DE2541475A1 - NEW DERIVATIVES OF ACETYL SALICYLIC ACID, THEIR PRODUCTION AND COMPOSITIONS OF THESE - Google Patents

Description

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Dr. F. Zumstein Sr. - Dr. E. Assmann - Dr. R. Koenigsberger Dlpl.-Phys. R. Holzbauer - Dipl.-Ing. F. Klingseisen - Dr. F. Zumstein jun.

PATENT LAWYERS TELEPHONE: COLLECTIVE NO. 22S341 8 MUNICH 2. TELEX 828878 BRAUHAUSSTRASSE 4 TELEQRAMS: ZUMPAT CHECK ACCOUNT: MONKS 81138-8O8. Bank code 70010080 BANK ACCOUNT: BANKHAUS H. AUFHAUSER

ACCOUNT NO. 387887, bank code 70030600

SC 4446/4537
14 / hü

RHONE-POULENC INDUSTRIES, Paris / France
New derivatives of acetylsalicylic acid, their production and

compositions containing them.

The present invention relates to new derivatives of acetylsalicylic acid the general formula

(XX) H.

' _R / - ^(C Vn - f - ^C0 < _R ⁵ CD

2 ^ H

their manufacture and medicinal compositions containing them.

In the general formula (I)

R ₁ and Rp, which may be the or different from same, is a hydrogen atom or an optionally by a hydroxy reet substituted alkyl group having 1 to 4 carbon atoms, R, and Ru, which may be identical or different, a Waeeerstoffatom or an alkyl group with 1 to 4 carbon atoms or form together and with the carbon atom to which

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they are bound, a saturated ring with 5 or 6 ring members,

one of the symbols R ₁ or R ₂ with one of the symbols R_ or R ₂ , and the nitrogen and carbon atoms to which they are respectively bonded, can form a nitrogen heterocycle with 5 or 6 members,

Rj. and Rg *, which can be the same or different, denote a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, which is optionally substituted by a hydroxy radical,
η is an integer, namely 0 or 1.

According to the invention, the new salts of acetylsalicylic acid can be prepared by reacting a base of the general formula

¹ V- CCH ₂ ) _n - G - CO «( ⁵
Λ * 4 ⁶

possess, Rg and η are as defined above, are obtained with acetylsalicylic acid - in which R _1, R _2, R ,, R ,, R _{2. 1}

In general, the reaction takes place in an organic solvent such as an alcohol (methanol, ethanol, isopropanol), a ketone (acetone) or an ether (dirnethoxyethane) at a temperature of around 20.degree. It is particularly advantageous to use anhydrous solvents.

The reaction can also be carried out in an aqueous medium and the product of the general formula (I) can according to Concentration and lyophilization of its aqueous solution can be isolated.

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The salts of the general formula (I) can, if appropriate, by recrystallization in an organic solvent such as Ethanol to be cleaned *

The new salts of the general formula (I) have the same anti-inflammatory, analgesic and anti-thermal properties like acetylsalicylic acid, which at the same time has a considerably greater solubility in water and a considerably lower solubility Have acid strength.

These special properties allow greater simplification administration of the product and better tolerance by the stomach. The injectable option Getting solutions that are well tolerated by the veins and muscles is an especially great benefit.

The new salts according to the invention have the ■ in the mouse same acute toxicity as acetylsalicylic acid.

Of particular interest are the products of general formula (I), in which the symbols R _1, R _2, R ,, R ₂ ^, R ₁ - and Rg, which may be the or different, the same, are hydrogen atoms or; lkylreste having 1 to Represent 3 carbon atoms.

The following examples illustrate the invention and show how it can be put into practice.

example 1

Is added to a solution of 32.4 g of acetylsalicylic acid in 480 cnr absolute ethanol, a solution of 18.4 g of 2-amino-2-methyl-propionamide in 420 cnr absolute ethanol and stirred for 30 min. At a temperature of about 20 ⁰ C The precipitate is separated off by filtration, washed over a filter with 270 cnr absolute ethanol, then for 18 hours under reduced pressure (0.1 mm Hg) at a temperature of about 20 ° C. and then for 1 hour at 60 ° C dried. 26.8 g are obtained in this way

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2-Amino-2-methyl-propionamide-acetylsalicylate with a Melting point from 14O to 142 ° C.

The 2-amino-2-methylpropionamide can be prepared according to A. DAVIS, J. Chem. Soc, 2419 (1951).

Example 2

72.0 g of acetylsalicylic acid are dissolved at 20 ° C. in a solution of 40.8 g of 2-amino-2-methylpropionamide in 500 cnr of water. The solution is filtered and then lyophilized under reduced pressure (0.1 mm Hg) for 42 hours. The lyophilized product is dried in the presence of phosphorus pentoxide under reduced pressure (0.1 mm Hg) for 27 hrs. At 20 ⁰ C. 112.4 g of 2-amino-2-methyl-propionamide-acetylsalicylate with a melting point of 141 to 142 ° C. are obtained in this way.

Example 3

A solution of 10.1 g of 2-methyl-2-methylamino-propionamide in 150 cm of dry isopropanol is added to a solution of 16.2 g of acetylsalicylic acid in 300 cpm of anhydrous isopropanol and the mixture is stirred for 50 minutes at a temperature of approx. 2O ⁰ C. The precipitate is separated by filtration, washed with 80 cm of anhydrous isopropanol, then under reduced pressure (0.1 mm Hg) for 20 hrs. at a temperature of about 20 ⁰ C and then for 10 hrs. at 5O ⁰ C dried. Are thus obtained 24.0 g of 2-methyl-2-methylamino-pröpionamid acetylsalicylate having a melting point of 148 to 15O ⁰ C.

The 2-methyl-2: -methylamino-propionamide can according to A. PINCHUK, Zhur. Obshchei Khim., J59, 583 Ο9β9), Chem. Abstr., 71_, 613ΟΟ k (1969).

Example 4

Is added to a solution of 7.21 g of acetylsalicylic acid in 80 cnr anhydrous 2 ⁰ C cooled ethanol 2.96 g aminoacetamide and stirred for 20 min. At 2 ° C. The precipitate is through

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Filtration separated, washed with 30 cnr anhydrous ethanol and dried for 18 hrs. Under reduced pressure (0.1 mm Hg) at a temperature of 20 ⁰ C. This gives 9.12 g of aminoacetamide acetyl salicylate with a melting point of approx. 115 C.

The aminoacetamide can according to RG JONES, J. Am. Chem. Soc. 71 , 79 (1949).

Example 5

3.6o g of acetylsalicylic acid and 3 × 03 g of i-amino-cyclohexanecarboxamide are dissolved in 15 cm of anhydrous acetone with stirring. Crystallization is initiated and the mixture is stirred for 20 minutes at a temperature of around 20 ° C. The precipitate is separated off by filtration, washed with 15 ml of anhydrous acetone and under reduced pressure (0.1 mm Hg) for 4 hours at one temperature 20 ⁰ C and then for 2 hrs. at 50 ° C dried. 5 * 07 g of 1-amino-cyclohexanecarboxamide acetylsalicylate with a melting point of 127 to 129 ° C. are thus obtained.

The 1-amino-cyclohexanecarboxamide can be prepared according to A. PINCHUK, Zhur. Obshchei. Khim. 37 » ⁸ 5β (19β7), Chem. Abstr., 6J, 108 169j (1967).

Example 6

A solution of 13.0 g of 2-dimethylamino-2-methylpropionamide in 50 ml of absolute ethanol is added to a solution of 18.0 g of acetylsalicylic acid in 160 cnr absolute ethanol and the mixture is stirred for 50 minutes at a temperature of 8 to 10 ⁰ C. The precipitate is separated by filtration, washed with absolute ethanol and 90 cnr under reduced pressure (0.1 mm Hg) for 18 hrs. at a temperature of about 20 ⁰ C and then for 5 hrs. at 57-58 ⁰ C dried. 26.3 g of 2-dimethylamino-2-methyl-propionamide-acetylsalicylate with a melting point of 132 to 134 ° C. are obtained in this way.

The 2-dimethylamino-2-methyl-propionamide can be prepared according to the process described in German Patent 2,246,728. _b U a β 1 3/1 0 7 8

Example 7

To a solution of 27.0 g of acetylsalicylic acid in 200 cm. The precipitate is separated by filtration, washed with 100 cnr absolute ethanol and dried under reduced pressure (0.1 mm Hg) for 15 hrs. At a temperature of about 2O ⁰ C and then for 2 hrs. At 50 ⁰ C dried. This gives 41.9 g of 2-carbamoyl-piperidin-acetylsalicylate with a melting point of 174-176 ⁰ C.

The 2-carbamoyl-piperidine can be prepared according to H.FOX, J. Org. Chem., _17 * 5 ^ 2 (1952).

Example 8

One adds to a solution of 24.1 g of acetylsalicylic acid in

■ 5
300 cnr anhydrous isopropanol a solution of 15 * 1 g 2-amino-2-methyl-butyramide in 80 cm anhydrous isopropanol and stir for 50 min. At a temperature of 11 to 15 ° C. The precipitate is separated by filtration, washed with 120 cnr anhydrous isopropanol, and under reduced pressure (0.1 mm Hg) for 16 hrs. At a temperature of about 20 ⁰ C and then for 6 hrs. At 50 ° C and finally for 2 hrs dried at 60 ° C. Are thus obtained 35.3 g of 2-amino-2-methyl-butyramide acetylsalicylate having a melting point of 136-138 ⁰ C.

The 2-amino-2-methyl-butyramide can be prepared according to A.PINCHUK, Zhur. Obshchei, Khim., 37, 856 (1967), Chem. Abstr., 67, 108 169 J (1967).

Example 9

A solution of 17 * 3 K 2-amino-2,4-dimethylpentanamide is added to a solution of 22.3 g of acetylsalicylic acid in 150 cnr of anhydrous acetone in 190 cnr anhydrous acetone and stir

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for 19 hours at a temperature of around 2 ° C. The precipitate is separated durcn filtration, washed with 90 cnr anhydrous acetone and dried under reduced pressure (0.1 mm Hg) for 21 hrs. At a temperature of about 20 ⁰ C dried. Are thus obtained 30.1 g of 2-amino-2,4-dimethyl-pentanamide acetylsalicylate having a melting point of II8 to 120 ⁰ C.

The 2-amino-2,4-dimethylpentanamide can be prepared according to that described in German Patent 2,139,641 Procedure.

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The pharmaceutical compositions containing at least one product of the general formula (I) in the presence of a diluent or contain coating agents relate to a further subject matter of the present invention. These compositions can be administered by the oral, rectal or parenteral routes.

As solid compositions for oral administration, tablets, pills, powders or granules can be used. In the active ingredient according to the invention is added to these compositions with one or more inert diluents or adjuvants, such as sucrose, lactose or starch. These compositions can also contain other substances as diluents, for example a lubricant such as magnesium stearate.

As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, Use syrups and elixirs that contain inert diluents such as water or paraffin oil. These compositions can also contain other substances as diluents, such as wetting, sweetening or flavoring products.

The compositions for parenteral administration can be sterile, aqueous or non-aqueous solutions, suspensions or Be emulsions. Propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, can be used as solvents or carriers or use injectable organic esters such as ethyl oleate. These compositions can also contain adjuvants, in particular Contain wetting, emulsifying or dispersing agents. The sterilization can take place in various ways, for example with the aid of a bacteriological filter by incorporating sterilizing agents into the composition, by irradiation or by heating.

They can also be made in the form of sterile, solid compositions that are sterile at the time of use

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Water or any other injectable, sterile medium.

The compositions for rectal administration are suppositories, which, in addition to the active ingredient, can contain excipients such as cocoa butter or soup wax.

In human therapy, the compositions of the invention are especially for the treatment of migraines, neuralgia, rheumatic diseases, pain of various origins (rheumatic, after injuries of a cancerous kind, caused by circulatory disorders, caused by internal Organs) and febrile conditions of infectious or cancerous origin or caused by injuries.

The doses to be used depend on the desired effect and the duration of the treatment. They are generally between 0.5 ^and 2 g per day for oral, intramuscular or intravenous administration, these doses being expressed based on the weight of the acetylsalicylic acid.

The following examples illustrate compositions according to the invention.

Example A.

Tablets containing 0.5 g of acetylsalicylic acid and having the following composition are prepared using conventional techniques: 2-Amino-2-methyl-propionamide-acetylsalicylate 0.700 g

Starch 0.160 g

colloidal silica 0.055 g

Magnesium stearate 0.005 g

Example B.

According to the usual technique to set tablets containing 0.5 g of acetylsalicylic acid of the following composition is prepared:

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2-methyl-2-methylamino-propionamide acetyl salicylate 0.820 g

Starch 0.120 g

colloidal silicon dioxide 0.055 g

Magnesium stearate 0.005 g

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Claims (2)

■ 2F4U75 - 11 claims Π_0 'New derivative of acetylsalicylic acid, characterized that it corresponds to the general formula COOH ρ R _V Γ ³ -OCOCH ,,, ¹ N- (CH) - C - COi R ₂ - ² - I in the R. and Rp, which can be the same or different Hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, which may be substituted by a hydroxy radical can represent R., and R ₂ ,, which can be identical or different, represent a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms or together and with the carbon atom to which they are bonded form a saturated ring with 5 or 6 members, one of the symbols R ₁ or Rp with one of the symbols R ^ or R ₂ , and the nitrogen and carbon atoms to which they are each bonded, can form a heterocycle with 5 or 6 members, R ₁ - and R / -, which can be identical or different, denote a hydrogen atom or an alkyl radical having 1 to 4 alkyl radical optionally substituted by a hydroxyl group, and η denotes an integer equal to 0 or 1. 2.) Process for the preparation of a product according to claim 1, characterized in that there is an amide of the general formula 609813/1078 f _{3 έ} ¹ N - (CH ₀ ) - C - CON
/ 2 η ι \ _R ^R 2 R ⁶ 2 ^R 4 in which R ₁ , R ₂ , R ,, Ru, Rt-, Rg and η have the meaning given in claim 1, are reacted with acetylsalicylic acid in an organic solvent or in water and the salt obtained is isolated. 3) Pharmaceutical composition, characterized in that that they as active ingredient at least one product according to claim 1 together with one or more beneficial and pharmaceutical contains acceptable diluents or adjuvants. 609813/1078