DE2605111A1 - M-ACYLOXY-ALPHA- SQUARE CLIP ON (METHYLAMINO) -METHYL SQUARE CLIP ON -BENZYL ALCOHOLS AND THEIR SALES, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS - Google Patents

Description

Dr. Hans-Heinrich Willrath

Dr. Dieter Weber Dipl.-Phys. Klaus Seiffert

PATENT LAWYERS

D-GLMVIES'iAHEN 1 9. Fob. 1976

Plague compartment G145

Ciistav-Freytaß-Stralie 25 Il / Wh

ϊί (06121) 37 £ 7 20

TeU-uramnudrcsse: WILLPATENT Telex: 4-1B6247

Rx 26 / 26a / 234

INTIiRx Research Corporation, 2201 West 21st Street, Lawrence, Kansas 66044, USA

m-Acyloxy-4- / 7-methylamino) -methyV-benzyl alcohols and their salts, processes for their preparation and medicaments containing them

Priority: Serial Nos. 548 606 and 578 079 of February 10, 1975 and May 16, 1975 in USA

The present invention relates to certain esters of m-hydroxy-c ^ - / Trnethylamino) -methyi7-benzyl alcohols, their pharmaceutically acceptable acid addition salts and certain intermediates, which are useful in their manufacture. The present invention also relates to a new synthesis for preparation the optically active form (hereinafter "R") or the racemate form of the compounds identified above.

609834/1006

i » ^{; | l;} _ 9 -

When administered, these compounds split enzymatically and give optically active m-IIydroxy-c ^ - / 7niethylamino) methyl / benzyl alcohol (Phonylephrine), the therapeutically active residue of these compounds.

U.S. Patent No. 3,825,583 describes an ester of m-hydroxy-M- / Tmethylamir. ~>) -methy! / - benzyl alcohol, namely m- (3) -Pivaloxy-i ^ - // (methylamino) -methyl / ~ benzyl alcohol.

A consideration of the way in which this connection was made clearly shows that one is a racemic mixture (a mixture that contains the biologically active and the biologically contains inactive isomer). Since the "R" isomer, i.e. the optically active isomer, is the only isomer, the therapeutic one Has activity, (R) -m-pivaloxy - ^ \ - / 7methylamino) -methylZ-benzyl alcohol usually administered in the form of a racemic mixture as no agent has yet been found has to separate the optically active form from the racemic mixture.

There is therefore a need to determine the optically active form to synthesize m-acyloxy-ci -, / (methylamino) -methylV-benzyla alcohols, among which there are m-pivaloxy-0 (/ ~ önethylamino) methyl / benzyl alcohol is located, thus avoiding the need to obtain a racemic mixture of this compound and to use.

In addition to the above, it can be seen that, since only the active isomer of the compounds described herein is therapeutic is active, the dosage amount of a racemic mixture containing this active isomer required for therapy

60983 ^ / 1006

is much larger than the amount that would be required if the
optically active form would be administered as such. Thus, there is an 'additional need for an agent which can synthesize the optically active isomer per se in order to minimize the required therapeutic dose and
avoid toxic reactions that may occur.

It is therefore the main aim of the present invention to synthesize the optically active form of certain m-acyloxy-d - / (methylamino) -methyl7-benzyl alcohols in the manner described here, which when administered to warm-blooded animals (such as humans) break down enzymatically and optically active phenylephrine, namely, the therapeutically ^aki: ven residual release of these compounds.

It is another object of the present invention that is above
to synthesize and to synthesize optically active forms described
obtained to get therapy with a smaller dose of the optically active form versus the required dose of the racemic roman.

These and other goals are achieved with esters of the following
Forx 2I:

H ■, OH
11 ^
(D

wherein R is a straight-chain or branched-chain alkyl group with 1 to 20 carbon atoms (C ₁ -C ₅ is preferred), an ethoxycarbony group, a benzyloxycarbonyl group, a phenyl radical,

609834/1006

OR ₃

the group "·, wherein R is as defined above and R ₀ is

K - L - U - Cti - j

A hydrogen atom, a methyl group or a phenyl radical, or a 2-, 3- or 4-pyridyl group, or with the HX salts of these esters, where X is a pharmaceutically acceptable acid addition salt anion and is derived from the corresponding acid, such as a chloride, bromide, sulfate, sulfonate, phosphate, nitrate, acetate, propionate, succinate, glycolate, stearate, lactate, tartrate, citrate, ascorbate, pamoate, maleate -, hydroxymaleate, phenyl acetate, glutamate, benzoate, salicylate, sulfonylate, fumarate or toluenesulfonate anion.

According to the invention, these esters are prepared as follows:

Optically active phenylephrine is reacted with an excess of a carbonyl compound of the general formula R-CO-R ₉ , in which R ₁ and R _{9 can be} identical or different and a hydrogen atom, a C -C. -Alkyl group or a di- (C ₁ -C ₉ ) -alkylamino- (C ₁ -C ₁₀ ) -alkyl group or, taken together with the carbonyl group to which they are attached, a _{C 1 -C 7} cycloalkanone group (pentanone, hexanone or heptanone group) or a substituted or unsubstituted N- or 0-heterocyclic (C ₅ -C) -alkanone group (such as the piperidone, pyrrolidone, - - N-methylpiperidone =. or JN-methylpyrrolidone group) - form, ~ in which the Substituent means a C.-C ₉ -alkyl group, and carries out this reaction in the presence of a dehydrating one. By means of an alkaline earth carbide (e.g. calcium carbide, magnesium carbide or the like), a molecular sieve with 4 to 5 Å, calcium chloride, magnesium sulfate or sodium sulfate, or in the presence of a conventional inert aromatic carbon

609834/1006

hydrogen solvents (such as benzene, toluene, xylene, etc.) plus an organic or inorganic acid catalyst (such as p-toluenesulfonic acid, sulfosalicylic acid, benzenesulfonic acid, Sulfuric acid or hydrochloric acid) and eliminated so the water formed as an azeotropic mixture, these measures at a temperature of 20 to 140 C (preferably but at the boiling point of the solvent or solvent mixture used) at standard pressure and for a period of 48 hours and the intermediate product

(id

forms, wherein R ₁ and R_ are as defined above.

2. The intermediate product of step 1. is set with an M-hydroxide, M-hydride or an M-alkoxide, where M is an alkali metal, an alkaline earth metal or potassium (such as NaOH, KOH, Ca (OH) ₂ , Mg (OH) ₂ , Ba (OH) ₂ , NaH, CaH ₃ , NaOCH ₃ , NaOC ₃ H ₅ , NaOC H ₇ , TlOC ₂ H ₅ , etc.) means in the presence of an inert organic solvent from the group of aliphatic hydrocarbon solvents with 5 to 10 Carbon atoms (such as pentane, hexane, heptane, octane or decane), the aromatic hydrocarbon solvents (such as benzene, toluene or xylene), the aliphatic C ₁ -C ₄ alkoxides (such as methanol, ethanol, propanol or butanol),. conventional ethers (such as diethyl ether, tetrahydrofuran or dioxane) or dimethylformamide, at room temperature, standard pressure and for 1 to 24 hours, with the intermediate product

609834/1006

(III)

forms, wherein M, R. and R _{9 are} as defined above.

3. One sets the intermediate product of stage 2. with a stoichiometric Amount of an acyl halide of the general formula R-CO-Y, in which R is as defined above and Y is a halogen atom (chlorine, bromine, iodine), in the presence of an inert organic Solvent from the group of the aliphatic hydrocarbons solvents with 5 to 10 carbon atoms, aromatic hydrocarbon solvents (such as benzene, Toluene, xylene, etc.). Methanol, propanol, butanol, more conventional Ether (such as diethyl ether, tetrahydrofuran or dioxane) or dimethylformamide at room temperature, standard pressure (normal pressure) and during 1 to 24 hours, during which the intermediate product

• P ^ ^ K N

(IV)

forms, wherein R, R ₁ and R _{2 are} as defined above.

4. The radical R ₁ -CO-R _{9 of} the intermediate product of stage 3 is cleaved in an organic inert solvent from the group of aliphatic hydrocarbon solvents with 5 to 10 carbon atoms, aromatic hydrocarbon solvents (such as benzene, toluene or xylene), the aliphatic

9834/1006

C ^ -C.-alcohols, conventional ethers (such as diethyl ether, tetrahydrofuran or dioxane) or dimethylformamide and in the presence of a stoichiometric or excess amount of water and a catalytic amount (usually, but not necessarily, 0.01 to 1.0% of the stoicometric amount) of an acid HX, where X is as defined above, at a temperature of 20 to TOO C, at standard pressure and for 1 to 24 hours from, the free base of the formula (I) being obtained.

5. If necessary, the catalytic amount of the acid HX is replaced in stage 4. by the stoichiometric amount thereof, wherein the HX salt of the free base of the compound represented by formula (I) is obtained.

The compounds according to the invention can be used therapeutically in warm-blooded animals (such as humans) against asthma and nasal congestion and against rush of blood, as a vasoconstrictor, as mydriatic agents and as antiglaucomatous agents in ophthalmology. When administered, they break down enzymatically and give phenylephrine, their therapeutically active ones. Rest free.

At this point it should be noted that the intermediates formed in steps 1, 2 and 3 as new compounds and to be considered specific to the method described or any method equivalent thereto. As such these intermediates are therefore also considered to be part of the present invention.

A number of solvents and acid catalysts have been described above by way of example. It is evident, however, that every solvent and every acid catalyst not here

609834/1006

are expressly described but serve the same purpose as required by the present invention within of the inventive idea lie.

Finally, it is evident that the method described above used in the same way for the synthesis of racemic mixtures which contain the compound described above by simply using racemic phenylephrine in place of the optically active stage 1 phenylephrine. The concept of the invention thus also includes the preparation of the racemates.

The term "pharmaceutically acceptable acid addition salts", how it is used here excludes the non-toxic acid - • 'Addition salts of the compounds of the formula (I) with non-toxic inorganic or organic acids. For example, the salts include those of inorganic acids such as hydrogen chloride acid, hydrobromic acid, sulfuric acid, sulfamic acid, Phosphoric acid, nitric acid and the like, and the salts of organic acids such as acetic acid, propionic acid, Succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, Tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, Hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, ■ · salicylic acid, ■ ■ sulfanilic acid, ■ fumaric acid, · .toluene ---- .. - ■ sulfonic acid and the like.

The following examples serve to further illustrate the invention.

609834/1006

example 1

Production of optically active m- (Triraethylacetoxy) -ό \ -

/ Tmethylamino) methyl7-benzyl alcohol hydrochloride

(R-) - Phenylephrine (9.0 g, 0.05 mol), acetone (11), and calcium carbide (4.0 g, 0.06 mol) were stirred and refluxed together for 24 hours. The solid material formed was filtered off and the filtrate concentrated in vacuo. The residue was recrystallized from a mixture of acetone and hexane to give 7.0 g of (R) -2,2,3-trimethyl-5- (m-hydroxyphenyl) -i, 3-oxazolidine in 70% yield. F. = up to 120 C, <* _D = -17.9 ° (CH ₃ OH), IR (KBr): 2980, 2360, 2700, 1600, 1450, 1260 and 1120 cm "" ¹ . NMR TcD _{3 COCD 3} ): λ 7.4-6.6 (m, 4H), 5.2 (b, 1H), 5.0 (t, 1H, J = 7Hz), 3.3 (dd, 1H , J = and 9Hz), 2.7 dd, 1H, J = 7 and 9Hz), 2.4 (s, 3H) and 1.3 (s, 6H) ppm.

Analysis for C ₁₂ H ₁₇ NO ₃ :
Calculated: C 69.6, H 8.2, N 6.8
Found: C 70.3, H 8,: ·, N 6.7

To a solution of the (R) -2,2,3 ~ trimethyl-5- (m-hydroxyphenyl) -1,3-oxazolidine, that was obtained above (1.32 g, 6.38 mmol), in 60 ml of ether was thallium-I-ethoxide (1.59 g, 6.38 mmol) was added and the mixture was stirred at room temperature for 1 hour. Pivalyl chloride (0.79 ml, 6.38 mmol) was then added, and stirring was continued for 2 more hours. The solid material formed in the reaction was filtered off, and the filtrate (this solution was usually used directly in the subsequent reaction without evaporation) for

809834/1006

-1G-

Evaporated dry to give 1.8 g of oily product, (R) -2,2,3-TrJmethyl-5- (m-trimethylacetoxyphenyl) -1,3-oxazolidine, 95%

_oc -0

Yield. ^ ^D = -10.6 (C ₉ HOH). IR (neat): 2690, 1760, 1610, 1590, 1480, 1450, 1370, 1360, 1260, 1230, 1140 and 1105 cm " ^1. NMR (CCl ₄ ): £ 7.4 to 6.8 (in, 4H ), 5.0 (t, 1H, J = 7Hz), 3.3 (dd, 1H, J = 7 and 9Hz), 2.8 (dd, 1H, J = 7 and 9 Hz), 2.3 ( s, 3H), 1.4 (s, 9H) and 1.3 (s, 6H) ppm.

The filtrate obtained in the above reaction, which contained (R) -2,2,3-trimethyl-5- (m-trimethylacetoxyphenyl) -1,3-oxazolidine (1.8 g, 6.2 mmol) in 60 ml of ether , was treated with hydrogen chloride gas until the solution was no longer cloudy. This mixture was then evaporated to dryness and the residue dissolved in a small amount of ethanol and then diluted with hexane. The hydrolysis and crystallization took place in the solution and gave 1.2 g of the end product, (R) -m- (trimethylacetoxy) -c ^ -7thylamino) -methyl7-; i> enzyl alcohol hydrochloride. Yield 70%, m.p. = 128 to 130 ° C. ^ ²⁵ = -36.7 ° (C ₂ H ₅ OH), IR (KBr): 3370, 2960, 2795, 2420, 1750, 1610, 1590, 1460, 1240 and 1110 cm " ^1. NMR (CD ₃ COCD _3. D ₂ O): 6 7.5 to 6.8 (m, 4H), 5.3 (dd, 1H, J = 5 and 10Hz), 3, 8 (b, 3H), 3.4 (m, 2H), 2.9 (s, 3H) and 1.4 (s, 9H) ppm.

Analysis for CH ₀₀ NO ₀ Cl:

14 22 ^ 3 '■ »

Calculated: C 58.4, H 7.7, N 4.9
Found: C 58.4, H 7.7, N 4.6

The remaining compounds of formula (I) can be prepared with similar success by following the general or specific named reactants and / or working conditions according to the

6G9834 / 10QS

Invention for those in the example above. Similar this procedure can be used to prepare the enantiomeric (S) isomers or the racemic (R, S) isomers.

Example 2

Hydrolysis (cleavage) of optically active m- (trimethylacetoxy- ^ - / ^ (methylamino) -methyl ./- benzyl alcohol hydrochloride) to optically active phenylephrine (m-hydroxy-c ^ - ^ / Tmeihylamino) -methyiy-ben-

zy! alcohol) '

The following study clearly shows the fact that the compounds of the present invention hydrolytically cleave and (R) -phenylephrine hydrochloride, the therapeutic ones The remainder of the present compounds.

(R) -m- (trimethylacetoxy) -fA- / 7methylamino) -methylZ-benzyl alcohol hydrochloride, obtained in Example 1 (1.0 g) was dissolved in 10 ml of methanol, which concentrated 1 ml Contained hydrochloric acid. The resulting solution was then refluxed for 24 hours, after which the solvent became then removed in vacuo to give 0.7 g (90% yield) of (R) -phenylephrine as by conventional optical activity determination methods was determined.

25 ° η 25 °
^ _n = -47.0 (Lit. ck ° = -46.2, Dictionary of Organic Compounds, 4th Edition, Oxford University Press, 1965).

Example 3 Mydriatic examinations

Standard doses of 50 μl of the following isotonic solutions were made male and female rabbits administered in the eyes:>

609834/1008

0.15% (R) -m- (trimethylacetoxy) - (5 (- / 7methylamino) -methyjLZ -benzyl alcohol hydrochloride (1-PPE according to the invention), 0.5% of a racemic mixture of m-pivaloxy - (> (- / (methylamino) -methyl / -benzyl alcohol hydrochloride (d, 1-PPE) according to U.S. Patent 3,825,583 and 2.5% (Rj-phenylephrine hydrochloride (1-PPE). All tried Compounds gave the same mydriatic response, as can be seen from the attached FIG. This clearly shows that the compounds of the invention readily give a mydriatic response at much smaller dosages than that closest comparison compound (m-pivaloxy-fX ^ V (methylamino) methyl alcohol hydrochloride) or phenylephrine hydrochloride as such.

If the above procedure is followed, equivalents are observed mydriatic reactions also for the other compounds of the formula (I).

Those made by the process of the present invention Compounds can be used in the usual pharmaceutical and / or veterinary manner for the treatment of glaucoma, Bronchial asthma and nasal congestion combined with hay fever and allergic rhinitis in warm-blooded animals (such as humans) A variety of pharmaceutical preparations can be used as described in U.S. Patent 3,825,583.

The new compounds and their pharmaceutically acceptable salts can be prepared according to conventional pharmaceutical and veterinary Methods for ophthalmic treatment and for the treatment of bronchial asthma including hay fever and allergic rhinitis in a variety of pharmaceutical preparations

δ0983Α / 100θ

rate can be used. The new compounds and their non-toxic salts are thus administrable in the form of injectables Preparations, tablets, capsules, solutions, suppositories, ointments, emulsions, jellies, cheek plasters, oral fluids for inhalation, nasal inhalation fluids, aerosols and other suitable forms. The pharmaceutical or Veterinary preparations containing the compounds are conventionally used at about 0.1 µg to 10 g

a non-toxic pharmaceutical organic or inorganic Carrier mixed. Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents, such as low molecular weight alkanols or aralkanols, vegetable oils, polyalkylene glycols, jellies petroleum-based, ethyl cellulose, ethyl oleate, carboxymethyl cellulose, polyvinylpyrrolidone, isopropyl myristate and others commonly used acceptable carriers. The pharmaceutical preparation can also contain non-toxic auxiliary substances, such as substances that promote disintegration, binders, emulsifiers, protective substances, crosslinking agents, viscosity-increasing agents and the like, such as polyethylene glycols 200, 300, 400 and 600, Carbowaxes 1000, 1500, 4000 and 10,000, antibacterial Ie Components such as quaternary ammonium compounds, phenyl mercury II salts, which are known to have cold sterilizing properties and no impairment in use result, thimerosal, propyl paraben, buffer substances,

such as sodium chloride, sodium borate, sodium acetate, gluconate buffer and other conventional ingredients such as sorbitol monolaurate, triethanol amine oleate, polyoxyethylene sorbitol monopalmitylate, dioc-

609834/1006

sodium sulfosuccinate, monothioglycerin, thiosorbitol, ethylenediaminetetraacetic acid and the same. In addition, suitable vehicles can be used as carrier media for the present purpose such as conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like.

With regard to the therapeutic dose required for the compounds prepared by the process of the invention, although the dose limit will of course vary with the size and clinical picture of the particular patient being treated, the dose will normally be in a very similar range as that for the racemic compound m-pivaloxy (^ - ^ / Tmethylamino) -methylj-benzyl alcohol is described in US Pat. No. 3,825,583. However, therapy was observed with as little as one third of the dose of m-pivaloxy-0 (- / (methylamino) methyl / -benzyl alcohol · (racemate). Thus, the administered dose, whether as a single dose or as a daily dose, varies specifically to Depending on the route of administration chosen and the size of the patient, there may be no limit to the dose of administration, but it will usually be an effective amount or the clear equivalent of the pharmacologically active form produced upon metabolic release of the active agent and thereby gives the desired pharmacological and physiological effect. Generally, a range of 0.01 to 10.0% is satisfactory. However, the following explanations serve to further define the parameters: The medicinal dose for warm-blooded mammals (such as humans and primates) for intramuscular or

60 9 8 34/1006

subcutaneous administration is about 100 µg to 5 mg administered in 0.1 to 1.5 ml of a 0.1 to 0.5% oil suspension, the usual intramuscular dose being 200 to 750 µg in
0.2 to 0.75 ml of a 0.1 to 0.5% solution. For oral inhalation the dose is around 0.01 to 2.0%, given ρIs fine mist. For typical administration to the
Nose and larynx solutions from 0.002 to 0.97% can be used. For typical oral administration, tablets or capsules containing 5 to 250 mg can be used. In general, the dosage form for a typical non-toxic salt is such as
for example the hydrochloride, in a solution for inhalation, at about 0.025 to 4%. The dose for farm animals is generally about 4 to 10 ml when administered subcutaneously or intramuscularly to horses and cattle and to Hunc m
at about 0.2 to 0.6 ml.

It should be noted that the optically active
Compounds according to the invention are so optically pure that
only the left rotating connection (R) - (-) is obtained. this
is based on the fact that the present invention
initially used left-rotating (R) - (-) - phenylephrine and
keep the left-hand rotation throughout the synthesis
can. So far this has not been possible.

The above ideas fall under the inventive concept accordingly
Information also includes intermediate products of the formulas

HO-

609834/1006

260S111

(IV) "

wherein R ₁ and R 1, which can be identical or different, are hydrogen atoms, C ₁ -C -alky! groups, di- (C ₁ -C ₉ ) -alkylamino- (CC _1n ) -alky l groups or taken together with the carbonyl group to which they are attached, a cyclo- (C ₁ -C ₇ ) -alkanone group, an N- or O-heterocyclic (C ₅ -C) -alkanone group or a substituted N- or O-heterocyclic (Cc ^- C) -Alcanon group, the substituent of which is a C ₁ -C "-alkyl group, M denotes an alkali or alkaline earth metal and R denotes a straight-chain or branched-chain alkyl group having 1 to 20 carbon atoms, an ethoxycarbonyl group, a benzyloxycarbonyl group, a phenyl group, a 2-pyridyl group , represents a 3-pyridyl group or a 4-pyridyl group.

If R ₁ and R "together with-the carbonyl group denote a CyCIo- (C ₅ -C) alkanone group, they are preferably a pentanone group, hexanone group or heptanone group, and if they are an N- or O-heterocyclic (C ₅ -C) -Alcanone group mean, they are preferably a piperidone, pyrrolidone, N-methyl! Piperidone or N-methylpyrrolidone group.

609834/1006

Claims (1)

Claims 1. pptically pure and biologically active compound of the general λ formula - IiHCIi wherein R is a straight-chain or branched-chain alkyl group with 1 to 20 carbon atoms, an ethoxycarbony group, a Benzyloxycarbonyl group, a phenyl group, a group of 0 R ₃
Formula "', v / orin R is as defined above and R_ is a water .K-C- (J-L-Ii- j is a hydrogen atom, a methyl group or a phenyl radical, or a 2-, 3- or 4-pyridy group or their HX salts, wherein X is a pharmaceutically acceptable acid addition salt anion means. 2. A compound according to claim 1, wherein R is a straight-chain or branched chain Denotes an alkyl group having 1 to 5 carbon atoms, and their pharmaceutically acceptable acid addition salts. . m- (Trimethylacetoxy) -c (- / _ (methyl amino) -methyl.7 -benzyl alcohol and its pharmaceutically acceptable acid addition salts. 4. Process for the preparation of compounds according to Claim 1 to 3, characterized in that one 1 . optically active phenylc ^ -hrin with an excess of a carbonyl compound of the general formula R ₁ -CO-R ₉ / in which R and R "are the same or different and are a hydrogen atom, a C.-C. -Alkyl group or a di- (C -C «) - alkylamino- 609834/1006 - 13 - (C.-C ₁₀ ) -alky! Group or the carbonyl group to which they are attached together is a C 1 -C cycloalkanone group or a substituted or unsubstituted N or O-heterocyclic (C 1 -C) alkanone group , in which the substituent is optionally a Cj-C ^ -alkyl group, form, ontv. "the in the presence of a dehydrating or dehydrating agent from the group of alkaline earth metal carbides, molecular sieves with 4 to 5 Å, calcium chloride, magnesium sulfate and Sodium sulfate or in the presence of a conventional inert aromatic hydrocarbon solvent plus an organic or inorganic acid catalyst with removal of the water formed as an azeotropic mixture at a temperature of 20 to 140 C, at standard or ambient pressure and for 2 to 48 hours, 2 formed compound of the general formula (II) wherein R and R "are as defined above, with an M-hydroxide, an M-hydride and / or an M-alkoxide, wherein M is a Alkaline earth metal, an alkali metal or thallium means in the presence of an inert organic solvent the group of aliphatic hydrocarbons, solvents with 5 to 10 carbon atoms, the aromatic hydrocarbons f solvents, the aliphatic C -C.alcohols, the conventional ether and dimethylformamide at room temperature, standard or ambient pressure and for 1 to 24 hours implements, 609834/1006 3. the resulting compound of the general formula (ITI) wherein M, R ₁ and R _{9 are} as defined above, with a stoichiometric amount of an acyl halide of the general formula R-CO-Y, wherein R is as defined above and Y is a halogen atom, in the presence of an inert organic solvent from the group of aliphatic hydrocarbon solvent with 5 to 10 carbon atoms, the aromatic hydrocarbon solvent, methanol, propanol, butanol, conventional ether and dimethylformamide, at room temperature, standard or ambient pressure and for 1 to 24 hours and reacts
4. of the compound of the general formula thus obtained (IV) R-C-O- wherein R, R ₁ and R _{9 are} as defined above, the radical R-CO-R in an organic inert solvent from the group of the aliphatic hydrocarbon solvents with 5 to 10 carbon atoms, the aromatic hydrocarbon solvents, the aliphatic C ₁ -C ₄ -AlkOhOIe , the conventional ether and dimethylformamide and further in the presence of a stoichiomic or excess amount of water and a catalytic amount of HX-acid, where X is de- 609834/1006 is fined, at a temperature of 20 to 100 ° C Standard or ambient pressure and split off for 1 to 24 hours and so the free base of the Fo: el (I) is obtained. 5 ^ The method according to claim 4, characterized in that in " the stage 4. a stoichiometric amount of the acid HX is used and so the pharmaceutically acceptable acid addition salt of Compound of formula (I) wins. 5 _# Process according to claim 4, characterized in that the catalytic amount of the acid HX used in step 4 is 0.01 to 1.0% of the stoichiometric amount. 7. The method according to claim 4 to 6, characterized in that one in stage 1. a temperature applies which corresponds to the boiling point of the solvent or solvent mixture used - " speaks. 8. The method according to claim 4 to 7, characterized in that one in stage 1. as the carbonyl compound pentanone, hexanone, heptanone, piperidone, pyrrolidone, N-methyl piperidone and / or N-methylpyrrolidoi used. _# 9 The method of claim 4 to 8, characterized in that 1. is used as the aromatic hydrocarbon solvent, benzene, toluene and / or xylene in the stage. 10. The method according to claim 4 to 9, characterized in that one in stage 1. as acid catalyst p-toluenesulfonic acid, sulfosalicylic acid, Benzenesulfonic acid, sulfuric acid and / or hydrogen chloride acid used. -j _m process according to claim 4 to 10, characterized in that in step 2. the metal hydroxide, hydride or alkoxide 609834/1006 Sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, Barium hydroxide, sodium inhydride, calcium hydride, sodium IieLhoxid, sodium ethoxide, sodium propoxide and / or thallium-I-ethoxide used. 12. The method according to claim 4 to 11, characterized in that one in stage 2. as an inert organic solvent pentane, hexane, heptane, octane, t-ionane, decane, enzene, toli -> 1, xylene, methanol, Ethanol, butanol, propanol, diethyl ether, tetrahydrofuran, dioxane and / or dimethylformamide are used. 13. The method according to claim 4 to 12, characterized in that one in stage 3, as an inert organic solvent, pentane, hexane, heptane, oclane, nonane, decane, benzene, toluene, xylene, methanol, Propanol, butanol, diethyl ether, tetrahydrofuran, dioxane and / or dimethylformamide are used. 14. The method according to claim 4 to 13, characterized in that in step 4. the acid HX is hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, vinegar. ^c acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid. e, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, fumaric acid and / or toluene sulfonic acid are used. 15. The method according to claim 4 to 14, characterized in that one uses the output sinater la lien, in which R is a straight chain or represents branched chain alkyl group having 1 to 5 carbon atoms. 609834/1006 16. The method according to claim 4 to 16, characterized in that instead of the optically active phonylephrine, racemic phenylophrine is used used and thus wins the corresponding racemate. 17. Medicines containing at least one optically pure and biological active compound according to claims 1 to 3 or pharmaceutically thereof contract]! .ehe acid addition salts in a non-toxic organic or inorganic pharmaceutically acceptable ( η carrier material. . Medicament according to claim 17, characterized in that it contains the optically pure and biologically active compounds or their salts in an amount of 0.01 to 10.0% by weight. 19.. : Zneimittel according to claim 17 and 18, characterized in, that it is the optically pure and biologically active compounds in an amount of 5 to 250 mg and as a carrier material an orally Contains ingestible solid or liquid carrier material. 20. Medicaments according to Anspiach 15 to 19, characterized in that that there is a carrier material that can be introduced into the eyes, a carrier material suitable for inhalation or a carrier material contains intranasal carrier material. 21. Medicament according to claim 17 to 20, characterized in that it is sympathicomimetically effective. BATH ORIGINAL 809834/1006