WO1995019336A1 - PHENYL ETHANOL AMINE ETHERS AND USES THEREOF AS β-ADRENO-RECEPTOR AGONISTS - Google Patents

PHENYL ETHANOL AMINE ETHERS AND USES THEREOF AS β-ADRENO-RECEPTOR AGONISTS Download PDF

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Publication number
WO1995019336A1
WO1995019336A1 PCT/EP1995/000082 EP9500082W WO9519336A1 WO 1995019336 A1 WO1995019336 A1 WO 1995019336A1 EP 9500082 W EP9500082 W EP 9500082W WO 9519336 A1 WO9519336 A1 WO 9519336A1
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WIPO (PCT)
Prior art keywords
phenyl
compounds
ethanol
alkyl
hexylamino
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PCT/EP1995/000082
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German (de)
French (fr)
Inventor
Jan Bron
Geert Jan Sterk
Hendrik Timmerman
Meta E. J. Veerman
Jan Fetze Van Der Werf
Albert D. Windhorst
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Iovis Biomedical And Pharmaceutical Consultants
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Priority to AU15334/95A priority Critical patent/AU1533495A/en
Publication of WO1995019336A1 publication Critical patent/WO1995019336A1/en

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    • 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
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
    • C07C217/10—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/16—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring not being further substituted

Definitions

  • the invention relates to new compounds, processes for their preparation and their use as active ingredients in pharmaceuticals.
  • Rl is hydrogen or 1-4C-alkyl
  • R2 is a phenyl radical substituted by R3 and R4, a pyridyl radical, a phenoxy radical, a naphthyl radical, a thienyl radical or one
  • R3 is hydrogen, halogen, hydroxy (-0H), 1-4C-alkyl, 1-4C-alkoxy,
  • R3 and R4 together form a methylenedioxy (-0-CH - 0-) or ethylenedioxy radical (-0-CH - CH - 0-), is an integer from 4 to 10 and n is an integer from 0 to 7, and the salts of these compounds, where m is not the number 4 or 5 when n is the number 0.
  • 1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially the methyl radical.
  • Halogen in the sense of the present invention is bromine, chlorine and fluorine.
  • 1-4C-alkoxy radicals contain one of the 1-4C-alkyl radicals mentioned above.
  • the methoxy radical is preferred.
  • 1-4C-alkoxycarbonyl radicals contain one of the 1-4C-alkoxy radicals mentioned above.
  • the methoxycarbonyl and ethoxycarbonyl radicals may be mentioned as the 1-4C-alkoxycarbonyl ester R3.
  • Di-1-4C-alkylcarbamoyl radicals are substituted on the nitrogen atom by two identical or different of the above-mentioned 1-4C-alkyl radicals.
  • the diethylcarbamoyl radical may be mentioned as dial-4C-alkylcarbamoyl radical R3.
  • Examples of mono- or di-1-4C-alkylamino residues are methylamino, dimethylamino and diethyla inorest.
  • Suitable salts for compounds of the formula I are preferably all acid addition salts.
  • 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, maleic acid Lauric 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 in the salt production - depending on whether it is a mono- or respectful 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, ni
  • Rl is hydrogen or 1-4C-alkyl
  • R2 represents a phenyl radical substituted by R3 and R4 or a pyridyl radical, where
  • R3 is hydrogen, halogen, hydroxy (-0H), 1-4C-alkyl, 1-4C-alkoxy, benzyloxy, nitro (-NC) or trifluoromethyl (-CF 3 ) and
  • R4 is hydrogen, hydroxy (-0H), 1-4C-alkyl or 1-4C-alkoxy, or wherein
  • R3 and R4 together form a methylenedioxy (-0-CH - 0-) or ethylenedioxy radical (-0-CH - CH - 0-), m is an integer from 4 to 8 and n is an integer from 1 to 5, and the salts of these compounds.
  • Particularly noteworthy are compounds of the formula I in which
  • Rl is hydrogen
  • R2 represents a phenyl radical substituted by R3 and R4 or a pyridyl radical, where
  • R3 is hydrogen, halogen, hydroxy (-0H), 1-4C-alkyl or 1-4C-alkoxy and
  • R4 is hydrogen or 1-4C-alkyl, is an integer from 4 to 6 and n is an integer from 2 to 4, and the salts of these compounds.
  • the invention further relates to a process for the preparation of the compounds of the formula I and their salts.
  • the method is characterized in that a) compounds of the formula II,
  • Rl, R2, m and n have the meanings given above and Bz represents a benzyl group, reductively debenzylated, or that one
  • R2, m and n have the meanings given above and L represents a suitable leaving group, and that, if desired, the compounds I obtained according to a) or b) are subsequently converted into their salts, or if desired subsequently subsequently obtained salts of the compounds I releases the compounds I.
  • Debenzylation according to process variant a) is carried out in a manner familiar to the person skilled in the art, e.g. with hydrogen in the presence of palladium as a catalyst (in methanol or ethanol at room temperature) or with sodium in liquid ammonia (at -80'C).
  • the reaction of the compounds III with the compounds 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, dimethyl formate, 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.
  • the reaction is carried out in the presence of a base, for example 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 the mesylate group but especially halogen atoms, and especially chlorine or bromine, are suitable.
  • chlorine or bromine compounds 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 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 precisely calculated stoichiometric amount - is then added.
  • 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 precisely calculated stoichiometric amount - is then added.
  • the salts are obtained by filtration, rep
  • the starting compound II is obtained by reacting the benzylamines V,
  • the reaction of the benzylamines V with the epoxides VI is carried out in a manner known per se (for example analogously to RK Atkins, J. Frazier, LL Moore and LO Wiegel, Tetrahedron Lett. 1986, 27, 2451-2454), for example by several hours Heating under reflux in a suitable inert solvent, such as 2-propanol.
  • the benzylamines V are obtained by reacting the compounds IV with benzylamine in a manner known per se, for example by heating to 100 to 150 ° C. without a further solvent with the addition of a suitable auxiliary base, e.g. a tertiary amine, or using an excess of benzylamine.
  • a suitable auxiliary base e.g. a tertiary amine
  • the compounds of the formula IV are known or they can be prepared by methods known per se (for example analogously to A. McKillop, J.-C. Fiaud and RP Hug, Tetrahedron, 1974, 30, 1379-1382 or analogously to HH Freedman and RA Dubois , Tetrahedron Lett. 1975, 38, 3251-3254).
  • a solution of 7 mmol of the starting compound IV, 10 mmol of the compound III, 1.0 g of potassium iodide and 4 ml of diisopropylethylamine in 50 ml of diethyl amide is heated to 90 ° C. for 2 h with nitrogen gas. After concentration, the residue is taken up in a mixture of aqueous sodium carbonate solution and ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated, the residue is purified by chromatography and / or recrystallization.
  • the chromatography is carried out on silica gel using ethyl acetate / triethylamine (mixture P) or petroleum ether 60-80 / ethyl acetate / triethylamine (mixture Q).
  • 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 ß 2 -stimulating effect, whereby they are characterized by their good solubility.
  • 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 for treatment (peri- circulatory disorders are used, they lead to a relaxation of 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 to treat glaucoma, they influence the metabolism and are suitable, for example for the treatment of obesity, and because of their ß - sympathomimetic effect they are particularly suitable for the treatment of respiratory diseases of various origins.
  • bronchial diseases due to the broncholytic effectiveness of the compounds according to the invention can be treated.
  • the compounds according to the invention are distinguished by a low toxicity, a large therapeutic breadth, 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 them to be used in human and veterinary medicine, and they are used for the treatment and prophylaxis of diseases which are based on diseases of the bronchi.
  • diseases which are based on diseases of the bronchi.
  • acute and chronically obstructive respiratory diseases of various origins bronchitis, allergic see bronchitis, bronchial asthma
  • bronchitis acute and chronically obstructive respiratory diseases of various origins
  • bronchitis allergic see bronchitis, bronchial asthma
  • the properties of the compounds according to the invention also enable their use in the topical treatment of dermatoses, for example in the case of 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.
  • dermatoses for example in the case of 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.
  • metabolic 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
  • Another object of the invention is therefore 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 furthermore 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 on account of their activity 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.
  • doses from 0.5 to 50 mg per day, if appropriate in the form of several individual doses, are to be administered.
  • the excellent bronchospasmolytic effect 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 120 mM NaCl, 6 M KCl, 1 mM MgSO 4 , 2.5 mM CaCl 1 M NaH -P0 4 , 2.5 M NaHC0 3 and 6 mM glucose at 35 ⁇ C suspended.
  • Oxygen mixed with 5% CO 2 , is continuously passed through the solution. After stabilization, the trachea is contracted with a suitable dose of methacholine. A dose-response curve is then recorded in a cumulative manner with the test substances. The concentration ( ⁇ mol / 1) is then determined from this curve, which corresponds to 50% of the maximum effect (EC 5Q ). This EC. Q is thus a measure of the activity of the compounds according to the invention.

Abstract

The disclosure is of compounds of the formula (I): C6-H5-CH(OH)-CH(R1)-NH-(CH2)m-O-(CH2)n-R2, wherein R1 represents hydrogen or 1-4C-alkyl; R2 represents a phenyl group substituted by R3 and R4, a pyridyl group, phenoxy group, naphthyl group, thienyl group or benzhydryl group, R3 and R4 representing respectively hydrogen, a halogen, hydroxyl (-OH), 1-4C-alkyl, 1-4C-alkoxy, benzyloxy, nitro (-NO2), trifluoromethyl (-CF3), 1-4C-alkoxycarbonyl (-CO-O-1-4C-alkyl), carbamoyl (-CO-NH2), di-1-4C-alkyl carbamoyl [-CO-N(1-4C-alkyl)2], amino (-NH2) or mono- or di-(1-4C-alkyl) amino R4, and hydrogen, a halogen, hydroxyl (-OH), 1-4C-alkyl or 1-4C-alkoxyl, or alternatively, R3 and R4 can together form a methylene dioxy (-O-CH2-O-) or ethylene dioxy (-O-OCH2-CH2-O-) group; m is an integer between 4 and 10, n is an integer between 0 and 7, m being not equal to 4 or 5 if n is 0. The compounds according to the invention possess useful pharmacological properties. They are above all effective β-adreno-receptor agonists (β-sympathomimetics) with predominantly β2-stimulating properties and characterised by good solubility.

Description

PHENYLETHANOLA INETHER UND IHRE VERWENDUNG ALS BETA-ADRENOREZEPTOR-AGONISTENPHENYLETHANOLA INETHER AND THEIR USE AS A BETA ADRENORE RECEPTOR AGONIST
Anwendungsgebiet der ErfindungField 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 HintergrundKnown technical background
Aus dem Stand der Technik sind eine Vielzahl von substituierten Phenyletha- nola inverbindungen bekannt, die sich aufgrund ihrer ß--adrenozeptor-ago- nistischen Eigenschaften insbesondere zur Behandlung von Atemwegserkrankun¬ gen eignen sollen. Charakteristisches Merkmal all dieser Verbindungen ist, daß sie einen Phenylrest aufweisen, der durch mindestens einen Substituen- ten substituiert sein muß.From the prior art, a variety of substituted phenylethanol Nola inverbindungen are known, which due to their ß - to be suitable gene adrenoceptor AGO nist properties, in particular for the treatment of Atemwegserkrankun ¬. A characteristic feature of all these compounds is that they have a phenyl radical which must be substituted by at least one substituent.
Beschreibung der ErfindungDescription of the invention
Überraschenderweise wurde nun gefunden, daß - im Gegensatz zu dem, was auf¬ grund des Standes der Technik zu erwarten war - auch solche Phenylethanol- aminoverbindungen ausgeprägte ß»-adrenozeptor-agonistische Eigenschaften aufweisen, die am Phenylring unsubstituiert sind. Gegenstand der Erfindung sind somit in einem ersten Aspekt Verbindungen der Formel I,Surprisingly, it has now been found that - in contrast to what was to be expected on the basis of the prior art - those phenylethanol amino compounds also have pronounced β-adrenoceptor agonistic properties which are unsubstituted on the phenyl ring. The invention thus relates in a first aspect to compounds of the formula I
C 6H5-CH(OH)-CH(R1)-NH-(CH2)m111-0-(CH2n11-R2 (I)C 6H5-CH (OH) -CH (R1) -NH- (CH2) m 111-0- (CH2 n 11-R2 (I)
worinwherein
Rl Wasserstoff oder 1-4C-Alkyl bedeutet,Rl is hydrogen or 1-4C-alkyl,
R2 einen durch R3 und R4 substituierten Phenylrest, einen Pyridylrest, einen Phenoxyrest, einen Naphthylrest, einen Thienylrest oder einenR2 is a phenyl radical substituted by R3 and R4, a pyridyl radical, a phenoxy radical, a naphthyl radical, a thienyl radical or one
Benzhydrylrest bedeutet, wobeiBenzhydrylrest means, wherein
R3 Wasserstoff, Halogen, Hydroxy (-0H), 1-4C-Alkyl, l-4C-Alkoxy,R3 is hydrogen, halogen, hydroxy (-0H), 1-4C-alkyl, 1-4C-alkoxy,
Benzyloxy, Nitro (-N0-), Trifluor ethyl (-CF..), l-4C-Alkoxycarbonyl (-C0-0-l-4C-Alkyl), Carbamoyl (-C0-NH-), Di-l-4C-alkylcarbamoyl [-C0-N(l-4C-Alkyl)2], Amino (-NH-) oder Mono- oder Di-(l-4C-al- kyl)amino bedeutet und R4 Wasserstoff, Halogen, Hydroxy (-0H), 1-4C-Alkyl oder l-4C-Alkoxy bedeutet, oder wobeiBenzyloxy, nitro (-N0-), trifluoroethyl (-CF ..), 1-4C-alkoxycarbonyl (-C0-0-1-4C-alkyl), carbamoyl (-C0-NH-), di-1-4C-alkylcarbamoyl [-C0-N (1-4C-alkyl) 2 ], amino (-NH-) or mono- or di- (1-4C-alkyl) amino and R4 is hydrogen, halogen, hydroxy (-0H), 1-4C-alkyl or 1-4C-alkoxy, or wherein
R3 und R4 gemeinsam einen Methylendioxy- (-0-CH--0-) oder Ethylendioxy- rest (-0-CH--CH--0-) bilden, eine ganze Zahl von 4 bis 10 bedeutet und n eine ganze Zahl von 0 bis 7 bedeutet, und die Salze dieser Verbindungen, wobei m nicht die Zahl 4 oder 5 bedeutet wenn n die Zahl 0 bedeutet.R3 and R4 together form a methylenedioxy (-0-CH - 0-) or ethylenedioxy radical (-0-CH - CH - 0-), is an integer from 4 to 10 and n is an integer from 0 to 7, and the salts of these compounds, where m is not the number 4 or 5 when n is the number 0.
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 Methylrest.1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially the methyl radical.
Halogen im Sinne der vorliegenden Erfindung ist Brom, Chlor und Fluor.Halogen in the sense of the present invention is bromine, chlorine and fluorine.
l-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.
l-4C-Alkoxycarbonylreste enthalten neben der Carbonylgruppe einen der vor¬ stehend genannten l-4C-Alkoxyreste. Als l-4C-Alkoxycarbonyl este R3 seien der Methoxycarbonyl - und der Ethoxycarbonylrest erwähnt.In addition to the carbonyl group, 1-4C-alkoxycarbonyl radicals contain one of the 1-4C-alkoxy radicals mentioned above. The methoxycarbonyl and ethoxycarbonyl radicals may be mentioned as the 1-4C-alkoxycarbonyl ester R3.
Di-l-4C-alkylcarbamoylreste sind am Stickstoffatom durch zwei gleiche oder verschiedene der vorstehend genannten 1-4C-Alkylreste substituiert. Als Di- l-4C-alkylcarbamoylrest R3 sei der Diethylcarbamoylrest erwähnt.Di-1-4C-alkylcarbamoyl radicals are substituted on the nitrogen atom by two identical or different of the above-mentioned 1-4C-alkyl radicals. The diethylcarbamoyl radical may be mentioned as dial-4C-alkylcarbamoyl radical R3.
Als Mono- oder Di-l-4C-alkylaminoreste seien beispielsweise der Methylami- no, der Dimethylamino- und der Diethyla inorest genannt.Examples of mono- or di-1-4C-alkylamino residues are methylamino, dimethylamino and diethyla inorest.
Als Salze kommen für Verbindungen der Formel I bevorzugt alle Säureadditi¬ onssalze in Betracht. Besonders erwähnt seien die pharmakologisch verträg¬ lichen Salze der in der Galenik üblicherweise verwendeten anorganischen und organischen Säuren. Pharmakologisch unverträgliche Salze, die beispielswei¬ se bei der Herstellung der erfindungsgemäßen Verbindungen im industriellen Maßstab als Verfahrensprodukte zunächst anfallen können, werden durch dem Fachmann bekannte Verfahren in pharmakologisch verträgliche Salze überge¬ führt. Als solche eignen sich wasserlösliche und wasserunlösliche Säuread¬ ditionssalze mit Säuren wie beispielsweise Salzsäure, Bromwasserstoffsäure, Phosphorsäure, Salpetersäure, Schwefelsäure, Essigsäure, Zitronensäure, D-Gluconsäure, Benzoesäure, 2-(4-Hydroxybenzoyl)-benzoesäure, Buttersäure, Sulfosalicylsäure, Maleinsäure, Laurinsäure, Äpfelsäure, Fumarsäure, Bern¬ steinsäure, 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 ehrba- sige Säure handelt und je nachdem, welches Salz gewünscht wird - im äquimo- laren oder einem davon abweichenden Mengenverhältnis eingesetzt werden.Suitable salts for compounds of the formula I are preferably all acid addition salts. The pharmacologically tolerable salts of the inorganic and .alpha organic acids. 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, maleic acid Lauric 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 in the salt production - depending on whether it is a mono- or respectful acid and, depending on which salt is desired, be used in an equimolar or a different ratio.
In den Verbindungen der Formel I liegt mindestens ein Chiralitätszentrum [am Kohlenstoffatom -CH(OH)-] vor, durch entsprechende Substitution am Nachbaratom (Rl = 1-4C-Alkyl) kann noch ein weiteres Chiral itätszentrum hinzukommen. Die Erfindung umfaßt alle Enantiomeren und Diastereomeren so¬ wie 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.There is at least one chiral center [at the carbon atom -CH (OH) -] in the compounds of the formula I, and a corresponding chiral center can be added by appropriate substitution at the neighboring atom (Rl = 1-4C-alkyl). 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, worinTo be emphasized are those compounds of the formula I in which
Rl Wasserstoff oder 1-4C-Alkyl bedeutet,Rl is hydrogen or 1-4C-alkyl,
R2 einen durch R3 und R4 substituierten Phenylrest oder einen Pyridylrest bedeutet, wobeiR2 represents a phenyl radical substituted by R3 and R4 or a pyridyl radical, where
R3 Wasserstoff, Halogen, Hydroxy (-0H), 1-4C-Alkyl, l-4C-Alkoxy, Benzyloxy, Nitro (-NC ) oder Trifluormethyl (-CF3) bedeutet undR3 is hydrogen, halogen, hydroxy (-0H), 1-4C-alkyl, 1-4C-alkoxy, benzyloxy, nitro (-NC) or trifluoromethyl (-CF 3 ) and
R4 Wasserstoff, Hydroxy (-0H), 1-4C-Alkyl oder l-4C-Alkoxy bedeutet, oder wobeiR4 is hydrogen, hydroxy (-0H), 1-4C-alkyl or 1-4C-alkoxy, or wherein
R3 und R4 gemeinsam einen Methylendioxy- (-0-CH--0-) oder Ethylendioxy- rest (-0-CH--CH--0-) bilden, m eine ganze Zahl von 4 bis 8 bedeutet und n eine ganze Zahl von 1 bis 5 bedeutet, und die Salze dieser Verbindungen. Besonders hervorzuheben si nd sol che Verbi ndungen der Formel I , worinR3 and R4 together form a methylenedioxy (-0-CH - 0-) or ethylenedioxy radical (-0-CH - CH - 0-), m is an integer from 4 to 8 and n is an integer from 1 to 5, and the salts of these compounds. Particularly noteworthy are compounds of the formula I in which
Rl Wasserstoff bedeutet,Rl is hydrogen,
R2 einen durch R3 und R4 substituierten Phenylrest oder einen Pyridylrest bedeutet, wobeiR2 represents a phenyl radical substituted by R3 and R4 or a pyridyl radical, where
R3 Wasserstoff, Halogen, Hydroxy (-0H), 1-4C-Alkyl oder l-4C-Alkoxy bedeutet undR3 is hydrogen, halogen, hydroxy (-0H), 1-4C-alkyl or 1-4C-alkoxy and
R4 Wasserstoff oder 1-4C-Alkyl bedeutet, eine ganze Zahl von 4 bis 6 bedeutet und n eine ganze Zahl von 2 bis 4 bedeutet, und die Salze dieser Verbindungen.R4 is hydrogen or 1-4C-alkyl, is an integer from 4 to 6 and n is an integer from 2 to 4, and the salts of these compounds.
Als beispielhafte erfindungsgemäße Verbindungen seien die folgenden Verbin¬ dungen der Formel I anhand ihrer Substituentenbedeutungen genannt:The following compounds of the formula I may be mentioned as exemplary compounds according to the invention on the basis of their substituent meanings:
Rl R2 R3 R4 m nRl R2 R3 R4 m n
H Ph 2-NO- H 6 2H Ph 2 -NO-H 6 2
H Ph 4-OCH3 H 6 2H Ph 4-OCH 3 H 6 2
H Ph 3-CF3 H 6 2H Ph 3-CF 3 H 6 2
H Ph 4-CH3 H 6 2H Ph 4-CH 3 H 6 2
H Ph 4-C-H5 H 6 2H Ph 4-CH 5 H 6 2
H Ph 3-C1 H 6 2H Ph 3-C1 H 6 2
H Ph 4-C1 H 6 2H Ph 4-C1 H 6 2
H Ph 4-F H 6 2H Ph 4-F H 6 2
H Ph 3-F H 6 2H Ph 3-F H 6 2
H Ph 3-OCH3 4-OCH3 6 2H Ph 3-OCH 3 4-OCH 3 6 2
H Ph -0-CH- -0- 6 2H Ph -0-CH- -0- 6 2
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 ge¬ kennzeichnet, daß man a) Verbi ndungen der Formel I I ,The invention further relates to a process for the preparation of the compounds of the formula I and their salts. The method is characterized in that a) compounds of the formula II,
C 6 H5 - CH(OH) - CH(R1 ) - NBz - (CH 2 )m 111 - 0 - (CH 2„)nι l - R2 (II)C 6 H5 - CH (OH) - CH (R1) - NBz - (CH 2) m 111 - 0 - (CH 2 „) n ι l - R2 (II)
worin Rl, R2, m und n die oben angegebenen Bedeutungen haben und Bz eine Benzylgruppe darstellt, reduktiv debenzyliert, oder daß manwherein Rl, R2, m and n have the meanings given above and Bz represents a benzyl group, reductively debenzylated, or that one
b) Verbindungen der Formel III,b) compounds of the formula III,
C 6H5-CH(OH)-CH(R1)-NH2 (III)C 6H5-CH (OH) -CH (R1) -NH2 (III)
worin Rl die oben angegebene Bedeutung hat, mit Verbindungen der Formel IV,wherein Rl has the meaning given above, with compounds of the formula IV,
L-(CH2)m-0-(CH2)n-R2 (IV)L- (CH 2 ) m -0- (CH 2 ) n -R2 (IV)
worin R2, m und n die oben angegebenen Bedeutungen haben und L eine geeig¬ nete Abgangsgruppe darstellt, umsetzt, und daß man gewünschtenfalls an¬ schließend die nach a) oder b) erhaltenen Verbindungen I in ihre Salze überführt, oder daß man gewünschtenfalls anschließend aus erhaltenen Salzen der Verbindungen I die Verbindungen I freisetzt.in which R2, m and n have the meanings given above and L represents a suitable leaving group, and that, if desired, the compounds I obtained according to a) or b) are subsequently converted into their salts, or if desired subsequently subsequently obtained salts of the compounds I releases the compounds I.
Die Debenzylierung gemäß Verfahrensvariante a) erfolgt in einer für den Fachmann geläufigen Weise, z.B. mit Wasserstoff in Gegenwart von Palladium als Katalysator (in Methanol oder Ethanol bei Raumtemperatur) oder mit Na¬ trium in flüssigem Ammoniak (bei -80'C).Debenzylation according to process variant a) is carried out in a manner familiar to the person skilled in the art, e.g. with hydrogen in the presence of palladium as a catalyst (in methanol or ethanol at room temperature) or with sodium in liquid ammonia (at -80'C).
Die Umsetzung der Verbindungen III mit den Verbindungen IV erfolgt auf eine dem Fachmann an sich vertraute Weise in inerten, vorzugsweise polaren Lö¬ sungsmitteln, beispielsweise in Methanol, Ethanol, 1- oder 2-Propanol, Di- methylforma id, Tetrahydrofuran, Aceton, Methylethylketon, Methylisobutyl- keton oder Dioxan, bei Temperaturen zwischen 10 und 120βC, vorzugsweise zwischen 50 und 100βC, gegebenenfalls bei der Siedetemperatur des verwende¬ ten Lösungsmittels. Die Umsetzung wird in Gegenwart einer Base, z.B. eines tertiären organi¬ schen Amins, wie Diisopropylethylamin, oder eines anorganischen Carbonates, wie Kaliu carbonat, durchgeführt.The reaction of the compounds III with the compounds 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, dimethyl formate, tetrahydrofuran, acetone, methyl ethyl ketone , Methyl isobutyl ketone or dioxane, at temperatures between 10 and 120 β C, preferably between 50 and 100 β C, optionally at the boiling point of the solvent used. The reaction is carried out in the presence of a base, for example 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 IV kann die Umsetzung vorteilhafterweise auch in Gegenwart katalytischer Mengen eines Iodids, wie beispielsweise Kaliu iodid 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 the mesylate group, but especially halogen atoms, and especially chlorine or bromine, are suitable. If chlorine or bromine compounds 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.
Je nach Art der Ausgangsverbindungen, die gegebenenfalls auch in Form ihrer Salze eingesetzt werden können, und in Abhängigkeit von den Reaktionsbedin¬ gungen werden die erfindungsgemäßen Verbindungen zunächst entweder als sol¬ che 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 Kohlenwasser¬ stoff, wie Methylenchlorid oder Chloroform, einem niedermolekularen ali- phatischen 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. Die Salze werden durch Fil¬ trieren, Umfallen, Ausfällen oder durch Verdampfen des Lösungsmittels ge¬ wonnen. Erhaltene Salze können durch Alkalisieren, z.B. mit wäßrigem Natri- u hydrogencarbonat, 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.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 precisely calculated stoichiometric amount - is then added. The salts are obtained by filtration, reprecipitation, precipitation or by evaporation of the solvent. Salts obtained can be obtained by alkalizing e.g. with aqueous sodium bicarbonate, are converted into the free compounds, 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 Ausgangsverbindung II erhält man durch Umsetzung der Benzylamine V,The starting compound II is obtained by reacting the benzylamines V,
BzNH-(CH2)m-O-(CH.)n-R2 (V)BzNH- (CH 2 ) m -O- (CH.) N -R2 (V)
worin R2, m und n die oben angegebenen Bedeutungen haben und Bz einen Ben- zylrest darstellt, mit den Epoxiden VI,
Figure imgf000009_0001
in which R2, m and n have the meanings given above and Bz represents a benzyl radical, with the epoxides VI,
Figure imgf000009_0001
worin Rl die oben angegebene Bedeutung hat.where Rl has the meaning given above.
Die Umsetzung der Benzylamine V mit den Epoxiden VI erfolgt in an sich be¬ kannter Weise (z.B. analog R.K. Atkins, J. Frazier, L.L. Moore und L.O. Wiegel, Tetrahedron Lett. 1986, 27, 2451-2454), beispielsweise durch mehr¬ stündiges Erwärmen unter Rückfluß in einem geeigneten inerten Lösungs¬ mittel, wie z.B. 2-Propanol.The reaction of the benzylamines V with the epoxides VI is carried out in a manner known per se (for example analogously to RK Atkins, J. Frazier, LL Moore and LO Wiegel, Tetrahedron Lett. 1986, 27, 2451-2454), for example by several hours Heating under reflux in a suitable inert solvent, such as 2-propanol.
Die Benzylamine V erhält man durch Umsetzung der Verbindungen IV mit Benz- ylamin in an sich bekannter Weise, beispielsweise durch Erhitzen ohne wei¬ teres Lösungsmittel auf 100 bis 150°C unter Zusatz einer geeigneten Hilfs¬ base, z.B. eines tertiären Amins, oder unter Verwendung eines Überschusses an Benzylamin.The benzylamines V are obtained by reacting the compounds IV with benzylamine in a manner known per se, for example by heating to 100 to 150 ° C. without a further solvent with the addition of a suitable auxiliary base, e.g. a tertiary amine, or using an excess of benzylamine.
Die Verbindungen der Formel IV sind bekannt oder sie können nach an sich bekannten Verfahren (z.B. analog A. McKillop, J.-C. Fiaud und R.P. Hug, Te¬ trahedron, 1974, 30, 1379-1382 oder analog H.H. Freedman und R.A. Dubois, Tetrahedron Lett. 1975, 38, 3251-3254) hergestellt werden.The compounds of the formula IV are known or they can be prepared by methods known per se (for example analogously to A. McKillop, J.-C. Fiaud and RP Hug, Tetrahedron, 1974, 30, 1379-1382 or analogously to HH Freedman and RA Dubois , Tetrahedron Lett. 1975, 38, 3251-3254).
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); Hochauflösungsmassenspektrometrie (Finnigan MT 90); Schmelzpunkt- (Mettler FP 5 mit Mikroskop) oder Siedepunktbestimmung; Dünnschichtchromatographie (DC; E. Merck No. 37333, Kieselgel 60 F-rH nuclear magnetic resonance spectrometry (NMR; Bruker AC 200); High resolution mass spectrometry (Finnigan MT 90); Melting point (Mettler FP 5 with microscope) or boiling point determination; Thin layer chromatography (TLC; E. Merck No. 37333, silica gel 60 F-r
Die in den Beispielen namentlich genannten Verbindungen der Formel I sowie die Salze dieser Verbindungen sind bevorzugter Gegenstand der Erfindung.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.
Die Abkürzung h steht für Stunde(n), RT für Raumtemperatur, Fp für Schmelz¬ punkt und Kp für Siedepunkt. Bei spi el eThe abbreviation h stands for hour (s), RT for room temperature, Fp for melting point and Kp for boiling point. At game e
AusgangsverbindungenOutput connections
Allgemeine Herstellungsvorschrift zur Herstellung der Verbindungen IV:General preparation instructions for the preparation of compounds IV:
0,017 mol des betreffenden Alkohols, 0,052 mol des ω-Dibromalkans, 0,0015 mol Tetrabutylamoniumhydrogensulfat und 8 g Natriumhydroxid werden in 16 ml Wasser gelöst und 26 h bei RT gerührt. Die Lösung wird mit 100 ml Wasser verdünnt und mit Diethylether extrahiert. Nach dem Trocknen der etherischen Phase über Magnesiumsulfat wird eingeengt und der Rückstand (sofern nichts anderes angegeben ist) durch Vakuumdestillation gereinigt.0.017 mol of the alcohol in question, 0.052 mol of the ω-dibromoalkane, 0.0015 mol of tetrabutylamonium hydrogen sulfate and 8 g of sodium hydroxide are dissolved in 16 ml of water and stirred at RT for 26 h. The solution is diluted with 100 ml of water and extracted with diethyl ether. After the ethereal phase has dried over magnesium sulfate, the mixture is concentrated and the residue (unless stated otherwise) is purified by vacuum distillation.
Die folgenden Ausgangsverbindungen wurden nach dieser Methode hergestellt:The following starting compounds were prepared using this method:
AI. 4-(6-Brom-l-hexyloxy)-l-butylbenzol (Kp: 160-163°C, 0,1 mbar) A2. 3-(6-Brom-l-hexyloxy)-l-phenyl-l-proρylbenzol (Kp: 190-195°C,AI. 4- (6-bromo-l-hexyloxy) -l-butylbenzene (bp: 160-163 ° C, 0.1 mbar) A2. 3- (6-bromo-l-hexyloxy) -l-phenyl-l-propylbenzene (bp: 190-195 ° C,
0,2 mbar) A3. 2-(6-Brom-l-hexyloxy)-l-ethylbenzol (Kp: 130-135°C, 0,2 mbar) A4. 3-(6-Brom-l-hexyloxy)-l-propylbenzol (Kp: 126-144°C, 0,2 mbar) A5. 4-(8-Brom-l-octyloxy)-l-butylbenzol (Kp: 147-156βC, 0,2 mbar) A6. 4-(4-Brom-l-butyloxy)-l-butylbenzol (Kp: 106-132βC, 0,2 mbar) A7. 2-[2-(6-Brom-l-hexyloxy)-l-ethyl]pyridin [gereinigt durch Chromatogra- fie (Petrolether 60-80/Ethylacetat 5:2)], 1H-NMR(CDC13) : 1,30-1,97 ppm, m, 9,0 H, (C-(CH2)4-C); 3,04 ppm, t, J=6,7 Hz, 1,9 H, (CH2-Pyridin); 3,32-3,51 ppm, m, 4,7 H, (CH--0, CH2-Br); 3,91 ppm, t, J=6,7 Hz, 1,8 H, (CH2-0); 7,08-7,70 ppm, m, 2,8 H, (arom. H); 8,49-8,61 ppm, m, 0,9 H, (arom H) A8. 5-(6-Brom-l-hexyloxy)-l-pentylbenzol (Kp: 128-145'C, 0,2 mbar) A9. 6-Brom-l-hexyloxymethylbenzol (Kp: 138-144βC, 0,2 mbar) A10. 6-Brom-l-hexyloxybenzol (Kp: 102βC, 0,2 mbar) All. 2-(5-Brom-l-pentyloxy)-l-ethylbenzol (Kp: lll-142βC, 0,2 mbar) A12. 2-(7-Brom-l-heptyloxy)-l-ethylbenzol (Kp: 135-155βC, 0,2 mbar) A13. 3-(5-Brom-l-pentyloxy)-l-propylbenzol (Kp: 135-152βC, 0,2 mbar) A14. 7-Brom-l-heptyloxymethylbenzol (Kp: 140-162°C, 0,2 mbar) A15. 2-(4-Brom-l-butyloxy)-l-ethylbenzol (Kp: 120-135βC, 0,2 mbar) A16. l-Benzyloxy-4-[2-(6-brom-l-hexyloxy)-l-ethyl jbenzol [gereinigt durch Chromatografie (Petrolether 60-80/Ethylacetat 9:1)], 1H-NMR(CDC13) : 1,22-1,91 ppm, m, 9,0 H (C-(CH2)4-C); 2,80 ppm, t, J=6,7 Hz, 2,0 H (P:°nyl-CH2); 3,31-3,45 ppm, m, 4,0 H (CH--0, Br-CH2); 3,58 ppm, t, J-. ,7 Hz, 2,0 H (0-CH2); 5,01 ppm, s, 2,0 H (Phenyl-CH2-0) ; 6,83-7,44 ppm, m, 9,1 H (arom. H)0.2 mbar) A3. 2- (6-bromo-l-hexyloxy) -l-ethylbenzene (bp: 130-135 ° C, 0.2 mbar) A4. 3- (6-bromo-l-hexyloxy) -l-propylbenzene (bp: 126-144 ° C, 0.2 mbar) A5. 4- (8-bromo-l-octyloxy) -l-butylbenzene (bp: 147-156 β C, 0.2 mbar) A6. 4- (4-bromo-l-butyloxy) -l-butylbenzene (bp: 106-132 β C, 0.2 mbar) A7. 2- [2- (6-bromo-l-hexyloxy) -l-ethyl] pyridine [purified by chromatography (petroleum ether 60-80 / ethyl acetate 5: 2)], 1H-NMR (CDC1 3 ): 1.30 -1.97 ppm, m, 9.0 H, (C- (CH 2 ) 4 -C); 3.04 ppm, t, J = 6.7 Hz, 1.9 H, (CH 2 pyridine); 3.32-3.51 ppm, m, 4.7 H, (CH - 0, CH 2 -Br); 3.91 ppm, t, J = 6.7 Hz, 1.8 H, (CH 2 -0); 7.08-7.70 ppm, m, 2.8 H, (aroma H); 8.49-8.61 ppm, m, 0.9 H, (aroma H) A8. 5- (6-bromo-l-hexyloxy) -l-pentylbenzene (bp: 128-145'C, 0.2 mbar) A9. 6-bromo-l-hexyloxymethylbenzene (bp: 138-144 β C, 0.2 mbar) A10. 6-bromo-l-hexyloxybenzene (bp: 102 β C, 0.2 mbar) All. 2- (5-Bromo-l-pentyloxy) -l-ethylbenzene (bp: III-142 β C, 0.2 mbar) A12. 2- (7-bromo-l-heptyloxy) -l-ethylbenzene (bp: 135-155 β C, 0.2 mbar) A13. 3- (5-Bromo-l-pentyloxy) -l-propylbenzene (bp: 135-152 β C, 0.2 mbar) A14. 7-bromo-l-heptyloxymethylbenzene (bp: 140-162 ° C, 0.2 mbar) A15. 2- (4-bromo-l-butyloxy) -l-ethylbenzene (bp: 120-135 β C, 0.2 mbar) A16. l-benzyloxy-4- [2- (6-bromo-l-hexyloxy) -l-ethyl jbenzene [purified by chromatography (petroleum ether 60-80 / ethyl acetate 9: 1)], 1H-NMR (CDC1 3 ): 1, 22-1.91 ppm, m, 9.0 H (C- (CH 2 ) 4 -C); 2.80 ppm, t, J = 6.7 Hz, 2.0 H (P: ° nyl-CH 2 ); 3.31-3.45 ppm, m, 4.0 H (CH - 0, Br-CH 2 ); 3.58 ppm, t, J-. , 7 Hz, 2.0 H (0-CH 2); 5.01 ppm, s, 2.0 H (phenyl-CH 2 -0); 6.83-7.44 ppm, m, 9.1 H (aroma H)
Allgemeine Herstellungsvorschrift zur Herstellung der Benzylamine V:General manufacturing instructions for the manufacture of Benzylamine V:
0,033 mol der Verbindung IV und 0,20 mol Benzyla in werden unter Rühren und Stickstoffbegasung für 2 h auf 130°C erhitzt. Nach dem Abkühlen auf RT werden 250 ml einer wäßrigen 2N Salzsäurelösung zugefügt, und das erhaltene Gemisch wird für 1 h gerührt. Der entstandene Niederschlag wird abfil¬ triert, nacheinander mit Wasser und dann mit Diethylether gewaschen und an¬ schließend getrocknet.0.033 mol of compound IV and 0.20 mol of benzyla in are heated to 130 ° C. for 2 h with stirring and nitrogen gas. After cooling to RT, 250 ml of an aqueous 2N hydrochloric acid solution are added, and the mixture obtained is stirred for 1 h. The resulting precipitate is filtered off, washed successively with water and then with diethyl ether and then dried.
Die fo c-nden Ausgangsverbindungen wurden nach dieser Methode hergestellt:The following starting compounds were prepared by this method:
Bl. N-[6-(4-Phenyl-l-butoxy)-l-hexyl]benzylamin-hydrochlorid (Fp: 90-102βC)Bl. N- [6- (4-phenyl-l-butoxy) -l-hexyl] benzylamine hydrochloride (mp: 90-102 β C)
B2. N-[6-(2-Phenylethoxy)-l-hexyl]benzylamin-hydrochlorid (Fp: 100-110βC)B2. N- [6- (2-phenylethoxy) -l-hexyl] benzylamine hydrochloride (mp: 100-110 β C)
B3. N-[6-(3-Phenyl-l-propoxy)-l-hexyl]benzylamin-hydrochlorid (Fp: 109,5-122,4βC)B3. N- [6- (3-phenyl-l-propoxy) -l-hexyl] benzylamine hydrochloride (mp: 109.5-122.4 β C)
B4. N-[8-(4-Phenyl-l-butyloxy)l-octyl]benzylamin-hydrochlorid (Fp: 113,3-122,4βC)B4. N- [8- (4-phenyl-1-butyloxy) 1-octyl] benzylamine hydrochloride (mp: 113.3-122.4 β C)
B5. N-[4-(4-Phenyl-l-butyloxy)-l-butyl]benzylamin-hydrochlorid (Fp: 105,4-117,4βC)B5. N- [4- (4-phenyl-l-butyloxy) -l-butyl] benzylamine hydrochloride (mp: 105.4-117.4 β C)
B6. N-{6-[2-(2-Pyridyl)ethoxy]-l-hexyl)benzylamin [gereinigt durch Chro¬ matografie (Petrolether 60-80/Ethylacetat/Triethylamin 2:1:1)], 1H-NMR(CDC13): 1,22-1,84 ppm, m, 9,8 H, (C-(CH-)4-C, NH); 2,59 ppm, t, J=6,7 Hz, 1,9 H, (CH2-N); 3,04 ppm, t, J=6,7 Hz, 1,9 H, (CH--Pyridin) ; 3,43 ppm, t, J=6,7 Hz, 2,0 H, (CH--0); 3,72-3,84 ppm, m, 3,8 H, (CH--0, CH2-Phenyl); 7,05-7,63 ppm, m, 7,7 H, (arom H; 8,48-8,56 ppm, , 0,9 H, (arom H)B6. N- {6- [2- (2-pyridyl) ethoxy] -l-hexyl) benzylamine [purified by chromatography (petroleum ether 60-80 / ethyl acetate / triethylamine 2: 1: 1)], 1H-NMR (CDC1 3 ): 1.22-1.84 ppm, m, 9.8 H, (C- (CH-) 4 -C, NH); 2.59 ppm, t, J = 6.7 Hz, 1.9 H, (CH 2 -N); 3.04 ppm, t, J = 6.7 Hz, 1.9 H, (CH-pyridine); 3.43 ppm, t, J = 6.7 Hz, 2.0 H, (CH - 0); 3.72-3.84 ppm, m, 3.8 H, (CH - 0, CH 2 -phenyl); 7.05-7.63 ppm, m, 7.7 H, (aroma H; 8.48-8.56 ppm,, 0.9 H, (aroma H)
B7. N-[6-(5-Phenyl-l-pentyloxy)-l-hexyl]benzylamin-hydrochlorid (Fp: 125,0-133,5βC) EndprodukteB7. N- [6- (5-phenyl-l-pentyloxy) -l-hexyl] benzylamine hydrochloride (mp: 125.0-133.5 β C) End products
Verfahrensvariante a (allgemeine Vorschrift):Process variant a (general regulation):
Eine Lösung von 7,1 mmol des Benzylamins V und 10 mol des Epoxids VI in 50 ml 2-Propanol wird 7 h unter Rückfluß zum Sieden erhitzt. Nach dem Ein¬ engen wird der Rückstand in Ethanol gelöst. Die Lösung wird in Gegenwart von 0,5 g 5 % Pd/C hydriert. Das Endprodukt wird durch Chromatografie und/oder Umkristallisation gereinigt, wobei die Chromatografie an Kieselgel unter Verwendung von Ethylacetat/Triethylamin (Gemisch P) oder Petrolether 60-80/Ethylacetat/Triethylamin (Gemisch Q) erfolgt.A solution of 7.1 mmol of benzylamine V and 10 mol of epoxide VI in 50 ml of 2-propanol is heated to boiling under reflux for 7 h. After concentration, the residue is dissolved in ethanol. The solution is hydrogenated in the presence of 0.5 g 5% Pd / C. The end product is purified by chromatography and / or recrystallization, the chromatography on silica gel using ethyl acetate / triethylamine (mixture P) or petroleum ether 60-80 / ethyl acetate / triethylamine (mixture Q).
Verfahrensvariante b (allgemeine Vorschrift):Process variant b (general regulation):
Eine Lösung von 7 mmol der Ausgangsverbindung IV, 10 mmol der Verbindung III, 1,0 g Kaliu iodid und 4 ml Diisopropylethylamin in 50 ml Di ethyl- for amid wird für 2 h unter Stickstoffbegasung auf 90°C erhitzt. Nach dem Einengen wird der Rückstand in einer Mischung aus wäßriger Natriumcarbonat- lösung und Ethylacetat aufgenommen. Die organische Phase wird über Magne¬ siumsulfat getrocknet und eingeengt, der Rückstand durch Chromatografie und/oder Umkristallisation gereinigt. Die Chromatografie erfolgt an Kiesel¬ gel unter Verwendung von Ethylacetat/Triethylamin (Gemisch P) oder Petrol¬ ether 60-80/Ethylacetat/Triethylamin (Gemisch Q).A solution of 7 mmol of the starting compound IV, 10 mmol of the compound III, 1.0 g of potassium iodide and 4 ml of diisopropylethylamine in 50 ml of diethyl amide is heated to 90 ° C. for 2 h with nitrogen gas. After concentration, the residue is taken up in a mixture of aqueous sodium carbonate solution and ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated, the residue is purified by chromatography and / or recrystallization. The chromatography is carried out on silica gel using ethyl acetate / triethylamine (mixture P) or petroleum ether 60-80 / ethyl acetate / triethylamine (mixture Q).
1 . l -Phenyl -2- r6- (4-phenv1 - l -butyl oxy) - l -hexyl ami nolethanol1 . l -phenyl -2- r6- (4-phenv1 - l -butyl oxy) - l -hexyl aminolethanol
Hergestellt aus Styroloxid und der Ausgangsverbindung Bl nach Verfahrens¬ variante a. Gereinigt durch Chromatografie (Gemisch P, 3:1), umkristalli¬ siert aus Methanol. Fp: 45,9-48,2βC.Manufactured from styrene oxide and the starting compound B1 according to process variant a. Purified by chromatography (mixture P, 3: 1), recrystallized from methanol. Mp: 45.9-48.2 β C.
2. (R)-1-Phenyl -2-T6-(4-phenyl-l-butyloxy)-l-heχy1amino!ethanol -oxalat2. (R) -1-phenyl -2-T6- (4-phenyl-l-butyloxy) -l-heχy1amino! Ethanol oxalate
Hergestellt aus R-(-)-Styroloxid und der Ausgangsverbindung Bl nach Verfah¬ rensvariante a. Gereinigt durch Chromatografie (Gemisch P, 3:1), umkristal¬ lisiert aus Aceton. Fp: 117-119°C. 3. (S)-l-Phenyl -2-T6-f4-phenyl -l-butyloxy)-l-hexylaminolethanol-oxalatMade from R - (-) - styrene oxide and the starting compound B1 according to process variant a. Purified by chromatography (mixture P, 3: 1), recrystallized from acetone. Mp: 117-119 ° C. 3. (S) -l-phenyl -2-T6-f4-phenyl -l-butyloxy) -l-hexylaminolethanol oxalate
Hergestellt aus S-(+)-Styroloxid und der Ausgangsverbindung Bl nach Verfah¬ rensvariante a. Gereinigt durch Chromatografie (Gemisch P, 3:1), umkristal¬ lisiert aus Aceton. Fp: 117-119βC.Made from S - (+) - styrene oxide and the starting compound B1 according to process variant a. Purified by chromatography (mixture P, 3: 1), recrystallized from acetone. Mp: 117-119 β C.
4. l-Phenyl-2-r6-(2-phenylethoχy)-l-heχylaminolethanol4. l-phenyl-2-r6- (2-phenylethoχy) -l-heχylaminolethanol
Hergestellt aus Styroloxid und der Ausgangsverbindung B2 nach Verfahrens¬ variante a., umkristallisiert aus Methanol. Fp: 79-81βC.Prepared from styrene oxide and the starting compound B2 according to process variant a., Recrystallized from methanol. Mp: 79-81 β C.
5. 1-Phenyl-2-r6-(3-phenyl-l-propoχy)-l-hexylaminolethanol5. 1-phenyl-2-r6- (3-phenyl-l-propoχy) -l-hexylaminolethanol
Hergestellt aus Styroloxid und der Ausgangsverbindung B3 nach Verfahrens¬ variante a. Gereinigt durch Chromatocrafie (Gemisch P, 4:1), umkristalli¬ siert aus Methanol. Fp: 44,8-46,7°C.Manufactured from styrene oxide and the starting compound B3 according to process variant a. Purified by chromatography (mixture P, 4: 1), recrystallized from methanol. Mp: 44.8-46.7 ° C.
6. l-Phenyl-2-r8-(4-phenyl-l-butyloχy)-l-octylaminolethanol6. l-phenyl-2-r8- (4-phenyl-l-butyloχy) -l-octylaminolethanol
Hergestellt aus Styroloxid und der Ausgangsverbindung B4 nach Verfahrens¬ variante a. Gereinigt durch Chromatografie (Gemisch Q, 3:3:1), umkristalli¬ siert aus Methanol. Fp: 66,4-67,2βC.Manufactured from styrene oxide and the starting compound B4 according to process variant a. Purified by chromatography (mixture Q, 3: 3: 1), recrystallized from methanol. Mp: 66.4-67.2 β C.
7. 1-Phenyl-2-r4-(4-phenyl-l-butyloxy)-l-butylaminolethanol7. 1-phenyl-2-r4- (4-phenyl-l-butyloxy) -l-butylaminolethanol
Hergestellt aus Styroloxid und der Ausgangsverbindung B5 nach Verfahrens¬ variante a. Gereinigt durch Chromatografie (Gemisch P, 4:1), umkristalli¬ siert aus Petrolether. Fp: 53,8-56,5βC.Manufactured from styrene oxide and the starting compound B5 according to process variant a. Purified by chromatography (mixture P, 4: 1), recrystallized from petroleum ether. Mp: 53.8-56.5 β C.
8. 1-Phenyl -2-176- (2-pyridin-2-yl )ethoxyl-l-heχylamino ethanol8. 1-phenyl -2-176- (2-pyridin-2-yl) ethoxyl-l-heχylamino ethanol
Hergestellt aus Styroloxid und der Ausgangsverbindung B6 nach Verfahrens¬ variante a. Gereinigt durch Chromatografie (Gemisch P, 3:1), umkristalli¬ siert aus Petrolether. Fp: 56,2-58,lβC. 9. 1 -Phenyl -2 - T6- ( 5-phenyl - I -penty1 oxy) - l -hexyl ami nolethanolManufactured from styrene oxide and the starting compound B6 according to process variant a. Purified by chromatography (mixture P, 3: 1), recrystallized from petroleum ether. Mp: 56.2-58, l β C. 9. 1-phenyl -2 - T6- (5-phenyl - I-penty1 oxy) - 1 -hexyl aminolethanol
Hergestellt aus Styroloxid und der Ausgangsverbindung B7 nach Verfahrens¬ variante a. Gereinigt durch Chromatografie (Gemisch P, 3:1), umkristalli¬ siert aus Petrolether. Fp: 38,8-39,9°C.Manufactured from styrene oxide and the starting compound B7 according to process variant a. Purified by chromatography (mixture P, 3: 1), recrystallized from petroleum ether. Mp: 38.8-39.9 ° C.
10. R-(-)-l-Phenyl-2-r6-(2-pheny1ethoχy)-l-heχylaminolethanol10. R - (-) - l-phenyl-2-r6- (2-pheny1ethoχy) -l-heχylaminolethanol
Hergestellt aus R-(-)-Styroloxid und der Ausgangsverbindung B2 nach Verfah¬ rensvariante a. Gereinigt durch Chromatografie (Gemisch P, 3:1), umkristal¬ lisiert aus Petrolether. Fp: 54,7-56,lβC.Prepared from R - (-) - styrene oxide and the starting compound B2 to procedural ¬ rensvariante a. Purified by chromatography (mixture P, 3: 1), recrystallized from petroleum ether. Mp: 54.7-56, l β C.
11. S-(+)-l-Phenyl -2-r6-(2-phenylethoxy)-l-hexylaminolethanol11. S - (+) - l-phenyl -2-r6- (2-phenylethoxy) -l-hexylaminolethanol
Hergestellt aus S-(+)-Styroloxid und der Ausgangsverbindung B2 nach Verfah¬ rensvariante a. Gereinigt durch Chromatografie (Gemisch P, 3:1), umkristal¬ lisiert aus Petrolether. Fp: 53,7-55,2°C.Manufactured from S - (+) - styrene oxide and the starting compound B2 according to process variant a. Purified by chromatography (mixture P, 3: 1), recrystallized from petroleum ether. Mp: 53.7-55.2 ° C.
12. 1-Phenyl -2-r6-(phenylmethoxy)-l-hexylaminolethanol12. 1-phenyl -2-r6- (phenylmethoxy) -l-hexylaminolethanol
Hergestellt aus 2-Amino-l-phenylethanol und der Ausgangsverbindung A9 nach Verfahrensvariante b. Gereinigt durch Chromatografie (Gemisch P, 3:1), um¬ kristallisiert aus Petrolether. Fp: 57,7-60,2'C.Made from 2-amino-l-phenylethanol and the starting compound A9 according to process variant b. Purified by chromatography (mixture P, 3: 1), recrystallized from petroleum ether. Mp: 57.7-60.2'C.
13. 1-Phenyl-2-(6-phenoχy-l-hexylamino)ethanol13. 1-phenyl-2- (6-phenoχy-l-hexylamino) ethanol
Hergestellt aus 2-Amino-l-phenylethanol und der Ausgangsverbindung AlO nach Verfahrensvariante b, umkristallisiert aus Methanol. Fp: 103,4-104,6°C.Made from 2-amino-l-phenylethanol and the starting compound AlO according to process variant b, recrystallized from methanol. Mp: 103.4-104.6 ° C.
14. 1-Phenyl -2-r5-(2-phenylethoχy)-l-pentylaminolethanol14. 1-phenyl -2-r5- (2-phenylethoχy) -l-pentylaminolethanol
Hergestellt aus 2-Amino-l-phenylethanol und der Ausgangsverbindung All nach Verfahrensvariante b. Gereinigt durch Chromatografie (Gemisch P, 3:1), um¬ kristallisiert aus Petrolether. Fp: 47,9-50,2"C. 15. 1-Phenyl -2-r7-(2-phenylethoxy)-l-heptylaminolethanolMade from 2-amino-l-phenylethanol and the starting compound All according to process variant b. Purified by chromatography (mixture P, 3: 1), recrystallized from petroleum ether. Mp: 47.9-50.2 "C. 15. 1-phenyl -2-r7- (2-phenylethoxy) -l-heptylaminolethanol
Hergestellt aus 2-Amino-l-phenylethanol und der Ausgangsverbindung A12 nach Verfahrensvariante b. Gereinigt durch Chromatografie (Gemisch P, 3:1), um¬ kristallisiert aus Petrolether. Fp: 54,2-55,9°C.Made from 2-amino-l-phenylethanol and the starting compound A12 according to process variant b. Purified by chromatography (mixture P, 3: 1), recrystallized from petroleum ether. Mp: 54.2-55.9 ° C.
16. l-Phenyl-2-r5-(3-phenyl-l-propoxy)-l-pentylaminolethanol16. l-Phenyl-2-r5- (3-phenyl-l-propoxy) -l-pentylaminolethanol
Hergestellt aus 2-Amino-l-phenylethanol und der Ausgangsverbindung A13 nach Verfahrensvariante b. Gereinigt durch Chromatografie (Gemisch P, 3:1), um¬ kristallisiert aus Petrolether. Fp: 57,5-59,4βC.Made from 2-amino-l-phenylethanol and the starting compound A13 according to process variant b. Purified by chromatography (mixture P, 3: 1), recrystallized from petroleum ether. Mp: 57.5-59.4 β C.
17. 1-Phenyl-2-(7-benzyloxy-l-heptylamino)ethanol17. 1-phenyl-2- (7-benzyloxy-l-heptylamino) ethanol
Hergestellt aus 2-Amino-l-phenylethanol und der Ausgangsverbindung A14 nach Verfahrensvariante b. Gereinigt durch Chromatografie (Gemisch P, 3:1), um¬ kristallisiert aus Petrolether. Fp: 55,5-57,8°C.Made from 2-amino-l-phenylethanol and the starting compound A14 according to process variant b. Purified by chromatography (mixture P, 3: 1), recrystallized from petroleum ether. Mp: 55.5-57.8 ° C.
18. 1-Phenyl -2-r4-(2-phenylethoχy)-l-buty1aminolethanol18. 1-phenyl -2-r4- (2-phenylethoχy) -l-butylaminolethanol
Hergestellt aus 2-Amino-l-phenylethanol und der Ausgangsverbindung A15 nach Verfahrensvariante b, umkristallisiert aus Methanol. Fp: 82,6-83,7βC.Prepared from 2-amino-l-phenylethanol and the starting compound A15 according to process variant b, recrystallized from methanol. Mp: 82.6-83.7 β C.
19. (lS.2Rl-2-Methv1-l-Dhenv1-2-r6-f2-phenylethoxyl-l-hexylaminolethano1- maleat19. (IS.2Rl-2-Methv1-l-Dhenv1-2-r6-f2-phenylethoxyl-l-hexylaminolethano1-maleate
Hergestellt aus lS,2R-(+)-Norephedrin und der Ausgangsverbindung A3 nach Verfahrensvariante b. Gereinigt durch Chromatografie (Gemisch Q, 1:3:1), umkristallisiert aus Diethylether. Fp: 103,7-104,9°C.Made from IS, 2R - (+) - norephedrine and the starting compound A3 according to process variant b. Purified by chromatography (mixture Q, 1: 3: 1), recrystallized from diethyl ether. Mp: 103.7-104.9 ° C.
20. (lR.2Sl-2-Methyl-l-phenyl-2-r6-f2-phenylethoxy)-l-heχylaminolethanol20. (IR.2Sl-2-methyl-l-phenyl-2-r6-f2-phenylethoxy ) -l-heylaminolethanol
Hergestellt aus lR,2S-(-)-Norephedrin und der Ausgangsverbindung A3 nach Verfahrensvariante b. Gereinigt durch Chromatografie (Gemisch Q, 9:3:1), umkristallisiert aus Petrolether. Fp: 42,3-43,2°C. 21. 2-(6-r2-(4-Benzyloxyphenyl )ethoxyl-l-hexyl amino)-!-phenylethanolMade from IR, 2S - (-) - norephedrine and the starting compound A3 according to process variant b. Purified by chromatography (mixture Q, 9: 3: 1), recrystallized from petroleum ether. Mp: 42.3-43.2 ° C. 21. 2- (6-r2- (4-Benzyloxyphenyl) ethoxyl-l-hexylamino) -! - phenylethanol
Hergestellt aus 2-Amino-l-phenylethanol und der Ausgangsverbindung A16 nach Verfahrensvariante b, umkristallisiert aus Methanol. Fp: 98,9-99,4βC.Prepared from 2-amino-l-phenylethanol and the starting compound A16 according to process variant b, recrystallized from methanol. Mp: 98.9-99.4 β C.
22. 2-(6-r2-(4-Hvdroxyphenyl)ethoxy1-l-hexylamino)-!-phenylethanol22. 2- (6-r2- (4-Hydroxyphenyl) ethoxy1-l-hexylamino) -! - phenylethanol
Hergestellt aus 2-[6-{2-(4-Benzyloxyphenyl )ethoxy}-l-hexylamino]-l-phenyl - ethanol durch hydrierende Debenzylierung an 5 % Pd/C in Ethanol. Umkristal¬ lisation der wachsartigen Substanz in Diethylether. 1H-NMR(CDC13) : 1,10-1,59 ppm, , 8,0 H (C-(CH2)4-C); 2,44-2,92 ppm, m, 5,8 H (Phenyl-CH2, CH2-N-CH2); 3,38 ppm, t, J=6,7 Hz, 1,9 H (C5-CH--0); 3,48-3,80 ppm, , 6,3 H (NH, OH, Phenyl-C-CH2, H-0) ; 4,72-4,86 ppm, m, 1,0 H (CHO); 6,77 ppm, d, J=8,0 Hz, 2,0 H (2xH Hydroxyphenyl); 7,08 ppm, d, J=8,0 Hz, 2,0 H (2xH Hydroxyphenyl); 7,18-7,50 ppm, m, 5,9 H (arom. H, Phenyl-OH).Made from 2- [6- {2- (4-benzyloxyphenyl) ethoxy} -l-hexylamino] -l-phenylethanol by hydrogenating debenzylation at 5% Pd / C in ethanol. Recrystallization of the waxy substance in diethyl ether. 1 H NMR (CDC1 3 ): 1.10-1.59 ppm, 8.0 H (C- (CH 2 ) 4 -C); 2.44-2.92 ppm, m, 5.8 H (phenyl-CH 2 , CH 2 -N-CH 2 ); 3.38 ppm, t, J = 6.7 Hz, 1.9 H (C5-CH - 0); 3.48-3.80 ppm,, 6.3 H (NH, OH, phenyl-C-CH 2 , H-0); 4.72-4.86 ppm, m, 1.0 H (CHO); 6.77 ppm, d, J = 8.0 Hz, 2.0 H (2xH hydroxyphenyl); 7.08 ppm, d, J = 8.0 Hz, 2.0 H (2xH hydroxyphenyl); 7.18-7.50 ppm, m, 5.9 H (aromatic H, phenyl-OH).
23. 2-T6-(3.3-Diphenyl -l-propoxy)-l-heχy1aminol-l-phenylethanol23. 2-T6- (3.3-diphenyl-l-propoxy) -l-heχy1aminol-l-phenylethanol
Hergestellt aus 2-Amino-l-phenylethanol und der Ausgangsverbindung A2 nach Verfahrensvariante b. Gereinigt durch Chromatografie; als Hydrochlorid umkristallisiert aus Diethylether. Fp (Hydrochlorid): 110-112βC.Made from 2-amino-l-phenylethanol and the starting compound A2 according to process variant b. Purified by chromatography; recrystallized as hydrochloride from diethyl ether. Mp (hydrochloride): 110-112 β C.
Auf analoge Weise werden erhalten:The following are obtained in an analogous manner:
2-{6-[2-(2-Naphthyl)ethoxy]-l-hexylamino)-l-phenylethanol
Figure imgf000016_0001
2- {6- [2- (2-naphthyl) ethoxy] -l-hexylamino) -l-phenylethanol
Figure imgf000016_0001
2-{6-[2-(1-Naphthyl )ethoxy]-l-hexylamino}-l-phenylethanol
Figure imgf000016_0002
2- {6- [2- (1-naphthyl) ethoxy] -l-hexylamino} -l-phenylethanol
Figure imgf000016_0002
2-{6- [2- (3-Hydroxyphenyl )ethoxy] -l -hexyl amino} - l -phenyl ethanol (Fp . des2- {6- [2- (3-Hydroxyphenyl) ethoxy] -l-hexylamino} - l -phenylethanol (mp. Des
Hydrochl orids : 99- 103βC) ,Hydrochloride: 99-103 β C),
2- (6- [2- (4-Methoxyphenoxy)ethoxy] - l -hexyl ami no} - l -phenyl ethanol2- (6- [2- (4-methoxyphenoxy) ethoxy] -1-hexyl amine no} -1-phenyl ethanol
(Fp . : 77-78βC) ,(Mp: 77-78 β C),
2-{6-[2-(2-Thienyl)ethoxy]-l-hexylamino)-l-phenylethanol (Fp.: 71,7-73βC),2- {6- [2- (2-thienyl) ethoxy] -l-hexylamino) -l-phenylethanol (mp .: 71.7-73 β C),
2-(6-[2-(4-Methylphenyl)ethoxy]-l-hexylamino}-l-phenylethanol (Fp. des2- (6- [2- (4-Methylphenyl) ethoxy] -l-hexylamino} -l-phenylethanol (mp. Des
Hemihydrats: 76,4-78,9βC),Hemihydrate: 76.4-78.9 β C),
2-(6-[2-(2-Nitrophenyl)ethoxy]-l-hexylamino}-l-phenylethanol (Fp. des2- (6- [2- (2-nitrophenyl) ethoxy] -l-hexylamino} -l-phenylethanol (mp. Des
Hydrats: 56,3-56,5°C),Hydrate: 56.3-56.5 ° C),
2-[6-(2-Phenoxyethoxy)-l-hexylamino]-l-phenylethanol (Fp. 55-56°C) . Gewerbliche Anwendbarkeit2- [6- (2-phenoxyethoxy) -l-hexylamino] -l-phenylethanol (mp 55-56 ° 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 ß2-stimulierender Wirkung dar, wobei sie sich vor allem durch ihre gute Löslichkeit 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 ß 2 -stimulating effect, whereby they are characterized by their good solubility.
Aufgrund ihrer ß-sympathomimetischen Wirkung eignen sich die erfindungs¬ gemäßen 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 (peri- pherer) Durchblutungsstörungen eingesetzt werden, sie führen zu einer Erschlaffung der Blasenwandmuskulatur und eignen sich zur Behandlung von Blasenentleerungsstörungen, sie senken den (krankhaft erhöhten) Augeninnen- druck und können zur Behandlung des Glaukoms eingesetzt werden, sie be¬ einflussen den Stoffwechsel und eignen sich z.B. zur Behandlung der Adi- positas, und sie eignen sich aufgrund ihrer vor allem ß--sympathomimeti- schen Wirkung vor allem zur Behandlung von Atemwegserkrankungen verschie¬ dener Genese.Because of their β-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 for treatment (peri- circulatory disorders are used, they lead to a relaxation of 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 to treat glaucoma, they influence the metabolism and are suitable, for example for the treatment of obesity, and because of their ß - sympathomimetic effect they are particularly suitable for the treatment of respiratory diseases of various origins.
Insbesondere können (Allergen- und inflam atorisch induzierte) Bronchial - erkrankungen aufgrund der broncholytisehen Wirksamkeit der erfindungsge¬ mäßen Verbindungen behandelt werden. Dabei zeichnen sich die erfindungs¬ gemäßen Verbindungen durch eine geringe Toxizität, eine große therapeu¬ tische 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, bronchial diseases (allergenic and inflammatory induced) due to the broncholytic effectiveness of the compounds according to the invention can be treated. The compounds according to the invention are distinguished by a low toxicity, a large therapeutic breadth, 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 broncholytisehe Wirksamkeit der erfindungsgemäßen Verbindungen ermög¬ licht ihren Einsatz in der Human- und Veterinärmedizin, wobei sie zur Be¬ handlung und Prophylaxe von Krankheiten, die auf Erkrankungen der Bronchien beruhen, verwendet werden. Beispielsweise können akute und chronisch ob¬ struktive Atemwegserkrankungen verschiedener Genese (Bronchitis, allergi- sehe 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 ent¬ zündlichen 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 them to be used in human and veterinary medicine, and they are used for the treatment and prophylaxis of diseases which are based on diseases of the bronchi. For example, acute and chronically obstructive respiratory diseases of various origins (bronchitis, allergic see bronchitis, bronchial asthma) 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 the case of 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 Appli¬ kation bestimmter ß-Adrenozeptor-Agonisten positiv beeinflußt werden. So können beispielsweise aufgrund der hypoglycä isehen Wirkung der Verbindun¬ gen StoffwechselStörungen 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 Darmer¬ krankungen wie Colitis ulcerosa oder Morbus Crohn) durch die erfindungsge¬ mäßen 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 hypoglycic effect of the compounds, metabolic 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 Behand¬ lung 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.Another object of the invention is therefore 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 Krank¬ heiten.The invention furthermore 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 Verbin¬ dungen zur Herstellung von Arzneimitteln, die zur Behandlung und/oder Pro¬ phylaxe der genannten Krankheiten eingesetzt werden. Weiterhin sind Arzneimittel zur Behandlung und/oder Prophylaxe der genann¬ ten 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 erfin¬ dungsgemäßen 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 on account of their activity 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 Darreichun ind 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), if appropriate in the form of several individual doses, are to be administered.
Pharmakologiepharmacology
Die ausgezeichnete bronchospasmolytische Wirkung der erfindungsgemäßen Ver¬ bindungen 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 Seg¬ mente geteilt und jedes Segment wird in einem Organbad mit 120 mM NaCl , 6 M KC1, 1 mM MgS04, 2,5 mM CaCl-, 1 M NaH-P04, 2,5 M NaHC03 und 6 mM Glukose bei 35βC aufgehängt. Sauerstoff, versetzt mit 5 % C02, wird perma¬ nent durch die Lösung geleitet. Die Trachea wird nach Stabilisierung mit einer geeigneten Dosis Methacholin kontrahiert. Danach wird mit den Prüf¬ substanzen in kumulativer Weise eine Dosis-Wirkungskurve aufgenommen. Aus dieser Kurve wird dann die Konzentration (μmol/1) bestimmt, die 50 % des Maximaleffektes (EC5Q) entspricht. Diese EC-.Q ist somit ein Maßstab für die Aktivität der erfindungsgemäßen Verbindungen.The excellent bronchospasmolytic effect 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 120 mM NaCl, 6 M KCl, 1 mM MgSO 4 , 2.5 mM CaCl 1 M NaH -P0 4 , 2.5 M NaHC0 3 and 6 mM glucose at 35 β C suspended. Oxygen, mixed with 5% CO 2 , is continuously passed through the solution. After stabilization, the trachea is contracted with a suitable dose of methacholine. A dose-response curve is then recorded in a cumulative manner with the test substances. The concentration (μmol / 1) is then determined from this curve, which corresponds to 50% of the maximum effect (EC 5Q ). This EC. Q is thus a measure of the activity of the compounds according to the invention.
In der nachfolgenden Tabelle sind die EC-.Q-Werte (μm) für ausgewählte er¬ findungsgemäße 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.In the table below are the EC. Q values (μm) for selected compounds according to the invention are given. The serial number in the table matches the number of the connections in the examples. The number n indicates the number of examinations.
Tabelletable
lfd. Nr. EC50-Werte (μm) nSerial No.EC 50 values (μm) n
1 0,042 51 0.042 5
4 0,015 64 0.015 6
5 0,040 65 0.040 6
7 0,028 57 0.028 5
8 0,014 58 0.014 5
10 0,0098 610 0.0098 6
14 0,022 514 0.022 5
16 0,022 516 0.022 5
22 0,00033 6 22 0.00033 6

Claims

Patentansprüche claims
1. Verbi ndungen der Formel I ,1. compounds of the formula I,
C 6 H 5 - CH(OH) - CH(R1 ) - NH - (CH 2 )m 1 1 1 - 0 - (CH 2 n 1 1 - R2 (I)C 6 H 5 - CH (OH) - CH (R1) - NH - (CH 2) m 1 1 1 - 0 - (CH 2 n 1 1 - R2 (I)
wori nwori n
Rl Wasserstoff oder 1-4C-Alkyl bedeutet,Rl is hydrogen or 1-4C-alkyl,
R2 einen durch R3 und R4 substituierten Phenylrest, einen Pyridylrest, einen Phenoxyrest, einen Naphthylrest, einen Thienylrest oder einen Benzhydrylrest bedeutet, wobei R3 Wasserstoff, Halogen, Hydroxy (-0H), 1-4C-Alkyl, l-4C-Alkoxy,R2 represents a phenyl radical substituted by R3 and R4, a pyridyl radical, a phenoxy radical, a naphthyl radical, a thienyl radical or a benzhydryl radical, where R3 denotes hydrogen, halogen, hydroxy (-0H), 1-4C-alkyl, 1-4C-alkoxy,
Benzyloxy, Nitro (-N0-), Trifluormethyl (-CF3), l-4C-Alkoxycarbo- nyl (-C0-0-l-4C-Alkyl), Carbamoyl (-C0-NH-), Di-l-4C-alkylcarb- amoyl [-C0-N(l-4C-Alkyl)2], Amino (-NH-) oder Mono- oder Di-(1-4C- alkyl)amino bedeutet und R4 Wasserstoff, Halogen, Hydroxy (-0H), 1-4C-Alkyl oder l-4C-Alkoxy bedeutet, oder wobeiBenzyloxy, nitro (-N0-), trifluoromethyl (-CF 3 ), 1-4C-alkoxycarbonyl (-C0-0-1-4C-alkyl), carbamoyl (-C0-NH-), di-1-4C -alkylcarb- amoyl [-C0-N (1-4C-alkyl) 2 ], amino (-NH-) or mono- or di- (1-4C-alkyl) amino and R4 denotes hydrogen, halogen, hydroxy (-0H ), 1-4C-alkyl or 1-4C-alkoxy, or wherein
R3 und R4 gemeinsam einen Methylendioxy- (-0-CH2-0-) oder Ethylendioxy- rest (-0-CH2-CH2-0-) bilden, m eine ganze Zahl von 4 bis 10 bedeutet und n eine ganze Zahl von 0 bis 7 bedeutet, und die Salze dieser Verbindungen, wobei m nicht die Zahl 4 oder 5 bedeutet wenn n die Zahl 0 bedeutet.R3 and R4 together form a methylenedioxy (-0-CH 2 -0-) or ethylenedioxy radical (-0-CH 2 -CH 2 -0-), m is an integer from 4 to 10 and n is an integer from 0 to 7, and the salts of these compounds, where m is not the number 4 or 5 when n is the number 0.
2. Verbindungen nach Anspruch 1, wobei n eine ganze Zahl von 1 bis 7 be¬ deutet.2. Compounds according to claim 1, wherein n denotes an integer from 1 to 7.
3. Verbindungen der Formel I nach Anspruch 1, worin3. Compounds of formula I according to claim 1, wherein
Rl Wasserstoff oder 1-4C-Alkyl bedeutet,Rl is hydrogen or 1-4C-alkyl,
R2 einen durch R3 und R4 substituierten Phenylrest oder einen Pyridylrest bedeutet, wobei R3 Wasserstoff, Halogen, Hydroxy (-0H), 1-4C-Alkyl, l-4C-Alkoxy,R2 represents a phenyl radical substituted by R3 and R4 or a pyridyl radical, where R3 is hydrogen, halogen, hydroxy (-0H), 1-4C-alkyl, 1-4C-alkoxy,
Benzyloxy, Nitro (-N0-) oder Trifluormethyl (-CF- bedeutet und R4 Wasserstoff, Hydroxy (-0H), 1-4C-Alkyl oder l-4C-Alkoxy bedeutet, oder wobeiBenzyloxy, nitro (-N0-) or trifluoromethyl (-CF- means and R4 means hydrogen, hydroxy (-0H), 1-4C-alkyl or 1-4C-alkoxy, or wherein
R3 und R4 gemeinsam einen Methylendioxy- (-0-CH2-0-) oder Ethylendioxy rest (-0-CH2-CH2-0-) bilden, m eine ganze Zahl von 4 bis 8 bedeutet und n eine ganze Zahl von 1 bis 5 bedeutet, und die Salze dieser Verbindungen.R3 and R4 together form a methylenedioxy (-0-CH 2 -0-) or ethylenedioxy radical (-0-CH 2 -CH 2 -0-), m is an integer from 4 to 8 and n is an integer from 1 to 5 means, and the salts of these compounds.
4. Verbindungen der Formel I nach Anspruch 1, worin4. Compounds of formula I according to claim 1, wherein
Rl Wasserstoff bedeutet,Rl is hydrogen,
R2 einen durch R3 und R4 substituierten Phenylrest oder einen Pyridylrest bedeutet, wobeiR2 represents a phenyl radical substituted by R3 and R4 or a pyridyl radical, where
R3 Wasserstoff, Halogen, Hydroxy (-0H), 1-4C-Alkyl oder l-4C-Alkoxy bedeutet undR3 is hydrogen, halogen, hydroxy (-0H), 1-4C-alkyl or 1-4C-alkoxy and
R4 Wasserstoff oder 1-4C-Alkyl bedeutet, m eine ganze Zahl von 4 bis 6 bedeutet und n eine ganze Zahl von 2 bis 4 bedeutet, und die Salze dieser Verbindungen.R4 is hydrogen or 1-4C-alkyl, m is an integer from 4 to 6 and n is an integer from 2 to 4, and the salts of these compounds.
5. Verbindung ausgewählt aus der Gruppe bestehend aus l-Phenyl-2-[6-(4-phenyl-l-butyloxy)-l-hexylamino]ethanol (R)-l-Phenyl -2-[6-(4-phenyl-l-butyloxy)-l-hexylamino]ethanol (S)-l-Phenyl -2-[6-(4-phenyl-l-butyloxy)-l-hexylamino]ethanol l-Phenyl-2-[6-(2-phenylethoxy)-l-hexylamino]ethanol l-Phenyl-2-[6-(3-phenyl-l-propoxy)-l-hexylamino]ethanol l-Phenyl-2-[8-(4-phenyl-l-butyloxy)-l-octylamino]ethanol 1-Phenyl -2-[4-(4-phenyl -l-butyloxy)-l-butylamino]ethanol l-Phenyl-2-{[6-(2-pyridin-2-yl)ethoxy]-l-hexylamino)ethanol l-Phenyl-2-[6-(5-phenyl-l-pentyloxy)-l-hexylamino]ethanol5. Compound selected from the group consisting of l-phenyl-2- [6- (4-phenyl-l-butyloxy) -l-hexylamino] ethanol (R) -l-phenyl -2- [6- (4-phenyl -l-butyloxy) -l-hexylamino] ethanol (S) -l-phenyl -2- [6- (4-phenyl-l-butyloxy) -l-hexylamino] ethanol l-phenyl-2- [6- (2nd -phenylethoxy) -l-hexylamino] ethanol l-phenyl-2- [6- (3-phenyl-l-propoxy) -l-hexylamino] ethanol l-phenyl-2- [8- (4-phenyl-l-butyloxy ) -l-octylamino] ethanol 1-phenyl -2- [4- (4-phenyl -l-butyloxy) -l-butylamino] ethanol l-phenyl-2 - {[6- (2-pyridin-2-yl) ethoxy] -l-hexylamino) ethanol l-phenyl-2- [6- (5-phenyl-l-pentyloxy) -l-hexylamino] ethanol
R-(-)-1-Phenyl -2-[6-(2-phenylethoxy)-1-hexylamino]ethanol S-(+)-l-Phenyl-2-[6-(2-phenylethoxy)-l-hexylamino]ethanol 1-Phenyl -2-[6-(phenyl ethoxy)-l-hexylamino]ethanol 1-Phenyl -2-(6-phenoxy-1-hexylamino)ethanol l-Phenyl-2-[5-(2-phenylethoxy)-l-pentylamino]ethanolR - (-) - 1-phenyl -2- [6- (2-phenylethoxy) -1-hexylamino] ethanol S - (+) - l-phenyl-2- [6- (2-phenylethoxy) -l-hexylamino ] ethanol 1-phenyl -2- [6- (phenyl ethoxy) -l-hexylamino] ethanol 1-phenyl -2- (6-phenoxy-1-hexylamino) ethanol l-phenyl-2- [5- (2-phenylethoxy) -l-pentylamino] ethanol
1-Phenyl-2-[7-(2-phenylethoxy)-l-heptylamino]ethanol l-Phenyl-2-[5-(3-phenyl-l-propoxy)-l-pentylamino]ethanol1-phenyl-2- [7- (2-phenylethoxy) -l-heptylamino] ethanol l-phenyl-2- [5- (3-phenyl-l-propoxy) -l-pentylamino] ethanol
1-Phenyl-2-(7-benzyloxy-l-heptylamino)ethanol1-phenyl-2- (7-benzyloxy-l-heptylamino) ethanol
1-Phenyl-2-[4-(2-phenylethoxy)-l-butylamino]ethanol1-phenyl-2- [4- (2-phenylethoxy) -l-butylamino] ethanol
(IS,2R)-2-Methyl-l-phenyl-2-[6-(2-phenylethoxy)-l-hexylamino]ethanol(IS, 2R) -2-methyl-l-phenyl-2- [6- (2-phenylethoxy) -l-hexylamino] ethanol
(lR,2S)-2-Methyl-l-phenyl-2-[6-(2-phenylethoxy)-l-hexylamino]ethanol(IR, 2S) -2-methyl-l-phenyl-2- [6- (2-phenylethoxy) -l-hexylamino] ethanol
2-{6-[2-(4-Benzyloxyphenyl)ethoxy]-l-hexylamino)-1-phenylethanol2- {6- [2- (4-Benzyloxyphenyl) ethoxy] -1-hexylamino) -1-phenylethanol
2-{6-[2-(4-Hydroxyphenyl)ethoxy]-l-hexylamino)-1-phenylethanol und2- {6- [2- (4-hydroxyphenyl) ethoxy] -l-hexylamino) -1-phenylethanol and
2-[6-(3,3-Diphenyl-l-propoxy)-l-hexylamio]-l-phenylethanol , oder ein Salz davon.2- [6- (3,3-Diphenyl-l-propoxy) -l-hexylamio] -l-phenylethanol, or a salt thereof.
6. Verfahren zur Herstellung der Verbindungen der Formel I nach Anspruch 1 und ihrer Salze, dadurch gekennzeichnet, daß man6. A process for the preparation of the compounds of formula I according to claim 1 and their salts, characterized in that
a) Verbindungen der Formel II,a) compounds of the formula II,
C 6H5-CH(OH)-CH(R1)-NBz-(CH2)mlII-0-(CH2)n11-R2 (II)C 6H5-CH (OH) -CH (R1) -NBz- (CH2) m lII-0- (CH2) n 11-R2 (II)
worin Rl, R2, und n die in Anspruch 1 angegebenen Bedeutungen haben und Bz eine Benzylgruppe darstellt, reduktiv debenzyliert, oder daß manwherein Rl, R2, and n have the meanings given in claim 1 and Bz represents a benzyl group, reductively debenzylated, or that one
b) Verbindungen der Formel III,b) compounds of the formula III,
C 6H5-CH(OH)-CH(R1)-NH2 (III)C 6H5-CH (OH) -CH (R1) -NH2 (III)
worin Rl die in Anspruch 1 angegebene Bedeutung hat, mit Verbindungen der Formel IV,wherein Rl has the meaning given in claim 1, with compounds of the formula IV,
-(CH2)m-0-(CH2)n-R2 (IV)- (CH 2 ) m -0- (CH 2 ) n -R2 (IV)
worin R2, m und n die in Anspruch 1 angegebenen Bedeutungen haben und L eine geeignete Abgangsgruppe darstellt, umsetzt, und daß man gewünschten¬ falls anschließend die nach a) oder b) erhaltenen Verbindungen I in ihre Salze überführt, oder daß man gewünschtenfalls anschließend aus erhaltenen Salzen der Verbindungen I die Verbindungen I freisetzt. in which R2, m and n have the meanings given in Claim 1 and L represents a suitable leaving group, and that if desired the compounds I obtained according to a) or b) are subsequently converted into their salts, or if desired then subsequently obtained salts of the compounds I releases the compounds I.
7. Arzneimittel enthaltend eine oder mehrere Verbindungen der Formel I nach Anspruch 1 und/oder ihre pharmakologisch verträglichen Salze.7. Medicament containing one or more compounds of the formula I according to claim 1 and / or their pharmacologically acceptable salts.
8. Verbindungen der Formel I nach Anspruch 1 und/oder ihre pharmakologisch verträglichen Salze zur Anwendung bei der Behandlung von Erkrankungen der Bronchien oder des Gastrointestinaltrakts.8. Compounds of formula I according to claim 1 and / or their pharmacologically acceptable salts for use in the treatment of diseases of the bronchi or the gastrointestinal tract.
9. 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 oder des Gastrointestinal¬ trakts. 9. 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 or the gastrointestinal tract.
PCT/EP1995/000082 1994-01-12 1995-01-11 PHENYL ETHANOL AMINE ETHERS AND USES THEREOF AS β-ADRENO-RECEPTOR AGONISTS WO1995019336A1 (en)

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