DE4120698A1 - New phenoxy-alkanol derivs. which are 5-lipoxygenase inhibitors - used to treat asthma, thrombosis, shock, ischaemic coronary infarction, etc. - Google Patents

Abstract

Phenoxyalkanol derivs. of formula (I) are new, where R1 is H or COR5; R5 is 1-5C alkyl (opt. interrupted by an O or S atom), Ar1 or CH2Ar1; Ar1 is phenyl opt. substd. by 1-3 of F, Cl, OMe, CF3 or 1-3C alkyl; R2 is H, 1-5C alkyl, 5-7C cycloalkyl, benzyl or Ar2; Ar2 is phenyl opt. monosubstd. by F, Cl, OMe, CF3 or 1-3C alkyl; m is 2-11; R3 is 1-3C alkyl; and R4 is H or 2-5C alkanoyl. USE - (I) are selective 5-lipoxygenase inhibitors with little or no activity against cyclooxygenase (prostaglandin synthetase). They also inhibit xanthine oxidase and have antioxidant activity. They may be used as antiinflammatory, antiallergic, antianaphylactic, antiasthmatic, hypotensive and antithrombotic agents and as agent for treating myocardial infarction coronary and/or cerebral artery disease, shock and reperfusion injury.

Description

Polyunsaturated higher fatty acids, such as. As the arachidonic acid serve in the metabolism of humans and of mammals as substrates for the enzymatically catalyzed formation of physiologically important eicosanoids such as As prostaglandins and leukotrienes, one also under the name "Slow reacting Substance of Anaphylaxis" (SRS-A) known substance class. In this case, the prostaglandin formation by the cyclo-oxygenase (also called "prostaglandin synthetase"), leukotriene formation catalyzed by 5-lipoxygenase.

While the prostaglandins have a number of desirable effects in the organ From the leukotrienes or the SRS-A, it is known that they are responsible for the development of allergic reactions to anaphylactic Shock, bronchoconstrictions, inflammation, asthma and one Many other undesirable effects are responsible. It will therefore long sought after from different sides, over che to be able to have mixed or metabolically stable compounds which are present in the Organism leave the prostaglandin formation unaffected, at the same time but as selective or specific inhibit the 5-lipoxygenase and thus preventing the formation of unwanted leukotrienes. One in each Direction satisfactory solution of this problem is yet failed.

The present invention relates to certain, optionally esterified substituted phenoxyalkanols, which are chemically and metabolic (when used therapeutically) stable compounds which has a specific inhibitory action on 5-lipoxygenase as well as other biologically or pharmaceutically valuable properties have.  

These new substituted phenoxyalkanols according to the invention and their Esters correspond to the general formula:

That means
R₁ represents a hydrogen atom or a group of the formula -CO-R₅, in which R₅ is an atom which is optionally interrupted by an oxygen or sulfur atom and has 1 to 4 carbon atoms, or the group of the formula

where n is one of the numbers 1, 2 or 3, R₆ is a hydrogen, fluorine or chlorine atom or is a methoxy, tri fluoromethyl or an alkyl radical having 1 to 3 carbon atoms, and p is the number 0 or 1 is
R₂ is a hydrogen atom, an alkyl radical having 1 to 5 carbon atoms, a cycloalkyl radical having 5 to 7 carbon atoms, the benzyl radical or the group of the formula

in which R₇ stands for a hydrogen, fluorine or chlorine atom or for a methoxy, trifluoromethyl or an alkyl radical having 1 to 3 carbon atoms,
m is an integer from 2 to 11,
R₃ is an alkyl radical having 1 to 3 carbon atoms, preferably the methyl radical and
R₄ represents a hydrogen atom or a radical of the formula -COR₈, in which R₈ represents an alkyl radical having 1 to 4 carbon atoms, preferably the methyl radical.

If R₂ is different from hydrogen, the compounds may be in the form of Ra zemate or optically active forms. All of these isomers belong ren subject of the invention.

The encompassed by the definitions of the radicals R₂ to R₈ alkyl radicals can straight-chain or (if they contain more than 2 carbon atoms) ver branches present.

Preferably, R₅ is an alkyl radical having 1 to 4 carbon atoms (in particular the methyl group) or a phenyl or 4-chlorophenyl rest. In these preferred compounds of the formula I, therefore, n stands for the number 1, p for the number 0, X for a single bond and R₆ for Hydrogen or chlorine.

Preferred meanings of R₂ are n-pentyl, cyclohexyl, benzyl, phenyl, 4-chlorophenyl and especially hydrogen.

R₄ is preferably hydrogen or the acetyl radical.

As already stated in the introduction, the compounds of the formula I have a specific inhibitory effect on 5-lipoxygenase, which u. a. was determined by in vitro experiments.

To determine the 5-Lipoxygenasehemmung basophilic leukemic Leukocytes of the rat (RBL-1 cells) grown in vitro, from the nutrient medium centrifuged, washed with buffer (potassium phosphate 50 mM, pH 7.4) and then to a cell count of 1 × 10⁷ cells per ml provides. Each 1 ml of this cell suspension was incubated with 10 μM Indometha cin, 2 mM CaCl₂ and with test substance in concentration ranges of  0.1 μM to 100 μM or in appropriate controls with solvent Room temperature preincubated for 3 minutes and then with 20 uM radiolabeled arachidonic acid and 20 μM of the calcium ionophore A 23187 incubated for 10 minutes. After stopping the reaction by closing Addition of 20 ul of glacial acetic acid, the reaction products were with ethyl acetate extracted and run with a suitable for Lipoxygenaseprodukte Laufmit telmix separated by thin layer chromatography (Jakschik et al., Bio chem. Biophys. Res. Commun. 102, 624 (1981)).

The radioactivity distribution of the different arachidonic acid metabolabolites te was measured by means of a TLC linear analyzer. From the processes Tual Formation Parts of 5-Lipoxygenase Products (5-HETE, LTB₄ Isomers) in controls (absence of test substances) and ver various concentrations of the compounds of the formula I used became graphically from semilogarithmic charts "IC₅₀ values" (i.e. the concentrations that cause 50% inhibition of 5-lipoxygenase ken). For standardization, these values were in the same chen test determined IC₅₀ values for the standard substance Nordihydro guaiaretic acid related. These standardized "IC₅₀ values (A)" are in Table 1.

The influence of the compounds of formula I on the cyclooxygenase Aktivi It was done with the help of sheep seminal bubble microsomes, suspended in Puf Fer (potassium phosphate 50 mM, pH 7.0), by incubation with test substance or solvent (as a control) and radiolabelled arachidon acid. The "IC₅₀ values (B)" for the inhibition of cyclooxygen Nas was made by thin layer chromatography and TLC linear analyzer certainly.

For example, for the products listed in the following table Examples mentioned in each case the indicated IC₅₀ values found, from the quotient

was calculated.  

Table 1

From this Table 1 shows that the listed IC₅₀ values for cyclooxygenase inhibition is often more than 1000 times higher than the values for 5-lipoxygenase inhibition are d. H. that the testsub Very specifically, only inhibition of 5-lipoxygenase activity effect. The products listed in Table 1 are preferred compounds formulations of the formula I.

The marked inhibitory effect of substances of the formula I over 5-Lipoxygenase could also be used in experiments with cell-free 5-lipoxygenase be shown, d. H. that these substances have a direct effect to have 5-lipoxygenase activity.

In the enzymatically induced oxidation of hypoxanthine to uric acid Be reactive oxygen compounds such. B. superoxide anion radicals, Hydrogen peroxide, etc. formed in the presence of 3-amino phthalic acid hydrazide ("luminol") can be detected as chemiluminescence can. An inhibition of chemiluminescence induced by this reaction Zenz argues for a catching of the very reactive and cytotoxic sow  erstoffverbindungen, as far as a direct inhibition of xanthine oxidase excluded by the substances to be tested.

Luminol-mediated chemiluminescence was measured in a chemilumines zenz detector at 37 ° C for a period of 3 minutes continuous measured and integrated as relative light units (RLU). The approaches contained as final concentrations 100 .mu.mol / l hypoxanthine, 100 .mu.mol / l Ethylenediaminetetraacetate, 100 μmol / l luminol, potassium phosphate buffer (50 mmol / l, pH 7.4) and various concentrations of the test substance zen or their vehicle solution. The start of the reaction was carried out by Addition of commercially available xanthine oxidase (from cow's milk).

For the quantitative evaluation of the inhibitory effect of a test substance were IC₅₀ values (concentration with 50% reduction in RLU / 3 min via control approaches with vehicle solution). A direct enzyme Inhibition by the substances of formula I was by a parallel Test batch excluded under the same conditions in which the enzyme activity of xanthine oxidase was determined.

Table 2 shows the inhibitory effect (IC₅₀) of substances of the general NEN formula I to those induced by reactive oxygen compounds Chemiluminescence.

example IC₅₀ values [μM] 2 0.58 3 1.08 4 1.24 5a 0.61 5f 0.61 8th 0.79

It is known from a variety of studies that the Entzün in the living organism through the resulting reactive Oxygen compounds autocatalytically escalated. Because the connections  of formula I have pronounced antioxidant properties are suitable they are for the therapy and prophylaxis of all clinical pictures in which Course occur reactive oxygen compounds or where such involved.

On the other hand, since the compounds of formula I have an excellent and have selective inhibitory activity on 5-lipoxygenase, they possess numerous physiologically valuable properties such. Antianaphy lactic, anti-asthmatic, anti-allergic and anti-inflammatory, hypotensive and circulation-promoting (coronary and cerebral Circulation) effects, reduction of leukocyte aggregation or the Formation of leukocyte thrombi, etc. Since the Verbindun of the formula I chemically and metabolically for a therapeutic application stable and storable, they are suitable for use as a medic for example As antiallergic, antianaphylactic, antiphlogistic, Antiasthmatica, antihypertensives, antithrombotic agents, means of Prophylaxis or therapy of ischemic heart attack, disorders of the coronary and / or cerebral arteries, etc. Intravenous use The compounds are still suitable for the indication shock and for the treatment of reperfusion damage.

The compounds of the formula I according to the invention have only one ge toxicity, which is much higher than therapeutic or prophylactically applicable doses makes noticeable. You can Therefore, as such in suitable pharmaceutical preparations Be administered to humans or animals.

Accordingly, the invention also relates to medicaments which are effective substance one or more of the compounds of the formula I according to the invention contain. The administered to the patient drug amount vari depending on z. As the weight of the patient, the application away, the indication and the severity of the disease. Under Berück These factors account for the active ingredient content per single dose In general, about 0.01-50 mg, in the form of preparations for the parenteral administration preferably 0.01 to 10 mg.

Pharmaceuticals for parenteral administration may include both solutions also represent suspensions, but it also come easily reconstituted  bare dry preparations into consideration.

Well suitable forms of administration are also inhalation preparations and in particular sprays for the application of the substances via the bronchi.

For many prophylactic or therapeutic applications come purpose moderately and locally applicable preparation forms of the compounds of Formula I, such as ointments, creams, gels, solutions, etc., but also percutaneous Application preparations (such as, for example, the active ingredients in a depot in dissolved form, optionally with the addition of the skin penetration för medicated plaster or the like) into consideration.

Suitable formulations of the compounds of formula I are, for. B. also suppositories with an active ingredient content of generally about ever 0.1 to 50 mg.

These rectally or percutaneously applicable preparation become advantageous Formed so that it releases the drug delayed will last for a longer period of time (for example, 24 hours) a uniform supply of the patient with the active ingredient to ge währleisten.

All the above-mentioned pharmaceutical preparations are are known, and since the compounds of formula I are chemically stable, throws their incorporation in this preparation for men for the expert no problems. In this invention In accordance with the production of these drugs must of course with the usual care in the selection of excipients such as carrier materials, Ointment bases, solvents, etc., and esp especially in the preparation of parenterally applicable preparation molds is based on sterility and - if they are in liquid form - To respect isotonicity.

The preparation according to the invention of the compounds of the formula I takes place in that a compound of the formula

in which R₂, R₃ and m have the same meaning as above and R₉ for any acyl radical, preferably the group -CO-R₅ stands at temperatures below 0 ° C, preferably at temperatures from -10 to -70 ° C in an inert solvent with 1 to 3 equivalents of boron tri treated bromide or boron trichloride, wherein a compound of formula

in which R₂, R₃, R₉ and m have the same meaning as above, arises. Suitable indifferent solvents for this reaction are in particular anhydrous chloroform, dichloromethane or toluene. In principle, however, all come at the reaction temperature liquid, with the boron halides non-reactive solvent into consideration. It is Surprisingly, that it succeeds in this way, selectively the R₃O group to split in the 4-position.

If in the compound of the formula III R₉ represents the group -COR₅, then this compound of formula III at the same time a compound of formula I. Otherwise, or when R₁ is to mean a hydrogen atom, is from the compound of formula III, the radical R₉ by the action of basic Agents such as sodium or potassium carbonate, sodium, potassium or lithium hydroxide in z. B. optionally hydrous methanolic or ethanolic solution to form the corresponding compound of Formula I, wherein R₁ is a hydrogen atom, cleaved.

For the preparation of compounds of formula I in which R₄ for the Group -COR₈, it is advisable to start from a compound of formula III, in the R₉ represents the group -CO-R₅, and puts this in in a manner known per se in the presence of an inert solvent, such as z. As tetrahydrofuran, and an acid-binding agent such as pyridine, Quinoline or z. As an alkali carbonate or bicarbonate, etc., with a halide, preferably the acid chloride, or an anhydride a carboxylic acid of the formula

R₈-COOH (IV)

wherein R₈ has the meaning given above,
around.

Alternatively, for the preparation of compounds of formula I, in which R₄ represents the group -CO-R₈, also proceed so that one Compound of the formula

in which R₃ and R₈ have the same meaning as above in indifferent solvents having a boiling point in the range of about 55 ° to 120 ° C in the sodium compound (eg, by treatment with sodium hydride) and these or the compound of formula V in the presence of an acid-binding substance (in particular potassium or Sodium carbonate) with a compound of the formula

wherein R₁, R₂ and m have the same meaning as above and R₁₀ a Represents chlorine, bromine or iodine atom, at temperatures between room temperature and the boiling point of Implemented solvent. Suitable solvents for this reaction are z. For example, aliphatic ketones having up to 9 carbon atoms, in particular Acetone, and tetrahydrofuran, dioxane, dimethyl sulfoxide or dimethyl formamide.

The starting compounds of the formula II are known per se  accessible.

For example, a 3,4,5-trialkoxyphenol of formula

with a compound of the formula

in which R₂, R₁₀ and m have the same meaning as above and R₁₁ represents hydrogen or the acyl radical R₉,
reacting under the conditions described above for the reaction of the compound of formula V with the compound of formula VI and, optionally, then, if R₁₁ is a hydrogen atom, in the resulting compound of formula

in a manner known per se introduce the acyl radical R₉.

Compounds of formula IX in which R₂ different from hydrogen is, it can also be obtained so that an aldehyde of the formula

with a Grignard compound of the formula

R₁₀-Mg-R₂ (XI)

in the usual way using in particular ethereal solvents implements.

A compound of formula II can be further by reacting a Compound of the formula

in which R₂, R₃, R₁₀ and m have the same meaning as above
with the sodium or potassium salt of a carboxylic acid of the formula

HO-R₉ (XIII)

in the presence or optionally in the absence of polar solvents like As methanol, ethanol, tetrahydrofuran or preferably Dimethyl sulfoxide or dimethylformamide appropriate at temperatures of about 50 ° to 120 ° C obtained. In this case, the salt of the carboxylic acid of Formula XIII ready to be used preformed or only in the Lö solution of the carboxylic acid by adding z. As sodium or potassium carbonate, sodium alcoholate or hydride are formed.

The following examples serve to illustrate the invention proper process and the production of starting and Zwischenproduk In their implementation, the aim was to achieve maximum yields no value set.

All temperatures are uncorrected.  

The 1 H NMR spectra were recorded at 300 MHz with the company's AC 300 device Bruker measured.

The petroleum ether used in the examples has the boiling range 50-70 ° C.

Silica gel 60 was used as the stationary phase for the column chromatography (0.040-0.063 mm) from E. Merck, Darmstadt.

The thin-layer chromatographic investigations were carried out with "HPTLC Finished plates, Kieselgel 60 F 254 "from E. Merck, Darmstadt, Germany carried out. As far as the course of the reaction by thin-layer chromatography is controlled in the examples for this "DC control" each called the eluent.

The mixing ratios of the eluents for all chromatographic Examinations are always given in volume / volume.

Example 1 9- (3,5-dimethoxy-4-hydroxy-phenoxy) nonan-1-ol benzoate a) 1-Bromo-9- (3,4,5-trimethoxyphenoxy) -nonane

A mixture of 10.0 g of 3,4,5-trimethoxyphenyl, 9.76 g of potassium car carbonate and 27.5 ml of 1,9-dibromonon are dissolved in 100 ml of acetone (DC-Kon control: petroleum ether / ethyl acetate - 2: 1) to reflux hitzt. After the end of the reaction, the solvent is removed in vacuo evaporated and the residue with ice water cooling with dilute Hydrochloric acid neutralized. It is extracted three times with 100 ml of vinegar each time acid ethyl ester, the extracts washed twice with saturated Sodium chloride solution and dried over sodium sulfate. That after one evaporated crude product is purified by chromatography with Pe trol ether and then with petroleum ether / ethyl acetate (2: 1). cleaned. This gives 17.89 g (84.6% of theory) of the title Ver Bond in the form of a colorless oil.

1 H-NMR (CDCl₃): 1.33-1.48 (m, 10H, CH₂); 1.72-1.88 (m, 4H, CH₂); 3.39-3.43 (t, 2H, CH₂Br); 3.78 (s, 3H, OCH₃); 3.84 (s, 6H; OCH₃); 3.89-3.93 (t, 2H, OCH₂); 6.14 (s, 2H, aromat.).

b) 9- (3,4,5-trimethoxyphenoxy) nonan-1-ol benzoate

1.128 g of benzoic acid are dissolved in 20 ml of anhydrous dimethylsulfoxide dissolved and at room temperature with the stoichiometric amount of Na triumhydride (50% dispersion in oil) to the sodium salt. It is then added dropwise with a solution of 3.0 g of in Example 1a incurred product in 3 ml of anhydrous dimethyl sulfoxide and the reaction mixture heated to 80 ° C in an oil bath. (DC Control: petroleum ether / ethyl acetate - 2: 1). After success The reaction is extracted with 200 ml of n-hexane, the extract three washed once with saturated ammonium chloride solution, over sodium dried sulfate and evaporated in vacuo. The residue will be by chromatography with petroleum ether / ethyl acetate (2: 1) purified to give 2.595 g (78.2% of theory) of the title compound incurred in the form of a colorless oil.

1 H-NMR (CDCl₃): 1.36-1.45 (m, 10H, CH₂); 1.72-1.81 (m, 4H, CH₂); 3.78 (s, 3H, OCH₃); 3.78 (s, 6H, OCH₃); 3.89-3.93 (t, 2H, OCH₂); 4.29-4.33 (t, 2H, OCH₂); 6.14 (s, 2H, aromat.); 7.41-7.58 (m, 3H, aromat.); 8.03-8.06 (m, 2H, aromat.).

c) 9- (3,5-Dimethoxy-4-hydroxy-phenoxy) -nonan-1-ol-benzoate

A solution of 1.01 g of the product obtained in Example 1b 10 ml of dichloromethane is added while stirring and passing dry Nitrogen at -70 ° to -60 ° C dropwise with a solution of 0.48 ml of boron tribromide in 10 ml of dichloromethane. (TLC control: Petroleum ether / ethyl acetate - 2: 1). After finished Um 5 ml of saturated sodium chloride solution in a cold bath added dropwise, and after dilution with 50 ml of acetic acid  ethylester, the cold bath is removed. Once the extract has a tem temperature has reached 0 ° C, he is three times with saturated Na Triumchloridlösung, dried over sodium sulfate and in Vacuum evaporated. Column chromatography with petroleum ether / acetic acid ethyl ester (2: 1) provides 0.793 g (82.1% of theory) of Ti Telverbindung in the form of an almost colorless oil.

1 H-NMR (CDCl₃): 1.36-1.45 (m, 10H, CH₂); 1.71-1.79 (m, 4H, CH₂); 3.86 (s, 6H, OCH₃); 3.89 to 4.10 (t, 2H, OCH₂); 4.29-4.34 (t, 2H, OCH₂); 6.18 (s, 2H, aromat.); 7.41 to 7.58 (m, 3H, aromat.); 8.02-8.06 (m, 2H, aromat.).

example 2 6- (3,5-dimethoxy-4-hydroxy-phenoxy) hexane-1-ol acetate a) 1-Bromo-6- (3,4,5-trimethoxyphenoxy) -hexane

Analogously to Example 1a is obtained from 10.0 g of trimethoxyphenol and 16.5 ml of 1,6-dibromohexane in the presence of 9.01 g of anhydrous Ka lium carbonate and 80 ml of acetone after chromatography, first with Pe trol ether and then with petroleum ether / ethyl acetate (2: 1) 14.89 g (79.0%). the theory) of the title compound in the form of a colorless oil.

1 H-NMR (CDCl₃): 1.45-1.57 (m, 4H, CH₂); 1.74 to 1.95 (m, 4H, CH₂); 3.41-3.45 (m, 2H, CH₂Br); 3.78 (s, 3H, OCH₃); 3.84 (s, 6H, OCH₃); 3.90-3.94 (t, 2H, OCH₂); 6.14 (s, 2H, aromat.).

b) 6- (3,4,5-Trimethoxy-phenoxy) -hexan-1-ol-acetate

The procedure is as in Example 1b, but using a Lö of 2.972 g of the product obtained in Example 2a in 25 ml anhydrous dimethyl sulfoxide and 1.05 g of anhydrous sodium acetate did. This gives 2.498 g (89.4% of theory) of the title compound in the form of a viscous oil that slowly crystallizes.

1 H-NMR (CDCl₃): 1.37-1.62 (m, 4H, CH₂); 1.64 to 1.83 (m, 4H, CH₂); 2.05 (s, 3H, COCH₃); 3.78 (s, 3H; OCH₃); 3.84 (s, 6H, OCH₃); 3.90-3.94 (t, 2H, OCH₂); 4.05 to 4.16 (t, 2H, OCH₂); 6.14 (s, 2H, aromat.).

c) 6- (3,5-Dimethoxy-4-hydroxy-phenoxy) -hexan-1-ol-acetate

In the manner described in Example 1c treated 1.148 g of the in Example 2b product obtained in 10 ml of dichloromethane with a Dissolve 0.67 ml boron tribromide in 10 ml dichloromethane. After chroma Tographie of the crude product with ether / petroleum ether (2: 1) is obtained 0.632 g (57.7% of theory) of the title compound as white Crystals that melt at 43-44 ° C.

1 H-NMR (CDCl₃): 1.39-1.55 (m, 4H, CH₂); 1.62 to 1.83 (m, 4H, CH₂); 2.05 (s, 3H, COCH₃); 3.86 (s, 6H, OCH₃); 3.88 to 3.92 (t, 2H, OCH₂); 4.05-4.10 (t, 2H, OCH₂); 6.18 (s, 2H, aromat.).

example 3 6- (3,5-dimethoxy-4-hydroxy-phenoxy) hexane-1-ol benzoate a) 6- (3,4,5-trimethoxyphenoxy) -hexan-1-ol benzoate

A mixture of 21.63 g of 3,4,5-trimethoxyphenol, 19.49 g of potassium car carbonate, 36.85 g of benzoic acid (6-bromohexyl) ester [A. Franke et al. Monatsh. 66, 406-432 (1935)] and 200 ml of acetone becomes reflux heated and after completion of the reaction (TLC control: ether / Pe trolether - 1: 1) worked up analogously to Example 1a. By chroma Tography with ether / petroleum ether (1: 1) gives 45.60 g (89.3%). the theory) of the title compound in the form of a colorless viscous Oil.

1 H-NMR (CDCl₃): 1.53-1.64 (m, 4H, CH₂); 1.79 to 1.83 (m, 4H, CH₂); 3.78 (s, 3H, OCH₃); 3.83 (s, 6H, OCH₃); 3.84-3.95 (t, 2H, OCH₂); 4.32-4.36 (t, 2H, OCH₂); 6.14 (s, 2H, aromat.); 7.40-7.45 (m, 2H, aromat.); 7.52-7.58 (m, 1H, aromat.); 8.02-8.05 (m, 2H, aromat.).

b) 6- (3,5-Dimethoxy-4-hydroxy-phenoxy) -hexan-1-ol-benzoate

A solution of 3.14 g of the product obtained in Example 3a is treated with 1.51 ml Bortri in the manner described in Example 1c bromide in 20 ml of dichloromethane and then analogously to Example 1c worked up. After chromatography with ether / petroleum ether (2: 1) to obtain 1.82 g (60.2% of theory) of the title compound in the form a colorless oil.

1 H-NMR (CDCl₃): 1.53-1.57 (m, 4H, CH₂); 1.78-1.84 (m, 4H, CH₂); 3.85 (s, 6H, OCH₃); 3.89 to 3.93 (t, 2H, OCH₂); 4.32-4.36 (t, 2H, OCH₂); 6.18 (s, 2H, aromat.); 7.40-7.46 (m, 2H, aromat.); 7.52-7.58 (m, 1H, aromat.); 8.02-8.05 (m, 2H, aromat.).

example 4 11- (3,5-dimethoxy-4-hydroxy-phenoxy) undecane-1-ol acetate a) 11- (3,4,5-trimethoxyphenoxy) undecan-1-ol

A mixture of 3.0 g of 3,4,5-trimethoxyphenol, 2.39 g of potassium carbonate and 4.50 g of 11-bromo-undecan-1-ol in 25 ml of acetone is added to the Been tion of the reaction (TLC control: ether / petroleum ether - 2: 1) for Reflux heated. It is cooled to room temperature, the evaporated Acetone, the residue is taken up in ethyl acetate and washed the organic phase with saturated sodium chloride solution. After this Dry over sodium sulfate is evaporated in vacuo and the crude product by chromatography with toluene / ether (4: 3). This gives 4.212 g (72.9% of theory) of the title compound in the form  white crystals melting at 60 ° C.

1 H-NMR (CDCl₃): 1.26-1.59 (m, 16H, CH₂); 1.72-1.81 (m, 2H, CH₂); 3.62-3.66 (t, 2H, OCH₂); 3.78 (s, 3H, OCH₃); 3.84 (s, 6H, OCH₃); 3.89-3.91 (t, 2H, OCH₂), 6.15 (s, 2H, aromat.).

b) 11- (3,4,5-trimethoxyphenoxy) undecane-1-ol acetate

A solution of 1.0 g of the product obtained in Example 4a 10 ml of anhydrous tetrahydrofuran and 2.26 ml of pyridine is added Ice water cooling dropwise with 2.38 ml of acetic anhydride ver puts. The mixture is allowed to warm to room temperature and evaporated 20 hours in a vacuum. The residue is chromatographed with Petroleum ether / ethyl acetate (3: 1). You get 1.021 g (91.3% of theory) of the title compound in the form of a colorless oil.

1 H-NMR (CDCl₃): 1.26-1.64 (m, 16H, CH₂); 1.72-1.83 (m, 2H, CH₂); 2.04 (s, 3H, COCH₃); 3.78 (s, 3H, OCH₃); 3.84 (s, 6H, OCH₃); 3.89-3.93 (t, 2H, OCH₂); 4.03 to 4.07 (t, 2H, OCH₂); 6.14 (s, 2H, aromat.).

c) 11- (3,5-dimethoxy-4-hydroxy-phenoxy) undecane-1-ol acetate

The procedure is analogous to Example 1c and obtained from 1.10 g of the in in 4b of product and 0.59 ml boron tribromide according to Chroma Tography with petroleum ether / ethyl acetate (3: 1) 0.732 g (80.4% of theory) of the title compound as white crystals, which melt at 54-56 ° C.

1 H-NMR (CDCl₃): 1.23-1.64 (m, 16H, CH₂); 1.71 to 1.80 (m, 2H, CH₂); 2.04 (s, 3H, COCH₃); 3.86 (s, 6H, OCH₃); 3.86 to 3.91 (t, 2H, OCH₂); 4.02-4.07 (t, 2H, OCH₂); 6.18 (s, 2H, aromat.).  

example 5

The procedure is analogous to Examples 1-4 and obtained from the corresponding Starting materials:

a) 9- (3,5-dimethoxy-4-hydroxy-phenoxy) -nonan-1-ol-acetate

Melting point: 45 ° C

1 H-NMR (CDCl₃): 1.33-1.83 (m, 14H, CH₂); 2.04 (s, 3H, COCH₃); 3.86 (s, 6H, OCH₃); 3.86-3.91 (t, 2H, OCH₂); 4.03 to 4.07 (t, 2H, OCH₂); 6.18 (s, 2H, aromat.).

b) 6- (3,5-Dimethoxy-4-hydroxy-phenoxy) -hexan-1-ol-n-valerate

Colorless oil

1 H-NMR (CDCl₃): 0.89-0.93 (t, 3H, CH₃); 1.25 to 1.82 (m, 12H, CH₂); 2.27 to 2.32 (t, 2H, COCH₂); 3.87 (s, 6H, OCH₃); 3.88-3.92 (t, 2H, OCH₂); 4.05 to 4.10 (t, 2H, OCH₂); (s, 2H, aromat.).

c) 12- (3,5-Dimethoxy-4-hydroxy-phenoxy) -dodecan-1-ol-acetate

Melting point: 56-57 ° C

1 H-NMR (CDCl₃): 1.22-1.53 (m, 16H, CH₂); 1.58-1.70 (m, 2H, CH₂); 1.73-1.84 (m, 2H, CH₂); 2.05 (s, 3H, COCH₃); 3.87 (s, 6H, OCH₃); 3.85-3.92 (t, 2H, OCH₂); 4.03 to 4.08 (t, 2H, OCH₂); 6.19 (s, 2H, aromat.).

d) 6- (3,5-Dimethoxy-4-hydroxy-phenoxy) -hexane-1-ol-trimethylacetate

Colorless oil

1 H-NMR (CDCl₃): 1.19 (s, 9H, C (CH₃) ₃), 1.40-1.84 (m, 8H, CH₂); 3.86 (s, 6H, OCH₃): 3.88-3.92 (t, 2H, OCH₂); 4.05 to 4.09 (t, 2H, OCH₂); 6.18 (s, 2H, aromat.).

e) 7- (3,5-Dimethoxy-4-hydroxy-phenoxy) -heptan-1-ol-acetate

Colorless viscous oil

1 H-NMR (CDCl₃): 1.39-1.83 (m, 10H, CH₂); 2.05 (s, 3H, COCH₃); 3.86 (s, 6H, OCH₃); 3.89-4.04 (t, 2H, OCH₂); 4.06 to 4.10 (t, 2H, OCH₂); 6.18 (s, 2H, aromat.).

f) 8- (3,5-Dimethoxy-4-hydroxy-phenoxy) -octan-1-ol-acetate

Melting point: 43-45 ° C

1 H-NMR (CDCl₃): 1.36-1.71 (m, 10H, CH₂); 1.73 to 1.83 (m, 2H, CH₂); 2.05 (s, 3H, COCH₃); 3.86 (s, 6H, OCH₃); 3.86 to 3.91 (t, 2H, OCH₂); 4.03-4.08 (t, 2H, OCH₂); 6.18 (s, 2H, aromat.).

g) 6- (3,5-Dimethoxy-4-hydroxy-phenoxy) -hexan-1-ol (4-chlorobenzoate)

Melting point: 87-88 ° C

1 H-NMR (CDCl₃): 1.51-1.59 (m, 4H, CH₂); 1.75-1.85 (m, 4H, CH₂); 3.86 (s, 6H, OCH₃); 3.89-3.93 (t, 2H, OCH₂); 4.31 to 4.35 (t, 2H, OCH₂); 6.17 (s, 2H, aromat.); 7.38-7.43 (m, 2H, aromat.); 7.95-7.99 (m, 2H, aromat.).

h) 9- (3,5-Dimethoxy-4-hydroxy-phenoxy) -nonan-1-ol (4-chlorobenzoate)

Melting point: 46-47 ° C

1 H-NMR (CDCl₃): 1.36-1.43 (m, 10H, CH₂); 1.71 to 1.80 (m, 4H, CH₂); 3.86 (s, 6H, OCH₃); 3.89-4.10 (t, 2H, OCH₂); 4.28 to 4.33 (t, 2H, OCH₂); 6.18 (s, 2H, aromat.); 7.39-7.43 (m, 2H, aromat.); 7.95-7.99 (m, 2H, aromat.).

i) 4- (3,5-dimethoxy-4-hydroxy-phenoxy) -butan-1-ol-benzoate)

Colorless oil

1 H NMR (CDCl₃): 1.90-1.97 (m, 4H, CH₂); 3.85 (s, 6H, OCH₃); 3.96-4.00 (t, 2H, OCH₂); 4.39 to 4.43 (t, 2H, OCH₂); 6.18 (s, 2H, aromat.); 7.43-7.45 (m, 2H, aromat.); 7.53-7.59 (m, 1H, aromat.); 8.02-8.06 (m, 2H, aromat.).

example 6 6- (4-acetoxy-3,5-dimethoxy-phenoxy) hexane-1-ol acetate

A solution of 0.42 g of the product obtained in Example 2 in 6 ml Anhydrous tetrahydrofuran and 1.07 ml of pyridine is added under ice-water Cooling added dropwise with 1.13 ml of acetic anhydride. (DC-Kon trolls: ether / petroleum ether - 2: 1). After the reaction is in vacuo evaporated and the oily residue by chromatography with ether / Petroleum ether (2: 1). This gives 0.423 g (88.9% of theory) the title compound in the form of white crystals at 68-70 ° C melt.

1 H-NMR (CDCl₃): 1.39-1.83 (m, 8H, CH₂); 2.05 (s, 3H, COCH₃); 2.31 (s, 3H, COCH₃); 3.79 (s, 6H, OCH₃); 3.91-3.95 (t, 2H, OCH₂); 4.05 to 4.10 (t, 2H, OCH₂); 6.16 (s, 2H, aromat.).

example 7

Using the reaction conditions described in Example 6  is obtained analogously from the products of Examples 1, 5a, 5e, 5f or 5h:

a) 9- (4-acetoxy-3,5-dimethoxyphenoxy) nonan-1-ol benzoate

Colorless oil that slowly crystallizes

1 H-NMR (CDCl₃): 1.36-1.45 (m, 10H, CH₂); 1.75 to 1.82 (m, 4H, CH₂); 2.32 (s, 3H, COCH₃); 3.79 (s, 6H, OCH₃); 3.90-3.94 (t, 2H, OCH₂); 4.29-4.34 t, 2H, OCH₂); 6.16 (s, 2H, aromat.); 7.42-7.44 (m, 2H, aromat.); 7.46-7.58 (m, 1H, aromat.); 8.03-8.06 (m, 2H, aromat.).

b) 9- (4-Acetoxy-3,5-dimethoxyphenoxy) nonan-1-ol acetate

Colorless oil

1 H-NMR (CDCl₃): 1.33-1.83 (m, 14H, CH₂); 2.05 (s, 3H, COCH₃); 2.32 (s, 3H, COCH₃); 3.79 (s, 6H, OCH₃); 3.90-3.92 (t, 2H, OCH₂); 4.03 to 4.07 (t, 2H, OCH₂); 6.16 (s, 2H, aromat.).

c) 7- (4-Acetoxy-3,5-dimethoxy-phenoxy) -heptan-1-ol-acetate

Colorless oil

1 H-NMR (CDCl₃): 1.39-1.66 (m, 8H, CH₂); 1.73-1.82 (m, 2H, CH₂); 2.05 (s, 3H, COCH₃); 2.32 (s, 3H, COCH₃); 3.79 (s, 6H, OCH₃); 3.90-3.94 (t, 2H, OCH₂); 4.04 to 4.08 (t, 2H, OCH₂); 6.14 (s, 2H, aromat.).

d) 8- (4-acetoxy-3,5-dimethoxy-phenoxy) -octan-1-ol-acetate

Colorless oil

1 H-NMR (CDCl₃): 1.36-1.65 (m, 10H, CH₂); 1.72-1.83 (m, 2H, CH₂); 2.05 (s, 3H, COCH₃); 2.31 (s, 3H, COCH₃); 3.79 (s, 6H, OCH₃); 3.90-3.94 (t, 2H, OCH₂); 4.03 to 4.08 (t, 2H, OCH₂); 6.16 (s, 2H, aromat.).

e) 9- (4-acetoxy-3,5-dimethoxy) -nonan-1-ol (4-chlorobenzoate)

Viscous oil

1 H-NMR (CDCl₃): 1.36-1.59 (m, 10H, CH₂); 1.72-1.81 (m, 4H, CH₂); 2.31 (s, 3H, COCH₃); 3.79 (s, 6H, OCH₃); 3.90-3.94 (t, 2H, OCH₂); 4.28-4.33 (t, 2H, OCH₂); 6.16 (s, 2H, aromat.); 7.39-7.43 (m, 2H, aromat.); 7.95-7.99 (m, 2H, aromat.).

example 8 a) 9- (3,5-Dimethoxy-4-hydroxy-phenoxy) -nonan-1-ol

0.20 g of the product obtained in Example 1 are dissolved in 3 ml of metha dissolved nol and 3 ml of tetrahydrofuran and dropwise with 1.42 ml 1 N sodium hydroxide added. (TLC control: ethyl acetate / Pe trolether - 1: 1). After the reaction is evaporated in vacuo, the residue with ice water cooling with dilute hydrochloric acid acidified and extracted three times with ethyl acetate. The ver The extracts are washed with water and washed over sodium sulphate dried fat. The crude product yields after column chromatography with ethyl acetate / petroleum ether (1: 1) 0.132 g (88.8% of Theory) of the title compound as white crystals of enamel point 58-59 ° C.

1 H-NMR (CDCl₃): 1.34-1.59 (m, 12H, CH₂); 1.71 to 1.80 (m, 2H, CH₂); 3.62-3.66 (t, 2H, CH₂OH); 3.86 (s, 6H, OCH₃); 3.89 to 3.93 (t, 2H, OCH₂); 6.18 (s, 2H, aromat.).  

b)

The product prepared in Example 8a can be prepared analogously by reaction of 1.0 g of the product of Example 5a in 10 ml of methanol and 10 ml Tetrahydrofuran with 8.46 ml of 1 N sodium hydroxide in a yield of 90.2% are obtained. The physical data of the thus obtained Products are with those of Example 8a Verbin produced identical.

example 9 6- (3,5-dimethoxy-4-hydroxy-phenoxy) hexane-1-ol

The procedure is analogous to Example 8a and obtained from 0.40 g of that in Example 3 0.899 g (88.7% of theory) of the title compound in the form of a viscous oil.

1 H-NMR (CDCl₃): 1.43-1.66 (m, 6H, CH₂); 1.73 to 1.90 (m, 2H, CH₂); 3.64-3.69 (t, 2H, CH₂OH); 3.86 (s, 6H, OCH₃); 3.88 to 3.92 (t, 2H, OCH₂); 6.18 (s, 2H, aromat.).

example 10 7- (3,5-dimethoxy-4-hydroxy-phenoxy) -1-phenyl-heptan-2-ol acetate a) 6- (3,4,5-Trimethoxyphenoxy) hexan-1-ol

The reaction is carried out using 4.35 g of 3,4,5-trimethoxyphenol, 5.71 g of 6-iodo-hexan-1-ol, 3.06 g of potassium carbonate and 60 ml of acetone analogously to Example 1a and thus obtains 5.79 g (88.5% of theory) of Title compound in the form of a colorless oil.

1 H-NMR (CDCl₃): 1.38-1.85 (m, 8H, CH₂); 3.64-3.68 (t, 2H, CH₂OH); 3.79 (s, 3H, OCH₃); 3.84 (s, 6H, OCH₃); 3.90-3.95 (t, 2H, OCH₂); 6.15 (s, 2H, aromat.);  

b) 6- (3,4,5-trimethoxyphenoxy) hexanal

A solution of 5.70 g of the product of Example 10a in 200 ml of Di Chloromethane is at 20 ° C with stirring and passing dry Nitrogen first with 3.30 g of anhydrous sodium acetate, then added in portions with 6.60 g of pyridinium chlorochromate. To completed reaction (TLC control: petroleum ether / ether - 1: 2) the reaction mixture was evaporated to a volume of 20 ml and the Residue by column chromatography with petroleum ether / ether (1: 2) cleaned. This gives 3.46 g (61.3% of theory) of the title Ver Bond in the form of a colorless oil.

1 H-NMR (CDCl₃): 1.44-1.60 (m, 2H, CH₂); 1.67 to 1.87 (m, 4H, CH₂); 2.47-2.52 (m, 2H, CH₂C (O)); 3.79 (s, 3H, OCH₃); 3.84 (s, 6H, OCH₃); 3.91-3.95 (t, 2H, OCH₂); 6.14 (s, 2H, aromat.); 9.78 to 9.81 (m, 1H, CHO).

c) 1-phenyl-7- (3,4,5-trimethoxy-phenoxy) -heptan-2-ol

To a freshly prepared Grignard solution of 0.34 g of magnesium shavings and 1.65 ml of benzyl bromide in 30 ml of absolute ether is added 0-5 ° C, a solution of 3.38 g of the product of Example 10b in 25 ml of absolute ether added dropwise. The mixture is stirred for 1 hour at 5-10 ° C. then added dropwise 25 ml of ammonium chloride solution and extracted three times with 30 ml of ethyl acetate. The verei Saturated organic phases are washed twice with saturated sodium chloride solution and then dried over sodium sulfate. After chromatography with petroleum ether / ether (1: 2) 2.19 g (48.7% of theory) of the title compound in the form of a color loose viscous material.

1 H-NMR (CDCl₃): 1.42-1.84 (m, 8H, CH₂); 2.62 to 2.87 (m, 2H, CH₂-Ar); 3.77-3.85 (m, 1H, OCH); 3.79 (s, 3H, OCH₃); 3.84 (s, 6H, OCH₃); 3.90-3.94 (t, 2H, OCH₂); 6.14 (s, 2H, aromat.); 7.20-7.35 (m, 5H, aromat.).  

d) 1-phenyl-7- (3,4,5-trimethoxy-phenoxy) -heptan-2-ol-acetate

A solution of 2.15 g of the product of Example 10c and 0.8 ml Pyridine in 30 ml of absolute tetrahydrofuran is at 20 ° C with 0.63 ml of acetyl chloride and the reaction mixture for 6 hours touched. It is diluted with 50 ml of water and ether, separating the organic phase and extracts the aqueous layer with 30 ml Ether. The combined organic phases are washed twice with ge saturated solutions of sodium bicarbonate or sodium chloride washed and then dried over sodium sulfate. After evaporation to give 2.31 g (96.6% of theory) of the title compound in the form a colorless oil.

1 H-NMR (CDCl₃): 1.30-1.80 (m, 8H, CH₂); 1.99 (s, 3H, COCH₃); 2.77-2.92 (m, 2H, CH₂-Ar); 3.79 (s, 3H, OCH₃); 3.84 (s, 6H, OCH₃); 3.87-3.91 (t, 2H, OCH₂); 5.04 to 5.12 (m, 1H, OCH); 6.13 (s, 2H, aromat.); 7.18-7.32 (m, 5H, aromat.).

e) 7- (3,5-Dimethoxy-4-hydroxy-phenoxy) -1-phenyl-heptan-2-ol-acetate

2.29 g of the product from Example 10d are analogous to Example 1c with 1 ml boron tribromide reacted. After chromatographic purification of Crude product with petroleum ether / ether (2: 3) gives 1.38 g (62.5% of theory) of the title compound in the form of a colorless Oil.

1 H-NMR (CDCl₃): 1.33-1.78 (m, 8H, CH₂); 1.99 s, 3H, COCH₃); 2.77-2.91 (m, 2H, CH₂-Ar); 3.85-3.89 (t, 2H, OCH₂); 3.86 (s, 6H, OCH₃); 5.04-5.13 (m, 1H, OCH); 6.17 (s, 2H, aromat.); 7.17-7.31 (m, 5H, aromat.).

example 11

Using the procedure described in Example 10 will be  obtained the corresponding starting materials:

a) 11- (3,5-dimethoxy-4-hydroxy-phenoxy) undecane-6-ol acetate

Colorless viscous oil

1 H-NMR (CDCl₃): 0.86-0.90 (t, 3H, CH₃); 1.21 to 1.60 (m, 14H, CH₂); 1.70-1.82 (m, 2H, CH₂); 2.04 (s, 3H, COCH₃); 3.86 to 3.91 (t, 2H, OCH₂); 3.86 (s, 6H, OCH₃); 4.84-4.93 (m, 1H, OCH); 6.18 (s, 2H, aromat.).

b) 1-Cyclohexyl-6- (3,5-dimethoxy-4-hydroxy-phenoxy) -hexan-1-ol-acetate

Colorless viscous oil

1 H-NMR (CDCl₃): 0.92-1.90 (m, 19H, CH, CH₂); 2.05 (s, 3H, COCH₃); 3.86-3.91 (t, 2H, OCH₂); 3.87 (s, 6H, OCH₃); 4.72-4.78 (m, 1H, OCH); 6.18 (s, 2H, aromat.).

c) 6- (3,5-Dimethoxy-4-hydroxy-phenoxy) -1-phenyl-hexan-1-ol-acetate

Reddish viscous oil

1 H-NMR (CDCl₃): 1.23-1.58 (m, 4H, CH₂); 1.70 to 2.02 (m, 4H, CH₂); 2.07 (s, 3H, COCH₃); 3.85-3.89 (t, 2H, OCH₂); 3.86 (s, 6H, OCH₃); 5.72-5.77 (m, 1H, CH); 6.17 (s, 2H, aromat.); 7.25-7.37 (m, 5H, aromat.).

d) 1- (4-chlorophenyl) -6- (3,5-dimethoxy-4-hydroxy-phenoxy) -hexan-1-ol acetate

Colorless viscous oil

1 H-NMR (CDCl₃): 1.22-2.00 (m, 8H, CH₂); 2.06 (s, 3H, COCH₃); 3.85-3.89 (t, 2H, OCH₂); 3.86 (s, 6H, OCH₃); 5.67-5.72 (t, 1H, CH); 6.17 (s, 2H, aromat.); 7.24-7.32 (m, 4H, aromat.).

e) 1-Cyclohexyl-9- (3,5-dimethoxy-4-hydroxy-phenoxy) -nonan-1-ol-acetate

Colorless viscous oil

1 H-NMR (CDCl₃): 0.92-1.82 (m, 27H, CH, CH₂); 2.05 (s, 3H, COCH₃); 3.86 to 3.91 (t, 2H, OCH₂); 3.87 (s, 6H, OCH₃); 4.70-4.76 (m, 1H, OCH); 6.19 (s, 2H, aromat.).

Claims (14)

1. Substituted phenoxyalkanols and their esters of the general formula wherein
R₁ represents a hydrogen atom or a group of the formula -CO-R₅ be, in which R₅ represents an optionally substituted by an oxygen or sulfur atom interrupted alkyl radical having 1 to 4 carbon atoms or the group of the formula where n is one of the numbers 1, 2 or 3, R₆ is a hydrogen, fluorine or chlorine atom or is a methoxy, trifluoromethyl or an alkyl radical having 1 to 3 carbon atoms and p is the number 0 or 1 .
R₂ is a hydrogen atom, an alkyl radical having 1 to 5 carbon atoms, a cycloalkyl radical having 5 to 7 carbon atoms, the benzyl radical or the group of the formula in which R₇ is a hydrogen, fluorine or chlorine atom or a methoxy, trifluoromethyl or an alkyl radical having 1 to 3 carbon atoms,
m is an integer from 2 to 11,
R₃ represents an alkyl radical having 1 to 3 carbon atoms and
R₄ represents a hydrogen atom or a radical of the formula -COR₈ tet, in which R₈ represents an alkyl radical having 1 to 4 carbon atoms, preferably the methyl radical. 2. Substituted phenoxyalkanols and their esters according to claim 1, in where R₂ is n-pentyl, cyclohexyl, benzyl, phenyl, 4-chlorophenyl and in particular represents a hydrogen atom. 3. Substituted phenoxyalkanols and their esters according to claims 1 and 2, in which R₃ is the methyl radical. 4. Substituted phenoxyalkanols and their esters according to claims 1 to 3, in which R₄ is a hydrogen atom or the acetyl radical stands. 5. Substituted Phenoxyalkanolester according to claims 1 to 4, in R₅ is an alkyl radical having 1 to 4 carbon atoms or represents a phenyl or 4-chlorophenyl radical. 6. Medicament, characterized in that it has little active ingredient at least one compound of formula I according to claims 1 to 5 ent and parenteral, local, percutaneous or rectal appli cation or is suitable for inhalation. 7. Medicament according to claim 6, characterized in that as an active ingredient per single dose 0.01 to 50 mg of a compound of the formula I according to claims 1 to 5. 8. Medicaments according to claims 6 and 7, characterized gekennzeich net, that it is suitable for parenteral administration and 0.01 to 10 mg of a compound of the formula I according to claims 1 to 5 contains.   9. Medicament according to claim 6 for the administration of a Ver Binding of formula I according to claims 1 to 5 in spray form or through inhalation. 10. Medicament according to claim 6 for percutaneous administration, consisting of a applied to the skin, a compound of the formula I according to claims 1 to 5 in dissolved form, preferably wise with the addition of skin penetration promoting agents, containing reservoir. 11. A process for the preparation of the medicaments according to claims 6 to 10, characterized in that the compound of the For mel I according to claims 1 to 5 in the usual way with Trägermate materials, solvents or diluents and other auxiliaries processed from the resulting mixture and the individual dosage forms manufactures. 12. A process for preparing the substituted phenoxyalkanols and their esters of the formula I from claim 1, characterized in that

• a) a compound of the formula in which R₂, R₃ and m have the same meaning as above and R₉ is an acyl radical, preferably the group -CO-R₅,
  at temperatures below 0 ° C, preferably at temperatures from -10 ° C to -70 ° C, treated in an inert solvent with 1 to 3 equivalents of boron tribromide or boron trichloride and from the resulting compound of formula in which R₂, R₃, R9 and m have the same meaning as above,
  if R₁ is to represent a hydrogen atom or if R₉ is other than -COR₅, the R₉ radical is split off by the action of basic agents and, if R₄ is to be -COR₈, the compound of the formula III in which R₉ is the group -COR₅, in the presence of an acid-binding agent in an inert solvent with a halide or anhydride of a carboxylic acid of the formula R₈-COOH (IV) in which R₈ has the abovementioned meaning,
  implements, or
• b) that for the preparation of compounds of formula I in which R₄ represents the group -CO-R₈, a compound of formula in which R₃ and R₈ have the same meaning as above
  in indifferent solvents having a boiling point in the range of from about 55 ° to 120 ° C leads in the sodium compound and this or the compound of formula V in the presence of an acid-binding substance with a compound of formula wherein R₁, R₂ and m have the same meaning as above and R₁₀ represents a chlorine, bromine or iodine atom,
  at temperatures between room temperature and the boiling temperature of the solvent.

13. Method of treating patients suffering from pathological States in which leukotrienes are involved as mediators den, characterized in that the patient as a 5-Lip oxygenase inhibitor effective dose of a substance of the formula I. administered. 14. Method for the therapy and prophylaxis of clinical pictures, in whose course reactive oxygen compounds occur at Human and animal, characterized in that one to the patient one due to their antioxidant properties to catch the reactive oxygen compounds sufficient dose of a substance of formula I administered.