DE1169920B - Process for the preparation of p-allyloxybenzylamines which are particularly suitable as enzyme inhibitors - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C 07 c

German class: 12 ο -19/03

Number: 1169 920

File number: U 7343 IVb / 12 ο

Filing date: July 27, 1960

Opening day: May 14, 1964

According to the process of the present invention, derivatives of p-allyloxybenzylamine and win their acid addition salts. These previously unknown compounds have the general formula

(D

O - CH ₂ - CH = CH ₂

in which Ri and R ₂ denote hydrogen or alkyl with 1 to 3 carbon atoms and R ₂ denotes alkyl with 1 to 3 carbon atoms, the total number of carbon atoms in the radicals Ri, R ₂ and R3 not being more than 6 .

The term "alkyl containing 1 to 3 carbon atoms" includes methyl, ethyl, propyl and isopropyl groups.

The new compounds according to the present invention have a valuable pharmacological one Effectiveness as enzyme inhibitors. So inhibit z. B. the compounds of the invention the enzyme system monoamine oxidase and have an inhibitory effect on this when administered orally Enzyme system in the brain and liver. The monoamine oxidase is responsible for the breakdown of many physiologically active amines in the body, e.g. B. Serotomins, and for this reason make such Compounds that inhibit this enzyme system provide a means of reducing the rate at which these amines in the body are destroyed to be able to regulate.

From a work by B i e 1 in J. Am. Chem. Soc, 80 (1958), p. 1519, it was known that the 1-phenyl-2-hydrazinopropane has a monoamine oxidase activity shows.

Investigations were therefore carried out to determine the monoamine oxidase activity. The monoamine oxidase was determined manometrically with the Barcroft-Warburg apparatus using a modified method from B hag ν at et al., (Biochem. J., 33, p. 1338, 1939). Guinea pig liver, which was homogenized in a phosphate buffer (0.25 m), was used as a source of monoamine oxidase enzyme. The mixture showed a _pH value of 7.4. The following was placed in the main part of the apparatus:

Process for the production of als
Enzyme inhibitor particularly suitable
p-allyloxybenzylamines

Applicant:

The Upjohn Company, Kalamazoo, Mich.

(V. St. A.)

Representative:

Dr. W. Beil, A. Hoeppener

and Dr. H.-J. Wolff, lawyers,

Frankfurt / M.-Höchst, Antoniterstr. 36

Named as inventor:

Alan James Lemin, Richland, Mich. (V. St. A.)

Claimed priority:

V. St. v. America August 4, 1959 (831 487)

1. 1 cm ^{3 of} the tissue suspension,

2. 0.2 cm ^{3 of} the compound to be examined (10 ~ ² m), dissolved in a phosphate buffer

(Ph = 7.4),

3. 0.1 cm ³ sodium cyanide solution (m / 15),

4. 0.5 cm ³ phosphate buffer (pH = 7.4),

5. Water ad 2 cm ³ .

The following were introduced into the interior of the apparatus:

1. 0.1 cm ³ potassium hydroxide (0.02n),

2. 0.1 cm ³ sodium cyanide (0.02 m),

3. A roll of filter paper (Whatman # 1) approximately 1.8 x 3.6 cm.

The vessel was connected to the manometer and the apparatus was placed on a shaker. The jar was immersed in a 37 ° C water bath and shaken for 1 hour held at this temperature. At the end of this period, the amount of oxygen that was used during of the reaction had been absorbed, measured manometrically. The inhibitory activity of the test compound on the enzyme activity in percent was determined by determining the amount of oxygen in the presence of the Test compound ingested was found to be in contrast to the amount ingested if the experiment was carried out under identical conditions but in the absence of the test

409 589 + 54

connection has been made. The difference between the two numbers was expressed as a percentage of the amount of oxygen taken in the absence of the test compound.

The method described above was repeated with decreasing amounts of the test compound, and from the results thus obtained, the (I) 50 value, that is, the concentration of Compound necessary to produce 50% inhibition.

Applying the method described above were made for the following compounds the specified (I) so values are determined.

link

4-allyloxy-N-methylbenzylamine 4-allyloxy-N, N-dimethylbenzylamine, 4-phenyl-2-hydrazinopropane

(I) BO

3.2 IO ⁴ 3.1 10 ⁵ 2 · 10 ~ ⁵

p-Allyloxybenzoyl halide is combined with an amine the formula

/ R,
HNC

^X R ₂

in which Ri and R _{2 have} the meaning given, condensed to the corresponding p-allyloxybenzamine. The p-allyloxybenzamide thus obtained

ίο is reduced with lithium aluminum hydride, which the desired benzylamine with the above formula (I) is formed. It is beneficial to go through the reduction Add the amide to a suspension of lithium aluminum hydride in an inert solvent

like ethyl to carry out under anhydrous conditions. When the addition is complete, the reaction mixture becomes preferably heated under reflux for a period of several hours before it is done Addition of water and aqueous alkali metal hydroxide is split. The amine with the above Formula (I) is according to known methods, for example by extraction in a solvent and subsequent recrystallization if the amine is a solid, or by distillation if that

As can be seen from this report, own
the compounds of B ie 1 and the inventions according to the invention as enzyme inhibitors
Activity of about the same order of magnitude. The 25 amine is liquid, isolated. It is advantageous that the lithium aluminum used in the compounds according to the invention, in addition to the above reduction, have advantages which the hydride described by Biel has in excess over the stoichiometric compounds. The Biel connections are to be used.

sit in addition to their activity as enzyme inhibitors The compounds of formula (I) can also

Still various other pharmacological compounds can be prepared by using o-oxybenzoic acid

Effects. So they are highly effective stimulants after the process already described the amide

for the central nervous system, have a strong effect on blood pressure, whereby the corresponding p-oxy-

lowering and intensifying the effect of other pharmaceuticals benzamide arises. This is in its allyl ether

zeutica, especially of barbiturates, when they are converted, for example by reaction with

can be fed into the body together with these. 35 allyl bromide in the presence of a base, such as water-

So if you add the Biel compounds to a free potassium carbonate, and that is what it is

Patients too, so they not only unfold their mono- this way obtained p-allyloxybenzamide under

amine oxidase activity, but in addition we use lithium aluminum hydride to that

kungen in the direction indicated above, which in the corresponding p-aliyloxybenzylamine of the formula (I)

may be undesirable in many cases. In contrast, 40 reduced.

Set to show the compounds according to the prior to the present invention obtainable acids In addition to a strong effect as storage salts, the free base salts belong to the invention Enzyme inhibitor no further pharmacological formula (I) with organic and inorganic effects. This must be considered to be a significant further and polybasic acids. It's beneficial. Acids step should be considered as in the application of the 45 such as hydrochloric acid, hydrobromic acid, hydrogen iodide agents on the patient not with undesirable secondary acid, sulfuric acid, phosphorus, nitric, vinegar, reactions must be expected. Benzoic, salicylic, glycolic and succinic acid, nico

That for the implementation according to the present tin, ascorbic, tartaric, maleic acid and apple,

Invention used p-AIlyloxybenzamid can be in lactic and alginic acid or cyclohexyl-sulfamine

In a manner not claimed here, it is advantageous to add 50 acids, pharmacologically acceptable acids

be prepared: A p-allyloxy-benzoic acid of the use. The acid addition formula of the invention

COOH

salts can suitably by reaction of stoichiometric amounts of acid and a free Base of the formula (I) in the presence of a suitable solvent such as water or acetone. Dioxane, ethyl acetate, Methanol, ethanol, isopropanol or ether can be produced.

The compounds according to the invention can be used for therapeutic purposes, especially in mammals both in the form of their free base and in the form of their pharmacologically acceptable salts in the conventional solid or liquid pharmaceutical dosage forms can be used. Strength and similar carriers can be used,

is by reaction with thionyl halides, Phos-65 especially with those compounds, which with Temphorylhalogeniden or similar acid halogen temperatures below about 50 ° C are in solid form, in the corresponding acid halide for compounds that are at normal temperatures implemented, and the liquid created in this way, encapsulation is recommended. the

(H)

CH ₂ - CH = CH ₂

in which R3 has the meaning already given and which in turn was formed by etherification of the corresponding p-oxybenzoic acid with allyl halide,

New compounds of the invention can also be administered orally in suitable solvents or carriers or parenteral administration.

example 1

4-Allyloxy-N, N-dimethylbenzylamine and its hydrochloride

A. 4-Allyloxy-N, N-dimethylbenzamide

4-Allylbenzoic acid and 1.37Mol thionyl chloride were first reacted under reflux. After the excess thionyl chloride had been removed under reduced pressure, the residue was slowly poured into 25% strength aqueous dimethylamine solution (corresponding to 0.6 mol of dimethylamine) with stirring. After the violent reaction had subsided, it was worked up in the usual way by etherification. The organic layer was separated off, washed successively twice with water, three times with 10% hydrochloric acid and finally with water until the washing liquid was neutral. The ethereal solution was then dried over anhydrous sodium sulfate, filtered and the filtrate evaporated to dryness. The oily residue (29.5 g) was distilled under reduced pressure. 4-Allyloxy-N, N-dimethylbenzamide was obtained in the form of an oil, boiling point 116 ° C .; n ² g = 1.5517.

Analysis for Ci ₂ Hi ₅ NO ₂ :

Calculated ... C 70.21, H 7.37, N 6.82%;
Found ... C 70.23, H 7.42, N 6.70%.

B. 4-Allyloxy-N, N-dimethylbenzylamine

A solution of 26.0 g (0.127MoI) of 4-allyloxy-Ν, Ν-dimethylbenzamide in 100 cm ^{3 of} anhydrous ether was slowly added with stirring to a suspension of 9.65 g (0.253 mol) of lithium aluminum hydride in 250 cm ^{3 of} anhydrous ether . The resulting mixture was stirred and refluxed for 22 hours. The reaction mixture was then cooled. The product was cleaved by adding 80 cm ^{3 of} ethyl acetate and then 120 cm ^{3 of} saturated aqueous sodium sulfate solution. ^{250 cm 3 of} ether and 50 g of anhydrous sodium sulfate were added to the two-phase mixture obtained, which contained a white precipitate. The resulting mixture was filtered and the precipitate on the filter was ^{washed with 100 cm 3 of} ether. The filtrate and wash solution were combined and distilled to remove the solvent. The residue was then distilled under reduced pressure. 21.82 g of 4-allyloxy-N, N-dimethylbenzylamine, boiling point 0.05, 66 to 67 ° C. were obtained; nl ⁵ = 1.5140.

Analysis for Ci ₂ Hi ₇ NO:

Calculated ... N 7.32%;
found ... N 7.53%.

C. 4-Allyloxy-N, N-dimethylbenzylamine hydrochloride

Dry hydrogen chloride gas was introduced through a solution of 17.2 g of 4-allyloxy-N, N-dimethylbenzylamine in 150 cm ^{3 of} anhydrous ether until no further precipitate separated out. The oily precipitate formed was separated off by filtration and recrystallized from ether which contained 10 percent by volume of ethanol. Thus there was obtained 15.47 g of the hydrochloride of 4-allyloxy-N, N-dimethylbenzylamine in the form of a solid crystalline substance, mp. 131 ⁰ C.

Analysis for Ci ₂ Hi ₈ ClNO:

Calculated ... C 63.30, H 7.97, N 6.13, Cl 15.61%; Found ... C 63.38, H 7.98, N 6.39, Cl 15.58%.

Example 2

4-Allyloxy-N-methylbenzylamine and its

Hydrochloride A. 4-Allyloxy-N-methylbenzamide

100 g (0.51 mol) of 4-allyloxybenzoyl chloride (prepared according to the description in Example 1, A) were added slowly and with stirring to 284 g of 25% strength aqueous methylamine solution (corresponds to 2.29 mol of methylamine). The resulting mixture was heated in the steam bath for two hours and then allowed to cool ^{to about 29 ° C.} The mixture was extracted with ether and the ethereal extract was washed successively with water, dilute hydrochloric acid, and water again before drying over anhydrous sodium sulfate. The dried solution was filtered and the filtrate evaporated. The solid residue was recrystallized from aqueous ethanol. 78.7 g of 4-allyloxy-N-methylbenzamide were thus obtained in the form of a white crystalline solid, melting point 101 ° to 102 ° C.

Analysis for CnHi3NO ₂ :

Calculated ... C 69.09, H 6.85, N 7.33%; Found ... C 69.19, H 6.88, N 7.25%.

B. 4-Allyloxy-N-methylbenzylamine

A solution of 58 g (0.3 mol) of 4-allyloxy-N-methylbenzamide in 300 cm ^{3 of} dry tetrahydrofuran was added slowly and with stirring to 18 g (0.5 mol) of lithium aluminum hydride in 500 cm ^{3 of anhydrous ether.} The mixture was heated under reflux for 6 hours, then allowed to cool to about 25 ⁰ C. ^{92.5 cm 3 of} ethyl acetate, 20 cm ^{3 of} water, 15 cm ^{3 of} 20% strength aqueous sodium hydroxide solution and 70 cm ^{3 of} water were added in succession to this mixture. The resulting mixture was filtered and the residue on the filter was washed with ether. The filtrate and washing liquid were combined and ^{extracted with 200 cm 3 of} dilute hydrochloric acid. The acidic extract was washed with ether and then made alkaline by adding excess aqueous sodium hydroxide solution. The separating oil was with

Ether extracted, and the essential extract was washed with water and then with saturated aqueous sodium chloride solution before being dried over anhydrous potassium carbonate. The dried solution was filtered and the filtrate evaporated. The residue was distilled under reduced pressure. 47.5 g of 4-allyloxy-N-methylbenzylamine were thus obtained in the form of an oil, boiling point 025 76 ° C .; n% ⁵ = 1.5193.

C. 4-Allyloxy-N-methylbenzylamine hydrochloride

A solution of 20 g of 4-Aylqxy-N-methylbenzylamine in 300 cm ^{3 of} anhydrous ether was made by adding hydrogen chloride dissolved in ethanol

acidified. The solid which separated out was isolated by filtration and recrystallized from methyl ethyl ketone. In this way, 4-allyloxy-N-methylbenzylamine hydrochloride was obtained in the form of a solid, white, crystalline substance with a melting point of 162 to 163 ^° C.

Analysis for ChH ₁₆ CINO:

Calculated ... C 61.82, H 6.55, N 6.56, Cl 16.59%; found ... C 61.89, H 7.88, N 6.41, Cl 16.43% ..

Example 3

4-Allyloxy-3-propyl-N, N-dimethylbenzylamine and its hydrochloride

A. Ethyl 4-hydroxy-3-propyl benzoate

A solution of 103 g (0.5 mol) of ethyl 3-allyl-4-oxybenzoate in 150 cm ^{3 of} ethanol was shaken with 0.2 g of platinum oxide in the presence of hydrogen at an initial pressure of 3.50 kg / cm ^2. The theoretical amount of hydrogen was absorbed within one hour. The reaction mixture was then filtered and the filtrate was combined with those from four similar experiments. The combined filtrates represented the entire crude reaction product of 503.3 g (2.44 mol) of ethyl 3-allyl-4-oxybenzoate. They were distilled to remove the solvent and the solid residue was collected, washed with pentane and dried. As were 453.6 g of ethyl-4-oxy-3-propylbenzoate in the form of a crystalline solid substance having a melting point 77.5 to 80.5 C ⁰ obtained. Another 21.3 g of this substance was obtained by concentrating the pentane washing liquid

B. Ethyl 4-allyloxy-3 ^: propyl benzoate

A mixture of 424.3 g (2.04 moles) of ethyl 4-hydroxy-3-propyl benzoate, 414 g (3 mol) potassium carbonate, 363 g (3 mol) allyl bromide and 2.2 1 Acetone was refluxed and stirred for 10 hours. The solid matter that was deposited became isolated by filtration and washed with acetone. The filtrate and washing substance were evaporated together, the oily residue was dissolved in ether. The ethereal solution was successively with cold 10% aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate evaporated. The residue was distilled under reduced pressure. So you got 479.6 g of ethyl 4-allyloxy-3-propylbenzoate, b.p. 005 116 ° C; «£ = 1.5178.

Analysis for C15H20O3:

Calculated ... C 72.55, H 8.12%; found ... C 72.77, H 8.02%.

55

C. 4-Allyloxy-3-propylbenzoic acid

A solution of 429.8 g (1.73 mol) of ethyl 4-allyI-oxy-3-propylbenzoate and 460 g (11.5 mol) of sodium hydroxide in a mixture of 5 1 of water and 1.5 1 of ethanol was used for 6 hours heated to reflux. The resulting mixture was evaporated to remove most of the ethanol and the residue treated with water. The aqueous solution was extracted with ether and then acidified by adding hydrochloric acid. The solid which separated out was isolated by filtration, washed with water and dried. There were 349.8 g of 4-allyl-oxy-3-propylbenzoic acid as a crystalline solid having a melting point of 125-126 ⁰ C obtained.

D. 4-Allyloxy-3-propyl-N, N-dimethylbenzamide

A solution of 160 g (0.8 mol) of 4-allyloxy-3-propylbenzoic acid and 105 cm ^{3 of} thionyl chloride in 260 cm ^{3 of} benzene was refluxed for 4 hours. Solvent and excess thionyl chloride were removed by distillation under reduced pressure, and 445 g of 25% strength aqueous dimethylamine solution (corresponding to 2.47 mol of dimethylamine) were slowly added to the residue with stirring. The mixture was stirred for 1/2 hour and then extracted with ether. The ether extract was washed successively with water, dilute hydrochloric acid, water and saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The dried solution was filtered and the filtrate evaporated to remove the solvent. The residue was distilled under reduced pressure. 163.2 g of 4-allyloxy-3-propyl-N, N-dimethylbenzamide were obtained in the form of a crystalline solid substance with a melting point of 40 to 41 ^° C.
Analysis for C15H21NO2:

Calculated ... C 72.84, H 8.56, N 5.66%; found ... C 72.97, H 8.61, N 5.74%.

E. 4-AUyloxy-3-propyl-N, N-dimethylbenzylamine

A solution of 112.8 g (0.45 mol) of 4-allyloxy-3-propyl-N, N-dimethylbenzamide in 350 cm was slowly added to 25 g (0.66 mol) of lithium aluminum hydride in 600 cm ^{3 of anhydrous ether 3} tetrahydrofuran added. The mixture was refluxed and stirred for 15 hours. The cooled reaction mixture was treated successively with stirring with 122 cm ^{3 of} ethyl acetate, 26.4 cm ^{3 of} water, 19.8 cm ^{3 of} 20% strength aqueous sodium hydroxide solution and 92.5 cm ^{3 of} water. The solid which separated was isolated by filtration and washed on the filter with ether. The filtrate and washing liquid were washed together with water and extracted with dilute hydrochloric acid. The aqueous acidic solution was washed with ether and then made basic by adding aqueous sodium hydroxide solution. The oil which separated out was extracted with ether, and the ether extract was washed with water and then with saturated aqueous sodium chloride solution and then dried over anhydrous potassium carbonate. The dried ether solution was filtered and the filtrate evaporated. The residue was distilled under reduced pressure. This gave 97 g of 4-allyloxy-3-propyl-N, N-dimethylbenzylamine in the form of an oil, boiling point 0.25 ° C. to 82 ° C., n% = 1.5078.

Analysis for Ci ₅ H ₂₃ NO:

Calculated ... C 77.20, H 9.94, N 6.00%; found ... C 77.85, H 10.45, N 6.46%.

F. 4-Allyloxy-3-propyl-N, N-dimethylbenzylamine hydrochloride

A solution of 66.5 g of yyPPy

Ν, Ν-dimethylbenzyIamin in anhydrous ether

acidified by adding hydrogen chloride dissolved in ethanol. The solid which separated out was separated off by filtration, washed with ether and recrystallized from methyl ethyl ketone. In this way, 73.2 g of + -allyloxy-S-propyl-Ν, Ν-dimethylbenzylamine hydrochloride in the form of a crystalline solid substance with a melting point of 123 to 124 ^° C. were obtained.

Analysis for Ci ₅ H ₂₄ ClNO:

Calculated ... C 66.77, H 8.97, N 5.19, Cl 13.14%; Found ... C 66.66, H 8.67, N 5.13, Cl 13.10%.

Claims (1)

Claim: Process for the preparation of p-allyloxybenzylamines which are particularly suitable as enzyme inhibitors the formula / Ri
CH ₂ -N ( 10 0-CH ₂ -CH = CH ₂ in which Ri and R3 are hydrogen atoms or alkyl 10 radicals with 1 to 3 carbon atoms and R _{2 is} an alkyl radical with 1 to 3 carbon atoms, the number of carbon atoms in the radicals Ri, R ₂ and R3 not being more than 6, characterized in that an amide of the formula • N Ri R ₂ 0-CH ₂ -CH = CH ₂ in which Ri, R ₂ and R3 have the meaning given, is reduced in a manner known per se with lithium aluminum hydride. Considered publications: HeIv. Chim. Acta, 33/2 (1950), p. 1444 ff;
Bull. Soc. chim. de France (5), 19: 688, 689 (1952);
I am. Chem. Soc, 80 (1958), p. 1519.