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DE4327365A1 - Use of phenols and phenol derivatives as drugs with a fibrinogen-lowering effect - Google Patents

Use of phenols and phenol derivatives as drugs with a fibrinogen-lowering effect

Info

Publication number
DE4327365A1
DE4327365A1 DE4327365A DE4327365A DE4327365A1 DE 4327365 A1 DE4327365 A1 DE 4327365A1 DE 4327365 A DE4327365 A DE 4327365A DE 4327365 A DE4327365 A DE 4327365A DE 4327365 A1 DE4327365 A1 DE 4327365A1
Authority
DE
Germany
Prior art keywords
group
hydroxy
alkyloxy
carbonyl
para position
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Withdrawn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
DE4327365A
Other languages
German (de)
Inventor
Ernst-Christian Dipl Che Witte
Karlheinz Dipl Chem Stegmeier
Liesel Dr 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
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 Boehringer Mannheim GmbH filed Critical Boehringer Mannheim GmbH
Priority to DE4327365A priority Critical patent/DE4327365A1/en
Priority to AU76533/94A priority patent/AU7653394A/en
Priority to JP7506754A priority patent/JPH09501670A/en
Priority to PCT/EP1994/002709 priority patent/WO1995005358A1/en
Priority to CA002169187A priority patent/CA2169187A1/en
Priority to EP94926836A priority patent/EP0712388A1/en
Publication of DE4327365A1 publication Critical patent/DE4327365A1/en
Withdrawn legal-status Critical Current

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    • 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
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    • 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
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    • 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
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    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • 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
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    • 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
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    • 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
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    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • 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
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    • C07C255/00—Carboxylic acid nitriles
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    • 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
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
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    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
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    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—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
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    • 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
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    • 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
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    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
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Description

Die vorliegende Erfindung betrifft die neue Verwendung von Phenolen und Phenolderivaten zur Herstellung von Arzneimitteln mit fibrinogensenkender Wirkung. Gegenstand der Erfindung sind außerdem neue Phenole und Phenolderivate, Verfahren zu deren Herstellung und Arzneimittel, die diese Verbindungen enthal­ ten.The present invention relates to the new use of Phenols and phenol derivatives for the manufacture of pharmaceuticals with fibrinogen-lowering effect. The subject of the invention are also new phenols and phenol derivatives, processes for their Manufacture and pharmaceuticals containing these compounds ten.

Die Erfindung betrifft die Verwendung von Phenolen und Phenol­ derivaten 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,
in welcher
R Wasserstoff oder ein bis drei Substituenten bedeutet, die unabhängig voneinander aus der Reihe Halogen, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, Hydroxy, Cyano oder Trifluormethyl ausge­ wählt sind,
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, und
X in meta- oder para-Stellung zu B steht und folgende Gruppen bedeutet:for the production of drugs with a fibrinogen-lowering effect,
in which
R is hydrogen or one to three substituents which are independently selected from the group consisting of halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, hydroxy, cyano or trifluoromethyl,
B 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 adjacent saturated C atoms can also be replaced together by a group -CONH- or -NHCO-, and
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 unsubsti­ tuierte Phenylurethangruppe,- A hydroxy group or one derived therefrom C₁-C₄ alkyl urethane or substituted or unsubsti tuated phenyl urethane group,
  • - eine unverzweigte oder eine durch eine oder zwei Methylgruppen in beliebiger Stellung substituierte C₁-C₆-Alkyloxy-, omega-Hydroxy-C₂-C₆-alkyloxy-, omega-Halogen-C₂-C₆-alkyloxy oder omega-Cyano-C₁-C₆- alkyloxygruppe,- one unbranched or one by one or two Methyl groups substituted in any position C₁-C₆-alkyloxy-, omega-hydroxy-C₂-C₆-alkyloxy-, omega-halogen-C₂-C₆-alkyloxy or omega-cyano-C₁-C₆- alkyloxy group,
  • - eine von der omega-Hydroxy-C₂-C₆-alkyloxygruppe abgeleitete C₁-C₄-Alkylurethan-, substituierte oder unsubstituierte Phenylurethan-, Phosphorsäureester-, aliphatische Carbonsäureester- oder, gegebenenfalls substituierte, Benzoesäureestergruppierung,- One of the omega-hydroxy-C₂-C₆-alkyloxy group derived C₁-C₄ alkyl urethane, substituted or unsubstituted phenyl urethane, phosphoric acid ester, aliphatic carboxylic acid ester or, optionally substituted, benzoic acid ester grouping,
  • - eine Aminocarbonly-C₁-C₆-alkyloxy- oder eine N- Hydroxy-aminocarbonyl-C₁-C₆-alkyloxygruppe- an aminocarbonly-C₁-C₆-alkyloxy or an N- Hydroxy-aminocarbonyl-C₁-C₆-alkyloxy group
  • - Carboxymethoxy, 1-Carboxy-ethoxy, 1-Carboxy-propyloxy oder 3-Carboxy-propyloxy - carboxymethoxy, 1-carboxy-ethoxy, 1-carboxypropyloxy or 3-carboxypropyloxy  
  • - den Rest -O-C(CH₃)₂-CH₂-O-CO-(CH₂)₂-COOH- The rest -O-C (CH₃) ₂-CH₂-O-CO- (CH₂) ₂-COOH
  • - den Benzoyloxyrest, der gegebenenfalls substituiert ist,- The benzoyloxy radical, which is optionally substituted is

sowie deren Enantiomere, Diastereomere, Z- oder E-Isomere und gegebenenfalls deren physiologisch verträgliche Salze oder Ester.and their enantiomers, diastereomers, Z or E isomers and optionally their physiologically tolerable salts or esters.

R bedeutet ein bis drei Substituenten, die unabhängig voneinan­ der gleich oder verschieden sind und sich zum Substituenten B in beliebiger Stellung am Benzolring befinden. In der Defini­ tion von R bedeutet Halogen Fluor, Chlor, Brom und Jod, wobei Chlor bevorzugt ist. C₁-C₄-Alkyl oder -Alkoxy beinhaltet einen geradkettigen oder verzweigten Alkylrest mit 1-4 C-Atomen, wobei Methyl und Isopropyl bevorzugt sind.R represents one to three substituents which are independent of one another which are the same or different and are substituted by the substituent B in any position on the benzene ring. In the defini tion of R means fluorine, chlorine, bromine and iodine, where Chlorine is preferred. C₁-C₄ alkyl or alkoxy includes one straight-chain or branched alkyl radical with 1-4 C atoms, methyl and isopropyl are preferred.

Für B sind unverzweigte Alkylenketten mit 2-6 C-Atomen bevor­ zugt, 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-Stel­ lung zu dem Phenoxy-Sauerstoff der Gruppe X. Gleiches gilt für die bevorzugte Position einer einzelnen Carbonylgruppe <C=O bzw. für eine sek. Alkoholgruppe <CH-OH. Für den Fall jedoch, daß <C=O bzw. <CH-OH Teil einer Kette B aus drei Kohlenstoff­ atomen ist, stehen diese Gruppen bevorzugt in alpha-Stellung zu einem der beiden Benzolringe.For B there are unbranched alkylene chains with 2-6 C atoms moves, whereby one of the saturated carbon atoms can be replaced by an oxygen atom or by one of the groups -NH, <CO or <CH-OH. However, two adjacent saturated C- Atoms can be replaced together by a group -CONH- or -NHCO-. In the event that a carbon atom is replaced by an oxygen atom is replaced, the oxygen atom is preferably in para position to the phenoxy oxygen of group X. The same applies to the preferred position of a single carbonyl group <C = O or for a sec. Alcohol group <CH-OH. In the event, however, that <C = O or <CH-OH part of a chain B of three carbon atoms, these groups are preferably in the alpha position 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=CH-CO- bevorzugt ("Chalkone"). There are no preferences for the position of amino or Carbonylamino groups. Among the compounds with unsaturated Group B are in particular the groups -CO-CH = CH- and -CH = CH-CO- preferred ("chalcones").  

Als Verbindungen, die als Bestandteil der Gruppe B neben einer Doppelbindung eine Carbonylaminogruppe tragen, sind die Zimt­ säureamide mit den Resten -CH=CH-CONH- und -NHCO-CH=CH- bevor­ zugt.As compounds that are part of group B in addition to a Cinnamon is a double bond with a carbonylamino group acid amides with the residues -CH = CH-CONH- and -NHCO-CH = CH- before moves.

Der Substituent x steht in meta- oder para-Stellung zum Substi­ tuenten B. C₁-C₆-Alkyloxy für den Substituenten x bedeutet eine geradkettige oder verzweigte Alkyloxykette, vorzugsweise Methoxy, Ethoxy und n-Butyloxy.The substituent x is in the meta or para position to the substituent tuenten B. C₁-C₆-alkyloxy for the substituent x means one straight-chain or branched alkyloxy chain, preferably Methoxy, ethoxy and n-butyloxy.

Besonders bevorzugt sind folgende Alkoxy-Gruppen, die am endständigen C-Atom durch eine Hydroxy-, Halogen- oder Cyangruppe substituiert sind: a) omega-Hydroxy-C₂-C₆-alkyloxy, b) omega-Halogen-C₂-C₆-alkyloxy und c) omega-Cyano-C₁-C₆- alkyloxy oder/und an dem dem Ethersauerstoff benachbarten C- Atom eine oder zwei Methylgruppen tragen. Omega-Hydroxy-C₂-C₆- alkyloxy bedeutet vorzugsweise 2-Hydroxy-ethoxy, 4-Hydroxy­ butoxy, 3-Hydroxy-2-propoxy oder 3-Hydroxy-2-methyl-2-propoxy. Omega-Halogen-C₂-C₆-alkyloxy bedeutet bevorzugt omega-Chlor-C₂- C₆-alkyloxy, und hier insbesondere 2-Chlor-ethoxy- und 4-Chlor­ butoxy. Omega-Cyano-C₁-C₆-alkyloxy bedeutet bevorzugt Cyanmethyloxy- und 5-Cyano-pentyloxy.The following alkoxy groups, which are most preferred terminal C atom by a hydroxy, halogen or Cyano group are substituted: a) omega-hydroxy-C₂-C₆-alkyloxy, b) omega-halogen-C₂-C₆-alkyloxy and c) omega-cyano-C₁-C₆- alkyloxy or / and at the C- adjacent to the ether oxygen Atomic carry one or two methyl groups. Omega-hydroxy-C₂-C₆- alkyloxy preferably means 2-hydroxy-ethoxy, 4-hydroxy butoxy, 3-hydroxy-2-propoxy or 3-hydroxy-2-methyl-2-propoxy. Omega-halogen-C₂-C₆-alkyloxy preferably means omega-chlorine-C₂- C₆-alkyloxy, and in particular 2-chloro-ethoxy and 4-chloro butoxy. Omega-cyano-C₁-C₆-alkyloxy means preferred Cyanomethyloxy and 5-cyano-pentyloxy.

Umfaßt die Gruppe X eine C₁-C₄-Alkylurethangruppe, so kann die Alkylgruppe geradkettig 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.If the group X comprises a C₁-C₄-alkyl urethane group, the Alkyl group can be straight-chain or branched. Are preferred Methyl, ethyl and t-butyl urethane. The phenyl residue in Phenyl urethane can be unsubstituted or halogenated, preferably chlorine, in the 3- or 4-position.

Umfaßt der Substituent X einen Benzoesäureesterrest, so ist der Phenylrest gegebenenfalls 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 substituiert sein, vorzugsweise durch Halogen. If the substituent X comprises a benzoic acid ester residue, then the Phenyl radical optionally substituted one or more times, preferably with halogen, methoxy or methyl. As an aliphatic Carboxylic ester residues are preferably those of acetic acid, Propionic acid or n- or iso-butyric acid in question. Means X the benzoyloxy radical, this can optionally in meta- or para position may be substituted, preferably by halogen.  

Besonders bevorzugte Reste R sind 4- oder 3-Chlor, 4-Fluor, 4- oder 3-Trifluormethyl, 4-Methyl, 4-Methoxy, 4-Cyano, 2,4-di- Chlor und 2-Methoxy-5-Chlor.Particularly preferred radicals R are 4- or 3-chloro, 4-fluorine, 4- or 3-trifluoromethyl, 4-methyl, 4-methoxy, 4-cyano, 2,4-di- Chlorine and 2-methoxy-5-chlorine.

Besonders bevorzugte Reste B sind -CONHCH₂CH2-, -CH=CH-CO-, -CO-CH=CH-, -NHCH₂-, -CH₂NH-, -CH₂NHCH₂-, <CHOH, -NHCO-, -CONH-, NHCOCH₂-, -CH₂NHCO-, Carbonyl, unverzweigtes C₁-C₆-Alkylen oder unverzweigtes C₂-C₅-Alkylencarbonyl, insbesondere Ethylencarbonyl, Trimethylencarbonyl und Pentamethylencarbonyl.Particularly preferred radicals B are -CONHCH₂CH2-, -CH = CH-CO-, -CO-CH = CH-, -NHCH₂-, -CH₂NH-, -CH₂NHCH₂-, <CHOH, -NHCO-, -CONH-, NHCOCH₂-, -CH₂NHCO-, carbonyl, unbranched C₁-C₆ alkylene or unbranched C₂-C₅ alkylene carbonyl, in particular Ethylene carbonyl, trimethylene carbonyl and pentamethylene carbonyl.

Bevorzugte Reste X stehen in para-Stellung zu B und sind 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 der Rest -O-C(CH₃)₂-CH₂-O-CO-(CH₂)₂-COOH.Preferred radicals X are in the para position to B and are Hydroxy, carboxymethoxy, 1-carboxy-ethoxy, 1-carboxypropyloxy, 3-carboxypropyloxy, 2-hydroxy-ethoxy, 3-hydroxypropyl-2-oxy, 3-hydroxy-2-methyl-propyl-2-oxy, propyl-2-oxy and the rest -O-C (CH₃) ₂-CH₂-O-CO- (CH₂) ₂-COOH.

Insbesondere bevorzugt sind Verbindungen der allgemeinen Formel I, in denen R 4-Chlor, 4-Trifluormethyl oder 4-Cyano bedeutet, B <CHOH, -CONHCH₂CH₂-, Trimethylen, Trimethylen­ carbonyl 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 -O-C(CH₃)₂-CH₂-O-CO- (CH₂)₂-COOH darstellt.Compounds of the general are particularly preferred Formula I in which R is 4-chloro, 4-trifluoromethyl or 4-cyano means, B <CHOH, -CONHCH₂CH₂-, trimethylene, trimethylene is carbonyl or pentamethylene carbonyl, X is in the para position B stands and 1-carboxy-ethoxy, propyl-2-oxy, 3-hydroxypropyl-2- represents oxy or the radical -O-C (CH₃) ₂-CH₂-O-CO- (CH₂) ₂-COOH.

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 para to B stands and 1-carboxy-ethoxy and B means trimethylene, Represents trimethylene carbonyl or pentamethylene carbonyl.

Gegenstand der vorliegenden Erfindung sind auch neue unter die Formel I fallende Phenole und Phenolderivate. The present invention also relates to new ones Formula I falling phenols and phenol derivatives.  

In der Literatur sind bereits unter die Formel I fallende Verbindungen beschrieben,
in denenCompounds falling under formula I have already been described in the literature,
in 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 -CONHCH₂CH₂-, R is the chlorine atom in is para position, X in para position is the hydroxy group, Carboxymethoxy, 1-carboxypropyloxy or the is p-chlorobenzoyloxy,
  • 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 hydroxy group is while B is the group -CONHCH₂CH₂-,
  • 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 is the Trimethylene group means and X in para position Represents hydroxyl group,
  • 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 of the 1-carboxy-ethoxy radical and R in para is the chlorine atom, while B is the methylene, Is carbonyl or aminomethylene group,
  • e) X in para-Stellung den 3-Hydroxy-propyl-2-oxy-rest bedeu­ tet, R in para-Stellung das Chloratom ist und B die Gruppe <CHOH bedeutet.e) X in the para position means the 3-hydroxypropyl-2-oxy radical tet, R in the para position is the chlorine atom and B the group <CHOH means.

So wird die Verbindung mit R = H, B = -CONHCH₂CH₂- und X = 4-OH im Zusammenhang mit Phosphomonoesterase-Hemmung von Aso und Murakoshi in den Symposia on Enzyme Chem. 8, 64-65 (1953) (Jap.) genannt. Andere Arbeiten beschreiben 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 21 49 070 als Vorstufe für die Herstellung lipidsenkender Substanzen beschrieben. So the connection with R = H, B = -CONHCH₂CH₂- and X = 4-OH related to Aso and phosphomonoesterase inhibition Murakoshi in the Symposia on Enzyme Chem. 8, 64-65 (1953) Called (Jap.). Other works describe their use as Starting material or as a reaction component. It will too like the compound with R = Cl, B = -CONHCH₂CH₂- and X = 4-OH e.g. B. in DE-OS 21 49 070 as a preliminary stage for the production described lipid-lowering substances.  

Die Verbindung mit R = 4-Cl, B = -CONHCH₂CH₂- und X = 4-OCH₂- COOH ist ebenfalls Gegenstand der DE-OS 21 49 070. Sie gehört zu einer Reihe sowohl die Serumlipide als auch die Cholesterin­ spiegel senkender Substanzen, die z. B. gegen Atherosclerosis wirksam sind.The connection with R = 4-Cl, B = -CONHCH₂CH₂- and X = 4-OCH₂- COOH is also the subject of DE-OS 21 49 070. It belongs to a number of both serum lipids and cholesterol mirror-lowering substances that z. B. against atherosclerosis are effective.

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. Co., Ltd., J. Med. Chem. 31, 1205-9 (1988)). Sie erwies sich als Hemmstoff für Pilzwachstum (Bultman et al., CA 89 : 85 632), als antimikrobielles Agens (Jurd et al., US 39 15 889, CA 84 : 39 706; Jurd et al., US 38 67 548, CA 83 : 23 435; Jurd et al., US 37 75 541, CA 81 : 22 227d; 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 = - (CH₂) ₃- and X = 4-OH served as Starting material for the synthesis of lipid-lowering compounds of the "fibrate" type (Kyushin Pharm. Co., Ltd., J. Med. Chem. 31, 1205-9 (1988)). It proved to be an inhibitor of fungal growth (Bultman et al., CA 89: 85 632) as an antimicrobial agent (Jurd et al., US 39 15 889, CA 84: 39 706; Jurd et al., US 38 67 548, CA 83: 23,435; Jurd et al., US 37 75 541, CA 81: 22 227d; King et al., Antimicrobial. Agents chemother. 1, 263-7 (1972); Jurd et al., J. Pharm. Sci. 60, 1753-5 (1971); as an inhibitor of algae growth Substance (Chan and Jurd, Experientia 29, 1196-7 (1973)), and as Sporostaticum (LeWis and Jurd, Spores 5, 384-9 (1972)).

Es wurde nun gefunden, daß die Verbindungen der Formel I hoch­ wirksame Substanzen sind, die die Fibrinogenkonzentration im Blut vermindern, was vor allem zur Behandlung von cardiovaskulären Erkrankungen wie der peripheren arteriellen Verschlußkrankheit, der coronaren Herzkrankheit und von cerebralen Durchblutungsstörungen von Bedeutung ist.It has now been found that the compounds of the formula I are high are effective substances that the fibrinogen concentration in Decrease blood, which is mainly for the treatment of cardiovascular diseases such as peripheral arterial Occlusive disease, coronary artery disease and cerebral circulatory disorders is important.

Die Auswertung epidemiologischer Studien machte deutlich, daß erhöhte Plasma-Fibrinogenspiegel beim Menschen mit einem deut­ lich 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 akkumulier­ tes Fibrinogen soll die Proliferation glatter Muskelzellen fördern (Naito et al, Atherosclerosis 83 (1990), 9) und die Einlagerung von LDL und anderen Lipiden beschleunigen (Smith, Eur. Heart J. 11 (1990), 72). Die wichtigsten rheologischen Faktoren der Mikrozirkulation sind die fibrinogenabhängigen Parameter 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 Blutfließeigenschaften und damit eine Steigerung der Mikro­ zirkulation mit verbesserter Sauerstoffabgabe.The evaluation of epidemiological studies made it clear that increased plasma fibrinogen levels in humans with a noticeable increased risk of developing coronary artery disease fall ill, are linked. High fibrinogen levels apply Different ways of atheroma formation in: By increasing the Plasma viscosity, as a cofactor in platelet aggregation, by influencing the amount of fibrin that is deposited when the coagulation is initiated. Accumulate in the artery wall fibrinogen is said to proliferate smooth muscle cells promote (Naito et al, Atherosclerosis 83 (1990), 9) and the  Accelerate storage of LDL and other lipids (Smith, Eur. Heart J. 11 (1990), 72). The main rheological Microcirculation factors are fibrinogen dependent Plasma viscosity and erythrocyte aggregation parameters. Height Concentrations of fibrinogen (and other protein fractions) lead to an enormous increase in plasma viscosity and Red cell aggregation. A therapeutic lowering of the Plasma fibrinogen levels mean a significant improvement the blood flow properties and thus an increase in the micro circulation with improved oxygen release.

Die Verbindungen der Formel I besitzen eine ausgeprägte fibri­ nogensenkende Wirkung, die der des als fibrinogensenkend be­ schriebenen Bezafibrats (Cook et al., TIPS Reviews 11 (1990), 450) überlegen ist.The compounds of formula I have a pronounced fibri narcotic lowering effect, that of the be as a fibrinogen lowering Bezafibrats (Cook et al., TIPS Reviews 11 (1990), 450) is superior.

Die Wirkungsweise der erfindungsgemäßen Verbindungen ist nicht zu verwechseln mit der von "Fibrinogen-Antagonisten". Es han­ delt sich bei letzteren um Stoffe, die in der Lage sind, die Bindung von Fibrinogen an einen auf den Blutplättchen befindlichen GP IIb-IIIa-Rezeptor zu verhindern, während die Verbindungen der allgemeinen Formel I die Konzentration von Fibrinogen im Blut vermindern.The mode of action of the compounds according to the invention is not to be confused with that of "fibrinogen antagonists". It han the latter are substances that are capable of Binding of fibrinogen to one on the platelets prevent GP IIb-IIIa receptor located during the Compounds of general formula I the concentration of Decrease fibrinogen in the blood.

Die Herstellung der erfindungsgemäß verwendeten Verbindungen der allgemeinen Formel I ist an sich bekannt.The preparation of the compounds used according to the invention the general formula I is known per se.

So stellt man z. B. die unter die allgemeine Formel I der vorliegenden Erfindung fallenden Phenole der allgemeinen Formel Ia her,So you put z. B. under the general formula I of present invention falling phenols of the general formula Yeah,

indem man ein Amin der allgemeinen Formel IIby 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 general formula III

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 21 49 070) oder Triethylamin in Frage.or a reactive derivative thereof. In the formulas (I) and (III) R has the meaning given above. Suitable reactive derivatives are the acid halides, especially the acid chlorides, or also acid imidazolides. When Acid binding agents come e.g. B. alkali metal hydroxides (implementation under Schotten-Baumann conditions) or organic bases such as Pyridine (see e.g. DE-AS 21 49 070) or triethylamine in question.

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 21 49 070 durch Umsetzen der Phenole (Ia) mit alpha-Halogenessigsäureestern bzw. alpha-Halogenpropionsäu­ reestern in inerten Lösungsmitteln wie Butanon-2 und in Gegenwart von Säureakzeptoren wie pulverisiertem 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 are also precursors to those below general formula I falling phenoxyalkyl carboxylic acids or esters with B = -CONHCH₂CH₂- and X = carboxymethoxy or 1- Carboxy-ethoxy. Such phenoxyalkyl carboxylic acids are e.g. B. according to DE-AS 21 49 070 by reacting the phenols (Ia) with alpha-Haloacetic acid esters or alpha-Halogenpropionsäu reesters in inert solvents such as butanone-2 and in Presence of acid acceptors such as powdered potassium carbonate manufactured. Preferred as the halocarboxylic acid esters Ethyl esters of bromo or chlorocarboxylic acids used. The emerging oxycarboxylic acid esters are then by  Warm up with alcoholic alkali to the carboxylic acids saponified.

Verbindungen der allgemeinen Formeln Ib₁ oder Ib₂Compounds of the general formulas Ib₁ or Ib₂

in denen R und X die oben genannte Bedeutung haben, erhält man durch Kondensation eines Acetophenons der allgemeinen Formel IVa bzw. IVb,in which R and X have the meaning given above, one obtains 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 aqueous alkaline Milieu, e.g. B. in the presence of aqueous sodium hydroxide solution. In individual Condensation can also be preferred in the presence of Mineral acid, e.g. B. aqueous-alcoholic hydrochloric acid.

Die Reduktion der Chalkone Ib₁ bzw. Ib₂ zu den erfindungsgemäßen Trimethylenverbindungen Id verläuft bevorzugt in zwei Stufen: Zunächst werden die Chalkone zu den Dihydrochaikonen der allgemeinen Formel Ic₁ bzw. Ic₂ reduziert,The reduction of the chalcon Ib₁ or Ib₂ to Trimethylene compounds Id according to the invention preferably proceeds in two stages: First, the chalets become the Dihydrochaic icons of the general formula Ic₁ or Ic₂ 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.what by catalytic hydrogenation of the former z. B. in the present of precious metals or in the presence of homogeneous catalysts from Triphenylphosphine / rhodium salt type at room temperature and Normal pressure in a solvent such as B. THF.

Anschließende Reduktion der Dihydrochalkone unter den Bedingungen der WOLFF-KISHNER-Reduktion, d. h. durch Erhitzen mit Hydrazinhydrat in starkem Alkali, liefert die Trimethylenverbindungen der allgemeinen Formel IdSubsequent reduction of the dihydrochalcones among the Conditions of the WOLFF-KISHNER reduction, i. H. by heating with hydrazine hydrate in strong alkali, provides the Trimethylene 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 IeCompounds of the general formula Ie

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 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 K₂CO₃. Die weitere Umsetzung der Verbindungen der allgemeinen Formel Ie 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 K₂CO₃. The further implementation of the compounds of the general Formula Ie with alkyl or phenyl isocyanates leads to alkyl or phenyl urethanes of the general formula Ig

in der R und B die oben genannte Bedeutung haben, Alk den C₁-C₄-Alkylrest und Phe unsubstituiertes oder substituiertes Phenyl bedeutet.in which R and B have the meaning given above, Alk the C₁-C₄-alkyl radical and Phe unsubstituted or substituted Phenyl means.

Ebenso führt die weitere Umsetzung der Verbindungen der allge­ meinen Formel If mit Alkyl- oder Phenylisocyanaten unter übli­ chen Bedingungen zu Alkyl- oder Phenylurethanen der allgemeinen Formel IhLikewise, the further implementation of the connections of the general my formula if with alkyl or phenyl isocyanates under übli Chen conditions for 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 IiCompounds of the general formula Ii

in der R die oben genannte Bedeutung hat, n = 1 ist und R₁ Wasserstoff oder Methyl bedeutet, werden hergestellt durch Friedel-Crafts-Acylierung eines Phenoxycarbonsäureesters der allgemeinen Formel VIIin which R has the meaning given above, n = 1 and R₁ Means hydrogen or methyl are made by Friedel-Crafts acylation of a phenoxycarboxylic acid ester general formula VII

in der R₁ die oben genannte Bedeutung hat und R₂ C₁-C₄-Alkyl bedeutet, mit einer Carbonsäure der allgemeinen Formel VIIIin which R₁ has the meaning given above and R₂ is C₁-C₄-alkyl means 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 Gegenwart von Polyphosphorsäure als F.-C.- Katalysator. Der dabei erhaltene Ester wird anschließend verseift.in which R has the meaning given above and n is the numbers 1-6 means in the presence of polyphosphoric acid as 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 IXin 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 isolieren, bei Normaldruck in Gegenwart z. B. von Platindioxid zu Verbindung Ik hydriert.for example can react in ethanol to the Schiff base and the latter, without isolating them, at normal pressure in the presence e.g. B. hydrogenated by platinum dioxide to compound Ik.

Gewünschtenfalls können die hergestellten Verbindungen der allgemeinen Formel I, wenn sie saurer oder basischer Natur sind, in physiologisch verträgliche Salze überführt werden, und im Falle von Carbonsäuren ist ihre Umwandlung in Ester mit physiologisch unbedenklichen Alkoholen möglich.If desired, the compounds produced can general formula I when acidic or basic in nature are converted into physiologically acceptable salts, and in the case of carboxylic acids, their conversion into esters is included physiologically harmless alcohols possible.

Zur Bildung von Salzen aus Carbonsäuren der allgemeinen Formel I eignen sich pharmakologisch verträgliche anorganische oder organische Basen wie z. B. Natriumhydroxid, Kaliumhydroxid, Calciumhydroxid, 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 the formation of salts from carboxylic acids of the general formula I are pharmacologically acceptable inorganic or organic bases such as B. sodium hydroxide, potassium hydroxide, Calcium hydroxide, methylglucamine, morpholine or ethanolamine. Suitable for salt formation on bases of the general formula I. as acids e.g. B. 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 funktionelle Gruppen tragen, wie z. B. Ethanolamin.In the event that the compounds of general formula I contain a carboxyl function, come as an ester of this Carboxylic acids with lower monohydric alcohols (such as e.g. As methanol or ethanol) or with polyhydric alcohols (such as glycerin) in question. But they are also such Alcohols included, the other functional groups wear such. B. ethanolamine.

Aus den erhaltenen Razematen der Verbindungen der allgemeinen Formel I können die reinen Enantiomeren durch Razematspaltung (über Salzbildung mit optisch aktiven Basen) hergestellt wer­ den. Zu reinen Enantiomeren kommt man auch, indem man in der Synthese jeweils optisch aktive Ausgangsstoffe einsetzt.From the racemates obtained of the compounds of the general Formula I can the pure enantiomers by racemate resolution (via salt formation with optically active bases) who the. Pure enantiomers can also be obtained by using the Synthesis uses optically active starting materials.

Zur Herstellung von Arzneimitteln werden die Substanzen der allgemeinen Formel I mit geeigneten pharmazeutischen Trägersub­ stanzen, 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.The substances of the general formula I with suitable pharmaceutical carrier sub  punching, flavoring, flavoring and coloring mixed and for example shaped as tablets or coated tablets or under Add appropriate auxiliaries in water or oil, e.g. B. in Olive oil, suspended or dissolved.

Die Substanzen der allgemeinen Formel I und ihre Salze können in flüssiger oder fester Form enteral oder parenteral appli­ ziert 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 Ethylendiamintetraessigsäure und deren untoxische Salze) und hochmolekulare Polymere wie flüssiges Polyethyloxid zur Viskositätsregulierung. Feste Trägerstoffe sind z. B. Stärke, Lactose, Mannit, Methylcellu­ lose, Talcum, hochdisperse Kieselsäuren, hochmolekulare Fett­ säuren (wie Stearinsäure), tierische und pflanzliche Fette und feste hochmolekulare Polymere (wie Polyethylenglykole). Für orale Applikation geeignete Zubereitungen können gewünschten­ falls Geschmacks- und Süßstoffe enthalten.The substances of general formula I and their salts can in liquid or solid form enteral or parenteral appli be decorated. Water is preferably used as the injection medium for use, which is the usual for injection solutions Additives such as stabilizers, solubilizers or Contains buffers. Such additives are e.g. B. tartrate and Citrate buffer, complexing agent (such as ethylenediaminetetraacetic acid and their non-toxic salts) and high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation. Celebrations Carriers are e.g. B. starch, lactose, mannitol, methylcellu loose, talcum, highly disperse silicas, high molecular fat acids (such as stearic acid), animal and vegetable fats and solid high molecular polymers (such as polyethylene glycols). For Preparations suitable for oral administration can be desired if it contains flavorings and sweeteners.

Die Dosierung kann von verschiedenen Faktoren wie Applikations­ weise, Spezies, Alter oder individuellem Zustand abhängen. Üblicherweise werden die Verbindungen 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 Applikationen zu verteilen, wobei bei jeder Applikation zwei Tabletten mit einem Wirkstoffgehalt von je 85 bis 200 mg verabreicht werden. Die Tabletten können auch retardiert 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 application depend on species, age or individual condition. Usually, the compounds of formula I in amounts from 1.5 to 15 mg, preferably 5-10 mg per day and per kg Body weight applied. It is preferred to set the daily dose to distribute two applications, with each application two tablets with an active ingredient content of 85 to 200 mg each be administered. The tablets can also be delayed whereby only one tablet with 100-1000 mg per day Active ingredient must be given.  

Bevorzugt im Sinne der vorliegenden Erfindung sind außer den in den Beispielen genannten Verbindungen und der durch Kombination aller in den Ansprüchen genannten Substituenten die folgenden Verbindungen der Formel I, die als Reinenantiomere, als Enantiomerengemische/Razemate, als E- oder Z-Isomere oder deren Gemische, sowie ggf. als Salze oder/und Ester vorliegen können:Preferred in the sense of the present invention are in addition to those in the examples mentioned and the combination all the substituents mentioned in the claims the following Compounds of formula I, which as pure enantiomers, as Enantiomeric mixtures / racemates, as E or Z isomers or their Mixtures, and optionally as salts or / and esters can:

Im Nachfolgenden werden beispielhaft experimentelle Verfah­ ren zur Darstellung neuer Verbindungen beschrieben:In the following, experimental procedures are exemplified described for the representation of new connections:

AusführungsbeispieleEmbodiments Beispiel 1example 1 2-[4-[3-(4-Cyanophenyl)propyl]phenoxy]propionsäure2- [4- [3- (4-Cyanophenyl) propyl] phenoxy] propionic 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-Carboxybenz­ aldehyd und läßt 36 Stdn. reagieren. Dann wird Wasser zugegeben, zweimal mit Essigester extrahiert und die wäßrige Phase mit verd. HCl 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 dilute 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 the mp.
283-284 ° C.

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. HClO₄ und 5 g 10-proz. Palla­ diumkohle zwei Std. 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 out 800 ml THF, 3.5 ml 70 percent. HClO₄ and 5 g 10 percent. Palla Hydrogenated carbon for two hours at 20 ° C and 40 mbar. To  Removal of the catalyst 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 Dimethylamino­ pyridin 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 Ether­ phase (Na₂SO₄) und dampft ein. Der Rückstand wird aus 66- proz. Ethanol umkristallisiert. Ausb. 12.0 g (51% d. Th.), Schmp. 134-136°C.20 g (78 mmol) of the hydroxy compound from b) are with 40 ml (246 mmol) acetic anhydride and 1.0 g dimethylamino pyridine stirred at 0 ° C for one hour. Then you put in 0 ° C 20 ml of ethanol, stir for 5 min and then add 600 ml Water too. It is extracted with ether, the ethers are dried phase (Na₂SO₄) and evaporates. The residue is 66- percent Recrystallized ethanol. Educ. 12.0 g (51% of theory), Mp 134-136 ° C.

d) 4-[3-(4-Acetoxyphenyl)propyl]benzamidd) 4- [3- (4-acetoxyphenyl) propyl] benzamide

Ein Gemisch aus 12.0 g (40 mmol) der nach c) hergestell­ ten 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 Methylen­ chlorid. Ausb. 11.4 g (95.3% d. Th.), Schmp.: 104-106°C (Ethanol).A mixture of 12.0 g (40 mmol) prepared according to c) ten benzoic acid, 20 ml (0.27 mmol) thionyl chloride and three Drop of DMF is stirred at 60 ° C for two hours. Then steams one dries to dryness, the residue is dissolved in methylene chloride and fumigates at 0 ° C until complete amidation Ammonia. It is evaporated and washed with cold methylene chloride. Educ. 11.4 g (95.3% of theory), melting point: 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 Acetoxyverbindung, 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 mit 2N-HCl 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) according to d) is stirred holding acetoxy compound, 45 ml of 2N-NaOH (90 mmol) and 90 ml of ethanol for 20 min at 50 ° C, then distilled that Ethanol off and diluted with water. By acidifying with The 2N-HCl precipitates the phenol. You vacuum, wash with water and dries. Educ. 9.1 g (93% of theory), mp. 174-175 ° C (ethanol).  

f) 2-[4-[3-(4-Aminocarbonyl-phenyl)propyl]phenoxy]propion-säuremethyles-terf) 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 Std. bei 80°C. Dann wird warm abgesaugt, das Filtrat eingedampft und der Rückstand mit Isohexan zur Kristalli­ sation 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 that obtained according to e) Phenol, 100 ml butanone and 9.5 g (69 mmol) anhydrous, powdered K₂CO₃ is stirred at 80 ° C for 15 min, then you give a spatula tip of potassium iodide in succession and a few mg of Kronenether Crown (18.6) and 5.0 g (30 mmol) 2-bromo-propionic acid methyl ester and stirred 16 hours at 80 ° C. The filtrate is then suctioned off while warm evaporated and the residue with isohexane to crystallize sation brought. 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 Carbon­ amids 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 Öles zurück. Praktisch analysenrein.9.0 g (2.9 mmol) of the carbon obtained in f) are dissolved amids at 140 ° C in 90 ml toluene, gives 7.0 g (5.6 mmol) Phosphorus pentoxide and stirred at 140 ° C for 10 min. To after cooling, the toluene is decanted off and treated Unsolve twice with hot ethyl acetate and combine the Ethyl acetate extracts with the toluene phase. The organic The solution is evaporated and 7.2 g (85% of theory) remain. Product in the form of a colorless oil. Practically pure analysis.

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. HCl an. A mixture of 7.0 g (20 mmol) of the prepared according to g) Ester, 20 ml of 2N NaOH and 40 ml of ethanol is used for one hour long at 50 ° C, then distilled the ethanol from. The residue is diluted with water and shaken aqueous phase for the removal of neutral substances twice with ether and finally acidified with dil. HCl.  

Die saure Lösung wird dreimal mit Ether extrahiert. Man trocknet den Ether (Na₂SO₄), dampft ein und chromato­ graphiert das zurückbleibende Rohprodukt mittels Kurzsäule an Kieselgel Nr. 60 und dem Laufmittel Methylenchlorid +1% Essigsäure. Ausb. 5.0 g (74.6% d. Th.) farbloses Öl.The acidic solution is extracted three times with ether. Man dries the ether (Na₂SO₄), evaporates and chromato graphs the remaining raw product using a short column on silica gel No. 60 and the eluent methylene chloride + 1% Acetic acid. Educ. 5.0 g (74.6% of theory) colorless oil.

Beispiel 2Example 2 [4-[3-(4-Chlorphenyl]propyl]phenol[4- [3- (4-chlorophenyl] propyl] phenol 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 Stick­ stoff 48 Std. bei Raumtemperatur. Danach wird mit Wasser verdünnt, mit verd. HCl 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-hydroxy-acetophenone are dissolved in one Solution from 10.0 g NaOH and 100 ml water gives 14.1 g (0.1 mol) 4-chlorobenzaldehyde and now stir under a stick fabric 48 hours at room temperature. After that, use water diluted, acidified with dil. HCl and the precipitating Suction filtered. After washing with water and Drying (in vacuo 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 Methanol, 10 ml conc. HCl und 5 g 10-proz. Palladiumkohle wird bei Raumtemperatur und Normaldruck in einer Schüttelapparatur mit Wasserstoff bis zur beendeten Aufnahme begast. Dann saugt man den Katalysator ab, dampft i. Vak. ein und löst den Rückstand in Ether. Die Ether­ phase wird durch Ausschütteln mit gesätt. NaHCO₃-Lösung neutral gewaschen, dann trocknet man mit Na₂SO₄ und dampft ein. Es folgt eine Reinigung an einer RP-18-Mitteldruck- Chromatographiesäule mit dem Laufmittel Methanol:Wasser = 8 : 2 Vol.-Ausb. 14.2 g (68% d. Th.). A mixture of 22.0 g (85 mmol) 4'-hydroxy-4-chlorine chalkon, 500 ml methanol, 10 ml conc. HCl and 5 g 10 percent. Palladium carbon is in at room temperature and normal pressure a shaker with hydrogen until the end Recording fumigated. Then you sucked off the catalyst, steamed i. Vac. and dissolves the residue in ether. The ether phase is extracted by shaking with sat. NaHCO₃ solution washed neutral, then dried with Na₂SO₄ and steamed a. This is followed by cleaning on an RP-18 medium pressure Chromatography column with the mobile solvent methanol: water 8: 2 vol. 14.2 g (68% of theory).  

Beispiel 3Example 3 2-[4-[3-(4-Chlorphenyl)propyl]phenoxy]propionsäure2- [4- [3- (4-chlorophenyl) propyl] phenoxy] propionic 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-propionsäuremethylester in Analogie zu Beispiel 1f) dargestellt. Das Produkt wurde in ungereinigter Form (Öl, Ausb. nahe 100%) in die unter b) beschriebene Versei­ fung eingesetzt.Is made from 4- [3- (4-chlorophenyl) propyl] phenol (see above) and Methyl 2-bromo-propionate in analogy to example 1f). The product was in an unpurified form (Oil, yield close to 100%) in the versei described under b) used.

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. HCl die Säure aus. Sie wird abge­ saugt, mit Wasser gewaschen und i. Vak. über KOH getrock­ net. Ausb. 5.3 g (88% d. Th.), Schmp. 81-82°C (Heptan).The mixture of 6.3 g (18.9 mmol) shown in a) Ester, 60 ml of methanol and 30 ml of 2N NaOH is added for 4 hours Stirred 50 ° C, then evaporated the methanol i.Vak. every now and then the acid precipitates using dilute HCl. It will be abge sucks, washed with water and i. Vac. dry over KOH net. Educ. 5.3 g (88% of theory), mp 81-82 ° C (heptane).

Beispiel 4Example 4 2-[4-[2-(Benzoylamino)ethyl]phenoxy]ethanol2- [4- [2- (benzoylamino) ethyl] phenoxy] ethanol

Eine Suspension aus 60 ml abs. Toluol, 8.0 g (33 mmol) 4-[2-(Benzoylamino)ethyl]phenol und 4.7 g pulv., trocknem K₂CO₃ wird 15 min bei 120°C gerührt, dann gibt man 5.8 g (66 mmol) Ethylencarbonat zu und hält weitere zwei Std. auf 120°C. Man verdünnt mit Aceton, saugt heiß ab, dampft das Filtrat i.Vak. ein und kristallisiert den Rückstand aus Ethanol um. Ausb. 4.6 g (49% d. Th.), Schmp. 135-136°C.A suspension of 60 ml abs. Toluene, 8.0 g (33 mmol) 4- [2- (benzoylamino) ethyl] phenol and 4.7 g powder, dry  K₂CO₃ is stirred for 15 min at 120 ° C, then 5.8 g are added (66 mmol) of ethylene carbonate and hold for a further two hours 120 ° C. It is diluted with acetone, suction filtered while hot, and evaporated Filtrate in vac. and crystallizes the residue Ethanol around. Educ. 4.6 g (49% of theory), mp. 135-136 ° C.

Beispiel 4aExample 4a

In analoger Weise wird aus 3-[2-(Benzoylamino)ethyl]phenol und Ethylencarbonat dargestellt:In an analogous manner, 3- [2- (benzoylamino) ethyl] phenol and ethylene carbonate shown:

2-[3-[2-(Benzoylamino)ethyl]phenoxy]ethanol Ausb. 61% d. Th., farbloses Öl.2- [3- [2- (benzoylamino) ethyl] phenoxy] ethanol Educ. 61% of theory Th., Colorless oil.

Beispiel 5Example 5 2-[4-[6-(4-Chlorphenyl]-1-oxo-hexyl]phenoxy]propionsäure2- [4- [6- (4-chlorophenyl] -1-oxo-hexyl] phenoxy] propionic acid a) -ethylestera) ethyl ester

Ein Gemisch aus 8.1 g (35.7 mmol) 6-(4-Chlorphenyl)hexan säure, 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 Eiswasser einge­ rührt. Man extrahiert mit Ether, trocknet die Etherphase mit Na₂SO₄ und dampft anschließend ein. Der Rückstand wird in Methylenchlorid gelöst. Man filtriert über eine kurze Kieselgel-Säule und dampft ein. Ausb. 10.2 g (71% d. Th.), farbloses Öl. A mixture of 8.1 g (35.7 mmol) 6- (4-chlorophenyl) hexane acid, 6.9 g (35.7 mmol) ethyl 2-phenoxypropionate and 50 g of polyphosphoric acid is stirred for 10 minutes kept at 80 ° C and then soaked in ice water stirs. The mixture is extracted with ether and the ether phase is dried with Na₂SO₄ and then evaporated. The backlog will dissolved in methylene chloride. It is filtered over a short Silica gel column and evaporate. Educ. 10.2 g (71% of theory), colorless oil.  

b) Titelverbindungb) Title link

Der Ester wird in Analogie zu Beispiel Ih) verseift und zum Schluß aus einem Cyclohexan-Toluol-Gemisch umkristal­ lisiert. Ausb. 87% d. Th., Schmp. 74-76°C.The ester is saponified in analogy to example Ih) and finally crystallized from a mixture of cyclohexane and toluene lized. Educ. 87% of theory Th., Mp 74-76 ° C.

Claims (13)

1. Verwendung von Phenolen und Phenolderivaten der allgemeinen Formel I zur Herstellung von Arzneimitteln mit fibrinogensenkender Wirkung,
in der
R Wasserstoff oder ein bis drei Substituenten bedeutet, die unabhängig voneinander aus der Reihe Halogen, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, Hydroxy, Cyano oder Tri­ fluormethyl ausgewählt sind,
B eine unsubstituierte oder gegebenenfalls durch ein oder zwei Methylgruppen in beliebiger Stellung sub­ stituierte, 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, und
X in meta- oder para-Stellung zu B steht und folgende Gruppen bedeutet:
  • - eine Hydroxygruppe oder eine von dieser abgelei­ tete C₁-C₄-Alkylurethan- oder substituierte oder unsubstituierte Phenylurethangruppe,
  • - eine unverzweigte oder eine durch eine oder zwei Methylgruppen in beliebiger Stellung substi­ tuierte C₁-C₆-Alkyloxy-, omega-Hydroxy-C₂-C₆- alkyloxy-, omega-Halogen-C₂-C₆-alkyloxy oder omega-Cyano-C₁-C₆-alkyloxygruppe,
  • - eine von der omega-HydroxyC₂-C₆-alkyloxygruppe abgeleitete C₁-C₄-Alkylurethan-, substituierte oder unsubstituierte Phenylurethan-, Phosphor­ säureester-, aliphatische Carbonsäureester­ oder, gegebenenfalls substituierte, Benzoesäureestergruppierung,
  • - eine Aminocarbonyl-C₁-C₆-alkyloxy oder eine N- Hydroxy-aminocarbonyl-C₁-C₆-alkyloxygruppe
  • - Carboxymethoxy, 1-Carboxy-ethoxy, 1-Carboxy­ propyloxy oder 3-Carboxy-propyloxy
  • - den Rest -O-C(CH₃)₂-CH₂-O-CO-(CH₂)₂-COOH
  • - den Benzoyloxyrest, der gegebenenfalls substituiert ist,
1. Use of phenols and phenol derivatives of the general formula I for the production of drugs with a fibrinogen-lowering effect,
in the
R is hydrogen or one to three substituents which are selected independently of one another from the series halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, hydroxy, cyano or tri fluoromethyl,
B 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 of 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 is in the meta or para position to B and means the following groups:
  • - A hydroxy group or a C₁-C₄ alkyl urethane derived therefrom or substituted or unsubstituted phenyl urethane group,
  • - An unbranched or one substituted by one or two methyl groups in any position C₁-C₆-alkyloxy, omega-hydroxy-C₂-C₆-alkyloxy, omega-halogen-C₂-C₆-alkyloxy or omega-cyano-C₁-C₆ -alkyloxy group,
  • a C₁-C₄-alkyl urethane derived from the omega-hydroxyC₂-C₆-alkyloxy group, substituted or unsubstituted phenyl urethane, phosphoric acid ester, aliphatic carboxylic acid esters or, optionally substituted, benzoic acid ester grouping,
  • - An aminocarbonyl-C₁-C₆-alkyloxy or an N-hydroxy-aminocarbonyl-C₁-C₆-alkyloxy group
  • - Carboxymethoxy, 1-carboxy-ethoxy, 1-carboxypropyloxy or 3-carboxypropyloxy
  • - The rest -OC (CH₃) ₂-CH₂-O-CO- (CH₂) ₂-COOH
  • the benzoyloxy radical, which is optionally substituted,
sowie deren Enantiomere, Diastereomere, Z- oder E-Isomere und gegebenenfalls deren physiologisch verträgliche Salze oder Ester. and their enantiomers, diastereomers, Z or E isomers and optionally their physiologically tolerable salts or esters.   2. 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 3-Trifluormethyl, 4-Methyl, 4-Methoxy, 4-Cyano, 2,4-di-Chlor oder 2-Methoxy-5-Chlor bedeutet.2. Use of compounds of the formula I according to claim 1, characterized in that the radical R with respect to the Substituents B 4- or 3-chloro, 4-fluorine, 4- or 3-trifluoromethyl, 4-methyl, 4-methoxy, 4-cyano, 2,4-di-chlorine or 2-methoxy-5-chlorine means. 3. Verwendung von Verbindungen der Formel I gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß der Rest B die Grup­ pen -CONHCH₂CH₂-, -CH=CH-CO-, -CO-CH=CH-, -NHCH₂-, -CH₂NH-, -CH₂NHCH₂-, <CHOH, -NHCO-, -CONH-, -NHCOCH₂-, -CH₂NHCO-, Carbonyl, unverzweigtes C₁-C₆-Alkylen oder unverzweigtes C₂-C₅-Alkylencarbonyl, insbesondere Ethylencarbonyl, Trimethylencarbonyl und Pentamethylencarbonyl, bedeutet.3. Use of compounds of formula I according to claim 1 or 2, characterized in that the remainder B the group pen -CONHCH₂CH₂-, -CH = CH-CO-, -CO-CH = CH-, -NHCH₂-, -CH₂NH-, -CH₂NHCH₂-, <CHOH, -NHCO-, -CONH-, -NHCOCH₂-, -CH₂NHCO-, carbonyl, unbranched C₁-C₆ alkylene or unbranched C₂-C₅ alkylene carbonyl, in particular Ethylene carbonyl, trimethylene carbonyl and Pentamethylene carbonyl. 4. 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 -O-C(CH₃)₂-CH₂-O-CO-(CH₂)₂-COOH bedeutet.4. Use of compounds of formula I according to one of the Claims 1, 2 or 3, characterized in that the Radical X is in para position to B and hydroxyl, Carboxymethoxy, 1-carboxy-ethoxy, 1-carboxypropyloxy, 3- Carboxypropyloxy, 2-hydroxy-ethoxy, 3-hydroxypropyl-2- oxy, 3-hydroxy-2-methyl-propyl-2-oxy, propyl-2-oxy and the Radical -O-C (CH₃) ₂-CH₂-O-CO- (CH₂) ₂-COOH means. 5. Verwendung von Verbindungen der Formel I gemäß der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß R 4-Chlor, 4-Trifluormethyl oder 4-Cyano bedeutet, B <CHOH, -CONHCH₂CH₂-, Trimethylen, Trimethylencarbonyl oder Penta­ methylencarbonyl ist, X in para-Stellung zu B steht und 1-Carboxy-ethoxy, Propyl-2-oxy, 3-Hydroxy-propyl-2-oxy darstellt oder den Rest -O-C(CH₃)₂-CH₂-O-CO-(CH₂)₂-COOH darstellt. 5. Use of compounds of formula I according to Claims 1 to 4, characterized in that R 4-chlorine, 4-trifluoromethyl or 4-cyano means B <CHOH, -CONHCH₂CH₂-, trimethylene, trimethylene carbonyl or penta is methylene carbonyl, X is para to B and 1-carboxy-ethoxy, propyl-2-oxy, 3-hydroxypropyl-2-oxy represents or the radical -O-C (CH₃) ₂-CH₂-O-CO- (CH₂) ₂-COOH represents.   6. Verwendung von Verbindungen der Formel I gemäß Anspruch 5, dadurch gekennzeichnet, daß R 4-Chlor bedeutet, X in para- Stellung zu B steht und der 1-Carboxy-ethoxy bedeutet und B Trimethylen, Trimethylencarbonyl oder Pentamethylen­ carbonyl darstellt.6. Use of compounds of the formula I according to claim 5, characterized in that R is 4-chlorine, X in para- Position stands for B and the 1-carboxy-ethoxy means and B trimethylene, trimethylene carbonyl or pentamethylene represents carbonyl. 7. Phenole und Phenolderivate der allgemeinen Formel I in der
R Wasserstoff oder ein bis drei Substituenten bedeutet, die unabhängig voneinander aus der Reihe Halogen, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, Hydroxy, Cyano oder Tri­ fluormethyl ausgewählt sind,
B eine unsubstituierte oder gegebenenfalls durch ein oder zwei Methylgruppen in beliebiger Stellung sub­ stituierte, 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, und
X in meta- oder para-Stellung zu B steht und folgende Gruppen bedeutet:
  • - eine Hydroxygruppe oder eine von dieser abgelei­ tete C₁-C₄-Alkylurethan- oder substituierte oder unsubstituierte Phenylurethangruppe,
  • - eine unverzweigte oder eine durch eine oder zwei Methylgruppen in beliebiger Stellung substi­ tuierte C₁-C₆-Alkyloxy-, omega-Hydroxy-C₂-C₆- alkyloxy-, omega-Halogen-C₂-C₆-alkyloxy oder omega-Cyano-C₁-C₆-alkyloxygruppe,
  • - eine von der omega-Hydroxy-C₂-C₆-alkyloxygruppe abgeleitete C₁-C₄-Alkylurethan-, substituierte oder unsubstituierte Phenylurethan-, Phosphor­ säureester-, aliphatische Carbonsäureester­ oder, gegebenenfalls substituierte, Benzoesäureestergruppierung,
  • - eine Aminocarbonyl-C₁-C₆-alkyloxy oder eine N- Hydroxy-aminocarbonyl-C₁-C₆-alkyloxygruppe
  • - Carboxymethoxy, 1-Carboxy-ethoxy, 1-Carboxy­ propyloxy oder 3-Carboxy-propyloxy
  • - den Rest -O-C(CH₃)₂-CH₂-O-CO-(CH2)₂-COOH
  • - den Benzoyloxyrest, der gegebenenfalls subsi­ tuiert ist,
7. Phenols and phenol derivatives of the general formula I in the
R is hydrogen or one to three substituents which are selected independently of one another from the series halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, hydroxy, cyano or tri fluoromethyl,
B 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 of 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 is in the meta or para position to B and means the following groups:
  • - A hydroxy group or a C₁-C₄ alkyl urethane derived therefrom or substituted or unsubstituted phenyl urethane group,
  • - An unbranched or one substituted by one or two methyl groups in any position C₁-C₆-alkyloxy, omega-hydroxy-C₂-C₆-alkyloxy, omega-halogen-C₂-C₆-alkyloxy or omega-cyano-C₁-C₆ -alkyloxy group,
  • a C₁-C₄-alkyl urethane derived from the omega-hydroxy-C₂-C₆-alkyloxy group, substituted or unsubstituted phenyl urethane, phosphoric acid ester, aliphatic carboxylic acid ester or, optionally substituted, benzoic acid ester grouping,
  • - An aminocarbonyl-C₁-C₆-alkyloxy or an N-hydroxy-aminocarbonyl-C₁-C₆-alkyloxy group
  • - Carboxymethoxy, 1-carboxy-ethoxy, 1-carboxypropyloxy or 3-carboxypropyloxy
  • - The rest -OC (CH₃) ₂-CH₂-O-CO- (CH2) ₂-COOH
  • the benzoyloxy radical, which may be subsi
mit Ausnahme der Verbindungen, in denen
  • a) B die Gruppe -CONHCH₂CH₂- bedeutet, R das Chlor­ atom in para-Stellung ist, X in para-Stellung die Hydroxygruppe, Carboxymethoxy, 1-Carboxy­ propyloxy oder der p-Chlorbenzoyloxyrest ist,
  • b) R Wasserstoff und X in para-Stellung die Hydroxygruppe ist, während B die Gruppe -CONHCH₂CH₂- bedeutet,
  • c) R das Chloratom in para-Stellung ist, B die Trimethylengruppe bedeutet und X in para- Stellung die Hydroxygruppe darstellt,
  • 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,
  • 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,
with the exception of the connections in which
  • a) B is the group -CONHCH₂CH₂-, 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 is hydrogen and X in the para position is the hydroxy group, while B is the group -CONHCH₂CH₂-,
  • 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 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 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 gegebenenfalls deren physiologisch verträgliche Salze oder Ester.and their enantiomers, diastereomers, E or Z isomers and optionally 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. Medicament containing pharmaceutical auxiliary or Carriers at least one phenol or phenol derivative general formula I according to claim 7. 9. Verwendung von Phenolen oder Phenolderivaten der allgemei­ nen Formel I gemäß Anspruch 7 zur Herstellung von Arznei­ mitteln zur Behandlung von cardiovaskulären Erkrankungen. 9. Use of phenols or phenol derivatives of the general NEN formula I according to claim 7 for the manufacture of medicament agents for the treatment of cardiovascular diseases.   10. Verwendung von Phenolen oder Phenolderivaten gemäß Anspruch 9 zur Herstellung von Arzneimitteln zur Behandlung der peripheren arteriellen Verschlußkrankheit, der coronaren Herzkrankheit und von cerebralen Durchblutungsstörungen.10. Use of phenols or phenol derivatives according to Claim 9 for the manufacture of medicaments for Treatment of peripheral arterial disease, coronary artery disease and cerebral Circulatory disorders.
DE4327365A 1993-08-14 1993-08-14 Use of phenols and phenol derivatives as drugs with a fibrinogen-lowering effect Withdrawn DE4327365A1 (en)

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JP7506754A JPH09501670A (en) 1993-08-14 1994-08-13 Use of Phenol and Phenol Derivatives as Pharmaceutical Agents with Fibrinogen Lowering Action
PCT/EP1994/002709 WO1995005358A1 (en) 1993-08-14 1994-08-13 Use of phenols and phenol derivates as medicaments with fibrinogen-reducing effect
CA002169187A CA2169187A1 (en) 1993-08-14 1994-08-13 Use of phenols and phenol derivatives as pharmaceutical agents with a fibrinogen-lowering action
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