DE1141294B - Process for the preparation of p-alkylamino-salicylic acid esters - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY KL.12q 34

INTERNAT. KL. C 07 C

GERMAN

PATENT OFFICE

EXPLAINING EDITORIAL 1141 294

C 13584 IVb / 12 q

INMKLDFUG: AUGUST 25, 1956

NOTICE THE APPLICATION AND ISSUE OF THE EDITORIAL DATE: DECEMBER 20, 1962

The invention relates to the preparation of p-alkylaminosalicylic acid esters of the general formula

R-NH-

CO- (O- CH ₂ - CH ₂ ) "- OR '

OH

where R is an alkyl radical having 4 or 5 carbon atoms, R 'is a hydrogen atom or the methyl radical and η is an integer from 7 to 15.

The new esters show valuable pharmacological properties. They have a pronounced local anesthetic effect; in particular, they act selectively on the stretch receptors in the lungs. They are intended to be used as a remedy, preferably as a cough suppressant. With regard to this use, the new compounds have significant advantages over those in which η represents lower or higher numbers.

Process for the preparation of p-alkylamino-salicylic acid esters

Applicant: CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36, Neuer Wall 10,

Claimed priority: Switzerland of September 2, 1955 (No. 23 804)

Dr. Max Matter, Worb, Dr. Albert Kobler and Max Kuhn, Gümligen (Switzerland), have been named as inventors

The connections of the formulas

(n) - C4H9 - NH

(n) - C4H9 - NH

OH

y ν CO- (O- CH ₂ - CHg) ₀ - OCH ₃ (according to the process)

CO- (O- CH ₂ - CH ₂ ) ₉ - OCH ₃ (U.S. Patent 2,714,608)

were tested for their effect on the stretch receptors in the lungs. The examination method is in principle in Helvetica Physiologica Acta, Vol. 10 (1952), p. 62, and is based on the phenomenon that the lengthening of a rabbit's exhalation phase experiences when one reflexively closes its trachea at the moment when it is about to begin to exhale the state of excitement of the stretch receptors is caused. A pharmacodynamic decrease the stretch receptor activity (i.e. anesthesia of the same) is therefore expressed in the strength this expiratory phase lengthening by reducing it. Is to be measured that is, the dose of a substance with which this phase extension is reduced by a certain degree will. The following figure shows the importance of the individual variables that are measured.

DL ₅₀

15th

209 748/330

It means:

VL is the extension of the expiratory breathing phase with tracheal occlusion as a percentage of the normal phase duration. DL50 is the dose which - infused at a regular rate - kills the animals on average in 12.5 minutes. VEmax the strongest ever achievable tracheal

occlusive reaction.
VEhw is the half value of VEmax · DVEhw the dose (in g / kg) that is necessary to achieve VEhw.

TI is the therapeutic index obtained by dividing DL50 by DVEhw ■

The experiments are carried out on rabbits anesthetized with urethane. The substance to be tested is infused intravenously.

The table below shows the required test results.

Another embodiment of the process consists in compounds of the formula

X-

y%

- (O- CHa- CHa) n - O - R '

OH

link DL ₆₀ VEmax
% VEhw
% DVEhw TI I.
II 0.020
0.015 100
100 50
50 0.004
0.003 5
5

30 It follows that the connection I with something

reduced activity, but the same therapeutic range is more tolerable.

The new esters are known per se

Way made. So you can get benzoic acids of the general formula

R-NH

COOH

OR "

optionally in the form of their reactive derivatives with polyglycols of the general formula

HO - (CH ₂ ~ CH ₂ - O) _n - R '

where R 'and η have the meanings given and R "is a hydrogen atom or the benzyl radical. The procedure here is to react corresponding benzoic acids directly with the polyglycols mentioned, advantageously using the customary esterification catalysts, or to react the benzoic acids , optionally in the form of their reactive derivatives or alkali metal salts with the polyglycols mentioned, advantageously in the presence of basic condensing agents such as pyridine, metal alcoholates ^, optionally those of the corresponding polyglycols themselves. Reactive derivatives of benzoic acids are anhydrides, halides or esters of volatile alcohols, such as the If a benzyloxybenzoic acid is used as the starting compound, the benzyloxy group is then cleaved from the ester obtained in a conventional manner by hydrogenation.

in which R 'and n have the meanings mentioned and X is an amino or nitro group, the radical X is converted into the group R - NH by processes known per se, where R has the meanings mentioned. For example, a free amino group can be converted in a manner known per se into a monoalkylamino group having 4 or 5 carbon atoms by reaction with reactive esters of corresponding alcohols. But you can also do one

so connection with a free amino group or nitro group in the presence of the corresponding oxo compounds reductively alkylate.

The reactions are carried out in the presence or absence of diluents and / or condensation agents or catalysts at ordinary or elevated temperature in open or closed Vessels carried out under pressure.

It is noteworthy that the new esters generally have considerable solubility in water. These solutions have the property, when heated at a certain, of the Concentration dependent temperature to cloudy. This temperature value determined on a 10% solution is known as the cloud point and represents a physical constant for the the compound concerned. The turbidity is reversible; on cooling, the solution clears up again. The compounds mentioned as starting materials are known or can be based on known ones Establish methods.

The invention is illustrated in the following examples described.

example 1

2.23 g of p- (n-butylamino) salicylic acid methyl ester are after the addition of 8.6 g of nonethylene glycol monomethyl ether and 0.15 cm ^{3 of} 30% sodium methylate solution in anhydrous methanol with exclusion of moisture for 4 hours in a bath at 190 to 200 ^° C. heated. At the same time, 150 cm ^{3 of} anhydrous toluene are allowed to run evenly below the ^{surface of the liquid so rapidly that it distills off at 130 to 135 °} C., and the vapors are condensed in a descending condenser after passing through an empty, central section of the column.

The cooled reaction mixture is taken up in 100 cm ^{3 of} benzene and shaken in succession twice with 20 cm ^{3 of} 10% strength aqueous soda solution and 20 cm ^{3 of} water. The aqueous layers are washed in succession two more times with 100 cm ^{3 of} benzene each time and, after combining, they are extracted three times with 100 cm ^{3 of} chloroform each time. By evaporating the chloroform extracts, 4.5 g of non-ethylene glycol monomethyl ether can be regenerated, while the benzene extracts freed from water give 6.3 g of a brownish, viscous oil that contains the p- (n-butylamino) salicylic acid ester of the nona-

ethylene glycol monomethyl ethers of the formula

(n) - C ₄ H ₉ NH

CO (OCh ₂ CH ₂ ^ OCH ₃

contains.

Its purification can be carried out, for example, by chromatography on neutral aluminum oxide with the solvents carbon tetrachloride, benzene, methylene chloride and chloroform. The pure ester is obtained in the form of a colorless oil which is readily soluble in water and which is precipitated as a milky cloudiness ^{from a 10% strength aqueous solution when heated above 42 ° C.} .

Example 2

3,28g o-benzyloxy-p- (n-pentylamino) -benzoic acid methyl ester of melting point 92 to 93 ⁰ C with 17.5 g Heptaäthylenglykol in the presence of 0.2 cm ³ of 25% absolute methanolic sodium methylate solution for 2 hours by heating

ίο transesterified in a bath at 110 ⁰ C in a water jet vacuum with exclusion of moisture and passing through 130 cm ^{3 of} anhydrous xylene. Working up as in Example 1 gives 5.9 g of a viscous, almost colorless oil which is derived from the o-benzyloxyp (n-pentylamino) benzoic acid monoester of heptethylene glycol of the formula

(n) - H11C5 - NH

CO (O - CH ₂ - CH ₂ )? - OH

O - CH ₂

consists.

For purification, the crude product in ether is allowed to flow through a column of 200 g of aluminum oxide, small amounts of impurities being eluted. Further proportions of by-products can be eluted with methylene chloride. The monoester is obtained by eluting with chloroform. By shaking a solution of the monoester in 50 cm ^{3 of} methanol in the presence of 1.5 g of 5% palladium carbon and hydrogen, the benzyl group is hydrogenated off in the course of a few minutes with a theoretical consumption of hydrogen.

After filtering off the catalyst with suction and washing the residue with methanol, the Evaporation in vacuo to leave a viscous residue, which can be determined by chromatography can be cleaned on aluminum oxide. An almost colorless, viscous oil is obtained that has the Monoester of p- (n-pentylamino) salicylic acid with heptaethylene glycol of the formula

(n) -H11C5 -NH

OH CO (O - CH ₂ - CH ₂ )? - OH

represents. It is easily soluble in cold water and some of the common organic solvents and is excreted as a milky cloudiness ^{from a 10% strength aqueous solution when heated above 33 ° C.}

The methyl o-benzyloxy-p- (n-pentylamino) -benzoate used as starting compound in this example can be obtained in the following ways:

First the o-benzyloxy-p-aminobenzoic acid methyl ester with a melting point of 128 to 129 ° C. is prepared, for example by the method known for the ethyl ester (cf. "Journal of the American Chemical Society", Vol. 73 [1951], p. 3679) ). 27.1 g of this are ^{stirred in 180 cm 3 of} benzene, and 26 g of zinc dust and 24 cm ^{3 of} glacial acetic acid are added. While stirring vigorously at the boiling point, 12 g of n-valeraldehyde are added dropwise over a period of about 30 minutes. After one hour at the boiling point, the insolubles are filtered off while hot and the residue is washed out thoroughly with benzene-glacial acetic acid 10: 1. The combined filtrates are extracted twice with water and then with saturated sodium bicarbonate solution until the benzene solution is acid-free. This is evaporated, whereupon the new ester is obtained in the form of colorless, flat rhombohedra, which ^{melt at 92 to 93 °} C., by recrystallizing the residue from benzene-gasoline 1: 4 and from methanol.

Example 3

5.0 g of p-aminosalicylic acid monoester of heptaethylene glycol are ^{stirred in 20 cm 3 of} benzene, and 2.8 g of zinc dust are added. The mixture is then heated under reflux and treated with 2.6 g of glacial acetic acid. A solution of 1.2 g of valeraldehyde in 5 cm ^{3 of} benzene is then added dropwise over the course of 20 minutes. The mixture is then stirred under reflux for a further hour, filtered hot and the residue is washed with hot benzene. The filtrate is shaken while cooling with 50 cm ^{3 of} water and 10 cm ^{3 of} concentrated ammonia, whereupon the aqueous layer is separated off. The benzene solution is washed with saturated sodium hydrogen carbonate solution and with water, the aqueous layers being washed with fresh benzene. The combined benzene solutions contain the monoester of p- (n-pentylamino) salicylic acid

with heptethylene glycol of the formula

(η) - HuC ₅ - NH - <> - CO (O - CH ₂ - CH ₂ )? - OH

OH

The pure ester is readily soluble in cold water, in chloroform and ethanol and is excreted as a milky cloudiness ^{from a 10% strength aqueous solution when it is heated to above 33 ° C.}

In the same way, starting from p-aminosalicylic acid monoester from nonethylene glycol monomethyl ether and butyraldehyde, the p- (n-butylamino) salicylic acid ester is obtained of non-ethylene glycol monomethyl ether with a cloud point of 42 ° C.

Claims (1)

PATENT CLAIM: Process for the preparation of p-alkylaminosalicylic acid esters the general formula R-NH CO- (CH ₂ -CH ₂ ) _M -OR ' OH in which R is an alkyl radical having 4 or 5 carbon atoms, R 'is a hydrogen atom or the methyl radical and η is an integer from 7 to 15, characterized in that a p-aminosalicylic acid of the general formula OR " in the R - NH the meaning given above 35 and R "is a hydrogen atom or the benzyl radical, optionally in the form of their esters with lower alkanols, acid chlorides or acid anhydrides with a polyglycol of the general formula HO - (CH ₂ - CH ₂ - O) _n - R ' in which R 'and η have the abovementioned meaning, optionally esterified in a manner known per se in the presence of condensing agents and, if R "has the meaning of a benzyl radical, the benzyloxy group in the esters obtained cleaves the benzyloxy group in a conventional manner by hydrogenation, or in a compound the general formula CO- (O- CH ₂ - CH ₂ ) _re - OR ' OH where R 'and η have the abovementioned meaning and X denotes an amino or nitro group, the radical X is converted into the group R - NH by processes known per se, where R has the abovementioned meaning. Considered publications:
U.S. Patents Nos. 2,714,608, 2,714,609,
2714610. © 209 748/330 12.62