DE3316155A1 - 2-[2'-Hydroxy-3'-(1,1-dimethylpropylamino)propoxy]-1-thienyl- propiophenone, its acid addition salts, process for its preparation and medicaments - Google Patents

Abstract

2-[2'-Hydroxy-3'-(1,1-dimethylpropylamino)propoxy]-1-thienyl- propiophenone of the formula I <IMAGE> and its acid addition salts are described. The preparation of this compound and its acid addition salts are also described. The compound and its acid addition salts have an antiarrhythmic action. They can therefore be used for the treatment of cardiac arrhythmias.

Description

The invention relates to the new 2- / 2'-hydroxy-3 ¹ - (1,1-dimethylpropylamino) -propoxyJ-1-thienylpropiophenone of the formula I.

CH

"•• I 3 (D

^ O-CH ₂ -CHOh-CH ₂ -HH-C-CH ₂ -CH ₃

OIL

" Ί 2 6 5
O

and its acid addition salts and a process for its preparation. The invention also relates to medicaments which the compound of formula I or its acid addition salt, preferably a physiologically acceptable acid addition salt, contain.

DE-PS 2 001 4 $ 1 describes 2- (2 ^! -Hydroxy-3'-alkylaminopropoxy) -ß-phenylpropiophenones of the general formula II 0 9 ₂ 2 C.-H, - -CH ₀ CH ₀ -C- I ⁸ Hj MD

and from EP-OS 53 603 the corresponding 1/3 (2-hydroxy-3-alkylaininopropoxy) -2-thienyl7-3-phenyl-1-propanones of the "general formula III
30th

R 0-CH ₂ -CHOH-CH ₂ -NH-R ₂

/ \ SCCH, -CH -C, H,
1 "2265

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as well as their acid addition salts are known. The radical R ₂ in these formulas means the n-propyl group (-CH ₂ -CH ₂ -CH ₃ ), the n-butyl group (-CH ₂ -CH ₂ -CH ₂ -CH ₃ ), the 1-methylpropyl group (-CH (CH ₃ ) -CH ₂ -CH ₃ ) or the tert-buty! Group (-C (CH-) ₃ ). The n-propyl group is preferred.

These publications also describe a process for the preparation of these compounds * These known compounds and their salts are medicinal substances. The n-propylamino compound (R = nC _: .H- _? ) Is the only one of the compounds described that exhibits cintiarrhythmic activity.

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The model arrhythmias were triggered by the following measures: Infusion of adrenaline plus chloroform inhalation or infusion of digoxin, calcium chloride or aconitin, and by occlusion of the left coronary artery. In medium (1-3 mg / kg) and higher (5 mg / kg) intravenous doses

Propafenone (II; R ^ nC ₃ H ₇ ) has an antihypertensive, negative inotropic and corona-widening effect. The heart rate is not significantly changed in antiarrhythmic doses.

Of the compounds of general formula II, the compound with R ^ nC ₃ H ₇ (propafenone) is used in human medicine as an antiarrhythmic with a local anesthetic / quinidine-like, but also ß-receptor-blocking effect for the therapy of cardiac arrhythmias; see, for example, W. Baedeker, G. Klein and G. Ertl, Herz-Kreis, Zeitschrift für Kardiologie und Angiologie, Vol. 11, 330 (1979).

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. δ investigations on the other three, from the German patent specification 2 001 4-31 known 2- (2'-hydroxy-3-alkylaminopropoxy ) -ß-phenylpropiophenone compounds, namely the η-butyl amino, the 1-methyIpropylamino and the tert-butyl amino compound, have shown that these compounds at medium (1-3 mg / kg) intravenous doses practically no antiarrhythmic effect in animal experiments with model arrhythmias demonstrate.

The invention is based on the object of providing a new 2- (2 ^f -hydroxy-3'-alkylajiinopropoxy) -1-th: tenylpropiophenone and its acid addition salts which are characterized by an antiarrhythmic but not highly toxic effect. Another object of the invention is to provide a process for the preparation of this compound and its acid addition salts. Finally, it is an object of the invention to provide medicaments for the therapy of cardiac arrhythmias which contain this compound or its acid addition salt, preferably a physiologically acceptable acid addition salt.

The invention thus relates to the 2- / 2'-hydroxy-3 ^! - (1,1-dimethylpropylamino) -propox2 ./- 1-thienylpropiophenone der

Formula I given above and its acid addition salts. ;

The invention also relates to a process for the preparation of the compound of the formula I and its acid addition salts.

The compound of the formula I can be prepared by the following method getting produced:

1- (3-Hydroxy-2-thienyl) -3-phenyl-i-propanone of the formula IV

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JOE

(IV)

η 2 2 6 5
0

is in a manner known per se with an epihalohydrin or an Of, (^ -dihalogen-2-propanol for the connection of the general formula V

"^^^ - C-CH_-CH _n -C _c H _c

H ί ZOD

implemented, in which A is the radical -CH-CH ₂ or -CHOH-CH ₉ -B and B is a halogen atom (nucleofuge leaving group). Then the compound obtained with the 1,1-dimethylpropylamine of the formula VI

H ₃ NC-CH ₂ -CH ₃ (VI)

CH ₃

implemented. The 1,1-dime obtained is optionally thylpropylamino compound with an acid into an acid addition salt convicted. The implementation can, for example according to those described in DE-PS 2 001 431 and DE-OS 20 07 751 Procedure.

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The leaving group B preferably represents a halogen atom, in particular a chlorine, bromine or iodine atom. Furthermore, aromatic or aliphatic sulfonic acid radicals come in Consider how the p-toluenesulfonic acid, the p-bromobenzenesulfonic acid or the methanesulfonic acid residue.

The reaction is JDemperaturen at temperatures of 10 to 120 ⁰ C, that is at room temperature or at higher!, Expediently carried out at temperatures of 50 to 12O ⁰ C, under atmospheric pressure or in a closed vessel under elevated pressure.

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The starting compounds of the formula ν and Vi can be used without Diluents or solvents are implemented. Appropriately however, the reactions are carried out in the presence of an inert diluent or solvent, for example a lower alcohol with 1 to 4 carbon atoms, such as methanol, ethanol or propanol, preferably isopropanol or ethanol, a lower saturated dialkyl ether, dialkyl glycol ether or cyclic ether, such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, a benzene hydrocarbon such as benzene itself or an alkylbenzenes, in particular toluene or xylene, or an aliphatic hydrocarbon such as hexane, heptane or octane, dimethyl sulfoxide or in the presence of water or mixtures of the solvents mentioned.

The 1,1-dimethylpropylamine (2-methyl-2-aminobutane) used in excess is also optionally suitable as a diluent or solvent. 20th

Preferred solvents in the reaction of compounds

of the formula V wherein A is the radical-CH-CH _2, with the amine of formula III are lower alcohols, especially ethanol or isopropanol, wherein the reaction is preferably performed at temperatures of 50 to 120 ⁰ C is performed. If appropriate, the reaction can be carried out in a closed vessel under pressure.

In the nucleophilic substitution of the radical B, a cyclic aliphatic ether, in particular tetrahydrofuran or dioxane, or dimethyl sulfoxide, and temperatures of 90 to 120 ^° C. are preferred as the solvent. Optionally, the reaction is carried out in the presence of a catalytic amount of sodium or potassium iodide.

The thiophene ether of the general formula V can optionally also in the form of a mixture of an epoxy with one

Balogenhydrin are used because in technical production of the starting compounds, such mixtures may arise under certain circumstances.

In an expedient embodiment for the nucleophilic substitution of the radical B by the amine of the formula viwird the reaction carried out in the presence of a base as an acid-binding agent. Preferred bases are alkali metal hydroxides, carbonates, hydrogen carbonates, alcoholates, in particular Methylates and ethylates, or a tertiary amine such as pyridine, or a trialkylamine such as trimethylamine or Triethylamine. The alkali compounds come in particular those of sodium and potassium are taken into account. The base is used in a stoichiometric amount or in a slight excess used.

The amine used for the reaction can optionally be used in excess at the same time as an acid-binding agent will.

Complete conversion depends on the reaction temperature and is generally within 2 to 15 hours completed. The reaction product can be obtained in a conventional manner, for example by filtration or distillation the diluent from the reaction mixture. The compound obtained is purified in a customary manner, for example by recrystallization from a solvent, conversion to an acid addition salt or by column chromatography.

When epihalohydrins come epichlorohydrin, epibromohydrin and epiiodohydrin, and as of, & J-dihalo ~ 2-propanol are particularly _r 1 3-dichloro-2-propanol and 1,3-dibromo-2-propanol into consideration.

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The reaction of the compounds IV to prepare the starting compounds of the formula V is expediently carried out at temperatures from 0 to 120 ^° C. and under normal pressure or in a closed vessel under increased pressure. A lower aliphatic ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a lower alcohol with 1 to 4 carbon atoms such as methanol, ethanol, propanol or butanol, a lower aliphatic or cyclic ether such as Diethyl ether, tetrahydrofuran or dioxane, a dialkylformamide such as dimethylformamide or diethylformamide, or dimethyl sulfoxide or hexamethylphosphoric triamide or excess alkylating agent are used.

The reactions in the presence of a base are preferred carried out as an acid-binding agent. Suitable bases are alkali metal carbonates, bicarbonates, hydroxides, hydrides or alcoholates, in particular of sodium and potassium, basic oxides such as aluminum oxide or calcium oxide, organic tertiary bases such as pyridine, lower trialkylamines, such as trimethylamine or triethylamine, or piperidine. The bases can be used in relation to the alkylating agent used can be used in a catalytic amount or in a stoichiometric amount or in a slight excess.

1- (3-Hydroxy-2-thienyl) -3-phenyl-1-propanone with Epichlorhydria, Epxbrpmhydrln or 1,3-Dibromopropanol-2 in a polar, aprotic solvent, in particular dimethyl sulfoxide, in the presence of at least one is preferred molar equivalent of base, in particular sodium hydride, based on the alkylating agent is reacted, at temperatures from 0 to 50 ⁰ C.

The starting compound of the formula IV, i.e. 1- (3-hydroxy-2-thienyl) -3-phenyl-1-propanone, and its manufacture is well known.

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The compound of the formula I has a center of chirality on the carbon atom in the 2-position of the aliphatic side chain on. In general, it is obtained as a hacemate which can be obtained by known methods, for example by Formation of diastereomeric salts with optically active auxiliary acids, such as di-benzoyl-tartaric acid, camphor-10-sulfonic acid, ditoluyltartaric acid or 3-B3rom-oampher-8-sulfonic acid, in the optically active antipodes can be split.

The compound of the invention obtained is optionally used of the formula I into an acid addition salt, preferably. converted into a salt of a physiologically acceptable acid. Usual physiologically compatible inorganic and organic acids are, for example, hydrochloric acid, hydrobromic acid, Phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, Citric acid, salicylic acid, adipic acid and benzoic acid. Other acids that can be used are described, e.g. in progress der Arzneimittelforschung, Vol. 10, Pages 224-225, Birkhäuser Verlag, Basel and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, Vol. 66, pp. 1-5 (1977) · Hydrochloric acid is preferred.

The acid addition salts are generally better known per se Way by mixing the free base or their. Solutions with the corresponding acid or its solutions in an organic solvent, for example a lower alcohol such as MstJianol / ethane oil / n-propanol or isopropanol, or a lower ketone such as acetone or methyl ethyl ketone or methyl isobutyl ketone, or an ether such as diethyl ether, Tetrahydrofuran or dioxane. Mixtures of the above can also be used for better crystal separation Solvents can be used. In addition, you can

pharmaceutically acceptable aqueous solutions of acid-35

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] addition compounds of the compound of formula I are prepared in an aqueous acid solution.

The acid addition salts of the compound of the formula I can be used in a manner known per se, e.g. with alkalis or ion exchangers, be converted into the free base. The free base can be reacted with inorganic or organic acids, especially those which are suitable for the formation of therapeutically useful salts are gaining more salts. These or other salts of the new compound, such as the picrate, can also be used for Purification of the free base is used by converting the free base into a salt, separating this and removing it from the salt again releases the base.

The present invention also relates to medicaments for oral, rectal, intravenous or intramuscular Application which, in addition to customary carriers and diluents, the compound of the formula I or its acid addition salt contained as an active ingredient, as well as the use of the new compound and its physiologically acceptable salts the treatment of cardiac arrhythmias.

The medicaments of the invention are used with the usual solid or liquid carriers or diluents and the commonly used pharmaceutical-technical auxiliaries according to the desired type of application prepared with a suitable dosage in a known manner. The preferred preparations consist in A dosage form that is suitable for oral administration. Such dosage forms are, for example, tablets, Film-coated tablets, coated tablets, capsules, pills, powders, solutions or suspensions or depot forms.

Of course, parenteral preparations are also available, such as injection solutions. Suppositories may also be mentioned as preparations, for example.

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Corresponding tablets can, for example, by mixing the active ingredient with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, Lubricants such as magnesium stearate or talc and / or Means to achieve a depot effect such as carboxypolymethylene, Carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.

Correspondingly, coated tablets can be produced by coating cores produced analogously to tablets with usually in Dragee coatings used agents, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. The The coated tablet shell consists of several layers, the excipients mentioned above for the tablets being used

can.
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Solutions or suspensions with the active ingredient according to the invention can additionally taste-improving agents such as Contain saccharin, cyclamate or sugar as well as flavorings such as vanillin or orange extract. You can also Suspending aids such as ITodium carboxymethyl cellulose or preservatives such as p-hydroxybenzoates. Capsules containing active ingredients can, for example, be produced by mixing the active ingredient with an inert carrier such as lactose or sorbitol and placing in gelatin capsules encapsulated.

Suitable suppositories can be prepared, for example, by mixing them with suitable carriers such as new tral fats or polyethylene glycol or their derivatives, produce.

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The single dose for human oral use is between 0.5-5 mg / kg for the i.v. Use between 0.05 - 2 mg / kg for the i.m. Use between 0.1-3 mg / kg for rectal use between 0.5-10 mg / kg.

Surprisingly, the compound of formula I has below that of H.-J. Hapke and E. Prigge, Arzneimittel-Forsch. (Drug Res.), 26, 10, 1849-1857 (1976) described conditions ■ jQ in model arrhythmias an antiarrhythmic effectiveness be already at 0.1 mg / kg with intravenous administration.

This surprisingly high anti-arrhythmic effectiveness is not accompanied by an equally high level of toxicity - tion.

The antiarrhythmic activity of the compound of the formula I was determined in dogs according to H.-J. Hapke and E .. Prigge, Medicinal Research (Drug Res.), Op cit. It was with Using a chloroform infusion and adrenaline infusion, a model arrhythmia is generated, which is essentially due to ventricular Extrasystoles was characterized in absolute arrhythmia. Immediately after these arrhythmias occur the compound according to the invention was injected intravenously as an aqueous solution of the hydrochloride.

An intravenous dose of 0.1 mg / kg was complete within 45 seconds in all dogs treated with it effective, i.e. a normal sinus rhythm was established in the electrocardiogram (ECG).

The excellent antiarrhythmic effectiveness can be determined

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the. By occlusion of a branch the coronary arteries were Arrhythmias generated. An intragastric application of the compound according to the invention in the form of the hydrochloride took place the next day. 10 minutes after the application of 10 mg / kg, an unchanged extrasystole was detectable, 30 minutes after the administration there were no more extrasystoles established. A normal EKG was observed for up to 24 hours.

It is surprising and was not to be expected that the connection according to the invention - despite their great similarity . with the known 2- (2'-hydroxy-3'-alkylaminopropoxy) -ßphenylpropiophenon compounds in comparable doses no effect on the peripheral and coronary blood flow and despite similar hemodynamic effects, at least the same effect on cardiac arrhythmias aufiveist like Prop ~ afenon.

It is also noteworthy that in contrast to propafenone the compound of the invention at a dose of 0.5 mg / kg i.v. a decrease in heart rate causes. This is desirable for tachycardiac arrhythmias.

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The examples illustrate the invention.

Example 1 1

a) 'Preparation of 1- £ 3- (2,3 ~ epoxypropoxy) -2-thienyl ^ -3-phenyl-1-propanone

1.74 g (0.076 mol) of Na are dissolved in 50 ml of anhydrous methanol solved. Then 17.55 g (0.076 mol) of 1- (3-hydroxy-2-thienyl) -3-phenyl-1-propanone are obtained entered and the solution becomes 35

evaporated to dryness under reduced pressure. The received crystalline residue (the sodium salt) is mixed with 50 ml of epichlorohydrin and refluxed for 4 hours. The reaction mixture is then filtered off with suction over diatomaceous earth, rinsed with a little benzene and the filtrate evaporated under reduced pressure. The crystalline residue is dissolved in 1250 ml of cyclohexane with the addition of activated charcoal boiled, filtered off with suction over diatomaceous earth and the filtrate evaporated under reduced pressure. It will be about 16 g Receive product that is sufficiently pure for further use. Mp (cyclohexane): 59 to 61 ° C.

b) 2- £ l '-Hydroxy-3' - (1,1-dimethylpropylamino) -propoxy-7 ~ 1 thienylpropiophenone · HCl

14.4 g (0.05 mol) of crude 1- / 3- (2,3-epoxypropoxy) -2-thienyl7-3-phenyl-1-propanone are dissolved in 100 ml of methanol and mixed with 35 ml of 1,1-dimethylpropylamine 4 hours with stirring and heated under reflux. The reaction mixture is evaporated under reduced pressure, the residue is _{partitioned between 250 ml of CH 3} Cl ₂ and 150 ml of 1N HCl. The phases are separated, the aqueous phase is extracted _{twice with 50 ml of CH 3} Cl _{2 each time.} The combined organic phases are dried (Na ₃ SO ₄ ) and evaporated under reduced pressure. The crude product obtained in crystalline form can be recrystallized from acetone / methanol 8: 2 (approx. 100 ml) with activated charcoal.

Example 2

Manufacturing instructions for tablets 30

a) recipe

Compound I as the hydrochloride 75.00 g

Microcrystalline cellulose
(Powder, 50 µm) 15.75 g

Poly (1-vinyl-2-pyrrolidone) 5.00 g

Hydroxypropyl methyl cellulose 2910 3.75 g

Magnesium stearate "0.50 g

100.00 g ^L COPY - ¹

• / 16 ·

b) Mixing and granulating

The drug is then "sieved" if necessary all raw materials except magnesium stearate in one rüscher mixed and also in the mixer with a suitable amount of a granulating liquid (e.g. water or isopropanol-dichloromethane 1: 1) moistened. The wet mixture is sieved with a suitable sieve, in the dry cupboard dried and sieved again. The dry granulate is mixed with the magnesium stearate in the mixer. 10

c) Cover mix 70.0 % talc 26.7% Calcium sulfate herbal hydrate 3.3% Fumed silica

100.0 %

d) coating suspension

Sucrose, 4-7.8 %

Talc 9.6%

Calcium sulfate hemihydrate 4-, 8 %

'' Arabic gum. 3.6%

Corn syrup. 3.2%

MacrogoÄoOO '2.9%

Titanium (IV) oxide ■ -. 1.6%

Sodium dodecyl sulfate 0.1%

least. Water '26.4%

100.0%

Coating the tablet cores

The tablet cores are first placed in the rotating kettle; moistened with the coating solution and then powdered with enough cover mixture until they roll freely again. After this This process is repeated to dry the kernels. Then the cores in the. Drying cabinet afterwards. Then the kernels with the coating suspension

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ι coated in layers until the desired final weight is reached is. The cores must be dried after each layer has been applied.

Compression of tablets

From the mixture prepared according to a) tablets with a weight between 40 and pressed 400.mg. The pressing force and the tablet diameter are chosen so that the disintegration time in the test device according to Ph. Eur. is less than 15 minutes and the tablets are mechanically stable enough.

Example 3

Manufacturing instructions for film-coated tablets 15

A. Recipe

a) tablet

(see manufacturing instructions for tablets, example 2).
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b) 3 film cover

Total order amount $ -20 % of the tablet weight of which:

Hydroxypropyl methyl cellulose 2910 77 %

'ift ■

Macrogoί% 000 (plasticizer). 23 %

B. Manufacture of the tablets

(see manufacturing instructions for tablets, example 2).

C. Manufacture of the film-coated tablets

The components of the film coating are dissolved in a suitable solvent (e.g. water or ethanol / water 70:30) solved. The tablets are in a film coating line with the solution of the film former and the plasticizer sprayed and dried in a stream of hot air. The film-coated tablets are then dried in the drying cabinet.

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Γ example 3316155 - ¹ 4th Manufacturing instructions for coated tablets 1 A. Recipe a) Dragee core (see manufacturing instructions for tablets) 5 b) Dragee cover Total order amount 25-100 % of the core weight of that: Sucrose 51.4 % talc 24.0 ⁰ A 10 Calcium sulfate hemihydrate 10.3 % Corn syrup 5.0 % Arabic gum 3.9 % MacrogoJ? 6000 2.9% Titanium (IV) oxide 1.6% 15th Fumed silica 0.8 % Sodium dodecyl sulfate 0.1 %

20 100.0 %

B. Manufacture of the tablet cores

(see manufacturing instructions for tablets)

25. C. Manufacture of the coated tablets.

Composition of the coating solution used,
Cover mix and coating suspension

a) Coating solution

₃₀ sucrose 4-7.6%

Corn syrup 19.1 %

Arabic gum 3.8 %

least. Water 29.5 %

100.0 % 35

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example

Manufacturing instructions for capsules
A. Active ingredient dosage from 75

Recipe 75.00 g Compound I as the hydrochloride Microcrystalline cellulose 16.25 g Powder, 50 μm £ 5.00 Poly-Ci-vinyl-2-pyrrolidone) 3.75 ε Hydroxypropyl methyl cellulose 2910

100.00 g

2. Mixing and granulating according to Example 2b).

3. Filling the granules into capsules The granules are filled into Hard gelatine capsules of size 3, 2, 1 or 0 filled. The filling amount per capsule depends on the desired one Dosage of the active ingredient.

B. Dosage of active ingredient 30-75 mg

1. Recipe

, Compound I as hydrochloride ■ 3O ₉ OO - 75.00 g of microcrystalline cellulose

Powder, 50 pm ■ 61.25 - 16.25 g

Poly (1-vin; 7l-2-pyrrolidone) '5, ° 0 g Hydroxypropylmethyl cellulose 2910 3.75 g

100.00 g

The total of the initial weights of active ingredient and microcrystalline cellulose should always be 91.25 g. The amount of active ingredient is a thousand times the single dose.

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2. Mixing and granulating according to Example 2 b).

3. Filling the granules into capsules 100 mg each of granules are filled with the help of a capsule filling machine Filled in hard gelatine capsules of size 3 or 2.

Example 6 Manufacturing instructions for ampoules i. Recipe

Compound I as the hydrochloride 1.5 g

Water ¹ for injections ad 100.0 ml

2. Preparation of the solution

90% of the water required for the selected batch size are presented; the active ingredient is heated in it solved. After cooling, the solution is made up to the final volume.

3 · Bottling the solution

The finished solution is filled into glass ampoules, the filling quantity of which depends on the desired dosage. The glass ampoules are then melted shut.

M-. sterilization

The ampoules are sterilized in steam ^{at 120 ° C. for 20 minutes.}

Example7

Manufacturing instructions for suppositories 1. Recipe

Link. Γ as hydrochloride 30 - 200 mg

Hard fat (melting point 35-36.5 ° C) ad 2000 mg *

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^ Αλ τ 2. Production of the active ingredient-containing melt

* The amount of hard fat required for a certain number of suppositories is ^{melted at 40 °} C. in a water bath. The active ingredient is pressed through a 0.8 mm sieve and stirred into the melt, so that a suspension is formed.

3. Making the suppositories

The melt is allowed to cool to 37-38 ⁰ C and then filled under constant stirring into suppository forms, that the weight of a suppository is 2000 mg. The suppository shape is closed after the melt has solidified.

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Claims (4)

JJ Ib Ibt) VOSSlUS VOSSIUS -TAUCH NER · H EUNEMANN · RAUH - PATENT LAWYERS SIEBERTSTRASSE 4 ■ BOOO MÜNCHEN 86 · PHONE: (O8S) 47 4O75 CABLE: BENZOL PATENT MÖNCHEN TELEX 5-29 453 VOPAT D Oa Hai 1983 lt .: p 407 HELOPHARM W. PETRIK & CO. KG
Berlin ¹¹ 2- / 2 '-Hydroxy-3' - (1,1 -dimethylpropylamino) -propoxy. 7-1 - thienylpropiophenone, its acid addition salts, process for its manufacture and medicinal products " P a t en ta η s p "r ü c h e Γ 1 / 2- & '-Hydroxy-3 ^f - (1,1 -dimethylpropylamino) -pr.opoxyj-1-thienylpropiophenone of the formula I. CH ! 3 ■ O-CH ₂ -GHOH-CH ₂ -IiS-C-CH ₂ -CH ₅  X ₂₅ OS ₅ (I) C-CH _O -CH "-C, H _C ti O and its acid addition salts. 2. 1-Q '-hydroxy-3' - (1,1-dimethylpropylamino) -propoxyj-1-thienylpropiophenone hydrochloride. 3. Process for the preparation of 2 - ^ '- hydroxy-3 ¹ - (1, 1-dimethylpropylamino) -propoxyj-i-thienylpropiophenone of the formula I. COPY CH -, _ T ₁ TtT U-. and its acid addition salts, characterized that an ether of the general formula V .0-CH ₂ -A (V) C-CH ₀ -CH ₀ -C ₄ -H _n .
" Z 2 ο 5 0 OH / \ t in which A denotes the radical -CH-CH ₂ or -CH-CH ₃ -B and B is a nucleofugal leaving group with the 1,1-dimethy1-propylamine of the formula VI CH ₃ H ₂ NC-CH ₂ -CH ₃ (VI) CHo brings to implementation and optionally the compound obtained of the formula I splits into the isomers with an optically active acid and / or by reaction with an acid in transferred to an acid addition salt. 4. Medicines for the treatment of cardiac arrhythmias, characterized by a content of 2- / 2 ^s -hydroxy-3 '- (1,1-dimethyIpropylamino} -propoxyJ-1-thienylpropxophenone or its physiologically acceptable acid addition salt. COPY j