DE1006850B - Process for the production of analgesic ethers of salicylic acid amide - Google Patents

Description

GERMAN

The invention relates to processes for the preparation of new analgesically effective derivatives of Salicylic acid amides of the general formula

CONH ₂
/ Y_ ο - alkylene - O - alkylene - Am I

in which "alkylene" the meaning of lower Alkylene radicals, "Am" those of a primary, secondary or tertiary amino group or a quaternary Ammonium salt group, as well as salts of such compounds with inorganic and organic acids. The main process for the preparation of these compounds is characterized by the fact that one salicylic acid amide or its sodium or potassium salt is etherified by reaction with a reactive ester of an alcohol of the formula

HO - alkylene - O - alkylene - Z,

II

in which "alkylene" the meaning defined at the beginning and Z is a primary secondary or tertiary amino group or a reactive ester group, and the latter then by aminating agents into a primary, secondary or tertiary amino group or a Quaternary ammonium group converted, and that you optionally the amino group in known per se Way converted into a salt or further alkylated.

The etherification of salicylic acid amide can also be carried out with a compound of formula II, in which Z or alkylene-Z is represented by a) an alkylene group, b) a cyano group, c) an oxo group, d) a dibenzylamino, di-benzhydrylamino or benzylalkylamino group is replaced; then after the etherification this group is formed by a) addition of ammonia, primary or secondary amines, b) reduction or reductive conversion with alkylamines, c) reductive amination, d) Hydrogenolysis into an amino, alkylamino, aralkylamine, dialkylamino group or its quaternary group Salts converted, the amino group obtained optionally by known alkylation methods can be further alkylated or converted into a salt.

The reaction with the alcohol II can also be carried out in stages by adding salicylic acid amide first with a reactive monoester (a) or a diester (b) of an alcohol of the formula

HO -alkylene-OH III

or a corresponding alkylene oxide and then the reaction product with a reac-

Method of manufacture

analgesic ether

of salicylic acid amide

Applicant:

EPROVA Aktiengesellschaft,
Schaffhausen (Switzerland)

Representative: Dipl.-Chem. Dr. A. Ullrich, patent attorney,

Neckargemünd near Heidelberg,

Peter-Schnellbach-Str. 10

Claimed priority:
Switzerland from August 15, 1953

Dr. Hans Suter, Dörflingen, Schaffhausen,

and Werner Kündig, Schaffhausen (Switzerland),

have been named as inventors

tion capable ester (a) or an alcoholate (b) of an alcohol of the formula

HO —alkylene —Z

continues to implement.

The processes described can also be carried out with salicylic acid esters instead of with salicylic acid amide will.

In this case, the compounds according to the invention are obtained by subsequent treatment of the ester group with amidating agents - in a last or a particularly suitable intermediate stage - into the acid amides converted.

Compared to the usable analgesic derivatives of salicylic acid amide which have become known to date - O- and N-alkyl derivatives - and this itself the substances obtained by the above process or their salts are distinguished by very good solubility in water.

It has also been found that, despite their high solubility in water, the substances according to the invention are valuable and Outstanding analgesic and good antipyretic properties paired with remarkably good tolerability own.

This finding is surprising and was by no means foreseeable. To this day, namely, the introduction Water-solubilizing groups always lead to a deterioration in the usefulness of the salicylamide derivatives in question guided.

709 505 / 4-29

So found ζ. B. E. L. Way et al. (J. Pharmacol. Exp. Therap. 108,450, [1953]; that by replacing the phenolic Η-atom of salicylic acid amide against, a diethylaminoethyl radical the therapeutic index is decreased; the toxicity is more than doubled.

Through the same exchange, in the case of the core · substituted Salicylic acid amides also greatly increase the toxicity or reduce the effectiveness. By replacing the phenolic Η atom with alkyl radicals will in some cases - e.g. B. with the introduction of the ethyl and alkyl radicals - the effectiveness increases; however, this change is usually accompanied by a decrease in tolerance.

Replacement of the phenolic Η atom by oxyalkyl radicals reduces the effectiveness.

In no previously known case was the change in salicylic acid amide while the same Tolerance increases the analgesic effectiveness as much as in the present invention. Due to their additional property of good solubility in water, those according to the invention are produced Connections also opens up a wide field of application that is useful for all previously known Salicylamides - which are known to be sparingly soluble in water

ίο are - is locked.

The following table shows the results of comparative tests on a manufactured according to the present invention Salicylic acid amide derivatives with two constitutionally closest, known, similarly used Links.

U Formula of the compound CONH ₂ (see for example the German patent 849551) ■ [ ( JO-CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -N
C ₂ H ₅
(see Example 2 of the present invention) Toxicity (24hLD50) mouse
subcutaneous t 1.7 1.7 analgesia 6.5 Relative
Effective
speed Connection N CONH ₂
I. / V - o - CH ₂ - CH ₃ A.
ν g / ^k g
per os (peroral ver
submission)
■, j .., total
Effective,
_ability analgesia 1 (see for example the Swedish patent specification
127 563) 1.6 I. 1.0 I.
V- OH CONH ₂ C ₂ H ₅
I - / 1.5 1.6 1.4 1.0. 1.0 \ .} 2 I. 3.0 2.8 \ 3.6 3 5.2 5.0

Explanation

. The compound no. 3 prepared according to the invention is - as a chlorohydrate - very easily soluble in water. The solution reacts neutrally.

The known compounds 1 and 2 are hardly soluble in water.

There are / used by compound no. 1 5 to 10 ° / ₀ by weight solutions in Mucil-gum arabic, of compound no. 2 5 to 10 ° ₀ strength suspensions in the same vehicle, namely for the per os and subcutaneous administration. The analgesia was tested on mice and rats using one of the customary focal beam methods on animal tails.

. The strength of the analgesia was determined by measuring the change in reaction time after stimulation.

. For each preparation and for each dose evaluated, the tests were carried out on 15 male mice performed.

During the evaluation, the results were always based on substance no.1 to facilitate comparison (Salicylic acid amide) as a standard with the defined value of 1.0. Effectiveness = peak value of the response time extension at the same doses. Total analysis value = product (area) of reaction time extension (Ordinate) and its duration (abscissa).

Relative effectiveness = activities of one tenth of the (24h LD 50) dose.

When the three active substances were administered orally and subcutaneously, the mouse and rat reacted in the same way, and so did it practically the same potency ratio of the preparations resulted.

Compounds nos. 1 and 2 worked about 10% with subcutaneous versus peroral application. weaker, connection no. 3, on the other hand, about 25% stronger. Those determined with oral administration Numerical values in the table would therefore be shifted in favor of the subcutaneous application method Compound No. 3 obtained by the methods of the invention.

summary

Compared to salicylic acid amide (Compound No. 1) and 2-ethoxybenzamide (Compound No. 2), FIG according to the invention, compound no. 3 produced an almost six-fold increase with practically the same toxicity or almost doubled analgesic effectiveness. Clinical trials showed same picture.

example 1

41.1 g (0.3 mol) of salicylic acid amide are added to 6.9 g (0.3 gram atom) of sodium in 150 ecm of ethanol and then 215 g (1.5 mol) of β, / 3-dichlorodiethyl ether are added in a thin stream with turbines . The reaction mixture is vigorously refluxed for 6 hours. It is now allowed to cool, the precipitated sodium chloride is filtered off with suction and washed with benzene. Quantity: 16 g, that's 91% of theory.

The ethanolic and benzene filtrate are repeated together with saturated soda solution and Water washed, dried and on the boiling water bath in vacuo from the solvent and excess Dichlorodiethyl ether freed. The residue solidifies to colorless when rubbed with ligroin 60 to 65 ° melting crystals. Yield: 62.6 g, that is 85% of theory.

Repeated reprecipitation from benzene-ligroin (b.p. 60 to 90 °) gives 2- [ _/ 9- ( _j 3'-chloroethoxy) ethoxy] benzamide in the form of beautiful needles with a melting point of 63.5 to 64 °. The compound dissolves easily in warm methanol, ethanol, acetone, ethyl acetate, benzene, but with difficulty in hot ligroin and water.

The compound described in this example forms the starting material for the following exemplary embodiments.

Example 2

Hydrochloric acid - ■ melts after recrystallization from iso-propanol at 152 to 153 °, it is easily soluble in water and ethanol.

The method according to the example can be changed by taking the conversion with diethylamine by heating under pressure (in a tube or autoclave) by long refluxing (96 hours) undertakes. In this case, a large excess of diethylamine is advantageously used.

Another change is that the free base is not removed after the neutral substances have been separated off combined by recrystallization from ligroin, but by adding HCl in iso-propanol directly into the Hydrochloride transferred, which can be easily cleaned by recrystallizing once from fresh isopropanol leaves.

Example 3

1 g of 2 - [/? - (jS'-chloroethoxy) -ethoxy] -benzamide, 1 g of piperidine and 10 ecm of benzene are heated to 140 ° in the tube.

The precipitated piperidine chlorohydrate is filtered off with suction and washed out with benzene. The benzene Solution is evaporated. The residue (1.1 g of crude oil) is dissolved in 10 ecm 2 N HCl, washed with benzene and alkalized with 15 ecm 2N NaOH. The eliminated Base is extracted with chloroform, the extract is washed with water, dried and evaporated. Of the Residue crystallizes on scratching with a glass rod. After repeated recrystallization from petroleum ether 0.5 g of 2 - [/? - (/? '- N-piperidinoethoxy) ethoxyj-benzamide is obtained from melting point 72 to 72.5 °.

Microanalysis: Calculated 65.27% C,

8.27% H,
9.58% N;

found 65.58% C,
8.02% H,
9.79% N.

The compound is in dilute mineral acids, dilute acetic acid, furthermore in methanol, ethanol, ether, Easily soluble benzene. It is sparingly soluble in petroleum ether and water. The chlorohydrate melts at 140 °, it is Easily soluble in water and ethanol.

Example 4

2 g of 2- [ _j e- ( _j ß'-chloroethoxy) ethoxy] benzamide, 3 g of diethylamine and 10 ecm of benzene are heated to 100 ° in the tube for 18 hours. The reaction solution is evaporated, the residue is dissolved in 10 ecm 2 N HCl, the solution is washed with benzene and 10 ecm 30% sodium hydroxide solution is added. The basic components are taken up in benzene, the benzene solution is washed with water, dried, decolorized with activated charcoal and evaporated. The residue (1.7 g of light brown oil) crystallizes on standing in the refrigerator for a long time. Repeated recrystallization from about 200 ecm petroleum ether (b.p. 40 to 60 °) gives 2- [jff - (/ 3'-diethylammoethoxy] benzamide in the form of very beautiful, centimeter-long, colorless needles with a melting point of 47 to 47.5 ° The yield is 1.6 g, that is 69% of theory. N content calculated 9.99%, found 10.01%.

The compound is easily soluble in dilute mineral acids, acetic acid, citric acid and tartaric acid, and also in methanol, ethanol, acetone, chloroform and benzene. The compound is very sparingly soluble in water and cold petroleum ether. The chlorohydrate of the new base - obtained by adding an ethereal solution of 2- [ß- (ß'- diethylaminoethoxy) ethoxy] benzamide with a little less than the calculated amount of essential 2 g 2 - [/ S - (/? '- Chlorethoxy) ethoxy] benzamide, 3.6 g of dibenzylamine and 10 ecm of benzene are heated in a tube to 140 ° for 14 hours. The precipitated dibenzylamine chlorohydrate is filtered off with suction, washed out with benzene and the benzene solution evaporated. The residue is triturated with petroleum ether, taken up in hot benzene, filtered and carefully precipitated with ligroin. After recrystallization from ligroin, 2 g, ds

60% 2 - [^ - (j8'-Dibenzylaminoethoxy) ethoxy] benzamide from melting point 98 to 100 °. The compound is readily soluble in most organic solvents. By dissolving the base in 2 n-H Cl, the hydrochloride is obtained, which recrystallizes from ethanol at 174 ° to 181 ° melts.

Analysis: Calculated 68.09% C, 6.63% H, 6.35% N;
found 68.00% C, 6.61% H, 6.23% N.

Example 5

Ig 2- [ß - (/ 3'-chloroethoxy) ethoxy] benzamide, 1.8 g Ethylamine and 10 g of benzene are heated to 140 ° in a tube for 14 hours. The reaction solution is evaporated, the residue dissolved in 1N HCl, the solution washed with benzene and with excess concentrated sodium hydroxide solution offset.

The oily base which precipitates is taken up in benzene, washed with water, dried and evaporated. The residue (1 g) is distilled at 150 ° outside temperature and 0.005 Torr. One receives a light yellow oil, easily soluble in organic solvents. The picrate melts, recrystallized from ethanol, at about 148 °, at 138 to 142 °, rearrangement into another crystal form took place.

The microanalysis provides values for the CH and N content which agree satisfactorily with the values calculated for the picrate of 2- [ß- (ß ' -ethylaminoethoxy) -ethoxy] -benzamide.

Example 6

3 g of 2 - [/ ^ (/? '- chloroethoxy) -ethoxy] -benzamide in about * 5 20 ecm of liquid ammonia are kept in a closed vessel at 70 ° for 23 hours and then at room temperature for a further 24 hours. The clear solution obtained is evaporated at room temperature, leaving a colorless oil contaminated by ammonium chloride. When 2N hydrochloric acid is added, 0.3 g, that is about 10%, of pure hydrochloride of bis - [/ 3 - (/ T-2-aminocarbonyl-phenoxyethoxy) -ethyl] -amine precipitate. This chlorine hydrate is sparingly soluble even in boiling water. After recrystallization from 6η-acetic acid, colorless needles melting at 178 ° to 179 ° are obtained. The hydrochloric acid filtrate is mixed with an excess of concentrated sodium hydroxide solution, extracted quickly with chloroform, the extract is dried and evaporated. The residue - the crude 2- [ß- (ß'- aminoethoxy) -ethoxy] -benzamide - is a colorless oil that dissolves easily in cold water, dilute mineral acids, etc. Crude yield: 2.4 g, that is 87% of theory. The picrate can be precipitated from an acetic acid solution with an aqueous picric acid solution. After recrystallizing twice from 6η-acetic acid, this melts at 212 to 213 °, after individual small droplets have formed at 205 °.

The 2 - [/ 3 - (^ '- Aminoethoxy) ethoxy] benzamide can be can also be obtained by hydrogenolytic cleavage of the corresponding dibenzyl compound (see Example 4).

Example 7

2 g of 2 ~ [/? - (/ 3'-Diethylaminoethoxy) -ethoxy] -benzamide, 1.2 g of ethyl iodide and 10 ecm of benzene are heated to 140 ° in the tube for 14 hours. The desired quaternization but can also be achieved by boiling on a water bath. The separated oil crystallizes after some time. One sucks off. Crude yield: quantitative. After recrystallization from 20 ecm ethanol one obtains the {2- [jS - (/? '- triethylammonium ethoxy) ethoxy-benzamidj-iodide as pale yellowish crystals with a melting point of 149 to 153 °.

The compound is very easily soluble in cold water, boiling methanol and ethanol, practically insoluble in boiling isopropanol, acetone, ethyl acetate.

Analysis: Calculated 6.42% N, 29.08% J; found 6.30% N, 28.85% J.

The following processes can also be used to manufacture:

2- ( _/ S- [β'-N- (2'-methylpiperidino) ethoxy] ethoxy} benzamide; mp 70 ° to 71 °.

2- {ß- [ß '- {±) A-copellidyl- (l') -ethoxy] -ethoxy} -

benzamide; F. 69 to 70 °.

2- {ß- [ß '- (+) A-copellidyl- (1') -ethoxy] -ethoxy} -benzamide; F. 67 to 68 °.

M ¹ D = + 35.5 ° (c = 4 in chloroform); [α] ' _D ⁸ = + 30.3 °, (c = 3.77 in ethanol).

H3H- ) A-KopeUidyl- (1 ') -ethoxy] -ethoxy} -benzamide; F. 67 to 68 °.

[α] «= - 35.2 ° (c = 4.3 in chloroform; [a] ¹ I = - 29.6 ° (c = 3.7 in ethanol).

2r {ß- [ß '- (±) B-copellidyl- (1') -ethoxy] -ethoxy} -benzamide; F. 59 to 61 °.

(Designations according to von Braun et al. Ber. D. German, former Ges. 56. [1923], 1565; see Beilstein's Handbook of Organic Chemistry E II 20, 62 Note 1). The compounds obtained according to these examples are intended to be used as medicaments, primarily as analgesics and Antipyretics find use.

Claims (1)

PATENT CLAIM: Process for the preparation of analgesic ethers of salicylic acid amide of the general formula CONH, 7-O-alkylene-O-alkylene-Am in which "alkylene" the meaning of lower alkylene radicals, "Am." which has a primary, secondary or tertiary amino group or a quaternary ammonium salt group, as well as salts of such ethers with inorganic and organic acids, characterized in that one salicylic acid amide or its sodium or Potassium salt with a reactive ester of an alcohol of the formula HO-alkylene-O-alkylene-Z in which "alkylene" has the meaning defined above and Z is a primary, secondary or tertiary Amino group or a reactive ester group means, reacts in a manner known per se and the latter then by known methods into a primary, secondary or tertiary amino group or a quaternary ammonium group is converted, and that one optionally contains the amino group in itself in a known manner converted into a sentence or further alkylated, or that the etherification with a Compound of the formula II, in which Z or alkylene-Z denotes another group, which according to known methods can easily be converted into "Am", and that after etherification this grouping is converted into "Am" or that the reaction with alcohol II is carried out in stages, by first reacting salicylic acid amide with a reactive monoester (a) or a diester (b) an alcohol of the formula HO-alkylene-OH III or a corresponding alkylene oxide and then the reaction product with a reactive ester (a) or an alcoholate (b) of an alcohol of the formula HO — alkylene — Z IV further converts or that instead of salicylic acid amide a salicylic acid ester is used for the reaction brings and the ester group subsequently or in a suitable intermediate stage by amidating agents in the acid amide group transferred. Documents considered: Swedish Patent No. 127 563. © 709 506/429 4.