DE2320945A1 - NEW ESTERS OF ACETYL SALICYLIC ACID - Google Patents

Description

23,737 n / wa

Synthelabo, Paris / France

New esters of acetylsalicylic acid

The present invention relates to new esters of acetylsalicylic acid of the general formula (i)

O - (CH ₂ ) - A

CH,

309845/1182

(D

η is an integer from 2 to 5 with the proviso that A represents a cyano radical and η in the other cases is an integer from 1 to 5;

A is a carbalkoxy radical -C

wherein R represents a straight or branched chain alkyl radical with 1 to 6 carbon atoms;

a carbamoyl radical

wherein R, and Rp are identical or different and represent a hydrogen atom or an alkyl radical with a straight or branched chain with 1 to 5 carbon atoms, or R ₁ and Rp and the nitrogen atom of the carboxamide function together form a heterocyclic radical, which optionally has one or more further heteroatoms has, for example a piperidine, morpholine, thiomorpholine radical, etc ..

a cyano radical -C N, or

is an acyl radical -C ^,

^ R

wherein R is an alkyl radical with a straight or branched chain with 1 to 6 carbon atoms,

3098 45/1182 "Λ" '

The invention also relates to a method of manufacture of the compounds of the general formula (i) by reacting acetic anhydride with a salicylic acid ester of the general Formula (II)

(II)

CH ₀ ) - A 2'n ^ O - (

converts, in which η and A are those given for the general formula (i) Have meanings.

The reaction is preferably durchg in pyridine at a temperature of 90 ⁰ C <
ge minutes.

door of 90 ⁰ C carried out, whereby the heating time

Finally, the invention relates to industrial use and in particular to pharmaceutical use of the compounds (i). These have interesting pharmacological properties Properties that give them therapeutic significance. In particular, these have an antagonistic effect against an aggregation or clumping of blood cells and also show analgesic and antipyretic Properties of the same intensity as those of acetylsalicylic acid, from which they are directly derived.

Compared to this, however, they have the significant advantage that they are much less toxic and - even at very high doses - do not cause stomach ulcers, which is what they do gives an exceptionally favorable therapeutic index. For example, the DL50 on the Swiss mouse is

_ 4 -S / 113 2

per os of the compound (I), in which η = 1 and A = -Cp

(The preparation of this compound is described in Example 1 and the compound designated by "Compound Ia,") is 4000 mg / kg, while that of acetylsalicylic acid is 1500 mg / kg. In the same way, the gastric ulcer rate eliciting dose of compound Ia, determined on the Sherman rat, 2000 mg / kg while that of acetylsalicylic acid, determined under the same test conditions, is 500 mg / kg. . . .,

The compounds (i) are used for preventive treatment of Thrombosis and of various inflammatory and jieumatic Syndromes used.

The invention therefore includes all pharmaceutical preparations which use the compounds (i) as active ingredients, together with any suitable additives for their administration, which is preferably by the oral route contain. These pharmaceutical preparations can also contain further therapeutically active substances with which the compounds (i) pharmaceutically and therapeutically are compatible.

For oral administration, any suitable for this administration suitable pharmaceutical forms, i.e. tablets, capsules, coated tablets, etc. are used, the unit dose of the compound (i) being between 1 and 1000 mg and the daily dose can be between 1 and 3000 mg.

The following examples serve to illustrate the invention without restricting it.

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Example 1: Acetylsalicyloylglycolamide

A mixture of 10 g (0.05 mol / g) salicyloylglycolamide and 20 ml acetic anhydride in 40 ml pyridine is heated to 90 ° C. for 10 minutes. The reaction mixture is allowed to cool, poured onto crushed ice and solid sodium hydrogen carbonate is added until no further reaction occurs. The deposited precipitate is extracted twice successively with an average of 100 ml of ethyl acetate, the combined extracts are washed with 100 ml of a saturated aqueous sodium chloride solution, the extracts are dried over sodium sulfate and filtered, the solvent in the filtrate is driven off on a water bath in vacuo and the residue is recrystallized from benzene. In this way, 9 S (yield 76 %) acetylsalicyloylglycolamide is obtained as a white, crystallized compound which is insoluble in water. Melting point ⁰

Analysis: ( αι ^Η ΐ] L ^N0 5 C. 55, (237 ) H K 68 N 5, 91 Calculated 55, 75 il ·, 66 5, 91 Found % \ 55, 68 68 _ 55

Example 2: ψ -Cyanopropylacetylsalicylic acid ester

A mixture of 25 g (0.122 mol / g) of 'T'-cyanopropylsalicylic acid ester, 80 ml of pyridine and 40 ml of acetic anhydride is heated for 15 minutes. The pyridine and acetic anhydride are evaporated on a water bath in vacuo and the residue is rectified. This gives 25 g (yield 83 %)

309845/1 182

T'-cyanopropylacetylsalicylic acid ester in the form of a viscous colorless oil, which passes at 178 ° / 0.5 mm and is insoluble in water, but soluble in alcohols.

Analysis: C ₁₃ H ₁₅ NO ₄ (247)

Calculated % \ C 65.22 H 5.31

Found % \ 63.18 5.55

Example 3: ethyl ester of acetylsalicyloylglycolic acid

A mixture of 20.5 g (0.091 mol / g) of ethyl ester of sal ^ cyloylglycolic acid and 40 ml of acetic anhydride in 80 ml of anhydrous pyridine is heated to reflux temperature for 20 minutes. The pyridine and the excess acetic anhydride are evaporated on a water bath in vacuo and the residue is rectified. This gives 18 g (yield 75 ^) of ethyl ester of acetylsalicyloylglycolic acid in the form of a viscous oil which passes over at 148 ° / 0.5 mm and solidifies in the flask. Melting point ⁰

Analysis: ^c i-5 ^H i4 ° 6 (266)

Calculated % \ C 58.65 H 5.31

Found #: 58.66 5.24

Example 4: β-oxopropyl acetylsalicylate

A mixture of 7.5 g (0.042 mol / g) salicylic acid-ß-oxopropyl ester and 10 ml of acetic anhydride in 20 ml of anhydrous

309845/1182 " ⁷ "

Pyridine is heated to reflux temperature for 10 minutes. The pyridine and the excess acetic anhydride are evaporated off in a water bath in vacuo and crystallized the solid residue from isopropyl ether. You get hered by 6 g (yield 60 #) acetylsalicylic acid β-oxopropyl ester in the form of a white, crystallized, water-insoluble, alcohol-soluble compound that melts at 60 °.

Analysis: ^c l2 ^H l2 ° 5 (236)

Calculated #: C 61.07 H 5.13 Found % x 60.94 5.36

60.82 5.13

3CK- ■ - ■■ b / 1 182

Claims (5)

- ■ 8 - claims 1.) New esters of acetylsalicylic acid of the general formula (i) (CH ₂ ) _n -A (D wherein η means an integer from 2 to 5 with the proviso that A represents a cyano radical and η in the other cases is an integer from 1 to 5, A is a carbalkoxy radical - wherein R is an alkyl radical with a straight or branched chain having 1 to 6 carbon atoms represents; a carbamoyl residue - 309845/1182 - 9 - wherein R ^ and R _{2 are} identical or different and represent a hydrogen atom or an alkyl radical with a straight or branched chain having 1 to 5 carbon atoms, or R, and Rp and the nitrogen atom of the carboxamide function together form a heteroyclic radical, which may optionally contain one or more other Has heteroatoms, for example a piperidine, morpholine, thiomorpholine residue, etc ... a cyano radical -C = E = N, or • ° is an acyl radical -C ^, ^ R wherein R is an alkyl radical with a straight or branched chain having 1 to 6 carbon atoms represents. 2. Process for the preparation of the compounds (I) according to Claim 1, characterized in that acetic anhydride with a salicylic acid ester of general formula (II) 0 - (CH ₂ ) _n - A converts, in which η and A are the for the general formula (i) have given meaning. - 10 - 309845/1182 3. "The method according to claim 2, characterized in that ge k e η η, that the reaction is carried out in pyridine. k. A method according to any one of claims 2 and j5, boiled ennzeichnet characterized in that one carries out the reaction at about 90 ⁰ C, the duration of heating is several minutes. 5. Pharmaceutical preparation, labeled by a content of at least one of the compounds according to claim 1, optionally together with customary, pharmaceutically suitable auxiliaries and / or carriers. 30 98 45/1182