CA1231970A

CA1231970A - Dialkyl-amino-alkoxy-benzylalcohol derivatives, process for their preparation and pharmaceutical compositions containing them

Info

Publication number: CA1231970A
Application number: CA000444257A
Authority: CA
Inventors: Edit Toth; Jozsef Torley; Gyorgy Fekete; Laszlo Szporny; Laszlo Vereczkey; Eva Palosi; Imre Klebovich; Pal Vittay; Sandor Gorog; Istvan Hajdu
Original assignee: Richter Gedeon Vegyeszeti Gyar RT
Current assignee: Richter Gedeon Vegyeszeti Gyar Nyrt
Priority date: 1982-12-28
Filing date: 1983-12-23
Publication date: 1988-01-26
Also published as: US4645779A; ES8604102A1; FI834800L; JPS6340780B2; ES8608476A1; DK163182C; GR78771B; IL70560A0; EP0114410A1; DK601683A; DK601683D0; HU187208B; ES543803A0; FI834800A0; FI78459C; FI78459B; ES528462A0; ES8600205A1; ES543805A0; JPS59134756A

Abstract

Abstract The invention relates to new dialkylamino-alkoxybenzylalcohol derivatives of the formula (I) wherein R1 is hydrogen, halogen 7 trihalomethyl, alkyl having from one to 4 carbon atoms or alkoxy having from one to 4 carbon atoms;
R2 is halogen, trihalomethyl, alkyl having from one to 4 carbon atoms or alkoxy having from one to 4 carbon atoms;
R3 and R4 independently stand for an alkyl group having from 3 to 5 carbon atoms; and n is 2, 3, 4 or 5, and acid addition and quanernary ammonium salts thereof.
According to another aspect of the invention there are provided processes for the preparation of these compounds.
The new compounds provided by the invention are pharmaceutically active, in particular, they are suitable for the treatment of acute ethanolic in-toxication. Pharmaceutical compositions containing them as active ingredient are another aspect of the invention.

Description

3~37~

DIALKYLAMINOALKOXYBENZYLALCOtlOL DERIVATIVES, PROCESS
FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS
CONTAINING THEM

The invention relates -to new dialkylamino-alkoxybenzylalcohol deriva-tives of the formula (I) lo R~H ~,0--(CH2),,--N~

wherein Rl is hydrogen, halogen, trihalomethyl, alkyl having from one to 4 ca:rbon atoms or alkoxy having from one to 4 carbon atoms;
R2 is halogen, trihalomethyl, alkyl ha~ing ~rom one to 4 carbon atoms or alkoxy having from one to 4 carbon atoms;
R3 and R4 independently stand for an alkyl grnup having ~rom three to 5 carbon atoms; and n is 2, 3, 4 or 5, and acid addition and quaternary ammonium salts thereof. The compounds of the formula (I) are suitable for the treatment of acute ethanolic intoxication.

~23~

Pharmaceutical compositions containing them as active ingredient are another aspect of -the invention.
The term "halogen" as used herein embraces all of the halogens, and may be fluorine, chlorine~ bramine or iodine, preferably fluorine or chlorine.
The term "alkyl" refers -to straight or branched chained aliphatic hydrocarbon groups. If the alkyl groups contain from one to 4 carbon atoms, they include methyl, ethyl, n- or i-propyl, n-, sec- or tert-butyl. The alkyl groups containing from 3 to 5 carbon atoms may be n- and i-propyl, n-, sec- or tert-butyl, n- or i-pentyl groups.
The term "alkoxy having from one to 4 carbon atoms" is used herein to refer to straight or branched chained alkoxy groups containing from one to 4 carbon atoms, e.g. methoxy, ethoxy, n- and i-propoxy, n-, sec-or tert-butoxy, preferably methoxy.
The trihalomethyl groups may contain any of the halogens listed above, preferably fluorine.
Compounds of analogous structure are disclos~d ~ for example in the follawing references:
C.A. 22, 4101; 35, 17812; 40, 47125; 42, P 1015 b;
47, 9548 e; 50, 12390 c; 50, 2509 i; 55, 17915 e;
55, 15413 b; 75, P 10~682 b; 76, P 119921 k; 82, 16477 9; 90, 86082 9; 92, 52927 b. None of these citations does, however, mention any pharmaceutical activity of the disclosed compounds.
The new compounds o~ the formula ~I) can be prepared by ~ 3 ~ 7~

a) reacting a propiophenone of the formula (II) ~R3 ~CH~n N~ (II) ~H5 wherein R3, R4 and n each have the sams meanings as defined above, with an organometallic compound of the formula (III) R~l ~ (III) ~,~

wherein Rl and R2 are as defined above, and M is an alkali metal, preferably lithium, sodium or potassium, or an MgX group, in which X is halogen; or b) reacting a compound of the formula (IV~

/r~ ~H~o~(~::H2)n--X (I\~) 2n5 - 4 - ~3~9~0 wherein Rl, R2 and n each have the same meanings as defined above, and X is halogen, with an amine of the formula (V) HN \ (~) wherein R~ and R4 are as defined above, preferably in the presence of a base; or c) reacting a ben70phenone of the formula (VI) R2 ~ ( ~ VI~

wherein Rl, R2, R3, R4 and n each have the same meanings as defined above, with an organometallic compound containing an ethyl group, preferably an ethyl magnesium 0 halide or ethyl lithium; or d) reacting a propiophenone of the formula (VII) .
~ ( VI I ) C2H5\=~F~

~;~3~

wherein Rl and R2 are as defined above, wlth a GrignarrJ
compound of the formula (VIII) 3\
N - (C~23n~ ~ ~} ( VIII) wherein R3, R~ and n each have the same meanings a10 defined above, and X is halogen; or e) reacting a compound o~ the formula (IX) ~IH ~, OH

R2 C;~R~

wherein Rl and R2 are as defined above, preferably in the form of an alkali metal or quaternary ammonium phenolate thereof, with an amine of the formula (X) X - (C~i2)n N ~ R3 (X) wherein R3 and R4 are as defirted attove, and X is halogen, alkylsulfonyloxy or arylsulfonyloxy group, or a salt thereof, preferably in the presence of an acid binding agen-t; or f) reducing a compound of -the formula (XI) f~1 ~R3 ~ ~C ~ t23n--N (XI) wherein Rl, R2, R3, R4 and n each have the same meanings as defined above, and Z is ethinyl or vinyl, and,if desired, converting any of the products obtained by process variants a) to f) into their acid addition or quaternary ammonium salts, or convert.ing a product obtained as an acid addition salt into a corresponding base and/or converting a ~ree base into an acid addition or quaternary ammonium sal-t -thereof.

According to a preferred embodiment of process variant a) propiophenones o~ the formula (II) are reacted with the organametallic compounds of -the ~ormula (III), preferably with an appropriately substituted phenyl magnesium chloride or bromide or an appropriately substituted phenyl li-thium, in an anhydrous inert organic solvent. The reaction is carried out pre~erably in an aprotic organic solvent, e.g. in an aliphatic ether such as diethyl ether, d.i-n-butyl ether or diethylene glycol dimethyl ether, an alicycl-ic ether such as tetrahydro-furane, dioxane, an alipha-tic or aromatic hydrocarbon such as ligroin, benzene, toluene, xylene, dimethyl sulfoxide or hexamethyl phosphorus amide 9 or a mixture 7 ~

of these solvents. The organometallic compound is used in an at least equimolar amoun-t. The reaction is preferably performed in an inert gas atmosphere, e.g.
in nitrogen or argon. The reaction temperature may range from -60 C up to -the boiling point of the solvent, and preferably is between -30 C and 100 C. When the reaction is complete, the reac-tion mixture is decomposed, preferably with an aqueous ammonium chloride solution, and the obtained compound of the formula (I) is separated.
The product can be purified by known techniques, e.g.

by distillation or crystallization.
According to process variant b) compounds of the formula (IV), in which X preferably represents chlorine or bromine, are reacted with a secondary amins of the formula (V). The reaction is preferably accomplished in an organic solvent, in the presence of a base suitable for binding the acid formed in the reaction. As a solv~nt for example hydrocarbons such as ligroin, benzene, toluene, halogenated hydrocarbons such as chloro~orm, ethers such as dioxane, alcohols such as ethanol, esters such as ethyl acetate, acid amides such as dimethyl formamide, ketones such as acetone or methyl isobutyl ketone, or a mixture of these solvents can be employed.

As an acid binding agent preferably inorganic or tertiary organic bases or an excess of the amine of the formula (V) is employed~ I~ the excess of the amine of formula (V) is a tertiary organic base and it is used to bind the hydrogen halide formed in the reaction, it may well serve as ~ ,;

~ 3~

- a solvent, too. The reaction is carried out at a temperature between 20 C and the boiling point of the solvent. After termination of the reaction the product is isolated, e.g. by pouring the reaction mixture onto water, and separating the product by solvent extraction. The organic phase is washed to halogen-free with water, dried and evaporated. The crude product can be purified for instance by distillation or crystallization.
According to process varian-t c) a benzophenone of the formula (VI) is preferably reac-ted with an at least equimolar amount of ethyl magnesium bromide or ethyl magnesium iodide or ethyl lithium. The reaction is accomplished in an inert, dry organic solvent, essentially as described in connection with process variant a).
According to process variant d) the Grignard compounds of the formula (VIII), in particular those in which X is bromine, are reacted with an at least equimolar amoun-t of propiophenones of the formula (VII) in an anhydrous inert organic solvent, similarly to process variant a).
According to a preferred embodiment of process variant e) compounds of the formula (IX) in form of their alkali metal or quaternary ammonium phenolates~ are condensed with the tertiary amines of the formula (X).
As a tertiary amine e.g. dialkylaminoalkyl mesylates, tosylates, bromides or preerably chlorides are employed as a free base or a salt, e.g. hydrogen halide thereof.
The reaction is preferably carried out in an inert organic , .
. .

9 _ ~z ~

solvent, in the presence of an acid binding agen-t, - under anhydrous conditions or in a mixture of water and an organic solvent. As organic solvents for example esters such as ethyl acetate, ethers such as dioxane, tetrahydrofurane or diethyl ether, hydrocarbons such as ligroin, benzene, toluenR or xylene, halogenated hydro-carbons such as chloroform, chlorobenzene, acid amides such as dimethyl formamide, ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone, alcohols such as ethanol, propanol, etc. are employed. Compounds of the formula (IX) can be converted into their phenolates by methods known in the art, e.g. with alkali metal alcoholates, amides, hydrides, hydroxides, carbonates or quaternary ammonium compounds. Preferred acid binding agents include inorganic and tertiary organic bases, e.g. sodium hydroxide, potassium hydroxide, potassium carbonate 9 triethyl amine~ pyridine, etc. The reaction is optionally performed in the presence of a catalyst.
As a catalyst for example alkali metal halides, preferably alkali metal iodide may be used. The reaction temperature may be varied within a wide range, and preferably is between 20 C and the boiling point of the solvent.
According to a pre~erred embodiment of process variant f) the ethinyl or vinyl compounds of the forrnula (XI) are reduced by catalytic hydrogenation. 5uitable catalysts include metals such as ruthenium, palladium, pla-tinum, nickel, iron, copper, cobalt, chromium, zinc, molybdenum, tungsten, etc. and the oxides and sulfides 3~

of these metals. The ca-talysts may be prepared by reducing - their stable Dxides with hydrogen, directly in the reaction vessel. This procedure is especially suitable for the preparation of a finely dispersed platinum or palladium catalyst. Catalytic hydrogenation may be accomplished also in the presence of catalys-ts precipitated on the surface of a carrier, e.g. charcoal, silica, alumina or sulfates or carbonates of the alkali earth me-tals. The reaction may be carried out also in the presence of a Raney-nickel catalyst. The catalytic hydrogenation is preferably performed in the presence of palladlum, in particular palladium-on-charcoal or Raney--nickel, in an organic solvent inert under the reaction conditions. As a solvent for example lower aliphatic alcohols, ethers, esters, aliphatic, cycloaliphatic and aromatic hydrocarbons or mixtures of these solvents may be employed. The hydrogenation may be carried out under atmospheric or higher pressure, preferably not exceeding 506 kPa, at a temperature bet~een 20 C and the boiling point of the solvent employed. The reduction is preferably carried out at room temperature, under atmospheric pressure until ceasing of the hydro~en uptake. The catalyst is then filtered off, the filtrate is evaporated and,if desired, the product is purified, e.g. by distillation or crystallization.

If desired, the compounds of the formula (I) can be converted into their acid addition salts or quaternary ammonium salts by methods well kno~ln in the ~: .

3~.~'7~

art. The acid addition salts can be prepared by means of inorganic or organic acids, e.g. hydrogen halides such as hydrochloric acid, hydrogen bromide, etc.
sulfuric acid, phosphoric acids, formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, ascorbic acid, citric acid, cinnamic acid, asparaginic acid, glutaminic acid, N-acetyl-asparaginic acid, N-acetyl--glutaminic acid, alkyl-sulfonic acids such as p-toluene--sulfonic acid, etc. According to a preferred embodiment the corresponding acid is added to a solution of a compound of the formula (I) in an inert solvent, e.g.
ethanol, and the salt ~ormed is precipitated, preferably with a water-immiscible organic solvent such as diethyl ether. Quaternization is preferably carried out with a lower alkyl, alkenyl or benzyl halide or alkyl sulfate.
The reaction is performed in an organic solvent, prefer-ably acetone, acetonitrile, ethanol or in a mixture of these solvents, at a te~perature between room temperature and the boiling point of the solvent. The quaternary salts can be isolated e.g. by filtration and, if desired, are purilied by crystalli~ation.
The starting materials are known in the art or can be prepared by well known methods. Ketones of the formulae (Il), (VI) and (VII) can for example be prepared by the Friedel-Crafts type ketone synthesis (G.A. Olah: Friedel-Crafts and related reactions, III/l, Ed.: Interscience Publishers (1964), pp. 1-63) ~3~

The Grignard compounds of the formulae (III) and (VIII) are for example prepared from the correspond-ing substituted aryl halides by known techniques (M.S. Kharash et al.: Grignard reactions of nonmetallic substances, Ed., Prentice-Hall. Inc. (1954) 5-90), while the alkali metal-organic compounds can be prepared following the method disclosed in Houben-Weyl: Methoden der Organischen Chemie, XIII/l, pp. 134-159 and 3a9-405 (1970).
The compounds of the formulae (IV) and (IX) can for example be synthetized starting from the correspond-ing substituted propiophenones, by Grignard reactants, ~ollowing techniques well known in the art (e.g. M.S.
Kharash et al.: Grignard reactions of nonmetallic substances, Ed.: Prentic-Hall Inc. (1954) pp. 13B-143).
Compounds of the formula (XI), in which Z
represents a vinyl group, are for example obtained by reacting a benzophenone of the formula (VI) with a vinyl magnesium halide, while compounds o~ the formula (XI), in which Z is an ethinyl group, are easily prepared by ethinylation of a benzophenone of the formula (VI), following the procedure described in the Hungarian Patent Specification No. 166,769.
The new compounds of the formula tI) and their ~5 salts possess valuable pharmacological properties. More particularly, these compounds are suitable fnr the trea-tmen-t of acute e-thanolic intoxication and can, there-fore, widely be used in therapy. Acute alcoholic intoxica-- l3 -tion is characterized by euphoria, general stimulation, - ataxia, somnolence, paralytic condition, etc. The dangers of this -toxic, pathologic condition are well known and cannot be neglected. The in-toxicated person is a threat to his environment (e.g. driving while intoxicated) and exposes his own health to danger. The acute alcoholic intoxication is an essential "risk factor" of cerebral ischaemic infarcts (Hillbom, M. et al.: Lancet, 2, 1181 (1978); Stroke, 12, 422 (1981).
The ethanolic intoxicated condition has no satisfactory antidote. Although O~-methyl-paratyrosine normalizes the ethanolic locomotoric hyperactivity on mice, it is effec-tive in a dose range in which a decrease of the spontaneous locomotoric activity of animals takes also place L~arlsson, A. et al: Psychopharm., 26, 307 (1972)7.
On the other hand, stimulants like caf~eine and amphetamine moderate the narcotizing effect o~ alcohol, they also prolong the motoric incoordination (ataxia) /Wallagsen, H. et. al.: Actions of alcohol, Amsterdam;
Elsevier 1970; R.H. Rech et al.: Ann. N.Y. Acad. Sci.,

2~, 426 ~1976); Todzy, I. et al.: Psychopharm., 59, 143 (1976)7. The alcoholic intoxication, i.e. the narcosis period,is shortened by L-cysteine /Sprince, H. et al.:
Agents and Actions, 4, 125 (1974); Nagasawa, H.T. et al.:
Li~e Sci., 17~ 707 (1975)7. This compound was used as a reference substance in our ethanolic narcosis period tests.
The effect of the compounds according to the A ~, L4 - ~3~7~

invention on ethanolic narcosis period was -tes-ted on - Hann.-Wistar rats of both sexes, weighing 160 -to 180 9.
each. The animals were fasted for 16 hours prior to treatment. Groups of ten were then treated with various doses of the compounds of the formula (I) orally. One hour after treatmen-t the animals were given a 3.5 g./kg.
dose of ethanol, intraperitoneally. The narcosis period of the animals was measured from the elapse of the righting reflex until a spontaneous correction of the body position.
The average of the narcosis period, the standard error were calculated, and the results are given in percentage of the control in Table 1.
Abbreviations: x ~ S.E. = mean value + standard error n = number of animals The control group was treated with placebo and a 3.5 mg./kg.

dose of ethanol.
Narcosis period of the control:
88.5 + 3.54 x + S.E. minutes A = cC-ethyl- ~-(~-methoxyphenyl)-4-L 3-(di-n-propyl-amino)-propox~7-benzylalcohol B = ~-ethyl- o~-(3-chlorophenyl)-4-/ 3-(di-n-propyl-amino)-propoxy7-benzylalcohol C = c~-ethyl-C~(2-trifluoromethylphenyl)-4-L 3-(di~

isopropylamino)-ethoxy7-benzylalcohol ~, .

- l5 ~

Table l CompoundDoseEthanolic narcosis n (mg./kg.) period control + 5.E. %

_ Control lO0 ~ 4.0 lO
A 5.0 60 + lO.l lO
10.0 50 + 6.9 lO
B 0.3 65 + 6.8 lO
l.0 53 + 4.7 lO
10.0 49 + 2.B lO
C ~0.0 62 + 5.1 lO
L-cysteine 500.0 63 + 4.2 lO

As appears from the datà set forth in Table l, the compounds provided by the invention are potent antagonizers of the central nervous system depressing activity of ethanol and substantially shorten the ethanolic narcosis period. Their activity is the same or higher than the activity of L-cysteine when administered in 1-3 orders of magnitude smaller doses. Ethanol exerts a dose-dependent stimulating effect on the central nervous system and induces hyperactivity.
The effect of the compounds provided by the invention on ethanolic locomotoric hyperactivity was tested on BALB/c mice of both sexes, each weighing 16 to 18 9. The test materials were administered to groups ~ 1 - It. ~3~C~

of 15 in a 40 mg./kg. oral dose, one hour before administering placebo orally or a 2 g./kg. dose of ethanol intraperitoneally. The control animals were treated with placebo. The locomotor activity of the animals was measured for two hours, using an Animex BSE
motimeter. The results are shown in Table 2, in percentage of the control.

Table 2 CompoundDose Locomotor activity n (mg./kg.) total motion/
Comp. Ethanol 2 hour (%) .
Control - - lOU + 9.8 15 Ethanol +
placebo 2000.0170 + 11.8 15 B + placebo 40 108 + 13.3 15 B + Ethanol 40 2000.0 70 + 8.4 15 . . _ .
Control (treated with placebo): x + S.E. =
3118.3 _ 305.6 total motion/2 hours The compounds according to the invention substantially reduce the ethanol-induced increased locomotor activity, at the same time have no ef~ect on the spontaneous locomotor activity of untreated animals.
The acute toxicity of the compounds provided by the invention was determined on Wistar ra-ts of both sexes, each weighing 160 to 180 9., which had been treated ,.

l7 ~'~3~7r~

with a single 500 mg./kg. dose of the test compounds, orally. The animals were observed for 14 days after treatment. In Table 3 the percentage of the perished animals is given.

Table 3 CompoundPerished animals n (500 mg./kg. (%) p . o . ) L-cysteine 0 10 The toxicity o~ the compounds according to the invention is ~avourably low related to the ef-fective dose.
The central nervous activities of the compollnds according to the invention were examined on mice and rats with the following methods:
electroshock LSwinyard, E.A., Bro~n, W.C., Goodman, L.S.: J. Pharmacal. Exp. Ther. 106, 319 (1952)7, metrazole spasm /Everett, G.M., Richards, R.K.: 3. Pharmacol. Exp.
Ther. Bl, 402 (1944)7, thiosemicarbazide spasm /aa Venzo, J.P., Greig, M.E., Cormin, M.A.: Amer. J. Physiol. 201, B}3 (1961)_7, strychnine spasm LKerley, T.L., Richards, A.G., Begley, R.W., Abreu, 8.B., Wesver, L.C.: J. Pharmacol, - l8 ~

Exp. Ther. 132, 360 (1961)_7, nicotine spasm / Stone, C.A., Mecklenburg, K.L., Torhans, M.L.: Arch. Int.
Pharmacodyn. 117, 419 (195B)_7, rotarod test / Kinnard, W.C., Carr, C.J.: J. Pharmacol. Expt. Ther. 121, 354 (1957)_7, physostigmine lethality preventing effect L Nose, T., Kojima, M.: Europ. J. Pharmacol. 10, 83 (1970)7, yohimbine potentiation effect L Quinton, R.M.: Brit. B.
Pharmacol. 21, 51 (1963)_7, and analgesic activity /Bianchi, G., Francheschini, ~.: Brit. J. Pharm. Chemother. 9, 280 (1954)7.
When administered in a 160 mg./kg. dose, the compounds according to the invention showed no CNS-activity in the above tests.
The results show that the compounds provided by the invention have a lavourable influence on the behaviour forms altered by ~thanol. They antagoni7e both the CNS-stimulating and the CNS-depressing effect of alcohol, shorten tha time in which the intoxicated person becomes intact again, have a fa~ourable toxicity and a great therapeutic width.
The pharmacologically active compounds according to the invention can be used in therapy in the form of pharmaceutical compositions, which are formulated as preparations suitable for oral, rectal and/or parenteral administration. For oral administration tablets, dragees or capsules are prepared. The oral formulations contain as a vehicle e.g. lactose or starch, as an excipient or a granulation aid e.g. gelatîne, carboxymethyl cellulose, ~', polyvinyl pyrrolidone or starch gum, as a disintegrating substance e.g. potato starch or microcrystalline cellulose, ultraamylopectine or formaldehyde casein, etc. The formulations may also contain antiadhesives and lubricants such as talc, colloidal silica, stearine, calcium or magnesium stearate, etc.
Tablets are prepared for example by wet granulation and subsequent pressing. ~ mixture of the active ingredient and the vehicle and optionall~ a portion of the disintegrating agent are granulated with an aqueous, alcoholic or aqueous-alcoholic solution of the excipients in a suitable equipment, and the granulate is dried. The remaining por-tions of the disintegrating substance, lubricant, antiadhesive or optional fur-ther additives are then added to -the granules, and the mixture is pressed to tablets. If desired, the -tablets are prepare~
with a dividing line which facilitates administration.
Tablets can be prepared also from a mix-ture of the active ingredient and suitable additives by direct pressing.
If desired, the tablets can be converted to dragées, using protecting, flavouring agents and pigments generally known for the preparation of pharmaceutical compositions, e.g. sugar, cellulose derivatives (methyl or ethyl cellulose, carboxymethyl cellulose sodium etc.), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food pigment, food oil varnishes, aroma substances, iron oxide pigments, etc.
Capsules are prepared by filling a mixture of ~'

3~
- 2~ -the active inyredient and the additives into suitable capsules.
For rectal administration the compositions are formulated as suppositories, which contain in addition to the active ingredient a carrier mass, called adeps pro suppository. Suitable carriers include vegetable fats, e.g. hardened vegetable oils, triglycerides of fatty acids having 12 to 18 carbon atoms, preferably Witepsol (a registered trade mark). The active ingredient is homogeneously distributed in the melted carrier mass, and suppositories are prepared by casting.
For parenteral administration injectable preparations are prepared. To prepare an injectable solution the active ingredient is dissolved in distilled water and~or various organic solven-ts, e.g. glycol ethers, optionally in the presence of dissolution aids, e.g. polyoxyethylene sorbitane monolaurate, monooleate or monostearate (Tween 20, Tween 60, Tween B0). The injectable solu-tions may contain also various additives, e.g. preserving agents such as benzyl alco'nol, p-oxy--benzoic acid methyl or propyl ester, benzalkonium chloride or phenyl mercury borate, etc., antioxidants such as ascorbic acid, tocopherol, sodium pyrosulfate and optionally complexing agents to bind the metal traces such as ethylene diamine ~tetraacetate, buffers to adjust the pH and optionally local anaesthetics such as lidocaine.
The injec-table solutions are ~iltered, filled into ampoules and sterili~ed.

. ,~
, ~,;

- 2l - ~ ~3~

The daily dose, depending on the patient's condition, varies between 0.1 and 300.0 mg./kg., preferably 2.0 and 160 mg./kg., preferably administered in more smaller portions.
The invention will be further described with reference to the following illustrative E~amples.

Example 1 ~-Ethyl- ~(2-methoxyphenyl)-4-/ 2-(diiso-propylamino)-ethoxy7-benzylalcohol To a Grignard reactant prepared from l.E2 9.
of magnesium turnings and 14 9. of 2-bromo-anisole in 53 ml. of tetrahydrofurane a solution of 14 9. of 4-/ 2-(diisopropylamino~-ethoxy7-propiophenone in 30 ml. of tetrahydrofurane is added dropwise, with stirring under slight reflux. The reaction mixture i5 boiled for an additional hour. It is cooled to room temperature and poured onto a saturated aqueous ammonium chloride solution. Tetrahydrofurane is distilled off under reduced pressure, and the residue is extracted with ~enzene.
The benzene solution is washed with a saturated aqueous sodium chloride solution and subsequently with water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. Crystallization of the residue from n-hexane yields 15 9. of the aimed compound, which melts at 4S to 47 C.

- 22 - ~3 Analysis for C24H3~N03:
Calculated: C 74.78 ~0, H 9.15 %, N 3.63 %;
Found: C 74.87 %, H 9.23 %, N 3.77 %.

Example 2 o~-Ethy1- ~(4-fluoropheny1)~4 -L 3-(di-n-propylamino)-propox~7-benzylalcohol To an e-thyl magnesium bromide solution prepared from 3.6 9. of magnesium turnings and 16.3 9. of ethyl bromide in 60 ml. of dry ether a solution of 13.2 9.
of 4-fluoro-4'-L 3-(dipropylamino)-propox~7-benzophenone in 70 ml. of dry ether is added dropwise, with stirring at 0 to 5 C. The reaction mixture is stirred at room temperature for 30 minutes, and is then poured onto a solution of ammonium shloride in ice water. The agueous phase is extrac-ted with ether, the solvent phases are combined, washed to neutral with water and dried over anhydrous magnesium sulfate. Ether is distilled o~f under reduced pressure, and the residue is distilled off in vacuo. 11.7 9. of the title compound are obtained, boiling at 196 to 198 C/13 Pa.
Analysis for C24H34FN02:
Calculated: C 74.38 %, H 8.84 %, F 4.90 %, N 3.61 %;
Found: C 74.48 %, H B.87 %, F 5.11 %, N 3.72 %.
By treating the base in a dry ethanolic solution with an ethanolic solution of an equimolar amount of fumaric acid and adding ether to the solution cooled to -lO C the corresponding hydrogen fumarate is ,, - 23 - ~ J~

precipitated. The hydrogen fumarate salt is filtered - off, washed with ether and dried. Melting point: B7 to Example 3 oL-Ethyl- ~ (4-chlorophenyl)-4-L 3-(di-n-propylamino)-propoxv7-benzylalcohol 13.1 9. of ~ethyl-~-(4-chlorophenyl)-4-hydroxy-benzylalcohol, 14 9. of anhydrous potassium carbonate, 9.8 9. of dipropylaminopropyl chloride and O.B5 9. of tetrabutyl ammonium hydrogensulfate in 135 ml. of ethyl acetate are slightly boiled for 20 hours, under stirring. After cooling the mixture, the solvent is evaporated in vacuo. To the residue water and benzene are added. The phases are separated, the benzene solu-tion is washed with water, dried over anhydrous potassium carbonate, filtered and evaporated.
The residue is purified by vacuum fractionation. 13.8 g.
of the desired end product are obtained, boiling at 198 to 200 C/1.3} Pa.
Analysis for C24H34ClN02:
Calculated: C 71.35 %, H 8.48 %, Cl 8.7B %, N 3.47 %;
Found: C 71.41 %, H 8.53 %, Cl B.94 ~ N 3.59 %.

Example 4 ~-Ethyl-c~-(2,4-dichlorophenyl~-4-L 3-~di-propylamino)-propoxy7-benzylaloohol 21.7 9. of d-ethinyl-c~-(2,4-dichlorophenyl)-.,l,:i.

33L~

4-/ 3-(dipropylamino)-propoxy7-benzylalcohol are dis-solved in 210 ml. of benzene, and the solution is hydrogenated in the presence of 1.1 9. of a 10 %
palladium-on-charcoal catalyst. When the uptake of the calculated amount of hydrogen is complete (about 3 hours), catalyst is filtered off and benzene is distilled off.
The crude product weighing 21 9. is distilled in vacuo, to yield a product boiling at 194 to 196 C/6.6 Pa.
Analysi5 for C24H29C12N2 Calculated: C 65.74 ~, H 7.59 %, Cl 16.17 ~0, N 3.19 %;
Found: C 65.83 %, H 7.74 ~0, Cl 16.40 %, N 3.15 %.
~ Ethyl- d_-(2,4-dichlorophenyl)-4-L 3-(di-propylamino)-propoxy7-benzylalcohol methoiodide:
4.4 9. of -the above base and 12.4 9. of methyl iodide are dissolved in 22 ml. of acetone, and tne reaction mixture is slightly refluxed for two hours, whereupon it is cooled -to room temperature. The crystals precipitated upon addition of ether are filtered off and dried. 3.6 g. of the above quaternary compound are obtained, melting at 136 to 137 C.

Example 5 ~-Ethyl- d~-(4-bromoPhenyl)-4-L 3-(di-n-propyl-amino)-propoxYt-benzylalcohol To a Grignard reactant prepared from 2.2 9. of magnesium turnings and 28.2 9. of 4-L 3-(di-n-propyl-amino)-propoxy7-bromobenzene in 170 ml. of dry tetra-hydrofurane a solution of 12.8 9. of 4-bromopropiophenone ,~

~ 3 ~ 3 in 60 ml. of tetrahydro~urane is added dropwise, at - 20 C, and the mixture is stirred at room temperature for two additional hours. When the reaction is co~plete, the reaction mixture is decomposed with a 20 % aqueous ammonium chloride solution, under cooling. Tetrahydro-furane i5 distilled off under reduced pressure. The residue is extracted with benzene. The benzene phase is washed to neutral with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is Eractionated in vacuo. 19.9 9.
of the desired end product are obtained, boiling at 220 to 224 C/6.6 Pa.
Analysis for C24H34BrN02:
Calculated: C 64.28 %, H 7.64 ~0, Br 17.82 %, N 3.12 %;
Found: C 64.40 %, H 7.75 %, Br 17.94 ~0, N 3.28 %.
The corresponding hydrogen fumarate melts at 106 to 107 C.

Example 6 ~-Ethyl- d-(3-chlorophenyl)-4-/ -(di-n-propylamino)-propox~7-benzylalcohol 13.1 9. of d~ethyl-~-(3-chlorophenyl)-4--hydroxy-benzylalcohol, 22.8 9. of anhydrous potassium carbonate and 0.4 ml. of a 40 % tetrabutyl ammonium hydroxide solution in 130 ml. of methyl isobutyl ketone are brought,to the boil, and a solution of 11.8 9. of di-n-prnpylaminopropyl chloride hydrochloride in 12 ml.
of wal:er is added, whereupon the reaction mixture is - 26 - ~ 3~. 3 d~ ~ 3 boiled for further 5 hours. The solvent is -then distilled of~ under reduced pressure, to the residue water is aclded, and it is extracted with benzene. The benzene phases are combined, washed to neutral with a

5 % aqueous potassium hydroxide solution and then with wa-ter, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, the residue is fractionated. 13.5 9. of the desired compound are obtained, boiling at 200 to 202 C/6.6 Pa.
Analysis for C24H34ClN02:

Calculated: C 7135 %, H 8.48 ~, Cl ~.78 %, N 3.47 %;
Found: C 71.48 %, H 9.55 %, Cl 8.8~ %, N 3.52 %.
Melting point of the corresponding hydrogen fumarate: 136 to 137 C.

Example 7 ~-Ethyl-~C-(3-trifluoromethylphenyl)-4-/ 3-(di-n-propylamino)-propoxy7-benzylalcohol 20.8 9. of ~-ethyl-oC-S3-trifluoromethyl-phenyl)-4-(3-bromopropoxy)-benzylalcahol and 41 ml. of dipropyl amine are slightly refluxed with stirring for

6 hours. After cooling, the reaction mixture is evaporated under reduced pressure. To the residue water is added and it is ex-tracted with benzene. The benzene phase is washecl with water, dried over anhydrous potassium carbonate and evaporated. The residue is fractionated in vacuo to yiel~ 17.2 9. of the aimed compound, boiling at 176 to 178 C/6.6 Pa.

- 27 - ~3 Analysis for C25H34F3N~2 Calculated: C 68.62 %, H 7.83 %, F 13.03 %, N 3.20 %;
Found: C 68.57 %, H 7.88 %, F 13.17 %, N 3.41 %.
Melting point of the corresponding hydrogen fumarate: B5 -to 86 C.
The following compounds can be prepared on the analogy of the above Examples, by proper selection of the starting substances.
~-Ethyl-d -(3-trifluoromethylphenyl)-4-/ 2-(diisopropyl-amino)-e-thoxy7-benzylalcohol, boiling point: 172 to 174 C/6.6 Pa Analysis for C24H32F3N02:
Calculated: C 68.08 %, H 7.62 %, F 13.46 %, N 3.31 %;
Found: C 68.22 %, H 7.38 %, F 13.70 %, N 3.54 %.
b~-Ethyl- ~(4-chlorophenyl)-4-,~ 2-(diisopropylamino~-ethoxy7-benzylalcohol, boiling point: 204 to 206 C/6.6 Pa Analysis for C23H32C12 2 Calculated: C 70.84 %, H B.27 %, Cl 9.09 %, N 3.59 %;
Found: C 70.B1 ~0, H 8.18 %, Cl 9.28 %, N 3.77 %.
~-Ethyl- C~-(2-trifluoromethylphenyl)-4-/ 2-(diiso-propylamino)-ethoxy7-benzylalcohol, boiling point: 197 to 201 C/20 Pa Analysis for C2~H32F3N02:
Calculated: C 6B.06 %, H 7.62 %, F 13.56 %, N 3.31 %;
Found: C 67.BB %, H 7.73 %, F 13.50 %, N 3.10 %.

,,, - 2~ J~

~ -Ethyl- ~_(2-methoxyphenyl)-2-L 2-(diisopropylamino)--ethoxy7-benzylalcohol, melting point: 71 -to 72 C
Analysis ~or C24H35N03:
Calcula-ted: C 74.7~ %, H 9.15 %, N 3.63 %;
Found: C 74.70 %, H 9.17 %, N 3.84 %.
d~-Ethyl-~-(4-fluorophenyl)-4-L 2-(diisopropylamino)--ethox~7-benzylalcohol, boiling point: 191 to 194 C/13.3 Pa Analysis for C23H32FN02:
Calculated: C 73.98 %, H 8.64 %, F 5.D9 %, N 3.75 %;
Found: C 74.23 %, H 9.80 %, F 5.34 %, N 3.67 %.
oC-E-thyl-0~(2,5-dimethylphenyl)-4-/ 2-(diisopropyl-amino)-ethoxy7-benzylalcohol, boiling point: 200 to 20~ C/13.3 Pa Analysis for C25H37~l2 Calculated: C 78.28 %~ H 9.72 %, N 3.65 %;
Found: C 78.53 %, H10.01 %, N 3.55 %.
oL-E-thyl-~C~(3-chlorophenyl)-4-/ 2-(diisopropylamino)--ethoxy7-benzylalcohol, boiling point: 190 to 192 C/6.6 Pa Analysis for C23~32ClN02:
Calculated: C 70.P4 %, H 8.27 %, Cl 9.09 %, N 3.59 %;
Found: C 71.10 %, H 8.52 %, Cl 9.17 %, N 3.44 %.
o~-Ethyl-C~-(2-methoxyphenyl)-4-L 3-(di-n-propylamino)-propoxy7-ben~ylalcohnl, boiling point: 212 to 214 C/6.6 Pa ~,. . .

~3iL~7~

Analysis for C25H37N03:
Calculated: C 75.15 %, H 9.33 %, N 3.50 %;
Found: C 75.23 %, H 9.28 %, N 3.63 %.
Melting point of the corresponding hydrogen fumarate: 107 to 108 C.

Example 8 The new compounds according to the invention can be converted ~or example into the following pharma-ceutical compositions.

_ablets Composition of a single -t~blet:

active ingredient 100.0 mg.

lactose 184.0 mg.

potato starch 80.0 mg.
polyvinyl pyrrolidone 8.0 mg.
talc 12.0 mg.

magnesium stearate 2.0 mg.

aerosil (colloidal silica) 2.0 mg.

ultraamylopectine 12.0 mg.
From the above ingredients 400 mg. tablets are prepared by wet granulation and subsequent pressing.

Active ingredient: o~-ethyl- ~(2-methoxyphenyl)-4-/ 3-(di-n-propylamino)-propoxY7-benzylalcoh Dragées Tablets as described above are coated with a '~"' layer prepared from sugar and talc in a known manner.
Dragées are polished with a mixture oE bee wax and carnauba wax. Weight of a dragée: 500.0 mg.

5 Suppositories Composition of a suppository:
active ingredient 100.0 mg.
lactose 200.0 mg.

basic substance (e.g. Witepsol H) 1700.0 mg.
The basic substance is melted and then cooled to 35 C. The active ingredient is thoroughly admixed with the lactose, and the mixture is homogenized in the basic substance in a suitable equipment. The obtained rnass is poured into cool moulds. One suppository weights 2000 mg.

Active ingredient: ~b-ethyl-c[-(3-chlorophenyl)-4-L 3-~i-n-propylamino)-propoxv7-benzylalcohol.

Ca~sules Composition of a capsule:

active ingredient 50.0 mg.

lactose 100.0 mg.
talc 2.0 mg.

potato starch 30.0 mg.
cellulose (microcrystalline)8.0 mg.

The active ingredient and the additives are thoroughly biended, the mixture is passed through a 0.32 mm. sieve and filled into hard gelatine capsules ' ~

-30a- ~ ~ 3 (size 4).
Active ingredient: ~-ethyl- ~(3-chlorophenyl)-4-L 3-(di-n-propylamino)-propox~7-benzylalcohol Suspensions Composition of 100 ml. of suspension:
active ingredient 1.0 g.
sodium hydroxide 0.26 9.

citric acid 0.30 9.
nipagin (4-hydroxybenzoic acid methylester sodium salt) 0.10 g.
Carbopol 940 (polyacrylic acid) 0.30 9.
ethanol (96 ~, 1.00 9.
raspberry aroma 0.60 9.
sorbitol (70 % aqueous solution) 71.00 9.
distilled wa-ter ad100.0 ml.
To a solution of nipagin and ci-tric acid in 20 ml.
of distilled water Carbopol is added in small portions, with vigorous stirring, and the solution is allol~ed to stand for 10 to 12 hours. Thereafter a solution of the above amount of sodium hydroxide in 1 ml. of distilled water is added dropwise, followed by dropwise addition of an aqueous solution of sorbitol and an ethanolic raspberry aroma solution, with stirring. Active ingredient is added in small portions, and the mixture is homogenized.
The suspension is supplemented with distilled water ad 100 ml., and the suspension syrup is passed through a colloidal mill.

-30b~ 3~

Active ingredient: ~-ethyl-o~-(2-trifluoromethyl-phenyl)-4-L ~-(diisopropylamino)-ethoxv7-benzyl-alcohol.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of dialkylaminoalkoxy-benzylalcohol derivatives of the formula (I):

(I) wherein R1 is hydrogen, halogen, trihalomethyl, alkyl having from one to 4 carbon atoms or alkoxy having from one to 4 carbon atoms;
R2 is halogen, trihalomethyl, alkyl having from one to 4 carbon atoms or alkoxy having from one to 4 carbon atoms;
R3 and R4 independently stand for an alkyl group having from 3 to 5 carbon atoms; and n is 2, 3, 4 or 5, and acid addition and quaternary ammonium salts thereof, which comprises a) reacting a propiophenone of the formula (II):
(II) wherein R3, R4 and n each have the same meanings as defined above, with an organometallic compound of the formula (III):

(III) wherein R1 and R2 are as defined above, and M is an alkali metal, preferably lithium, sodium or potassium, or an MgX group, in which X is halogen; or b) reacting a compound of the formula (IV):

(IV) wherein R1, R2 and n each have the same meanings as defined above, and X is halogen, with an amine of the formula (V):

(V) wherein R3 and R4 are as defined above; or c) reacting a benzophenone of the formula (VI):
(VI) wherein R1, R2, R3, R4 and n each have the same meanings as de-fined above, with an organometallic compound containing an ethyl group; or d) reacting a propiophenone of the formula (VII):

(VII) wherein R1 and R2 are as defined above, with a Grignard compound of the formula (VIII):

(VIII) wherein R3, R4 and n each have the same meanings as defined above, and X is halogen; or e) reacting a compound of the formula (IX):

(IX) wherein R1 and R2 are as defined above, with an amine of the formula (X):

(X) wherein R3 and R4 are as defined above, and X is halogen, alkyl-sulfonyloxy or arylsulfonyloxy group, or a salt thereof f) reducing a compound of the formula (XI) (XI) wherein R1, R2, R3, R4 and n each have the same meanings as defin-ed above, and Z is ethinyl or vinyl, and if required, converting any of the products obtained by process variants a) to f) into their acid addition or quaternary ammonium salts, or converting a product obtained as an acid addit-ion salt into a corresponding base or converting a free base into an acid addition or quaternary ammonium salt thereof.

2. Dialkylaminoalkoxybenzylalcohol derivatives of the formula (I):

(I) wherein R1 is hydrogen, halogen, trihalomethyl, alkyl having from one to 4 carbon atoms or alkoxy having from one to 4 carbon atoms;
R2 is halogen, trihalomethyl, alkyl having from one to 4 carbon atoms or alkoxy having from one to 4 carbon atoms;
R3 and R1 independently stand for an alkyl group having from 3 to 5 carbon atoms; and n is 2, 3, 4 or 5, and acid addition and quaternary ammonium salts thereof when made by the process of claim 1 or an obvious chemical equivalent.

3. The process of claim 1 step (b) wherein the compound of formula (IV) as defined in claim 1, is reacted with the compound of formula (V) as defined in claim 1 in the presence of a base.

4. The process of claim 1 step (c) wherein the organo-metallic compound containing lithium is an ethyl magnesium halide or ethyl lithium.

5. The process of claim 1 step (e) wherein the compound of formula (IX) as defined in claim 1 is in the form of an alkali metal or quaternary ammonium phenolate thereof.

6. The process of claim 1 step (e) wherein the compound of formula (IX) as defined in claim 1 is reacted with the compound of formula (X) as defined in claim 1 in the presence of an acid binding agent.

7. The process of claim 1 wherein R1 is hydrogen, chlorine or methyl, R2 is bromine, chlorine or fluorine, trifluoromethyl, methyl or methoxy, R3 and R4 independently are propyl, n-propyl or isopropyl and n is 2 or 3.

8. A process for preparing .alpha.-ethyl-.alpha.-(2-methoxyphenyl)-4-[2-(diisopropylamino)-ethoxy]-benzylalcohol which comprises reacting 4-[2-(dilsopropylamino)-ethoxy]-propiophenone with a Grignard reagent of magnesium and 2-bromo-anisole.

9. .alpha.-Ethyl-.alpha.-(2-methoxyphenyl)-4-[2-(diisopropylamino)-ethoxy]-benzylalcohol when prepared by the process of claim 8 or an obvious chemical equivalent thereof.

10. A process for preparing .alpha.-ethyl-.alpha.-(4-fluorophenyl)-4-[3-(di-n-propylamino)-propoxy]-benzylalcohol which comprises reacting 4-fluoro-4'-[3-(dipropylamino)-propoxy]-benzophenone with ethyl magnesium bromide.

11. .alpha.-Ethyl-.alpha.-(4-fluorophenyl)-4-[3-(di-n-propylamino)-propoxy]-benzylalcohol when prepared by the process of claim 10 or an obvious chemical equivalent thereof.

12. A process for preparing .alpha.-ethyl-.alpha.-(4-chlorophenyl)-4-[3-(di-n-propylamino)-propoxy]-benzylaleohol which comprises reacting .alpha.-ethyl-.alpha.-(4 chlorophenyl)-4-hydroxy-benzylalcohol with dipropylaminopropyl chloride.

13. .alpha.-Ethyl-.alpha.-(4-chlorophenyl)-4-[3-(di-n-propylamino)-propoxy]-benzylalcohol when prepared by the process of claim 12 or an obvious chemical equivalent thereof.

14. A process for preparing .alpha.-ethyl-.alpha.-(2,4-dichlorophenyl)-4-[3-(di-n-propylamino)-propoxy]-benzylalcohol which comprises reducing .alpha.-ethinyl-.alpha.-(2,4-dichlorophenyl)-4-[3-(dipropylamino)-propoxy]-benzylalcohol with hydrogen.

15. .alpha.-Ethyl-.alpha.-(2,4-dichlorophenyl)-4-[3-(di-n-propylamino)-propoxy]-benzylalcohol when prepared by the process of claim 14 or an obvious chemical equivalent thereof.

16. A process for preparing .alpha.-ethyl-.alpha.-(4-bromophenyl)-4-[3-(di-n-propylamino)-propoxy]-benzylalcohol which comprises reacting 4-bromopropiophenone with a Grignard reagent of magnesium and 4-[3-(di-n-propylamino)-propoxy]-bromobenzene.

17. .alpha.-Ethyl-.alpha.-(4-bromophenyl)-4-[3-(di-n-propylamino)-propoxy]-benzylalcohol when prepared by the process of claim 16 or an obvious chemical equivalent thereof.

18. A process for preparing .alpha.-ethyl-.alpha.-(3-chlorophenyl)-4-[3-(di-n-propylamino)-propoxyl-benzylalcohol which comprises reacting .alpha.-ethyl-.alpha.-(3-chlorophenyl)-4-hydroxy-benzylalcohol with di-n-propylamlnopropyl chloride hydrochloride.

19. .alpha.-Ethyl-.alpha.-(3-chlorophenyl)-4-[3-(di-n-propylamino)-propoxy]-benzylalcohol when prepared by the process of claim 13 or an obvious chemical equivalent thereof.

20. A process for preparing .alpha.-ethyl-.alpha.-(3-trifluoromethyl-phenyl)-4-[3-(di-n-propylamino)-propoxy]-benzylalcohol which comprises reacting .alpha.-ethyl-.alpha.-(3-trifluoromethylphenyl)-4-(3-bromopropoxy)-benzylalcohol with dipropylamine.

21. .alpha.-Ethyl-.alpha.-(3-trifluoromethylphenyl)-4-[3-(di-n-propylamino)-propoxy]-benzylalcohol when prepared by the process of claim 20 or an obvious chemical equivalent thereof.