DE1768970A1 - New Diarylaethylamines and Processes for Their Preparation - Google Patents

Description

Dr. F. Zumsfein - Dr. E. Assmann

Dr. R. Koeriiqiberqer Dipl. _Pfiyi . R. Hol-bjuer

Palentanwuiia Munich 2, Bräuhaussfrafre 4 / lli

45/30 / l. ^r o

Case 4-2650 / GC 148 CIP *

J.R. Geigy AG, Basel / Switzerland

New diurylethylamines and processes for their preparation

The invention relates to new diarylethylamines, in particular üubr.ti tu Lert e N- / 2-phenyl-r '- (2-hydroxy-Inaph thyl ^ / äthy'l-N-subat i tu Lert e-anitne and their salts j process for the hera te! ment diciit'i · prebindings and pharmaceutical Zuari-nraernj et ignite, which contain the:; e compoundi ': 4> en ak; active Beatanäteil.

It was found that U'M, (vitt die Vei'bindurx ^ en der .1 l ^ eme Lnen Form ':] I

v. ff /

'1 i \

MR

H ₅

^{ »BAD ORIGINAL

109882/1785

in the

W is hydrogen, fluorine, chlorine, bromine or hydroxyreate, X and Y, independently of one another, are each a V / as3oxid, fluorine, chlorine, hydroxy or lower alkoxy radical, Z is a hydrogen, hydroxy or hydroxymethyl radical, R _{1 is} a hydrogen, methyl or ethyl radical, R ₂ * Rz »R, and R ^ independently of one another a V / ass first off or methyl radical and

R ^ is a water, methyl, phenyl or hydroxyphenyl radical mean

and their acid addition salts with inorganic or organic Acids have valuable pharmacological properties. In particular these compounds of the formula I have the ability to normalize irregularities in the rhythm of the candlestick and are therefore suitable for normalizing various arrhythmic conditions. They also exhibit connections also has hypotensive and local anesthetic properties. Those found for the compounds of general formula I. pharaakological properties indicate that they are particularly useful in the treatment of primary arrhythmias, both those caused by drugs, btJinpLeLswise due to an overdose of adrenaline or Cardiac glycosides, such as digitalis or ouabain, as well as those which occur in certain heart diseases.

The term "lower alkoxy" used means alkoxy groups, which contain more than 3 carbon atoms. examples for such lower alkoxy groups are methoxy, xthoxy, propoxy and [nopropoxy groups.

109882/1785

The compounds of formula I and their acid addition salts are prepared by adding a compound of the general Formula II

-CO-N-C-CH

R.

I \

(II)

in the

Z ^{1 is} a hydrogen, hydroxy, carboxy or IT-lower alkoxycarbonyl radical and

W, X, Y, R., R ₂ , R 1, R ₄ , R ₅ and Rg have the meanings given in formula I, reduced with the aid of a reducing agent in an inert solvent and, if desired, the product obtained in an acid addition salt converts with an organic or inorganic acid.

Suitable agents for the reduction of amides of formula II are hydride-donating agents such as the boranes, for example Borane, diborane and the like, and complex hydrides such as e.g. Lithium aluminum hydride, llodium borohydride in the presence of a Lewis acid and the like, with diborane and lithium aluminum hydride being preferred. The reduction with the help of these reducing agents becomes wacky in an anhydrous, etherealike Solvents, for example diethyl ether or tetrahydrofuran carried out. The mixing of the reactants is carried out

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ft

preferably at low temperatures in the range of -10 to 15 ° and carried out in a nitrogen atmosphere, especially when diborane is used to counteract the then occurring Convenient to control implementation, in the final stages of the process generally at the reflux temperature the reaction mixture is completed. Any carboxyl or carboxyl group present in a compound of the formula II Lower alkoxycarbonyl group, e.g. methoxy or ethoxycarbonyl group, becomes the hydroxymethyl group in the process reduced.

The new amides used as starting materials, which by the Formula II are included and have the structure of the general formula III

OH | 3/4

CH-CO-N-C-CH (III)

R «Ro

in which V /, X, Y, Z ¹ , R ₁ , R ₂ , R ,,, R ₄ and R have the meanings given in formula II, by reacting a compound of the general formula IV

(IV) BAD OBiGiNAL

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in which V /, X, Y and Z ^{1 have} the meanings given above, with an amine of the general formula V

Κ · - »“ R.

I ^3/4

H-N-C-CH (V)

R ₁ R ₂ R ₅

in the R, R _? , R- ,, R. and R ₁ . have the meanings given above,

getting produced.

The reaction can be carried out using a sufficient excess of the amine of formula V, which acts as a solvent. Alternatively, as the solvent, a Nieclriga] Kanol, ^eg ethanol, used v / ground, in which case the amount of the amine used be considerably reduced k-inn, to 1.1 Bi, K) e molar equivalent, based on the Vf The reaction used in this conversion; temperatures are in the range from I ^ to ζ U ν Il ück t L Ufi L ern ρ era t tu ¹ , *

The new aniids, ..1Lo die, structure folded over by the i'crmel EE der a 1 1.:;·'·ΐηοίηι-.·η form fs ί v'I Ijaben

(VI)

CH ■ Jt) - ■: -i - C - iJH

BAD ORiC; U9B82 / 1785 ---

in the

W is a hydrogen, fluorine, chlorine or bromine radical, Rg is a methyl radical and

X, Y, R ₁ , Rpf R3 »R ₄ and R ₁ - have the meanings given in formula II,

can be prepared, for example, by adding a compound of the formula VII

CH - COCl (VII)

in which V / ¹ , X, Y and RJ- have the meanings given above, treated with an amine of the formula V in the presence of an acid-binding agent. An excess of amine can serve as an acid binding agent.

The acid chlorides of the formula VII can in turn be prepared by reacting the carboxylic acid corresponding to them with a Chlorinating agents, for example thionyl chloride, treated.

The carboxylic acids corresponding to the acid chlorides of the formula VII can also use compounds of the general formula VIII

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_M * 7

(VIII)

in which W, X and Y have the meanings given in formula VI,

can be obtained by treating them with a low-alkylene agent treated in the presence of a base, for example with dimethyl sulfate in the presence of sodium hydroxide.

A number of the compounds encompassed by Formulas IV and VIII are known * others can be prepared using the compounds disclosed in US Pat Process described in the literature for the preparation of substituted 1-phenyl-2-oxo-1,2-dihydronaphtho / 2,1-bJ7-furane be, for example by condensation of ß-naphthol or a substituted ß-uaphthol with! .land el acid, an ester thereof or any substituted: i derivative thereof at increased Temperature, if appropriate in the presence of an acidic catalyst.

A number of the compounds encompassed by Formula I having the structure of Formula I-A

- HH - CH - CH

R.

Rr

(I-A)

Y "

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in the

W "a hydrogen or hydroxy radical, X" and Y "independently of one another a hydrogen, hydroxy or lower alkoxy radical,
RX is a methyl radical and

R ₄ and Rr independently of one another mean a hydrogen or methyl radical,

and their acid addition salts with inorganic or organic acids can be prepared by adding a compound of the general formula IX

- N = C - CH

(IX)

Y "

in which W ", X", Y ", RJl, R ^ and R ₁ - have the meanings given above, reduced in an inert solvent with a reducing agent and, if desired, the product obtained in an acid addition salt with an inorganic or an organic acid converts.

The reducing agents expediently used for the reduction of the imines of Formula IX are catalytically activated hydrogen or hydride donating agents. I) as the hydrogenation process is advantageously carried out in a low-alkanol solution, for example in methanol, ethanol, propanol or isopropanol, at elevated pressures up to 50 atmospheres, optionally at

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elevated temperatures. This procedure is of particular importance for the preparation of compounds of the formula I-A, in which X "and Y" independently represent a hydrogen, hydroxy or Ethoxy radical, R, a llethyl radical and R. and R, - a 7 / hydrogen radical mean. Furthermore, imines of the formula IX can be obtained by hydride-supplying agents, for example diborane or Lithium aluminum hydride, in an ethereal solvent, for example diethyl ether or tetrahydrofuran, or by an alkali borohydride such as I sodium borohydride can be reduced in a low alkanol solvent.

The imines of the formula IX can be prepared from an amine of the general Formula X

.CH - CH ₂ -

(X)

in which W ", X" and Y "have the meanings given in formula IX are prepared by reacting this with a compound of the general formula XI

(XI)

'Rrr

I ³ /

O = C - CH

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in the

R4 is a methyl radical and

R. and R _{5 have} the meanings given in formula IX,

in the presence of a strong acid, wherein the reaction is carried out in an inert solvent.

Suitable solvents are lower alkanols, for example ethanol, and suitable acidic condensing agents are, for example, hydrochloric acid or p-toluenesulphonic acid. The condensation of the amines of the formula X with the carbonyl compounds of the formula XI is advantageously carried out at the reflux temperature.

A number of the starting amines of the formula X are known; others can be prepared by known processes, for example from suitably substituted β-naphthols and * -aminomethylbenzyl alcohols.

According to a second process, the compounds encompassed by the formula I can have the structure of the general formula IB

S CH ₃

CH - CH ₂ -HH-CH- (IB)

^ CH,

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- 1 Λ _

in the

X "denotes an hydrogen, hydroxy or lower alkoxy radical, and their acid addition salts with inorganic or organic acids are prepared by reacting β-naphthol with a compound of the general formula XIII

OH _CH

. CH - CH ₂ - KH-CH (XIII)

^ CH,

³ i

in the

X "'is a hydrogen, hydroxy, lower alkoxy or Lower alkanoyloxy radical means in an inert solvent condensed in the presence of an acidic condensing agent and optionally converting the product obtained into an acid addition salt with an inorganic or organic acid.

The reaction is expediently carried out in a solvent such as a lower alkanecarboxylic acid, preferably vinegar -

acid. Although 3 ^e <it is suitable for carrying out the condensation * acidic condensing agent which can XI protonate the hydroxy group in the compounds of Pormel, it has been found advantageous, as condensate! Onsmittel p-toluenesulfonic acid to be used, whereby also hydrochloric acid or sulfuric acid can be. Compounds of formula IB, in which X denotes the hydroxyl group, are obtained in a one-step process from compounds of formula XIII in which X "* denotes a lower alkanoyloxy group which

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Serves as a convenient protecting group because the alkanoyloxy group is converted to the hydroxy group in the process.

Examples of lower alkanecarboxylic acids are acetic acid, propionic acid and butyric acid; lower alkanoyloxy groups are defined as acetoxy and propionoxy groups, with the acetoxy group being preferred.

This method is particularly useful for preparing the compounds of Formula I-E in which X is the hydroxy group means.

]) he starting compounds of the formula XIII are known or can be prepared from known compounds by methods described in the literature.

The compounds of the formula I have at least one asymmetric carbon atom and therefore occur in optically active, enaniiomorphic forms which are isolated from the reaction mixtures as hacemates. These racemates are known by the well-known process of salt formation with an optically active iic acid, for example d- or 1-V / one-acid, and fractional crystallization in which the diastereoisomeric salts obtained are separated from one another. Both the racernisciion al r, as well as the optically active forms of the compounds of the formula I belong to the range of the present ^ n Jid

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The compounds of formula I form with inorganic and organic acids acid addition salae. Particularly useful Acid addition salts are those that are pharmaceutically acceptable and are non-toxic. These salts include those those of inorganic or organic acids, for example Hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, Lactic acid, succinic acid, malic acid, aconitic acid, phthalic acid and tartaric acid.

The following examples are intended to explain the processes for the preparation of the compounds according to the invention in more detail. but without limiting it to that. The temperatures are given in C.

BAD ORiGSNAL

7 β ΰ

example 1

a) A solution of 51.4 g of N-isopropyl-2- (2-hydroxy-1-naphthyl) ~ 2- (4-hydroxyphenyl) acetamide, P. 178 ° (decomp.) In 500 ml of tetrahydrofuran was added dropwise to 462 ml of a 1m solution of diborane in Tetrahydrofuran added. After the addition was complete, the reaction mixture was refluxed for 4 hours, the cooled reaction mixture was acidified by the careful addition of 800 ml of 3N aqueous hydrochloric acid, and

the tetrahydrofuran was removed by distillation. The pesticide separated from the aqueous phase was collected and recrystallized from ethanol / ether and gave N-isopropyl-2- (2-hydroxy-1-naphthyl) -2- (4-hydroxyphenyl) ethylamine hydrochloride, P. 248 ° (decomp.). The free base made from this hydrochloride with aqueous sodium hydroxide melted 162.5 ° The acetamide derivative used as starting material in the above reduction was prepared as follows:

b) A mixture of 25 g of ethyl p-methoxymandelate, 34.3 g of β-haphthol and 1.5 g of p-toluenesulfonic acid was used Heated to 180 ° for 75 minutes and then to 200 ° for 45 minutes The cooled! .Lasse was crushed under 25 ml of ethanol, and the insoluble portion was collected and washed with some ice-cold ethanol. After the recrystallization from dilute acetic acid, 1- (p-methoxyphenyl) -2-oxo-1,2-dihydronaphtho / 2,1-b / -furan was obtained in the form of white crystals, P. 146.5 am 147, '3 °.

109882/1785

BATH ORIGINAL

the

The used used for preparing / in the following examples as starting materials N-substituted s 2, 2-diaryl 3-substituted acetamides 1-phenyl-2-oxo-1,2-dihyäronaphtho- / 2 "1-b_7-furan derivatives can in an analogous manner from suitably substituted luandelic acid derivatives or their lower alkyl esters and β-naphthols by the process described above.

c) A mixture of 25.7 g of 1- (p-I.Iethoxyphenyl) -2-oxo-1,2- | j

dihydronaphtho / 2,1-by-furan, 274 ml of glacial acetic acid and 103 ml of 4B aqueous hydrogen bromide were refluxed for 4 hours. Each standing for Geesthacht at 0, the precipitate was collected and v with ^one,: enig washed dilute ethanol to give 1- (p-Eydroxyphenyl) -2-oxo-1,2-dihydronaphtho / 2,1-b / -furan in Form of gray-white crystals, P. 220 to 221 °.

d) A solution of 47.6 g of 1- (p-hydroxyphenyl) -2-oxo-1,2-dihydronaphtho / 2,1-b / -furan in 350 ml of isopropyl amine was refluxed for 2.75 hours. The excess An.in was removed by distillation, never leaving last traces prevented! »jerk. The residue was dissolved in 1 liter of allyl acetate and this solution was added twice in 200 ml portions 3N aqueous hydrochloric acid and then once with 200 ml V / a sr. he washed. The solution was over or sodium sulfate dried and concentrated under reduced pressure. The oily one iiCr. The stand was dissolved in benzene and used as a solution

109882/1785 1 L

gray-white crystals separated from U-isopropyl-2- (2-hydroxy- 1-naphthyl) -2- (4-hydroxyphenyl) acetamide from, mp 178 ° (dec.).

The starting materials used in the following examples N-substituted 2,2-diarylacetamides can be used in an analogous manner after the process just described from a substituted 1-PhenyJ-2-OXO-1,2-dihydronaphtho / 2,1-b / -furan and dem suitable amine produced.

Example 2

A solution of 14.0 g of N-isopropyl-2- (2-hydroxy-1-naphthyl) -2- (4-methoxyphenyl) acetamide, M.p. 138 ° (dec.) In 200 ml of tetrahydrofuran was added dropwise to 120 ml of an at O under Nitrogen-held 1m solution of diborane in tetrahydrofuran was added. After the addition was complete, the reaction mixture was refluxed for 12 hours. The chilled The reaction mixture was acidified by carefully adding 480 ml of 3N aqueous hydrochloric acid and the tetrahydrofuran was then removed by distillation. The white solid separating out of the aqueous phase became collected and dried by azeotropic distillation with ethanol / berzol. The gray-white solid obtained in this way, mp 228 ° (decomp.) was uracrystallized twice from ethanol / ether and yielded N-Isopropyl-2- (2-hydroxy-1-naphthyl) -2- (4-methoxyphenyl) ethylamine hydrochloride in the form of white crystals, F. 236 (dec.).

BAD ORIG / NAL 109882/178 5

Delopie L 3

A solution of 7.1 g of N-13opropyl-2- (4-chlorophenyl) -2- (2-hydrox, γ-1-naphthyl) acetamide, mp 165 ° (Zera.) In 44 ml of tetrahydrofuran was added dropwise 61 ml of a 1m solution of diborane in tetrahydrofuran kept ^{at 0 0 under nitrogen were added.} After the addition and refluxing for 4 hours, the cooled reaction mixture was acidified by carefully adding 260 ml of 3N aqueous hydrochloric acid. The tetrahydrofuran was removed by destination, and the solid which had separated out in the aqueous phase was recrystallized from ethanol / ether and yielded N-1 ου propyl-2 - (? - hydroxy-1-naphLhy 1) -2- (4-oh lorpheny1 ) -äthylaminhydroeblorid, P. 2 ?? ° (Zerr ,.).

B a ρ ij-, ν) 4_

A solution of 10.1 g of N- [nopropy] .-;.! - (3-chl (jr-4-hydroxyphutjy L) 2- (i'-hyüroxy-l-naphthy l) -acetaraide, I · ¹ 172 ° (cert.) In Ii) O mi

Tetrahyürüfur.m was added dropwise to 82 ml of one at 0 under ™

^ tickst Oi fg final t en ^ n 1m solution of Iüboran in tetrahydrofuran i'.u [', e <' :. ijb (: ii. N; -> h der "u ^ ü, ■■ · ur.d" 5, S-hour cooking at the Hüf.'K.-i'luü v.'Uf: Ui di *; gfcKüh II f lit::; ·. Ti on: -üri i u-hun. ·; By vorsi -lit L- '>:

Encore! volt 3.:'ü hi 1:>: i, vii I ¹ I ₁ -; er 'h lor .tu ; ers to ff rsäuro ii! ;; esäucri. l'ci.5 ^r i; _; : t, rai: yii \): U ^ -ui became du.fc; h i'e 31 11 lation entl't-i'nt., and ti; ■?! · iiK'i der wäßri ', -. ; ih'tst- ab 5 -hi t-dr: riti Feiit.- .; t .. · Ti 'viu'de ge: Kur; Uit'1 t and i'-weirnaJ au .; EthaiuiJ. > ^f k tiier iiiakrl st a I 1 L :: i tr t. and orgal- i \ ^r -Ioopr -ipyl-P- i. . ^; --hy -Ivcizj 1-ntpii ttiy! ) -? - (^ - chl-u ¹ - 1 ■

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hydroxyphenyl) ethylamine hydrochloride in the form of white crystals, mp 258 ° (Zero.).

Example 5

A solution of N-isopropyl-2- (3-chloro-4-methoxyphenyl) -2- (2-hydroxy-1-naphthyl) acetamide in 105 ml of tetrahydrofuran was added dropwise to 140 ml of one at 0 under nitrogen held in solution of diborane in tetrahydrofuran added. After the addition was completed, the reaction mixture became Boiled under reflux for 4 hours, cooled and acidified by careful addition of 6], ° ml of 3N hydrochloric acid. The tetrahydrofuran was removed by distillation, and the solid which separated out from the aqueous phase was collected by filtration and several Ials out Ethano L / ether recirculated and yielded N-isopropyl-2- (3-oh lor-4-methoxypheny O-i '- ^ - hydroxy-i-naphthy ^ ethylamine hydrochloride in the form of white crystals, mp 254.5 ° (decomp.).

Example 6

A solution of 14.8 g of II-Lert.-Butyl-2- (2-hydroxy-1-naphthyl) - ?. ~ (<\ - hydvüZj _t henyl.) -Acetamide, m.p. 178, ^r > ° (dec .) in 10 ml Tetrahydro for. tu was added dropwise to 130 ml of a 1m solution of diborane in tetrahydrofuran / lu kept at 0 ° under nitrogen; e, -; above. After boiling under reflux for 4 hours, the cooled (0) reaction mixture was acidified by careful t: von S7ü nil in hydrogen chloride. That

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Tetrahydrofuran was distilled off, and from the Solids deposited in the aqueous phase were collected. Kaeh four recrystallizations from ethanol / ether gave dark yellow crystals of N-tert.-3utyl-2- (2-hydroxy-1-naphthy1) -2- (4-hydroxyphenyl) ethylamine hydrochloride, P. 261.5 ° (decomp.)

Example 7

A solution of lI-p-hydroxypheneth-2'-yl-2- (4-hydroxyphenyl) -2- (2-hydroxy-1-naphthyl) acetamide, F. 155 to 160 in 75 ml of tetrahydrofuran was added dropwise to 100 ml of an at 0 kept under nitrogen in a solution of diborane in tetrahydrofuran admitted. After 4-st and ig a / punching at reflux the cooled (0 °) reaction mixture was acidified by carefully adding 400 ml of 3N hydrochloric acid. Bas Tetrahydrofuran was removed by distillation and the white solid separated from the aqueous phase became collected and recrystallized from ethanol / ether and gave 1- (4-hydroxyphenyl) -2- (2-hydroxy - 1-naphthyl) -2- (4 '-hydroxyphenethylamino) ethane hydrochloride, P. 242 ° (decomp.).

Example 8

A solution of 15 »0 g of N-isopropyl-2- (3» 4-dichlorophenyl) -2- (2-hydroxy-1-naphthyl) acetamide, M.p. 172.5 ° (decomp.) In 150 ml of tetrahydrofuran was added dropwise to 116 ml of a kept at 0 ° under nitrogen in a solution of diborane in. Tetrahydrofuran added. After refluxing for 4 hours

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the cooled (0 °) reaction mixture by careful Addition of 300 ml of 3N hydrochloric acid acidified. That Tetrahydrofuran was removed by distillation and the white pesticide which separated out was collected and off Ethanol / ether recrystallized and after the transition * at 170.5 ° N-isopropyl-2- (3,4-dichlorophenyl) -2- (2-hydroxy-1-naphthyl) ethylamine hydrochloride, P. 210 ° (decomp.).

Example 9

A solution of 14.4 g of N-2-butyl-2- (2-hydroxy-1-naphthyl) -2- (4-hydroxyphenyl) acetamide, P. 69-108 ° (dec.) In 150 ml of ⁱ ' Ethrahydrofuran was added dropwise to 124 ml of a 1M solution of diborane in tetrahydrofuran kept at 0 ° under nitrogen. After refluxing for 3.5 hours, the cooled (0 °) reaction mixture was acidified by carefully adding 320 ml of 3N hydrochloric acid. The tetrahydrofuran was removed by distillation and the solid which separated out from the aqueous phase was collected and recrystallized several times from ethanol / ether to give IT-2-butyl-2- (2-hydroxy-1-naphthyl) 2- (4-hydroxyphenyl) ) ethylamine hydrochloride in the form of gray-white crystals, P. 229 ° (decomp.),

Example 10

A solution of 15 g of N-tert-butyl-2 * - (2-hydroxy-'1-naphthyl) -2-pheny / acetamide, P. 190 ° (dec.) In 100 ml of tetrahydrofuran was added dropwise to 135 ml of one at 0 ° under nitrogen

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held 1m solution of diborane in tetrahydrofuran was added. After the addition, and 3, 5 hours at reflux, the reaction mixture was cooled and acidified by the careful addition of 400 ml of 3N hydrochloric acid. The tetrahydrofuran was removed by distillation and the white pesticide separated from the aqueous phase was collected and recrystallized from ethanol / ether to give Ntert-butyl-2- (2-hydroxy-1-naphthyl) -2-phenethylamine hydrochloride in the form of white Crystals, P. 250 ° (dec.) · M

Example 11

A solution of 11.8 g of N-isobutyl-2- (2-hydroxy-1-naphthyl) -2- (4-hydroxyphenyl) acetamide, P. 154 to 159 °, in 100 ml of tetrahydrofuran was added dropwise to 105 ml of a at 0 under Nitrogen-held 1m solution of diborane in tetrahydrofuran was added. After refluxing for 4 hours, the Reaction mixture cooled (0 °) and by careful addition acidified by 420 ml of 3N hydrochloric acid. The Tetra-

hydrofuran was removed by distillation, and that from the The sticky white pesticide deposited in the aqueous phase was dried by azeotropic distillation with ethanol / benzene. After recrystallization of the dried pesticide from ethanol / ether, N-isobutyl-2- (2-hydroxy-1-naphthyl) -2- (4-hydroxyphenyl) ethylamine hydrochloride was obtained in the form of white crystals, mp 217 ° (decomp.).

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Example 12

A solution of 13.1 g of N-tert-butyl-2- (4-fluorophenyl) -2- (2-hydroxy-1-naphthyl) acetamide, P. 147 ° (decomp.) »In 75 ml of tetrahydrofuran was added dropwise to 110 ml of a 1m solution of diborane in tetrahydrofuran kept at 0 ° under nitrogen. After refluxing the reaction mixture for 4 hours, it was cooled (0 °) and acidified by the careful addition of 300 ml of 3N hydrochloric acid. The tetrahydrofuran was removed by distillation and the deposited sticky white plague was collected and dried by azeotropic distillation with ethanol / benzene. The dried pesticide was recrystallized from ethanol / ether and gave N-tert-butyl-2- (4-fluorophenyl) -2- (2-hydroxy-1-naphthyl) ethylamine hydrochloride in the form of white crystals, P. 256 ° (dec.).

Example 13

15 g of N, N-diethyl-2- (2-hydroxy-1-naphthyl) -2- (4-hydroxyphenyl) acetamide, P. 134 ° (decomp.), Were added in portions to 138 ml of one at 0 ° under nitrogen held 1m solution of diborane in tetrahydrofuran was added. After the addition, the reaction mixture was refluxed for 4 hours, cooled, acidified by the careful addition of 355 ml of 3N hydrochloric acid, and the tetrahydrofuran was removed by distillation. The aqueous phase was decanted off and the remaining pesticide was dried by azeotropic distillation with ethanol / benzene. Recrystallization from ethanol / ether gave N, N-diethyl-2- (2-hydrQxy-1-naphthyl) -2- (4-hydroxy-

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phenyl) ethylamine hydrochloride (as Llonoethanolat) in the form white crystals, m.p. 165 to 170 ° (after the loss of the ethanol at 102). This connection was made by treating converted into the free base with aqueous sodium hydroxide, which was obtained in the form of a white powder, m.p. 198 ° (dec.)

Example 14

A solution of 15 g of K-tert-butyl-2- (2,3-dihydroxy-1-naphthyl) -2- (4-hydroxyphenyl) acetamide, melting point 94 to 97 ° (decomp.) »In 150 ml Tetrahydrofuran was added dropwise to 124 ml of a 1M solution of diborane in tetrahydrofuran kept at 0 ° under nitrogen. After the addition, the reaction mixture was refluxed for 4 hours, cooled, acidified by carefully adding 525 ml of 3N hydrochloric acid, and the tetrahydrofuran was distilled off. The precipitated from the aqueous phase solid was collected and dried by azeotropic distillation with ethanol / benzene to give a dark yellow crystalline solid which does not umkristal ~ λ

let lize. This solid hydrochloride was converted to the free base with ammonia, and the free base became absorbent on silica (Anasil Type B) Chromatograph! Ert. The elution with ethanol / benzene (1:10) gave a light yellow powder, which was an

/became. Silicon dioxide absorbent (Anasil type B) Chromatograph! Er tr Sei on elution with benzene, the amine was obtained as a dark yellow powder which was converted to the hydrochloride salt, which was recrystallized from ethanol / ether, and gave N-tert.-

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Butyl 2- (2,3-dihydroxy-1-naphthyl) -2- (4-hydroxyphenyl) ethylamine hydrochloride in the form of dark yellow crystals, P. 198 ° (decomp.)

Example 15

A solution of 15 g of N-tert-butyl-2- (2,7-dihydroxy-1-naphthyl) -2- (4-hydroxyphenyl) acetamide, M.p. 102 (dec.) In 150 ml of tetrahydrofuran was added dropwise to 124 ml of a at 0 ° below Nitrogen-held 1m solution of diborane in tetrahydrofuran was added. After the addition was completed, the reaction mixture became Refluxed for 4 hours. The cooled reaction mixture was made by carefully adding 525 ml 3n hydrochloric acid acidified, and the tetrahydrofuran was removed by distillation. The deposited solid was collected and by azeotropic distillation with ethanol / Benzene dried. Repeated recrystallization from ethanol / ether gave N-tert-butyl-2- (2,7-dihydroxy-1-naphthyl) -2- (4-hydroxyphenyl) ethylamine hydrochloride in the form of white crystals, mp 199.5 ° (decomp.).

Example 15

A solution of 9.0 g of IJ-isopropyl-2- (6-bron-2-hydroxy-1-naphthyl) -2- (4 -hydroxy phenyl) -ac et am id, m.p. 219 to 221 ° (decomp.) in 100 m] Tetrahydrofuran was added dropwise to 66 ml of one at 0 1m solution of diborane in tetrahydrofuran kept under nitrogen admitted. After the addition has ended, the reactions -

BAD ORIGINAL 109882/1785 .—

mixture refluxed for 4.5 hours. The chilled The reaction mixture was then carefully added by adding Hydrochloric acid (280ml, 3N) acidified and the tetrahydrofuran was removed by distillation. The Indian Solids deposited in the aqueous phase were collected and dried by azeotropic distillation with ethanol / bees oil. Several recrystallizations from ethanol / ether resulted N-Isopropyl-2- (2-hydroxy-6-bromo-1-naphthyl) -2- (4-hydroxyphenyl) ethylamine hydrochloride in the form of white crystals, mp 244.5 ° (decomp.).

Example 17

A solution of 12.0 g of N-isopropyl-2- (3-carboxy ~ 2 ~ hydroxy-1-naphthyl) -2- (4-methoxyphenyl) acetamide, M.p. 90 ° (dec.) In 130 ml of tetrahydrofuran was added dropwise to 98 ml of an at 0 1m solution of diborane in tetrahydrofuran kept under nitrogen was added. After the addition had ended, the The reaction mixture was refluxed for 3.5 hours. the The cooled reaction mixture was acidified by carefully adding 410 ml of 3N hydrochloric acid, and the tetrahydro- f

furan was removed by distillation. The solid separated from the aqueous phase was collected and azeotroped Distillation with ethanol / benzene, dried to give pale yellow crystals. These were recrystallized from ethanol / ether and gave N-isopropyl-2- (2-hydroxy-3-hydroxymethyl-1-naphthyl) -2- (4-methoxyphenyl) ethylamine hydrochloride in the form of white crystals, mp 179 ° (decomp.).

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'- 26 -

Example 18

a) A solution of 16.7 g of N-isopropyl-2- (2,8-dihydroxy-1-naphthyl) -2-phenylacetamide, P. 80 to 90 ° (decomp.) »In 100 ml of tetrahydrofuran was added dropwise to 150 ml of an at 0 1m solution of diborane in tetrahydrofuran kept under nitrogen was added. Each completion of the addition was the Reaction mixture refluxed for 3.5 hours, cooled, by carefully adding 500 ml of 3N aqueous Acidified hydrochloric acid, and the tetrahydrofuran was removed by distillation. The aqueous phase was decanted from the deposited yellow sticky pesticide. The pesticide was obtained by azeotropic distillation with ethanol / Dried benzene and then recrystallized from ethanol / ether to give N-isopropyl-2- (2,8-dihydroxy-1-naphthyl) -2-phenethy1-amine hydrochloride in the form of a gray powder, P. 238 ° (decomp.).

The acetamide derivative used as the starting material was manufactured as follows:

b) A mixture of 52 g of 1,7-dihydroxynaphthalene and 30.4 g of mandelic acid was heated to 210 ° for 3.5 hours, cooled and treated with 50 ml of hot ethanol. The ones from the Solution crystals were deposited after passing over Nscnt left to cool, collected and washed with a little ice-cold ethanol. The TJ crystallization from aqueous acetic acid gave 9-hydroxy-1-phenyl-2-oxo-1,2-dihydronaphtho / 2,1-b ^ -furan in the form of a gray powder, P. 223 | 5 to 228 °.

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c) A mixture of 11.9 g of 9-hydroxy-1-phenyl-2-oxo-1,2-dihydronaphtho / 2,1-b_7-furan and 100 ml of isopropylamine was refluxed for 3 hours. The excess amine was removed by distillation to give N-isopropyl-2- (2,8-dihydroxy-1-naphthyl) -2-phenylacetamide in the form of a dark powder, P. 80 to 90 ° (decomp.).

Example 19

A solution of 8.7 g of N- (n-propyl) -2- (4-hydroxyphenyl) -2- M

(2-hydroxy-i-naphthyl) acetamide, P. 156 to 160 ° (decomp.), In 80 ml of anhydrous tetrahydrofuran was added dropwise to 79 ml of a 1m solution of diborane in tetrahydrofuran kept at 0 ° under nitrogen. After the addition was ^di: e reaction mixture boiled for 4 hours under reflux. The cooled (0 °) reaction mixture was acidified with 305 ml of 3N aqueous hydrochloric acid, and then the tetrahydrofuran was distilled off. The aqueous liquids were decanted from the precipitated semi-solid and the semi-solid was azeotropically dried with ethanol / benzene. Two recrystallizations from ethanol / ether gave N- (n-propyl) -2- (4-hydroxyphenyl) -2- (2-hydroxy-1-naphthyl) ethylamine hydrochloride in the form of off-white crystals, P. 224 ° (decomp.).

109882/1785

T768970

Example 20

A solution of 9 »1 g of N-ethyl-2- (4-hydroxyphenyl) -2- (2-hydroxy-1-naphthyl) acetamide, M.p. 182 ° (dec.) »In 80 ml of dry tetrahydrofuran was added dropwise to 86 ml of a at 0 under nitrogen-held 1m solution of diborane in tetrahydrofuran was added. After the addition was complete, the reaction mixture was refluxed for 4 hours. The chilled The reaction mixture was acidified by carefully adding 366 ml of 3N aqueous hydrochloric acid, and then was the tetrahydrofuran is distilled off. The result of the watery White solid separating liquids was collected and washed with 3N hydrochloric acid. Two recrystallizations of the solid from ethanol / ether gave N-ethyl-2- (4-hydroxyph enyl) -2- (2-hydroxy-1-naphthyl) ethylamine hydrochloride in the form of white crystals, mp 237 °, (decomp.).

Example 21

a) A solution of 12.8 g of tert-butyl-2- (2-methoxy-1-naphthyl) ■ 2-phenylacetane: id, boiling point 65 ° / 10 "" ⁵ torr in 200 ml of dry tetrahydrofuran was added dropwise 76 ml of a 1m solution of diborane in tetrahydrofuran kept at 0 ° under nitrogen were added. When the addition was complete, the reaction mixture was refluxed for 4 hours. The cooled reaction mixture was acidified by carefully adding 300 ml of 3N aqueous hydrochloric acid, and then the tetrahydrofuran was distilled off. The from the aqueous liquid

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Any pesticide excreted was collected and carried through azeotropic distillation of ethanol / benzene dried. Two recrystallizations from ethanol / ether gave IT-tert-butyl-2- (2-methoxy-1-naphthyl) -2-phenethylamine hydrochloride in the form of white crystals, mp 228 °.

The acetamide derivative used as the starting material was manufactured as follows:

b) A mixture of 7.2 g of 1-phenyl-2-oxo-1,2-dihydronaphtho-

/ 2,1-b / -furan and 120 ml of 3N aqueous sodium hydroxide was %

Heated to 100 ° for 30 minutes. Became the hot solution 18 ml of dimethyl sulfate were added alternately with 200 ml of 1N aqueous sodium hydroxide solution over a period of 45 minutes.

After the final addition, the reaction mixture became basic refluxed until everything was dissolved. The cooled reaction mixture was washed with aqueous hydrochloric acid acidified, and the precipitated product was collected, washed with Y / ater and dried in vacuo to give 2'-kethoxy-

1'-naphthy! Phenylacetic acid in the form of a white powder, ^

98 ° (decomp.).

c) A solution of 5.2 g of 2'-methoxy-1'-naphthy! phenylacetic acid in 125 ml of benzene was treated with 5 ml of thionyl chloride. the Reaction mixture was left for 30 minutes at room temperature and then refluxed for 2 hours. The reaction mixture became 5 »8 g of one under reduced pressure concentrated dark yellow pest, which is then in 100 ml of ether

was added and treated with 10 ml of tert-butylamine. The reaction mixture was refluxed for 30 minutes at room temperature and then for 10 minutes. the

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filtered reaction mixture was concentrated under reduced pressure, and the residue was washed four times at 165 ⁰ ZiO ^- ^ distilled to give 3,1.g H-tert-butyl-2-methoxy-i-naphthyl phenylacetamide in the form of an amber glass.

Example 22

A solution of 9 »95 g of N-isopropyl-2- (2-hydroxy-1-naphthyl) -2- (4-hydroxy-3-methoxyphenyl) acetamide, P. 179 ° (decomp.) »In 80 ml of dry tetrahydrofuran was added dropwise to 82 ml added to a stirred 1m solution of diborane in tetrahydrofuran kept at 0 under nitrogen. After completion After the addition, the reaction mixture was refluxed for 4 hours. The cooled reaction mixture was through careful addition of 320 ml of 3N aqueous hydrochloric acid acidified, and then the tetrahydrofuran was distilled off. The solid separated from the aqueous liquids was collected and washed with 3N hydrochloric acid washed. Two recrystallizations from ethanol gave N-Isopropyl-2- (2-hydroxy-1-naphthy1) -2- (4-hydroxy-3-methoxyphenyl) ethylamine hydrochloride in the form of white crystals, m.p. 200 ° and above (decomp.).

Example 23

A solution of 19 »1 g of N-isopropyl- (2'-hydroxy-1'-naphthyl) -phenylacetamide, Mp 170.5 ° (dec.), In 150 ml of anhydrous tetrahydrofuran was added dropwise to 120 ml of an at 0 °

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1m solution of diborane in tetrahydrofuran kept under nitrogen was added. After the addition was complete, the reaction mixture was refluxed for 4 hours. The cooled reaction mixture was acidified by carefully adding 380 ml of 3N aqueous hydrochloric acid, and then the tetrahydrofuran was distilled off. The pesticide separated from the aqueous liquids was collected, dried in vacuo and recrystallized from methanol / ether and yielded N-isopropyl-2- (2-hydroxy-1-naphthyl) -2-phenylethylamine- %

hydrochloride in the form of white crystals, P. 225 ° (decomp.).

Example 24

Right-handed and left-handed IT-isopropyl-2- (4-hydroxyphenyl) -2- (2-hydroxy-1-naphthyl) -äth.ylair.inhydro chloride

Treatment with aqueous sodium hydroxide converted N-isopropyl-2- (4-hydroxyphenyl) -2- (2-hydroxy-1-naphthyl) ethylamine hydrochloride into the corresponding free base. The free base had a melting point of 162.5. A mixture of 22.1 g of the free d, l-base and 10.4 g of 1-V / one acid in 1000 ml of methanol was stirred at room temperature until a solution was obtained. The solution was filtered and the filtrate was concentrated under reduced pressure and gave 35 »5 g of the d, l-amine-l-tartrate as a dark yellow pest, & U-q = -8.9 ° (c = 0.993 in methanol) . 3514 g of the d, 1-amine-1-tartrate were extracted with acetone in a hot extractor. The extracts were filtered hot and gave 9 | 8 g of white crystals,

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= + 58.2 ° (c = 0.990 in methanol). Two further recrystallizations from acetone, as described above, gave 7 _f 2 g of pure d-amine-1-tartrate, P. 180 ° (decomp.), / <* / _D = + 60.3 ° (c = 1.44 in methanol). The d-amine-1-tartrate was suspended in water and the pH-7 / ert was adjusted to 4.5 by the addition of aqueous sodium hydroxide. Then the solution was made strongly acidic by the addition of hydrochloric acid and the precipitating α-amine hydrochloride was collected. The crystallization from ethanol / ether gave white crystals, P. 249 ° f / pe] ^ = + 52.2 ° (c = 1.045 in CH ₃ OH).

b) The mother liquors and residue from the above extractions and fractional crystallization consisted of Amintartraten that were enriched-amine L-tartrate 1. This material was converted into the free base (enriched with 1-amine) and then into the enriched 1-amine-d-tartrate by adding aqueous i «atrium hydroxide. 15 »8 g of this enriched 1-amine-dtartrate 5 was recrystallized from acetone in a hot extractor as described above until pure 1-amine-dtartrate, / cf / ^ = -60.7 ° (c - 0.961 in CK, OH). [) <* den rejiie.'i l-amine-d-tartr-'i ts in 300 ml of water were mixed with ?.?. m] 1n wfiL-irigerii Υ. · λ \ riumhydroxyd and then with 30 ml 1n Ch] orwas ;; ers1 off: -, Liure beh; u: delt. from the J.öoung f je] en at Xrhl ^ n 3 »4 g rei) .e :; ] .-, -. minhyoroch] orid in the form of cream-colored platelets aun, P. 250 °, / * 7 _} -. ~ b3, ^f J ° (c - 1,100 in CK, OH).

BATH 109882/17 85

Example 25

A solution of 5 »4 g of N-isopropyl-2- (2-hydroxy-1-naphthyl) -2- (4-hydroxyphenyl) acetamide in 50 ml of tetrahydrofuran was added dropwise over a period of 45 minutes to a suspension kept at room temperature of 2.0 g of lithium aluminum hydride in 100 ml of tetrahydrofuran was added. After the addition and an additional hour at ambient temperature, the reaction mixture was refluxed for 2.5 hours. 15 ml of ethanol was carefully added to the cooled reaction mixture, followed by 170 ml of 3 ri · hydrochloric acid. The organic solvents were removed by distillation and the sticky dark yellow solid separated from the aqueous phase became; collected and dried by azeotropic distillation with ethanol / benzene. The dried solid was extracted with ether, and the ether-insoluble material was recrystallized from ethanol / ether and gave N-1sotropy 1-2- (2-hydroxy-i-naphthyl) -2 - (4-hydroxyphenyl) -äthylamiiihydrochlorid, which was identical to the product prepared by the process of Example 1.

Example 26

a) A deletion from 5 ^ 3 IT-Isopropyl-2- (4-acetoxyphenyl) -2-hydroxyethylamine-oxalate, 8.7 g of β-haphthol and 3.4 g of p-toluenesulfonic acid in 10 ml of acetic acid was heated on a steam bath for 2 hours. laugh at the removal of acetic acid with reduced pressure, the residue was diluted with water and washed with ether. · The aqueous portion was washed with aqueous

109882/1785

Ammonia made basic and then kit zither extracted. The ethereal extracts were washed well with water, dried over sodium sulfate and concentrated under reduced pressure. The solid residue was dissolved in ethanol and treated with ethanolic hydrogen chloride. The solution was clarified with activated charcoal, filtered and diluted to the cloud point with Xther. Storage at -25 ° led to N-isopropyl-2- (2-hydroxy-1-naphthyl) -2- (4-hydroxyphenyl) ethylamine hydrochloride, P. 246 ° (decomp.) T ^{that described} with clem in Example 1 Substance was identical.

The starting material was prepared as follows:

b) 28 ml of an OK ^J 'aqueous sodium hydroxide solution was added to a cooled solution of 10 g of p-acetoxy benzaldehyde and 11 g of nitromethane in 50 ml of ethanol is added at such a rate that the Heaktionstemperatur did not rise above 0th After the addition was complete, 236 ml of 2% aqueous acetic acid was added and the reaction mixture was held at 0 for 4 hours. The reaction mixture was extracted with ether and these ethereal extracts were washed with water, dried over sodium sulfate and concentrated under reduced pressure to give 2- (4-acetoxyphenyl) -2-hydroxy-nitroethane as a heavy oil.

c) A solution of 12.5 g of 2- (4-acetoxyphenyl) ~? -hydroxynitroethane in 450 ml of acetone, the 5? » Palladium-on-activated carbon

109882/1785

held, was for 49 hours at room temperature under eir.em Shaken hydrogen pressure of 61.5 atmospheres. The reaction mixture was filtered and 5 g of oxalic acid was added to the piltrate. The resulting solution was reduced under reduced The pressure was concentrated, the temperature being kept below 38 °, and H-isopropyl 2- (4-acetoxyphenyl) -2-hydroxyethylamine oxalate was obtained as white pest, mp 212 to 214 °.

Example 27

a) To a solution of 0.8 ml of acetone and 2.79 g of 2- (4-Hydroxyphenyl) -2- (2-hydroxy-1-naphthyl) ethylane: hydrochloride (adjusted from the free amine, P. 214 bis 218 °) in 50 ml of ethanol a trace of concentrated hydrochloric acid turned into, just like that. The mixture was then refluxed for one hour and allowed to cool, after adding 0.? ^r > ml of Chlordan Herstoff acid v / urde the reaction mixture hydrogenated over palladium on carbon at 20 atmospheres pressure, up to 0.01 mole of hydrogen; had been absorbed. The reaction mixture was filtered, the catalyst removed and absolute ether added to the piltrate. The solid so formed was collected by filtration and dried over phosphorus ρ or. 1 oxide at 100 ° / 2 ^! ? orr dried and gave U-lRopropyl-2- (2-hy (iroxy-1-naphthyl) -? - (4-hydroxyphenyl) ethyl aminljj droci 1 orid, P. / Mf » ⁰ (?, cr ^.) .

In an analogous manner, from the (.-Nt. ^ Nrrr.Iwiti substituted 2,2-diarylethyamines and acetone icl ^ ci, - . <■} Ί> nnvte were obtained. '·!

BATH 109882/1785

b) N-isopropyl-2- (2-hydroxy-1-naphthyl) -2- (4-chlorophenyl) ethylamine hydrochloride, F. 222 ° (decomp.),

c) N-Isopropyl-2- (2-hydroxy-1-naphthyl) -2- (4-methoxyphenyl) ~ ethylamine hydrochloride, m.p. 256 ° (decomp.) »

d) H-2-butyl-2- (2 ~ h; hydroxy-1-naphthyl) -2- (4-hydroxyphenyl) -ethylainine hydrochloride, F. 229 ° (decomp.) »

e) N-Iaopropyl-2- (2,8-dihydroxy-1-naphthyl) -2-phenethyl-amine ~ hydrochloride, mp 238 ° (decomp.),

f) N-isopropyl-2- (2-hydroxy-1-naphthyl) -2- (4-hydroxy-3-methoxyphenyl) ethane hydrochloride, F. 200 ° (slow decomposition).

As already stated above, the compounds of the formula I have valuable pharmacological properties that make their * Show usefulness as therapeutic agents, in particular to treat arrhythmias.

This anti-arrhythmic property was used for example the compounds listed in Table I below with the aid of the experimental model according to Somani & Lum, J.Pharmacol. Exp.Ther. 147, 194-204 (1964). This model shows ouabain-induced ventricular tachycardia in dogs normalized after administration of these compounds, administration being either intravenous (i.v.) or intraduodenal (usually) takes place. The ranges of effective dose and the extent

109882 / 178S

the reaction are also given in the following table.

Table I.

link 2 Area of mg / kg Responsive animals according to 3 effective dose - 14.6 5 in 6th 1.8 ■ - 6.0 i.v. 5/5 example 1 24-a 3.0 i.v. 2/5 It 3.0 - - 4.0 i.v. 2/2 It 10 6.0 i.v. 2/2 It 12th 1.0 - i.v. 5/5 It 1.0 • 7.5 i.v. 1/1 Il 20.0 i.d. 2/3 7.0 - i.v. 2/2 It 3.0 i.v. 2/4 It

The above results show the antiarrhythmic activity, which in a number of cases is higher than or comparable to

is one of known antiarrhythmic agents. d

For the purpose of administration, the compounds of the invention were incorporated into compositions suitable for oral administration to mammals in solid and liquid unit dosage forms, such as tablets, capsules, powders, granules, syrups, elixirs and the like are suitable. This here The term unit dosage form as used means the physically discrete units, which are used as uniform dosing

109882/1785

genes are suitable for mammals, each unit being a predetermined amount of the active ingredient calculated to deliver the desired therapeutic effect in conjunction with the required pharmaceutical diluent, carrier or excipient. .

Powders are made by adding a compound according to the invention ground to a suitable small particle size and with an equally ground diluent mixes. The diluent can be an edible carbohydrate material, such as strength, be. A sweetener or sugar can also be present as well as a flavor oil.

Granules for processing into a liquid oral preparation are produced by adding water-soluble diluents used. A powder mixture of the finely divided compound and a water-soluble diluent such as sucrose, Glucose and the like, is mixed with a binder such as acacia jucilage, gelatin solution, ethyl cellulose solution, wetted and passed through a sieve to form granules that are allowed to dry. A suspending agent, such as L · · Tragacanth, may be included in the composition.

Capsules are made by preparing a powder mixture as described above and the gelatin shells formed fills. The powder mixture can be used as an adjuvant for the filling a lubricant such as talc before pulling Magnesium stearate and calcium tearate can be added.

109882/1785

The tablets are made by preparing a powder mixture, granulating or lumpy it, adding a lubricant and compressing it into tablets. The powder mixture is prepared by mixing the suitably comminuted compound with a diluent or a base such as starch, sucrose, kaolin, dicalcium phosphate and the like. The powder mixture can be granulated by wetting it with a binding agent such as syrup, starch paste or acacia mucilage and passed through a sieve M. As an alternative to granulation, the powder mixture can be pressed into lumps, ie run through the tabletting machine, and the incompletely formed tablets obtained can be broken into pieces (lumps). The lumps can be made lubricious by adding stearic acid, a stearate salt, talc or mineral oil to prevent them from sticking to the tablet-forming molds. The lubricious mixture is then compressed into tablets. A protective coating consisting of a Sohellac-seal coating, a coating of sugar and methylcellulose and a Vo ™ IierÜberzug AU3 carnauba wax can also be provided.

The oral fluids are made in unit dose formats, for example, as syrups and elixirs, in which a teaspoonful of the composition has a predetermined! »! tightness of the Contains compound for administration.

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A syrup is made by combining the compound in a suitable palatable aqueous sucrose solution is suspended. An elixir is made in a similar manner, whereby a non-toxic alcohol is used as an adjuvant.

Aqueous and oily liquid can be used for parenteral administration Unit dosage forms can be prepared. In the preparation of of the parenteral formulation, a measured amount of the compound is placed in a vial, the vial and its contents are sterilized and sealed. A second vial of sterile water can be used as an adjuvant to form a suspension be provided prior to administration.

The following examples are intended to explain the production of the dosage unit forms, but without restricting them to them.

Example 28 Component quantity

N-isopropyl-2- (2-hydroxy-1-naphthyi) -2-

(4-hydroxyphenyl) ethylamine hydrochloride 250 g

Lactose 150 g

Magnesium! Earat 3 g

The above ingredients are mixed and filled into 1000 two-piece # 2 hard gelatin capsules.

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Example 29 Component quantity

N-tert-butyl ~ 2- (2-hydroxy-1-naphthyl) -2-

(4-hydroxyphenyl) ethylamine hydrochloride 500 g

Lactose x 80 g

Corn starch 70 g

soluble starch 15 g

Magne siumst earat 5 g

The. first three ingredients are mixed carefully and granulated with a solution of the soluble starch. These granules are dried and mixed with the magnesium stearate and pressed into 1000 tablet cores coated with sugar will.

Example 3 0

50 g of 2- (2-hydroxy-1-naphthyl) -2- (4-hydroxyphenyl) ethylamine hydrochloride and 3 g of chlorobutanol are for injection in an amount sufficient to make up to 1000 ml of "water solved. The solution is introduced into a single or multiple dose vial and sterilized.

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OR! G? MAL («SPECfED

Claims (20)

Patent claims 1. Compound of the general formula I CH - CH ₀ - N - C - CH (I) ² Il \ R ₁ R ₂ R ₅ in the W is hydrogen, chlorine, fluorine, bromine or hydroxy radical, X and Y independently of one another are hydrogen, fluorine, chlorine, hydroxy or lower alkoxy radicals, Z is a hydrogen, hydroxy, or hydroxymethyl _{radical, R 1 is} a hydrogen, methyl or ethyl radical, Rp, R ,, R ₄ and Rg are, independently of one another, a hydrogen or methyl radical and He has a hydrogen, methyl, phenyl or hydroxyphenyl radical mean and the acid addition salt thereof with an inorganic one or organic acid. 2. A compound according to claim 1, characterized in that W and Z are hydrogen or hydroxy, Y are hydrogen or chlorine, R _{5 is} hydrogen or methyl and Rg is hydrogen. 10 98 8 2/1785 ORIGINAL 1M3F 3. A compound according to claim 2, characterized in that X is a hydrogen, chlorine, hydroxy or LIethoxy radical and Z, R ₁ , R and Rp. Mean a hydrogen radical. 4. A compound according to claim 1, characterized in that W is a hydrogen or hydroxy radical, X and Y independently
from each other a hydrogen, hydroxy or lower alkoxy radical, R, a methyl radical, R ₁ - a hydrogen or methyl radical and Z, R ₁ , Rp and R ^ a hydrogen radical. 5. - A compound according to claim 1, characterized in that X is hydrogen, hydroxy or lower alkoxy, R _{5 is} a methyl radical and W, Z, Y, R ₁ , R ₂ »R,» R ₅ and Rg are a hydrogen radical =. 6. A compound according to claim 5> characterized in that X is a hydroxy radical. 7. Process for the preparation of the compounds of the formula I. ? 3 CH-CHp-N-O-CH (I) R ^R 1 109882/1715 in the W is hydrogen, fluorine, chlorine, bromine or hydroxyl radical, X and Y independently of one another are hydrogen, fluorine, chlorine, hydroxy or ll-membered alkoxy radical, Z is hydrogen, hydroxy or hydroxymethyl radical, R _{1 is} hydrogen -, methyl or ethyl radical, Rpj R7, R, and. Rg independently of one another a hydrogen or methyl radical and R ₅ denotes a hydrogen, methyl, phenyl or hydroxyphenyl radical and cer acid addition salts thereof with an inorganic or organic acid, characterized in that a compound of the general formula II (II) CH-C-N-C-CI I! I I \ OR ₁ R ₂ R ₅ in the Z ^{1 is} a hydrogen, hydroxy, carboxy or IT-lower alkoxycarbonyl radical and W, X, Y ₁ R ₁ , Rp, _{R 1, R 4} , Rr and Rg have the meanings given above, is reduced in an inert solvent with a reducing agent in order to obtain a compound of the formula I, and optionally this product is converted into an acid addition salt with an inorganic or organic acid. 109882/1785 ORIGINAL INSPECTED 8. The method according to claim 7, characterized in that a hydride-supplying agent is used as the reducing agent will. 9. The method according to claim 8, characterized in that as Hydride-supplying agent borane or diborane and as a solvent Tetrahydrofuran is used. 10. The method according to claim 8, characterized in that λ a complex metal hydride is used as the hydride-supplying agent. 11. The method according to claim 10, characterized in that the complex metal hydride and lithium aluminum hydride Solvent tetrahydrofuran is used. 12. Process for the preparation of the compounds of the formula I-A .3 y 4 CH - CH ₀ - ITH - CH - CH (IA) C. in the W "a hydrogen or hydroxy radical, X" and Y "independently of one another a hydrogen or hydroxy or lliedrigalkoxyest, 109882/1785 R-t is a LIethylrest and R. and Rp. Independently of one another a hydrogen or Mean methyl radical and the acid addition salts thereof with an inorganic or organic acid, characterized in that that a compound of the formula IX CH - CH ₂ - N = C - CH (IX) in which V / ", X", Y ", R ', R. and Rf- have the meanings given above own, in an inert solvent with a reducing agent is reduced to produce a compound of the formula I-A and this product, if desired, into an acid addition salt is converted with an inorganic or organic acid. 13. The method according to claim 12, characterized in that catalytically activated hydrogen in an acidic medium is used. 14. The method according to claim 13, characterized in that palladium-on-carbon as a catalyst and as a reaction medium Hydrochloric acid in ethanol is used. 109882/1785 15. The method according to claim 12, characterized in that a hydride-supplying agent is used as the reducing agent will. 16. The method according to claim 15 »characterized in that as a hydride-supplying agent borane, diborane or a complex Metal hydride is used. 17 · The method according to claim 16, characterized in that as complex metal hydride lithium aluminum hydride and as ™ Solvent diethyl ether or tetrahydrofuran is used. 18. The method according to claim 15 »characterized in that the complex metal hydride is lithium, potassium or ITatriumbcrhydrid and as a solvent, methanol or ethanol or a Mixture thereof with tetrahydrofuran is used. 19 · Process for the preparation of compounds of formula 1-3 'CH. / ^CH 3 CH, CH - CH ₂ - KH - CH (IS) in the X "denotes a hydrogen, hydroxy or lower alkoxy radical and its acid addition salts with an inorganic or 109882/1785 original. ;?; g? "cted organic acid, characterized in that ß-l-taphthol with a compound of the formula XIII CH _ CH ₂ - KH - CH. (XIII) CH, in the X ^{111 is} a hydrogen, hydroxy, lower alkoxy or lower alkanoyloxy radical, is condensed in an inert solvent in the presence of an acidic condensing agent to form a compound of formula 1-3 and optionally this product into an acid addition salt with an inorganic or organic acid is converted. 20. The method according to claim 19 «characterized in that ^{p-toluenesulfonic acid is used as the acidic condensation with a} si and acetic acid as the solvent. 109882/1785