EP0664788A1 - Substituted ethanolamine esters - Google Patents

Substituted ethanolamine esters

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Publication number
EP0664788A1
EP0664788A1 EP93923482A EP93923482A EP0664788A1 EP 0664788 A1 EP0664788 A1 EP 0664788A1 EP 93923482 A EP93923482 A EP 93923482A EP 93923482 A EP93923482 A EP 93923482A EP 0664788 A1 EP0664788 A1 EP 0664788A1
Authority
EP
European Patent Office
Prior art keywords
amino
hydroxy
compounds
alkyl
dichlorophenyl
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Withdrawn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
EP93923482A
Other languages
German (de)
French (fr)
Inventor
Jan Bron
Geert Jan Sterk
Hendrik Timmerman
Meta E. J. Veerman
Jan Fetze Van Der Werf
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.)
Altana Pharma BV
Original Assignee
BYK Nederland BV
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Filing date
Publication date
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Publication of EP0664788A1 publication Critical patent/EP0664788A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/10—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of a carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/14—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/18—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
    • 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
    • C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/30—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the invention relates to new compounds, processes for their preparation and their use as active ingredients in pharmaceuticals.
  • the compounds disclosed in this patent represent in a certain way substituted phenylethylamines which are substituted on the nitrogen atom by an alkyleneoxycarbonylphenyl radical, which phenyl radical bonded directly to the carbonyl group must be substituted by three hydroxyl or alkoxy groups.
  • German Auslegeschrift 11 26889 also describes (derived from reserpine) substituted amines with hypotensive and spasmolytic effects, in which the phenyl radical bonded directly to the carbonyl group by at least one hydroxyl or alkoxy radical and optionally also by a further hydroxyl or alkoxy radical must be substituted.
  • X is 1-12C-alkylene, 1-6C-alkyleneoxy-1-6C-alkylene or cyclohexylene, E is carbonyloxy (-CO_O-) or oxycarbonyl (-O-CO-),
  • n is an integer from 0 to 10
  • Y is a bond, oxygen (0), sulfur (S), the group -CHR-, in which R is 1-4C-alkyl, phenyl or hydroxy, or the groups -CR ' 2 - or -CHR'-CH 2 is O-, in which R 'is 1 -4C-A1 kyl, where Y is not oxygen if n is the number 0,
  • Ar represents a phenyl radical substituted by R1, R2 and R3,
  • R1 is hydrogen, halogen, hydroxy (-OH), amino (-NH 2 ), ureido
  • R3 represents hydrogen or halogen
  • Ar 2 represents a phenyl radical substituted by R4 and R5, a thienyl radical, a pyridyl radical, a naphthyl radical, an indolyl radical, an indanyl radical or a benzo-1,4-dioxanyl radical, where
  • R4 is hydrogen, halogen, hydroxy (-OH), cyan (-CN), 1-4C-alkyl,
  • 1-4C-alkoxy benzyloxy, nitro (-NCL), trifluoromethyl (-CF 3 ), 1-4C-alkoxycarbonyl (-CO-O-1-4C-alkyl), carbamoyl (-CO-NH 2 ), di- 1-4C-alkylcarbamoyl [-CO-N (1-4C-alkyl) 2 ], amino (-NH 2 ),
  • R5 denotes hydrogen, halogen, hydroxy (-OH), 1 -4C-alkyl or 1-4C-alkoxy,
  • R4 is not hydroxy or 1-4C-alkoxy when E is oxycarbonyl (-O-CO-), n is 0 and Y is a hyphen, and where R1 and R2 are not simultaneously hydroxy when X is 1-4C-alkylene and E denotes carbonyloxy (-CO-O-),
  • 1-12C-A1 kylen stands for straight-chain or branched alkylene radicals with 1 to 12 carbon atoms.
  • the residues are methylene (-CH 2 -), ethylene (-CH 2 CH 2 -). Trimethylene (-CH 2 CH 2 CH 2 -), tetramethylene
  • 1-6C-Alkyleneoxy-1-6C-alkylene represents straight-chain or branched alkylene radicals having 1 to 6 carbon atoms which are substituted by straight-chain or branched 1-6C-alkyleneoxy radicals. Examples are the ethoxyethylene (-CH 2 -CH 2 -O-CH 2 -CH 2 -) and the methoxymethylene residue
  • the 1,2-, the 1,3- and in particular the 1,4-cyclohexylene radical may be mentioned as cyclohexylene radicals.
  • 1 -4C-alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples include butyl, iso-butyl, sec-butyl, tert. -Butyl, propyl, isopropyl, ethyl - and especially the methyl rest.
  • Halogen in the sense of the present invention is bromine, chlorine and fluorine.
  • the 1-4C-alkylcarbonylamino radical for example, is the acetylamido radical (-NH-CO-CH 3 ).
  • the dimethylcarbamoyloxy radical [-O-CO-N (CH 3 ) 2 ] may be mentioned as the di-1-4C-alkylcarbamoyloxy radical.
  • the 1-4C-alkyl carbonyl oxy group for example, the tert-butyl carbonyloxy group and the isopropyl carbonyl oxy group may be mentioned.
  • 1-4C-alkoxy radicals contain one of the 1-4C-alkyl radicals mentioned above.
  • the methoxy radical is preferred.
  • a 1-4C-alkylsulfonylamino radical for example, the methylsulfonylamino radical (-NH-SO 2 -CH 3 ) may be mentioned.
  • the methyl sulfonylmethyl radical (-CH 2 -SO 2 -CH 3 ) may be mentioned.
  • the methoxymethyl radical (-CH 2 -O-CH 3 ) may be mentioned as the 1-4C-alkoxy-1-4C-alkyl radical.
  • radicals Ar are the radicals 4-aminophenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3,5-bis-dimethylaminocarbonyloxyphenyl, 3,5-bis-toluoyloxyphenyl, 4-hydroxy-3-ureidophenyl, 3-formylamino-4-hydroxyphenyl, 4-hydroxyphenyl, 3-amino-5-hydroxyphenyl, 2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 4-amino-3-cyanophenyl, 3,5-di-tert-butylcarbonyloxyphenyl , 3,5-di-isopropylcarbonyloxyphenyl, 2-chloro-4-hydroxyphenyl, 2-fluoro-4-hydroxyphenyl, 3-fluoro-4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-hydroxy-3-methoxymethylphenyl, 4 -Hydroxy-3-methylsulfonamidoph
  • Ar to be emphasized are the residues phenyl, 2-chlorophenyl, 3-hydroxyphenyl and 4-amino-3-chloro-5-trifluoromethylphenyl.
  • the preferred residues Ar are the residues 3-hydroxymethyl-4-hydroxyphenyl, 4-amino-3,5-dichlorophenyl and 4-amino-3-chloro-5-cyanophenyl.
  • the methoxycarbonyl and the eihoxycarbonyl radicals may be mentioned.
  • the diethylcarbamoyl radical may be mentioned as the di-1-4C-alkylcarbamoyl radical R4.
  • the methyl sulfonyl radical may be mentioned as the 1-4C-alkylsulfonyl radical R4.
  • Ar 2 to be emphasized are the residues phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-methylphenyl, 4-Me- thylphenyl, 4-benzyloxyphenyl, 3,5-dimethylphenyl, 4-propoxyphenyl, 2-cyanphenyl, 4-cyanphenyl, 4-methyl sulfonylphenyl, 4-bromophenyl, 2-chloro-6-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4 -Ethoxyphenyl, 2-phenylcarbonylaminophenyl, 2-phenylphenyl, 3-phenylphenyl, 4-phenylphenyl, 2-naphthyl, 2-thienyl, 3-thienyl, 3-pyrid
  • Ar 2 are the preferred residues 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-fluorophenyl, 3-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-chlorophenyl, 1-naphthyl, 3-indolyl and 2- Called pyridyl.
  • Suitable salts for compounds of the formula I are preferably all acid addition salts. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids commonly used in galenics. Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
  • Suitable as such are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid , Malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids used in salt production - depending on whether it is a mono- or polybasic acid and depending on which salt is desired - be used in an equimolar or a different ratio.
  • acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfur
  • X denotes 1-6C-alkylene, 1-2C-alkyleneoxy-1-2C-alkylene or cyclohexylene
  • E denotes carbonyloxy (-CO-O-) or oxycarbonyl (-O-CO-),
  • n is an integer from 1 to 5
  • Y denotes a bond line, oxygen (0) or the group -CHR-, in which R denotes 1-4C-alkyl,
  • Ar 1 represents a phenyl radical substituted by R1, R2 and R3,
  • R1 denotes hydrogen, hydroxy or amino (-NH 2 ),
  • R2 is hydrogen, halogen, cyan, trifluoromethyl or hydroxymethyl
  • R3 represents hydrogen or halogen
  • Ar 2 represents a phenyl radical substituted by R4 and R5, a thienyl radical, a pyridyl radical, a naphthyl radical, an indolyl radical or an indanyl radical, where
  • R4 is hydrogen, halogen, hydroxy (-0H), cyano (-CN), 1-4C-alkyl, 1-4C-alkoxy, benzyloxy, nitro (-NCL) or trifluoromethyl (-CF 3 ), and
  • R5 denotes hydrogen, halogen or 1-4C-alkyl
  • E denotes carbonyloxy (-CO-O-) or oxycarbonyl (-O-CO-),
  • n the number 1 or 2
  • Ar 1 denotes phenyl, 4-amino-3-chloro-5-cyanophenyl, 4-hydroxy-3-hydroxymethylphenyl or 4-amino-3,5-dichlorophenyl,
  • Ar 2 represents a phenyl radical substituted by R4 and R5 or a 1-naphthyl radical, where
  • R4 is hydrogen, chlorine, fluorine, hydroxy (-OH), 1-4C-alkyl or 1-4C-alkoxy and
  • R5 means hydrogen
  • the invention further relates to a process for the preparation of the compounds of the formula I and their salts.
  • the process is characterized in that a) for the preparation of the compounds I in which E is oxycarbonyl, compounds of the formula II,
  • reaction of the compounds II with the compounds III or IV is carried out in a manner known per se to the person skilled in the art in inert, preferably polar solvents, for example in methanol, ethanol, 1- or 2-propanol, dimethylformamide, tetrahydrofuran, acetone, methyl ethyl ketone , Methyl isobutyl ketone or dioxane, at temperatures between 10 and 120 ° C, preferably between 50 and 100 ° C, optionally at the boiling point of the solvent used.
  • inert preferably polar solvents, for example in methanol, ethanol, 1- or 2-propanol, dimethylformamide, tetrahydrofuran, acetone, methyl ethyl ketone , Methyl isobutyl ketone or dioxane
  • the reaction is carried out in the presence of a base, e.g. a tertiary organic amine, such as diisopropylethylamine, or an inorganic carbonate, such as potassium carbonate.
  • a base e.g. a tertiary organic amine, such as diisopropylethylamine, or an inorganic carbonate, such as potassium carbonate.
  • leaving groups L are suitable on the basis of his specialist knowledge.
  • the tosylate or mesy lat group but especially halogen atoms, and especially chlorine or bromine. If chlorine or bromine compounds III or IV are used, the reaction can advantageously also take place in the presence of catalytic amounts of an iodide, such as, for example, potassium iodide.
  • the reaction of the compounds V with the compounds VI takes place in a manner known per se, as is known to the person skilled in the art on the basis of his specialist knowledge of esterification reactions.
  • 4-toluenesulfonic acid or in the presence of an auxiliary base (
  • the compounds according to the invention are initially obtained either as such or in the form of their salts.
  • the salts are obtained by dissolving the free compounds in a suitable solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol (ethanol, isopropanol), an ether (diisopropyl ether), a ketone (acetone) or water, which contains the desired acid, or which contains the desired acid - if necessary in the exact calculated stoichiometric amount - is then added.
  • a chlorinated hydrocarbon such as methylene chloride or chloroform
  • a low molecular weight aliphatic alcohol ethanol, isopropanol
  • an ether diisopropyl ether
  • a ketone acetone
  • the salts are obtained by filtration, reprecipitation, precipitation or by evaporation of the solvent. Salts obtained can be converted into the free compounds by alkalization, for example with aqueous sodium hydrogen carbonate, which in turn can be converted into the salts. In this way, the compounds can be purified or pharmacologically unacceptable salts can be converted into pharmacologically acceptable salts.
  • the starting compounds II, III, IV, V and VI are known, or they can be prepared by known processes in an analogous manner, as described by way of example in the examples.
  • Compounds V are obtained by reacting appropriately substituted styrene oxides with suitable amino alcohols, as described, for example, in: Houben-Weyl, Methods of Organic Chemistry VI / 3, pp. 366-387.
  • a solution of 50 mmol of an alcohol L-CH 2 -X-CH 2 -OH for compounds III or 50 mmol of an alcohol HO- (CH 2 ) n -Y-Ar 2 (for compounds IV) is mixed with 50 mmol Carboxylic acid HO-CO- (CH 2 ) -Y-Ar 2 (for compounds III) or with 50 mmol of a carboxylic acid L-CH 2 -X-CH 2 -CO-OH (for compounds IV) and with 0.5 g 4-Toluenesulfonic acid in toluene heated in a Dean-Stark device until the reaction has ended (TLC control).
  • the toluene is distilled off and the residue is purified by distillation, chromatography and / or crystallization.
  • the identity of the starting compounds obtained is characterized by 1 H-NMR.
  • the compounds according to the invention have valuable pharmacological properties which make them commercially usable. They are primarily effective ß-adrenoceptor agonists (ß-sympathomimetics) with a preferred ß -, - stimulating effect, whereby they are particularly characterized by their long duration of action, their stability and selectivity and by the absence of undesirable side effects.
  • ß-adrenoceptor agonists ß-sympathomimetics
  • the compounds according to the invention are suitable, for example, for the treatment of bradycardia and conduction disorders and increase the contractility of the heart, they can be used as tocolytics for the treatment of premature labor, they generally act as vasodilants and can be used to treat (peripheral) circulatory disorders are used, they relax the bladder wall muscles and are suitable for the treatment of bladder emptying disorders, they lower the (pathologically increased) intraocular pressure and can be used for the treatment of glaucoma, they influence the metabolism and are suitable for the treatment of obesity, for example are particularly suitable for the treatment of respiratory diseases of various origins due to their ß 2 -sympathomimetic effect.
  • bronchial diseases can be treated.
  • the compounds according to the invention are notable for low toxicity, a wide therapeutic range, a long-lasting effect and reduced systemic side effects. Of particular importance in this context is - compared to systemic application - the pronounced effectiveness with topical application.
  • the broncholytic activity of the compounds according to the invention enables their use in human and veterinary medicine, where they are used for the treatment and prophylaxis of diseases which are based on diseases of the bronchi. For example, acute and chronic whether structural respiratory diseases of various origins (bronchitis, allergic bronchitis, bronchial asthma) are treated in humans and animals.
  • the properties of the compounds according to the invention also enable their use in the topical treatment of dermatoses, for example in inflammatory and allergic skin diseases, such as, for example, toxic and allergic contact dermatitis, atopic eczema, seborrheic eczema, follicular and areal pyoderma, endogenous and exogenous acne and acne rosacea.
  • the compounds according to the invention are suitable for the treatment of those disease states which are known to be positively influenced by the application of certain ⁇ -adrenoceptor agonists.
  • metabolism disorders of various origins e.g. obesity or disorders such as those associated with diabetes
  • Gastrointestinal motility disorders and pathological changes in the gastrointestinal tract for example inflammatory bowel diseases such as ulcerative colitis or Crohn's disease
  • the invention therefore furthermore relates to a method for the treatment of mammals, including humans, who are suffering from one of the abovementioned diseases.
  • the method is characterized in that the sick mammal is administered a therapeutically effective and pharmacologically acceptable amount of one or more of the compounds according to the invention.
  • the invention further relates to the compounds according to the invention for use in the treatment and / or prophylaxis of the diseases mentioned.
  • the invention also relates to the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the diseases mentioned.
  • the invention furthermore relates to medicaments for the treatment and / or prophylaxis of the diseases mentioned which contain one or more of the compounds according to the invention and / or their pharmacologically tolerable salts.
  • the medicaments according to the invention are produced by methods known per se, reference being made, for example, to the statements in European patent 163 965 with regard to the preparations, the dosage forms (in particular with regard to inhalation administration), etc.
  • inhalative administration is particularly important in the treatment of bronchial diseases, for which the compounds according to the invention appear to be outstandingly suitable due to their action profile.
  • daily doses of 0.01 to 2.0 mg, in particular 0.05 to 1.0 mg are advantageously administered in several individual doses to, for example, 10 to 50 ⁇ g of active ingredient.
  • correspondingly higher doses from 0.5 to 50 mg per day, optionally in the form of several single doses, have to be administered.
  • the excellent bronchospasmolytic activity of the compounds according to the invention can be demonstrated by in vitro investigations on the guinea pig trachea.
  • the relaxing effect on a guinea pig trachea is measured for the compounds to be examined, which has previously been contracted with a suitable dose of metacholine.
  • the trachea of male guinea pigs (200-300 g) is removed, divided into individual segments and each segment is in an organ bath with 118.5 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO 4 , 2.5 mM CaCl 2 , 1.2 mM KH 2 PO 4 , 25 mM NaHCO 3 and 10 mM glucose at 37 ° C.
  • Oxygen mixed with 5% CO 2 , is continuously passed through the solution. After stabilization, the trachea is contracted with a suitable dose of methacholine. Then a dose-response curve is recorded in a cumulative manner with the test substances. From this curve, the concentration (mol / 1) is determined, which corresponds to 50% of the maximum effect (EC 50 ). This EC 50 is thus a measure of the activity of the compounds according to the invention.
  • the following table shows the -log [EC 50 (mol / l)] values for selected compounds according to the invention.
  • the serial number in the table matches the number of the connections in the examples.
  • the number n indicates the number of examinations.

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Abstract

The invention concerns compounds of the formula (I): Ar1-CH(OH)-CH2-NH-CH2-X-CH2-E-(CH2)n-Y-Ar2, in which the substituents and the symbols are as defined in the description. Such compounds are active substances with, in particular, a broncholytic action.

Description

Substituierte Ethanolaminester  Substituted ethanolamine esters
Anwendungsgebiet der Erfindung Field of application of the invention
Die Erfindung betrifft neue Verbindungen, Verfahren zu ihrer Herstellung und ihre Anwendung als Wirkstoffe in Arzneimitteln. The invention relates to new compounds, processes for their preparation and their use as active ingredients in pharmaceuticals.
Bekannter technischer Hintergrund Known technical background
In den deutschen Patentanmeldungen DE 37 04 223 und DE 4028398 sowie in den europäischen Patentanmeldungen EP 278 727, EP 278728, EP 286 242, EP 303 464, EP 303 465, EP 303 466 und EP 422 889 werden verschiedenartig substituierte Ethanolaminderivate beschrieben, die sich aufgrund ihrer ß2-adrenozeptor-agonistischen Eigenschaften insbesondere zur Behandlung von Atemwegserkrankungen eignen sollen. - Im britischen Patent 893,088 werden substituierte Amine beschrieben, die blutdrucksenkende und zum Teil auch spasmolytische Eigenschaften aufweisen sollen. Die in diesem Patent offenbarten Verbindungen stellen auf bestimmte Weise substituierte Phenylethylamine dar, die am Stickstoffatom durch einen Alkylenoxycarbonylphenylrest substituiert sind, wobei dieser direkt an die Carbonylgruppe gebundene Phenylrest durch drei Hydroxy- bzw. Alkoxygruppen substituiert sein muß. - In der deutschen Auslegeschrift 11 26889 werden ebenfalls (vom Reserpin hergeleitete) substituierte Amine mit blutdrucksenkender und spasmolyti scher Wirkung beschrieben, bei denen der direkt an die Carbonylgruppe gebundene Phenylrest durch mindestens einen Hydroxy- oder Alkoxyrest sowie gegebenenfalls noch durch einen weiteren Hydroxy- oder Alkoxyrest substituiert sei n muß. In the German patent applications DE 37 04 223 and DE 4028398 as well as in the European patent applications EP 278 727, EP 278728, EP 286 242, EP 303 464, EP 303 465, EP 303 466 and EP 422 889 variously substituted ethanolamine derivatives are described, which are due to their ß 2- adrenoceptor agonistic properties should be particularly suitable for the treatment of respiratory diseases. - British patent 893,088 describes substituted amines which are said to have hypotensive and in part also spasmolytic properties. The compounds disclosed in this patent represent in a certain way substituted phenylethylamines which are substituted on the nitrogen atom by an alkyleneoxycarbonylphenyl radical, which phenyl radical bonded directly to the carbonyl group must be substituted by three hydroxyl or alkoxy groups. - German Auslegeschrift 11 26889 also describes (derived from reserpine) substituted amines with hypotensive and spasmolytic effects, in which the phenyl radical bonded directly to the carbonyl group by at least one hydroxyl or alkoxy radical and optionally also by a further hydroxyl or alkoxy radical must be substituted.
Beschreibung der Erfindung Description of the invention
Es wurde nun eine neue Gruppe substituierter Ethanolaminderivate gefunden, die sich strukturell von den Verbindungen des Standes der Technik durch eine hydrol isi erbare Estergruppe bzw. durch eine größere Kettenlänge oder ei ne ganz bestimmte Substitution unterscheiden. Gegenstand der Erfindung sind somit in einem ersten Aspekt Verbindungen der Formel I, A new group of substituted ethanolamine derivatives has now been found, which differs structurally from the compounds of the prior art by a hydrolyzable ester group or by a larger chain length or egg distinguish a very specific substitution. The invention thus relates in a first aspect to compounds of the formula I
Ar1 -CH(OH)-CH2 -NH - CH2 -X-CH2 -E-(CH2)n -Y-Ar2 (I) worin Ar 1 -CH (OH) -CH 2 -NH - CH 2 -X-CH 2 -E- (CH 2 ) n -Y-Ar 2 (I) wherein
X 1-12C-Alkylen, 1-6C-Alkylenoxy-1-6C-alkylen oder Cyclohexylen bedeutet, E Carbonyloxy (-CO_O-) oder Oxycarbonyl (-O-CO-) bedeutet,  X is 1-12C-alkylene, 1-6C-alkyleneoxy-1-6C-alkylene or cyclohexylene, E is carbonyloxy (-CO_O-) or oxycarbonyl (-O-CO-),
n eine ganze Zahl von 0 bis 10 bedeutet, n is an integer from 0 to 10,
Y einen Bindungsstrich, Sauerstoff (0), Schwefel (S), die Gruppe -CHR-, in der R die Bedeutung 1-4C-Alkyl, Phenyl oder Hydroxy hat, oder die Gruppen -CR' 2- oder -CHR'-CH2O- bedeutet, in denen R' die Bedeutung 1 -4C-A1 kyl hat, wobei Y nicht Sauerstoff ist, wenn n die Zahl 0 bedeutet, Y is a bond, oxygen (0), sulfur (S), the group -CHR-, in which R is 1-4C-alkyl, phenyl or hydroxy, or the groups -CR ' 2 - or -CHR'-CH 2 is O-, in which R 'is 1 -4C-A1 kyl, where Y is not oxygen if n is the number 0,
Ar, einen durch R1, R2 und R3 substituierten Phenylrest bedeutet, Ar represents a phenyl radical substituted by R1, R2 and R3,
wobei  in which
R1 Wasserstoff, Halogen, Hydroxy (-OH), Amino (-NH2), Ureido R1 is hydrogen, halogen, hydroxy (-OH), amino (-NH 2 ), ureido
(-NH-CO-NH2), Formylamino (-NH-COH), 1-4C-Alkylcarbonyl amino (-NH-CO-1-4C-Alkyl), Di-1-4C-alkyl-carbamoyloxy [-O-CO-N(1-4C- Alkyl)2], Toluoyloxy (-O-CO-C6H4-CH3), Hydroxymethyl (-CH2OH), 1-4C-Alkylcarbonyloxy (-O-CO-1-4C-Alkyl), 1-4C-Alkyl, 1-4C-Alkoxy, 1-4C-Alkylsulfonyl amino (-NH-SO2-1-4C-Alkyl), 1-4C-Alkylsulfonylmethyl (-CH2-SO2-1-4C-Alkyl) oder 1-4C-Alkoxy-1-4C-alkyl bedeutet, R2 Wasserstoff, Halogen, Hydroxy (-OH), Cyan (-CN), Trifluormethyl (-CF3), Toluoyloxy (-O-CO-C6H4-CH3), Hydroxymethyl (-CH2OH) oder 1-4C-A1kylcarbonyloxy (-O-CO-1-4C-Alkyl) bedeutet und (-NH-CO-NH 2 ), formylamino (-NH-COH), 1-4C-alkylcarbonyl amino (-NH-CO-1-4C-alkyl), di-1-4C-alkyl-carbamoyloxy [-O- CO-N (1-4C-alkyl) 2 ], toluoyloxy (-O-CO-C 6 H 4 -CH 3 ), hydroxymethyl (-CH 2 OH), 1-4C-alkylcarbonyloxy (-O-CO-1- 4C-alkyl), 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylsulfonylamino (-NH-SO 2 -1-4C-alkyl), 1-4C-alkylsulfonylmethyl (-CH 2 -SO 2 - 1-4C-alkyl) or 1-4C-alkoxy-1-4C-alkyl means R2 means hydrogen, halogen, hydroxy (-OH), cyano (-CN), trifluoromethyl (-CF 3 ), toluoyloxy (-O-CO -C 6 H 4 -CH 3 ), hydroxymethyl (-CH 2 OH) or 1-4C-alkylcarbonyloxy (-O-CO-1-4C-alkyl) and
R3 Wasserstoff oder Halogen bedeutet,  R3 represents hydrogen or halogen,
und  and
Ar2 einen durch R4 und R5 substituierten Phenylrest, einen Thienylrest, einen Pyridylrest, einen Naphthylrest, einen Indolylrest, einen Indanyl- rest oder einen Benzo-1,4-dioxanylrest bedeutet, wobei Ar 2 represents a phenyl radical substituted by R4 and R5, a thienyl radical, a pyridyl radical, a naphthyl radical, an indolyl radical, an indanyl radical or a benzo-1,4-dioxanyl radical, where
R4 Wasserstoff, Halogen, Hydroxy (-OH), Cyan (-CN), 1-4C-Alkyl,  R4 is hydrogen, halogen, hydroxy (-OH), cyan (-CN), 1-4C-alkyl,
1-4C-Alkoxy, Benzyloxy, Nitro (-NCL), Trifluormethyl (-CF3), 1-4C-Alkoxycarbonyl (-CO-O-1-4C-Alkyl), Carbamoyl (-CO-NH2), Di-1-4C-alkylcarbamoyl [-CO-N(1-4C-Alkyl)2], Amino (-NH2), 1-4C-alkoxy, benzyloxy, nitro (-NCL), trifluoromethyl (-CF 3 ), 1-4C-alkoxycarbonyl (-CO-O-1-4C-alkyl), carbamoyl (-CO-NH 2 ), di- 1-4C-alkylcarbamoyl [-CO-N (1-4C-alkyl) 2 ], amino (-NH 2 ),
1-4C-Alkylsulfonyl, Phenyl oder Phenyl carbonyl amino bedeutet und R5 Wasserstoff, Halogen, Hydroxy (-OH), 1 -4C-Alkyl oder 1-4C-Alkoxy bedeutet, 1-4C-Alkylsulfonyl, phenyl or phenyl carbonyl amino means and R5 denotes hydrogen, halogen, hydroxy (-OH), 1 -4C-alkyl or 1-4C-alkoxy,
wobei R4 nicht Hydroxy oder l-4C-Alkoxy bedeutet, wenn E Oxycarbonyl (-O-CO-), n die Zahl 0 und Y einen Bindungsstrich bedeutet, und wobei R1 und R2 nicht gleichzeitig Hydroxy bedeuten, wenn X 1-4C-Alkylen und E Carbonyloxy (-CO-O-) bedeutet,  where R4 is not hydroxy or 1-4C-alkoxy when E is oxycarbonyl (-O-CO-), n is 0 and Y is a hyphen, and where R1 and R2 are not simultaneously hydroxy when X is 1-4C-alkylene and E denotes carbonyloxy (-CO-O-),
und die Salze dieser Verbindungen.  and the salts of these compounds.
1-12C-A1 kylen steht für geradkettige oder verzweigte Alkylenreste mit 1 bis 12 Kohlenstoffatomen. Beispielsweise seien die Reste Methylen (-CH2-), Et- hylen (-CH2CH2-). Trimethylen (-CH2CH2CH2-) , Tetramethylen 1-12C-A1 kylen stands for straight-chain or branched alkylene radicals with 1 to 12 carbon atoms. For example, the residues are methylene (-CH 2 -), ethylene (-CH 2 CH 2 -). Trimethylene (-CH 2 CH 2 CH 2 -), tetramethylene
(-CH2CH2CH2CH2-), Pentamethylen (-CH2CH2CH2CH2CH2-) , Hexamethylen (-CH 2 CH 2 CH 2 CH 2 -), pentamethylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexamethylene
(-CH2-(CH2)4-CH2-), Octamethylen (-CH2-(CH2)6-CH2-), Decamethylen (-CH 2 - (CH 2 ) 4 -CH 2 -), octamethylene (-CH 2 - (CH 2 ) 6 -CH 2 -), decamethylene
(-CH2-(CH2)8_CH2-), Dodecamethylen (-CH2-(CH2)10-CH2-), 1,2-Dimethylethylen [-CH(CH3)-CH(CH3)-], 1,1-Dimethylethylen [-C(CH3)2-CH2-], Isopropyliden [-C(CH3)2-], 2,2-Dimethylpropylen [-CH2-C(CH3)2-CH2-], 2-Methylpropylen [-CH2-CH(CH3)-CH2-] und 2-Methylethylen [-CH2-CH(CH3)-] genannt. l-6C-Alkylenoxy-1-6C-al kylen steht für geradkettige oder verzweigte Alkylenreste mit 1 bis 6 Kohlenstoffatomen, die durch geradkettige oder verzweigte 1-6C-Alkylenoxyreste substituiert sind. Beispielsweise seien der Ethoxyethylen- (-CH2-CH2-O-CH2-CH2-) und der Methoxymethylenrest (-CH 2 - (CH 2 ) 8 _CH 2 -), dodecamethylene (-CH 2 - (CH 2 ) 10 -CH 2 -), 1,2-dimethylethylene [-CH (CH 3 ) -CH (CH 3 ) -], 1,1-Dimethylethylene [-C (CH 3 ) 2 -CH 2 -], isopropylidene [-C (CH 3 ) 2 -], 2,2-dimethylpropylene [-CH 2 -C (CH 3 ) 2 -CH 2 -], 2-methylpropylene [-CH 2 -CH (CH 3 ) -CH 2 -] and 2-methylethylene [-CH 2 -CH (CH 3 ) -]. 1-6C-Alkyleneoxy-1-6C-alkylene represents straight-chain or branched alkylene radicals having 1 to 6 carbon atoms which are substituted by straight-chain or branched 1-6C-alkyleneoxy radicals. Examples are the ethoxyethylene (-CH 2 -CH 2 -O-CH 2 -CH 2 -) and the methoxymethylene residue
(-CH2-O-CH2-) genannt. (-CH 2 -O-CH 2 -) called.
Als Cyclohexylenreste seien der 1,2-, der 1,3- und insbesondere der 1,4-Cyclohexylenrest erwähnt. The 1,2-, the 1,3- and in particular the 1,4-cyclohexylene radical may be mentioned as cyclohexylene radicals.
1 -4C-Alkyl steht für geradkettige oder verzweigte Alkylreste mit 1 bis 4 Kohlenstoffatomen. Beispielsweise seien genannt der Butyl-, iso-Butyl-, sec.-Butyl-, tert. -Butyl-, Propyl-, Isopropyl-, Ethyl - und insbesondere der Methyl rest. 1 -4C-alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples include butyl, iso-butyl, sec-butyl, tert. -Butyl, propyl, isopropyl, ethyl - and especially the methyl rest.
Halogen im Sinne der vorliegenden Erfindung ist Brom, Chlor und Fluor. Halogen in the sense of the present invention is bromine, chlorine and fluorine.
Als 1-4C-Alkylcarbonylaminorest sei beispielsweise der Acetylamidorest (-NH-CO-CH3) genannt. Als Di-1-4C-alkylcarbamoyloxyrest sei beispielsweise der Dimethylcarbamoyloxyrest [-O-CO-N(CH3)2] genannt. The 1-4C-alkylcarbonylamino radical, for example, is the acetylamido radical (-NH-CO-CH 3 ). The dimethylcarbamoyloxy radical [-O-CO-N (CH 3 ) 2 ] may be mentioned as the di-1-4C-alkylcarbamoyloxy radical.
Als 1-4C-Alkyl carbonyl oxyrest seien beispielsweise der tert.-Butylcarbonyloxyrest und der Isopropyl carbonyl oxyrest erwähnt. As the 1-4C-alkyl carbonyl oxy group, for example, the tert-butyl carbonyloxy group and the isopropyl carbonyl oxy group may be mentioned.
1-4C-Alkoxyreste enthalten neben dem Sauerstoffatom einen der vorstehend genannten 1-4C-Alkylreste. Bevorzugt ist der Methoxyrest. In addition to the oxygen atom, 1-4C-alkoxy radicals contain one of the 1-4C-alkyl radicals mentioned above. The methoxy radical is preferred.
Als 1-4C-Alkylsulfonylaminorest sei beispielsweise der Methylsulfonylaminorest (-NH-SO2-CH3) genannt. As a 1-4C-alkylsulfonylamino radical, for example, the methylsulfonylamino radical (-NH-SO 2 -CH 3 ) may be mentioned.
Als 1-4C-Alkylsulfonylmethylrest sei beispielsweise der Methyl sulfonylmethylrest (-CH2-SO2-CH3) genannt. As the 1-4C-alkylsulfonylmethyl radical, for example, the methyl sulfonylmethyl radical (-CH 2 -SO 2 -CH 3 ) may be mentioned.
Als 1-4C-Alkoxy-1-4C-alkylrest sei der Methoxymethylrest (-CH2-O-CH3) erwähnt. The methoxymethyl radical (-CH 2 -O-CH 3 ) may be mentioned as the 1-4C-alkoxy-1-4C-alkyl radical.
Als beispielhafte Reste Ar, seien die Reste 4-Aminophenyl, 3,4-Dihydroxy- phenyl, 3,5-Dihydroxyphenyl, 3,5-Bis-dimethylaminocarbonyloxyphenyl, 3,5-Bis-toluoyloxyphenyl, 4-Hydroxy-3-ureidophenyl, 3-Formylamino-4-hydroxyphenyl, 4-Hydroxyphenyl, 3-Amino-5-hydroxyphenyl, 2-Fluorphenyl, 3-Amino-5-hydroxymethylphenyl, 4-Amino-3-cyanphenyl, 3,5-Di-tert.-butylcarbonyloxyphenyl, 3,5-Di-isopropylcarbonyloxyphenyl, 2-Chlor-4-hydroxyphenyl, 2-Fluor-4-hydroxyphenyl, 3-Fluor-4-hydroxyphenyl, 4-Hydroxy-3-methoxyphenyl, 4-Hydroxy-3-methoxymethylphenyl, 4-Hydroxy-3-methylsulfonamidophenyl und 4-Hydroxy-3-methylsulfonylmethyl phenyl genannt. Exemplary radicals Ar are the radicals 4-aminophenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3,5-bis-dimethylaminocarbonyloxyphenyl, 3,5-bis-toluoyloxyphenyl, 4-hydroxy-3-ureidophenyl, 3-formylamino-4-hydroxyphenyl, 4-hydroxyphenyl, 3-amino-5-hydroxyphenyl, 2-fluorophenyl, 3-amino-5-hydroxymethylphenyl, 4-amino-3-cyanophenyl, 3,5-di-tert-butylcarbonyloxyphenyl , 3,5-di-isopropylcarbonyloxyphenyl, 2-chloro-4-hydroxyphenyl, 2-fluoro-4-hydroxyphenyl, 3-fluoro-4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-hydroxy-3-methoxymethylphenyl, 4 -Hydroxy-3-methylsulfonamidophenyl and 4-hydroxy-3-methylsulfonylmethyl phenyl called.
Als hervorzuhebende Reste Ar, seien die Reste Phenyl, 2-Chlorphenyl, 3-Hydroxyphenyl und 4-Amino-3-chlor-5-trifluormethylphenyl genannt. Ar to be emphasized are the residues phenyl, 2-chlorophenyl, 3-hydroxyphenyl and 4-amino-3-chloro-5-trifluoromethylphenyl.
Als bevorzugte Reste Ar, seien die Reste 3-Hydroxymethyl-4-hydroxyphenyl, 4-Amino-3,5-dichlorphenyl und 4-Amino-3-chlor-5-cyanphenyl genannt. The preferred residues Ar are the residues 3-hydroxymethyl-4-hydroxyphenyl, 4-amino-3,5-dichlorophenyl and 4-amino-3-chloro-5-cyanophenyl.
Als 1-4C-Alkoxycarbonylreste R4 seien der Methoxycarbonyl - und der Eihoxy- carbonylrest erwähnt. Als Di-1-4C-alkylcarbamoylrest R4 sei der Diethylcarbamoylrest erwähnt. As the 1-4C-alkoxycarbonyl radicals R4, the methoxycarbonyl and the eihoxycarbonyl radicals may be mentioned. The diethylcarbamoyl radical may be mentioned as the di-1-4C-alkylcarbamoyl radical R4.
Als 1-4C-Alkylsulfonylrest R4 sei der Methyl sulfonyl rest erwähnt. The methyl sulfonyl radical may be mentioned as the 1-4C-alkylsulfonyl radical R4.
Als hervorzuhebende Reste Ar2 seien die Reste Phenyl, 3-Fluorphenyl, 4-Fluorphenyl, 4-Methoxyphenyl, 2-Trifluormethylphenyl, 3-Trifluormethylphenyl, 2-Nitrophenyl, 3-Nitrophenyl, 4-Nitrophenyl, 2-Methylphenyl, 4-Me- thylphenyl, 4-Benzyloxyphenyl, 3,5-Dimethylphenyl, 4-Propoxyphenyl, 2-Cyanphenyl, 4-Cyanphenyl, 4-Methyl sulfonylphenyl, 4-Bromphenyl, 2-Chlor-6- fluorphenyl, 3-Chlorphenyl, 4-Chlorphenyl, 4-Ethoxyphenyl, 2-Phenylcarbonylaminophenyl, 2-Phenylphenyl, 3-Phenylphenyl, 4-Phenylphenyl, 2-Naphthyl, 2-Thienyl, 3-Thienyl, 3-Pyridyl, 2-Indanyl und 2-Benzodioxanyl genannt. Ar 2 to be emphasized are the residues phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-methylphenyl, 4-Me- thylphenyl, 4-benzyloxyphenyl, 3,5-dimethylphenyl, 4-propoxyphenyl, 2-cyanphenyl, 4-cyanphenyl, 4-methyl sulfonylphenyl, 4-bromophenyl, 2-chloro-6-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4 -Ethoxyphenyl, 2-phenylcarbonylaminophenyl, 2-phenylphenyl, 3-phenylphenyl, 4-phenylphenyl, 2-naphthyl, 2-thienyl, 3-thienyl, 3-pyridyl, 2-indanyl and 2-benzodioxanyl.
Als bevorzugte Reste Ar2 seien die Reste 2-Hydroxyphenyl, 3-Hydroxyphenyl, 4-Hydroxyphenyl, 2-Fluorphenyl, 3-Methylphenyl, 2-Methoxyphenyl, 3-Methoxyphenyl, 2-Chlorphenyl, 1-Naphthyl, 3-Indolyl und 2-Pyridyl genannt. Ar 2 are the preferred residues 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-fluorophenyl, 3-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-chlorophenyl, 1-naphthyl, 3-indolyl and 2- Called pyridyl.
Als Salze kommen für Verbindungen der Formel I bevorzugt alle Säureadditionssalze in Betracht. Besonders erwähnt seien die pharmakologisch verträglichen Salze der in der Galenik üblicherweise verwendeten anorganischen und organischen Säuren. Pharmakologisch unverträgliche Salze, die beispielsweise bei der Herstellung der erfindungsgemäßen Verbindungen im industriellen Maßstab als Verfahrensprodukte zunächst anfallen können, werden durch dem Fachmann bekannte Verfahren in pharmakologisch verträgliche Salze übergeführt. Als solche eignen sich wasserlösliche und wasserunlösliche Säureadditionssalze mit Säuren wie beispielsweise Salzsäure, Bromwasserstoffsäure, Phosphorsäure, Salpetersäure, Schwefelsäure, Essigsäure, Zitronensäure, D-Gluconsäure, Benzoesäure, 2-(4-Hydroxybenzoyl)-benzoesäure, Buttersäure, Sulfosalicyl säure, Maleinsäure, Laurinsäure, Äpfelsäure, Fumarsäure, Bernsteinsäure, Oxalsäure, Weinsäure, Embonsäure, Stearinsäure, Toluolsulfon- säure, Methansulfonsäure oder 3-Hydroxy-2-naphtoesäure, wobei die Säuren bei der Salzherstellung - je nachdem, ob es sich um eine ein- oder mehrbasige Säure handelt und je nachdem, welches Salz gewünscht wird - im äquimolaren oder einem davon abweichenden Mengenverhältnis eingesetzt werden. In den Verbindungen der Formel I liegt mindestens ein Chiral itätszentrum [am Kohlenstoffatom -CH(OH)-] vor, durch entsprechende Verzweigungen in den Gruppen X und Y können noch weitere Chiralitätszentren hinzukommen. Die Erfindung umfaßt alle Enantiomeren und Diastereomeren sowie deren Gemische einschließlich der Racemate. Verbindungen der Formel I, in denen die Substituenten am Kohlenstoffatom -CH(OH)- in der absoluten Konfiguration R (gemäß den Regeln von Cahn, Ingold und Prelog) angeordnet sind, sind bevorzugt. Suitable salts for compounds of the formula I are preferably all acid addition salts. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids commonly used in galenics. Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art. Suitable as such are water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid , Malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids used in salt production - depending on whether it is a mono- or polybasic acid and depending on which salt is desired - be used in an equimolar or a different ratio. There is at least one chiral center [at the carbon atom -CH (OH) -] in the compounds of the formula I, and additional chiral centers can be added by corresponding branches in the groups X and Y. The invention encompasses all enantiomers and diastereomers and their mixtures, including the racemates. Compounds of the formula I in which the substituents on the carbon atom -CH (OH) - are arranged in the absolute configuration R (according to the rules of Cahn, Ingold and Prelog) are preferred.
Hervorzuheben sind solche Verbindungen der Formel I, Of particular note are those compounds of formula I
worin wherein
X 1-6C-Alkylen, 1-2C-Alkylenoxy-1-2C-alkylen oder Cyclohexylen bedeutet, X denotes 1-6C-alkylene, 1-2C-alkyleneoxy-1-2C-alkylene or cyclohexylene,
E Carbonyloxy (-CO-O-) oder Oxycarbonyl (-O-CO-) bedeutet, E denotes carbonyloxy (-CO-O-) or oxycarbonyl (-O-CO-),
n eine ganze Zahl von 1 bis 5 bedeutet, n is an integer from 1 to 5,
Y einen Bindungsstrich, Sauerstoff (0) oder die Gruppe -CHR- bedeutet, in der R die Bedeutung 1-4C-Alkyl hat,  Y denotes a bond line, oxygen (0) or the group -CHR-, in which R denotes 1-4C-alkyl,
Ar1 einen durch R1, R2 und R3 substituierten Phenylrest bedeutet, Ar 1 represents a phenyl radical substituted by R1, R2 and R3,
wobei  in which
R1 Wasserstoff, Hydroxy oder Amino (-NH2) bedeutet, R1 denotes hydrogen, hydroxy or amino (-NH 2 ),
R2 Wasserstoff, Halogen, Cyan, Trifluormethyl oder Hydroxymethyl bedeutet und  R2 is hydrogen, halogen, cyan, trifluoromethyl or hydroxymethyl and
R3 Wasserstoff oder Halogen bedeutet,  R3 represents hydrogen or halogen,
und  and
Ar2 einen durch R4 und R5 substituierten Phenylrest, einen Thienylrest, einen Pyridylrest, einen Naphthylrest, einen Indolylrest oder einen Inda- nylrest bedeutet, wobei Ar 2 represents a phenyl radical substituted by R4 and R5, a thienyl radical, a pyridyl radical, a naphthyl radical, an indolyl radical or an indanyl radical, where
R4 Wasserstoff, Halogen, Hydroxy (-0H), Cyan (-CN), 1-4C-Alkyl, 1-4C- Alkoxy, Benzyloxy, Nitro (-NCL) oder Trifluormethyl (-CF3), bedeutet und R4 is hydrogen, halogen, hydroxy (-0H), cyano (-CN), 1-4C-alkyl, 1-4C-alkoxy, benzyloxy, nitro (-NCL) or trifluoromethyl (-CF 3 ), and
R5 Wasserstoff, Halogen oder 1-4C-Alkyl bedeutet,  R5 denotes hydrogen, halogen or 1-4C-alkyl,
und die Salze dieser Verbindungen. and the salts of these compounds.
Besonders hervorzuheben sind solche Verbindungen der Formel I, Of particular note are those compounds of formula I
worin X 3-4C-Alkylen bedeutet, wherein X means 3-4C-alkylene,
E Carbonyloxy (-CO-O-) oder Oxycarbonyl (-O-CO-) bedeutet,  E denotes carbonyloxy (-CO-O-) or oxycarbonyl (-O-CO-),
n die Zahl 1 oder 2 bedeutet, n represents the number 1 or 2,
Y einen Bindungsstrich bedeutet,  Y means a dash,
Ar1 Phenyl, 4-Amino-3-chlor-5-cyanphenyl, 4-Hydroxy-3-hydroxymethyl phenyl oder 4-Amino-3,5-dichlorphenyl bedeutet, Ar 1 denotes phenyl, 4-amino-3-chloro-5-cyanophenyl, 4-hydroxy-3-hydroxymethylphenyl or 4-amino-3,5-dichlorophenyl,
und and
Ar2 einen durch R4 und R5 substituierten Phenylrest oder einen 1-Naphthylrest bedeutet, wobei Ar 2 represents a phenyl radical substituted by R4 and R5 or a 1-naphthyl radical, where
R4 Wasserstoff, Chlor, Fluor, Hydroxy (-OH), 1-4C-Alkyl oder 1-4C- Alkoxy bedeutet und  R4 is hydrogen, chlorine, fluorine, hydroxy (-OH), 1-4C-alkyl or 1-4C-alkoxy and
R5 Wasserstoff bedeutet,  R5 means hydrogen
und die Salze dieser Verbindungen. and the salts of these compounds.
Als beispielhafte erfindungsgemäße Verbindungen seien genannt Examples of compounds according to the invention are mentioned
[6-(2-Hydroxy-2-phenylethylamino)-1-hexyl]-diphenylacetat, [6- (2-hydroxy-2-phenylethylamino) -1-hexyl] diphenylacetate,
[6-(2-Hydroxy-2-phenylethylamino)-1-hexyl]-2-phenyl-butanoat, [6- (2-hydroxy-2-phenylethylamino) -1-hexyl] -2-phenyl butanoate,
[7-(2-Hydroxy-2-phenylethylamino)-1-heptyl]-4-phenyl-butanoat, [7- (2-hydroxy-2-phenylethylamino) -1-heptyl] -4-phenyl-butanoate,
3-Phenylpropyl-4-(2-hydroxy-2-phenylethylamino)butanoat, 3-phenylpropyl-4- (2-hydroxy-2-phenylethylamino) butanoate,
[6-(2-Hydroxy-2-phenylethylamino)-1-hexyl]nicotinat, [6- (2-hydroxy-2-phenylethylamino) -1-hexyl] nicotinate,
2-(2-Hydroxyphenoxy)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat, 2- (2-hydroxyphenoxy) ethyl 6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate,
{6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-phenyl¬glycolat,  {6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} phenyl glycolate,
2-(2-Trifluormethylphenyl)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat,  2- (2-trifluoromethylphenyl) ethyl 6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate,
2-Phenylethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-hexanoat,  2-phenylethyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate,
3-Phenylpropyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-hexanoat,  3-phenylpropyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate,
5-Phenylpentyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-hexanoat,  5-phenylpentyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate,
2-(4-Benzyloxyphenoxy)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat,  2- (4-benzyloxyphenoxy) ethyl 6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate,
2-(3,5-Dimethylphenoxy)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat, 3-(4-Hydroxyphenyl)propyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat, 2- (3,5-dimethylphenoxy) ethyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate, 3- (4-hydroxyphenyl) propyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate,
2-(4-Propoxyphenoxy)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat,  2- (4-propoxyphenoxy) ethyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate,
4-Phenylbutyl-[6-(2-hydroxy-2-phenylethylamino)]hexanoat,  4-phenylbutyl- [6- (2-hydroxy-2-phenylethylamino)] hexanoate,
2-(2-Nitrophenyl)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat,  2- (2-nitrophenyl) ethyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate,
2-(2-Cyanphenoxy)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat,  2- (2-cyanophenoxy) ethyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate,
(6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-5-phenylvalerat  (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -5-phenylvalerate
und die Salze dieser Verbindungen. and the salts of these compounds.
Weiterer Gegenstand der Erfindung ist ein Verfahren zur Herstellung der Verbindungen der Formel I und ihrer Salze. Das Verfahren ist dadurch gekennzeichnet, daß man a) zur Herstellung der Verbindungen I, in denen E die Bedeutung Oxycarbonyl hat, Verbindungen der Formel II, The invention further relates to a process for the preparation of the compounds of the formula I and their salts. The process is characterized in that a) for the preparation of the compounds I in which E is oxycarbonyl, compounds of the formula II,
Ar1 -CH(OH)-CH2-NH2 (II) worin Ar1 die oben angegebene Bedeutung hat, mit Verbindungen der Formel III, Ar 1 -CH (OH) -CH 2 -NH 2 (II) in which Ar 1 has the meaning given above, with compounds of the formula III,
L-CH2-X-CH2-O-CO-(CH2)n-Y-Ar2 (II!) wori n X , n , Y und Ar2 die oben angegebenen Bedeutungen haben und L eine geeignete Abgangsgruppe darstellt, umsetzt, oder daß man b) zur Herstellung der Verbindungen I, in denen E die Bedeutung Carbonyloxy hat, Verbindungen der Formel II, L-CH 2 -X-CH 2 -O-CO- (CH 2 ) n -Y-Ar 2 (II!) Where X, n, Y and Ar 2 have the meanings given above and L represents a suitable leaving group, implemented, or that b) for the preparation of the compounds I in which E is carbonyloxy, compounds of the formula II,
Ar1-CH(OH)-CH2-NH2 (II) worin Ar, die oben angegebene Bedeutung hat, mit Verbindungen der Formel IV, L- CH2 - X - CH2 - CO - O - (CH2)n - Y - Ar2 (IV) worin X, n, Y und Ar2 die oben angegebenen Bedeutungen haben und L eine geeignete Abgangsgruppe darstellt, umsetzt, oder daß man c) zur Herstellung der Verbindungen I, in denen E die Bedeutung Oxycarbonyl hat, Verbindungen der Formel V, Ar 1 -CH (OH) -CH 2 -NH 2 (II) in which Ar has the meaning given above with compounds of the formula IV, L - CH 2 - X - CH 2 - CO - O - (CH 2 ) n - Y - Ar 2 (IV) in which X, n, Y and Ar 2 have the meanings given above and L represents a suitable leaving group, or that c) for the preparation of the compounds I in which E is oxycarbonyl, compounds of the formula V,
Ar1-CH(OH)-CH2-NH-CH2-X-CH2-OH (V) worin Ar, und X die oben angegebenen Bedeutungen haben, mit Verbindungen der Formel VI, Ar 1 -CH (OH) -CH 2 -NH-CH 2 -X-CH 2 -OH (V) in which Ar and X have the meanings given above, with compounds of the formula VI,
2-CO-(CH2)n-Y-Ar2 (VI) worin n, Y und Ar- die oben angegebenen Bedeutungen haben und Z OH 2-CO- (CH 2 ) n -Y-Ar 2 (VI) wherein n, Y and Ar- have the meanings given above and Z OH
(Hydroxy) oder eine geeignete Abgangsgruppe darstellt, umsetzt, und daß man gewünschtenfalls anschließend die nach a), b) oder c) erhaltenen Verbindungen I in ihre Salze überführt, oder daß man gewünschtenfalls anschließend aus erhaltenen Salzen der Verbindungen I die Verbindungen I freisetzt.  Represents (hydroxy) or a suitable leaving group, and that, if desired, the compounds I obtained according to a), b) or c) are subsequently converted into their salts, or if desired the compounds I are subsequently released from the salts of the compounds I obtained.
Die Umsetzung der Verbindungen II mit den Verbindungen III bzw. IV erfolgt auf eine dem Fachmann an sich vertraute Weise in inerten, vorzugsweise polaren Lösungsmitteln, beispielsweise in Methanol, Ethanol, 1- oder 2-Pro- panol , Dimethylformamid, Tetrahydrofuran, Aceton, Methylethylketon, Methyl - isobutylketon oder Dioxan, bei Temperaturen zwischen 10 und 120°C, vorzugsweise zwischen 50 und 100ºC, gegebenenfalls bei der Siedetemperatur des verwendeten Lösungsmittels. The reaction of the compounds II with the compounds III or IV is carried out in a manner known per se to the person skilled in the art in inert, preferably polar solvents, for example in methanol, ethanol, 1- or 2-propanol, dimethylformamide, tetrahydrofuran, acetone, methyl ethyl ketone , Methyl isobutyl ketone or dioxane, at temperatures between 10 and 120 ° C, preferably between 50 and 100 ° C, optionally at the boiling point of the solvent used.
Die Umsetzung wird in Gegenwart einer Base, z.B. eines tertiären organischen Amins, wie Diisopropylethylamin, oder eines anorganischen Carbonates, wie Kaliumcarbonat, durchgeführt. The reaction is carried out in the presence of a base, e.g. a tertiary organic amine, such as diisopropylethylamine, or an inorganic carbonate, such as potassium carbonate.
Welche Abgangsgruppen L geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. So kommen beispielsweise die Tosylat- oder die Mesy- latgruppe, insbesondere aber Halogenatome, und hier vor allem Chlor oder Brom infrage. Bei Verwendung von Chlor- oder Bromverbindungen III bzw. IV kann die Umsetzung vorteilhafterweise auch in Gegenwart katalytischer Mengen eines Iodids, wie beispielsweise Kaliumiodid erfolgen. The person skilled in the art is familiar with which leaving groups L are suitable on the basis of his specialist knowledge. For example, the tosylate or mesy lat group, but especially halogen atoms, and especially chlorine or bromine. If chlorine or bromine compounds III or IV are used, the reaction can advantageously also take place in the presence of catalytic amounts of an iodide, such as, for example, potassium iodide.
Die Umsetzung der Verbindungen V mit den Verbindungen VI erfolgt in an sich bekannter Weise, wie sie dem Fachmann aufgrund seines Fachwissens über Veresterungsreaktionen bekannt ist. Die Veresterung erfolgt in inerten Lösungsmitteln, wie beispielsweise Dioxan oder Tetrahydrofuran, und je nach Art der Gruppe Z entweder in Gegenwart eines wasserabspaltenden bzw. Wasser chemisch bindenden Mittels, wie beispielsweise Dicyclohexylcarbodiimid (wenn Z = OH), oder in Gegenwart von 4-Toluolsulfonsäure. oder in Gegenwart einer Hilfsbase (z.B. Triethylamin), wenn Z eine Abgangsgruppe, beispielsweise ein Halogenatom (insbesondere Chlor) darstellt. Bevorzugt erfolgt die Veresterung ausgehend von der Carbonsäure (Z = OH) in einem Dean-Stark-Gerät, unter sauren Reaktionsbedingungen wie beschrieben von M. Bodanszky und A. Bodanszky in : "The Practice of Peptide Synthesis" (Springer-Verlag, Berlin, 1984, S. 37). The reaction of the compounds V with the compounds VI takes place in a manner known per se, as is known to the person skilled in the art on the basis of his specialist knowledge of esterification reactions. The esterification takes place in inert solvents, such as, for example, dioxane or tetrahydrofuran, and, depending on the type of group Z, either in the presence of a water-releasing or water-chemically binding agent, such as, for example, dicyclohexylcarbodiimide (if Z = OH), or in the presence of 4-toluenesulfonic acid. or in the presence of an auxiliary base (e.g. triethylamine) if Z represents a leaving group, for example a halogen atom (especially chlorine). The esterification is preferably carried out starting from the carboxylic acid (Z = OH) in a Dean-Stark device under acidic reaction conditions as described by M. Bodanszky and A. Bodanszky in: "The Practice of Peptide Synthesis" (Springer-Verlag, Berlin, 1984, p. 37).
Je nach Art der Ausgangsverbindungen, die gegebenenfalls auch in Form ihrer Salze eingesetzt werden können, und in Abhängigkeit von den Reaktionsbedingungen werden die erfindungsgemäßen Verbindungen zunächst entweder als solche oder in Form ihrer Salze gewonnen. Depending on the nature of the starting compounds, which can optionally also be used in the form of their salts, and depending on the reaction conditions, the compounds according to the invention are initially obtained either as such or in the form of their salts.
Im übrigen erhält man die Salze durch Auflösen der freien Verbindungen in einem geeigneten Lösungsmittel, z.B. in einem chlorierten Kohlenwasserstoff, wie Methylenchlorid oder Chloroform, einem niedermolekularen aliphatischen Alkohol (Ethanol, Isopropanol), einem Ether (Diisopropylether), einem Keton (Aceton) oder Wasser, das die gewünschte Säure enthält, oder dem die gewünschte Säure - gegebenenfalls in der genau berechneten stöchio- metrischen Menge - anschließend zugegeben wird. Otherwise, the salts are obtained by dissolving the free compounds in a suitable solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol (ethanol, isopropanol), an ether (diisopropyl ether), a ketone (acetone) or water, which contains the desired acid, or which contains the desired acid - if necessary in the exact calculated stoichiometric amount - is then added.
Die Salze werden durch Filtrieren, Umfallen, Ausfällen oder durch Verdampfen des Lösungsmittels gewonnen. Erhaltene Salze können durch Alkalisieren, z.B. mit wäßrigem Natriumhydro- gencarbonat, in die freien Verbindungen umgewandelt werden, welche wiederum in die Salze übergeführt werden können. Auf diese Weise lassen sich die Verbindungen reinigen, oder es lassen sich pharmakologisch nicht verträgliche Salze in pharmakologisch verträgliche Salze umwandeln. The salts are obtained by filtration, reprecipitation, precipitation or by evaporation of the solvent. Salts obtained can be converted into the free compounds by alkalization, for example with aqueous sodium hydrogen carbonate, which in turn can be converted into the salts. In this way, the compounds can be purified or pharmacologically unacceptable salts can be converted into pharmacologically acceptable salts.
Die Ausgangsverbindungen II, III, IV, V und VI sind bekannt, oder sie können nach bekannten Verfahren in analoger Weise hergestellt werden, so wie dies exemplarisch in den Beispielen beschrieben ist. Verbindungen III beispielsweise können durch Umsetzung entsprechender ω-L-Alkohole mit geeigneten Carbonsäuren, Verbindungen IV durch Umsetzung entsprechender ω-L-Carbonsäuren mit geeigneten Alkoholen hergestellt werden (L = Abgangsgruppe, insbesondere Chlor oder Brom). Die Umsetzung erfolgt jeweils in einem Dean-Stark-Gerät mit saurer Katalyse, wie beispielsweise beschrieben in: Houben-Weyl, Methoden der organischen Chemie VII 1/3 , S. 503-546. Verbindungen V werden erhalten durch Umsetzung entsprechend substituierter Styroloxide mit geeigneten Aminoalkoholen, wie beispielsweise beschrieben in: Houben-Weyl, Methoden der organischen Chemie VI/3, S. 366-387. The starting compounds II, III, IV, V and VI are known, or they can be prepared by known processes in an analogous manner, as described by way of example in the examples. Compounds III, for example, can be prepared by reacting corresponding ω-L alcohols with suitable carboxylic acids, compounds IV by reacting corresponding ω-L carboxylic acids with suitable alcohols (L = leaving group, in particular chlorine or bromine). The reaction takes place in each case in a Dean-Stark device with acid catalysis, as described for example in: Houben-Weyl, Methods of Organic Chemistry VII 1/3, pp. 503-546. Compounds V are obtained by reacting appropriately substituted styrene oxides with suitable amino alcohols, as described, for example, in: Houben-Weyl, Methods of Organic Chemistry VI / 3, pp. 366-387.
Die folgenden allgemeinen Methodenbeschreibungen und Beispiele dienen der näheren Erläuterung der Erfindung. Die Reinheit und Identität der in den Beispielen beschriebenen Verbindungen sind bestätigt worden unter Anwendung der folgenden Methoden: The following general method descriptions and examples serve to explain the invention in more detail. The purity and identity of the compounds described in the examples have been confirmed using the following methods:
H-Kernspinresonanzspektrometrie (NMR; Bruker AC 200);  H nuclear magnetic resonance spectrometry (NMR; Bruker AC 200);
Hochauflösungsmassenspektrometrie (Finnigan MT 90); High resolution mass spectrometry (Finnigan MT 90);
Schmelzpunkt- (Mettler FP 5 mit Mikroskop) oder Siedepunktbestimmung; Melting point (Mettler FP 5 with microscope) or boiling point determination;
Dünnschichtchromatographie (DC; E. Merck No. 37333, Kieselgel 60 F254) Thin layer chromatography (TLC; E. Merck No. 37333, silica gel 60 F 254 )
Die in den Beispielen namentlich genannten Verbindungen der Formel I sowie die Salze dieser Verbindungen sind bevorzugter Gegenstand der Erfindung. Beispiele The compounds of the formula I mentioned by name in the examples and the salts of these compounds are a preferred subject of the invention. Examples
Ausgangsverbindungen Output connections
Allgemeine Methodenbeschreibung zur Herstellung der Verbindungen III und IV: General method description for the preparation of compounds III and IV:
Eine Lösung von 50 mmol eines Alkohols L-CH2-X-CH2-OH für Verbindungen III bzw. von 50 mmol eines Alkohols HO-(CH2)n-Y-Ar2 (für Verbindungen IV) wird mit 50 mmol einer Carbonsäure HO-CO-(CH2) -Y-Ar2 (für Verbindungen III) bzw. mit 50 mmol einer Carbonsäure L-CH2-X-CH2-CO-OH (für Verbindungen IV) und mit 0,5 g 4-Toluolsulfonsäure in Toluol in einem Dean-Stark-Gerät so lange erhitzt, bis die Reaktion beendet ist (DC-Kontrolle). Das Toluol wird abdestilliert und der Rückstand wird mittels Destillation, Chromatographie und/oder Kristallisation gereinigt. Die Identität der erhaltenen Ausgangsverbindungen wird mittels 1H-NMR charakterisiert. A solution of 50 mmol of an alcohol L-CH 2 -X-CH 2 -OH for compounds III or 50 mmol of an alcohol HO- (CH 2 ) n -Y-Ar 2 (for compounds IV) is mixed with 50 mmol Carboxylic acid HO-CO- (CH 2 ) -Y-Ar 2 (for compounds III) or with 50 mmol of a carboxylic acid L-CH 2 -X-CH 2 -CO-OH (for compounds IV) and with 0.5 g 4-Toluenesulfonic acid in toluene heated in a Dean-Stark device until the reaction has ended (TLC control). The toluene is distilled off and the residue is purified by distillation, chromatography and / or crystallization. The identity of the starting compounds obtained is characterized by 1 H-NMR.
Die folgenden Verbindungen werden gemäß dieser Methodenbeschreibung hergestellt: The following connections are made according to this method description:
A1. 6-Brom-1-hexylbenzoat A1. 6-bromo-1-hexyl benzoate
Aus 6-Brom-1-hexanol und Benzoesäure. Ausbeute: 85 %. From 6-bromo-1-hexanol and benzoic acid. Yield: 85%.
A2. {4-Brommethylrtranslcyclohexylmethyl)-(3,3-diphenyl)oropionat A2. {4-Bromomethyltranslcyclohexylmethyl) - (3,3-diphenyl) oropionate
Aus 4-Brommethyl[trans]cyclohexylmethanol und 3,3-Diphenylpropionsäure. Ausbeute: 60 % (Öl). From 4-bromomethyl [trans] cyclohexylmethanol and 3,3-diphenylpropionic acid. Yield: 60% (oil).
A3. (6-Brom-1-hexyl)-4-phenylbutanoat A3. (6-bromo-1-hexyl) -4-phenylbutanoate
Aus 6-Brom-1-hexanol und 4-Phenylbuttersäure. Aufarbeitung mittels Destillation. Ausbeute: 72 %. Siedepunkt: 158°C (0,01 mbar). From 6-bromo-1-hexanol and 4-phenylbutyric acid. Working up by distillation. Yield: 72%. Boiling point: 158 ° C (0.01 mbar).
A4. (4-Phenylbutyl)-6-bromhexanoat A4. (4-phenylbutyl) -6-bromohexanoate
Aus 6-Bromcapronsäure und 4-Phenyl-1-butanol. Aufarbeitung mittels From 6-bromcaproic acid and 4-phenyl-1-butanol. Refurbishment using
Destillation. Ausbeute: 80 %. Siedepunkt: 158°C (0,008 mbar). A5. (6-Brom-1-hexyl)-3-phenylpropionat Distillation. Yield: 80%. Boiling point: 158 ° C (0.008 mbar). A5. (6-bromo-1-hexyl) -3-phenylpropionate
Aus 6-Brom-1-hexanol und 3-Phenylpropionsäure. Ausbeute: 85 % (Öl). From 6-bromo-1-hexanol and 3-phenylpropionic acid. Yield: 85% (oil).
A6. (12-Brom-1-dodecyl)-4-phenyl butanoat A6. (12-bromo-1-dodecyl) -4-phenyl butanoate
Aus 12-Brom-1-dodecanol und 4-Phenylbuttersäure. Ausbeute: 85 % (Öl). From 12-bromo-1-dodecanol and 4-phenylbutyric acid. Yield: 85% (oil).
A7. Benzyl-6-bromhexanoat A7. Benzyl 6-bromohexanoate
Aus Benzylalkohol und 6-Bromcapronsäure. Ausbeute: 85 % (Öl). From benzyl alcohol and 6-bromcaproic acid. Yield: 85% (oil).
A8. (6-Brom-1-hexyl)-(3-(4-hydroxyphenyl))propionat A8. (6-bromo-1-hexyl) - (3- (4-hydroxyphenyl)) propionate
Aus 6-Brom-1-hexanol und 3-(4-Hydroxyphenyl)propionsäure. Aufarbeitung mittels Destillation. Ausbeute: 70 %. Siedepunkt: 205°C (0,05 mbar). From 6-bromo-1-hexanol and 3- (4-hydroxyphenyl) propionic acid. Working up by distillation. Yield: 70%. Boiling point: 205 ° C (0.05 mbar).
A9. ( 4-(Brommethyl)[translcyclohexylmethyl)-4-phenyl-butanoat A9. (4- (bromomethyl) [translcyclohexylmethyl) -4-phenyl butanoate
Aus 4-(Brommethyl)[trans]cyclohexylmethanol und 4-Phenyl buttersäure. Ausbeute: 80 %. From 4- (bromomethyl) [trans] cyclohexylmethanol and 4-phenyl butyric acid. Yield: 80%.
A10. (2-(1-Naphthyl)ethyl)-6-bromhexanoat A10. (2- (1-naphthyl) ethyl) -6-bromohexanoate
Aus 2-(1-Naphthyl)ethanol und 6-Bromcapronsäure. Aufarbeitung mittels Destillation. Ausbeute: 88 % (Öl). Siedepunkt 150°C (0,008 mbar). From 2- (1-naphthyl) ethanol and 6-bromcaproic acid. Working up by distillation. Yield: 88% (oil). Boiling point 150 ° C (0.008 mbar).
A11. (3-Phenylpropyl)-4-brombutanoat A11. (3-phenylpropyl) -4-bromobutanoate
Aus 4-Brombuttersäure und 3-Phenylpropanol . Ausbeute: 95 %. From 4-bromobutyric acid and 3-phenylpropanol. Yield: 95%.
A12. (3-Chlorphenyl)-3-phenylpropionat A12. (3-chlorophenyl) -3-phenylpropionate
Aus 3-Chlorpropanol und 3-Phenylpropionsäure. Aufarbeitung mittels From 3-chloropropanol and 3-phenylpropionic acid. Refurbishment using
Destillation. Ausbeute: 88 % (Öl). Siedepunkt 115°C (0,05 mbar). A13. (2 - (3-Thi enyl )ethyl ) -6-bromhexanoat Distillation. Yield: 88% (oil). Boiling point 115 ° C (0.05 mbar). A13. (2 - (3-Thienyl) ethyl) -6-bromohexanoate
Aus 2-(3-Thienyl)ethanol und 6-Bromcapronsäure. Ausbeute: 70 % (Öl). From 2- (3-thienyl) ethanol and 6-bromcaproic acid. Yield: 70% (oil).
A14. (9-Brom-1-nonyl)-4-phenylbutanoat A14. (9-bromo-1-nonyl) -4-phenylbutanoate
Aus 9-Brom-1-nonanol und 4-Phenylbuttersäure. Ausbeute: 78 % (Öl). From 9-bromo-1-nonanol and 4-phenylbutyric acid. Yield: 78% (oil).
A15. (2-Phenoxyethyl)-6-bromhexanoat A15. (2-phenoxyethyl) -6-bromohexanoate
Aus 2-Phenoxyethanol und 6-Bromcapronsäure. Ausbeute: 80 % (Öl). From 2-phenoxyethanol and 6-bromcaproic acid. Yield: 80% (oil).
A16. (6-Brom-1-hexyl)-3-fluorphenylacetat A16. (6-bromo-1-hexyl) -3-fluorophenylacetate
Aus 6-Brom-1-hexanol und 3-Fluorphenylessigsäure. Ausbeute: 70 % (Öl). From 6-bromo-1-hexanol and 3-fluorophenylacetic acid. Yield: 70% (oil).
A17. (6-Brom-1-hexyl)-4-(4-methoxyphenyl)butanoat A17. (6-bromo-1-hexyl) -4- (4-methoxyphenyl) butanoate
Aus 6-Brom-1-hexanol und 4-(4-Methoxyphenyl)buttersäure. Ausbeute: 70 % (Öl). From 6-bromo-1-hexanol and 4- (4-methoxyphenyl) butyric acid. Yield: 70% (oil).
A18. (6-Chlor-1-hexyl)-phenylacetat A18. (6-chloro-1-hexyl) phenyl acetate
Aus Phenylessigsäure und 6-Chlor-1-hexanol. Ausbeute: 80 %. From phenylacetic acid and 6-chloro-1-hexanol. Yield: 80%.
A19. Benzyl-6-bromhexanoat A19. Benzyl 6-bromohexanoate
Aus Benzylalkohol und 6-Bromcapronsäure. Ausbeute: 70 % (Öl). From benzyl alcohol and 6-bromcaproic acid. Yield: 70% (oil).
A20. (6-Brom-1-hexyl)-3-phenylbutanoat A20. (6-bromo-1-hexyl) -3-phenylbutanoate
Aus 3-Phenylbuttersäure und 6-Brom-1-hexanol. Ausbeute: 80 % (Öl). From 3-phenylbutyric acid and 6-bromo-1-hexanol. Yield: 80% (oil).
A21. (2-(4-Methylphenoxy)ethyl)-6-bromhexanoat A21. (2- (4-methylphenoxy) ethyl) -6-bromohexanoate
Aus 6-Bromcapronsäure und 2-(4-Methylphenoxy)ethanol. Ausbeute: 80 % (Öl). A22. (12-Brom-1-dodecyl)-2-nitrophenylacetat From 6-bromcaproic acid and 2- (4-methylphenoxy) ethanol. Yield: 80% (oil). A22. (12-bromo-1-dodecyl) -2-nitrophenylacetate
Aus 12-Brom-1-dodecanol und 2-Nitrophenylessigsäure. Ausbeute: 80 %. From 12-bromo-1-dodecanol and 2-nitrophenylacetic acid. Yield: 80%.
A23. (2-(2-Pyridyl)ethyl)-6-bromhexanoat A23. (2- (2-pyridyl) ethyl) -6-bromohexanoate
Aus 6-Bromcapronsäure und 2-(2-Pyridyl)ethanol. Ausbeute: 70 % (Öl). From 6-bromcaproic acid and 2- (2-pyridyl) ethanol. Yield: 70% (oil).
Allgemeine Methodenbeschreibung zur Herstellung der Verbindungen V: General method description for the preparation of compounds V:
Eine Lösung von 0,1 mol eines Styroloxides und 0,1 mol eines A solution of 0.1 mol of a styrene oxide and 0.1 mol of one
Aminoalkohols NH2-CH2-X-CH2-OH in 250 ml 2-Propanol werden für 8 h unter Rückfluß zum Sieden erhitzt. Das Lösungsmittel wird abdestilliert und der Rückstand chromatographisch gereinigt. Amino alcohol NH 2 -CH 2 -X-CH 2 -OH in 250 ml of 2-propanol are heated to boiling under reflux for 8 h. The solvent is distilled off and the residue is purified by chromatography.
Die folgenden Verbindungen werden gemäß dieser Methodenbeschreibung hergestellt: The following connections are made according to this method description:
B1. 2-(6-Hydroxy-1-hexylamino)-1-phenyl ethanol B1. 2- (6-hydroxy-1-hexylamino) -1-phenyl ethanol
Aus Styroloxid und 6-Amino-1-hexanol. Ausbeute nach Chromatographie (Methanol): 30 % (Öl). From styrene oxide and 6-amino-1-hexanol. Yield after chromatography (methanol): 30% (oil).
B2. 1-(2-Chlorohenyl)-2-(6-hydroxy-1-hexylamino)ethanol B2. 1- (2-chlorohenyl) -2- (6-hydroxy-1-hexylamino) ethanol
Aus 2-Chlorstyroloxid und 6-Amino-1-hexanol. Aufarbeitung mittels Chromatographie (Ethyl acetat/Methanol 1:1). Ausbeute: 41 %. Endprodukte From 2-chlorostyrene oxide and 6-amino-1-hexanol. Working up by means of chromatography (ethyl acetate / methanol 1: 1). Yield: 41%. End products
I. Allgemeine Methodenbeschreibung zur Herstellung der Endprodukte aus den Ausgangsverbindungen II und III (Verfahrensvariante a) bzw. aus den Ausgangsverbindungen II und IV (Verfahrensvariante b): I. General method description for the preparation of the end products from the starting compounds II and III (process variant a) or from the starting compounds II and IV (process variant b):
Eine Lösung von 5 mmol der Verbindungen II, 4,5 mmol der Verbindung III bzw. IV, 1,0 g Kaliumiodid und 3 mmol Diisopropylethylamin in einem geeigneten Lösungsmittel wird so lange (gegebenenfalls unter Rückfluß zum Sieden) erhitzt, bis die Reaktion im wesentlichen abgeschlossen ist (DC-Kontrolle). Das Lösungsmittel wird abdestilliert und der Rückstand wird mittels Chromatographi e und/oder Kristallisation gereinigt. A solution of 5 mmol of the compounds II, 4.5 mmol of the compound III or IV, 1.0 g of potassium iodide and 3 mmol of diisopropylethylamine in a suitable solvent is heated (if necessary under reflux to the boil) until the reaction is essentially is completed (DC control). The solvent is distilled off and the residue is purified by chromatography and / or crystallization.
II. Allgemeine Methodenbeschreibung zur Herstellung der Endprodukte aus den Ausgangsverbindungen V und VI (Verfahrensvariante c): II. General description of the methods for the preparation of the end products from the starting compounds V and VI (process variant c):
Eine Mischung von 5 mmol der Verbindung V, 5 mmol der Verbindung VI (mit Z = OH), 7 mmol 4-Toluolsulfonsäure und 100 ml Toluol werden in einem Dean-Stark-Gerät für 5 Stunden erhitzt. Das Toluol wird verdampft und der Rückstand wird in Ethylacetat aufgenommen und mit einer wäßrigen Natriumcarbonatlösung ausgeschüttelt. Die organische Phase wird mit Magnesiumsulfat getrocknet und eingedampft. Der Rückstand wird mittels Chromatographie und/oder Kristallisation gereinigt. A mixture of 5 mmol of compound V, 5 mmol of compound VI (with Z = OH), 7 mmol of 4-toluenesulfonic acid and 100 ml of toluene are heated in a Dean-Stark device for 5 hours. The toluene is evaporated and the residue is taken up in ethyl acetate and shaken with an aqueous sodium carbonate solution. The organic phase is dried with magnesium sulfate and evaporated. The residue is purified by chromatography and / or crystallization.
Die folgenden Verbindungen werden analog Methodenbeschreibung I oder II hergestellt: The following compounds are prepared analogously to method description I or II:
1. {6-[2-(4-Amino-3,5-dichlorphenyl)-2-hvdroxyethylaminol-1-hexyl}benzoat-maleat × ½ ethylacetat 1. {6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylaminol-1-hexyl} benzoate maleate × 1/2 ethyl acetate
Nach Methode I (Tetrahydrofuran, Rückfluß 4 Tage) aus 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol und 6-Brom-1-hexylbenzoat. Aufarbeitung mittels Chromatographie (Ethyl acetat/Petrolether 60-80/Triethylamin 6:4:1). Umkristallisiert als Maleat aus Ethylacetat. Schmp.: 78-79°C. 2. [6-(2-Hydroxy-2-phenylethylamino)-1-hexyl]-benzoat-oxalat According to method I (tetrahydrofuran, reflux for 4 days) from 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol and 6-bromo-1-hexylbenzoate. Working up by means of chromatography (ethyl acetate / petroleum ether 60-80 / triethylamine 6: 4: 1). Recrystallized as maleate from ethyl acetate. Mp: 78-79 ° C. 2. [6- (2-Hydroxy-2-phenylethylamino) -1-hexyl] benzoate oxalate
Nach Methode II aus 2-(6-Hydroxy-1-hexylamino)-1-phenylethanol und Benzoesäure. Aufarbeitung mittels Chromatographie (Ethyl acetat/Methanol 1:1). Umkristallisiert als Oxalat aus Aceton. Schmp.: 121-125°C. According to method II from 2- (6-hydroxy-1-hexylamino) -1-phenylethanol and benzoic acid. Working up by means of chromatography (ethyl acetate / methanol 1: 1). Recrystallized as oxalate from acetone. Mp: 121-125 ° C.
3. {6-[2-(2-Chlorphenyl)-2-hvdroxyethylaminol-1-hexyl)-benzoat-oxalat 3. {6- [2- (2-chlorophenyl) -2-hydroxyethylaminol-1-hexyl) benzoate oxalate
Nach Methode II aus 1-(2-Chlorphenyl)-2-(6-hydroxy-1-hexylamino)ethanol und Benzoesäure. Aufarbeitung mittels Chromatographie (Ethyl acetat/Methanol 1:1). Umkristallisiert als Oxalat aus Aceton. Schmp.: 144-148°C. According to method II from 1- (2-chlorophenyl) -2- (6-hydroxy-1-hexylamino) ethanol and benzoic acid. Working up by means of chromatography (ethyl acetate / methanol 1: 1). Recrystallized as oxalate from acetone. Mp: 144-148 ° C.
4. {6-[2 -(2-Chlorphenyl)-2-hydroxyethylaminol-1-hexyl)-phenylacetat- oxalat 4. {6- [2 - (2-chlorophenyl) -2-hydroxyethylaminol-1-hexyl) phenylacetate oxalate
Herstellung nach Methode II aus 1-(2-Chlorphenyl)-2-(6-hydroxy-1-hexylamino)ethanol und Phenylessigsäure. Aufarbeitung mittels Chromatographie (Ethylacetat/Methanol/Triethylamin 42,5:7,5:1,0). Umkristallisiert als Oxalat aus Aceton. Schmp.: 114-117°C. Preparation according to method II from 1- (2-chlorophenyl) -2- (6-hydroxy-1-hexylamino) ethanol and phenylacetic acid. Working up by means of chromatography (ethyl acetate / methanol / triethylamine 42.5: 7.5: 1.0). Recrystallized as oxalate from acetone. Mp: 114-117 ° C.
5. [6-(2-Hydroxy-2-phenylethylamino)-1-hexyl]-phenylacetat-oxalat 5. [6- (2-Hydroxy-2-phenylethylamino) -1-hexyl] phenyl acetate oxalate
Nach Methode II aus 2-(6-Hydroxy-1-hexylamino)-1-phenylethanol und Phenylessigsäure. Aufarbeitung mittels Chromatographie (Ethyl acetat/Methanol 1:1). Umkri stall is-iert als Oxalat aus Aceton. Schmp.: 116-121°C. According to method II from 2- (6-hydroxy-1-hexylamino) -1-phenylethanol and phenylacetic acid. Working up by means of chromatography (ethyl acetate / methanol 1: 1). Crystallized as oxalate from acetone. Mp: 116-121 ° C.
6. [6-(2-Hydroxy-2-phenylethylamino)-1-hexyl]-(3,3-diphenyl)propionat-oxalat 6. [6- (2-Hydroxy-2-phenylethylamino) -1-hexyl] - (3,3-diphenyl) propionate oxalate
Nach Methode II aus 2-(6-Hydroxy-1-hexylamino)-1-phenylethanol und 3,3-Diphenylpropionsäure. Aufarbeitung mittels Chromatographie (Ethyl acetat/Methanol 1:1). Umkristallisiert als Oxalat aus Aceton. Schmp.: 136-139°C. According to method II from 2- (6-hydroxy-1-hexylamino) -1-phenylethanol and 3,3-diphenylpropionic acid. Working up by means of chromatography (ethyl acetate / methanol 1: 1). Recrystallized as oxalate from acetone. Mp: 136-139 ° C.
7. (4-[2-(4-Amino-3.5-dichlorphenyl)-2-hydroxyethylamino-methyl]- [trans]cyclohexylmethyl)-(3,3-diphenylpropionat)-maleat 7. (4- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino-methyl] - [trans] cyclohexylmethyl) - (3,3-diphenylpropionate) maleate
Nach Methode I (Tetrahydrofuran, Rückfluß 4 Tage) aus 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol und [4-Brommethyl[trans]c]clohexylmethyl]-3,3- diphenyl-propionat. Aufarbeitung mittels Chromatographie (Ethylacetat/Petrolether 60-80/Tri ethyl ami n 4:4:1). Umkristallisiert als Maleat aus Ethylacetat. Schmp.: 156-158°C. According to method I (tetrahydrofuran, reflux for 4 days) from 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol and [4-bromomethyl [trans] c] clohexylmethyl] -3,3- diphenyl propionate. Working up by means of chromatography (ethyl acetate / petroleum ether 60-80 / triethylamine 4: 4: 1). Recrystallized as maleate from ethyl acetate. Mp: 156-158 ° C.
8. {6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl)-4- phenylbutanoat-maleat 8. {6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl) -4-phenylbutanoate maleate
Nach Methode I (Tetrahydrofuran, Rückfluß 4 Tage) aus 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol und (6-Brom-1-hexyl)-4-phenylbutanoat. Aufarbeitung mittels Chromatographie (Ethylacetat/Petrolether 60-80/Tri ethyl amin 6:4:1). Umkristallisiert als Maleat aus Ethylacetat. Schmp.: 69-74°C. According to method I (tetrahydrofuran, reflux for 4 days) from 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol and (6-bromo-1-hexyl) -4-phenylbutanoate. Working up by means of chromatography (ethyl acetate / petroleum ether 60-80 / triethylamine 6: 4: 1). Recrystallized as maleate from ethyl acetate. Mp: 69-74 ° C.
9. 4-Phenyl-1-butyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat-maleat 9. 4-phenyl-1-butyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate maleate
Nach Methode I (Tetrahydrofuran, Rückfluß 4 Tage) aus 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol und (4-Phenylbutyl)-6-bromhexanoat. Aufarbeitung mittels Chromatographie (Ethylacetat/Petrolether 60-80/Triethylamin 6:4:1). Umkristallisiert als Maleat aus Ethylacetat. Schmp.: 77-79°C. According to method I (tetrahydrofuran, reflux for 4 days) from 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol and (4-phenylbutyl) -6-bromhexanoate. Working up by means of chromatography (ethyl acetate / petroleum ether 60-80 / triethylamine 6: 4: 1). Recrystallized as maleate from ethyl acetate. Mp: 77-79 ° C.
10. [6-(2-Hydroxy-2-phenylethylamino)-1-hexyl]-5-phenyl-valerat-oxalat 10. [6- (2-Hydroxy-2-phenylethylamino) -1-hexyl] -5-phenylvalerate oxalate
Nach Methode II aus 2-(6-Hydroxy-1-hexylamino)-1-phenylethanol und 5-Phenylvaleriansäure. Aufarbeitung mittels Chromatographie (Ethyl acetat/Methanol 1:1). Umkristallisiert als Oxalat aus Aceton. Schmp.: 130-134°C. According to method II from 2- (6-hydroxy-1-hexylamino) -1-phenylethanol and 5-phenylvaleric acid. Working up by means of chromatography (ethyl acetate / methanol 1: 1). Recrystallized as oxalate from acetone. Mp: 130-134 ° C.
11. [6-(2-Hydroxy-2-phenylethylamino)-1-hexyl]-4-phenyl-butanoat-oxalat 11. [6- (2-Hydroxy-2-phenylethylamino) -1-hexyl] -4-phenyl-butanoate oxalate
Nach Methode II aus 2-(6-Hydroxy-1-hexylamino)-1-phenylethanol und 4-Phenyl buttersäure. Aufarbeitung mittels Chromatographie (Ethyl acetat/Methanol 1:1). Umkristallisiert als Oxalat aus Aceton. Schmp.: 124-129°C. According to method II from 2- (6-hydroxy-1-hexylamino) -1-phenylethanol and 4-phenyl butyric acid. Working up by means of chromatography (ethyl acetate / methanol 1: 1). Recrystallized as oxalate from acetone. Mp: 124-129 ° C.
12. [6-(2-Hydroxy-2-phenylethylamino)-1-hexyl]-3-phenylpropionat-oxalat 12. [6- (2-Hydroxy-2-phenylethylamino) -1-hexyl] -3-phenylpropionate oxalate
Nach Methode II aus 2-(6-Hydroxy-1-hexylamino)-1-phenylethanol und 3-Phenylpropionsäure. Aufarbeitung mittels Chromatographie (Ethylacetat/Methanol 1:1). Umkristallisiert als Oxalat aus Aceton. Schmp.: 129-133°C. 13. 4-Phenyl-1-butyl-6-[2-(2-chlorphenyl)-2-hydroxyethylamino]hexanoatoxalat According to method II from 2- (6-hydroxy-1-hexylamino) -1-phenylethanol and 3-phenylpropionic acid. Working up by means of chromatography (ethyl acetate / methanol 1: 1). Recrystallized as oxalate from acetone. Mp: 129-133 ° C. 13. 4-phenyl-1-butyl-6- [2- (2-chlorophenyl) -2-hydroxyethylamino] hexanoate oxalate
Nach Methode I (Tetrahydrofuran, Rückfluß 4 Tage) aus 2-Amino-1-(2-chlorphenyl)ethanol und (4-Phenylbutyl)-6-bromhexanoat. Aufarbeitung mittels Chromatographie (Ethylacetat/Petrolether 60-80/Triethylamin 6:4:1). Umkristallisiert als Oxalat aus Aceton. Schmp.: 149-150°C. According to method I (tetrahydrofuran, reflux for 4 days) from 2-amino-1- (2-chlorophenyl) ethanol and (4-phenylbutyl) -6-bromohexanoate. Working up by means of chromatography (ethyl acetate / petroleum ether 60-80 / triethylamine 6: 4: 1). Recrystallized as oxalate from acetone. Mp: 149-150 ° C.
14. {6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl)- 3-phenylpropionat-oxalat 14. {6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl) -3-phenylpropionate oxalate
Nach Methode I (Tetrahydrofuran, Rückfluß 4 Tage) aus 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol und (6-Brom-1-hexyl)-3-phenylpropionat. Aufarbeitung mittels Chromatographie (Ethylacetat/Petrolether 60-80/Triethylamin 6:4:1). Umkristallisiert als Oxalat aus Aceton. Schmp.: 114-115°C. According to method I (tetrahydrofuran, reflux for 4 days) from 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol and (6-bromo-1-hexyl) -3-phenylpropionate. Working up by means of chromatography (ethyl acetate / petroleum ether 60-80 / triethylamine 6: 4: 1). Recrystallized as oxalate from acetone. Mp: 114-115 ° C.
15. [12-(2-Hydroxy-2-phenylethylamino)-1-dodecyl]-4-phenyl butanoat 15. [12- (2-Hydroxy-2-phenylethylamino) -1-dodecyl] -4-phenyl butanoate
Nach Methode I (Tetrahydrofuran, Rückfluß 4 Tage) aus 2-Amino-1-phenylethanol und (12-Brom-1-dodecyl)-4-phenylbutanoat. Aufarbeitung mittels Chromatographie (Ethylacetat/Petrolether 60-80/Triethylamin 6:4:1). Umkristallisiert aus Diethylether. Schmp.: 73-74°C. According to method I (tetrahydrofuran, reflux for 4 days) from 2-amino-1-phenylethanol and (12-bromo-1-dodecyl) -4-phenylbutanoate. Working up by means of chromatography (ethyl acetate / petroleum ether 60-80 / triethylamine 6: 4: 1). Recrystallized from diethyl ether. Mp: 73-74 ° C.
16. Benzyl-[6-(2-hydroxy-2-phenylethylamino)]hexanoat 16. Benzyl- [6- (2-hydroxy-2-phenylethylamino)] hexanoate
Nach Methode I (Tetrahydrofuran, Rückfluß 4 Tage) aus Benzyl-6-bromhexanoat und 2-Amino-1-phenylethanol. Aufarbeitung mittels Chromatographie (Ethylacetat/Methanol/Triethylamin 3:1:0,1). Schmp.: 77-78°C. According to method I (tetrahydrofuran, reflux for 4 days) from benzyl 6-bromohexanoate and 2-amino-1-phenylethanol. Working up by means of chromatography (ethyl acetate / methanol / triethylamine 3: 1: 0.1). Mp: 77-78 ° C.
17. (6-[2-(4-Amino-3.5-dichlorphenyl)-2-hvdroxyethylamino!-1-hexyl)-[3-(4- hydroxyphenyl)]propionat-hydrochlorid 17. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino! -1-hexyl) - [3- (4-hydroxyphenyl)] propionate hydrochloride
Nach Methode I (Dimethylformamid, 2 Std. bei 90°C) aus 2-Amino-1-(4-amiπo- 3,5-dichlorphenyl)ethanol und 6-Brom-1-hexyl-{3-(4-hydroxyphenyl) }propionat. Der Rückstand nach Verdampfung des Lösungsmittels wird verteilt in Ethylacetat und 0,2 M Salzsäure. Die organische Phase wird mit Magnesiumsulfat getrocknet und eingeengt. Schmp.: 109-112°C. 18. (4-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino-methyl]- [trans]cyclohexylmethyl}-4-phenylbutanoat-maleat According to method I (dimethylformamide, 2 hours at 90 ° C.) from 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol and 6-bromo-1-hexyl- {3- (4-hydroxyphenyl) propionate. The residue after evaporation of the solvent is distributed in ethyl acetate and 0.2 M hydrochloric acid. The organic phase is dried with magnesium sulfate and concentrated. Mp: 109-112 ° C. 18. (4- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino-methyl] - [trans] cyclohexylmethyl} -4-phenylbutanoate maleate
Nach Methode I (Dimethylformamid, 2 Std. bei 90°C) aus 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol und (4-(Brommethyl)[trans]cyclohexylmethyl}-(4-phenyl)butanoat. Aufarbeitung mittels Chromatographie (Ethylacetat/Petrolether 60-80/Tri ethyl amin 4:2:1). Umkristallisiert als Maleat aus Ethylacetat. Schmp.: 155-157°C. According to method I (dimethylformamide, 2 hours at 90 ° C) from 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol and (4- (bromomethyl) [trans] cyclohexylmethyl} - (4-phenyl Working up by means of chromatography (ethyl acetate / petroleum ether 60-80 / triethylamine 4: 2: 1), recrystallized as maleate from ethyl acetate, mp: 155-157 ° C.
19. 2-(1-Naphthyl)ethyl-6-[2-(4-amino-3.5-dichlorphenyl)-2-hydroxyethylaminolhexanoat 19. 2- (1-Naphthyl) ethyl 6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylaminolhexanoate
Nach Methode I (Dimethylformamid, 2 Std. bei 90°C) aus 2-Amino-1-(4-amino-3,5-dich!orphenyl)ethanol und (2-(1-Naphthyl)ethyl}-6-bromhexanoat. Aufarbeitung mittels Chromatographie (Ethylacetat/Methanol/Triethylamin 16:2:1). Umkristallisiert als freie Base aus Ethylacetat. Schmp.: 60-61°C. According to method I (dimethylformamide, 2 hours at 90 ° C) from 2-amino-1- (4-amino-3,5-dich! Orphenyl) ethanol and (2- (1-naphthyl) ethyl} -6-bromhexanoate Working up by means of chromatography (ethyl acetate / methanol / triethylamine 16: 2: 1), recrystallized as free base from ethyl acetate, mp: 60-61 ° C.
20. 3-Phenylpropyl-4-[2-(4-amino-3,5-dichlorphenyl)-2-hvdroxyethylaminolbutanoat-maleat 20. 3-Phenylpropyl-4- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylethylaminol butanoate maleate
Nach Methode I (Dimethylformamid, 2 Std. bei 90°C) aus 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol und (3-Phenylpropyl)-4-brombutanoat. Aufarbeitung mittels Chromatographie (Ethylacetat/Methanol/Triethylamin 20:2:1). Umkristallisiert als Maleat aus Aceton. Schmp.: 70-71°C. According to method I (dimethylformamide, 2 hours at 90 ° C) from 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol and (3-phenylpropyl) -4-bromobutanoate. Working up by means of chromatography (ethyl acetate / methanol / triethylamine 20: 2: 1). Recrystallized as maleate from acetone. Mp: 70-71 ° C.
21. {3-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino!-1-propyl)-3- phenylpropionat-oxalat 21. {3- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino! -1-propyl) -3-phenylpropionate oxalate
Nach Methode I (Tetrahydrofuran, Rückfluß 4 Tage) aus 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol und (3-Chlorpropyl)-3-phenylpropionat. Aufarbeitung mittels Chromatographie (Ethyl acetat/Triethyl amin 8:1). Umkristallisiert als Oxalat aus Aceton. Schmp.: 133-134°C. 22. 2-(3-Thienyl)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat According to method I (tetrahydrofuran, reflux for 4 days) from 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol and (3-chloropropyl) -3-phenylpropionate. Working up by means of chromatography (ethyl acetate / triethylamine 8: 1). Recrystallized as oxalate from acetone. Mp: 133-134 ° C. 22. 2- (3-Thienyl) ethyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate
Nach Methode I (Tetrahydrofuran, Rückfluß 4 Tage) aus (2-(3-Thienyl)- ethyl}6-bromhexanoat und 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol. Aufarbeitung mittels Chromatographie (Ethylacetat/Triethylamin 8:1). Umkristallisiert als Base aus Diethylether. Schmp.: 71-73°C. According to method I (tetrahydrofuran, reflux for 4 days) from (2- (3-thienyl) ethyl} 6-bromhexanoate and 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol. Working up by means of chromatography (ethyl acetate / Triethylamine 8: 1), recrystallized as base from diethyl ether, mp: 71-73 ° C.
23. 9-(2-Hydroxy-2-phenylethylamino)-1-nonyl-4-phenyl-butanoat-oxalat 23. 9- (2-Hydroxy-2-phenylethylamino) -1-nonyl-4-phenyl-butanoate oxalate
Nach Methode I (Tetrahydrofuran, Rückfluß 4 Tage) aus (9-Brom-1-nonyl)-4- phenylbutanoat und 2-Amino-1-phenylethanol. Aufarbeitung mittels Chromatographie (Ethylacetat). Umkristallisiert als Oxalat aus Aceton. Schmp.: According to method I (tetrahydrofuran, reflux for 4 days) from (9-bromo-1-nonyl) -4-phenylbutanoate and 2-amino-1-phenylethanol. Working up by means of chromatography (ethyl acetate). Recrystallized as oxalate from acetone. Mp:
132-135°C.  132-135 ° C.
24. 2-Phenoxyethyl-6-[2-(4-amino-3,5-dich1orophenyl)-2-hydroxyethylamino]hexanoat 24. 2-Phenoxyethyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate
Nach Methode I (Dimethylformamid, 1 Std. bei 100°C) aus (2-Phenoxyethyl)-6-bromhexanoat und 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethano!. Aufarbeitung mittels Chromatographie (Ethylacetat/Methanol/Triethylamin 16:2:1). Umkristallisiert als Base aus Diethylether. Schmp.: 46-47°C. According to method I (dimethylformamide, 1 hour at 100 ° C) from (2-phenoxyethyl) -6-bromhexanoate and 2-amino-1- (4-amino-3,5-dichlorophenyl) ethano !. Working up by means of chromatography (ethyl acetate / methanol / triethylamine 16: 2: 1). Recrystallized as a base from diethyl ether. Mp: 46-47 ° C.
25. {6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethy!amino!-1-hexyl)-3- fluorphenylacetat-oxalat 25. {6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl! Amino! -1-hexyl) -3-fluorophenylacetate oxalate
Nach Methode I (Dimethylformamid, 3 Std. bei 90°C) aus (6-Brom-1-hexyl)-3-fluorphenylacetat und 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol. Aufarbeitung mittels Chromatographie (Ethylacetat/Methanol/Triethylamin 16:2:1). Umkristallisiert als Oxalat aus Aceton. Schmp.: 70-71°C. According to method I (dimethylformamide, 3 hours at 90 ° C) from (6-bromo-1-hexyl) -3-fluorophenylacetate and 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol. Working up by means of chromatography (ethyl acetate / methanol / triethylamine 16: 2: 1). Recrystallized as oxalate from acetone. Mp: 70-71 ° C.
26. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino!-1-hexyl)-4- (4-methoxyphenyl)butanoat-maleat 26. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino! -1-hexyl) -4- (4-methoxyphenyl) butanoate maleate
Nach Methode I (Dimethylformamid, 2 Std. bei 90°C) aus (6-Brom-1-hexyl)-4-(4-methoxyphenyl)butanoat und 2-Amino-1-(4-amino-3.5-dichlorphenyl)ethanol. Aufarbeitung mittels Chromatographie (Ethylacetat/Triethylamin 5:1). Umkristallisiert als Maleat aus Diethylether. Schmp.: 66-67°C. 27. {6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylaminol-1-hexyl}- phenylacetat-hemifumarat According to method I (dimethylformamide, 2 hours at 90 ° C) from (6-bromo-1-hexyl) -4- (4-methoxyphenyl) butanoate and 2-amino-1- (4-amino-3.5-dichlorophenyl) ethanol . Working up by means of chromatography (ethyl acetate / triethylamine 5: 1). Recrystallized as maleate from diethyl ether. Mp: 66-67 ° C. 27. {6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylaminol-1-hexyl} phenyl acetate hemifumarate
Nach Methode I (Dimethylformamid, 3 Std. bei 90°C) aus (6-Chlor-1-hexyl)-phenylacetat und 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol. Aufarbeitung mittels Chromatographie (Ethylacetat/Methanol/Triethylamin 8:1:0,5).According to method I (dimethylformamide, 3 hours at 90 ° C) from (6-chloro-1-hexyl) phenylacetate and 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol. Working up by means of chromatography (ethyl acetate / methanol / triethylamine 8: 1: 0.5).
Umkristallisiert als Hemifumarat aus Aceton. Schmp.: 79-82°C. Recrystallized as a hemifumarate from acetone. Mp: 79-82 ° C.
28. Benzyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylaminolhexanoat-maleat 28. Benzyl 6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylaminolhexanoate maleate
Nach Methode I (Dimethylformamid, 3 Std. bei 90°C) aus Benzyl-6-bromhexan-oat und 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol. Aufarbeitung mittels Chromatographie (Ethylacetat/Methanol/Triethylamin 16:2:1). Umkristallisiert als Maleat aus Diethylether. Schmp.: 54-55°C. According to method I (dimethylformamide, 3 hours at 90 ° C) from benzyl 6-bromohexanate and 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol. Working up by means of chromatography (ethyl acetate / methanol / triethylamine 16: 2: 1). Recrystallized as maleate from diethyl ether. Mp: 54-55 ° C.
29. {6-{2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl)-3- phenylbutanoat-maleat 29. {6- {2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl) -3-phenylbutanoate maleate
Nach Methode I (Dimethylformamid, 3 Stunden 90°C) aus (6-Brom-1-hexyl)-3-phenylbutanoat und 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol. Aufarbeitung mittels Chromatographie (Ethylacetat/Methanol/Triethylamin 20:2:1). Umkristallisiert als Maleat aus Ethylacetat. Schmp.: 51-59°C. According to method I (dimethylformamide, 3 hours 90 ° C) from (6-bromo-1-hexyl) -3-phenylbutanoate and 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol. Working up by means of chromatography (ethyl acetate / methanol / triethylamine 20: 2: 1). Recrystallized as maleate from ethyl acetate. Mp: 51-59 ° C.
30. 2-(4-Methylphenoxy)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat-maleat × ½ ethylacetat 30. 2- (4-methylphenoxy) ethyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate maleate × 1/2 ethyl acetate
Nach Methode I (Dimethylformamid, 3 Stunden 90°C) aus (2-(4-Methylphenoxy)-ethyl}-6-bromhexanoat und 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol. Aufarbeitung mittels Chromatographie (Ethylacetat/Methanol/Triethylamin 20:2:1). Umkristallisiert als Maleat aus Ethylacetat. Schmp.: 77-78°C. 31. {12-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-dodecyl}-2-nitrophenylacetat-oxalat According to method I (dimethylformamide, 3 hours at 90 ° C.) from (2- (4-methylphenoxy) -ethyl} -6-bromhexanoate and 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol Chromatography (ethyl acetate / methanol / triethylamine 20: 2: 1), recrystallized as maleate from ethyl acetate, mp: 77-78 ° C. 31. {12- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-dodecyl} -2-nitrophenylacetate oxalate
Nach Methode I (Dimethylformamid, 3 Stunden 90°C) aus (12-Brom-1-dodecyl)- 2-nitrophenylacetat und 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol. Aufarbeitung mittels Chromatographie (Ethylacetat/Methanol/Triethylamin 20:2:1). Umkristallisiert als Oxalat aus Aceton. Schmp.: 67-68°C. According to method I (dimethylformamide, 3 hours 90 ° C) from (12-bromo-1-dodecyl) - 2-nitrophenylacetate and 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol. Working up by means of chromatography (ethyl acetate / methanol / triethylamine 20: 2: 1). Recrystallized as oxalate from acetone. Mp: 67-68 ° C.
32. 2-(2-Pyridyl)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat-hemifumarat 32. 2- (2-pyridyl) ethyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate hemifumarate
Nach Methode I (Dimethylformamid, 1 Stunde 90°C) aus {2-(2-Pyridyl)ethyl}-6-bromhexanoat und 2-Amino-1-(4-amino-3,5-dichlorphenyl)ethanol. Aufarbeitung mittels Chromatographie (Ethylacetat/Methanol/Triethylamin 20:2:1). Umkristallisiert als Hemifumarat aus Aceton. Schmp.: 75-76°C. According to Method I (dimethylformamide, 90 ° C for 1 hour) from {2- (2-pyridyl) ethyl} -6-bromhexanoate and 2-amino-1- (4-amino-3,5-dichlorophenyl) ethanol. Working up by means of chromatography (ethyl acetate / methanol / triethylamine 20: 2: 1). Recrystallized as a hemifumarate from acetone. Mp: 75-76 ° C.
Die nachfolgenden Verbindungen werden nach Methode I (in Dimethylformamid, 3 h bei 100°C) aus entsprechenden Ausgangsverbindungen hergestellt: The following compounds are prepared from corresponding starting compounds by method I (in dimethylformamide, 3 h at 100 ° C.):
33. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-phenoxyacetat, Schmp. 83-85°C. 33. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} phenoxyacetate, mp 83-85 ° C.
34. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-1- naphthylacetat-maleat, Schmp. 81-82°C. 34. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -1-naphthylacetate maleate, mp 81-82 ° C.
35. {6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl)-2- naphthylacetat-hemifumarat, Schmp. 129-132°C. 35. {6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl) -2-naphthyl acetate hemifumarate, mp. 129-132 ° C.
36. 2-(1-Naphthyloxy)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat, Schmp. 149-154°C. 36. 2- (1-Naphthyloxy) ethyl 6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate, mp. 149-154 ° C.
37. 2-(4-Hydroxyphenyl)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat, Schmp. 92-93°C. 37. 2- (4-Hydroxyphenyl) ethyl 6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate, mp 92-93 ° C.
38. (6-[2-(4-Amino-3.5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl)-4- methylsulfonyl-3-nitrophenylacetat-hemifumarat, Schmp. 111-113°C. 39. (6-[2-(4-Amino-3,5-dich!orphenyl)-2-hydroxyethylamino]-1-hexyl)-3- phenoxypropanoat-hemifumarat, Schmp. 110-114°C. 38. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl) -4-methylsulfonyl-3-nitrophenylacetate hemifumarate, mp 111-113 ° C. 39. (6- [2- (4-Amino-3,5-dich! Orphenyl) -2-hydroxyethylamino] -1-hexyl) -3-phenoxypropanoate hemifumarate, mp 110-114 ° C.
40. (4-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-butyl}- phenylacetat-hemifumarat, Schmp. 120-121 °C. 40. (4- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-butyl} phenyl acetate hemifumarate, mp 120-121 ° C.
41. (5-[2-(4-Amino-2,3-dich!orphenyl)-2-hydroxyethylamino]-1-pentyl}- phenylacetat-hemifumarat, Schmp. 142-144°C. 41. (5- [2- (4-Amino-2,3-dich! Orphenyl) -2-hydroxyethylamino] -1-pentyl} phenyl acetate hemifumarate, mp 142-144 ° C.
42. (7-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-heptyl)- phenylacetat-hemifumarat, Schmp. 121-122°C. 42. (7- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-heptyl) phenylacetate hemifumarate, mp 121-122 ° C.
43. (8-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-octyl}- phenylacetat-hemifumarat, Schmp. 116-118°C. 43. (8- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-octyl} phenyl acetate hemifumarate, mp 116-118 ° C.
44. 2-Phenylethyl-7-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]heptanoat-hemifumarat, Schmp. 127-129°C. 44. 2-Phenylethyl-7- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] heptanoate hemifumarate, mp. 127-129 ° C.
45. 2-Phenylethyl-8-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]octanoat-hemifumarat, Schmp. 124-125°C. 45. 2-Phenylethyl-8- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] octanoate hemifumarate, mp 124-125 ° C.
46. 2-Phenylethyl-5-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]pentanoat-fumarat, Schmp. 139-143°C. 46. 2-Phenylethyl-5- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] pentanoate fumarate, mp. 139-143 ° C.
47. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}- 4-bromphenylacetat-hemifumarat, Schmp. 129-130°C. 47. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} - 4-bromophenylacetate hemifumarate, mp. 129-130 ° C.
48. 2,2-Diphenylethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat-hemifumarat, Schmp. 121-123°C. 48. 2,2-Diphenylethyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate hemifumarate, mp 121-123 ° C.
49. {6-[2-(4-Amino-3,5-dichlorpheny!)-2-hydroxyethylamino]-1-hexyl}-4- phenoxybutanoat-hemifumarat, Schmp. 112-113 °C . 49. {6- [2- (4-Amino-3,5-dichloropheny!) - 2-hydroxyethylamino] -1-hexyl} -4-phenoxybutanoate hemifumarate, mp 112-113 ° C.
50. 3-Phenoxy-1-propyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat-hemifumarat, Schmp. 105-107°C. 51. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-2- naphthyloxyacetat-hemifumarat, Schmp. 113-116°C. 50. 3-Phenoxy-1-propyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate hemifumarate, mp 105-107 ° C. 51. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -2-naphthyloxyacetate hemifumarate, m.p. 113-116 ° C.
52. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl)-2- chlor-6-fluorphenylacetat, Schmp. 130-132°C. 52. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl) -2-chloro-6-fluorophenylacetate, mp 130-132 ° C.
53. (8-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-octyl)-2- phenoxyacetat-hemifumarat, Schmp. 124-125°C. 53. (8- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-octyl) -2-phenoxyacetate hemifumarate, mp 124-125 ° C.
54. 3-Phenyl-1-propyl-5-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]pentanoat-hemifumarat, Schmp. 107-111°C. 54. 3-Phenyl-1-propyl-5- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] pentanoate hemifumarate, mp. 107-111 ° C.
55. 2-(3-Hydroxyphenyl)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat-hemifumarat, Schmp. 157-159°C. 55. 2- (3-Hydroxyphenyl) ethyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate hemifumarate, mp. 157-159 ° C.
56. 2-(2-Hydroxyphenyl)ethy!-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat-hemifumarat, Schmp. 97-98°C. 56. 2- (2-Hydroxyphenyl) ethy! -6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate hemifumarate, mp 97-98 ° C.
57. 4-Phenyl-1-butyl-5-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]pentanoat-hemifumarat, Schmp. 130-132°C. 57. 4-Phenyl-1-butyl-5- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] pentanoate hemifumarate, mp 130-132 ° C.
58. 2-Phenylethyl-6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethy!amino]hexanoat-oxalat, Schmp. 119-122°C. 58. 2-Phenylethyl-6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethyl! Amino] hexanoate oxalate, mp 119-122 ° C.
59. (6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethylpheny!)ethylamino]-1-hexyl}- 1-naphthylacetat-xinafoat, Schmp. 125-128°C. 59. (6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylpheny!) Ethylamino] -1-hexyl} -1-naphthylacetate xinafoate, mp 125-128 ° C.
60. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl)-2- thienylacetat-hemifumarat, Schmp. 127-129°C. 60. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl) -2-thienyl acetate hemifumarate, mp. 127-129 ° C.
61. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl)-2-(4-ch!orphenyl)-2-methylpropanoat-hemifumarat, Schmp. 138-139°C. 61. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl) -2- (4-ch! Orphenyl) -2-methylpropanoate hemifumarate, mp. 138- 139 ° C.
62. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-1- naphthyloxyacetat-hemifumarat, Schmp. 113-116°C. 63. 2-(3-Hydroxyphenyl)ethyl-6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]hexanoat-xinafoat, Schmp. 67-69°C. 62. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -1-naphthyloxyacetate hemifumarate, mp 113-116 ° C. 63. 2- (3-Hydroxyphenyl) ethyl 6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] hexanoate xinafoate, mp 67-69 ° C.
64. 4-Phenylbutyl-6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]hexanoat-oxalat, Schmp. 119-121 °C - 64. 4-phenylbutyl-6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] hexanoate oxalate, mp. 119-121 ° C -
65. 2-(4-Methylphenyl)ethyl-6-[2-(4-amino-2,3-dichlorpheny!)-2-hydroxyethylamino]hexanoat-hemifumarat, Schmp. 129-132°C. 65. 2- (4-Methylphenyl) ethyl-6- [2- (4-amino-2,3-dichloropheny!) - 2-hydroxyethylamino] hexanoate hemifumarate, mp. 129-132 ° C.
66. 2-(4-Fluorphenyl)ethyl-6-[2-(4-amino-2,3-dichlorphenyl)-2-hydroxyethylamino]hexanoat-hemifumarat, Schmp. 138-141°C. 66. 2- (4-fluorophenyl) ethyl-6- [2- (4-amino-2,3-dichlorophenyl) -2-hydroxyethylamino] hexanoate hemifumarate, mp. 138-141 ° C.
67. {7- [2- (4-Amino-2, 3-dichl orphenyl) -2-hydroxyethyl amino] -1-heptyl)- benzoat-hemifumarat, Schmp. 142-144°C. 67. {7- [2- (4-Amino-2, 3-dichlorophenyl) -2-hydroxyethylamino] -1-heptyl) benzoate hemifumarate, mp 142-144 ° C.
68. (5-[2-(4-Amino-2,3-dichlorphenyl)-2-hydroxyethylamino]-1-penty!)-3- phenylpropionat-hemifumarat, Schmp. 129-130°C. 68. (5- [2- (4-Amino-2,3-dichlorophenyl) -2-hydroxyethylamino] -1-penty!) - 3-phenylpropionate hemifumarate, mp. 129-130 ° C.
69. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl)-4- nitrophenoxyacetat-hemifumarat, Schmp. 167-168°C. 69. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl) -4-nitrophenoxyacetate hemifumarate, m.p. 167-168 ° C.
70. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl)-3- methoxyphenylacetat-hemifumarat, Schmp. 117-120°C. 70. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl) -3-methoxyphenylacetate hemifumarate, mp 117-120 ° C.
71. 2-Phenylethyl-6-[2-(4-amino-3-chlor-5-trifluormethylphenyl)-2-hy- droxyethylamino]hexanoat-hemifumarat, Schmp. 125-127°C. 71. 2-Phenylethyl-6- [2- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-hydroxyethylamino] hexanoate hemifumarate, mp. 125-127 ° C.
72. (6-[2-(4-Amino-3-chlor-5-trifluormethylpheny!)-2-hydroxyethylamino]- 1-hexyl)-1-naphthylacetat-hemifumarat, Schmp. 141-144°C. 72. (6- [2- (4-Amino-3-chloro-5-trifluoromethylpheny!) - 2-hydroxyethylamino] - 1-hexyl) -1-naphthylacetate hemifumarate, mp. 141-144 ° C.
73. 2-(1-Naphthyl)ethyl-6-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethylamino]hexanoat-xinafoat, Schmp. 151-153°C. 73. 2- (1-Naphthyl) ethyl-6- [2- (4-hydroxy-3-hydroxymethylphenyl) -2-hydroxyethylamino] hexanoate xinafoate, mp 151-153 ° C.
74. 2-Phenylethyl-6-[2-(4-amino-5-ch!or-3-cyanphenyl)-2-hydroxyethylamino]hexanoat-hemifumarat, Schmp. 147-149°C. 75. (6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-1-hexyl}- phenylacetat-oxalat, Schmp. 115-118°C. 74. 2-Phenylethyl-6- [2- (4-amino-5-chloro-3-cyanophenyl) -2-hydroxyethylamino] hexanoate hemifumarate, mp. 147-149 ° C. 75. (6- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -1-hexyl} phenyl acetate oxalate, mp 115-118 ° C.
76. (5-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-1-pentyl}-(3-hydroxyphenyl)acetat-xinafoat, Schmp. 95-100°C. 76. (5- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -1-pentyl} - (3-hydroxyphenyl) acetate xinafoate, mp 95-100 ° C.
77. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-4- methoxyphenylacetat-hemifumarat, Schmp. 119-120°C. 77. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -4-methoxyphenylacetate hemifumarate, mp. 119-120 ° C.
78. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl)-2- methoxyphenylacetat-hemifumarat, Schmp. 123-124°C. 78. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl) -2-methoxyphenylacetate hemifumarate, m.p. 123-124 ° C.
79. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-2- methylphenylacetat, Schmp. 96-97°C. 79. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -2-methylphenylacetate, mp 96-97 ° C.
80. {6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-3- methylphenylacetat-hemifumarat, Schmp. 130-132°C. 80. {6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -3-methylphenylacetate hemifumarate, m.p. 130-132 ° C.
81. (6-[2-(4-Amino-3,5-dichlorpheny!)-2-hydroxyethylamino]-1-hexyl}-2- nitrophenylacetat-hemifumarat, Schmp. 153-167°C. 81. (6- [2- (4-Amino-3,5-dichloropheny!) - 2-hydroxyethylamino] -1-hexyl} -2-nitrophenylacetate hemifumarate, mp 153-167 ° C.
82. (6-[2-(4-Amino-2,3-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-2- chlorphenylacetat-hemifumarat, Schmp. 138-141°C. 82. (6- [2- (4-Amino-2,3-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -2-chlorophenylacetate hemifumarate, mp. 138-141 ° C.
83. (6-[2-(4-Amino-2,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-3- chlorphenylacetat-hemifumarat, Schmp. 119-122°C. 83. (6- [2- (4-Amino-2,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -3-chlorophenylacetate hemifumarate, mp. 119-122 ° C.
84. {6-[2-(4-Amino-2,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-4- chlorphenylacetat-hemifumarat, Schmp. 120-123°C. 84. {6- [2- (4-Amino-2,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -4-chlorophenylacetate hemifumarate, mp 120-123 ° C.
85. 1-(2-Phenyl)propyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethyl- amino]hexanoat-hemifumarat, Schmp. 119-120°C. 85. 1- (2-phenyl) propyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate hemifumarate, mp. 119-120 ° C.
86. {5-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-pentyl}-3- (1-naphthyl)propionat-hemifumarat, Schmp. 127-128°C. 87. (5-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-1-pentyl}-3-(1-naphthyl)propionat-xinafoat, Schmp. 114-115°C. 86. {5- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-pentyl} -3- (1-naphthyl) propionate hemifumarate, mp. 127-128 ° C. 87. (5- [2-Hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -1-pentyl} -3- (1-naphthyl) propionate xinafoate, mp 114-115 ° C.
88. (4-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-butyl}-4- phenylbutyrat-hemifumarat, Schmp. 126-127°C. 88. (4- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-butyl} -4-phenylbutyrate hemifumarate, mp 126-127 ° C.
89. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-4- cyanphenoxyacetat-hemifumarat, Schmp. 149-152°C. 89. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -4-cyanophenoxyacetate hemifumarate, mp. 149-152 ° C.
90. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-2- fluorphenylacetat-hemifumarat, Schmp. 136-137°C. 90. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -2-fluorophenylacetate hemifumarate, mp 136-137 ° C.
91. (6-[2-(4-Amino-3.5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-4- ethoxyphenylacetat-hemifumarat, Schmp. 114-116°C. 91. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -4-ethoxyphenyl acetate hemifumarate, mp. 114-116 ° C.
92. (6-[2-(4-Amino-5-chlor-3-cyanpheny!)-2-hydroxyethylamino]-1-hexyl}- phenylacetat-hemifumarat, Schmp. 153°C. 92. (6- [2- (4-Amino-5-chloro-3-cyanpheny!) - 2-hydroxyethylamino] -1-hexyl} - phenylacetate hemifumarate, mp. 153 ° C.
93. 3-(1-Naphthyl)propyl-6-[2-(4-amino-3,5-dich!orphenyl)-2-hydroxyethylamino]hexanoat-hemifumarat, Schmp. 153-155°C. 93. 3- (1-Naphthyl) propyl-6- [2- (4-amino-3,5-dich! Orphenyl) -2-hydroxyethylamino] hexanoate hemifumarate, mp 153-155 ° C.
94. 3-(1-Naphthyl)propyl-6-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethylamino]hexanoat-xinafoat, Schmp. 118-119°C. 94. 3- (1-Naphthyl) propyl-6- [2- (4-hydroxy-3-hydroxymethylphenyl) -2-hydroxyethylamino] hexanoate xinafoate, mp 118-119 ° C.
95. (6-[2-(4-Amino-5-chlor-3-cyanphenyl)-2-hydroxyethylamino]-1-hexyl}- 1-naphthylacetat-hemifumarat, Schmelzbereich 138-279°C. 95. (6- [2- (4-Amino-5-chloro-3-cyanophenyl) -2-hydroxyethylamino] -1-hexyl} -1-naphthylacetate hemifumarate, melting range 138-279 ° C.
96. (6-[2-Hydroxy-2-(3-hydroxyphenyl)ethylamino]-1-hexyl}-1-naphthylacetat-hemifumarat, Schmelzbereich 117- 131°C. 96. (6- [2-Hydroxy-2- (3-hydroxyphenyl) ethylamino] -1-hexyl} -1-naphthylacetate hemifumarate, melting range 117-131 ° C.
97. (6-[2-(4-Amino-3,5-dichlorpheny!)-2-hydroxyethylamino]-1-hexyl}-11- phenoxyundecanoat. Schmp. 71-72°C. 97. (6- [2- (4-Amino-3,5-dichloropheny!) - 2-hydroxyethylamino] -1-hexyl} -11-phenoxyundecanoate. Mp. 71-72 ° C.
98. 1-Phenoxy-2-propyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat-hemifumarat. Schmp. 103-105°C. 99. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl)-2- phenylphenoxyacetat-hemifumarat, Schmp. U6-118°C. 98. 1-Phenoxy-2-propyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate hemifumarate. 103-105 ° C. 99. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl) -2-phenylphenoxyacetate hemifumarate, mp U6-118 ° C.
100. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethy!amino]-1-hexyl}-3- phenylphenoxyacetat-hemifumarat, Schmp. <40°C. 100. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethyl! Amino] -1-hexyl} -3-phenylphenoxyacetate hemifumarate, m.p. <40 ° C.
101. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-4- phenylphenoxyacetat-hemifumarat, Schmp. <40°C. 101. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -4-phenylphenoxyacetate hemifumarate, m.p. <40 ° C.
102. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-!-hexyl}-2- phenylaminocarbonylphenoxyacetat, Schmp. 105-107°C. 102. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -! - hexyl} -2-phenylaminocarbonylphenoxyacetate, mp 105-107 ° C.
103. 2-(3-Indolyl)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethyl- amino]hexanoat-hemifumarat, Schmp. 125-126°C. 103. 2- (3-Indolyl) ethyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate hemifumarate, mp. 125-126 ° C.
104. (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}- phenylthioacetat-hemifumarat, Schmp. 154-155°C. 104. (6- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} phenylthioacetate hemifumarate, mp 154-155 ° C.
105. 2-(1,4-Benzodioxanyl)methyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hy- droxyethylamino]hexanoat-hemifumarat, Schmp. 105-107°C. 105. 2- (1,4-Benzodioxanyl) methyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate hemifumarate, mp. 105-107 ° C.
106. (2-[2-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]ethoxy]- ethyl}-phenylacetat-fumarat, Schmp. 118-120°C. 106. (2- [2- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] ethoxy] ethyl} phenylacetate fumarate, mp 118-120 ° C.
107. 2-Phenylethyl-3-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]- propionat-hemifumarat, Schmp. 128-131°C. 107. 2-Phenylethyl-3- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] propionate hemifumarate, mp. 128-131 ° C.
108. 2-Indanyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]- hexanoat-fumarat, Schmp. 123-129°C . Gewerbliche Anwendbarkeit 108. 2-Indanyl-6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate fumarate, mp 123-129 ° C. Industrial applicability
Die erfindungsgemäßen Verbindungen besitzen wertvolle pharmakologische Eigenschaften, die sie gewerblich verwertbar machen. Sie stellen in erster Linie wirksame ß-Adrenozeptor-Agonisten (ß-Sympathomimetika) mit bevorzugt ß-,-stimulierender Wirkung dar, wobei sie sich besonders durch ihre lange Wirkungsdauer, ihre Stabilität und Selektivität sowie durch das Fehlen unerwünschter Nebenwirkungen auszeichnen. The compounds according to the invention have valuable pharmacological properties which make them commercially usable. They are primarily effective ß-adrenoceptor agonists (ß-sympathomimetics) with a preferred ß -, - stimulating effect, whereby they are particularly characterized by their long duration of action, their stability and selectivity and by the absence of undesirable side effects.
Aufgrund ihrer ß-sympathomimeti sehen Wirkung eignen sich die erfindungsgemäßen Verbindungen beispielsweise zur Behandlung von Bradykardien und Überleitungsstörungen und erhöhen die Kontraktilität des Herzens, sie können als Tokolytika zur Behandlung vorzeitiger Wehen eingesetzt werden, sie wirken allgemein als Vasodilantien und können zur Behandlung (peripherer) Durchblutungsstörungen eingesetzt werden, sie führen zu einer Erschlaffung der Blasenwandmuskulatur und eignen sich zur Behandlung von Blasenentleerungsstörungen, sie senken den (krankhaft erhöhten) Augeninnendruck und können zur Behandlung des Glaukoms eingesetzt werden, sie beeinflussen den Stoffwechsel und eignen sich z.B. zur Behandlung der Adipositas, und sie eignen sich aufgrund ihrer vor allem ß2-sympathomimetisehen Wirkung vor allem zur Behandlung von Atemwegserkrankungen verschiedener Genese. Because of their ß-sympathomimetic effect, the compounds according to the invention are suitable, for example, for the treatment of bradycardia and conduction disorders and increase the contractility of the heart, they can be used as tocolytics for the treatment of premature labor, they generally act as vasodilants and can be used to treat (peripheral) circulatory disorders are used, they relax the bladder wall muscles and are suitable for the treatment of bladder emptying disorders, they lower the (pathologically increased) intraocular pressure and can be used for the treatment of glaucoma, they influence the metabolism and are suitable for the treatment of obesity, for example are particularly suitable for the treatment of respiratory diseases of various origins due to their ß 2 -sympathomimetic effect.
Insbesondere können (Allergen- und inflammatorisch induzierte) Bronchialerkrankungen aufgrund der broncholytischen Wirksamkeit der erfindungsgemäßen Verbindungen behandelt werden. Dabei zeichnen sich die erfindungsgemäßen Verbindungen durch eine geringe Toxizität, eine große therapeutische Breite, eine langanhaltende Wirkung und verringerte systemische Nebenwirkungen aus. Von besonderer Bedeutung ist in diesem Zusammenhang die - im Vergleich zur systemischen Applikation - stark ausgeprägte Wirksamkeit bei topischer Applikation. In particular (due to the broncholytic activity of the compounds according to the invention), bronchial diseases (allergen and inflammation-induced) can be treated. The compounds according to the invention are notable for low toxicity, a wide therapeutic range, a long-lasting effect and reduced systemic side effects. Of particular importance in this context is - compared to systemic application - the pronounced effectiveness with topical application.
Die broncholytische Wirksamkeit der erfindungsgemäßen Verbindungen ermöglicht ihren Einsatz in der Human- und Veterinärmedizin, wobei sie zur Behandlung und Prophylaxe von Krankheiten, die auf Erkrankungen der Bronchien beruhen, verwendet werden. Beispielsweise können akute und chronisch ob struktive Atemwegserkrankungen verschiedener Genese (Bronchitis, allergische Bronchitis, Asthma bronchiale) bei Mensch und Tier behandelt werden. Die Eigenschaften der erfindungsgemäßen Verbindungen ermöglicht außerdem ihren Einsatz bei der topischen Behandlung von Dermatosen, etwa bei entzündlichen und allergischen Hauterkrankungen, wie beispielsweise bei toxischem und allergischem Kontaktekzem, atopischem Ekzem, seborrhoischem Ekzem, follikulären und flächenhaften Pyodermien, endogener und exogener Akne sowie Akne rosacea. The broncholytic activity of the compounds according to the invention enables their use in human and veterinary medicine, where they are used for the treatment and prophylaxis of diseases which are based on diseases of the bronchi. For example, acute and chronic whether structural respiratory diseases of various origins (bronchitis, allergic bronchitis, bronchial asthma) are treated in humans and animals. The properties of the compounds according to the invention also enable their use in the topical treatment of dermatoses, for example in inflammatory and allergic skin diseases, such as, for example, toxic and allergic contact dermatitis, atopic eczema, seborrheic eczema, follicular and areal pyoderma, endogenous and exogenous acne and acne rosacea.
Weiterhin eignen sich die erfindungsgemäßen Verbindungen zur Behandlung solcher Krankheitszustände, von denen bekannt ist, daß sie durch die Applikation bestimmter ß-Adrenozeptor-Agonisten positiv beeinflußt werden. So können beispielsweise aufgrund der hypoglycämi sehen Wirkung der Verbindungen Stoffwechsel Störungen verschiedener Genese (z.B. Fettleibigkeit oder Störungen, wie sie etwa im Zusammenhang mit dem Diabetes stehen) behandelt werden. Auch können gastrointestinale Motilitätsstörungen sowie krankhafte Veränderungen im Gastrointestinaltrakt (beispielsweise entzündliche Darmerkrankungen wie Colitis ulcerosa oder Morbus Crohn) durch die erfindungsgemäßen Verbindungen behandelt werden. Furthermore, the compounds according to the invention are suitable for the treatment of those disease states which are known to be positively influenced by the application of certain β-adrenoceptor agonists. For example, due to the hypoglycemic effects of the compounds, metabolism disorders of various origins (e.g. obesity or disorders such as those associated with diabetes) can be treated. Gastrointestinal motility disorders and pathological changes in the gastrointestinal tract (for example inflammatory bowel diseases such as ulcerative colitis or Crohn's disease) can also be treated by the compounds according to the invention.
Ein weiterer Gegenstand der Erfindung ist daher ein Verfahren zur Behandlung von Säugern einschließlich Menschen, die an einer der oben genannten Krankheiten erkrankt sind. Das Verfahren ist dadurch gekennzeichnet, daß man dem erkrankten Säuger eine therapeutisch wirksame und pharmakologisch verträgliche Menge einer oder mehrerer der erfindungsgemäßen Verbindungen verabreicht. The invention therefore furthermore relates to a method for the treatment of mammals, including humans, who are suffering from one of the abovementioned diseases. The method is characterized in that the sick mammal is administered a therapeutically effective and pharmacologically acceptable amount of one or more of the compounds according to the invention.
Weiterer Gegenstand der Erfindung sind die erfindungsgemäßen Verbindungen zur Anwendung bei der Behandlung und/oder Prophylaxe der genannten Krankheiten. The invention further relates to the compounds according to the invention for use in the treatment and / or prophylaxis of the diseases mentioned.
Ebenso betrifft die Erfindung die Verwendung der erfindungsgemäßen Verbindungen zur Herstellung von Arzneimitteln, die zur Behandlung und/oder Prophylaxe der genannten Krankheiten eingesetzt werden. Weiterhin sind Arzneimittel zur Behandlung und/oder Prophylaxe der genannten Krankheiten, die eine oder mehrere der erfindungsgemäßen Verbindungen und/oder ihre pharmakologisch verträglichen Salze enthalten, Gegenstand der Erfindung. The invention also relates to the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the diseases mentioned. The invention furthermore relates to medicaments for the treatment and / or prophylaxis of the diseases mentioned which contain one or more of the compounds according to the invention and / or their pharmacologically tolerable salts.
Die erfindungsgemäßen Arzneimittel werden nach an sich bekannten Verfahren hergestellt, wobei bezüglich der Zubereitungen, der Darreichungsformen (insbesondere bezüglich der inhalativen Applikation) etc. beispielsweise auf die Ausführungen im Europäischen Patent 163 965 verwiesen wird. Von besonderer Bedeutung bei der Behandlung von Bronchialerkrankungen ist in diesem Zusammenhang die inhalative Verabreichung, für welche die erfindungsgemäßen Verbindungen aufgrund ihres Wirkungsprofiles hervorragend geeignet erscheinen. The medicaments according to the invention are produced by methods known per se, reference being made, for example, to the statements in European patent 163 965 with regard to the preparations, the dosage forms (in particular with regard to inhalation administration), etc. In this connection, inhalative administration is particularly important in the treatment of bronchial diseases, for which the compounds according to the invention appear to be outstandingly suitable due to their action profile.
Sollen die erfindungsgemäßen Verbindungen inhalativ verabreicht werden, so werden Tagesdosen von 0,01 bis 2,0 mg, insbesondere von 0,05 bis 1,0 mg, vorteilhafterweise in mehreren Einzeldosen zu beispielsweise 10 bis 50 μg Wirkstoff verabfolgt. Bei der oralen Darreichung sind entsprechend höhere Dosierungen (von 0,5 bis 50 mg pro Tag), gegebenenfalls in Form mehrerer Einzeldosen zu verabreichen. If the compounds according to the invention are to be administered by inhalation, daily doses of 0.01 to 2.0 mg, in particular 0.05 to 1.0 mg, are advantageously administered in several individual doses to, for example, 10 to 50 μg of active ingredient. In the case of oral administration, correspondingly higher doses (from 0.5 to 50 mg per day), optionally in the form of several single doses, have to be administered.
Pharmakologie pharmacology
Die ausgezeichnete bronchospasmolytische Wirkung der erfindungsgemäßen Verbindungen kann durch In-vitro-Untersuchungen an der Meerschweinchen-Trachea nachgewiesen werden. Hierzu wird für die zu untersuchenden Verbindungen die relaxierende Wirkung an einer Meerschweinchentrachea gemessen, die vorher mit einer geeigneten Dosis Metacholin kontrahiert worden ist. Die Trachea von männlichen Meerschweinchen (200-300g) wird entfernt, in einzelne Segmente geteilt und jedes Segment wird in einem Organbad mit 118,5 mM NaCl , 4,7 mM KCl, 1,2 mM MgSO4, 2,5 mM CaCl2, 1,2 mM KH2PO4, 25 mM NaHCO3 und 10 mM Glukose bei 37ºC aufgehängt. Sauerstoff, versetzt mit 5 % CO2, wird permanent durch die Lösung geleitet. Die Trachea wird nach Stabilisierung mit einer geeigneten Dosis Methacholin kontrahiert. Danach wird mit den Prüfsubstanzen in kumulativer Weise eine Dosis-Wirkungskurve aufgenommen. Aus dieser Kurve wird dann die Konzentration (mol/1) bestimmt, die 50 % des Maximal effektes (EC50) entspricht. Diese EC50 ist somit ein Maßstab für die Aktivität der erfindungsgemäßen Verbindungen. The excellent bronchospasmolytic activity of the compounds according to the invention can be demonstrated by in vitro investigations on the guinea pig trachea. For this purpose, the relaxing effect on a guinea pig trachea is measured for the compounds to be examined, which has previously been contracted with a suitable dose of metacholine. The trachea of male guinea pigs (200-300 g) is removed, divided into individual segments and each segment is in an organ bath with 118.5 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO 4 , 2.5 mM CaCl 2 , 1.2 mM KH 2 PO 4 , 25 mM NaHCO 3 and 10 mM glucose at 37 ° C. Oxygen, mixed with 5% CO 2 , is continuously passed through the solution. After stabilization, the trachea is contracted with a suitable dose of methacholine. Then a dose-response curve is recorded in a cumulative manner with the test substances. From this curve, the concentration (mol / 1) is determined, which corresponds to 50% of the maximum effect (EC 50 ). This EC 50 is thus a measure of the activity of the compounds according to the invention.
In der nachfolgenden Tabelle sind die -log[EC50(mol/l)]-Werte für ausgewählte erfindungsgemäße Verbindungen angegeben. Die laufende Nummer in der Tabelle stimmt mit der Nummer der Verbindungen in den Beispielen überein. Die Zahl n gibt die Zahl der Untersuchungen an. The following table shows the -log [EC 50 (mol / l)] values for selected compounds according to the invention. The serial number in the table matches the number of the connections in the examples. The number n indicates the number of examinations.
Tabelle lfd. Nr. -log[EC50] n Table no. -Log [EC 50 ] n
17 7,7 6 17 7.7 6
19 8,2 3  19 8.2 3
32 7,8 3  32 7.8 3
34 8,5 5  34 8.5 5
37 8,7 6  37 8.7 6
64 8,0 4  64 8.0 4
74 8,4 6  74 8.4 6
82 8,0 6  82 8.0 6
103 8,5 5  103 8.5 5
106 8,1 3  106 8.1 3

Claims

Patentansprüche Claims
1. Verbindungen der Formel I, Ar1-CH(OH)-CH2-NH-CH2-X-CH2-E-(CH2)n-Y-Ar2 (I) worin 1. Compounds of formula I, Ar 1 -CH (OH) -CH 2 -NH-CH 2 -X-CH 2 -E- (CH 2 ) n -Y-Ar 2 (I) wherein
X 1-12C-Alkylen, 1-6C-Alkylenoxy-1-6C-alkylen oder Cyclohexylen bedeutet, E Carbonyloxy (-CO-O-) oder Oxycarbonyl (-O-CO-) bedeutet,  X is 1-12C-alkylene, 1-6C-alkyleneoxy-1-6C-alkylene or cyclohexylene, E is carbonyloxy (-CO-O-) or oxycarbonyl (-O-CO-),
n eine ganze Zahl von 0 bis 10 bedeutet, n is an integer from 0 to 10,
Y einen Bindungsstrich, Sauerstoff (0), Schwefel (S), die Gruppe -CHR-, in der R die Bedeutung 1-4C-Alkyl, Phenyl oder Hydroxy hat, oder die Gruppen -CR' - oder -CHR'-CH20- bedeutet, in denen R' die Bedeutung 1-4C-Alkyl hat, wobei Y nicht Sauerstoff ist, wenn n die Zahl 0 bedeutet, Y is a bond, oxygen (0), sulfur (S), the group -CHR-, in which R is 1-4C-alkyl, phenyl or hydroxy, or the groups -CR '- or -CHR'-CH 2 Is 0, in which R 'is 1-4C-alkyl, where Y is not oxygen if n is 0,
Ar, einen durch R1, R2 und R3 substituierten Phenylrest bedeutet, Ar represents a phenyl radical substituted by R1, R2 and R3,
wobei  in which
R1 Wasserstoff, Halogen, Hydroxy (-OH), Amino (-NH2), Ureido R1 is hydrogen, halogen, hydroxy (-OH), amino (-NH 2 ), ureido
(-NH-CO-NH2), Formylamino (-NH-COH), 1-4C-Alkylcarbonylamino (-NH-CO-1-4C-Alkyl), Di-1-4C-alkyl-carbamoyloxy [-O-CO-N(1-4C- Alkyl)2], Toluoyloxy (-O-CO-C6H4-CH3), Hydroxymethyl (-CH2OH), 1-4C-Alkylcarbonyloxy (-O-CO-1-4C-Alkyl), 1-4C-Alkyl, l-4C-Alkoxy, 1-4C-Alkylsulfonylamino (-NH-SO2-1-4C-Alkyl), 1-4C-Alkylsulfonylmethyl (-CH2-SO2-1-4C-Alkyl) oder l-4C-Alkoxy-1-4C-alkyl bedeutet, R2 Wasserstoff, Halogen, Hydroxy (-OH), Cyan (-CN), Trifluormethyl (-CF3), Toluoyloxy (-O-CO-C6H4-CH3), Hydroxymethyl (-CH2OH) oder 1-4C-Alkylcarbonyloxy (-O-CO-1-4C-Alkyl) bedeutet und (-NH-CO-NH 2 ), formylamino (-NH-COH), 1-4C-alkylcarbonylamino (-NH-CO-1-4C-alkyl), di-1-4C-alkyl-carbamoyloxy [-O-CO -N (1-4C-alkyl) 2 ], toluoyloxy (-O-CO-C 6 H 4 -CH 3 ), hydroxymethyl (-CH 2 OH), 1-4C-alkylcarbonyloxy (-O-CO-1-4C -Alkyl), 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylsulfonylamino (-NH-SO 2 -1-4C-alkyl), 1-4C-alkylsulfonylmethyl (-CH 2 -SO 2 -1- 4C-alkyl) or 1-4C-alkoxy-1-4C-alkyl means R2 is hydrogen, halogen, hydroxy (-OH), cyano (-CN), trifluoromethyl (-CF 3 ), toluoyloxy (-O-CO-C 6 H 4 -CH 3 ), hydroxymethyl (-CH 2 OH) or 1-4C-alkylcarbonyloxy (-O-CO-1-4C-alkyl) and
R3 Wasserstoff oder Halogen bedeutet,  R3 represents hydrogen or halogen,
und  and
Ar2 einen durch R4 und R5 substituierten Phenylrest, einen Thienylrest, einen Pyridylrest, einen Naphthylrest, einen Indolylrest, einen Indanyl- rest oder einen Benzo-l,4-dioxanylrest bedeutet, wobei Ar 2 represents a phenyl radical substituted by R4 and R5, a thienyl radical, a pyridyl radical, a naphthyl radical, an indolyl radical, an indanyl radical or a benzo-1,4-dioxanyl radical, where
R4 Wasserstoff, Halogen, Hydroxy (-OH), Cyan (-CN), 1-4C-Alkyl,  R4 is hydrogen, halogen, hydroxy (-OH), cyan (-CN), 1-4C-alkyl,
1-4C-Alkoxy, Benzyloxy, Nitro (-NO2), Trifluormethyl (-CF3), 1-4C-Alkoxycarbonyl (-CO-O-1-4C-Alkyl), Carbamoyl (-CO-NH2), Di-1-4C-alkylcarbamoyl [-CO-N(1-4C-Alkyl)2], Amino (-NH2), 1-4C-Alkylsulfonyl, Phenyl oder Phenylcarbonyl amino bedeutet und R5 Wasserstoff, Halogen, Hydroxy (-OH), 1-4C-Alkyl oder 1-4C-Alkoxy bedeutet, 1-4C-alkoxy, benzyloxy, nitro (-NO 2 ), trifluoromethyl (-CF 3 ), 1-4C-alkoxycarbonyl (-CO-O-1-4C-alkyl), carbamoyl (-CO-NH 2 ), di-1-4C-alkylcarbamoyl [-CO-N (1-4C-alkyl) 2 ], amino (-NH 2 ), 1-4C-alkylsulfonyl, phenyl or phenylcarbonylamino and R5 is hydrogen, halogen, hydroxy (-OH), 1-4C-alkyl or 1-4C-alkoxy,
wobei R4 nicht Hydroxy oder 1-4C-Alkoxy bedeutet, wenn E Oxycarbonyl (-O-CO-), n die Zahl 0 und Y einen Bindungsstrich bedeutet, und wobei where R4 is not hydroxy or 1-4C-alkoxy when E is oxycarbonyl (-O-CO-), n is 0 and Y is a dash, and wherein
R1 und R2 nicht gleichzeitig Hydroxy bedeuten, wenn X 1-4C-Alkylen und E Carbonyloxy (-CO-O-) bedeutet, R1 and R2 are not simultaneously hydroxyl if X is 1-4C-alkylene and E is carbonyloxy (-CO-O-),
und die Salze dieser Verbindungen.  and the salts of these compounds.
2. Verbindungen der Formel I nach Anspruch 1, 2. Compounds of formula I according to claim 1,
worin wherein
X 1-12C-Alkylen oder Cyclohexylen bedeutet,  X denotes 1-12C-alkylene or cyclohexylene,
E Carbonyloxy (-CO-O-) oder Oxycarbonyl (-O-CO-) bedeutet, E denotes carbonyloxy (-CO-O-) or oxycarbonyl (-O-CO-),
n eine ganze Zahl von 0 bis 8 bedeutet, n is an integer from 0 to 8,
Y einen Bindungsstrich, Sauerstoff (O) oder die Gruppe -CHR- bedeutet, in der R die Bedeutung 1-4C-Alkyl, Phenyl oder Hydroxy hat, wobei Y nicht Sauerstoff ist, wenn n die Zahl 0 bedeutet,  Y denotes a bond line, oxygen (O) or the group -CHR-, in which R denotes 1-4C-alkyl, phenyl or hydroxyl, where Y is not oxygen if n denotes the number 0,
Ar, einen durch R1, R2 und R3 substituierten Phenylrest bedeutet, Ar represents a phenyl radical substituted by R1, R2 and R3,
wobei  in which
R1 Wasserstoff, Hal ogen , Hydroxy ( -OH) , Ami no ( -NH2) , Ureido R1 hydrogen, halogen, hydroxy (-OH), amino (-NH 2 ), ureido
(-NH-CO-NH2), Formylamino (-NH-COH), 1-4C-Alkylcarbonylamino (-NH-CO-1-4C-Alkyl), Di -1-4C-al kyl -carbamoyloxy [-O-CO-N(1-4C- Alkyl)2], Toluoyloxy (-O-CO-C6H4-CH3), Hydroxymethyl (-CH2OH), 1-4C-A1 kyl carbonyl oxy (-O-CO-1-4C-Alkyl), 1-4C-Alkyl, l-4C-Alkoxy, 1-4C-A1 kyl sul fonyl amino ( -NH-SO2-1-4C-Alkyl), 1-4C-Alkylsulfonylmethyl (-CH2-SO2-1-4C-Alkyl) oder 1-4C-Alkoxy-1-4C-alkyl bedeutet, R2 Wasserstoff, Halogen, Hydroxy (-OH), Cyan (-CN), Trifluormethyl (-CF3), Toluoyloxy (-O-CO-C6H4-CH3), Hydroxymethyl (-CH2OH) oder 1-4C-Alkylcarbonyl oxy (-O-CO-1-4C-Alkyl) bedeutet und (-NH-CO-NH 2 ), formylamino (-NH-COH), 1-4C-alkylcarbonylamino (-NH-CO-1-4C-alkyl), di -1-4C-alkyl-carbamoyloxy [-O- CO-N (1-4C-alkyl) 2 ], toluoyloxy (-O-CO-C 6 H 4 -CH 3 ), hydroxymethyl (-CH 2 OH), 1-4C-A1 alkyl carbonyl oxy (-O-CO -1-4C-alkyl), 1-4C-alkyl, 1-4C-alkoxy, 1-4C-A1 kyl sul fonyl amino (-NH-SO 2 -1-4C-alkyl), 1-4C-alkylsulfonylmethyl (- CH 2 -SO 2 -1-4C-alkyl) or 1-4C-alkoxy-1-4C-alkyl means R2 means hydrogen, halogen, hydroxy (-OH), cyano (-CN), trifluoromethyl (-CF 3 ), Toluoyloxy (-O-CO-C 6 H 4 -CH 3 ), hydroxymethyl (-CH 2 OH) or 1-4C-alkylcarbonyl oxy (-O-CO-1-4C-alkyl) means and
R3 Wasserstoff oder Halogen bedeutet,  R3 represents hydrogen or halogen,
und  and
Ar2 einen durch R4 und R5 substituierten Phenylrest, einen Thienylrest, einen Pyridylrest oder einen Naphthylrest bedeutet, wobei Ar 2 represents a phenyl radical substituted by R4 and R5, a thienyl radical, a pyridyl radical or a naphthyl radical, where
R4 Wasserstoff, Halogen, Hydroxy (-0H), Cyan (-CN), 1-4C-Alkyl, 1-4C-Alkoxy, Benzyloxy, Nitro (-NO2), Trifluormethyl (-CF3), l-4C-Alkoxycarbonyl (-CO-O-1-4C-Alkyl), Carbamoyl (-CO-NH2), Di-1-4C-alkylcarbamoyl [-CO-N(1-4C-Alkyl)2] oder Amino (-NH2) bedeutet und R4 is hydrogen, halogen, hydroxy (-0H), cyan (-CN), 1-4C-alkyl, 1-4C-alkoxy, benzyloxy, nitro (-NO 2 ), trifluoromethyl (-CF 3 ), 1-4C-alkoxycarbonyl (-CO-O-1-4C-alkyl), carbamoyl (-CO-NH 2 ), Di -1-4C-alkylcarbamoyl [-CO-N (1-4C-alkyl) 2 ] or amino (-NH 2 ) means and
R5 Wasserstoff, Halogen, Hydroxy (-OH), 1-4C-Alkyl oder 1-4C-Alkoxy bedeutet,  R5 denotes hydrogen, halogen, hydroxy (-OH), 1-4C-alkyl or 1-4C-alkoxy,
wobei R4 nicht Hydroxy oder l-4C-Al.koxy bedeutet, wenn E Oxycarbonyl (-O-CO-), n die Zahl 0 und Y einen Bindungsstrich bedeutet, und wobei R1 und R2 nicht gleichzeitig Hydroxy bedeuten, wenn X 1-4C-Alkylen und E Carbonyloxy (-CO-O-) bedeutet, where R4 is not hydroxy or 1-4C-Al . koxy means when E is oxycarbonyl (-O-CO-), n is the number 0 and Y is a dash, and where R1 and R2 are not simultaneously hydroxy when X is 1-4C-alkylene and E is carbonyloxy (-CO-O- ) means
und die Salze dieser Verbindungen. and the salts of these compounds.
3. Verbindungen der Formel I nach Anspruch 1, worin n eine ganze Zahl von 1 bis 10 bedeutet, und die Salze dieser Verbindungen. 3. Compounds of formula I according to claim 1, wherein n is an integer from 1 to 10, and the salts of these compounds.
4. Verbindungen der Formel I nach Anspruch 1, worin E Carbonyloxy (-CO-O-) bedeutet, und die Salze dieser Verbindungen. 4. Compounds of formula I according to claim 1, wherein E is carbonyloxy (-CO-O-), and the salts of these compounds.
5. Verbindungen der Forme! I nach Anspruch 1, worin E Oxycarbonyl (-O-CO-) bedeutet, und die Salze dieser Verbindungen. 5. Connections of forms! I according to claim 1, wherein E is oxycarbonyl (-O-CO-), and the salts of these compounds.
6. Verbindungen der Formel I nach Anspruch 1, 6. Compounds of formula I according to claim 1,
worin wherein
X 1-6C-Alkylen, 1-2C-Alkylenoxy-1-2C-al kylen oder Cyclohexylen bedeutet, X denotes 1-6C-alkylene, 1-2C-alkyleneoxy-1-2C-alkylene or cyclohexylene,
E Carbonyloxy (-CO-O-) oder Oxycarbonyl (-O-CO-) bedeutet, E denotes carbonyloxy (-CO-O-) or oxycarbonyl (-O-CO-),
n eine ganze Zahl von 1 bis 5 bedeutet, n is an integer from 1 to 5,
Y einen Bindungsstrich, Sauerstoff (O) oder die Gruppe -CHR- bedeutet, in der R die Bedeutung 1-4C-Alkyl hat,  Y denotes a bond line, oxygen (O) or the group -CHR-, in which R denotes 1-4C-alkyl,
Ar1 einen durch R1, R2 und R3 substituierten Phenylrest bedeutet, Ar 1 represents a phenyl radical substituted by R1, R2 and R3,
wobei  in which
R1 Wasserstoff, Hydroxy oder Amino (-NH2) bedeutet, R1 denotes hydrogen, hydroxy or amino (-NH 2 ),
R2 Wasserstoff, Halogen, Cyan, Trifluormethyl oder Hydroxymethyl bedeutet und  R2 is hydrogen, halogen, cyan, trifluoromethyl or hydroxymethyl and
R3 Wasserstoff oder Halogen bedeutet,  R3 represents hydrogen or halogen,
und Ar2 einen durch R4 und R5 substituierten Phenylrest, einen Thienylrest, einen Pyridylrest, einen Naphthylrest, einen Indolylrest oder einen Inda- nylrest bedeutet, wobei and Ar 2 represents a phenyl radical substituted by R4 and R5, a thienyl radical, a pyridyl radical, a naphthyl radical, an indolyl radical or an indanyl radical, where
R4 Wasserstoff, Halogen, Hydroxy (-OH), Cyan (-CN), 1-4C-Alkyl, 1-4C- Alkoxy, Benzyloxy, Nitro (-NO2) oder Trifluormethyl (-CF3), bedeutet und R4 is hydrogen, halogen, hydroxy (-OH), cyano (-CN), 1-4C-alkyl, 1-4C-alkoxy, benzyloxy, nitro (-NO 2 ) or trifluoromethyl (-CF 3 ), and
R5 Wasserstoff, Halogen oder 1-4C-Alkyl bedeutet,  R5 denotes hydrogen, halogen or 1-4C-alkyl,
und die Salze dieser Verbindungen.  and the salts of these compounds.
7. Verbindungen der Formel I nach Anspruch 1, 7. Compounds of formula I according to claim 1,
worin  wherein
X 3-4C-Alkylen bedeutet,  X means 3-4C-alkylene,
E Carbonyloxy (-CO-O-) oder Oxycarbonyl (-O-CO-) bedeutet,  E denotes carbonyloxy (-CO-O-) or oxycarbonyl (-O-CO-),
n die Zahl 1 oder 2 bedeutet,  n represents the number 1 or 2,
Y einen Bindungsstrich bedeutet,  Y means a dash,
Ar1 Phenyl, 4-Amino-3-chlor-5-cyanphenyl, 4-Hydroxy-3-hydroxymethylphenyl oder 4-Amino-3,5-dichlorphenyl bedeutet, Ar 1 is phenyl, 4-amino-3-chloro-5-cyanphenyl, 4-hydroxy-3-hydroxymethylphenyl or 4-amino-3,5-dichlorophenyl,
und  and
Ar2 einen durch R4 und R5 substituierten Phenylrest oder einen 1-Naphthyl- rest bedeutet, wobei Ar 2 represents a phenyl radical substituted by R4 and R5 or a 1-naphthyl radical, where
R4 Wasserstoff, Chlor, Fluor, Hydroxy (-OH), 1-4C-Alkyl oder 1-4C- Alkoxy bedeutet und  R4 is hydrogen, chlorine, fluorine, hydroxy (-OH), 1-4C-alkyl or 1-4C-alkoxy and
R5 Wasserstoff bedeutet,  R5 means hydrogen
und die Salze dieser Verbindungen. and the salts of these compounds.
8. Verbindungen der Formel I nach Anspruch 1, 8. Compounds of formula I according to claim 1,
worin wherein
X 1-6C-Alkylen bedeutet,  X denotes 1-6C-alkylene,
E Carbonyloxy (-CO-O-) oder Oxycarbonyl (-O-CO-) bedeutet,  E denotes carbonyloxy (-CO-O-) or oxycarbonyl (-O-CO-),
n eine ganze Zahl von 1 bis 3 bedeutet, n is an integer from 1 to 3,
Y einen Bindungsstrich, Sauerstoff (0) oder die Gruppe -CHR- bedeutet, in der R die Bedeutung 1-4C-Alkyl hat,  Y denotes a bond line, oxygen (0) or the group -CHR-, in which R denotes 1-4C-alkyl,
Ar1 Phenyl oder 4-Amino-3,5-dich!orphenyl bedeutet, Ar 1 means phenyl or 4-amino-3,5-dich! Orphenyl,
und and
Ar2 einen durch R4 und R5 substituierten Phenylrest, einen 3-Thienylrest, einen 2-Pyridylrest oder einen 1-Naphthylrest bedeutet, wobei R4 Wasserstoff, Fluor, Hydroxy (-OH), 1-4C-Alky! oder 1-4C-Alkoxy bedeutet und Ar 2 represents a phenyl radical substituted by R4 and R5, a 3-thienyl radical, a 2-pyridyl radical or a 1-naphthyl radical, where R4 hydrogen, fluorine, hydroxy (-OH), 1-4C-alky! or 1-4C-alkoxy means and
R5 Wasserstoff oder 1-4C-Alkyl bedeutet,  R5 denotes hydrogen or 1-4C-alkyl,
und die Salze dieser Verbindungen. and the salts of these compounds.
9. Verbindung nach Anspruch 1, ausgewählt aus der Gruppe bestehend aus 2-(1-Naphthyl)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-hexanoat, 9. A compound according to claim 1 selected from the group consisting of 2- (1-naphthyl) ethyl 6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate,
{6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-1-naphthylacetat,  {6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -1-naphthylacetate,
2-(4-Hydroxyphenyl)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat,  2- (4-hydroxyphenyl) ethyl 6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate,
(5-[2-(4-Amino-2,3-dichlorphenyl)-2-hydroxyethylamino]-1-pentyl}phenylacetat,  (5- [2- (4-amino-2,3-dichlorophenyl) -2-hydroxyethylamino] -1-pentyl} phenylacetate,
2-(3-Hydroxyρhenyl)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat,  2- (3-hydroxyphenyl) ethyl 6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate,
2-(2-Hydroxyphenyl)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylamino]hexanoat,  2- (2-hydroxyphenyl) ethyl 6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] hexanoate,
2-Phenylethyl-6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylaminolhexanoat,  2-phenylethyl-6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylaminolhexanoate,
{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-1-hexyl}-1-naphthylacetat,  {6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -1-hexyl} -1-naphthylacetate,
2-(3-Hydroxyphenyl)ethyl-6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]hexanoat,  2- (3-hydroxyphenyl) ethyl 6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] hexanoate,
4-Phenylbutyl-6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylaminojhexanoat,  4-phenylbutyl-6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylaminojhexanoate,
{6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-3-methoxyphenyl acetat,  {6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -3-methoxyphenyl acetate,
2-(1-Naphthyl)ethyl-6-[2-(4-hydroxy-3-hydroxymethylphenyl)-2-hydroxyethylaminolhexanoat,  2- (1-naphthyl) ethyl-6- [2- (4-hydroxy-3-hydroxymethylphenyl) -2-hydroxyethylaminolhexanoate,
2-Phenylethyl-6-[2-(4-amino-5-chlor-3-cyanphenyl)-2-hydroxyethylamino]-hexanoat,  2-phenylethyl-6- [2- (4-amino-5-chloro-3-cyanophenyl) -2-hydroxyethylamino] hexanoate,
(6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-1-hexyl}phenylacetat,  (6- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -1-hexyl} phenylacetate,
{5-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethy!amino]-1-pentyl}-(3-hydroxyphenyl)acetat, (6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-2-methoxyphenylacetat, {5- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethy! Amino] -1-pentyl} - (3-hydroxyphenyl) acetate, (6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -2-methoxyphenylacetate,
(6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-3-methylphenylacetat,  (6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -3-methylphenylacetate,
(6-[2-(4-Amino-2,3-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl}-2-chlorphenylacetat,  (6- [2- (4-amino-2,3-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl} -2-chlorophenylacetate,
{5-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-pentyl}-3-(1-naphthyl)propionat,  {5- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-pentyl} -3- (1-naphthyl) propionate,
{5-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]-1-pentyl}-3-(1-naphthyl)propionat,  {5- [2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -1-pentyl} -3- (1-naphthyl) propionate,
{6-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]-1-hexyl>-2-fluorphenylacetat,  {6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylamino] -1-hexyl> -2-fluorophenylacetate,
2-(3-Indolyl)ethyl-6-[2-(4-amino-3,5-dichlorphenyl)-2-hydroxyethylaminolhexanoat und  2- (3-indolyl) ethyl 6- [2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethylaminolhexanoate and
(2-[2-[2-(4-Amino-3,5-dichlorphenyl)-2-hydroxyethylamino]ethoxy]ethyl}-phenylacetat  (2- [2- [2- (4-Amino-3,5-dichlorophenyl) -2-hydroxyethylamino] ethoxy] ethyl} phenyl acetate
und ihre Salze. and their salts.
10. Verfahren zur Herstellung der Verbindungen der Formel I nach Anspruch 1, und ihrer Salze, dadurch gekennzeichnet, daß man a) zur Herstellung der Verbindungen I, in denen E die Bedeutung Oxycarbonyl hat, Verbindungen der Formel II, Ar1-CH(OH)-CH2-NH2 (II) worin Ar1 die in Anspruch 1 angegebene Bedeutung hat, mit Verbindungen der Formel III, 10. A process for the preparation of the compounds of the formula I according to claim 1, and their salts, characterized in that a) for the preparation of the compounds I in which E is oxycarbonyl, compounds of the formula II, Ar 1 -CH (OH ) -CH 2 -NH 2 (II) in which Ar 1 has the meaning given in claim 1, with compounds of the formula III,
L-CH2-X-CH2-O-CO-(CH2)n-Y-Ar2 (III) worin X, n, Y und Ar2 die in Anspruch 1 angegebenen Bedeutungen haben und L eine geeignete Abgangsgruppe darstellt, umsetzt, oder daß man b) zur Herstellung der Verbindungen I, in denen E die Bedeutung Carbonyloxy hat, Verbindungen der Formel II, Ar1 - CH(OH) - CH2- NH2 (II) worin Ar, die in Anspruch 1 angegebene Bedeutung hat, mit Verbindungen der Formel IV, L-CH 2 -X-CH 2 -O-CO- (CH 2 ) n -Y-Ar 2 (III) in which X, n, Y and Ar 2 have the meanings given in Claim 1 and L represents a suitable leaving group, implements, or that one b) for the preparation of the compounds I in which E has the meaning carbonyloxy, compounds of the formula II, Ar 1 - CH (OH) - CH 2 - NH 2 (II) in which Ar, which has the meaning given in claim 1, with compounds Formula IV,
L-CH2-X-CH2-CO-O-(CH2)n-Y-Ar2 (IV) worin X, n, Y und Ar2 die in Anspruch 1 angegebenen Bedeutungen haben und L eine geeignete Abgangsgruppe darstellt, umsetzt, oder daß man c) zur Herstellung der Verbindungen I, in denen E die Bedeutung Oxycarbonyl hat, Verbindungen der Formel V, L-CH 2 -X-CH 2 -CO-O- (CH 2 ) n -Y-Ar 2 (IV) in which X, n, Y and Ar 2 have the meanings given in Claim 1 and L represents a suitable leaving group, implemented, or that c) for the preparation of the compounds I in which E is oxycarbonyl, compounds of the formula V,
Ar1-CH(OH)-CH2-NH-CH2-X-CH2-OH (V) worin Ar, und X die in Anspruch 1 angegebenen Bedeutungen haben, mit Verbindungen der Formel VI, Ar 1 -CH (OH) -CH 2 -NH-CH 2 -X-CH 2 -OH (V) in which Ar and X have the meanings given in claim 1, with compounds of the formula VI,
Z-CO-(CH2)n-Y-Ar2 (VI) worin n, Y und Ar2 die in Anspruch 1 angegebenen Bedeutungen haben und Z OH (Hydroxy) oder eine geeignete Abgangsgruppe darstellt, umsetzt, und daß man gewünschtenfalls anschließend die nach a), b) oder c) erhaltenen Verbindungen I in ihre Salze überführt, oder daß man gewünschtenfalls anschließend aus erhaltenen Salzen der Verbindungen I die Verbindungen I freisetzt. Z-CO- (CH 2 ) n -Y-Ar 2 (VI) in which n, Y and Ar 2 have the meanings given in Claim 1 and Z represents OH (hydroxy) or a suitable leaving group, and that if desired, subsequently converting the compounds I obtained according to a), b) or c) into their salts, or if desired subsequently releasing the compounds I from the salts of the compounds I obtained.
11. Arzneimittel enthaltend eine oder mehrere Verbindungen der Formel I nach Anspruch 1 und/oder ihre pharmakologisch verträglichen Salze. 11. Medicament containing one or more compounds of the formula I according to claim 1 and / or their pharmacologically acceptable salts.
12. Verbindungen der Formel I nach Anspruch 1 und/oder ihre pharmakologisch verträglichen Salze zur Anwendung bei der Behandlung von Erkrankungen der Bronchien. 12. Compounds of formula I according to claim 1 and / or their pharmacologically acceptable salts for use in the treatment of diseases of the bronchi.
13. Verwendung von Verbindungen der Formel I nach Anspruch 1 und/oder ihren pharmakologisch verträglichen Salzen zur Herstellung von Arzneimitteln für die Behandlung von Erkrankungen der Bronchien. 13. Use of compounds of formula I according to claim 1 and / or their pharmacologically acceptable salts for the manufacture of medicaments for the treatment of diseases of the bronchi.
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