DE2301160A1 - ANTI-INFLAMMATORY AND PAIN RELIEF BENZYLAMINE - Google Patents

Description

PATENT ADVOCATE DR. HANS-GUNTHER EGGERT, DIPLOMA CHEMIST

5 COLOGNE 51, OBERLÄNDER UFER 90? ^ Π 1 1 K Π

Cologne, the lo. January 1973 Fü / pz / 199

SA BOTTU, 115, rue ND des Champs, 75oo6 Paris / France

Anti-inflammatory and analgesic benzy! Amines

The invention relates to new derivatives of benzylamine which are of particular interest because of their anti-inflammatory and analgesic effects.

The compounds according to the invention correspond to the general formula I.

in the R a chain-like or branched Älky! group, which can be saturated or unsaturated, with up to 6 carbon atoms, means a dialkylaminoalkyl or a cycloalkyl group.

The addition salts of these basic derivatives with therapeutically useful organic or inorganic acids, such as hydrochloric acid, maleic acid, fumaric acid, Citric acid, oxalic acid, etc. are also a subject of the invention.

3 0 9 R 3 R / η 9 7

The process for the preparation of compounds of the formula I, in which R has the meanings given above, is characterized in that the compound of the general Formula I, in which R is hydrogen, with a halide of the formula XR, in which R has the above meanings and X is a halogen atom such as chlorine, bromine or iodine, converts. The reaction is carried out in acetone in the presence carried out by potassium carbonate.

The starting product for I (R = H) can be obtained from chloro-3-hydroxy-4-acetophenone by the reductive amination described in the literature getting produced.

The starting product for I (R = H) can also be obtained by demethylation of the product I, where R is CH-. means in acidic medium be won.

The compounds of the formula I in which R is a chain or branched alkyl group can also be carried out by reductive amination of compounds of the general Formula II

-CO-CH ₃ II

Cl
can be obtained. The compounds of the formula II are prepared by reacting the chloro-3-hydroxy-4-acetophenone already described with an alkyl halide.

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The reductive amination used in these processes is carried out in two steps: The first step are added to the ketone, which is the starting compound, in the presence of magnesium chloride or ammonium formate Formamide was added over several hours at temperatures in the range from 16o to 195 ° C.

The second step represents the hydrolysis of the formylated Intermediate compound and is carried out in the presence of hydrochloric acid.

The products obtained in this way are obtained either directly in the form of the hydrochloride or, after adding lye to the reaction mixture, in the form of the free base.

Other therapeutically useful salts with inorganic or organic acids can also be added to the base obtain.

The following examples illustrate the implementation of the invention.

A) Alkylation of chloro-3-hydroxy-4-acetophenone _{13.8 g of K 9} CO- are added to a solution of 17. o5 g of chloro-3-hydroxy-4-acetophenone in 200 ml of acetone. add and let Io min reflux. 6.83 ml of anhydrous methyl iodide are then added in portions and the mixture is refluxed for 7 h. After filtration, it is evaporated to dryness and 18.5 g of chloro-3-methoxy-4-acetophenone are obtained (yield 99%, mp 75-76 ° C.).

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Similarly, when the corresponding alkyl iodides are used, one obtains:

Chlor-S-ethoxy - ^ - acetophenone, m.p. 74 ° C
Chloro-3-propoxy-4-acetophenone, m.p. 58 ° C
Chloro-3-butoxy-4-acetophenone, m.p. 49-5o ° C
Chlor-S-isobutoxy - ^ - acetophenone, m.p. 45-46 ° C
Chloro-3-pentyloxy-4-acetophenone, m.p. 42-43 ° C

B) Reductive amination of the ketones

Preparation of chloro-3-methoxy-4 _/ QC-methyl-benzylamine

You wear at an elevated temperature of about 150 to 195 ° C
a solution of 95 g of chloro-3-methoxy-4-acetophenone in
166 g of ammonium formate and 3.5 g of MgCl ₂ . 45 ml is added during this procedure, which takes several hours
Formamide added.

After dilution, subsequent extraction with benzene and subsequent evaporation, the crude formylated product is hydrolyzed with HCl. The base is precipitated by adding lye, which is extracted with ether, washed and dried
will. The product obtained is distilled at 1 torr and 126 to 135 ° C. and 18.3 g are obtained in the form of the free base.
(Yield 52%). By adding hydrochloric acid
the hydrochloride of the desired product is obtained,
F. ^. 19o ° C (isopropanol).

The chlorohydrate of chloro-3-ethoxy-4 is obtained in an analogous manner, «-Methylbenzylamine from chloro-3-ethoxy-4-acetophenone, mp 220 ° C .;

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the chlorohydrate of chloro-3-propoxy-4, <t-methylbenzylamine,

Mp 2o4-2o5 ° C;

the chlorohydrate of chloro-3-butoxy-4, öc-methylbenzylamine,

189 ° C;

the chlorohydrate of chloro-3-isobutoxy-4, tt-methylbenzylamine,

189-19o ° C;

the chlorohydrate of chloro-3-pentyloxy-4, Oi-methylbenzylamine ,

F. 19o ° C.

C) Representation of chloro-3-hydroxy-4, QC-methylbenzyl amine

In a flask with 24 g of chloro-3-methoxy-4, <ar-methylbenzylamine 125 ml of 48% hydrobromic acid are added and the mixture is refluxed for 3 hours. After cooling, the precipitate becomes washed with acetone and dried. 24.5 g of bromine hydrate of the desired product are obtained (yield 75%), F. 24o ° C.

D) alkylation of chloro-3-hydroxy-4, Oc-methylbenzylamine

Preparation of chloro-3-isopropoxy-4 _/ df-methylbenzylamine To a solution of 7.85 g of chloro-3-hydroxy-4, # - methylbenzylamine in 2oo ml of acetone, 4.98 ml of isopropyl iodide ( 8.5 g). Boil Io h under reflux and allow to cool. After filtration, it is evaporated to dryness, taken up with ether and washed with the lye. Hydrogen chloride dissolved in ether is then added and the hydrochloride of the desired product (6.3o g, yield 64%) with a melting point of 199 ° C. is obtained directly. In the same way, the chlorohydrate of chloro-3-cyclopentyloxy-4, ar-methylbenzylamine is obtained with a temperature of 23o-232 ° C .;

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the chlorohydrate of chloro-3-allyloxy-4, ar-methylbenzylamine, Mp 214-215 ° C;

the chlorine hydrate of chlorine-S-dimethylaminoäthyloxy- ^ Cfc-methylbenzylamine, F. 21o C.

The new compounds of general formula I have interesting pharmacological properties, in particular as anti-inflammatory and analgesic agents. These properties are described using the below Trials proved. The codes used therein have the following meaning:

BO 1147: chloro-3-methoxy-4, α-methylbenzylamine; BO 1167: chloro-3-butoxy-4, cc -methylbenzylamine; BO 1166: chloro-3-ethoxy-4, or-methylbenzylamine; BO 1184: chloro-3-pentyloxy-4, a-methylbenzylamine.

1. Anti-inflammatory effects

The carrageenin rat paw edema test (according to Winter CA .; Proc.Soc.Exp.Biol.Med. 1962, 111, 544) was used for assessment applied to its anti-inflammatory effects.

The products are given orally 1 hour before the carrageenin is injected. You determine the effectiveness of the product Measurement of the decrease in paw volume in relation to the blind test in percent.

The results are shown in the following table:

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Product dose Effect in% (reduction in paw volume mg / kg based on comparison animals)

9o 2 h 3h 4h 5h BO 1147 9o 71 46 32 29 BO 1166 9o 68 69 46 33 BO 1167 9o 72 54 35 3o BO 1184 74 68 51 35

All compounds showed an interesting activity both in terms of intensity and in terms of Duration of the effect, which was only reduced by half after the lapse of 5 hours.

2. Soothing effect

This is shown by the analgesic test with acetic acid on mice (R. Koster et Coll. Fed. Proc. 1959, 18 , 412). The compounds are given 1 hour before the acid is injected.

The effectiveness of the product is based on the percentage reduction in the number of twists Comparison animals, definitely. The results are shown in the following table:

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product 1147 dose
mg / kg BO 6o 1166 12o BO 6o 1167 12o BO 6o 1184 12o BO 6o 12o

Percentage effectiveness (calculated from the reduction in the number of twists in relation to comparison animals)

79 97 75 93 58 97 91 99

All of the compounds in this series showed significant pain relievers Effectiveness.

In applying these new derivatives as anti-inflammatory and analgesic agents in humans, for example in the treatment of arthritis and various rheumatic ailments, depending on the route of administration and depending on the sensitivity of the patient, a total dose of 100 to 100 mg / 24 h is recommended.

The new compounds according to the invention are given to the sick in the form of compositions in which they are are mixed in a pharmaceutically acceptable vehicle suitable for oral, rectal or parenteral administration is, the single doses of active product between 5o and 5oo mg.

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Claims (6)

Claims in which R is a linear or branched, saturated or unsaturated alkyl group with 1 to 6 carbon atoms, means a dialkylaminoalkyl or cycloalkyl group and their salts of pharmaceutically acceptable acids. 2. As intermediate compounds in the preparation of compounds according to claim 1 usable compounds of the general formula II in which R is a chain-like saturated alkyl group having 1 to 6 carbon atoms. 3. A method for the preparation of compounds according to claim 1, characterized in that chlorine-3-hydroxy-4, tf-methylbenzylamine with the aid of an alkyl halide XR, where X can be chlorine, bromine or iodine and R the in Claim 1 has given meaning, alkylated in the presence of an alkali metal carbonate in a solvent under reflux. 309835/1197 4. A method for the preparation of compounds according to claim 1, wherein R is a chain-like, saturated Al- * means kyl group which has up to 6 carbon atoms, characterized in that compounds according to Claim 2 are subjected to a reductive amination with formamide and ammonium formate at elevated temperature and subjected for several hours, and the as Formylated derivatives formed intermediate compounds with hydrochloric acid to form compounds of the formula I hydrolyzed their chlorohydrates, which are converted in a known manner into the corresponding free bases and then into the acid addition salts transferred. 5. A method for the preparation of compounds according to claim 2, characterized in that one chlorine-3-hydroxy-4-acetophenone by reaction with an alkyl halide of the formula RX, in which R has the same meaning as in claim 2 and X represents a halogen atom, in the presence of an alkali carbonate in one Alkylated solvent at reflux. Means 6. Pharmaceutical compositions which are used in particular as anti-grove-inhibiting and analgesic agent and as active substance at least one ^e of the compounds of formula I, wherein R group is a chain-like or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms or a Cycloalky! . 309835/1197