (Chan and Jurd, Experientia 29, 1196-7 (1973)), and as a sporostaticum (Lewis and Jurd, Spores 5, 384-9 (1972)).
Es wurde nun gefunden, daß die Verbindungen der Formel I hochwirksame Sub¬ stanzen sind, die die Fibrinogenkonzentration im Blut vermindern, was vor allem zur Behandlung von cardiovaskulären Erkrankungen wie der peripheren arteriellen Ver¬ schlußkrankheit, der coronaren Herzkrankheit und von cerebralen Durchblutungs¬ störungen von Bedeutung ist.It has now been found that 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.
Die Auswertung epidemiologischer Studien machte deutlich, daß erhöhte Plasma- Fibrinogenspiegel beim Menschen mit einem deutlich erhöhten Risiko, an einer coronaren Herzkrankheit zu erkranken, verknüpft sind. Hohe Fibrinogenspiegel tragen auf verschiedenen Wegen zur Atherombildung bei: Durch Erhöhung der Plasmaviskosität, als Cofaktor bei der Plättchenaggregation, durch Beeinflussung der Fibrinmenge, die abgelagert wird, wenn die Koagulation initiiert wird. In der Arterienwand akkumuliertes Fibrinogen soll die Proliferation glatter Muskelzellen fördern (Naito et al, Atheroscierosis 83 (1990), 9) und die Einlagerung von LDL und anderen Lipiden beschleunigen (Smith, Eur.Heart J. 1 . (1990), 72). Die wichtigsten rheologischen Faktoren der MikroZirkulation sind die fibrinogenabhängigen Parame¬ ter Plasma-Viskosität und Erythrocyten-Aggregation. Hohe Konzentrationen von Fibrinogen (und anderen Proteinfraktionen) führen zu einer enormen Erhöhung der Plasmaviskosität und der Erythrocytenaggregation. Eine therapeutische Absenkung der Plasma-Fibrinogenspiegel bedeutet eine deutliche Verbesserung der Blutfließ- eigenschaften und damit eine Steigerung der MikroZirkulation mit verbesserter Sauerstoffabgabe.The evaluation of epidemiological studies made it clear that elevated plasma fibrinogen levels in humans are associated with a significantly increased risk of developing coronary heart disease. High levels of fibrinogen contribute to atheroma formation in various ways: by increasing plasma viscosity, as a cofactor in platelet aggregation, by influencing the amount of fibrin that is deposited when coagulation is initiated. Fibrinogen accumulated in the arterial wall is said to promote smooth muscle cell proliferation (Naito et al, Atheroscierosis 83 (1990), 9) and to accelerate the incorporation of LDL and other lipids (Smith, Eur.Heart J. 1. (1990), 72). 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.
Die Verbindungen der Formel I besitzen eine ausgeprägte fibrinogensenkende Wir¬ kung, die der des als fibrinogensenkend beschriebenen Bezafibrats (Cook et al., TIPS Reviews 11 (1990), 450) überlegen ist.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).
Die Wirkungsweise der erfindungsgemäßen Verbindungen ist nicht zu verwechseln mit der von "Fibrinogen-Antagonisten". Es handelt sich bei letzteren um Stoffe, die in der Lage sind, die Bindung von Fibrinogen an einen auf den Blutplättchen befind¬ lichen GP Ilb-Illa-Rezeptor zu verhindern, während die Verbindungen der allgemei¬ nen Formel I die Konzentration von Fibrinogen im Blut vermindern.The mode of action of the compounds according to the invention should not be confused with that of "fibrinogen antagonists". The latter 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.
Die Herstellung der erfindungsgemäß verwendeten Verbindungen der allgemeinen Formel I ist an sich bekannt.The preparation of the compounds of general formula I used according to the invention is known per se.
So stellt man z.B. die unter die allgemeine Formel I der vorliegenden Erfindung fallenden Phenole der allgemeinen Formel I a her,For example, the phenols of the general formula I a which come under the general formula I of the present invention,
indem man ein Amin der allgemeinen Formel II by using an amine of the general formula II
in Gegenwart säurebindender Agenzien mit einer Carbonsäure der allgemeinen Formel IIIin the presence of acid-binding agents with a carboxylic acid of the general formula III
R. 0"), oder einem reaktiven Derivat derselben zur Umsetzung bringt. In den Formeln (I) und (III) hat R die oben genannte Bedeutung. Als reaktive Derivate eignen sich die Säurehalogenide, insbesondere die Säurechloride, oder auch Säureimidazolide. Als säurebindende Agenzien kommen z.B. Alkalihydroxide (Umsetzung unter Schotten-Baumann-Bedingungen) oder organische Basen wie Pyridin (s. z.B. DE-AS 2 149 070) oder Triethylamin in Frage.R. 0 "), or a reactive derivative thereof. In formulas (I) and (III), R has the meaning given above. Suitable reactive derivatives are the acid halides, in particular the acid chlorides, or else acid imidazolides. Examples of 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.
Diese Phenole stellen wiederum auch Vorstufen für die unten die allgemeine Formel I fallenden Phenoxyalkylcarbonsäuren bzw. -ester mit B = -CONHCH2CH2- und X = Carboxymethoxy oder 1 -Carboxy-ethoxy dar. Derartige Phenoxyalkylcarbonsäuren werden z.B. gemäß DE-AS 2 149 070 durch Umsetzen der Phenole (la) mit alpha- Halogenessigsäureestern bzw. alpha-Halogenpropionsäureestern in inerten Lösungsmitteln wie Butanon-2 und in Gegenwart von Säureakzeptoren wie pulveri¬ siertem Kaliumcarbonat hergestellt. Bevorzugt werden als Halogencarbonsäureester die Ethylester von Brom- oder Chlorcarbonsäuren eingesetzt. Die entstehenden Oxycarbonsäureester werden anschließend durch Erwärmen mit alkoholischer Alkalilauge zu den Carbonsäuren verseift.These phenols in turn also represent precursors for the phenoxyalkyl carboxylic acids or esters with B = -CONHCH 2 CH 2 - and X = carboxymethoxy or 1-carboxyethoxy falling below the general formula I. 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.
Verbindungen der allgemeinen Formeln Ib.. oder lb2 Compounds of the general formulas Ib .. or lb 2
in denen R und X die oben genannte Bedeutung haben, erhält man durch Konden¬ sation eines Acetophenons der allgemeinen Formel IVa bzw. IVb, in which R and X have the meaning given above, by condensation of an acetophenone of the general formula IVa or IVb,
mit einem Benzaldehyd der allgemeinen Formel Va bzw. Vb.with a benzaldehyde of the general formula Va or Vb.
Die Kondensation erfolgt bevorzugt in wäßrig-alkalischem Milieu, z.B. in Gegenwart wäßriger Natronlauge. In einzelnen Fällen kann eine Kondensation auch bevorzugt in Gegenwart von Mineralsäure, z.B. wäßrig-alkoholischer Salzsäure, ablaufen.The condensation is preferably carried out in an aqueous alkaline medium, e.g. in the presence of aqueous sodium hydroxide solution. In individual cases, condensation may also be preferred in the presence of mineral acid, e.g. aqueous-alcoholic hydrochloric acid.
Die Reduktion der Chalkone Ib.. bzw. Ib2 zu den erfindungsgemäßen Trimethylen- verbindungen Id verläuft bevorzugt in zwei Stufen: Zunächst werden die Chalkone zu den Dihydrochalkonen der allgemeinen Formel Ic. bzw. Ic2 reduziert,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,
was durch katalytische Hydrierung ersterer z.B. in Gegenwart von Edelmetallen oder in Gegenwart von Homogenkatalysatoren vom Triphenylphosphin/Rhodiumsalz-Typ bei Raumtemperatur und Normaldruck in einem Lösungsmittel wie z.B. THF., erfolgt. Anschließende Reduktion der Dihydrochalkone unter den Bedingungen der WOLFF-KISHNER-Reduktion, d.h. durch Erhitzen mit Hydraziπhydrat in starkem Alkali, liefert die Trimethyienverbindungen der allgemeinen Formel Idwhich takes place by catalytic hydrogenation of the former, for example in the presence of noble metals or in the presence of homogeneous catalysts of the triphenylphosphine / rhodium salt type at room temperature and normal pressure in a solvent such as THF. Subsequent reduction of the dihydrochalcones under the conditions of the WOLFF-KISHNER reduction, ie by heating with hydrazine hydrate in strong alkali, gives the trimethyl compounds of the general formula Id
in der R und X die oben genannte Bedeutung haben. in which R and X have the meaning given above.
Verbindungen der allgemeinen Formel leCompounds of the general formula le
in der R und B die oben genannte Bedeutung haben, werden hergestellt, indem man ein Phenol der allgemeinen Formel Ifin which R and B have the meaning given above, are prepared by using a phenol of the general formula If
in der Hitze mit 1,3-Dioxolan-2-on (Ethylencarbonat) umsetzt. Die Reaktion erfolgt in einem Lösungsmittel in Gegenwart von ^CO«. Die weitere Umsetzung der Verbin¬ dungen der allgemeinen Formel le mit Alkyl- oder Phenylisocyanaten führt zu Alkyl- oder Phenylurethanen der allgemeinen Formel igin the heat with 1,3-dioxolan-2-one (ethylene carbonate). The reaction takes place in a solvent in the presence of ^ CO «. The further reaction of the compounds of the general formula I with alkyl or phenyl isocyanates leads to alkyl or phenyl urethanes of the general formula I
in der R und B die oben genannte Bedeutung haben, Alk den C ^AIk Irest und Phe unsubstituiertes oder substituiertes Phenyl bedeutet. in which R and B have the meaning given above, Alk is the C ^ AIk Irest and Phe is unsubstituted or substituted phenyl.
Ebenso führt die weitere Umsetzung der Verbindungen der allgemeinen Formel If mit Alkyl- oder Phenylisocyanaten unter üblichen Bedingungen zu Alkyl- oder Phenylurethanen der allgemeinen Formel IhLikewise, the further reaction of the compounds of the general formula If with alkyl or phenyl isocyanates under customary conditions leads to alkyl or phenyl urethanes of the general formula Ih
in der R, B, Alk und Phe die oben genannte Bedeutung haben.in which R, B, Alk and Phe have the meaning given above.
Verbindungen der allgemeinen Formel liCompounds of the general formula li
in der R die oben genannte Bedeutung hat, n = 1-6 ist und R1 Wasserstoff oder Methyl bedeutet, werden hergestellt durch Friedel-Crafts-Acylierung eines Phen- oxycarbonsäureesters der allgemeinen Formel VIIin which R has the meaning given above, n = 1-6 and R 1 is hydrogen or methyl, are prepared by Friedel-Crafts acylation of a phenoxycarboxylic acid ester of the general formula VII
in der R1 die oben genannte Bedeutung hat und R2 C-j-C^-Alkyl bedeutet, mit einer Carbonsäure der aligemeinen Formel VIII in which R 1 has the abovementioned meaning and R 2 C- j ^ -C alkyl, with a carboxylic acid of the general formula VIII
in der R die oben genannte Bedeutung hat und n die Zahlen 1-6 bedeutet, in Ge¬ genwart von Polyphosphorsäure als F.-C.-Katalysater. Der dabei erhaltene Ester wird anschließend verseift.in which R has the meaning given above and n denotes the numbers 1-6, in the presence of polyphosphoric acid as an F.C. catalyst. The ester obtained is then saponified.
Verbindungen der allgemeinen Formel Ik,Compounds of the general formula Ik,
in welcher R und X die oben angegebene Bedeutung haben, werden hergestellt, indem man ein Benzylamin der allgemeinen Formel IX in which R and X have the meaning given above, are prepared by using a benzylamine of the general formula IX
mit einem Benzaldehyd der allgemeinen Formel Xwith a benzaldehyde of the general formula X
zum Beispiel in Ethanol zur Schiff-Base reagieren läßt und letztere, ohne sie zu iso¬ lieren, bei Normaldruck in Gegenwart z.B. von Platindioxid zu Verbindung Ik hy¬ driert. Gewünschtenfalls können die hergestellten Verbindungen der allgemeinen Formel I, wenn sie saurer oder basischer Natur sind, in physiologisch verträgliche Salze über¬ führt werden, und im Falle von Carbonsäuren ist ihre Umwandlung in Ester mit phy¬ siologisch unbedenklichen Alkoholen möglich. Zur Bildung von Salzen aus Carbon¬ säuren der aligemeinen Formel I eignen sich pharmakologisch verträgliche anorga¬ nische oder organische Basen wie z.B. Natriumhydroxid, Kaliumhydroxid, Calcium- hydroxid, Methylglukamin, Morpholin oder Ethanolamin. Zur Salzbildung an Basen der allgemeinen Formel I eignen sich als Säuren z.B. Salzsäure, Schwefelsäure, Essigsäure, Citronensäure, Maleinsäure, Fumarsäure und Weinsäure.for example, can react in ethanol to form the Schiff base and, without isolating it, the latter is hydrogenated at normal pressure in the presence of, for example, platinum dioxide to give Ik. If desired, 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.
Für den Fall, daß die Verbindungen der allgemeinen Formel I eine Carboxylfunktion enthalten, kommen als Ester dieser Carbonsäuren solche mit niederen einwertigen Alkoholen (wie z.B. Methanol oder Ethanol) oder mit mehrwertigen Alkoholen (wie z.B. Glycerin) in Frage. Es seien aber auch solche Alkohole eingeschlossen, die noch andere funktioneile Gruppen tragen, wie z.B. Ethanolamin.In the event that the compounds of general formula I contain a carboxyl function, esters of these carboxylic acids with lower monohydric alcohols (such as methanol or ethanol) or with polyhydric alcohols (such as glycerol) are suitable. However, alcohols are also included which carry other functional groups, such as e.g. Ethanolamine.
Aus den erhaltenen Razematen der Verbindungen der allgemeinen Formel I können die reinen Enantiomeren durch Razematspaltung (über Salzbildung mit optisch akti¬ ven Basen) hergestellt werden. Zu reinen Enantiomeren kommt man auch, indem man in der Synthese jeweils optisch aktive Ausgangsstoffe einsetzt.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.
Zur Herstellung von Arzneimitteln werden die Substanzen der allgemeinen Formel I mit geeigneten pharmazeutischen Trägersubstanzen, Aroma-, Geschmacks- und Farbstoffen gemischt und beispielsweise als Tabletten oder Dragees ausgeformt oder unter Zugabe entsprechender Hilfsstoffe in Wasser oder Öl, z.B. in Olivenöl, suspendiert oder gelöst.For the production of pharmaceuticals, 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.
Die Substanzen der allgemeinen Formel I und ihre Salze können in flüssiger oder fester Form enteral oder parenteral appliziert werden. Als Injektionsmedium kommt vorzugsweise Wasser zur Anwendung, welches die bei injektionslösungen üblichen Zusätze wie Stabilisierungsmittel, Lösungsvermittler oder Puffer enthält. Derartige Zusätze sind z. B. Tartrat- und Citratpuffer, Komplexbildner (wie Ethylendiamin- tetraessigsäure und deren untoxische Salze) und hochmolekulare Polymere wie flüssiges Polyethyloxid zur Viskositätsregulierung. Feste Trägerstoffe sind z. B. Stärke, Lactose, Mannit, Methylcellulose, Talcum, hochdisperse Kieselsäuren, hochmolekulare Fettsäuren (wie Stearinsäure), tierische und pflanzliche Fette und feste hochmolekulare Polymere (wie Polyethylenglykole). Für orale Applikation ge¬ eignete Zubereitungen können gewünschtenfalls Geschmacks- und Süßstoffe ent¬ halten.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. Such 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. starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, high molecular fatty acids (such as stearic acid), animal and vegetable fats and solid high molecular polymers (such as polyethylene glycols). Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
Die Dosierung kann von verschiedenen Faktoren wie Applikationsweise, Spezies, Alter oder individuellem Zustand abhängen. Üblicherweise werden die Verbindun¬ gen der Formel I in Mengen von 1 ,5 bis 15 mg, vorzugsweise 5 - 10 mg pro Tag und pro kg Körpergewicht appliziert. Bevorzugt ist es, die Tagesdosis auf zwei Applika¬ tionen zu verteilen, wobei bei jeder Applikation zwei Tabletten mit einem Wirkstoff¬ gehalt von je 85 bis 200 mg verabreicht werden. Die Tabletten können auch retar¬ diert sein, wodurch nur noch pro Tag eine Tablette mit 100 - 1000 mg Wirkstoff gegeben werden muß.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.
Bevorzugt im Sinne der vorliegenden Erfindung sind außer den in den Beispielen genannten Verbindungen und der durch Kombination aller in den Ansprüchen ge¬ nannten Substituenten die folgenden Verbindungen der Formel I, die als Reinenan- tiomere, als Enantiomerengemische/Razemate, als E- oder Z-Isomere oder deren Gemische, sowie ggf. als Salze oder/und Ester vorliegen können:For the purposes of the present invention, preference is given, in addition to the compounds mentioned in the examples and by combining all of the substituents mentioned in the claims, to the following compounds of the formula I which are used as pure antiomers, as enantiomer mixtures / racemates, as E- or Z- Isomers or their mixtures, and optionally also as salts and / or esters can be present:
Verb. R B X SchmD. °CVerb. R B X SchmD. ° C
1 H CONHCH2CH2 4-OH 164-1651 H CONHCH 2 CH 2 4-OH 164-165
2 4-CI CONHCH2CH2 4-OH 174-1752 4-CI CONHCH 2 CH 2 4-OH 174-175
3 4-CI CONHCH2CH2 4-OCO-C6H4-CI(p) 196-1973 4-CI CONHCH 2 CH 2 4-OCO-C 6 H 4 -CI (p) 196-197
4 4-CI CONHCH2CH2 4-OCH2-COOH 1994 4-CI CONHCH 2 CH 2 4-OCH 2 -COOH 199
5 4-CI CONHCH2CH2 4-OCH(Et)-COOH 166-1675 4-CI CONHCH 2 CH 2 4-OCH (Et) -COOH 166-167
6 4-CI (CH2)3 4-OH 336 4-CI (CH 2 ) 3 4-OH 33
7 4-CI CH2 4-OCH(Me)-COOH 119-1217 4-CI CH 2 4-OCH (Me) -COOH 119-121
8 4-CI CO 4-OCH(Me)-COOH 144-1468 4-CI CO 4-OCH (Me) -COOH 144-146
9 4-CI CH(OH) 4-OCH(Me)-CH2OH OEL9 4-CI CH (OH) 4-OCH (Me) -CH 2 OH OEL
10 4-CI NHCH2 4-OCH(Me)-COOH n.n.10 4-CI NHCH 2 4-OCH (Me) -COOH nn
11. 4-CI CONHCH2CH2 4-OCONHEt 194-19611. 4-CI CONHCH 2 CH 2 4-OCONHEt 194-196
12. 4-CI CONHCH2CH2 4-OCONHtBu 17512. 4-CI CONHCH 2 CH 2 4-OCONH t Bu 175
13. 4-CI CONHCH2CH2 4-OCONH-C6H5 195-19613. 4-CI CONHCH 2 CH 2 4-OCONH-C 6 H 5 195-196
14. 4-CI CONHCH2CH2 4-OCH2-CONHOH 162 14. 4-CI CONHCH 2 CH 2 4-OCH 2 -CONHOH 162
Verb. R B Schmp. °CVerb. R B mp ° C
49. 4-CI (CH2)3 3-OCH2-COOH49. 4-CI (CH 2 ) 3 3-OCH 2 -COOH
50. H (CH2)3 4-OCH2-COOH 94-9550. H (CH 2 ) 3 4-OCH 2 -COOH 94-95
51. 4-CI (CH2)3 4-OCH2-COOH 12-11351. 4-CI (CH 2 ) 3 4-OCH 2 -COOH 12-113
52. 4-F (CH2)3 4-OCH(Me)-COOH52. 4-F (CH 2 ) 3 4-OCH (Me) -COOH
53. 3-CI (CH2)3 4-OCH(Me)-COOH53. 3-CI (CH 2 ) 3 4-OCH (Me) -COOH
54. 2.4-di-CI (CH2)3 4-OCH(Me)-COOH54. 2.4-di-CI (CH 2 ) 3 4-OCH (Me) -COOH
55. 3-CF3 (CH2)3 4-OCH(Me)-COOH55. 3-CF 3 (CH 2 ) 3 4-OCH (Me) -COOH
56. 2-OCH3- 5-CI -"- 4-OCH(Me)-COOH56. 2-OCH 3 - 5-CI - "- 4-OCH (Me) -COOH
57. 4-CN CH=CH-CO 4-OCH(Me)-COOH57. 4-CN CH = CH-CO 4-OCH (Me) -COOH
58. 4-F CH=CH-CO 4-OCH(Me)-COOH58. 4-F CH = CH-CO 4-OCH (Me) -COOH
59 4-CN (CH2)2-CO 4-OCH(Me)-COOH59 4-CN (CH 2 ) 2 -CO 4-OCH (Me) -COOH
60. 4-F (CH2)2-CO 4-OCH(Me)-COOH60. 4-F (CH 2 ) 2 -CO 4-OCH (Me) -COOH
61. 4-CI (CH2)4 4-OCH(Me)-COOH61. 4-CI (CH 2 ) 4 4-OCH (Me) -COOH
62. 4-CI (CH2)6 4-OCH(Me)-COOH62. 4-CI (CH 2 ) 6 4-OCH (Me) -COOH
63. 4-CI NH 4-OCH(Me)-COOH63. 4-CI NH 4-OCH (Me) -COOH
64. H NHCO 4-OCH(Me)-COOH64. H NHCO 4-OCH (Me) -COOH
65. H NHCH2 4-OCH(Me)-COOH65. H NHCH 2 4-OCH (Me) -COOH
66. 4-CI NHCH2CH2 4-OCH2-COOH66. 4-CI NHCH 2 CH 2 4-OCH 2 -COOH
67. 4-CI NHCH2CH2 4-OCH(Me)-COOH67. 4-CI NHCH 2 CH 2 4-OCH (Me) -COOH
68. 4-CI CONHCH2CH2 4-OC(Me)2CH20-C0-NHMe 139-14168. 4-CI CONHCH2CH2 4-OC (Me) 2 CH 2 0-CO-NHMe 139-141
69. 4-CI 4-0C(Me)2CH20-C0-CH2 -CH2-C00H 134-13569. 4-CI 4-0C (Me) 2 CH 2 0-CO-CH 2 -CH 2 -C00H 134-135
70. 4-CI CH=CH-C0 3-OH 124-12570. 4-CI CH = CH-CO 3 -OH 124-125
71. 4-CI (CH2)2-C0 3-OCH2-COOH 117-11971. 4-CI (CH2) 2-CO 3 -OCH 2 -COOH 117-119
72. H CH2-NH-CH2 4-OCH2-COOH xHCI 222-22472. H CH2-NH-CH2 4-OCH 2 -COOH x HCI 222-224
73. 3-CI 4-OCH2-COOH xHCI 232-23473. 3-CI 4-OCH 2 -COOH xHCI 232-234
74. 4-CI 4-OCH2-COOH xHCI 244-24574. 4-CI 4-OCH 2 -COOH xHCI 244-245
75. H 4-OCH2CH2OH xHCI 172-17475. H 4-OCH 2 CH 2 OH x HCI 172-174
76. 4-CI 4-OCH2CH2OH xHCI 215-21876. 4-CI 4-OCH 2 CH 2 OH xHCI 215-218
77. H (CH2)3 4-OCH2-COOH 94-9577. H (CH2) 3 4-OCH 2 -COOH 94-95
78. 4-CI (CH2)3 4-OCH2-COOH 112-11378. 4-CI (CH2) 3 4-OCH 2 -COOH 112-113
79. H (CH2)3 3-OCH2-COOH 78-79 Im Nachfolgenden werden beispielhaft experimentelle Verfahren zur Darstellung neuer Verbindungen beschrieben:79. H (CH2) 3 3-OCH 2 -COOH 78-79 Experimental methods for the preparation of new compounds are described below as examples:
Ausführungsbeispiele:EXAMPLES
Beispiel 1:Example 1:
2-r4-f3-(4-Cvanophenyl)propynphenoxylpropionsäure2-r4-f3- (4-cvanophenyl) propynphenoxylpropionic acid
a) 4'-Hydroxy-4-carboxy-chalcona) 4'-Hydroxy-4-carboxy-chalcon
Zu einer Lösung aus 150 ml Wasser, 14.0 g (0.35 mol) Natriumhydroxid und 13.6 g (0.1 mol) 4-Hydroxyacetophenon unter Stickstoff gibt man 15.0 g (0.1 mol) 4-Carboxybenzaldehyd und läßt 36 Stunden reagieren. Dann wird Wasser zugegeben, zweimal mit Essigester extrahiert und die wässrige Phase mit verd. HC1 auf pH 7 gebracht. Man saugt das ausgefallene Produkt ab und wäscht es mit Wasser. Nach Trocknen und Umkristallisieren aus Ethanol erhält man 22.0 g (82 % d. Th.) Produkt mit dem Schmp. 283-284 °C.15.0 g (0.1 mol) of 4-carboxybenzaldehyde are added to a solution of 150 ml of water, 14.0 g (0.35 mol) of sodium hydroxide and 13.6 g (0.1 mol) of 4-hydroxyacetophenone under nitrogen and the mixture is left to react for 36 hours. Then water is added, extracted twice with ethyl acetate and the aqueous phase is brought to pH 7 with dil. HCl. The precipitated product is suctioned off and washed with water. After drying and recrystallization from ethanol, 22.0 g (82% of theory) of product with a melting point of 283-284 ° C. are obtained.
b) 4-[3-(4-Hydroxyphenyl)propyl]benzoesäureb) 4- [3- (4-Hydroxyphenyl) propyl] benzoic acid
22.0 g (81 mol) des Chalkons werden in einem Gemisch aus 800 ml THF, 3.5 ml 70-proz. HCI04 und 5 g 10-proz. Palla- diumkohle zwei Stdn. bei 20°C und 40 mbar hydriert. Nach Abtrennen des Katalysators wird eingedampft. Ausb. 20.5 g (98% d.Th.), Schmp. 129-131 °C (Toluol).22.0 g (81 mol) of the chalcone are mixed in a mixture of 800 ml THF, 3.5 ml 70 percent. HCI04 and 5 g 10 percent. Palladium-carbon hydrogenated for two hours at 20 ° C and 40 mbar. After the catalyst has been separated off, it is evaporated. Educ. 20.5 g (98% of theory), mp. 129-131 ° C (toluene).
c) 4-[3-(4-Acetoxyphenyl)propyl]benzoesäurec) 4- [3- (4-Acetoxyphenyl) propyl] benzoic acid
20 g (78 mmol) der Hydroxyverbindung aus b) werden mit 40 ml (246 mmol) Acetanhydrid und 1.0 g Dimethylaminopyridin eine Std. lang bei 0°C gerührt. Dann setzt man bei 0°C 20 ml Ethanol zu, rührt 5 min und gibt dann 600 ml Wasser zu. Man extrahiert mit Ether, trocknet die Etherphase (Na2SO4) und dampft ein. Der Rückstand wird aus 66-proz. Ethanol umkristallisiert. Ausb. 12.0 g (51% d.Th.), Schmp.134-136°C. d) 4-[3-(4-Acetoxyphenyl)propyl]benzamid20 g (78 mmol) of the hydroxy compound from b) are stirred with 40 ml (246 mmol) of acetic anhydride and 1.0 g of dimethylaminopyridine at 0 ° C. for one hour. Then 20 ml of ethanol are added at 0 ° C., the mixture is stirred for 5 minutes and then 600 ml of water are added. It is extracted with ether, the ether phase is dried (Na2SO4) and evaporated. The residue is 66 percent. Recrystallized ethanol. Educ. 12.0 g (51% of theory), mp. 134-136 ° C. d) 4- [3- (4-acetoxyphenyl) propyl] benzamide
Ein Gemisch aus 12.0 g (40 mmol) der nach c) hergestellten Benzoesäure, 20 ml (0.27 mmol) Thionylchlorid und drei Tropfen DMF wird zwei Stdn. bei 60°C gerührt. Dann dampft man zur Trockne ein, löst den Rückstand in Methylenchlorid und begast bei 0°C bis zur vollständigen Amidierung mit Ammoniak. Man dampft ein und wäscht mit kaltem Methylenchlorid. Ausb. 11.4 g (95.3% d.Th.), Schmp.104-106°C (Ethanol).A mixture of 12.0 g (40 mmol) of the benzoic acid prepared according to c), 20 ml (0.27 mmol) of thionyl chloride and three drops of DMF is stirred at 60 ° C. for two hours. Then it is evaporated to dryness, the residue is dissolved in methylene chloride and gassed at 0 ° C. until complete amidation with ammonia. It is evaporated and washed with cold methylene chloride. Educ. 11.4 g (95.3% of theory), mp. 104-106 ° C (ethanol).
e) 4-[3-(4-Hydroxyphenyl)propyl]benzamide) 4- [3- (4-Hydroxyphenyl) propyl] benzamide
Man rührt ein Gemisch aus 11.4 g (38 mmol) der nach d) er- haltenen Ace- toxyverbindung, 45 ml 2N-NaOH (90 mmol) und 90 ml Ethanol 20 min lang bei 50°C, destilliert dann das Ethanol ab und verdünnt mit Wasser. Durch Ansäuern mit2N-HCI wird das Phenol ausgefällt. Man saugt ab, wäscht mit Wasser und trocknet. Ausb. 9.1 g (93% d.Th.), Schmp. 174-175°C (Ethanol).A mixture of 11.4 g (38 mmol) of the acetoexy compound obtained according to d), 45 ml of 2N-NaOH (90 mmol) and 90 ml of ethanol is stirred for 20 minutes at 50 ° C., then the ethanol is distilled off and diluted with water. The phenol is precipitated by acidification with 2N-HCl. It is suctioned off, washed with water and dried. Educ. 9.1 g (93% of theory), mp. 174-175 ° C (ethanol).
f) 2-[4-[3-(4-Aminocarbonylphenyl)propyl]phenoxy]propionsäuremethylesterf) Methyl 2- [4- [3- (4-aminocarbonylphenyl) propyl] phenoxy] propionate
Ein Gemisch aus 7.0 g (27.5 mmol) des nach e) erhaltenen Phenols, 100 ml Butanon und 9.5 g (69 mmol) wasserfreiem, pulverisiertem K2CO3 wird 15 min lang bei 80°C gerührt, dann gibt man nach einander eine Spatelspitze Kaliumiodid und einige mg Kronenether Crown(18,6) sowie 5.0 g (30 mmol) 2-Brom-propionsäuremethylester zu und rührt 16 Stdn. bei 80°C. Dann wird warm abgesaugt, das Filtrat eingedampft und der Rückstand mit Isohexan zur Kristallisation gebracht. Man saugt ab und trocknet. Ausb. 9.2 g (98.3% d.Th.), Schmp. 102-103°C (Essigester).A mixture of 7.0 g (27.5 mmol) of the phenol obtained according to e), 100 ml of butanone and 9.5 g (69 mmol) of anhydrous, pulverized K2CO3 is stirred at 80 ° C for 15 min, then a spatula tip of potassium iodide and some are added in succession mg of crown ether Crown (18.6) and 5.0 g (30 mmol) of 2-bromo-propionic acid methyl ester and stirred at 80 ° C. for 16 hours. It is then suction filtered while warm, the filtrate is evaporated and the residue is crystallized with isohexane. It is suctioned off and dried. Educ. 9.2 g (98.3% of theory), mp. 102-103 ° C (ethyl acetate).
g) 2-[4-[3-(4-Cyanophenyl)propyl]phenoxy]propionsäuremethylesterg) Methyl 2- [4- [3- (4-cyanophenyl) propyl] phenoxy] propionate
Man löst 9.0 g (2.9 mmol) des nach f) erhaltenen Carbonamids bei 140°C in 90 ml Toluol, gibt 7.0 g (5.6 mmol) Phosphorpentoxid zu und rührt nun 10 min bei 140°C. Nach dem Abkühlen dekantiert man das Toluol ab, behandelt das Ungelöste zweimal mit heißem Essigester und vereinigt die Essigester- Extrakte mit der Toluolphase. Die organische Lösung wird eingedampft, und es bleiben 7.2 g (85% d.Th.) Produkt in Form eines farblosen Oeles zurück. Praktisch analysenrein.9.0 g (2.9 mmol) of the carbonamide obtained according to f) are dissolved in 90 ml of toluene at 140 ° C., 7.0 g (5.6 mmol) of phosphorus pentoxide are added and the mixture is then stirred at 140 ° C. for 10 min. After cooling, the toluene is decanted off, the undissolved is treated twice with hot ethyl acetate and the ethyl acetate extracts are combined with the toluene phase. The organic solution is evaporated, and 7.2 g (85% of theory) of product remain in the form of a colorless oil. Practically pure.
h) Titelverbindungh) title link
Ein Gemisch aus 7.0 g (20 mmol) des nach g) hergestellten Esters, 20 ml 2N-NaOH und 40 ml Ethanol wird eine Stunde lang bei 50°C gerührt, dann destilliert man das Ethanol ab. Man verdünnt den Rückstand mit Wasser, schüttelt die wässrige Phase zur Beseitigung von Neutralstoffen zweimal mit Ether aus und säuert sie schließlich mit verd. HCI an. Die saure Lösung wird dreimal mit Ether extrahiert. Man trocknet den Ether (Na2S04), dampft ein und chromatographiert das zurückbleibende Rohprodukt mittels Kurzsäule an Kieselgel Nr.60 und dem Laufmittel Methylenchlorid + 1% Essigsäure. Ausb. 5.0 g (74.6% d.Th.) farbloses Oel.A mixture of 7.0 g (20 mmol) of the ester prepared according to g), 20 ml of 2N NaOH and 40 ml of ethanol is stirred for one hour at 50 ° C., then the ethanol is distilled off. The residue is diluted with water, the aqueous phase is shaken out twice with ether to remove neutral substances and finally acidified with dil. HCl. The acidic solution is extracted three times with ether. The ether (Na2S04) is dried, evaporated and the crude product which remains is chromatographed by means of a short column on silica gel No.60 and the mobile phase methylene chloride + 1% acetic acid. Educ. 5.0 g (74.6% of theory) colorless oil.
Beispiel 2:Example 2:
r4-f3-(4-Chlorphenyl)propyπphenolr4-f3- (4-chlorophenyl) propyphenol
a) 4'-Hydroxy-4-chlor-chalkona) 4'-Hydroxy-4-chloro-chalcone
Man löst 13.6 g (0.1 mol) 4-Hydroxy-acetophenon in einer Lösung aus 10.0 g NaOH und 100 ml Wasser, gibt 14.1 g (0.1 mol) 4-Chlorbenzaldehyd zu und rührt nun unter Stickstoff 48 Stdn. bei Raumtemperatur. Danach wird mit Wasser verdünnt, mit verd. HCI angesäuert und der ausfallende Niederschlag abgesaugt. Nach dem Waschen mit Wasser und Trocknen (i. Vak. über KOH) Ausb. 23.8 g (92% d.Th.), Schmp. 187°C (Methanol).13.6 g (0.1 mol) of 4-hydroxyacetophenone are dissolved in a solution of 10.0 g of NaOH and 100 ml of water, 14.1 g (0.1 mol) of 4-chlorobenzaldehyde are added and the mixture is then stirred under nitrogen for 48 hours at room temperature. Then it is diluted with water, acidified with dil. HCI and the precipitate is filtered off with suction. After washing with water and drying (i. Vacuum over KOH) yield. 23.8 g (92% of theory), mp. 187 ° C (methanol).
b) Titelverbindungb) Title link
Ein Gemisch aus 22.0 g (85 mmol) 4'-Hydroxy-4-chlor-chalkon, 500 ml Met¬ hanol, 10 ml conc. HCI und 5 g 10-proz. Palladiumkohle wird bei Raumtempe¬ ratur und Normaldruck in einer Schüttelapparatur mit Wasserstoff bis zur be¬ endeten Aufnahme begast. Dann saugt man den Katalysator ab, dampft i. Vak. ein und löst den Rückstand in Ether. Die Etherphase wird durch Aus- schütteln mit gesätt. NaHC03-Lösung neutral gewaschen, dann trocknet man mit Na2S04 und dampft ein. Es folgt eine Reinigung an einer RP-18-Mittel- druck-Chromatographiesäule mit dem Laufmittel MethanohWasser = 8:2 Vol.-Ausb. 14.2 g (68% d.Th.),A mixture of 22.0 g (85 mmol) of 4'-hydroxy-4-chloro-chalcone, 500 ml of methanol, 10 ml of conc. HCI and 5 g 10 percent. Palladium carbon is gassed with hydrogen at room temperature and normal pressure in a shaker until the absorption is complete. Then you sucked off the catalyst, evaporated i. Vac. and dissolves the residue in ether. The ether phase is shake with sat. NaHC03 solution washed neutral, then dried with Na2S04 and evaporated. This is followed by cleaning on an RP-18 medium-pressure chromatography column with the mobile solvent methane / water = 8: 2 vol. 14.2 g (68% of theory),
Beispiel 3:Example 3:
2-r4-f3-(4-Chlorphenyl)propyllphenoxy1propionsäure2-r4-f3- (4-chlorophenyl) propyllphenoxy1propionic acid
a) 2-[4-[3-(4-Chlorphenyl)propyl]phenoxy]propionsäure-methylestera) Methyl 2- [4- [3- (4-chlorophenyl) propyl] phenoxy] propionate
Wird aus 4-[3-(4-Chlorphenyl)propyl]phenol (s.o.) und 2-Brom-propionsäure- methylester in Analogie zu Beispiel 1f) dargestellt. Das Produkt wurde in ungereinigter Form (Öl, Ausb. nahe 100%) in die unter b) beschriebene Verseifung eingesetzt.Is prepared from 4- [3- (4-chlorophenyl) propyl] phenol (see above) and 2-bromo-propionic acid methyl ester in analogy to Example 1f). The product was used in unpurified form (oil, yield close to 100%) in the saponification described under b).
b) Titelverbindungb) Title link
Das Gemisch aus 6.3 g (18.9 mmol) nach a) dargestelltem Ester, 60 ml Methanol und 30 ml 2N-NaOH wird 4 Stdn. bei 50°C gerührt, dann dampft man das Methanol i.Vak. ab und fällt mittels verd. HCI die Säure aus. Sie wird abgesaugt, mit Wasser gewaschen und i. Vak. über KOH getrocknet. Ausb. 5.3 g (88% d.Th.), Schmp. 81-82°C (Heptan).The mixture of 6.3 g (18.9 mmol) of the ester prepared according to a), 60 ml of methanol and 30 ml of 2N NaOH is stirred for 4 hours at 50 ° C., then the methanol is evaporated in vacuo. drops and the acid precipitates by means of dil. HCI. It is suctioned off, washed with water and i. Vak. dried over KOH. Educ. 5.3 g (88% of theory), mp. 81-82 ° C (heptane).
Beispiel 4:Example 4:
2-r4-r2-(Benzoylamino)ethvnphenoxy1ethanol2-r4-r2- (benzoylamino) ethnphenoxy1ethanol
Eine Suspension aus 60 ml abs. Toluol, 8.0 g (33 mmol) 4-[2-(Benzoyiamino)- ethyljphenol und 4.7 g pulv., trocknem K2C03 wird 15 min bei 120°C gerührt, dann gibt man 5.8 g (66 mmol) Ethylencarbonat zu und hält weitere zwei Stdn. auf 120°C. Man verdünnt mit Aceton, saugt heiß ab, dampft das Filtrat i.Vak. ein und kristalli¬ siert den Rückstand aus Ethanol um. Ausb. 4.6 g (49% d.Th.), Schmp. 135-136°C. Beispiel 4a:A suspension of 60 ml abs. Toluene, 8.0 g (33 mmol) of 4- [2- (benzoyiamino) ethyljphenol and 4.7 g of powdered, dry K2C03 are stirred at 120 ° C. for 15 min, then 5.8 g (66 mmol) of ethylene carbonate are added and a further two are kept Hours to 120 ° C. It is diluted with acetone, suction filtered while hot, and the filtrate is evaporated in vacuo. and crystallizes the residue from ethanol. Educ. 4.6 g (49% of theory), mp. 135-136 ° C. Example 4a
In analoger Weise wird aus 3-[2-(Benzoylamiπo)ethyl]phenol und Ethylencarbonat dargestellt:In an analogous manner, 3- [2- (benzoylamiπo) ethyl] phenol and ethylene carbonate are prepared:
2-[3-[2-(Benzoylamino)ethyl]phenoxy]ethanol Ausb. 61% d.Th.,farbloses Oel.2- [3- [2- (Benzoylamino) ethyl] phenoxy] ethanol yield 61% of theory, colorless oil.
Beispiel 5:Example 5:
2-f4-r6-(4-Chlorphenyl)-1-oxo-hexyπphenoxylpropionsäure2-f4-r6- (4-chlorophenyl) -1-oxo-hexyphenoxylpropionic acid
a) - ethylestera) - ethyl ester
Ein Gemisch aus 8.1 g (35.7 mmol)6-(4-Chlorphenyl)hexansäure, 6.9 g (35.7 mmol) 2-Phenoxypropionsäure-ethylester und 50 g Polyphosphorsäure wird unter Rühren 10 min lang auf 80°C gehalten und anschließend in Eis¬ wasser eingerührt. Man extrahiert mit Ether, trocknet die Etherphase mit Na2SO4 und dampft anschließend ein. Der Rückstand wird in Methylen¬ chlorid gelöst. Man filtriert über eine kurze Kieselgel-Säule und dampft ein. Ausb. 10.2g (71% d.Th.), farbloses Öl.A mixture of 8.1 g (35.7 mmol) of 6- (4-chlorophenyl) hexanoic acid, 6.9 g (35.7 mmol) of ethyl 2-phenoxypropionate and 50 g of polyphosphoric acid is kept at 80 ° C. for 10 minutes with stirring and then in ice water stirred in. It is extracted with ether, the ether phase is dried with Na2SO4 and then evaporated. The residue is dissolved in methylene chloride. It is filtered through a short silica gel column and evaporated. Educ. 10.2g (71% of theory), colorless oil.
b) Titelverbindungb) Title link
Der Ester wird in Analogie zu Beispiel 1h) verseift und zum Schluß aus einem Cyclohexan-Toluol-Gemisch umkristallisiert. Ausb. 87% d.Th., Schmp. 74-76°C. Beispiel 6:The ester is saponified analogously to Example 1h) and finally recrystallized from a cyclohexane-toluene mixture. Educ. 87% of theory, mp. 74-76 ° C. Example 6:
Pharmakoiogischer TestPharmacological test
Methode: Terpentin-induzierte Hyperfibrinogenämie der RatteMethod: Turpentine-induced rat hyperfibrinogenemia
Die i.m.-Applikation von 0.05 ml Terpentin löst bei der Ratte einen dramatischen Anstieg des Plasmafibrinogens aus. Es handelt sich hierbei vermutlich um eine Akutphasenreaktion, in deren Folge Fibrinogen als Akutphasenprotein ansteigt.The i.m. application of 0.05 ml turpentine triggers a dramatic increase in plasma fibrinogen in the rat. This is probably an acute phase reaction, as a result of which fibrinogen increases as an acute phase protein.
250 - 300 g schweren Sprague-Dawley-Ratten (Züchter: IFFA-CREDO, Frankreich) werden 500 μl Blut aus der Schwanzvene entnommen und darin mittels der CLAUSS-Methode mit einem 2-Kanal-Coaguiometer (Biomatik 2000 Coagulometer, Fa. Sarstedt) die basale Plasma-Fibrinogenkonzentration bestimmt. Danach erhal¬ ten die Tiere 50 mg/kg der Prüfsubstanz p.o. (Standarddosierung) in 1 % Tylose- lösung. Zwei Stunden nach Applikation der Prüfsubstanz wird eine i.m.-Injektion von 0.05 ml Terpentin in eine Hinterextremität gesetzt. Weitere zwei Stunden nach Ter¬ pentin-Applikation wird die Prüfsubstanz erneut p.o. verabreicht, sowie nach 24 und 48 Stunden. 24 und 72 Stunden nach Terpentin-Applikation werden den Tieren 500 μl Blut aus der Schwanzvene entnommen und Fibrinogen bestimmt. Die gemesse¬ nen Fibrinogenwerte werden ermittelt, in Relation zu den Fibrinogenwerten einer mitgeführten Kontrollgruppe, die substanzfreie Tylose erhielt, gesetzt und als pro¬ zentuale Hemmung angegeben.250 - 300 g Sprague-Dawley rats (breeder: IFFA-CREDO, France) take 500 μl 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. 24 and 72 hours after turpentine application, 500 μl of blood are removed from the tail vein from the animals and fibrinogen is determined. The measured fibrinogen values are determined, set in relation to the fibrinogen values of a control group carried along, which received substance-free tylose, and stated as a percentage inhibition.
Ergebnisse:Results:
Die nachfolgenden Substanzen wurden mit dieser Methode auf ihre Wirksamkeit als Fibrinogensenker untersucht. Angegeben sind jeweils die Werte der Messung 24 Stunden nach Terpentingabe. Terpentin-induzierte HyperfibrinogenämieThe following substances were tested for their effectiveness as fibrinogen-lowering agents with this method. The values of the measurement are given 24 hours after adding turpentine. Turpentine-induced hyperfibrinogenemia
Verbindung der Ratte (% Hemmung nach 24 h) mit 50Connection of the rat (% inhibition after 24 h) to 50
Bsp. mg/kg SubstanzEg mg / kg substance
1 171 17
3 213 21
5 225 22
23 1923 19
31 1731 17
42 2242 22
Verqleichs- verbindung:Comparative connection:
Bezafibrat 13 Bezafibrate 13

Claims

PatentansprücheClaims
1. Verwendung von Phenolen und Phenolderivaten der allgemeinen Formel I1. Use of phenols and phenol derivatives of the general formula I
zur Herstellung von Arzneimitteln mit fibrinogensenkender Wirkung,for the production of drugs with a fibrinogen-lowering effect,
in derin the
R Wasserstoff oder ein bis drei Substituenten bedeutet, die unabhängig voneinander aus der Reihe Halogen, C..-C4-Alkyl, C^C^AIkoxy, Hy¬ droxy, Cyano oder Trifluormethyl ausgewählt sind,R is hydrogen or one to three substituents which are selected independently of one another from the series halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, hydroxy, cyano or trifluoromethyl,
B eine unsubstituierte oder gegebenenfalls durch ein oder zwei Methyl¬ gruppen in beliebiger Stellung substituierte, gesättigte oder unge¬ sättigte Alkylenkette mit bis zu sechs C-Atomen symbolisiert, wobei eines der gesättigten C-Atome ersetzt sein kann durch ein Sauer¬ stoffatom oder durch eine der Gruppen >NH, >C=O oder >CH-OH, und zwei benachbarte gesättigte C-Atome auch gemeinsam durch eine Gruppe -CONH- oder -NHCO- ersetzt sein können, undB symbolizes an unsubstituted or optionally substituted by one or two methyl groups in any position, saturated or unsaturated alkylene chain with up to six carbon atoms, it being possible for one of the saturated carbon atoms to be replaced by an oxygen atom or by one the groups> NH,> C = O or> CH-OH, and two adjacent saturated C atoms can also be replaced together by a group -CONH- or -NHCO-, and
X in meta- oder para-Stellung zu B steht und folgende Gruppen bedeutet:X is in the meta or para position to B and means the following groups:
eine Hydroxygruppe oder eine von dieser abgeleitete C..-C4-Alkylurethan- oder substituierte oder unsubstituierte Phenylurethangruppe,a hydroxy group or a C ..- C 4 -alkyl urethane or substituted or unsubstituted phenyl urethane group derived therefrom,
eine unverzweigte oder eine durch eine oder zwei Methyl¬ gruppen in beliebiger Stellung substituierte C^-Cg-Alkyloxy-, omega-Hydroxy-C2-Cg-alkyloxy-, omega-Halogen-C2-C6- alkyloxy oder omega-Cyano-C1 -Cg-alkyloxygruppe,a straight-chain or a C 1 -C 6 -alkyloxy- substituted by one or two methyl groups in any position, omega-hydroxy-C 2 -Cg-alkyloxy, omega-halogen-C2-C6-alkyloxy or omega-cyano-C 1 -Cg-alkyloxy group,
eine von der omega-Hydroxy-C2-Cg-alkyloxygruppe abgeleitete C|-C4-Alkylurethan-, substituierte oder unsubstituierte Phenyl- urethan-, Phosphorsäureester-, aliphatische Carbonsäureester¬ oder, gegebenenfalls substituierte, Benzoesäureestergruppie- rung,a C | derived from the omega-hydroxy-C 2 -Cg-alkyloxy group -C 4 -alkyl urethane, substituted or unsubstituted phenyl urethane, phosphoric acid ester, aliphatic carboxylic acid ester group or, optionally substituted, benzoic acid ester grouping,
eine Aminocarbonyl-C 1 -Cg-alkyloxy- oder eine N-Hydroxy- aminocarbonyl-C1 -Cg-alkyloxygruppean aminocarbonyl-C 1 -Cg-alkyloxy or an N-hydroxy-aminocarbonyl-C 1 -Cg-alkyloxy group
Carboxymethoxy, 1 -Carboxy-ethoxy, 1-Carboxy-propyloxy oder 3-Carboxy-propyloxyCarboxymethoxy, 1-carboxy-ethoxy, 1-carboxypropyloxy or 3-carboxypropyloxy
den Rest -0-C(CH3)2-CH2-0-C0-(CH2)2-COOHthe radical -0-C (CH 3 ) 2 -CH 2 -0-C0- (CH 2 ) 2 -COOH
den Benzoyloxyrest, der gegebenenfalls substituiert ist,the benzoyloxy radical, which is optionally substituted,
sowie deren Enantiomere, Diastereomere, Z- oder E-Isomere und gegebe¬ nenfalls deren physiologisch verträgliche Salze oder Ester.and their enantiomers, diastereomers, Z or E isomers and, where appropriate, their physiologically tolerable salts or esters.
Verwendung von Verbindungen der Formel I gemäß Anspruch 1 , dadurch gekennzeichnet, daß der Rest R in Bezug auf den Substituenten B 4- oder 3-Chlor, 4-Fluor, 4- oder 3Trifluormethyl, 4-Methyl, 4-Methoxy, 4-Cyano, 2,4diChlor oder 2-Methoxy-5-Chlor bedeutet.Use of compounds of the formula I according to claim 1, characterized in that the radical R is 4- or 3-chlorine, 4-fluorine, 4- or 3-trifluoromethyl, 4-methyl, 4-methoxy, 4-cyano with respect to the substituent B. , 2,4diChlor or 2-methoxy-5-chlorine means.
Verwendung von Verbindungen der Formel I gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß der Rest B die Gruppen -CONHCH2CH2-, -CH=CH-CO-, -CO-CH=CH-, -NHCH2-, CH2NH-, -CH2NHCH2-, >CHOH, -NHCO-, -CONH-, -NHCOCH2-, -CH2NHCO-, Carbonyl, unverzweigtes C.-Cg-Alkylen oder unverzweigtes C2-Ce-Alkylencarbonyl, insbesondere Ethylencarbonyl, Trimethylencarbonyl und Pentamethylencarbonyl, bedeutet. Verwendung von Verbindungen der Formel I gemäß einem der Ansprüche 1 , 2 oder 3, dadurch gekennzeichnet, daß der Rest X in para-Stellung zu B steht und Hydroxy, Carboxymethoxy, 1 -Carboxy-ethoxy, 1-Carboxy-propyloxy, 3-Carboxy-propyloxy, 2-Hydroxy-ethoxy, 3-Hydroxy-propyl-2-oxy, 3-Hydroxy- 2-methyl-propyl-2-oxy, Propyl-2-oxy und den Rest -0-C(CH3)2-CH2-0-CO- (CH2)2-COOH bedeutet.Use of compounds of the formula I according to claim 1 or 2, characterized in that the radical B has the groups -CONHCH 2 CH 2 -, -CH = CH-CO-, -CO-CH = CH-, -NHCH 2 -, CH 2 NH-, -CH 2 NHCH 2 -,> CHOH, -NHCO-, -CONH-, -NHCOCH 2 -, -CH 2 NHCO-, carbonyl, unbranched C.-Cg-alkylene or unbranched C 2 -C e - Alkylene carbonyl, especially ethylene carbonyl, trimethylene carbonyl and pentamethylene carbonyl. Use of compounds of formula I according to one of claims 1, 2 or 3, characterized in that the radical X is para to B and hydroxy, carboxymethoxy, 1-carboxy-ethoxy, 1-carboxy-propyloxy, 3-carboxy -propyloxy, 2-hydroxy-ethoxy, 3-hydroxypropyl-2-oxy, 3-hydroxy-2-methyl-propyl-2-oxy, propyl-2-oxy and the rest -0-C (CH3) 2- CH2-0-CO- (CH 2 ) 2 -COOH means.
5. Verwendung von Verbindungen der Formel I gemäß der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß R 4Chlor, 4Trifiuormethyl oder 4-Cyano be¬ deutet, B >CHOH, CONHCH2CH2-, Trimethylen, Trimethylencarbonyl oder Pentamethylencarbonyl ist, X in para-Stellung zu B steht und 1 -Carboxy- ethoxy, Propyl-2-oxy, 3-Hydroxy-propyl-2-oxy darstellt oder den Rest -0-C(CH3)2-CH2-0-C0-(CH2)2-COOH darstellt.5. Use of compounds of the formula I according to claims 1 to 4, characterized in that R denotes 4 chlorine, 4 trifluoromethyl or 4-cyano, B> CHOH, CONHCH 2 CH 2 -, trimethylene, trimethylene carbonyl or pentamethylene carbonyl, X in is para to B and represents 1-carboxyethoxy, propyl-2-oxy, 3-hydroxypropyl-2-oxy or the radical -0-C (CH 3 ) 2 -CH 2 -0-C0- ( CH 2 ) 2 represents -COOH.
Verwendung von Verbindungen der Formel I gemäß Anspruch 5, dadurch ge¬ kennzeichnet, daß R 4-Chlor bedeutet, X in para- Stellung zu B steht und der 1 -Carboxy-ethoxy bedeutet und B Trimethylen, Trimethylencarbonyl oder Pentamethylencarbonyl darstellt.Use of compounds of the formula I according to claim 5, characterized in that R is 4-chlorine, X is in the para position to B and 1 is carboxyethoxy and B is trimethylene, trimethylene carbonyl or pentamethylene carbonyl.
7. Phenole und Phenolderivate der allgemeinen Formel I7. Phenols and phenol derivatives of the general formula I
in derin the
Wasserstoff oder ein bis drei Substituenten bedeutet, die unabhängig voneinander aus der Reihe Halogen, C1-C4-Alkyl, C..-C4-Alkoxy, Hydroxy, Cyano oder Trifluormethyl ausgewählt sind, B eine unsubstituierte oder gegebenenfalls durch ein oder zwei Methyl¬ gruppen in beliebiger Stellung substituierte, gesättigte oder ungesät¬ tigte Alkyienkette mit bis zu sechs C-Atomen symbolisiert, wobei eines der gesättigten C-Atome ersetzt sein kann durch ein Sauerstoffatom oder durch eine der Gruppen >NH, >C=O oder >CH-OH, und zwei be¬ nachbarte gesättigte C-Atome auch gemeinsam durch eine Gruppe -CONH- oder -NHCO- ersetzt sein können, undIs hydrogen or one to three substituents which are selected independently of one another from the series halogen, C 1 -C 4 -alkyl, C ..- C 4 -alkoxy, hydroxy, cyano or trifluoromethyl, B symbolizes an unsubstituted or optionally substituted by one or two methyl groups in any position, saturated or unsaturated alkyl chain with up to six carbon atoms, it being possible for one of the saturated carbon atoms to be replaced by an oxygen atom or by one of the groups >NH,> C = O or> CH-OH, and two neighboring saturated C atoms can also be replaced together by a group -CONH- or -NHCO-, and
X in meta- oder para-Stellung zu B steht und folgende Gruppen bedeutet:X is in the meta or para position to B and means the following groups:
eine Hydroxygruppe oder eine von dieser abgeleitete C..-C4-Alkylurethan- oder substituierte oder unsubstituierte Phenylurethangruppe,a hydroxy group or a C ..- C 4 -alkyl urethane or substituted or unsubstituted phenyl urethane group derived therefrom,
eine unverzweigte oder eine durch eine oder zwei Methylgrup¬ pen in beliebiger Stellung substituierte C^Cg-Alkyloxy-, omega-Hydroxy-C2Cg- alkyloxy-, omega-Halogen-C2-C6- alkyloxy oder omega-Cyano-C| -Cg-alkyloxygruppe,a straight-chain or a C 1 -C 6 -alkyloxy-, omega-hydroxy-C 2 Cg-alkyloxy-, omega-halogen-C2-C6-alkyloxy or omega-cyano-C | substituted by one or two methyl groups in any position -Cg alkyloxy group,
eine von der omega-Hydroxy-C2-Cg-alkyloxygruppe abgeleitete C..-C4-Alkylurethan-, substituierte oder unsubstituierte Phenyl- urethan-, Phosphorsäureester-, aliphatische Carbonsäureester¬ oder, gegebenenfalls substituierte, Benzoesäureestergruppie- rung,a C ..- C 4 -alkyl urethane derived from the omega-hydroxy-C 2 -Cg-alkyloxy group, substituted or unsubstituted phenylurethane, phosphoric acid ester, aliphatic carboxylic acid ester group or, optionally substituted, benzoic acid ester grouping,
eine Aminocarbonyl-C-.-Cg-alkyloxy- oder eine N-Hydroxy- aminocarbonyl-C^ -Cg-alkyloxygruppean aminocarbonyl-C-. Cg-alkyloxy or an N-hydroxy-aminocarbonyl-C ^ -Cg-alkyloxy group
Carboxymethoxy, 1 -Carboxy-ethoxy, 1-Carboxy-propyloxy oder 3-Carboxy-propyloxyCarboxymethoxy, 1-carboxy-ethoxy, 1-carboxypropyloxy or 3-carboxypropyloxy
den Rest -0-C(CH3)2-CH2-0-C0-(CH2)2-C00Hthe balance -0-C (CH 3 ) 2 -CH 2 -0-C0- (CH 2 ) 2 -C00H
den Benzoyloxyrest, der gegebenenfalls subsituiert ist, mit Ausnahme der Verbindungen, in denenthe benzoyloxy radical, which is optionally substituted, with the exception of the connections in which
a) B die Gruppe -CONHCH2CH2~ bedeutet. R das Chloratom in para-Stellung ist, X in para-Stellung die Hydroxygruppe, Car- boxymethoxy, 1 -Carboxy-propyloxy oder der pChlorbenzoyioxy- rest ist,a) B means 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 chlorobenzoyioxy radical,
b) R Wasserstoff und X in para-Stellung die Hydroxygruppe ist, während B die Gruppe CONHCH2CH2- bedeutet,b) R is hydrogen and X in the para position is the hydroxyl group, while B is the group CONHCH 2 CH 2 -,
c) R das Chloratom in para-Stellung ist, B die Trimethylengruppe bedeutet und X in para-Stellung die Hydroxygruppe darstellt,c) R is the chlorine atom in the para position, B represents the trimethylene group and X represents the hydroxy group in the para position,
d) X in para-Stellung der 1-Carboxy-ethoxy-Rest und R in para-Stellung das Chloratom ist, während B die Methylen-, Carbonyl- oder Aminomethylengruppe ist,d) X in the para position is the 1-carboxyethoxy radical and R in the para position is the chlorine atom, while B is the methylene, carbonyl or aminomethylene group,
e) X in para-Stellung den 3-Hydroxy-propyl-2-oxy-rest bedeutet, R in para-Stellung das Chloratom ist und B die Gruppe >CHOH bedeutet,e) X in the para position is the 3-hydroxypropyl-2-oxy radical, R in the para position is the chlorine atom and B is the group> CHOH,
sowie deren Enantiomere, Diastereomere, E- oder Z-Isomere und gegebe¬ nenfalls deren physiologisch verträgliche Salze oder Ester.and their enantiomers, diastereomers, E or Z isomers and, where appropriate, their physiologically tolerable salts or esters.
8. Arzneimittel enthaltend neben pharmazeutischen Hilfs- oder Trägerstoffen mindestens ein Phenol oder Phenolderivat der allgemeinen Formel I gemäß Anspruch 7.8. Medicaments containing, in addition to pharmaceutical auxiliaries or carriers, at least one phenol or phenol derivative of the general formula I according to claim 7.
Verwendung von Phenolen oder Phenolderivaten der allgemeinen Formel gemäß Anspruch 7 zur Herstellung von Arzneimitteln zur Behandlung von cardiovaskulären Erkrankungen. 10. Verwendung von Phenolen oder Phenolderivaten gemäß Anspruch 9 zurUse of phenols or phenol derivatives of the general formula according to claim 7 for the manufacture of medicaments for the treatment of cardiovascular diseases. 10. Use of phenols or phenol derivatives according to claim 9 for
Herstellung von Arzneimitteln zur Behandlung der peripheren arteriellen Ver¬ schlußkrankheit, der coronaren Herzkrankheit und von cerebralen Durchblu¬ tungsstörungen. Production of medicaments for the treatment of peripheral arterial occlusive disease, coronary heart disease and cerebral circulatory disorders.
EP94926836A 1993-08-14 1994-08-13 Use of phenols and phenol derivates as medicaments with fibrinogen-reducing effect Withdrawn EP0712388A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4327365 1993-08-14
DE4327365A DE4327365A1 (en) 1993-08-14 1993-08-14 Use of phenols and phenol derivatives as drugs with a fibrinogen-lowering effect
PCT/EP1994/002709 WO1995005358A1 (en) 1993-08-14 1994-08-13 Use of phenols and phenol derivates as medicaments with fibrinogen-reducing effect

Publications (1)

Publication Number Publication Date
EP0712388A1 true EP0712388A1 (en) 1996-05-22

Family

ID=6495210

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94926836A Withdrawn EP0712388A1 (en) 1993-08-14 1994-08-13 Use of phenols and phenol derivates as medicaments with fibrinogen-reducing effect

Country Status (6)

Country Link
EP (1) EP0712388A1 (en)
JP (1) JPH09501670A (en)
AU (1) AU7653394A (en)
CA (1) CA2169187A1 (en)
DE (1) DE4327365A1 (en)
WO (1) WO1995005358A1 (en)

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0666840A1 (en) * 1993-08-30 1995-08-16 Otsuka Pharmaceutical Co., Ltd. Benzylamine derivatives
FR2713637B1 (en) * 1993-12-15 1996-01-05 Cird Galderma New bi-aromatic compounds derived from amide, pharmaceutical and cosmetic compositions containing them and uses.
US5883294A (en) * 1997-06-18 1999-03-16 The Regeants Of The University Of California Selective thyroid hormone analogs
EP0947511A1 (en) * 1998-03-30 1999-10-06 F. Hoffmann-La Roche Ag Derivatives of phenoxy acetic acid and of phenoxymethyl tetrazole having antitumor activity
CA2384511A1 (en) * 1999-08-24 2001-03-01 Virginia Commonwealth University Substituted chiral allosteric hemoglobin modifiers
EP1246792B1 (en) * 2000-01-13 2014-08-13 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
GB0023983D0 (en) * 2000-09-29 2000-11-15 Prolifix Ltd Therapeutic compounds
ES2257441T3 (en) 2000-09-29 2006-08-01 Topotarget Uk Limited CARBON ACID COMPOUNDS THAT INCLUDE AN AMINO LINK AS HDAC INHIBITORS.
FR2841784B1 (en) * 2002-07-08 2007-03-02 COMPOSITION BASED ON SUBSTITUTED 1,3-DIPHENYLPROP-2EN-1-ONE DERIVATIVES, PREPARATION AND USES
FR2841900B1 (en) * 2002-07-08 2007-03-02 Genfit S A NOVEL SUBSTITUTED 1,3-DIPHENYLPROP-2-EN-1-ONE DERIVATIVES, PREPARATION AND USES
EP1611088B1 (en) 2003-04-07 2009-06-17 Pharmacyclics, Inc. Hydroxamates as therapeutic agents
JP2007517841A (en) 2004-01-08 2007-07-05 ジェンフィット 1,3-diphenylprop-2-en-1-one derivative compound, process for its preparation and use thereof
FR2864956B1 (en) * 2004-01-08 2006-04-28 Genfit S A DERIVED COMPOUND OF 1,3-DIPHENYLPROP-2-EN-1-ONE, PREPARATION AND USES
FR2875805B1 (en) * 2004-09-27 2006-12-29 Genfit S A SUBSTITUTED N- (BENZYL) PHENYLACETAMIDE DERIVATIVE COMPOUNDS, PREPARATION AND USES
US7737164B2 (en) 2006-05-18 2010-06-15 Wisconsin Alumni Research Foundation Cyanopyridine antibacterial agents
FR2902789A1 (en) 2006-06-21 2007-12-28 Genfit Sa SUBSTITUTED 1,3-DIPHENYLPROPANE DERIVATIVES, PREPARATIONS AND USES
RU2446796C2 (en) 2006-12-26 2012-04-10 Фармасайкликс, Инк. Method for using histone deacetylase and biomarker monitoring in combined therapy
CA2677000A1 (en) 2007-01-30 2008-08-07 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
MX365393B (en) 2011-09-13 2019-05-31 Pharmacyclics Llc Formulations of histone deacetylase inhibitor in combination with bendamustine and uses thereof.
TWI649081B (en) 2013-08-02 2019-02-01 製藥公司 Method for treating solid tumors

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2149070C3 (en) * 1971-10-01 1978-03-23 Boehringer Mannheim Gmbh, 6800 Mannheim Phenoxyalkylcarboxylic acid derivatives and their salts, processes for their production and pharmaceuticals
DE2432560A1 (en) * 1974-07-06 1976-01-22 Boehringer Mannheim Gmbh 2-(4-Carbaniloyl-alkyl) phenoxy) alkanoic acid derivs - prepd. e.g. by reacting 4-(carboxyalkyl) phenols with anilines and 2-halo-alkanoic acid derivs
JPS518228A (en) * 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 (en) * 1975-09-17 1977-03-31 Boehringer Mannheim Gmbh NEW PHENOXYALKYLCARBONIC ACIDS AND METHOD FOR PREPARING THE SAME
CH630879A5 (en) * 1977-08-29 1982-07-15 Siegfried Ag METHOD FOR PRODUCING LIPID-REDUCING ALKYLENE GLYCOLE DERIVATIVES.
EP0002408A1 (en) * 1977-11-26 1979-06-13 SOCIETE DE RECHERCHES INDUSTRIELLES S.O.R.I. Société anonyme dite: Substituted phenoxyalkanols, their preparation and their use as therapeutic agents
CA2020888A1 (en) * 1989-07-27 1991-01-28 Philippe Guerry Substituted aminoalkoxybenzene derivatives

Non-Patent Citations (1)

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

Also Published As

Publication number Publication date
AU7653394A (en) 1995-03-14
JPH09501670A (en) 1997-02-18
DE4327365A1 (en) 1995-02-16
WO1995005358A1 (en) 1995-02-23
CA2169187A1 (en) 1995-02-23

Similar Documents

Publication Publication Date Title
WO1995005358A1 (en) Use of phenols and phenol derivates as medicaments with fibrinogen-reducing effect
EP1216225B1 (en) Novel derivatives of dicarboxylic acid having pharmaceutical properties
US7319163B2 (en) Thyroid receptor antagonists for the treatment of cardiac and metabolic disorders
US4278680A (en) Hypoglycaemically and hypolipidaemically active derivatives of phenylacetic acid
DE10110749A1 (en) Substituted aminodicarboxylic acid derivatives
DE10110750A1 (en) Novel aminodicarboxylic acid derivatives with pharmaceutical properties
EP1216223A1 (en) Novel dicarboxylic acid derivatives with pharmaceutical properties
WO2001019776A2 (en) Novel derivatives of dicarboxylic acid having pharmaceutical properties
EP0600949A1 (en) New 3,5-di-tert.butyl-4-hydroxyphenyl derivatives, methods of preparing them and drugs containing them.
JP2012515177A (en) New eicosanoid derivatives
EP0124791A1 (en) Aralkanamidophenyl compounds
DE4219158A1 (en) Biphenyl derivatives, pharmaceutical compositions containing them and processes for their preparation
EP1368301B1 (en) Side-chain halogenated amino carboxylic acid derivatives as medicaments for treating cardiovascular diseases
DE10046029A1 (en) indazoles
WO2002016312A2 (en) Novel compounds inhibiting factor xa activity
EP0090369B1 (en) Salicylic-acid derivatives, process for their preparation, pharmaceutical preparations based on these compounds and their use
DE69911726T2 (en) Derivatives of arylcarboxylic acids and tetrazoles having a carbamoyloxy group
DE69014798T2 (en) THIONAPHTHALENE DERIVATIVES, METHOD FOR THE PRODUCTION AND ANTIALLERGIC MEANS THEREOF.
DE3306146A1 (en) PYRIDINE DERIVATIVES AND THEIR USE AS MEDICINAL PRODUCTS
EP0133935A2 (en) p-oxybenzoic acid derivatives, methods for preparing them, and their use for the preparation of medicaments with hypolipemic activity
JP2509286B2 (en) Substituted biphenyl derivative
EP1803452A1 (en) Ester derivative and pharmaceutical use thereof
DE69507254T2 (en) Bicyclic compounds to inhibit platelet aggregation
DE602004011064T2 (en) ANTIBROMOTIC AETHER
JP2000507562A (en) Dimethyl-substituted cyclohexanediene derivatives

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19960314

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU NL PT SE

17Q First examination report despatched

Effective date: 19970220

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19970903