DE1123314B - Process for the preparation of therapeutically active phenoxyacetic acid amides - Google Patents

Description

GERMAN

PATENT OFFICE

kl 12 ο 16

INTERNATIONAL KL.

C07c; d

REGISTRATION DAY:

NOTICE
THE REGISTRATION
AND ISSUE OF THE
EDITORIAL:

G 23321 IVb / 12 o

NOVEMBER 8, 1957 FEBRUARY 8, 1962

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

The amide and the monomethylolamide of eugenolglycolic acid and N-unsubstituted amides of 2-alkoxyphenoxyacetic acids have already been described in the literature; about a hypnotic, sedative however, nothing has become known of the narcotic effects of these compounds.

In the amide group by hydrocarbon radicals ίο substituted phenoxyacetic acid amides of the general formula

/ ¹ M

R ₃ -

-o-ch-co-n

OR ₄

R,

R ₉

in which R _{1 is} an alkyl or alkenyl radical having 2 to 4 carbon atoms or the phenyl radical, R _{2 is} an alkyl or alkenyl radical having 2 to 4 carbon atoms, R ₃ and R _{4 are} low molecular weight alkyl radicals and R _{5 is} a hydrogen atom or the methyl group, where the Alkyl radicals R ₁ and R _2, together with the nitrogen atom, can also mean the piperidine or morpholine radical, have not yet become known. Surprisingly, it has been found that, in contrast to the known compounds, these compounds have pharmacologically valuable properties, particularly excellent narcotic, hypnotic, sedative, anticonvulsant and generally anesthetic activity.

The compounds are prepared by adding a phenoxyacetic acid of the general formula in a manner known per se
OR ₄

R, - - O - CH-COOH

R.,

II

in which R ₃ , R ₁ and R _{5 have} the above meaning, or their reactive functional derivatives with a secondary amine of the general formula

H-N '

III

in which Rj and R _{2 have} the above meaning.

Suitable reactive, functional derivatives of phenoxyacetic acids of the general formula II are Process for the preparation of therapeutically active phenoxyacetic acid amides

Applicant: J. R. Geigy A.-G., Basel (Switzerland)

Representative: Dr. F. Zumstein and Dipl.-Chem. Dr. rer. nat. E. Assmann, Patent Attorneys, Munich 2, Bräuhausstr. 4th

Claimed priority: Switzerland of November 9, 1956 (No. 39 445)

Dr. Franz Litvan and Dr. Willy Stoll,

Basel (Switzerland) have been named as the inventor

for example their halides and mixed anhydrides with low molecular weight aliphatic carboxylic acids, especially acetic acid and its esters, especially the low molecular weight alkyl esters and the Phenyl ester.

The reactions are expediently carried out in solvents or diluents. As a solvent For the reactions with acid halides and anhydrides, there are on the one hand inert organic ones Solvents, such as ether or benzene hydrocarbons, and on the other hand water, for the reactions with esters, alcohols are also possible. As acid-binding agents in the reactions with Acid halides or mixed anhydrides in organic solvents have an excess of that to be reacted amine or a tertiary organic base, such as pyridine or dimethylaniline, in water In addition, inorganic compounds such as sodium or potassium carbonate are also used.

The method of the invention can e.g. B. with the following phenoxyacetic acids of the general formula II carried out: 2-methoxy-4-methyl-phenoxyacetic acid, 2 - methoxy - 4 - ethyl - phenoxyacetic acid, 2-methoxy-4-n-propyl-phenoxyacetic acid, 2-methoxy-4-n-butyl-phenoxyacetic acid, 2-methoxy-4-n-amylphenoxyacetic acid, 2 - methoxy - 4 - isoamyl - phenoxyacetic acid, 2- methoxy-4-n-hexyl-phenoxyacetic acid, 2 - ethoxy - 4 - ethyl - phenoxyacetic acid, 2 - ethoxy-4-n-propylphenoxyacetic acid, 2 - ethoxy - 4 - η - butyl phenoxyacetic acid, 2-n-butoxy-4-n-propyl-phenoxy-

209 508/328

acetic acid and a- (2-methoxy-4-n-propyl-phenoxy) -propionic acid.

As starting materials of the general formula III, for. B. diethylamine, di-n-butylamine, diallylamine, Piperidine, morpholine and N-ethylaniline in Consideration.

The compounds according to the process of the invention can also be prepared by in an known way is a carbaminyl chloride of the general formula

R ₁

ei - co - n:

in which R ₁ and R _{2 have} the above meaning in which heat reacts with a salt, especially an alkali salt, of a phenoxyacetic acid of the general formula II. With the development of carbon dioxide and the separation of corresponding chlorides, e.g. B. alkali metal chlorides, the N, N-disubstituted amides are formed. Possible starting materials of the general formula IV are, for example, the carbaminyl chlorides derived from the secondary amines of the general formula III mentioned.

Another production method for the phenoxyacetic acid amides of the general formula I consists in that in a known manner, a haloacetamide of the general formula

R ₁

Hal —CH-CO-

in which Hal denotes a halogen atom and R ₁ , R ₂ and R _{5 have} the meanings given above, with an alkoxy-alkyl-phenol of the general formula

OR ₄

OH

in which R ₃ and R _{4 have} the above meaning, in the presence of an acid-binding agent or with a salt of this phenol, especially an alkali salt. Amides of the general formula V suitable for reaction are, for example, the N-chloroacetyl, N-bromoacetyl, N- (α-chloropropionyl) and N - («- bromopropionyl) derivatives of the above-mentioned amines of the general formula III, which for example with 2-methoxy-4-methyl-phenol, 2-methoxy-4-ethyl-phenol, 2-methoxy-4-n-propyl-phenol and 2-ethoxy-4-n-propyl-phenol and 2-butoxy 4-ethylphenol or its alkali metal salts can be implemented.

Finally, the Phenoxyessigsäureamide of the general formula I can also be prepared by in a manner known per se, phenoxyacetic acid amides of the general formula

OR ₄

O —CH — CO —N

VII

in which R ₃ 'denotes a low molecular weight alkenyl radical and R ₁ , R ₂ , R ₄ and R _{5 have} the above meaning, hydrogenated with hydrogen in the presence of a catalyst until 1 mol of hydrogen is absorbed.

This process is less suitable for the preparation of compounds of the general formula I in which the radicals R ₁ and / or R ₂ contain easily hydrogenatable double bonds. Suitable starting materials of the general formula VII are, for example, the N, N-disubstituted eugenolglycolic acid amides, isoeugenolglycolic acid amides and 2-methoxy-4-buten (l) -yl-phenoxyacetic acid amides.

The following examples explain the process the invention. Parts mean parts by weight, which are parts by volume like grams to cubic centimeters behavior.

example 1

While stirring and cooling with ice, 24 parts of 2-methoxy-4-n-propyl-phenoxyacetic acid chloride are left in drop in a solution of 8 parts of diethylamine and 4 parts of sodium hydroxide in 100 parts of water.

The mixture is stirred for 2 hours at ⁰ ° C. and for a further 2 hours at room temperature. The

different oil is absorbed in ether and the ethereal solution successively with 2N hydrochloric acid, Washed 2N sodium hydroxide solution and water. After this

Drying the ethereal solution over sodium sulfate will

the ether is distilled off and the residue is distilled below 0.0015 mm Hg. 2-Methoxy-4-n-propyl-phenoxyacetic acid-N, N-diethylamide is obtained as

viscous oil of b.p. _{0) 0015} = 121 to 123 ° C. The yield is 22 parts or 80 ° / ₀ of theory.

Example 2

In a solution of 21.5 parts of 2-methoxy-4-methylphenoxyacetic acid chloride in 150 parts by volume of anhydrous ether is left with stirring and cooling an ice-salt mixture a solution of 15 parts

Drip diethylamine in anhydrous ether. When the addition of the amine is complete, the reaction mixture is _{refluxed for about 2} hours, then cooled and 100 parts of water are added. The ethereal layer is separated off, washed with dilute hydrochloric acid, with dilute sodium carbonate solution and finally with water, dried over sodium sulfate and the solvent is distilled off. Upon distillation of the residue _{0> 001} = 125 is obtained 2-methoxy-4-methyl-phenoxyacetic acid-N, N-diethylamide, bp. To 128 ⁰ C. The yield is 18.7 parts or 97 ° / ₀ of theory.

If the 2-methoxy-4-methyl-phenoxyacetic acid chloride is replaced by 22.9 parts of 2-methoxy-4-ethyl-phenoxyacetic acid chloride and if the rest of the procedure is as described above, 2-methoxy-4 is obtained - Ethyl - phenoxyacetic acid - N, N - diethylamide with a boiling point of o, oo5 = 129 to 131 ° C.

In an analogous manner, starting from 25.7 parts of 2-methoxy-4-n-butyl-phenoxyacetic acid chloride, 2-methoxy-4-n-butyl-phenoxyacetic acid-Ν, Ν-diethylamide, b.p. _{0 (001} = 133 to 134 ° C;. of 27.1 parts of 2-methoxy-4-n-amyl-phenoxyessigsäurechlorid the 2-methoxy-4-n-amyl-phenoxyacetate Ν, Ν-diethylamide, Kp _{0, 002} = 141-146 ° C;. of 28.5 parts of 2-methoxy-4-n-hexyl-phenoxyessigsäurechlorid the 2-methoxy-4-n-hexyl-phenoxyacetate Ν, Ν-diethylamide, _0l04 Kp = 152-155 ⁰ C.
If 24.3 parts of 2-methoxy-

4-n-propyl-phenoxyacetic acid chloride with 20 parts of diallylamine to give 2-methoxy-4-n-propyl-phenoxyacetic acid - N, N - diallylamide, b.p. _{0> 0004} = 135 to 137 ° C; with 17 parts of piperidine 2-methoxy-4-n-propyl-phenoxyessigsäurepiperidid, Kp _{0, 004} = 164-165 ⁰ C. with 17 parts of morpholine, 2-methoxy-4-n-propyl-phenoxyacetic acid morpholide, ^κ Ρ · ο, οοοι = 168 to 172 ⁰ C; dimethallylamine with 25 parts 2-methoxy-4-n-propyl-phenoxyacetate Ν, Ν-dimethallylamid, Kp. _{0, 001} = 124-129 ⁰ C.

Example 3

24 parts of 2-methoxy-4-n-propyl-phenoxyacetic acid chloride are added dropwise to a solution of 13 parts of di-n-butylamine and 8 parts of dry pyridine in 100 parts of dry ether with stirring and cooling with an ice-common salt mixture. The mixture is then heated _{to the boil for 2} hours, cooled and mixed with water. The ethereal layer is separated and washed successively with 2N sodium hydroxide solution, 2N hydrochloric acid and water. They are dried over sodium sulfate, the ether is distilled off and the residue is distilled under 0.0015 mm Hg pressure.

The obtained 2-methoxy-4-n-propyl-phenoxyacetate of N, N-di-n-butyl-amide is a viscous oil of boiling-0.0015 = 145-146 ⁰ C. The yield is 34 parts or 80 ° / ₀ the theory.

Example 4

The mixture is added to a solution of 24 parts of monoethylaniline in 100 parts of dry benzene with stirring and cooling with ice 24 parts of 2-methoxy-4-n-propylphenoxyacetic acid chloride in 25 parts of dry Benzene flow.

The mixture is then heated to the ^{boil for x} / ₂ hours, cooled and water is added. The separated benzene solution is washed successively with 2N hydrochloric acid, 2N sodium hydroxide solution and water. The residue remaining after the benzene has been distilled off is purified by distillation below 0.002 mm Hg. Yields the 2-methoxy-4-n-propyl-phenoxyacetate of N-ethyl-anilide as a viscous oil from Kp.o, oo2 = 161 to 163 ⁰ C. The yield is 24.5 parts or 75% of theory.

₀ is obtained in an analogous manner from 27 parts N-allylaniline, the 2-methoxy-4-n-propyl-N-allyl-phenoxyacetate anilide, bp., ₀₀₁ = 168 to 170 ° C.

Example 5

23.2 parts of sodium 2-methoxy-4-ethyl-phenoxyacetate and 14 parts of diethylcarbamic acid chloride are used in 100 parts of anhydrous xylene heated to boiling with stirring and under reflux for 6 hours. the Initially thick slurry of the sodium salt gradually becomes thin and it escapes Carbon dioxide. When the reaction has ended, the reaction mixture is allowed to cool and the precipitated material is sucked off Salt and wash it a few times with hot benzene. The benzene and xylene solutions are combined, washed repeatedly with water and dilute sodium hydroxide solution, over sodium sulfate dried and freed from the solvent at a pressure of about 15 mm Hg. The residue supplies distillation, the 2 - methoxy - 4 - ethyl - phenoxyacetic acid - N, N - diethylamide already described in Example 2. The yield is 19.1 parts, that is 72% of theory.

Example 6

16.6 parts of 2-methoxy-4-n-propyl-phenol are dissolved in 4 parts of sodium hydroxide and 4 parts of water and 100 parts of ethanol prepared alcoholic sodium hydroxide solution. 15 parts are added to this solution Chloracetic acid diethylamide and the reaction mixture is heated to boiling under reflux for 7 to 8 hours. Most of the alcohol is then distilled off, water is added to the residue and this is taken

ίο excreted oil in ether. The essential solution is washed with 2N sodium hydroxide solution and water and dried over sodium sulfate. The ether is evaporated and the residue is distilled below 0.002 mm Hg, the procedure already described in Example 1 being distilled 2 - methoxy - 4 - η - propyl - phenoxyacetic acid - N, N - diethylamide receives. The yield is 21 parts, that is 75% of theory.

If 18 parts of 2-methoxy-4-isobutylphenol are used in place of the 2-methoxy-4-n-propylphenol and the procedure is otherwise the same, 18 parts (62% yield) of 2-methoxy-4-isobutyl are obtained -phenoxyacetic acid-N, N-diethylamide of b.p. _{0> 005} = 128 to 130 ° C. Starting from 16 parts of 2-methoxy-4-n-propylphenol and 22.5 parts of <x -bromopropionic acid-Ν, Ν-diethylamide, 23 parts (80% yield) of a- (2'-methoxy-4 'are obtained in an analogous manner) n-propylphenoxy) -propionic acid N, N-diethylamide, bp. _{0, 003}

= 116-120 ° C. ". . . _
Example 7

27.7 parts of 2-methoxy-4-allyl-phenoxyacetic acid-Ν, Ν-diethylamide are dissolved in 150 parts of distilled alcohol and, after addition of 10 parts of Raney nickel, saturated with hydrogen at room temperature and normal pressure. The hydrogenation comes to a standstill ^{in about 3} 1/2 hours after the theoretical amount of hydrogen has been absorbed. The catalyst is nitrated, washed with alcohol, the alcohol is evaporated and the residue is distilled. The 2-methoxy-4-n-propyl-phenoxyacetic acid-N, N-diethylamide already described in Example 1 is obtained. The yield is 26.8 parts, that is 98% of theory.

In an analogous manner, 29.1 parts are obtained

2-Ethoxy-4-allyl-phenoxyacetic acid-N, N-diethylamide

2-ethoxy-4-n-propyl-phenoxyacetic acid-N, N-diethylamide, b.p. _o , oo4 == 122 to 123 ° C.

The anesthetic effect of the compounds prepared by the method of the invention and some known connections were based on the stages of anesthesia according to Magnus-Girndt (cf. O. Girndt, Archive for experimental pathology and pharmacology, Vol. 164, 1932, pp. 118 to 157) and compared to each other.

According to O. G ir η dt, six different stages of anesthesia are distinguished. The intravenous amount to be administered in the rabbit is determined in milligrams per kilogram of body weight, which is required to achieve stage IV. At this stage, the labyrinth and body positioning reflexes on the head, the head rotation reaction and the eye rotation nystagmus are extinguished, while the compensatory eye positions and the corneal reflex are weakened, but the eye rotation reactions and the spinal cord reflexes can be triggered normally. To calculate the amounts, the weight of the animals after 24 hours of fasting and thirst was used. The compounds to be tested were according to their therapeutic use in the form of freshly prepared solutions with a speed of 2 cm ³ each

Intravenously administered minute. One to three rabbits are used per quantity. By examining various Typical reflexes at certain time intervals can be the depth and duration of the anesthesia be determined. The period between the injection and the re-attainment of the anesthesia is considered to be the duration of anesthesia Stage I after the anesthesia has subsided.

The toxicity was determined as the lethal 50 dose (LD ₅₀ ) to rats or rabbits by intravenous administration in the usual manner. In the rabbits, the toxicity values were determined on 5 of the same test animals that were used to investigate the narcotic effect, namely by increasing the amounts.

link Necessary amount for
Stage IV (mg / kg animal)
given intravenously Duration of
anesthesia
in minutes LD ₅₀ intravenous ge
give (mg / kg animal) - O - CH ₂ - CO - NH ₂ OCH ₃ Chemical Abstracts, Vol. 44, Sp. 1936/37 at 200 mg / kg - 350 (rat) Chemisches Zentralblatt, 1950 II, p. 1494 not reached / Vo-CH ₂ -CO-NH ₂
II. ( OC ₂ H ₆ Chemical Abstracts, Vol. 44, Sp. 1936/37 at 150 mg / kg - 225 (rat) Chemisches Zentralblatt, 1950 II, p. 1494 not reached _χ \ - O - CH ₂ - CO - NH ₂ III. ^ = ^ OC ₃ H ₇ Chemical Abstracts, Vol. 44, Sp. 1936/37 about 55 8th 191 (rat) Chemisches Zentralblatt 1950 II, p. 1494 Allyl - << - Vo-CH ₂ CO-NH IV. ^{X /} ! OCH ₃ CH ₂ OH at 60 mg / kg LD ₁₀₀ = 80 (rabbit) German patent specification 208 255 not reached Compounds according to the invention: V. 2-methoxy-4-ethyl-phenoxyacetic acid 37 30th about 60 (rabbits) N, N-diethylamide VI. 2-methoxy-4-n-propyl-phenoxyacetic acid 20th 67 70 (rabbit) N, N-diethylamide VII. 2-Ethoxy-4-n-propyl-phenoxyacetic acid 6th 12th 60 (rabbit) N, N-diethylamide VIII. 2-Methoxy-4-n-butyl-phenoxyacetic acid 30th 45 about 60 (rabbits) N, N-diethylamide IX. 2-methoxy-4-n-amyl-phenoxyacetic acid 34 63 about 50 (rabbits) N, N-diethylamide X. 2-methoxy-4-isobutyl-phenoxyacetic acid 31 21 about 80 (rabbits) N, N-diethylamide XI. »- (2'-Methoxy-4'n-propyl-phenoxy) -propion- 30th 13th about 60 (rabbits) acid-N, N-diethylamide XII. 2-methoxy-4-n-propyl-phenoxyacetic acid 40 75 about 100 (rabbits) N, N-di-n-butylamide XIII. 2-methoxy-4-n-propyl-phenoxyacetic acid 40 90 about 60 (rabbits) N-ethyl anilide XIV. 2-methoxy-4-n-propyl-phenoxyacetic acid 19th 14th 50 (rabbit) piperidide XV. 2-methoxy-4-n-propyl-phenoxyacetic acid 31 9 53 (rabbit) morpholide XVI. 2-methoxy-4-n-propyl-phenoxyacetic acid 27 11 40 (rabbit) N, N-diallylamide

Of the known comparison compounds, only compound III has a weak anesthetic effect of short duration; with the other known compounds the anesthesia stage IV is either with very high amounts (Compounds I and II) or with amounts below the lethal dose (Compound IV) not reached.

In contrast, with all compounds V to XVI according to the invention in amounts between 6 and mg per kilogram of animal, which are still considerably below the LD ₅₀ , the anesthesia stage IV is reached, and a sometimes considerable duration of anesthesia can be determined.

Claims (1)

PATENT CLAIM: Process for the preparation of therapeutically active phenoxyacetic acid amides of the general ao my formula OR ₄ R ₁ R ₃ _ ^ _o -CH- CO-N ^ I R ₅ in which R _{1 is} an alkyl or alkenyl radical with 2 to 4 carbon atoms or the phenyl radical, R _{2 is} an alkyl or alkenyl radical with 2 to 4 carbon atoms, R ₃ and R _{4 are} low molecular weight alkyl radicals and R _{5 is} a hydrogen atom or the methyl group, where the Alkyl radicals R ₁ and R ₂ together with the nitrogen atom can also mean the piperidine or morpholine radical, as characterized in that one is carried out in a manner known per se
a) a phenoxyacetic acid of the general formula OR ₄
R ₃ - —O —CH — COOH II R ₅ 30th 35 45 b) a carbaminyl chloride of the general formula Cl-CO -N in which R ₁ and R _{2 have} the above meaning, in which heat is reacted with a salt, especially an alkali salt, of a phenoxyacetic acid of the general formula II or c) a haloacetamide of the general formula Hal —CH — CO —N in which Hal denotes a halogen atom and R ₁ , R ₂ and R _{5 have} the meanings given above, with an alkoxy-alkylphenol of the general formula OR ₄ R., - r OH in which R ₃ and R _{4 have} the meaning given, reacts in the presence of an acid-binding agent or with a salt of this phenol, especially an alkali salt, or d) 1 mole of a phenoxyacetic acid amide of the general formula OR ₄ R »'- o — CH-co — n: VII in which R ₃ 'denotes a low molecular weight alkenyl radical and R ₁ , R ₂ , R ₄ and R _{5 have} the meaning given, hydrogenated with hydrogen in the presence of a catalyst until 1 mol of hydrogen is absorbed. or their reactive functional derivatives with a secondary amine of the general formula H - N III implements or Considered publications: German patent specifications No. 616 785, 867 244, 807; British Patent No. 573 510; Journal of the American Chemical Society, Vol. 76, 1954, pp. 5127, 5128; Chemisches Zentralblatt, 1950, II, p. 1494, 1495, and 1952, p. 5395; Chemical Abstracts, Vol. 50, 1956, column 2765i; Vol. 44, 1950, column 1936 g to 1937 b. Θ 209 508/328 1.62