DE1064523B - Process for the preparation of quaternary salts of tropine and pseudotropine esters - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

kl. 12 p 13

INTEKNAT. KL. C 07 d

PATENT OFFICE

EXPLAINING PUBLICATION 1064 523

S50936IVb / 12p

REGISTRATION DATE: OCTOBER 19, 1956

NOTICE
THE REGISTRATION
AND ISSUE OF THE
EDITORIAL: SEPTEMBER 3, 1959

The invention relates to the preparation of quaternary salts of tropine esters and pseudotropine esters.

There are already quaternary salts of tropine esters, e.g. B. atropine methyl iodide, atropine methyl bromide, atropine methyl nitrate and of aralkyl tropines, as well as their ganglion-blocking effect, are known. Also bisquaternaries Salts and methobromides of some tropine compounds have already been described. the most effective known compounds contain the quaternary nitrogen atom with one exception (benzyl group) p-substituted phenyl groups.

Contain the tropine and pseudotropine compounds which can be prepared by the process of the invention in contrast, the unsubstituted phenacyl group

C -Ti ₂ CU Cg xig,

and, as can be seen from the following table, they are at least in their ganglion-blocking effect twice as effective as the known compounds.

Method of manufacture

quaternary salts of tropine

and pseudotropin esters

Applicant:

T. & H. Smith Limited, Edinburgh (Great Britain)

Representative: Dr.-Ing. F. Wuesthoff, Dipl.-Ing. G. Pulse and DipL-Chem. Dr. rer. nat. E. Frhr. v. Pechmann, patent attorneys, Munich 9, Schweigerstr.

Claimed priority:

Great Britain October 21, 1955

and August 28, 1956

Robert Goodman Johnston and Kenneth Eric Vincent Spencer, Edinburgh

(Great Britain) have been named as inventors

Ganglion blocking effect compared to tetraethylammonium bromide = 1

Tropine esters
Acyl group Y

links

after
invention

"Effect of Quaternizing Group

Well-known connections to N a dor and Gyermek

"Effect

Quaternizing group

Mandelylrest (homatropin)

Phenylacetyl radical

Benzoyl radical

Tropyl residue (atropine)

Acetyl radical

Diphenylacetyl radical

Diethylacetyl residue ... '

74
29.6
22.6
1.8.5
8.88
7.44
22.2 phenacyl radical like the same like the like the like the same

40

10

80, ^

8.5 2 10

p-phenylbenzyl radical p-phenylbenzyl radical p-B rombenzyl residue p-B rombenzoyl residue Benzyl residue p-Phenylbenzyl residue

These quaternary salts of tropine and pseudotropine esters of the general formula
HX CH CH ₂

H, C

CO- CH ₀ -N- CH

HC-Ο -Υ -CH ₂

in which X is the anion of an acid, especially a 50 ester of an organic acid, and

inorganic acid, η denotes the valency of X and Y is an acyl radical, are converted in a known manner into a salt of another acid by reacting a phenacyl halide, especially the chloride, in a known manner with the tropine or pseudotroping.

These quaternary salts can be called phenacyl

909 610/396

acyltropinium salts or phenacyl-acylpseudotropinium salts describe.

It is well known that tropine and pseudotropine are cistrans isomers, and neither they nor their quaternary salts can be distinguished by flat formulas. It is generally believed that tropine is the trans form.

The tropine ester that is preferably used is homatropin, i.e. the ester of mandelic acid.

From the phenacyl-acyltropinium halides or phenacyl-acylpseudotropinium halides, preferably the chlorides, one can prepare quaternary salts of other acids. This implementation can take different forms Way to be carried out, e.g. B.

a) by double conversion of an aqueous or aqueous alcoholic solution of a quaternary Chloride with a soluble alkali salt, for example sodium bromide or iodide,

b) by reacting a quaternary halide with, for example, a silver salt, preferably in Alcohol, or

c) by reacting an alcoholic solution of a quaternary halide with an acid in Presence of an organic epoxy. This procedure was described by O. Sackur in Bulletin de la Societe Chimique de France, 1952, 796.

The quaternary salts have valuable therapeutic properties. When injecting into the human blood flow they block the transmission of nervous impulses through the sympathetic Ganglia and lower blood pressure. At least some of the quaternary salts, especially Phenacyl-homatropinium halides, have an antihypertensive effect which is similar to that of Hexamethylene-1,6-di- (trimethylammonium) dibromide ("hexamethonium dibromide"), and they are also less toxic. The duration of action is significantly shorter than that of hexamethonium dibromide. The resulting decrease in blood pressure (hypotension) can, if necessary, easily be relieved by adrenaline or deoxyephedrine. The quaternary salts are therefore suitable for controlled blood pressure lowering, for example during surgical interventions.

The quaternary phenacyl salts of homatropin (see table) are preferably used. Quaternaries Phenacyl salts of other tropine and pseudotropine esters also show an antihypertensive effect. Their antihypertensive effects can be seen by comparative measurements of the reduction in contraction the nictitating membrane of the cat's eye is determined by irritation of the preganglionic Cervical sympathetic fibers is caused. With measurements carried out in this way, the efficiency of the Quaternary phenacyl bromide salts of seven tropine esters determined.

In contrast, the efficiency of hexamethonium dibromide is 10.

The phenacyl quaternary salts of pseudotropin esters generally appear to be less hypotensive Exert effect than the corresponding phenacyl quaternary salts of tropine esters. Nonetheless, some of them show when measured according to the one described above Method still has a favorable degree of efficiency. The ίο efficiency of the quaternary phenacyl chlorides of two pseudotropine esters and the corresponding tropine esters can be found in the following table:

Acyl radical = Y

Mandelyl, - CO - CH (OH) C ₄ H ₅ ..
Phenylacetyl, - CO - CH ₀ - C ₆ H ₅

Benzoyl, - ¹ CO- C ₆ H- .. "

Tropy'l, -CO-CH (CH ₂ OH) C ₆ H ₅

Acetyl, - CO - CH ₃

Diphenylacetyl, -CO-CH (C ₆ H-).,
Diiithylacetyl, - CO - CH (C, H ₅ ),

"Efficiency

Quaternary phenacyl chlorides of

Phenylacetyltropine

Phenylacetyl pseudotropine ...

Isobutyryl tropine

Isobutyryl pseudotropine

"Efficiency

40

20th

14th

100
40
30th
25th
12th
10
30th

In contrast, the efficiency of hexamethonium dibromide was 10.

The effectiveness of the quaternary salts preferably used, phenacyl homatropinium chloride, bromide and iodide, is the same, but their solubility in water is very different. The solubility in water, expressed in grams per 100 cm ³ , at 20 ° C is for the

Chloride 63.25

Bromide 1.59

Iodide 0.31

The chloride is therefore generally better as an antihypertensive agent in surgery suitable.

The manufacture of phenacyl-acyltropinium halides and the phenacyl acyl pseudotropinium halides takes place preferably in the presence of inert polar solvents, for example ketones. Phenacyl halides are very reactive and therefore it is not absolutely necessary to heat the reaction mixture, as you will get good yields achieved when the mixture is left to stand at room temperature for a long enough time. If you can implement it at room temperature, when quaternizing homatropin, it is useful in To work in the presence of excess inert solvents, otherwise part of the homatropin will crystallize out, before it takes effect. This difficulty does not arise when using tropine esters, for example Benzoyl or phenylacetyl tropine, used in cold inert solvents such as acetone, are more soluble. Preferably, however, the reactants are heated, since this results in the formation of Quaternary salts runs quickly.

example 1
Phenacyl-homatropinium chloride

330 g (1.2MoI) of homatropin are dissolved in 11% dry methyl ethyl ketone and the solution is gently refluxed on a water bath, a solution of 204 g (1.32 mol) of distilled phenacyl chloride in 200 cm ^{3 of} methyl ethyl ketone being added gradually. After 10 to 15 minutes, 1 g of homatropin phenacyl chloride is added to avoid the formation of a supersaturated solution of the quaternary compound. The mixture is refluxed for a further 9 hours, then left

■ Cool the thick suspension, filter and wash the precipitate with 200 cm ^{3 of} methyl ethyl ketone. The yield of phenacyl-homatropinium chloride is 490 g, corresponding to 95% of theory, a somewhat creamy solid compound with a melting point of 188 to 191 ° C.

For purification, the crude quaternary salt is dissolved in hot ethyl alcohol (2 cm ³ / g) and warm dry acetone (8 cm ³ / g) is added to the clear filtrate. After cooling the mixture, 382 g, corresponding to 78% of the crude salt, of a pure white powder with a melting point of 195 to 197 ° C, at which the determination of the ionizable chlorine was 99.7% of the theoretical value.

Following the procedure described here, but using other tropine esters instead of Homatropin, the corresponding quaternary phenacyl chlorides are obtained in good yield. The melting points some of these quaternary salts are shown in the table. a °

Used tropine ester

Phenylacetyltropine ...
Atropine (tropyltropine)

Acetyltropine

Isobutyryl tropine

Melting point

of the quaternary

Phenacyl chloride

° C

196

187 to 188

199 to 200

200

The chlorides can be converted into other salts.

Phenacyl-homatropinium iodide

35

8.60 g of phenacyl-homatropinium chloride are dissolved in 30 cm ^{3 of} warm ethyl alcohol, and 3 g of sodium iodide in 20 cm ^{3 of} alcohol are quickly added to this solution while shaking. After standing for 10 minutes at room temperature, 200 cm ^{3 of} water are added to the mixture, and the crystalline precipitate is filtered off, washed with water and dried; 9.28 g of quaternary iodide with a melting point of 186 to 187 ° C. are obtained with decomposition. The yield is 89%. After recrystallization from a mixture of ethanol and ethyl acetate, pure phenacyl-homatropinium iodide is obtained in 80% yield, which melts at 190 ° C. with decomposition. The iodine content is 24.39%, calculated as 24.35%.

If the alcohol is omitted during recrystallization, a sticky precipitate is obtained.

Phenacyl-homatropinium iodide can also be obtained by reacting phenacyl iodide with homatropin.

Phenacyl homatropinium sulfate

8.60 g (0.02 mol) of phenacyl-homatropinium chloride, dissolved in 70 cm ^{3 of} ethanol, are treated with 0.98 g (0.01 mol) of concentrated sulfuric acid while stirring. ^{3.4 cm 3} (0.07 mol) of ethylene oxide are added dropwise to this mixture with low cooling in order to keep the temperature below 20 ° C. The reaction mixture is then left to stand at room temperature until a few removed drops, which are diluted with distilled water, no longer react to chlorine ions, which is reached after one hour. After precipitation with ether, 8.50 g of crude phenacyl homatropinium sulfate with a melting point of 206 to 208 ° C. are obtained.

The yield is 96% of theory. Recrystallization from a mixture of isopropanol and ethyl acetate yields 6.11 g, corresponding to 69% of theory, of pure phenacyl homatropinium sulfate a melting point of 215 ° C with decomposition. The sulfur content is 3.60%, calculated 3.66%.

Phenacyl homatropinium nitrate

8.60 g (0.02 mol) of phenacyl-homatropinium chloride are dissolved in 150 cm ^{3 of} alcohol, and a solution of 3.40 g (0.02 mol) of silver nitrate in 50 cm ^{3 of} ethanol and 4 is added to this solution while stirring cm ^{3 of} water. After the mixture has stood in the dark for a short time, the precipitate is filtered off. The volume of the filtrate is reduced to about one third and hot ethyl acetate is added until it is almost permanently cloudy. After the mixture is left to stand overnight, only a small amount of crystals separates out. These are separated off and used for inoculation by stirring about twice the amount of ethyl acetate into the mixture. After the crystals obtained have been recrystallized twice from a mixture of ethyl alcohol and ethyl acetate, phenacylhomatropinium nitrate with a melting point of 140 to 142 ° C. which is free of chlorine ions is obtained in 50% yield.

Example 2
Phenacyl-homatropinium bromide

30.0 g (0.109MoI) of homatropin are dissolved in 150 cm ^{3 of} warm, dry acetone. After cooling, a solution of 23.9 g (0.12 mol) of phenacyl bromide in 150 cm ^{3 of} dry acetone is quickly added to this solution and the reaction mixture is gently heated on the steam bath at the reflux condenser. A precipitate forms after 10 minutes. After heating in the reflux condenser for a total of 4 hours and standing overnight, the precipitate is filtered off, washed with dry acetone and then with ether and finally dried at 100 ° C. for 1 hour. 45.7 g, corresponding to 88.8% of theory, of crude phenacylhomatropinium bromide, which melts at 193 to 195 ° C. with decomposition, are obtained.

To recrystallize, the compound is dissolved in 6 parts by volume of boiling ethyl alcohol and slowly added so much water that a clear solution is formed. On cooling, 42.6 g are obtained, corresponding to 81% of theory, white microcrystalline powder with a melting point of 198.5 to 199.5 ° C (not corrected). A determination of the bromine present in ionized form gives a value of 16.85%, calculated 16.86%.

Corresponding ones are obtained by the method described, but using other tropine esters quaternary phenacyl bromides in good yield. The melting points of some of these compounds are given below.

Ester used Melting point
of the quaternary
Phenacyl bromide
⁰ C Phenylacetyltropine
Benzoyl tropine
Atropine (tropyltropine)
Diphenylacetyltropine
Diethylacetyltropine 199 to 200
218
185 to 186
209 to 210
199 to 200

Example 3 Phenacyl-phenylacetyl pseudotropinium chloride

5.18 g (0.02 mol) of phenylacetyl pseudotropine and 3.40 g (0.022 mol) of phenacyl chloride are dissolved in 20 cm ^{3 of} methyl ethyl ketone and refluxed for 6 hours. When the mixture is left to stand for days at room temperature, only a small amount of crystals precipitates. Therefore a small amount of dry ether is added to the mixture and it is shaken well. After a short time, more dry ether is added until no more crystals separate out. The yield of the crude quaternary salt was 4.63 g, corresponding to 56% of theory. After recrystallization of the salt from a mixture of acetone and ether, 3.56 g, corresponding to 44% of theory, of white crystalline phenacyl-phenylacetylpseudotropinium chloride with a melting point of 174 to 175 ° C and a chlorine content of 8.38%, calculated 8 , 58%.

Following the procedure described in this example, but using equivalents Amounts of other pseudotropin esters, the corresponding quaternary phenacyl chlorides are obtained in good quality Yield. The table shows the melting points of some of these quaternary salts.

Ester used Melting point
of the quaternary
Phenacyl chloride
⁰ C Benzoyl pseudotropine
Isobutyryl pseudotropine 207
173 to 174

Example 4 Phenacyl-phenylacetyltropinium chloride

6.42 g of phenylacetyltropine are heated for 6 hours on a steam bath with 4.25 g of phenacyl chloride, resulting in a semi-solid mass which, after cooling, is triturated ^{under 20 cm 3 of methyl ethyl ketone.} After filtering off and washing the residue with 20 cm ^{3 of} methyl ethyl ketone, 5.30 g of quaternary salt with a melting point of 186 to 189 ° C. are obtained on drying. When the salt is recrystallized from a mixture of 6.5 cm ^{8 of} isopropanol and 32.5 cm ^{3 of} ethyl acetate, which contains activated charcoal for decolorization, 3.72 g of pure phenacylphenylacetyltropinium chloride with a melting point of 195.5 to 196.5 ° C. are obtained (corrected ).

The quaternary salts which can be prepared by the process of the invention are used as antihypertensive agents Appropriately in the form of aqueous solutions. One should be strong against these solutions Protect daylight and z. B. in amber-colored ampoules or in the dark. Phenacylhomatropinium chloride is marketed, for example, in 5% solution in ampoules. This solution should be used for intravenous infusion 20 to can be diluted 100 times. The 5% solution is sensitive to direct sunlight, whereby it is decomposed to form a precipitate. It is constant in the dark and decomposes in the scattered Daylight not so easy.

When using phenacyl-homatropinium chloride to lower blood pressure during surgery, an intravenous drip infusion of an aqueous solution containing 0.5 to 2.5 mg / cm ³ is administered. Blood pressure drops within 2 to 10 minutes, depending on the speed of the infusion. A total of about 50 to 500 mg can be used for such procedures. One can easily reverse the effect by adding, for example, 2 mg deoxyephedrine.

Claims (3)

Patent claims: 1. Process for the preparation of quaternary salts of tropine and pseudotropine esters of the general formula CH-CH ₂ H ₉ C- -CO-CH ₉ -N-CH, -CH-HC-Ο —Υ -CH ₅ , X " in which X is the anion of an acid, especially an inorganic acid, η is the valency of X and Y is an acyl radical, characterized in that a phenacyl halide, especially the chloride, is reacted in a known manner with the tropine or pseudotropine ester of an organic acid and optionally converting the quaternary halide formed into a salt of another acid in a known manner. 2. The method according to claim 1, characterized in that that one reacts a phenacyl halide with homatropin. 3. The method according to claim 1 or 2, characterized in that one carries out the reaction in one polar inert organic solvent, preferably in a ketone. Considered publications: Journal for experimental pathology and therapy, Vol. 19, 1917/18, pp. 99 to 117; Angewandte Chemie, Vol. 66, 1954, pp. 376 to 386; Chemical Abstracts, Vol. 48, 1954, Columns 5353 c to g, 8938 b to f and 10033 f; Vol. 47, 1953, Column 7110g through i and 7111a through e; Acta Chimica. Acad. May be. Hung., Vol. 3, 1953, p. 323 to 336; Acta Physiol. Acad. May be. Hung., Vol. 4, 1954, pp. 341 to 353; Vol. 5, 1955, pp. 163-169. © 909 610/396 8.59