SI8211907A8 - Process for obtaining 2-/2'-hydroxy-3'-(1,1-dimethylpropylamino)-propoxy)-beta-phenylpropi0- phenone - Google Patents

Description

HELOPHARM W. PETRICK & CO. KG, Berlin

Method for obtaining a 2- / 2 ^1-hydroxy-3- (1,1-dimethylpropylamino) -propoxy / -beta-phenylpropiophenone Region techniques u koju falls within the present invention

The invention relates to the synthesis of aminoether derivatives of beta-phenylpropiophenone having antiarrhythmic activity (International Patent Classification: C07C93 / 06).

•

Technical problem

A technical problem that is solved by the present invention is the expansion of the range of affordable drugs. for icy cardiac arrhythmias. This technical problem has been solved in such a way that an analogous procedure is provided to obtain a novel antiarrhythmic compound,

2- / 2 '-hydroxy-3' - (1,1-dimethylpropylamino) -propoxy / -beta-phenylpropiophenone (I). The new compound eliminates cardiac arrhythmia when given at 10 to 20 times the dose of propafenone, a drug nowadays clinically used to treat cardiac arrhythmias, the preparation of which, by a similar procedure, is described in German Patent 2,001,431 'belonging to the same Applicant as the present Applicant login.

Patent 2 QC1 431 Examples PrepoxyJ-Bate-Phenylpropiophenic (2'-Hydroxy-3 · -alkylaniline Cpcts Forrnd

G-CH

rC « ₂ CK ₂ -C

CKCH-CH ₂

NH-R and their addition salts with Gotatak R of this formula denotes the n-propyl group of "n-butyl group"

1-ethyl propyl group (-CHCCHgl-CMj-CH2) or tert-butyl group C-CtCN,),).

I i - '** **

(2) the aforementioned patent also describes a process for the preparation of compounds of the above formula which comprises the reaction of 2- (2 ', 3'-epoxypropoxy) beta-phenyl-propiophenone with an amine of formula R-NH ₂ wherein R is n-propyl, n-butyl. 1-methylpropyl or tert-butyl group.

rouicr.uta known compounds and their counterpart pharmaceuticals.

Investigations on the isolated hearts of the zithriterium (procedure according to

Lsngendorff) have shown that these compounds produce a significant increase in coronary flow. In addition, the compound is a lamina compound (R «nC ~ H ₇ ), which is lower than prepefenone here) and is only one of the compounds described which additionally exhibit antiarrhythmic afficacy. In experimenting with animals (dogs, cats and rabbits) who show "modal arrhythmia, the entiarrhythmic effect of propafenone was reported after intravenous ^ Π -" s / kg) ί orally ^ (2-10 kg) *

giving # see H. Kepkm and £. Prigge, Arzneim. Forsch. (Drug Res.) 26.10, 1343-1657 (1376).

Modal arrhythmias were induced by the following mersmat infusion of «adrenaline plus in ha Food j srn chloroform iii infusion« of digoxin, calcium chloride iii akor.itina iii coronary artery occlusion trauma. In prosaic (1-3 »g / kg) and higher (5 mg / kg), an intravenous dose of propafanone has a hypotensive, negative inotropic effect and dilutes coronary arteries. Aside from producing an anti-rhythmic sphincter, it does not concern heart rate attrition.

Currently, propafenone is used in human medicine as an ontiarrhythmic with local anesthetic quinidine-like, and also bstaracsptorskia blocking offacta for poramedeia orcai velocity therapy, see, for example, M. Baadeksr, G. Klein, and G. Ertl, Hoi ^ z-Kroislauf. Zoitocbrift fur Kerdiologia and Anglologio, Val. 11, 330 (1373).

.-3Istreiivonia is the other three 2- (2'-hierakai-V ^ _e lkil ^ in3propane S-phonylpropiophenone JadinJcnJ which I will know from Nemo Patent.2 001 «31, t, j., N-butylamino. -butylamino Compounds have shown that these pratctifino compounds do not produce antisrhythmic affective code / are administered in

X proc ^ I (1-3 sn ^ / ks :) intravenous .. * in tastes ea iivcfcinjojv.a Rojs has her mcdclbu eriviV.ZJa.

Description of a solution to a technical problem with Examples of Execution

The present invention relates to a process for the preparation of a new 2- (2'-hydroxy-3 '- (1,1-dimethylpropylamino) -propoxy / -beta-phenyl propiophenone of formula I:

CK ""

/ Λ-οι, ₀ OC « ₂ -CHCH-CH ₂ -KH-C-CH ₂ -CH ^ _O CH, -C

(1) 'V and its acid addition salts, preferably' physiologically acceptable acid addition salts.

«

According to the method of the invention, the compound of the above formula I can be prepared according to the following procedure:

With the reaction of a phenolic acid of general formula II:

£ ^> - ch ₂ -cb ₂ -Č

o-ch ₂ a

'V in which A represents the remainder -ϊΖ-Έη ₂ or ----- CH ₂ -B 1 B Is a certain group of respects, by the 1,1-dlmstllpropyl formula of ΧΣΧ

The 1,1-dlmethylpropylamine compound in question is optionally converted by acid to the acid adieion salt. The reaction may, for example, be carried out according to the procedure described in Namec Patent 2 001 431 and Nymphatic Offanlagungasehrift 20 07 751.

Preferably, the leaving group B is a halogen atom, in particular a chlorine, bromine or iodine atom. Also included are the aromatic or aliphatic aulfonic acid groups, such as the p-toluoleulfonic acid group, the p-bromobenzenesulfonic acid group, or the methane * sulfonic acid group.

The reaction ae is carried out at temperatures varying from 10 to 120 ° C, that is, at ambient temperature or at ambient temperatures, preferably at temperatures varying from 50 to 120 ° C, at atmospheric pressures or in the eud produced at elevated pressure.

The starting compounds of formulas II and III can react with the base of a diluent or solvent. However, the reaction is preferably carried out in the presence of an inert diluent or solvent, such as a lower alcohol having from 1 to 4 carbon atoms, such as methanol, ethanol 111 propanol, preferably Isopropanol or ethanol, lower sweetened dialkylatar, dialkylglycol, or cyclic ether, such as au dlatylether, 1,2-dlmethoxylethene, tetrahydrofuran 111 dloxane, benzene light hydrocarbon such as benzoyl or alkylbenzene, especially toluene 111 kellol, 111 ethylphenyl hydrocarbon such as eu hekeen, heptene or octene, dlmethylsulfon water or bold apomenutlh solvent.

When used in excess, 1,1-dimethylpropylamine (2-Mati1-2-aminobutane) may also be a suitable diluent or solvent.

Lower alcohols, in particular ethanol or isopropanol, and in the preferred solvents in the reaction a compound having formula II, wherein

A represents a residue with an amine of formula III, wherein the aa reaction is preferably carried out at temperatures ranging from 50 to 12C. The reaction may optionally be carried out in a closed pressure vessel.

In the nucleophilic substitution of residue B, as a solvent, a cyclic aliphatic ether, epethelially tetrahydrofuran iii diokean iii, dlmethylsulfoxide and temperatures ranging from 90 to 120 ° C are preferred. The ee reaction may optionally be carried out in the presence of a catalytic amount of sodium or potassium iodide.

The phenol ether of general formula II may optionally also be used in the form of mixtures of epokeids with halohydrin, since in the technical preparation of starting compounds such mixtures may be trimmed.

In the root realization of nucleophilic substitution of residue B by an amine of formula III, the reaction ee is carried out in the presence of a base as an acid binding agent. Preferred bases are alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alcohols and especially methylates and ethylates, or some tertiary amine, such as eu pyrldine or some trialkylamine, such as eu trimethylamine or triethylamine. Of the alkaline compounds, the sodium and potassium compounds are in particular coriander. The base is used in stoichiometric or slightly larger quantities.

When ee is used in large amounts, the amine used for the reaction can serve as a kieeline binding agent in the summer.

The entirety of the cacophony, which was driven by reaction temperature 1, generally began with a motto of 2 to 1S Sasova. The reaction product oo may obtain a non-conventional non-Son, for example, by filtration 111 with distillation diluted from the reaction mixture ·. Typically, the compounds will not be treated in a conventional manner, for example, by reclamation from a solvent, conversion by addition with acid 111 by column chromatography.

A fanolater of Formula II can be obtained by alkylation of 2-hydroxybeta-fanylproplofenone having Formula IV

aa by apihalohydrin 111 with alpha, omega-respiratory-2-propanol. Examples of apihalohydrin and in apichlorohydrin, epibromhydrin and apiohydrin. Examples of alpha, omaga-dlhalo-2-propanol and in particular 1,3-dichloro2-propanol and 1,3-dlbromo-2-propanol.

The reaction of Compound IV for the preparation of the starting compounds of Formula II aa affixed affectively at temperatures varying from 0 to 120 ° 6 1 at normal pressure 111 in closed aud at elevated pressure. Podaanl solvent! 111 diluent and some other allfatlSnl caton, such as it au aoaton, metHat11katon 111 motilisobutylketone, some nonalcohol having 1 to 4 carbon atoms, such as itin methanol, ethanol, propanol 111 butanol, otherl alllatlSll 111 elkatlSll 111lalkyl , tetrahydrofuran 111 diocaan, some dialkylformamide, such as dlmotllformamide 111 dlotllformamld,

111 dlmatilaulfokald 111 trlamld haksamstllfosfomo kiaeline 111 vliak amount of arodlate for alclloing.

The reaction aa preferably results in a base as an aid for the kiaelin production. Submitted base in alkali metal carbonates, alkali metal bicarbonates · alkali metal hydrides 111 alcohols and alkali metals, in particular sodium 111 potassium ·, ./7 base oxides, such as in aluminum oxides or calcium tin oxide, organic tertiary base, organic tertiary base, and pyridine, lower trialkylamines, such as Sto eu trimethylamine or triethylamine, or piperidine. The bases can be used in catalytic ill a tachiomatrl Steel quantities or in slightly larger quantities than the alkylating agent used.

2-Hydroxy-beta-phenylpropiophenone preferably reacts with epichlorohydrin, epibromhydrin or 1,3-dibromopropanol-2 in a polar, aprotic solvent, determined by dimethylsulfokeide, at temperatures ranging from 0 to 50 ° C in the presence of at least one base equivalent, especially of sodium hydride, based on an alkylating agent.

The starting compound of formula IV, that is, 2-hydroxy-beta-phenylpropiophenone, and its preparation are known in the art.

The compound of formula I exhibits a chiral center on the carbon atom in the 2-position of the aliphatic side sequence. It is mainly obtained as a racemate that can be decomposed into optically active antipodes by known methods, for example, by trimming diatheraisomal salts with optically active kyaelines, such as dibenzoyl-vinca acids, camphor-10-sulfonic acid, ditoluylic acid 111 3-bromo-camphor -8-sulfonic acid.

The compound of formula I obtained according to the invention is optionally converted into the addition salt with kiaelin, preferably into salt with physiologically acceptable kiaelin. Common physiologically acceptable inorganic and organic acids, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, aumpoma acid, oxalic acid, maleic acid, fumamic acid, lactic acid, tartaric acid, malic acid, salicylic acid

- 7 acids, adlpinac clathline 1 banzoic acid. Other acid divisions are described, not by example, in the Fortachritte Gift of Arznslmittelforaohung, vol. 10, page 224-225, Birkhaueer Publlsher,

Basel and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, vol. 66, pages 1-5 (1977). Desirable I hydrochloric acid.

The addition salts of ea with acids aa are normally obtained in a conventional manner by changing the free bases or their solutions with the corresponding acid or solutions in an organic solvent, for example, some lower alcohol, such as methanol, ethanol, n-propanol or isopropanol, some lower caton , such as Sto au acetone, methylllatylketone or motll-isobutylcaton, or some ether, such as Sto au diatilatar, tetrahydrofuran or diokaan. The mixtures of the solvents mentioned can also be used for better crystal deposition. In addition, pharmaceutically acceptable aqueous solutions of the addition salts with the acids of the compounds of formula I can be made in an aqueous kiaal solution.

The acid addition salts of the compounds of formula I can be converted to the allobod base in a manner known to itself as, for example, ea alkaljama iii. Further aoli aa can be obtained from the free base by aa aa inorganic or organic kieallnam, aa given to those which are suitable for the cropping of tsrapautaki useful salts. These and other aoles of the new compound, such as Jo Jo Plot, can also be used to purify z

free base whereby aa free base translates into ao, which aa separates and freezes the base from aoli.

The present invention also relates to formeutical preparations for oral, rectal, intravenous administration and intramuscular administration, which, in the form of a carrier and scavenger, comprise a compound of formula I 111 for its active ingredient as an active ingredient. Oil ·

I

v refers to the use of a new compound and its physiologically acceptable salts in the trotation of a heart rhythm disorder.

The pharmaceutical formulations of the invention are conventional in the conventional way with conventional Solid or Liquid carrier or diluents and conventional pharmaceutical dosage forms in the form of a suitable dose. according to the desired application form. Preferred preparations are preparations in the form of a single dose for oral administration. Such pharmaceutical forms are. for example, tablets, film-coated tablets, dragees, capsules, pills, powders !, dissolve iii suspensions or depot preparations.

Parenteral preparations, such as in solution for injection, are of course also adjusted. Another pharmaceutical form to be mentioned is, for example, suppositories.

Suitable tablets can be obtained, for example, by mixing the active ingredient aa with known excipients, for example, with inert diluents, such as decurosis, sugar, sorbitol, mannitol, polyvinylpyrrolidone, chopping agents such as corn starch or alginic acid. binders such as au starch iii gelatin, lubricating agents such as magnesium stearate iii talc and / or depot effecting agents such as eu carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may have several layers.

Orazes can be made suitably by coating the inner palms, produced in an analogous manner to tablets, ea preparations commonly used in the coating of dragons, such as polyvinylpyrrolidone iii Selak, gum arabic, talc, titanium dioxide or Bacar. The stimulus wrapper can also contain several layers, where they can use the nighttime remedies above in the tablet village.

Dilutions or suspensions comprising the active ingredient found may additionally contain flavoring agents, such as saccharin, clklamat 111 Sadar, and primary. flavors »such as vanillin or extract of pomorandis. Moreover, they may contain suspending aids such as sodium carbocalmethylcellulose or discolor. such as p-hydroxybenzoatl.

Capsules containing active aaatojak may aa. for example, "make a change of the actuator with some inert carrier" as

Lactose 111 sorbitol, 1 capsule into gelatin capsules.

Podssns suppositories can be made by mixing the active ingredient with a suitable carrier »such as the neutral fat 111 polylethyl glycol or their derivatives.

In humans »Single dose I of 0.5 - 5 mg / kg for oral administration of 0.05 - 2 mg / kg for intravenous administration of 0.1 - 3 mg / kg for intramuscular administration of 0.5 - 10 mg / kg for ractal administration.

Under the above mentioned conditions described in H.3. Hapke and E. Prlgga »Arznsim-Forach. (Drag Ras ·) · loc. cit. in the modal arrhythmias of "Formula I" conjugates, i.e., "2- / 2 * -hldrok8l-3 '- (1" 1-dimethylaminexpropylamino) -propoxy / -b * ta-phenylpropiophenone (dlprafanone) unexpectedly shows off with antiarrhythmic staccato 0.05 mg / kg in intravenous infusions, which is twice as long as the required dose of ra-Forant supapanoa propafanone.

This supposedly anti-arrhythmically fibril compound is not accompanied by a correspondingly large increase in toxicity. See this with motto 'from the comparison of U> _so vradnoatl on paoi 1 palm which au aumarl - ** called in tabliol X..

Table I

LO ₅ q (mg / kg) propafenone-HCl diprafenone-HCl rat iv rat oral dog iv

16.6

16.9

760

15.0

1060

10.0

From this it can be seen that the therapeutic quotient of diprafenone is increased 10 to 20 times compared to propafenone.

The antiarrhythmic effect of the compounds of Formula I was tested for pee according to the procedure of Hapke and Prigge, Arzneim.-Forech. (Drug Red.), Loc. cit.Modern arrhythmia, characterized essentially by bentricular extrasystoles at absolute arrhythmia, is produced by the infusion of chloroform and adrenaline (epinephrine). When these rhythm disorders occur, the compound of the invention is injected intravenously as an aqueous solution of hydrochloride.

An intravenous dose as small as 0.05 mg / kg was fully effective within 45 seconds on all furnaces

Being treated, that is, the sinus rhythm in the electrocardiogram (ECG) became normal.

Again on pslma, a great antiarrhythmic effect was also observed after oral administration. Rhythm disturbances are produced by occlusion of the coronary vessels branch. The compound of the invention is administered intragastrically in the form of a chloride hydrate of the day. Observed in unchanged ecetraaistol for 10 minutes after administration of 10 mg / kg.

Minutes of job receipts could not be observed extra-aistole.

ECG remained normal for 24 hours during which time I studied.

1 "Table XX shows further results of fan-like father-in-law tastes" with the aforementioned compound in the form of chlorhydrates and aa with propafsonone-HCl. For the testing procedure, see H. J. Hapke and E. Prigge, Arzneim.-Forsch. (Drug Ras.) «Loc. cit.

All of the above test results suggest that the compound of formula 1 (diprafenone) is also used in human medicine as an antiarrhythmic, similar to propafenone, however, at substantially lower doses and thus with lower toxicity.

z * .j · * * \ -; '-' 4 ../- ..- - ,. : ί.-'- '/ - Ν ·' - '^'

I <0 (Π

I

O rx i

«O 4 + rx en« Φ <f

I + β

C • Η

ΙΝ α

-ρ

S α

β r-4 α

Ρ ο

(The magnitude of mo t io in uo oot id q * t «n cn« t (\ io * t cn cn in (N m in

II II I II 0 4- I I + + + rx _ «t (N o Nr-O (NO (NO o and O T- oo o» III I + · + + + α

Ν

Ο

Ι ιη ο

<π β

ο ιη ο

_ Ǥ *?

• κ *?

-Ρ -Η

Si h- "J"

λ and ϊ

h

4 »s i

B U <n t · i

(Oh

I

CD

I o o o o o o ao. oo. oo. o α. oo. a o. a a. oo.

Ji «

Ji α

; 3 * 3 «

SE

1 '1 Si • P (0 o

c rH a

Ό

O> o «

c

N a

<0 α

ee * 5 α 5 o o i s α

c «?

a r

Se ss S

IHil

8 "31 8« P c • s s «} l H h li U Ji" il H K Π ih

$ 5 significant affect

Unexpected I 1 could not detect that when used in dose dosing, the compounds of the invention had no effect on perlema and coronary ejaculation, despite their strong similarities to the known 2- (2'-hydroxy-3'-alkylaminopropoxy-beta-phenylpropiophenone It has approximately 20-fold greater effect in heart rate disorders than propafenone in spite of the fact that it has an approximately hamodinanic activity, and ifiormula I can therefore be used at substantially lower doses than propafnone, which results in a significant reduction in side effects in the treatment of cardiac arrhythmias.

Moreover, it is significant that, in contrast to propafenone, the compound of the invention already produces a decrease in the speed of the heartbeats at doses of 0.5 mg / kgl.v.

Which is advisable in erratic speed rhythms.

The invention is illustrated by examples.

Example 1

a) Preparation of 2- (2 ', 3'-epoxypropoxy) -beta-phenylpropiophenone

22.6 g (0.1 mol) of 2-hydrocai-bsta-phenylpropiophenone were dissolved in 150 ml of 1-chloro-2,3-epoxypropane. Addition of 12 g of potassium carbonate The reaction mixture was warmed with stirring and refluxed until weekly high-pressure chromatography showed that the reaction was complete. The reaction mixture was then allowed to cool. The formed potassium chloride is subsequently filtered. The filtrate was condensed under reduced pressure while the excess of 1-chloro-2,3-epoxypropene was thus distilled from the 2- (2 ', 3'epoxypropoxy) -bot-phenylproplofenone obtained. The crude product obtained is a yellowish oil that solidifies at room temperature when the salt is allowed to settle for a while (yield 28 g »98%). The ns product must be refined for alsded fsza. The pure substance obtained by the lysaoic recovery from a quadruple amount of methanol has a melting point of 56 ° C.

^ε ΐβ ^Η 1β ° 3 'calculated calcd

76.58

76.92

6.42

6.38

b) Preparation of 2- (2'-hydroxy-3 * - (1,1-dimethylpropylamino) -propoxy / beta-phenylpropio-phenone-hydrochloride (diprafenone-HCl) g (0.1 mol) of the compound obtained according to Example 1a) was dissolved in 100 ml of methanol and treated with 26 g of 1,1-dimethylpropylamine (2-methyl-2-amino-butane). The reflux was then refluxed for 4 hours with stirring. The reaction mixture was then evaporated under alternating pressure. The resulting residue was dissolved in 100 ml of isopropanol _t with warming and adjusted to pH 1 with concentrated 36 t hydrochloric acid. The mixture was allowed to stand at room temperature while the hydrochloride was precipitated in the form of crystals. The common crude product (about 36 g) was recrystallized from the same volume of isopropanol. Chlorhydrate was obtained in a yield of approximately 33.0 g (81.3%) as a white crystalline substance having a melting point of 130 to 131 ° C. The values for pure substance analysis are consistent; theoretical values.

c ₂₃ ^h 32n ° ₃ and calculated

C H N 68.05 7.94 3.45 67.97 7.91 3.72

Example 2

2- ^(2-hydroxy-3 * -bromopropoksi) -beta-phenylpropiophenone is reacted with an equivalent količinom 2-methyl-2-aminobutane in the presence dimetilformomida as solvent and sodium carbonate as a kiselinskog acceptor refluksovanjem flow nekolikOo hrs. Diprafenone hydrochloride melting point 130 ° C is obtained after the reaction mixture is treated according to Example 1b).

- 15 - ^; '··

P rimar 3

Example 2 ee was repeated aa 2- (2'-chloroxyl-3 * ~ chloropropoxy) -beta-phenyl propiophenone, so that ee obtained dlprafenone-chlorochloride melting points 1S0-431 ° C.

Example 4

Production process for tablets

a) Saetojcl diprafenone-HCl 75.00 g microcletallic cellulose 15.75 g (powder, 50 µU) poly- (1-vinyl-2-pyrrolidone) 5.00 g hydrocapropylmatyl cellulose 2910 3.75 g magnesium etherate 0.50 g

100.00 g

b) Mixing and granulation

Diprafenone-HCl is optionally sown. All crude material except magnesium stearate is then moistened with an amount of granulation fluid (for example, water or isopropanol-dichloromethane 1: 1) The wet mixture is passed through a suitable sieve, dried in a drying cabinet and sown again. The dried granulate was mixed with aa magnesium stearate in a mixer.

c) Pre-coating preparation

70.01

26.71

3.31

100.001 talc calcium sulphate hemihydrate fine dieparginated ailic dioxide

d) Suspension for coating for dragons

aeharose 47.8% talk 9.6% calcium sulfate hemihydrate 4.8% gumiarabika 3.6% Starch syrup 3.2% Macrogol 6000 2.9% titanium (IV) -oxide 1.6% sodium um-dodecyl sulfate 0.1% distilled water 26.4%

100.00%

Dragging the inside of the dragons

The inner dragees of the dragee are first wetted in a rotating vessel with the dragee coating solution and then sprayed with enough pre-coating preparations to allow them to roll freely. once the internal parts have dried, this process is repeated. The internal parts are then further dried in the cabinet /

for drying. The inner parts are then coated layered with a drag suspension coating until the desired final weight has reached. The inner parts of the ee must dry before applying each layer.

Sifting tablets

The mixture made according to a) is transformed into tablets, in tablet presses, weighing from 40 to 400 mg. The compression power and the diameter of the tablet are selected so that the reading time is in the test unit at £ ur. Pharm. less than 15 minutes and the tablets are mechanically stable enough.

Example 5

Production process for film coated tablets' 7

A. SeatoJci

a) tablet (see manufacturing process for tablet, example 4)

b) Film coating

Total Aunt Received is 5-20% by weight of the tablet and amounts to hydroxylpropyl methylcellulose 2910 77%

Nacrogol 6000 (plasticizer) 23%

B. Making tablets (see tablet manufacturing process, Example 4)

C. Making film-coated tablets

The components of the film coating are dissolved in a separate solvent (for example water or ethanol / water 70:30). The tablets are sprayed in a film coating apparatus with a solution containing a film forming agent and a plasticizer of 1 liter with hot air stream. The film-coated tablets continue to dry in the drying cabinet.

Example 6

Manufacturing process for teasers

A, Ingredients

a) The inner part of the teaspoon (see manufacturing process for tablets)

b) Pellets irritate the total received amount of 25-100% of the inner weight! * also gave aadrha eharose

51.4¾ talc 24.0¾ calcium sulphate h emi hydrate 10.3¾ starch syrup 5.0¾ gum arabic 3.9¾ Macrogol 6000 2.9¾ titanium (IV) oxide 1.6% finely dispersed silicon dioxide 0.6% sodium um-clodeci lsulf at 0.1%

100.0%

B. Making the inner parts of the dragee (See tablet manufacturing process)

C. Making drags

A dragee preparation, a pre-coating preparation and a suspension with a dragee were used a) a dragee solution

sucrose 47.6% starch syrup 18.1% gumiablka 3.6% deethylated water 29.5% 100.0% Example 7 Production process for capsules А. Active ingredient dose of 75 mg i more 1. Ingredients diprafanone-HCl 75.00 microcrystalline cellulose powder. 16.25 50 ^ um poly- (1-vinyl-2-pyrrolidone) 5.00 hydroxypropyl methylcellulose 2910 3.75

100.00 g

a

2. Mixing 1 French according to Example 4b).

3. Fill granules into capsules

The srenulate is filled with the aid of a capsule-making machine into hard gelatin capsules of sizes 3, 2, 1 or 0, wherein the amount filled into each capsule depends on the desired dose of the active ingredient.

B. Active eaetose dose 30-75 mg

1. Saatojoii diprafenone-HCl 30.00-75.00 g microcrystalline cellulose powder, 50, _ 61.25-16.25 g poly- (1-vinyl-2-pyrrolidone) 5.00 g hydroxypropylmethylcellulose 2910 _3.75 g_

100.00 'Mr

The sum of the active eaetol and microcrystalline cellulose amounts should always be 91.25 g. The amount of active eaetol is 100 times the single dose.

2. Mixing and granulation according to Example 4b).

3. Fill the granules into capsules

100 mg of each granule is filled into hard gelatin capsules of size 3 or 2 using a capillary machine.

Example 6

Production process for ampoules

1. Ingredients of diprafenone-HCl water with a 1 in

1.5 g 100.0 ml ./·.· '·· M <

zv r ·

Making a solution

90% of the water required for the selected batch is placed in the reaction eud. The active eastwash ee dissolves in said water with heating. The final volume is achieved by adding the required amount of solution after cooling.

3. Fill the solution into ampoules

The refined solution will be filled into ethanol vials, with the charged amount dependent on the desired dose. The glass ampoules are then sealed by stepping.

4. Sterilization

The vials were steam sterilized for 20 minutes at 120 ° C.

Example 9

Production process for epositories

a. diprafenone - HCl 30-200 mg hard fat (melting point

35-36.5 ° C) to 2000 mg

b. Making a melt containing the active substance

The amount of hard fat required for a specific number of suppositories is thawed in a 40 ° C water bath. The active nozzle was pressed through a 0.8 mm sieve and mixed into the melt to give a suspension.

c. Making suppositories

The melt was allowed to cool to 37-38 [deg.] C. and filled ee with a gentle stirring into the suppository forms in such quantities that the weight of one epository was 2000 mg.

mostly nadln 'for the intestines of invention u prlvredl te ** it filmed by RnjaVlocu

Finding a note is best done at the same time as the following procedure:

g of 2- (2 ', 3'-epoxypropoxy) -beta-phenylpropiophenone was dissolved in 100 ml of methanol and treated with 26 g of 2-methyl * -2-amino-butane. the mixture is then heated under reflux of 4 Sasas with stirring. Then the reaction mixture was evaporated under reduced pressure. The resulting residue was dissolved in 100 ml of isopropanol with warming and adjusted to pH 1 with concentrated hydrochloric acid. The stable * was allowed to stand at room temperature while the hydrochloride was precipitated in the form of crystals. 38 g of the crude product obtained are recrystallized from 38 g of isopropanol.

33 g (81.3%) of 2- (2'-hydroxy-3 '- (1,1-dimethylpropylamino) propoxy / Hsetartheneproprophenone hydrochloride are obtained.

Claims (2)

A process for the preparation of 2- (2'-hydroxy-3 '- (1,1-dimethylpropylamino) propoxy / S - phenylpropiophenone of the formula: ch ₂ ch ₂ -c CHI ³ O-CH ₂ -CHOH-CH ₂ -NH-C-CH ₂ -CH ₃ CH (I) and its acid addition salts, which is phenol-ether of the general formula: o-ch ₂ -a time (II) A in which A represents either the -CH-CH ₂ group or the -CHOH-CH ₂ -B group, wherein B is a leaving group such as Cl or Br, reacts with 1,1-dimethylpropylamine of the formula: CH, I ³ H ₂ NC-CH ₂ CH ₃ CH-, (III) in an organic solvent such as methanol or dimethylformamide at reflux temperature and, when A represents the group CHOH-CH ₂ -B, in the presence of an acid acceptor such as Na ₂ CO ₃ , to give the desired compound of formula (I), which is converted to its acid addition salt as needed. HELOPHARM W. PETRICK & CO. KG - - $ 2 -. .. · 'V'. ^Γ · <'' s '' ABSTRACT 2- / 2'-Hydroxy-3 '- (1,1-dimethylpropylaroino) -propoxy / beta-phenylpropiophenone of formula I ^CH 3 _O -ch ₂ -choh-ch ₂ -nh-1-ch ₂ -ch ₃ (I) O- ^CH 2 ^CH 2- ^E Aj ki its acid addition salts. Further, the preparation of this compound and its acid addition salts is described. The compound and its acid addition salts have an antiarrhythmic effect. Therefore, they can be used to treat heart rhythm disorders.