DE1152402B - Process for the preparation of therapeutically active phenoxyacetic acid amides - Google Patents

Description

GERMAN

kl. 12 ο 16

INTERNAT. KL. C 07 C

PATENT OFFICE

G27611IVb / 12o

REGISTRATION DAY 29 JULY 1959

NOTICE THE REGISTRATION AND ISSUE OF THE EDITORIAL: AUGUST 8, 1963

The invention relates to a process for the preparation of phenoxyacetic acid amides with valuable pharmacological properties.

It has been found that substituted phenoxyacetic acid amides of the general formula

OCH ₃

-CH ₂ -CO-N

/ C ₂ H ₅ C ₂ H ₅

R — CO — X

in which X is the direct bond of the —CHOH — group to the phenyl radical or the ethylene (—CH ₂ —CH ₂ -) or the vinylene group (—CH = CH—) and R is an alkyl radical having 3 to 5 carbon atoms, if the —CHOH —- group is bonded directly to the phenyl radical, and a methyl group, when X is the ethylene or the vinylene group, means that they have pharmacologically valuable properties, particularly hypnotic, narcotic, anesthetic and local anesthetic activity.

The compounds are prepared by adding a substituted phenoxyacetic acid amide in a manner known per se the general formula

QCH ₃

/ C ₂ H ₅

-CH ₂ -CO-n (II

^X C ₂ H ₅

in which R and X have the preceding meaning, reduced. A solution of aluminum isopropylate in isopropanol, ie the reduction according to Meerwein-Ponndorf, is particularly suitable as a reducing agent. The reduction can also be carried out very well with sodium borohydride in a suitable organic solvent, e.g. B. a low molecular weight alkanol, such as anhydrous methanol, can be carried out. The starting materials of the general formula II are the diethylamide of 2-methoxy-4-butyryl-phenoxyacetic acid, 2-methoxy-4-isobutyryl-phenoxyacetic acid, 2-methoxy-4-valerylphenoxyacetic acid, 2-methoxy-4-isovaleryl-phenoxyacetic acid, 2- Methoxy-4-capronyl-phenoxyacetic acid, 2-methoxy-4- (butan ^{-3'-onyl) -phenoxyacetic acid and 2-methoxy-4- (zJ 1} " ² '-buten-3'-onyl) -phenoxyacetic acid are used. These amides are obtained by using haloacetamides of the general formula

Shark - CH ₂ - CO - N

/ C ₂ H ₅

III

where Hai means a halogen atom, with a method of making

of therapeutically effective

Phenoxyacetic acid amides

Applicant:
JR Geigy AG, Basel (Switzerland)

Representative: Dr. F. Zumstein,

Dipl.-Chem. Dr. rer. nat. E. Assmann

and Dipl.-Chem. Dr. R. Koenigsberger,

Patent Attorneys, Munich 2, Bräuhausstr. 4th

Claimed priority:
Switzerland of July 30, 1958 (No. 62 396)

Dr. Franz Litvan and Dr. Willy Stoll,

Basel, Switzerland),
have been named as inventors

substituted phenol of the general formula

OCH ₃

IX. v ^ Vj

OH

in which Ri, R ₂ and X have the above meaning, in the presence of an acid-binding agent, or with a salt of this phenol, especially an alkali salt.

The starting materials of the general formula II can also be obtained by adding a phenoxyacetic acid the general formula

OCH ₃

R - CO-X- \ J ^ O-CH ₂ -COOH V

in which R and X have the above meaning, or their reactive functional derivatives, z. B. a halide, a mixed anhydride with a low molecular weight carboxylic acid, especially Acetic acid, or an ester with diethylamine.

In addition, starting materials of the general formula are obtained if diethylcarbamic acid chloride is used in the warmth with a salt, especially one

309 650/270

Alkali salt, a phenoxyacetic acid of the general formula V converts, whereby the desired Ν, Ν-disubstituted amides with separation of the corresponding chlorides, e.g. B. alkali chlorides under Formation of carbon dioxide. For the preparation of the starting compounds of the general Formula II is not sought protection in the context of this invention.

The compounds of the general formula I can also be prepared by being known per se Way a haloacetamide of the general formula III with a substituted phenol of the general formula

freshly prepared 0.1 to 3% solutions of the compounds in 60 to 90% aqueous propylene glycol.

LD ₈₀ Local anesthetic Rabbits Effect on the link given intravenously Rabbit cornea, based on 58 "Pantocaine" = 1 - I. 40 <0.01 II 0.063

OH
R-CH-X

OCH ₃

VI

in which R and X have the above meaning, in the presence of an acid-binding agent, or _{2t is reacted} with a salt of this phenol, especially an alkali salt. Amides of the general formula III suitable for conversion are chloroacetic acid and bromoacetic acid diethylamide.

As phenols of the general formula VI in the process of the invention, for. B. 2-methoxy- (1'-hydroxy-n-butyl) -phenol, 2-methoxy-4- (1'-hydroxy-isobutyl) -phenol, 2-methoxy-4- (1'-hydroxyn-amyl ) -phenol, 2-methoxy-4- (l'-hydroxy-isoamyl) -phenol, 2-methoxy-4- (l'-hydroxy-n-hexyl) -phenol, 2-methoxy-4- (3'- hydroxy-butyl) phenol and 2-methoxy-4-hydroxy-3'-i used ⁽¹ '' ² '-butenyl) -phenol.

The local anesthetic effect of the following compounds was determined and each other compared:

I. 2-Methoxy-4-allyl-phenoxyacetic acid-N, N-diethylamide

(using the method of British Patent 792 490).

II. 2-Methoxy-4- (l'-hydroxy-n-hexyl) -phenoxyacetic acid-N, N-diethylamide
(according to the method of the invention).

35

The test is based on Regnier's method on the rabbit cornea with series of 250 irritations each from a stimulating hair within 2 ^ 2 minutes, for a total of one hour, with a series of stimuli being administered every 5 minutes (at the beginning even shorter intervals), until the eyelid closed. The compounds were administered in the form of their solutions in 60 to 90% strength aqueous propylene glycol, into the conjunctival sac. For all compounds, those concentrations of solutions were determined which had one to three different concentrations of the hydrochloric acid p-butylaminobenzoyl-dimethylaminoethanol, known under the trade name "Pantocain" (from 0.01 to 0.1%), to have the same effect. The quotient or the average of the quotients from the “pantocaine” concentration (s) and the concentrations of the compounds to be compared with the same effect is indicated in the column to the right of the table below (“pantocaine” = 1). _6s

The toxicity was calculated as the lethal dose 50 (LD50) to rabbits by intravenous administration in usually determined. That which can be produced by the process of the invention was used 2-methoxy-4- (1'-hydroxy-n-hexyl) -phenoxyacetic acid-N, N-diethylamide shows an at least six times stronger local anesthetic with only slightly higher toxicity Effect as the known compound I. The value of 0.063 for compound II is satisfactory, since the well-known hydrochloride of ω-diethylamino-2,6-dimethyl-acetanilide, known under the trade name »Xylocaine«, this test only yields a value of 0.033.

It was also the narcotic effect of the above-mentioned compound I in animal experiments on rabbits with that of the following compounds prepared by the process of the invention A, B and C compared:

2-methoxy-4- (l'-hydroxy-n-butyl) -phenoxyacetic acid-N, N-diethylamide (A), 2-methoxy-4- (3'-hydroxy-n-butyl) -phenoxyacetic acid-N, N-diethylamide (B) and 2-methoxy-4- (1'-hydroxy-n-amyl) -phenoxyacetic acid-N, N-diethylamide (C).

The amount of active ingredient to be administered intravenously in rabbits was given in milligrams per kilogram Body weight is determined with which the anesthesia level V according to Magnus-Girndt is achieved. It the lethal amount 50 (LD50) was also determined and the therapeutic index calculated, i.e. H. the Quotient of the LD 50 value and the amount required to achieve anesthesia level V. This amounts to for compound 11.3 and for compounds A 3.4, B 5.6 and C> 2.7; d. That is, the compounds A, B and C have a much more favorable therapeutic Index as connection I.

The following examples illustrate the process of the invention. Parts mean parts by weight, which are related to parts of volume like grams to cubic centimeters. The temperatures are in Degrees Celsius.

example 1

32.1 parts of 2-methoxy-4-n-valeryl-phenoxyacetic acid-N, N-diethylamide are with 100 parts of a molar solution of aluminum isopropylate in anhydrous isopropyl alcohol heated to boiling under reflux, whereby one by appropriate Cooling allows the acetone formed to distill off, while the isopropyl alcohol is returned to the reaction vessel flows back until acetone can no longer be detected in the distillate. The excess is now distilled Isopropyl alcohol in vacuo and the residue is treated with dilute while cooling with ice Sulfuric acid. The excreted oil is absorbed in ether, the ethereal solution is repeated washed with dilute sodium hydroxide solution and water, dried over sodium sulfate and the Ether distilled off. By distilling the back

At 170 to 175 ⁰ C and 0.0004 mm of mercury boiling oil, from which 2-methoxy-4- (1'-hydroxy-n-amyiyphenoxyacetic acid-N ^ N- by crystallization from n-heptane) is obtained. diethylamide with a temperature of 50 to 52 ° is obtained. The yield is 72% of theory.

Example 2

In a solution of 33.5 parts of 2-methoxy-4-n-capronyl-phenoxyacetic acid-N, N-diethylamide in

150 parts of anhydrous methanol are introduced at 0 ° to + 5 ° with stirring over the course of several hours, 3 parts of sodium borohydride in small portions and the mixture is then stirred in the cold for about 12 hours. After this time, no ketone can be detected with the dinitrophenylhydrazine reagent. By introducing carbon dioxide into the mixture, the excess sodium borohydride is decomposed and at the same time the hydroxy compound formed is set free. The methanol is distilled off on a water bath, water is added to the residue and the reaction product is taken up in chloroform. The chloroform solution is washed with water and dried over sodium sulfate and the solvent is distilled off. The residue, which gradually solidifies in crystalline form, is recrystallized from hexane and represents 2-methoxy-4- (l'-hydroxy-n-hexyl) -phenoxyacetic acid-N, N-diethylamide, which melts at 51 to 52 °. The yield is 68%.

Analogously, from 31 parts of 2-methoxy-4- (3'-oxo-n-butyl) -phenoxyacetic acid-N, N-diethylamide, 2-methoxy-4- (3'-hydroxyn-butyl) -phenoxyacetic acid-N is obtained by reduction ₅ N - diethylamide, a mercury under a pressure of 0.0001 mm

151 to 154 ° boiling oil.

Example 3

In the solution of 30.6 parts of 2-methoxy-4- (J ¹ '- ^{2 /} -butene-3 ^/ -onyl) -phenoxyacetic acid-N, N-diethylamide in 300 parts by volume of ethanol are within 5 hours with external ice cooling and magnetic stirring 4.5 parts of sodium borohydride entered in approximately equal proportions, whereupon ketone reactions turn out negative. With ice cooling and stirring, 10 parts by volume of glacial acetic acid are carefully added dropwise (strong foaming!). After evaporation of the excess solvent in vacuo, the residue is taken up in 75 parts of water and extracted once with 75 parts by volume and three times with 25 parts by volume of chloroform. The combined chloroform extracts are washed with a mixture of 40 parts by volume of saturated aqueous sodium bicarbonate solution and 20 parts of water, then with three times 25 parts of water

Washed neutral and dried over sodium sulfate. After filtration and evaporation of the solvent, 32.4 parts of oil remain. After Distillation gives 17.8 parts (58% of theory) of colorless resin with a boiling point of 0.07 = 210 °. The thus obtained 2-methoxy-4- (3'-hydroxy-n-buten- (l ') - yl) -phenoxyacetic acid-N, N-diethylamide crystallizes on standing and melts after recrystallization from methylene chloride-ether at 71 to 72.5 °.

Example 4

13.2 parts of 2-methoxy-4- (l'-hydroxy-n-butyl) -phenol become in a mixture of 2.69 parts of sodium hydroxide, 2.7 parts by volume of water and 30

share ethanol heated to boiling under reflux for 15 minutes. After adding 0.5 part of sodium iodide 10.75 parts of chloroacetic acid-N ^ -diethylamide are added dropwise and the mixture is refluxed for a further 6 hours. After cooling down Room temperature is filtered off with suction, washed with ethanol and the filtrate is evaporated in vacuo. The residue is taken up in 100 parts by volume of chloroform, twice 15 parts by volume 2 n-sodium hydroxide and then washed three times 20 parts by volume of sodium chloride solution, dried over sodium sulfate, nitrated and evaporated. The crude yield is 85% of theory. The 2-methoxy-4- (l'-hydroxy-n-butyl) -phenoxy-acetic acid-N, N-diethylamide obtained is distilled in a bulb tube at an air bath temperature of 220 ° and 0.002 mm of mercury.

Claims (1)

PATENT CLAIM: Process for the preparation of therapeutically active phenoxyacetic acid amides of the general formula OH OCH ₃ R-CH-X - γη - ν - / \ - n - PWo - ro - Mr O - CH ₂ - CO C ₂ H ₅
C ₂ H ₅ in which X is the direct bond of the - CHOH - group to the phenyl radical or the ethylene - (- CH2 - CH2 -) or the vinylene group (-CH = CH-) and R is an alkyl radical having 3 to 5 carbon atoms when the —CHOH— group is bound directly to the phenyl radical OCH ₃ R —CO —X in which R and X have the above meaning, with aluminum isopropylate in isopropanol or reduced with sodium borohydride in an organic solvent or and a methyl group, when X is the ethylene or the vinylene group, is characterized in that in a manner known per se a) a substituted phenoxyacetic acid amide of the general formula O - CH ₂ - CO - NC 'C2H5
'C ₂ H ₅ b) a haloacetamide of the general formula / C ₂ H ₅ Hal -CH ₂ -CO-N (III ^X C ₂ H ₅ 7 8 in which Hal means a halogen atom with one, in the presence of an acid-binding agent, substituted phenol of the general formula or with a salt of this phenol, especially _ηΓΠ an alkali salt. OH uujti3 _D Λττ _v ^ V _Λ ττ, „ ^S Considered publications: K. - Cxi - Λ .— <( / —UrI Vi \ = / German Patent No. 616 785; in which R and X the preceding meaning British Patent No. 792 490. 309 650/270 7.63