DE1518399A1 - Tert. aminoalkoxy-substituted 3,4-diphenylcoumarins and their derivatives including the acid addition salts and quaternary ammonium salts and processes for their preparation - Google Patents

Description

LAWYERS

DR. JUk. DIPL-CHEM. WALTER BEIL ALFRED HOG ³ PcNER

DR. J -.; -. Oi - \ -..- CKEM. H.-J. WOLFF SR. "Jüii.: ..N ¹ S QiR. BEIL

623 FSANKFUSTAM MAIN-HOCHST ADELONSTRASSE 58

Dec. 24, 1968

Our No. Io 7ol

THE UPJOHlJ COHPAIJY Kaianazoo, Michigan, V.St.A.

Tert. Aminoalkoxy-substituted 3 » 'f-Diphenylumarine and their derivatives including the acid addition salts and quaternary ammonium salts and processes for their preparation.

The invention relates to tertiary aminoalkoxy-substituted persons 3,4-diphenylcoumarins of the general formula

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(D

8AD ORIGINAL

in the'R._, R- and Yu. a lower alkyl, lower alkenyl, trifluoromethyl, lower alkoxy, lower alkenyloxy, lower alkylenedioxy, hydroxy, lower alkyl mercapto group, a halogen atom or the radical -0-AI ^ Jj, in which A is an alkylene group iait 2-6 C atoms and Rj. And R _{r represent} a lower alkyl group or a lower alkyl group which, with the adjacent nitrogen atom, form a saturated, heterocyclic radical having 5-7 ring atoms, and X ₃ y and ζ represent integers from 0-4, where at least one of the groups R _1, R ₀ and R, represents the group -OA-IJC whose Gäureadditionssalze one with ρharmakologisch verträclichen acids and their quaternary ammonium salts in which the anion of _a pharmacologically acceptable acid, and experience a "/ animals to manufacture.

The term “lower-alkyl group ⁿ means an alkyl group with 1 to G carbon atoms, xiie z.3. Itetnyl, iithyl, ropyl, butyl, amyl, eexyl, keptyl, octyl groups and in isory forms the same." The term "lower alkenyl group" means alkenyl groups with 2 to 8 carbon atoms, such as zE ¥ inyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl groups and their isomeric forms. The term "lower alkoxy group" refers to alkoxy groups having 1 to 8 carbon atoms including, such as, for example, ethoxy, ethoxy, tropoxy, butoxy, aniyloxy, hexyloxy, heptyloxy, cycloxy groups and their isomeric forms . The term ^ lower alkenyloxy group "means alkenyloxy groups with 2 to C carbon atoms, such as aD vinyloxyr, allyloxy, butenyloxy, pentenyloxy, iiexenyloxy, heptenyloxy, octenyloxy groups and their isomeric forms. The term valors" relates to chlorine , Bromine and iodine. The expression "lower

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SAD ORIGINAL

Alkyl mercapto group "means alkyl mercapto groups with 1 to 8 carbon atoms, such as methyl mercapto, ethyl mercapto, propyl mercapto, butyl mercapto, amyl mercapto-j Kexyl mercapto, heptyl mercapto, octyl mercapto groups and their isomeric forms. The term "lower alkylenedioxy group" means alkylenedioxy groups with 1 to 8 carbon atoms, such as a methylenedioxy, ethylenedioxy / propylenedioxy, butylenedioxy, pentylenedioxy, Hexylenedioxy, heptylenedioxy, octylenedioxy groups and their isomeric forms. The term "alkylene group With 2 to 6 carbon atoms inclusive "means ethylene, propylene, butylene, pentylene, hexylene groups and their isomeric forms. The term "lower alkyl groups which form one with the adjacent nitrogen atom saturated heterocyclic Hest with 5 to 7 ring atoms form "means pyrrolidine and lower alkylpyrrolidine groups, such as 2-methylpyrrolidine, 2,2-diinethylpyrrolidinoer 3-Iiethylpyrrolidinruppen, on piperazine and lower Alkylpiperazino groups, such as 2-methylpiperazine, 4-ilethylpiperazine or 2,4 diraethylpiperazine groups on pipoiidine and lower alkyIpiperidine groups, e.g. 2-methylpiperidine, 3-methylpiperidine, or 4,4-di-methylpiperidine groups on liorpholin-, eexamethylenirain-, Iiomopiporc-sin- or ionor.orpholine groups.

The erriiiduncsgenefien acid addition salts are salts of compounds of Forr.el (I) with pharmakolocisch acceptable acids, vrle example sulfuric acid, hydrochloric acid, Sal ^peters: xirej phosphoric acid, Ililchsäure, benzoic acid, Jlethansul.fonsiüire _s pr-toluenesulfonic acid, .Salicylsäure, Sssigsüure. Propionic acid, ilaleic acid, malic acid, V / monoic acid, citric acid, cyclohexylsulfamic acid, succinic acid, nicotinic acid or ascorbic acid.

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BATH

The quaternary ammonium salts according to the invention are obtained by reacting the compound of the formula (I) with quaternizing Agents such as lower alkyl halides, lower alkeny halides, lower dialkyl sulfacene, Obtained aralkyl halides or lower alkyl aryl sulfonates. The terms "lower alkyl groups" and "lower Alkeny! Gruppen "have the preceding meaning. The" term "Aralkyl" refers to aralkyl groups having 7 to 13 carbon atoms, such as benzyl-, phenitöfcrl-, phenylpropyl- or Benzhydry! groups. The term "lower alkyl aryl sulfonates" the esters, those of lower alkyl alcohols and Ary! Sulfonic acids, such as' Benzenesulfonic acids, toluenesulfonic acid, Xylene sulfonic acid and similar acids are formed will. Examples of quaternary salts of compounds of the formula (I) are methobromide, iiethiodide, ethobromide, Propyl chloride, butyl bromide, gctyl bromide, methyl methosulfate, iithylethosulfate, allyl chloride, allyl bromide, benzyl bromide, Benzhydryl chloride, methyl p-toluene sulfonate, ethyl p-toluene ~ sulfonate and the like.

The compounds according to the invention, including the free bases of the formula (I), the acid addition salts thereof and the quaternary ammonium salts thereof, have pharmacological activity. The compounds according to the invention are important, for example, as anti-fertility agents, anti-estrogenic agents, gonadotrophin-inhibiting agents and as agents for lowering the lipid and cholesterol blood level in mammals, both in hens and animals. In addition, the compounds erfindungsper.äßen] j _s anti-inflammatory effect so that they z.. Can be used in EU therapy for local relief of inflammations and burns, and in the treatment of atopic dermatitis and contact disease. In addition, the connections according to the invention act as stinulators on the central nervous system.

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BATH ORIGINAL

For example, it has been found that the compounds 3- (p-methoxyphenyl) -4- / p- (2-diethylaminoethoxy) phenyl7-cumarih, 3- (p ~ methoxyphenyl) -Jj-phenyl-7 - (2-diethylaminoethoxy) -coumarin and 3,4-diphenyl-7- (2-diethylaminoethoxy) coumarin As anti-inflammatory agents 'are as effective' as hydrocortisone when applied to rats with granuloma according to the method of Robert et al., Acta ICndocrinologica, Vol. 25 p. Io5a 1957 can be applied. The connection 3,4-Diphenyl-7- (2-diethylaminoethoxy) -coumarin showed in an attempt by the method of Duncan et al., Proc. Soc. Exp. Diol. song. Vol. 112, pp. 439-442, 1963 * for oral Administration to rats has a fertility-inhibiting effect.

For administration to mammals, the inventive Compounds combined with solid or liquid pharmaceutical carriers and made into tablets, powders, Capsules and similar solid dosage forms can be processed using starch or similar excipients which can also be dissolved in suitable solvents or carriers for oral or parenteral administration or be suspended.

The compounds according to the invention not only have a pharmacological activity, they can also be used as intermediates. For example, the compounds of formula (I) can be reacted with hydrofluoric acid ι the hydrofluoric acid salts formed are effective moth repellants in dilute aqueous solution, as described in more detail in US Patents 2,075,359 and 1,915,339.

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τ β -

The compounds of the formula (I) according to the invention can be obtained by first using the correspondingly substituted o-hydroxybenzophenone of Poriael (II) an alkali metal salt of the correspondingly substituted phenylacetic acid (III) is reacted, so that a coumarin of formula (IV) is obtained, and then this, as described below, is reacted.

The first implementation is shown below:

rv 7 s

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BATH ORIGINAL

rrr * r

in the above formulas, R 1, R 1 and R _n each represent

D / ν

lower alkyl, lower alkenyl, trifluoromethyl, lower alkoxy, lower alkenyloxy, lower alkylenedioxy, halogen, lower alkyl mercapto, hydroxy or acyloxy groups, the ayl radical being the radical of an organic carboxylic acid, preferably a hydrochloric acid which contains 1 to 12 carbon atoms inclusive, where at least one of the Rg, R ₇ or Rg groups is a hydroxyl or acyloxy group, R is hydrogen or an acyl group, which is listed above, II is an alkali metal, preferably sodium or Potassium, is and x, y and ζ have the same meaning as described above.

The expression "hydrocarbon-carboxylic acid with 1 to 12 carbon atoms inclusive" means saturated * and unsaturated aliphatic and aromatic acids with the! indicated number of carbon atoms understood, such as acetic acid, propionic, butter, isobutter, t-butylessirr, valerian, isovaleric, caproic, capryt, capric acid ₃ lauric acid, acrylic, crotonic, hexincarboxylic, lieptincarboxylic , Octincarbon-, Cyclobutancarbon-, Cyclopen-} tancarbon-, Cyclopentencarbon-, Cyclohexancarbon-, Dimethylcyclohexanarbon-, eenzoe-, toluyl-, naphthalenecarbon-, j iithylbenzoe-, phenylessig-, I. ^f aphthalinessic-, phenylvalerian-,! Zir .: t-, phenylpropiol-, phenylpriopionic or p-dutoxyphenyl- {propionic acid.

The foregoing Urasetzunc; is carried out under the same conditions as the. \ Ostaneki-Robinson reaction: compare, for example, "Heterocyclic Compounds" by RC Slderfield, Vol. II, ceiten I76, 2jH ("eiT York, 1951).

Contains one or both reactants (II) and (III) contain one or more free Kyiefroxygruppen as oub-

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substituents, these groups are acylated during the condensation described above and are present in the coumarin (IV) as corresponding acyloxy groups. The corresponding coumarin (IV) having a free hydroxy group or free hydroxyl groups can "by hydrolysis of the acyloxy group or groups can be obtained. The hydrolysis can be used as acid hydrolysis, for example using aqueous or aqueous alcoholic mineral acid or alkaline hydrolysis, for example using aqueous or alcoholic alcoholic alkali metal hydroxide or carbonate, such as sodium hydroxide, potassium hydroxide, potassium carbonate and the like, or using an alcoholic alkali metal alkoxide solution, such as ethanolic sodium ethoxide and the like.

The invention. Compounds of formula (I) is ₀ free hydroxyl groups from the corresponding coumarin (IV), wherein at least one of the groups Rg, R "and R, obtained by etherification of the latter compound with the corresponding tertiary aminoalkyl halide. The etherification is preferably carried out in such a way that the coumarin containing the free hydroxy group is mixed with the corresponding tertiary aminoalkyl halide,

UA-HaI ₃

in the Rj ,, P. _r and A have the meaning given above, und.LaI is a halogen, in an inert organic solvent, such as a lower alkanol, for example methanol, ethanol or isopropyl alcohol, in the presence of a base, such as z. B ο ilatriur; .hyc! Roxyd, Kaliurhydroxyd, "Tatriunimethoxyd or

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ÖAD

15183 * 9

I. ■ '' ■ -9 -

Sodium ethoxide converts.

The reaction is advantageously carried out at elevated temperatures, preferably at or near the reflux temperature of the reaction mixture, advantageously, the tertiary aminoalkyl halide is in a slight excess the stoichiometric amount of free hydroxy compound used. The desired compound (I) is obtained from the reaction mixture by conventional methods, for example by evaporation under reduced pressure, followed by treatment the residue with water and solvent extraction of the water-insoluble material obtained. The compound (I) obtained in this way is made by conventional methods drive, such as recrystallization, chromatography and. similar procedures cleaned.

The benzophenones of the formula (II) used as starting material in the above-described process are for the most part known and can, for example, according to the method described by Berliner ίκ "Organic Reactions" Vol. V, S-. 229 (John Wiley & Sons, Inc., New York, 19 ^ 9). Furthermore, the phenyl acetic acid salts from which the starting salts (III) are obtained are largely known.

- The tertiary aminoalkyl halides,

H-A-IIaI,

where R ,,, R_, A and PIaI have the meaning given above have, and which are used in the reaction described above, can be obtained by halogenation of the corresponding tertiary arainoalkanols are obtained,

909832 / U97. _0A d owe «* ÄL

/ JJ-I J J 4 j i * t

- Io -

the latter being in turn due to the action of the necessary secondary Amines

"to the corresponding haloalkanol, HaI-A-OH, where Hai and A have the meaning given above, according to known ones Procedures are obtained. The condensation between the secondary arain

and the haloalkane1 Hal-A-OH can be carried out, for example, according to the method described by Hoffet, in J.Org.Chem., Vol. Ih ₃ p. 062, 19 ^ 9. The desired tertiary aminoalkanols can also be obtained by heating the secondary amine

with the corresponding haloalkanoic acid ester and then Reduction of the resulting aminoalkanecarboxylic acid with lithium aluminum hydride according to the above process from Hoffet.

The coumarins (IV) used in the manufacture of the invention.;: Compounds (I) used four den, can be obtained by a different reaction sequence as follows:

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BATH ORIGINAL

t ι C

In the above formulas, l \> _a R _{r have} the meaning given above.

/ Rn_7z

R _ß!

unc, ζ

The above reaction v ^«r ill among Bueu-Hoi among others in'J.Org.Chem. 'Vol. 19, p. 1548, 1954 for the formation of T-hydroxy-jjil-diphenyl-, 3-P ^ inyl- ⁱ } - (p-hydroxyfahenyl) - and 3j.4 ~ di- (p-hydroxyphenyl) -coumarin the appropriately substituted o-I'lethoxybenzophenone and phenylacetonitrile described conditions carried out.

The acid addition salts of the compounds of the invention having the formula (I) can be obtained by methods known in the art. Lei spit la ^T .-. ^r ice can the

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BAD OBiQlNAt

acid addition salts according to the invention by reaction a free base of the formula (I) with one of the pharmacologically acceptable acids listed above in counter- .. ' waiting for an inert solvent * such as methanol, ethanol and the like to be obtained.

The quaternary ammonium salts of the present invention can be prepared by reacting a free base of the formula (I) with a quaternizing agent, for example an alkyl halide such as methyl iodide, ethyl chloride, isopropyl bromide and the like, an alkenyl halide such as allyl chloride j Al] ly lbromide and the like, a dialkyl sulfate such as dimethyl sulfate, diethyl sulfate and the like, an arfilkyl halide such as benzhydryl chloride, phenyl bromide and the like, or an alkyiarylsulfonate such as methyl p-toluenesulfonate and the like. The reaction is preferably carried out by heating the reactants in the presence of an inert solvent such as acetonitrile, acetone, methanol and the like. In general, the desired quaternary salt precipitates from the solution after cooling the reaction mixture and can then be filtered off. The purification of the quaternary salt can be achieved by conventional methods, for example by recrystallization. The anion of the quaternary ammonium salt obtained as described above can be replaced by any other desired anion using known techniques, for example the anions of the various acids listed above. For example, each of the quaternary ammonium salts according to the invention can be converted into the corresponding quaternary ammonium hydroxide, for example by treatment with. Silver oxide, are converted ^'1, and the quaternary ammonium hydroxide is obtained with the appropriate acid to the desired quaternary Ammöhiumöälz umgesetzt'i- ""' - '

_BATH ORIGINAL,

-.13 -

Example 1 3 _a 4-diphenyl-7- (2-diethylaminoethoxy) coumarin - and its hydrochloride

A. 7-Acetoxy-3,4-diphenylcoumarin.

A mixture of 9.5 g ilatriumpheny lace did 7j9o g 2 ₃ k-dihydroxybenzophenone and 60 cc Essiga ^ sureanhydrid heated at Rückflüßkühler 3o h. To boiling. The solution is cooled and poured into water and the mixture stirred for 1 hour. The resulting mixture is extracted with methylene chloride and the extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The oily solid residue twice imrde "from a mixture of benzene and recrystallized from ethanol. There were g T-acetoxy-3i ⁱ t-diphenylcumarin obtained in the form of crystals 3 _S 19, which had a melting point of 222-225 ° C.

B. 3j4 ~ Diphenyl-7-hydroxycoumarin

A total of 7 * 55 g of 7-acetoxy-3j ^i- diphenylcoumarin were slowly added to 75 ecm of ice-cold concentrated sulfuric acid with stirring. Once the solution was homogeneous, it was carefully poured into ice water. The precipitate which separated out was filtered off and recrystallized twice from ethanol. In this way, Ilan received 5 _S 95 E 3 ₃ ^ - liphenyl-7 ~ hydroxycoumarin in the form of crystals with a melting point of 287 to 209 ° C.

C. 3 _s . ⁱ t-Diphenyi-7 "(2-diethylaminoethoxy) -curiiarin and its iiydrouhl-örid,

Hin © solution of 2 ^ 09 g sodium methoxide in methanol <H _a 64

was mixed with stirring to form a suspension of 3 sec. 1 3 sec. of diphenyl 7-hydroxyl eumarin in 100 ecm of ethanol

4 & Φ Suspended solids in solution ge * & Φζ vmeumn 3 * 3 ⁵ S g a * solution Vöft S ^ Dietliylamiiuo'-

iia i & tfä ^ nöl Im ¥ erfiElttii-s iul ^ ia ^ egeis ^ ii ^ ναιύ das

BATH

The mixture obtained was heated to boiling on the refluxing unit for 20 hours. The resulting mixture is evaporated to dryness under reduced pressure and the residue is treated with a mixture of water, ether and ethylene chloride. The organic layer is separated off, washed with dilute aqueous potassium hydroxide solution and then with saturated sodium chloride solution and dried over anhydrous sodium sulphate The dried solution was filtered and the filtrate was evaporated to dryness. The oil was recrystallized twice from ligroin. 3.46 g of 3 _s ^ -diphenyl-7- (2 ~ diethylaminoethoxy) -coumarin were obtained in the form of crystals with a melting point of 95 ~ 97 ° C,

Analysis3 calculated for C ₀₇ K ₀₇ IIO.,: C lo, H2 ' ₃ II 6.58 * Ii 3.39 found: C 72 * 03; ü S ₃ Ch ^ H 3.02.

A solution of 1 ^ 3s ^ -diphenyl ~ 7- (2-diethylaninoethoxy) -coumarin (which was obtained as described above) in 25 ecm of absolute ethanol is saturated with gaseous hydrogen chloride. The resulting solution is evaporated to dryness under reduced pressure. ! lan receives the hydrochloric, from 3j ² i-diphenyl ~ 7- (2-diethylaminoethory) -coumarin in kr is 0.1 liner form.

Example 2 j- (pI.ethoxyphenyl) -H- / j> - (2-diethylarninoethoxy) -phenyl? -Coumarin and its hydrochloride

Λ. 3-Cp-rethoxyphenyl) -4- (p-acetoxyphenyl) -coumarin

i'.in a mixture of 9.95 g of 2, i! '- diacetoxybenzophenone and that of 5.56 c of p-uetiioxy-phenylacetic acid and 70 g of 25 tiger methanolic acid; Alcohol-free liatrium sala prepared with sodium methoxide was heated to boiling for ko hours on the reflux cooler with 50 ecm of sodium anhydride. The mixture obtained was cooled and poured into water

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Mixture was stirred for 2 hours before floating on top Liquid decanted and the guiurui-like residue was extracted with methylene chloride. The ethylene chloride extract was washed successively with water and saturated aqueous sodium bicarbonate solution and then dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate evaporated to dryness. The residue was once au3 Methanol and recrystallized twice from aqueous acetic acid. 1.85 g of 3- (p-methoxyphenyl) - *} - (pacetoxyphenyl) coumarin were obtained in the form of crystals, which had a melting point of 197 to 199 ° C.

Analysis calculated for 0 ^ 1ΐ ^ η0 _Γ : C 7 ² J, 6o; K * f, 7o Lefunds: C 7 * 1.37, H **, 37

k 3 ~ (p-iisthoxyphenyl) -4- (p-hydroxyplienyl) -coumarin

A mixture of 15.37 g of 3- (p ~ methoxyphenyl) - ⁱ l- (p-acetoxyphenyl) coumarin, 2 g of potassium hydroxide and 2oo ecm of water was shaken for 16 hours. At the end of this period the mixture was filtered and the filtrate acidified by adding hydrochloric acid. The precipitate which separated out was isolated by filtration, washed with water and recrystallized from aqueous acetic acid. This gave 11.6 g of I-Cp iiethoxyphenylJ-if-Cp-hydroxyphenyl) coumarin in the form of crystals which had a melting point of 232-235 ⁰ C. An analytically pure sample with a melting point of 235 to 237 ° C. was obtained by repeated recrystallization from the same solvent.

Analysis calculated for C ₂₂ II ₁₆ O ₂ : G 76.73; H, H, 68 found: "C-76.99; Ii 4.67.

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ι »1 i

- 16 -

C. 3- (p-MethoxphenyI) -4- / ρ- (2-diethylaminoethoxy) -phenyl? - coumarin and its hydrochloride.

To a suspension of 6.88 g * 3- (pH> letho »phenyl) -4- (hydroxyphenyl) coumarin 4.32 g of 25 percent strength by weight sodium methoxide in methanol were added to 100 ecm of ethanol. The resulting mixture was stirred for 1 hour before it with a solution of 6, og 2-diethylaminoethyl chloride was treated in 2oo coin ethanol. The resulting mixture Was heated to boiling at the reflux condenser for 20 hours and then cooled and reduced under reduced pressure to Evaporated to dryness. The residue became with a mixture treated from water, ether and methylene chloride. The organic layer was separated with dilute aqueous Potassium hydroxide solution and then with saturated sodium chloride solution washed and dried over anhydrous sodium sulfate. The dried solution was filtered, and the filtrate evaporated to dryness. The residue was recrystallized twice from methanol. 6.52 g were obtained 3- (p-Methoxyphenyl) -4- / Jp- (2-diethylaminoethoxy) -pheny l7-coumarin in the form of crystals with a melting point of 131.5 to 133 ° C.

Analysis calculated for Cggligg NO4: C, 75.82; H 6.59 • Found: C 75.55; K 6.46.

The above free base is nach.dem in Example 1, Process described in Part C converted into the hydrochloride.

Example "3-Phenyl-4- / p - (2-Mäthylaminoäthoxy) -phenyl? - r— coumarin and its lly dr ο chlor id.

A. 3-Phenyl-4- (p-acetoxyphenyl) coumarin

A mixture of 31.8 g of sodium phenyl acetate, 44.3 g of 2,4-dihydroxybenzophenone and 35o ecm acetic acid anhydride vmrde The reflux condenser is heated to boiling for 40 hours. The lleaktipnsprodukt was cooled and poured into uasserc. The watery

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The suspension was stirred for 2 hours and the aqueous layer was then removed by decantation. The gummy residue was triturated with ether, the ether-insoluble fraction was filtered off and recrystallized from aqueous acetic acid. 7.03 g of 3-phenyl-4- (p-acetoxyphenyl) coumarin were obtained in the form of crystals with a melting point of 231 to 234 ° C.

Analysis calculated for C ^ H ^ O ^: C, 77.51; H 4.53 Found: C, 77, ¹ Jo; II 4.75.

B. 3-phenyl-4- (p-hydroxyphenyl) coumarin

According to the method described in Example 2, Part B, but using 11.94 g of 3-phenyl-4- (p-acetoxyphenyl) coumarin instead of 3- (p-methoxyphenyl) -4- (p-acetoxyphenyl) -coumarin were, there was obtained 9.63 g of 3-phenyl-4- (p-hydroxyphenyl) coumarin in the form of crystals having a melting point 291.5 to 295 ⁰ C.

C. 3 ~ Phenyl-4 - / - p- (2-diethylaminoethoxy) -phenyl? -Coumarin and its hydrochloride. .

Following the procedure of Example 2, Part C, but using 3-phenyl-4- (p-hydroxyphenyl) -coumarin ^{instead of 3- (p-? Ie "thoxyphenyl) -4- (p-hydroxyphenyl) -coumarin} to yield 3-Pheny1-4- / p- (2-diäthylaminoäthoxy) -phenyl7-coumarin in the form of crystals having a melting point of 02.5 to 06 ⁰ C.

Analysis calculated for C ₂₇ H ₂₇ NO ₃ : C 7-4.22; η 6.5G; N 3.39. • Found: C 78.45; H 6.5o; II 3.37.

The free base obtained in this way is converted into the hydrochloride according to the method described in Example 1, Part C converted.

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i t ι • · I * '· ti

- 18 -

Example ¹ S 3- (P'-methoxyphenyl) -4-phenyl-7- (2-diethyl-: amino-ethoxy) -coumarin and its hydrochloride,

A. 7-Acetoxy ~ 3 ~ (p-methoxyphenyl) -H-phenyloumarin.

A mixture of 8.3o g of sodium p-methoxyphenyl acetate, 8,19og 2, ^ - dihydrobenzophenone and 85 ecm of acetic anhydride was heated to boiling ^{on a reflux condenser for 1 hour.} The reaction product was cooled and poured into water. The aqueous mixture was stirred for 2 hours before the aqueous layer was removed by decantation. The gummy residue was extracted with methylene chloride and the methylene chloride extract dried over anhydrous sodium sulfate. The dried extract was filtered and the PiI-entered evaporated to dryness. The residue was recrystallized from itthanol. Lan received 3.37 C 7 ~ acetoxy-3- (p-methoxyphenyl) -4-piieny! coumarin in a porri of crystals:.: ib a melting point of 175 * 5 * oi3 177 ₅ 5 C.

Analysis , calculated for C "j, IL oO _r : C 74.60 · Ii *;" o found: C 7 ^ .05; Π ^ι \ ₃ 53>

£ 3- (p-IIethoxyphenyl) -4-phenyl-7-'hydroxycoumarin.

A mixture of 13.2 g of 7-acetoxy-3- (p-methoxyphenyl) - ^ -phenyl-coumarin and 2, above-mentioned potassium hydroxide in 220 ecm 90 tiger ethanol was shaken for 18 hours. The heterogeneous mixture is acidified with hydrochloric acid and then filtered. The isolated pesticide was recrystallized from aqueous soluble acid. , lan received 9j9u; _ 3- (p - :; othozyphenyl) ~ 4-phenyl "7-hydroxycui)! arin in? orii from aistallen rait oineia cutting point from 2j ^l \ to 25 ° C.

Analysis: calculated for ^ 2 ¹¹ Io ⁰ Ir ^c 7 ^ s73; ^ ^] 1.63 invented ^ : C 76.73; Π Ml- ¹

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"BAD ORIGINAL

C, 3- (p-I-etiioapheny 1) -4-pheny1-7- (2-dietiiylaidnoätlioxy) coumarin and its hydrochloric!

After the method described in Example 1, Part C, but using 3- (p-ilethoxypheny 1) - 'i-pIienyl-7-hydro :: ycuiiarin instead of 3i * i-diphenyl-7-hydroxycuraarine, r. 'at 3 ~ (P "~ methoxyphenyl) ~' i-phenyl-7- (2-diethylaminoethoxy) -coumarin in Γωι von Ji'istallen. F: 95-97 ° C.

Analysis: Calculated for C _2f Ji _2n IIO _J} : C 75, "2; Ii C, 59; 3.1ί5 found: C 76.2o: I: 6.66; IT 3, o6.

This free i3ase is made according to the method described in Example 1, Part C. Process in the hydrochloride changes.

Example 5 3 * 4-Diphenyl-7- (3-diethylaninopropo :: y) cunarin _and its hydrochloride.

. iJach the procedure of Example I, ^r: eil C, except that instead of 2-Diäthylaininoäthylchlorid 3 ~ Dii "used 'ethylaminopropylchlorid vmrde, to give 3, ^ - diphenyl-7 ~ (3-diathylaminopropoxy) coumarin and its hydrochloride.

Example C 3 » ⁱ ~ Diphenyl-7- (2-diethylar; iinopropoxy) -cu-

^r -, 3, il-Diphenyl-7- (2-diethylar; iinopropoxy) ■ - marine and its hydrochloride

laugh the procedure of Example 1, ϊβϋ C, where each * * but instead of 2-diethylaminoethyl chloride, 2-diethylaninopropyl chloride if vmrde is used, you get 3j ^ ~ Diphenyl-7- (2-dieth; -laminopropoxy) -coumarin and its llydrochloria.

Example 7 3, ⁱ l-Diphenyl-7- (2-dibutylai.:inoethoxy) -cuiaarin and its Ilydrochlorid.

According to the: Veraliren des Deispic-ls 1, part C, ^T. 2-dibutylaminoethoxy) -cUHariii: Uhd its "hydrochloride.

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BATH ORIGINAL

■ ϊ ι

1 "

ι »·

Example 6 3,4-Diphenyl-7 ~ (2-H-methyl-N-ethylaminoethoxy)

• '■' coumarin and its hydrochloride.

Follow the procedure of Example 1, Part .C. however, instead of before, 2-Diäthylaxninoäthylchlorid 2-N-Hethyl-N-äthylam4ncä ^J: iiylchlorid were used, to give 3,4-DipheLy .. ~ 7 ~ (2-lT-me vhyl II äthylaiainoäthoxy) coumarin and its hydrochloride *

Example Q 3j ^ -Diphenyl-? ™ (3-diethylaminobutoxy) -coumarin

. ^ - « _unc j its hydrochloride. ;

After the Ve-. • 'drive example 1, part C, but one instead of 2-diethylaminoethyl chloride, 3-diethylaninobutyl chloride if used, 3 »4-diphenyl-7- (3-diet! iylaminobutoxy) -coumarin is obtained and its hydrochloride.

Example ic 3 _i ⁱ l ~ Diphenyl-7 ~ (2-pyrrolidinethoxy) coumarin and its hydrochloride.

liach the procedure of Example 1, Part C, where one but instead of 2-diethylaminoethyl chloride, 2-pyrrolidine ethyl chloride if used, one obtains 3 »^ * diphenyl-7" - (2-pyrrolidine-ethoxy) -coumarin and its hydrochloride.

Example 11 3 ^"i * diphenyl-7 ~ / ^ 2- _(2-J2 dimethylpyrrolidine) -: ethoxy-7-coumarin and its Kjidrochlorid.

Follow the procedure of Example 1, Part C, using however, instead of 2-diethylaminoethyl chloride, 2- (2,2-dinethylpyrrolidine) ethyl chloride If used, one obtains 5,! j ~ Dipheny 1-7 - / - 2- (2,2-dimethy lpyrrolidine) ethoxy / coumarin and its hydrochloride.

_m . Example 12 3, ^ - Dipheny1-7- (2-piperidinethoxy) -coumarin ^ j. _{un (} j its hydrochloride.

Following the procedure of Example 1, Part C, but using 2-piperi- ^ ₃ dinäthylehlorid _{instead of 2-diethylaminoethyl chloride 3} , one obtains Si-diphenyl -? - (2-piperidinethoxy) -coumarin and its' ydrochlcrid.

BAO ORIGINAL

- 21 -

Example 13 3 * 4-Diphenyl-7- (2-morpholineethoxy) -eumarin —————— and its hydrochloride.

After the process of Example I ₄ Part C, but using 2-morpholine ethyl chloride instead of 2-diethylaminoethyl chloride, 3,4-diphenyl-7- (2-morpholine ethoxy) coumarin and its glydrochloride are obtained.

Example 14 3,4-Diphenyl-7- / 2- (1'-methyl-4'-p.perazine) -ethoxjV-coumarin and its hydrochloride.

According to the procedure de3 Example 1, Part C, whereby r.ian jedo.ch uses 2- (l'-Methy1-4 ^f -piperazine) -ethylchloride instead of 2-diethylaminoethyl chloride, one obtains 3a4-diphenyl-7 / 2- (l'-methyl - ^ '- piperazinJ-ethoxy.? - cumauin and its hydrochloride.

Example 15 3a4-Diphenyl-7- (2-hexamethyleneiminoethoxy) -

coumarin and its hydrochloride,

Following the procedure of Example I ₃ Toil C, but using in place of 2-Diäthylaminoäthylchlorid 2-Hexamethylenininoäthylchlorid _s obtained 3 _a 4-Dipheny1-7- (2-hexamethyleniminoäthoxy) coumarin and its Ilydrochlorid.

Example 16 3,4-Jiphenyl-7- (2-homopiperaairiethoxy) -

coumarin and its ilydrochloride.

• Do the method to Example 1, Part C, but using in place of 2-Diäthylaminoäthylchlorid 2-Homopiperazinäthylchlorid, obtained 3J4-diphenyl-

• 7- (2-homopiperazine ethoxy) coumarin and its hydrochloride.

Example 17 3,4-Diphenyl-7- (homomorpholineethoxy) -coumarin

and its hydrochloride.

Following the procedure of Example 1, Part C, except that instead of 2-diethylaminoethyl chloride, 2-homomorpholine ethyl chloride used, 3,4-diphenyl-7- '(homomorpholineethoxy) -coumarin and its hydrochloride are obtained.

909832/1497

BAD ORIG'NAL

1 4 Λ Λ 4 YY Λ * * 4 * *

> i i JJJlJ Ji

JJ λ J > j, * »

J> i J J * J t Λ t

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-.- YYY * J i ί JJ »j * t

- 22 -

Example 18 3 - («i-TrifluonnethylDhenyl) -4- £ p- (2-diethyl-

: aminoethoxy) -phenyl / -coumarin and its

Hydrochloric *

Following the procedure of Example 2, Parts A, B and C ₅ , however, instead of p-methoxypheny / acetic acid in Part A, use is made of trifluoromethy / phenylacetic acid (Corse et al., J. Am. Chem. Sog., Vol.? O , P. 2837, 19 ^ 8), 3- (m-trifluoromethylphenyl) -4- / p- (2-diethylaminoethoxy) - ■ phenyl? -Coumarin and its hydrochloride are obtained.

Example 19 3- (p ~ methylmercaptophenyl) -4- / p- (2-diethyl-

_ aminoäfchoxy} -phenyl / - coumarin ~ and desaen

Hydrochloride

Following the procedure of Example 2, Parts A, B and C, but instead of p-IIethoxyphenylacetic acid in Part A p-methyl mercaptophenylacetic acid is used (Corse et al., See above), 3 ~ (p-MethylmercaptophenyI) -IWp- (2-diethyl-aminoethoxy) -phenyl7-coumarin is obtained and its hydrochloride.

Example 2o 3- (3-Allyl-4-methox2phenyl) - ^ - / p- (2-diethyl-

aminoethoxy) phenyl / coumarin and its

Hydrochloride.

Follow the procedure of Example 2, parts A, B and C, but instead of p-methoxyphenylessic acid in part A, 3-allyl-H-nethoxyphenylacetic acid is used (Van der Zanden et al., Rec. Trav. Chim., Vol. 71, P. 379, 1952), 3- (3 ~ allyl- ⁱ t-methoxyphenyl) - ⁱ H / p- (2-diethylaminoethoxy) phenyl7-coumarin and its hydrochloride are obtained.

Example 21 3- (2, U-dichlorodhenyl) -4- / p- (2-diethylamino- "

ethoxy) ~ pheny! / - coumarin and hydrochloride.

Following the procedure of Example 2, parts A, B and C, except that instead of ρ-methoxyphenylacetic acid in part A

909832/1497 bad original

15183S9

2, used ⁱ [-Dichlorphenylessig3äure, obtained 3- (2,4-Diehlorphenyl) - ² Wp- (2-diäthylariinoäfchoxy) -phenyl l7-coumarin and its Kydrochlorid.

Example 22 3 ~ (p ~ allyloxyphenylJ-i] - / p- {2-aietiylaninc-

ätlio:; y) -phenyl? -cuinarine and its hydro-

Chloride.

According to the procedure of Example 2, part r: Ί, _: and C _} where, however, instead of p-methoxypheryl acetic acid in Veil A, p-allyloxyphenyl acetic acid is used (see Uoi ^ se et al., vfie just), we get rr & n ^ "( ^ "Allylorryphenyl) -4- / p- (2-diet: .iylariinoSthoxy) -plienylJ-cui: ari" o \ ι :: ά its hydrochloride.

Example 21 3- (p-Lutylphenyl) - ^ - / p- (2-dietIiyIaininoätiioxy) -

phenylZ-coumarin and its iiydrochloride,

Follow the procedure of Example 2, parts Λ, Γ. and C, whereby one uses ap-butylphenyl-bifacic acid instead of p-het-hydroxy-phenyl-acetic acid in l'eil (Anderson et al., J. Ara. Pharm. Assec, Ccie, Ed, Vol, ^ l, 3. 6 ^ 3 * 1952), one obtains 3- (pi-utylphenyl) - ⁱ -: - / p- (2-diethyl * a: iinoethoxy) -phenyl7-cuinarine and des3en Lycrcchloride,

Example 2 ^? i 3- (3 »^ ~ '" ethylenediox2phenyl) -i! - / p-2-diäfchyl-

aninoethoxy) -phenyl / -cunarin and its

Hydrochloride.

According to the procedure of example 2, 1'eile A, II and C, v.-above, however, instead of p-IIethoxyphenylacetic acid in part A 3, ii - :: ethylenedioxyplienylessi-jäure was used (Shepard et al. »J.Oi · -. Chen., ^ D. 17, p. 563, 1932) one obtains ~ j- (5, HI ietli ^ yendioxyphenyI) - ^ - Zp- (2-diethy 1-a! .Iinoethoxy) -phenyl7-cui " iarin and its hydrochloride »

909832 / U97 _ΩΙΟ1Κ1Δ ,

BAD ORiG ¹ NAL

Example 25 3- (p-Methoxphenyl) -4-phenyl-5-diethylaminoethoxy-8-bromocoumarin and its hydrochloride.

Following the procedure of Example 2, parts, Λ, B and C, but using 5 ~ bromo-2,6-dihydroxybenzophenone instead of 2,4'-diacetoxybenzophenone in Part A (Setalvad et al., J.Ind.Chem.Soc ., Ld. 31, p. 6oo, 195 ¹ O »one obtains 3- (p-methoxyphenyl) -4-phenyl-5-diethylaminoethoxy-8-bromocoumarin and its hydrochloride.

Example 26 3- (p-Methoxyphenyl) -4- (p-chlorophenyl) ~ 7-— diethylaminoethoxycoumarin and its hydrochloride.

Following the procedure of Example 2, parts A, B and C, but using 4 ^f -chloro-2,4-dihydroxyphenone instead of 2,4'-diacetoxybenzophenone in part A (Van Allan et al., J.OrgiChem. Vol. 19, p. 1243, 1954), 3 ~ (p-Hethoxyphenyl) -4- (p-chlorophenyl) -7-diethylaminoethoxycoumarin and its hydrochloride are obtained.

Example 27 3- (p-Methoxyphenyl) -4-phenyl-6-hexyl-7-diethylaminoethoxycoumarin and cessen hydrochloride.

Follow the procedure of Example 2, Parts A, B and C, however, instead of 2,4'-diacetoxybenzophenone in Part A, 5-hexyl-2,4-dihydroxybenzophenone is used (Van Allan et al., See above), 3- (P-methoxyphenyl) -4-phenyl-6-hei: yl-7- ethylaminoethoxy is obtained coumarin and its hydrochloride.

Example 28 3 "(p-Methoxyphenyl) -4- (3,4-methylenedioxy-

-:; phenyl) -7-diethylejninoethoxycoumarin and

its hydrochloride.

Nach.dem method of the example, 2- _} parts A, B and C, but instead of 2,4'-diacotoxybenzophenone in part A 2,4 ~ dihydroxy-3 ^! , 4'-methylenedioxybenzophenone is used (Iiouben et al., J.Prakt. Cheu., P. 123, 909832 / U97

BATH ORIGINAL

I w w it U

-Sb X M H ι

Vol. 89, 1929), is obtained 3- (p-methoxyphenyl) -M3, ¹ J-methylendioxyrtenyl) -7-diäthylaminoäthoxyoumarin and its hydrochloride.

Example 29 3- (p-2-Diättiylaminoäthoxyphenyl) -Jj-phenyl-6-

¹ 'chlorallylcoumarin and its hydrochloride.

Following the procedure of Example 2, parts Λ, B and C, but instead of 2, il ^t -diacetoxybenzophenone and p-methoxyphenylacetic acid in part Λ 2-hydroxy-3 "allyl-5-chlorobenzophenone (US Patent 2,9ok, 529 ) or p-aoetoxyphenylacetic acid is used, one obtains 3- (p-2-diethylaminoethoxyphenylJ - ^ - phenyl-ö-chloro-S-allylcoumarin and its hydrochloride.

Example 30 "- (p-2-diethylaminoethoxyphenyl) - ⁱ ~ phenyl- ■ - '■■' ■ '7-allyloxycoumarin and its hydrochloride.

Following the procedure of Example Z ₃ parts A, B and C, but instead of 2, V-diacetoxyacetophenone and p ~ Iiethoxyphenylessi [; acid in part A 2-hydroxy- ^ ~ allyloxybenaophenone (US Pat. No. 2,937,157) or . p-Acetoxyphenylessigsäure verv / ends to give 3- (p-2-Diäthylaminoätlioxyphenyl) - ⁱ l-phenyl-7-allyloxycoumarin and its hydrochloride.

Example 31 3 > ^ i-Di- (p-2-diethylariinoethoxyphenyl) -coumarin and its Ilydrochlorid.

! Laid the process of example 1, part C, but instead of 3, ⁱ f-diphenyl-7-hydroxycoumarin 3j4-di- (p-hydroxyphenyl) -coumarin (Büu-Hoi et al., see above) and double the amount of 2-diethylaminoethyl chloride used, 3,4-di- (p-2-diethylaminoethoxyphenyl) coumarin and its dihydrochloride are obtained.

909832 / U97

•. »*» * · It J »Jj

'■ 1 Y 1 1 Y Y

''> 1 111 al

^j * »4 j ι ι;

- 26 -

Example 32 3, ^ - Diphenyl-7- (2-diethylaminoethoxy) - ■ * - ~ ——— coumarin methiodide

A solution of 1 g of 3 » ¹ HDiphenyl-7 ~ (2-diethylaminoetho: cy) -coumarin (Example 1, part c) in 12 ocni acetonitrile is cooled in Lis. Zn the cooled solution to give 1.5 cc Hethyliodid s letting the mixture! Are laughs and then poured os in loo cc Sther, The deposited precipitate is filtered off and umkrjetalliaiert ouch a Qenisch of acetonitrile and ether. 3 _a ^J i-diphenyl-7- (2-diethylar.dnoätho2y) -coumarin methiodide was obtained in crystalline Pon.i.

In a similar way, according to the above process, where, however, instead of the ethyl iodide, Kthylbror.iid, Propylbromid, Allylbromid and Eenzylbrornid av / ends, the Thobromid _a Propylbromid, Allylbromid or. Benzyl bromide of 3,4-Dipheny1-7- (2-diethylaminoethoxy) -coumarin.

In a similar way, iaan is obtained according to those described in Example 32 Method, however, where nan instead of 3, ^ Dipheny1-7- (2-diethylaminoethoxy) -coumarin a free Base, which was prepared according to the procedure of Examples 2 to 31 manufactured worcen is, used, the appropriate Ilethiodide and corresponding quaternary armaonium salts.

Example 33 3,4-Dipheny1-7- (2-diethylaminoethoxy) -cu -—---———— marine ethochloride.

A solution of 1 g of 3,4-Dipheny1-7- (3-diethylaminoethoxy) coumarin methiodide (Example 32). in Dinethylfori.iardd v / ird Shaken with a small excess of silver oxide for so long until the silver iodide has completely precipitated. The mixture obtained is filtered and the filtrate, which contains the corresponding quaternary alimonium hydroxide,

909832/1497 bad or, _g1nal

is neutralized by adding aqueous hydrochloric acid. The resulting mixture is evaporated to dryness; man thus obtains 3 ^ - diphenyl-7- "(2-diethylaminoethoxy) -curnarin methochloride

In a similar way, following the above procedure, one obtains however, instead of hydrochloric acid, other acids, such as, for example, sulfuric acid, hydrobromic acid off acid $ phosphoric acid, acetic acid, ilethanesulfonic acid and the like, the corresponding quaternary ammonium salts are used.

In the same way, nan can be made using the above Process the anion of each of the quaternary ammonium salts according to the invention by a different one that is desired Replace the anion with the formation of the corresponding quaternary ammonium base, which is then replaced with the corresponding Acid is converted.

Example 34 3, il-Diphenyl-7- (2-diethylaminoethylene; y) -coumarin hydrobromide.

To a solution of 1 g 3 _i ⁱ l-diphenyl-7- (2-diäthylarainoäthoxy) coumarin (Example 1, part C) in loo ecm ether, a slight excess of 0.1 N ethereal Dromwasserstoffsäurelösung is added dropwise with stirring . Of the. precipitated precipitate is filtered off, washed with iither and dried. ilan receives 3 »* J-diphenyl-7- (2-G.iäthylaninoäthcxy) -cunarinhydrobroinid.

In the same way one obtains by using the free Bases of Examples 1 to 31 and the corresponding acid the corresponding acid addition salts. So can through Use of the methods analogous to the above methods, the free Dasen of Examples 1 to 31 with sulfur,

909832 / U97

BATH

Nitric, phosphorus, milk, benzoin, methanesulfone, p-toluenesulfone, salicylic, essie, »propion, apple, Tartaric, lemon, cyclohexylsulfamine, succinic, nicotinic and ascorbic acids into the corresponding Acid addition salts are converted.

909832 / U97

^ß AD

Claims (1)

ι. . u α »ί. VS18399 Patent claims: 1st tert. aminoalkoxy-substituted 3,4-diphenylcuniarines the general formula in the IL ·, FL and Pi ₇ , a lower alkyl, lower alkenyl , trifluoromethyl, lower alkoxy, lower alkenyloicy, lower alkylenedio :: y ~, hydroxy, lower alky! mercapto groups a halo ₀ -er. atoi-i or the radical -Ο-Α-ϊΚ ^ ί, in which A is an alkylene group with 2-6 C atoms unci ll _}} and Γί _Γ a lower Al!: y! group or a lower alkyl ^ those with the adjacent nitrogen atom form a saturated, heterocyclic radical with 5 - 7 ring atoms form ₃ and Zi ₃ y and ζ mean numbers from 0 - k , where at least one of the groups R _1. , K ₀ and R-. the group -OA-'i ^ jj means * whose acid audition salts are nit pliari.iacologically acceptable acids and deron quaternary ammonium salts, whose anion C'.p.sjenifio is the pliarnakologically acceptable acid. 2. j ₃ '! -Diphenyl- J- (2-uiäthylar: dnoätho;: y) curiarin. ~ j ₃ H-iJiphenyl-7 ~ (2-üiilth ^ loj-vinoi [tlioy.y) ciwavin and iion pharr-iakolor: isch contractual i'-i-'ureadditions- '■ · Z' ~ (p-iletlioxyplionyl) - ^ - / p- (2 "cii- ^: ithylc:.". Dnor »tho>: y ony l7-cur-iarin. 909832/149 7 Documents (Art 7 § Τ Ab ;;. 2 , .r. Ι Jatr l <ic ^ unqsgea. V. 4. 9. T967 BATH ORIGINAL 18399 δ 3- (p-Igthoxyphenyl) ~ 4- / p- (2-diethylaininoethoxy) phenyl? coumarin and its pharmacologically acceptable lifts Acid addition salts. 6. 3-Hieny 1-Jl-Vp- (2-diethylaninoethoxy) phenyl7cuiiarin, 7. 3 - Phenyl - ^ - 7p- (2-diethylaminoethos-y) phenyl7cur.iarin and its pharmaceutically acceptable acid addition salts. S.:> - (p-i-ethoxyphenyl) -4-phenyl-7- (2-dietliylariinoethoxy) -coumarin. 9 J- (p-Hetho:; yphenyl) -4-phenyl ~ 7- (2-diethylariinoätlioi; y) curaarin and its ph £ irmakolo £; isch compatible fermentation addition salts. ok Process for the production of tert. aminoalko: -: y-substituted 3, 't-Dipiienylumarinen or /. their folds and quaternary Ar.aaoniiu! connections, thereby, - ekmarksj represent one at least one üyaroxygruppe Compound containing cer allsen a FoiT-iel -IJ ₁ year 909832 / U9 7 QAD ORIGINAL T518399 in which IV, R _{1 and R 0 are} a lower alkyl, lower alkenyl, tri fluorine thy 1, lower alkoxy, lower alkenyloxy, lower alkylenedioxy, halogen, lower alkylmercapto, hydroxy or acyl oxy group wherein ^e llcylrest of an organic carboxylic acid is derived xvobei at least one of the groups R / -, R ₇ and Rg is a hydroxy group, and x, y and ζ are integers from 0 to H, with a U tertiary aminoalkyl halide of the general formula : in the ¹ cine alkylene group has 2 to 6 carbon atoms, Ii ,, and Ti lower alkyl groups or lower alkyl groups which: it form a saturated heterocyclic radical with 5 to 7 ring atoms on the adjacent nitrogen atom, and I.'al i: alo £ "enator.> mean, in Gc £ -en ^T. " 7art o an inert organic solvent with an unset acetate, and the resulting tertiary alkyl ether possibly converted into the salt or the quaternary compound. For: THL UPJOIIIT CCMPAHY, Kaianazoo, Iiichiran, V.St.A. Lawyer 909832 / U97 _BA0