GB1567378A - Acetylsalicylic acid derivative process for its preparation and pharmaceutical compositions containing it - Google Patents

Description

(54) ACETYL-SALICYLIC ACID DERIVATIVE, PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT (71) We, PIERRE FABRE S.A., a French Societe Anonyme, of 125, Rue de la Faisanderie, 75116 Paris, France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to l,l-dimethylprop 2-ynylamine acetyl-salicylate, to a process for preparing it and to pharmaceutical compositions containing it.

Acetyl-salicylic acid occupies an important position in the field of therapeutics. The efficiency of this compound is undeniable, but it possesses some disadvantages because of its insolubility and the instability of its derivatives in aqueous solution. Under certain circumstances, its administration may cause gastric irritation, and even ulceration of the gastric mucous membrane in some cases. The known salts of acetyl-salicylic acid, that is to say, alkali metal salts, are, on the other hand, soluble and non-acidic, but have the disadvantage that they include alkali metals which are often undesirable. Furthermore, the stability of these salts in aqueous solution is very inadequate.

The present invention provides a salt of acetyl-salicylic acid which has the advantage that it overcomes the problems mentioned above, whilst retaining the known properties of other derivatives of acetyl-salicylic acid.

The present invention provides l,l-di- methylprop-2-ynylamine acetyl-salicylate of the formula

This compound has the advantage of being stable in aqueous solution, has a low hygroscopicity, crystallises well and is well defined.

The amine is such that an aqueous solution of the salt has a pH of 6, which imparts to it an optimal stability. It is known that a pH of 6 ensures almost perfect stability. In fact, at this pH, the stability of the salt in aqueous solution, lasts for several hours.

The compound of the invention can be prepared by reacting acetyl-salicylic acid with 3amino-3-methylbut-1-yne in solution, for example in ethanol, and isolating the salt from the solution. The salt may crystallise directly or may be precipitated by the addition of ether or may be isolated by lyophilisation.

The compound of the invention is especially useful as an analgesic and in the cardiovascular field on account of its anti-coagulation action.

The present invention therefore provides pharmaceutical compositions comprising as active ingredient l,l-dimethylprop-2-ynylamine acetyl-salicylate in admixture or conjunction with a pharmaceutically suitable carrier, for example in the form of tablets or a powder which can be administered orally, or in the form of an injectable aqueous solution.

More especially, the compound of the invention can be provided in the form of a dry powder, in an amount equivalent to from 0.3 to 2 g of acetyl-salicylic acid, in a glass ampoule, so that the powder can be mixed with a few ml of water and immediately administered parenterally. Alternatively, there can be provided an aqueous solution of 1,1-dimethylprop-2-ynylamine which can be mixed with an appropriate quantity of acetyl-salicylic acid and administered immediately.

The following Examples illustrate the invention.

EXAMPLE 1.

1,1-Dimethylprop-2-ynylamine acetyl salicylate 270.2 g (1.5 moles) of acetyl-salicylic acid are dissolved in 200 cm3 of absolute ethanol, then 124.7 g (1.5 moles) of 3-amino-3methylbutyne are added. The solution rapidly becomes turbid, then coagulates. Precipitation is achieved by the addition of 150 cm3 of ether and by chilling with ice.

After filtration and drying, 95 /O of the title compound are recovered, having the following characteristics: Empirical formula: Cl.Hl7NO4.

Molecular weight: 263.3.

Melting point: 112" C.

Solubility: 25% soluble in water.

pH of 25% solution: 6.

EXAMPLE 2.

Lyophilised 1,1 -dimethylprop-2-ynylamine acetyl-salicylate.

2.4 g of 3-amino-3-methylbutyne are introduced into 80 ml of distilled water. While stirring, 5.6 g of acetyl-salicylic acid are added. When dissolution is complete, the pH is 6. Filtration is carried out to eliminate the slight excess of acetyl-salicylic acid. The solution is divided between flasks containing 1.5 ml of solution and lyophilisation is effected for 10 hours. The product appears in the form of a white powder having the same characteristics as the product of Example 1.

EXAMPLE 3.

Pharmaceutical compositions.

A. The composition is presented in two separate parts, one solid (acetyl-salicylic acid) and the other liquid (water and l,l-dimethylprop-2-ynylamine). The amounts of the con; stituents are such that, upon mixing, there is obtained an aqueous solution of the salt at pH 6 to 7, which can be used directly for injection. The amount of water can be varied so as to obtain solutions having concentrations of from 1 to 25% by weight.

B. Injectable solutions, which must of neces sity be sterile, can be obtained by two methods: (a) by direct formulation of the pulverulent active principle in glass flasks.

This operation is carried out in a sterile cabinet; the materials necessary for the formulation are introduced into the sterile unit through a lock after being sterilised by passage through a kiln or an autoclave. The active compound is sterilised using ethylene oxide, then introduced through the lock.

(b) by formulating the active compound pre viously dissolved in distilled water to the appropriate concentration.

In this case, the sterilisation of the materials required for the formulation is carried out as above; the dissolved active compound is introduced into the sterile cabinet after sterilising filtration.

The final galenical form is then obtained by lyophilisation. This is possible owing to the stability of the l,l-dimethyl-prop-2-ynylamine acetyl-salicylate in aqueous solution.

C. The following compositions can be prepared by mixing (i) sachet: 1, 1-dimethylprop-2-ynyl acetyl salicylate 0.700 g aromatized excipient-sufficient for 1 sachet containing 1 gram of powder.

(ii) injection: 1,1 dimethylprop-2 -ynyl acetyl salicylate 0.700 g sorbitol for 1 ampoule for injection.

TESTS A. Stability in solution Derivatives of acetyl-salicylic acid in solution are subjected to de-acetylation to salicylic acid. The tests are carried out to measure the stability in solution by adding salicylic acid in measured quantities over a period of time.

In this manner it is confirmed that after keeping the solution for four hours at a temperature of 250 C., the quantity of acetylsalicylic acid formed by degradation was less than 1 g per 100 g of 1,1-dimethylprop-2ynylamine acetyl-salicylate. The full results of the test are set out in the accompanying drawing which is a plot of the amount of salicylic acid formed in grams against time.

B. Toxicology 1,1 - dimethylprop - 2 - ynylamine acetylsalicylate was subjected to toxicity checks by intraperitoneal administration to ordinary mice weighing 20 to 22 grams.

Compound LD,, i.p.

l,l-dimethylprop-2 900 mg/kg ynylamine acetyl sali cylate acetyl-sali cylic acid 495 mg/kg C. Pharmacology (a) Anti-algetic properties (Writhing test, BOISSIER LVOFF, in In flarnmation Biochemistry and Drug Interaction, 1969). These properties were investigated in mice after oral administration. At a time t,, the first oral administration of half the dose of the compound to be studied was carried out.

At a time t+2 hours, 2 mg of phenylbenzoquinone were injected intraperitoneally.

Finally, at a time t+2.05 hours to 2.10 hours, a summary was made of the contortions in groups of 16 male mice weighing 20 g each.

Compound ED5 0 mg/kg 1, i-dimethylprop-2- 36 ynylamine acetyl sali cylate lysine acetyl- 74 salicylate (b) Anti-coagulation activity 1,1 - dimethylprop - 2 - ynylamine acetylsalicylate, having demonstrated in vitro anticoagulation properties with respect to adeno sme diphosphonate and collagen, is tested for similar activity by administering the product intraperitoneally to rabbits.

This species of animal was chosen more especially in order for conditions to be similar to those in studies in vitro which were carried out using plasmas rich in platelets from rabbits.

20 mg of 1, 1-dimethylprop-2-ynylamine acetyl-salicylate in aqueous solution is admin istered to the rabbits of common breed, the animals having been starved for about 18 hours.

Previously, an adequate amount of their blood had been taken by cardiopuncture, the samples being mixed with 3.8% trisodium citrate (ratio of citrate to blood = 1:9) in plastic tubes to determine the coagulation parameters before treatment. The parameters studied are the following: - Coagulation of collagen . % maximum coagulation coagulation slope - . latency time Coagulation of DPA . % maximum coagulation coagulation slope de-coagulation slope On considering the first results, it is noted that 1,1 dimethylprop-2-ynylamine acetylsalicylate exerts a certain inhibiting effect on the coagulation of the collagen.

This effect is demonstrated by a corresponding reduction in the percentage of maximum coagulation, the coagulation slope and a tendency of the latency time to increase.

With respect to DPA, the inhibition is significant. A decrease in the percentage of maximum coagulation and in the slope of coagulation are observed.

D. Therapeutic application Having been assured, by studies of the subacute and chronic toxicity on two species of animals, of the perfect tolerance of 1,1dimethylprop-2-ynylamine acetyl-salicylate, progression is made to clinical tests on volunteers. The active compound is used, in particular in the field of treatment for rheumatism, various algias and in cardiovascular therapeutics, especially in thrombosis cases.

The treatment is implemented by means of suitable pharmaceutical compositions in the form of powders and injectable solutions.

When administered orally, the active compound has the properties of acetyl-salicylic acid: it is analgesic, anti-inflammatory and anti-pyretic. Its gastric tolerance is studied particularly both from the clinical point of view and from the point of view or rigorous controls, such as gastroscopy, fibroscopy and bioscopy, investigated from bleeding in the digestive tract using traditional chemical tests or by marking the red blood corpuscles.

When administered parenterally, the use of the soluble form is an important advantage as regards efficiency and 1,1 -dimethylprop-2- ynylamine acetyl-salicylate is useful in the treatment of various algias and in cardiovascular therapeutics because of its anti-coagulation action.

WHAT WE CLAIM IS: 1. 1,1-Dimethylprop-2-ynylamine acetylsalicylate.

2. A process for preparing the compound according to claim 1, which comprises reacting acetyl-salicylic acid with 3-amino-3-methylbut-l-yne in solution, and isolating the product formed.

3. A process according to claim 2, wherein the product is isolated by lyophilisation.

4. A process according to claim 2, carried out substantially as described in Example 1 or Example 2 herein.

5. The compound according to claim 1 whenever obtained by a process according to any one of claims 2 to 4.

6. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 in admixture or conjunction with a pharmaceutically suitable carrier.

7. A composition according to claim 6 which is in solid form and wherein the active ingredient is lyophilised.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (7)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   C. Pharmacology (a) Anti-algetic properties (Writhing test, BOISSIER LVOFF, in In flarnmation Biochemistry and Drug Interaction, 1969). These properties were investigated in mice after oral administration. At a time t,, the first oral administration of half the dose of the compound to be studied was carried out.

   At a time t+2 hours, 2 mg of phenylbenzoquinone were injected intraperitoneally.

   Finally, at a time t+2.05 hours to 2.10 hours, a summary was made of the contortions in groups of 16 male mice weighing 20 g each.

   Compound ED5 0 mg/kg 1, i-dimethylprop-2- 36 ynylamine acetyl sali cylate lysine acetyl- 74 salicylate (b) Anti-coagulation activity 1,1 - dimethylprop - 2 - ynylamine acetylsalicylate, having demonstrated in vitro anticoagulation properties with respect to adeno sme diphosphonate and collagen, is tested for similar activity by administering the product intraperitoneally to rabbits.

   This species of animal was chosen more especially in order for conditions to be similar to those in studies in vitro which were carried out using plasmas rich in platelets from rabbits.

   20 mg of 1, 1-dimethylprop-2-ynylamine acetyl-salicylate in aqueous solution is admin istered to the rabbits of common breed, the animals having been starved for about 18 hours.

   Previously, an adequate amount of their blood had been taken by cardiopuncture, the samples being mixed with 3.8% trisodium citrate (ratio of citrate to blood = 1:9) in plastic tubes to determine the coagulation parameters before treatment. The parameters studied are the following: - Coagulation of collagen . % maximum coagulation coagulation slope - . latency time Coagulation of DPA . % maximum coagulation coagulation slope de-coagulation slope On considering the first results, it is noted that 1,1 dimethylprop-2-ynylamine acetylsalicylate exerts a certain inhibiting effect on the coagulation of the collagen.

   This effect is demonstrated by a corresponding reduction in the percentage of maximum coagulation, the coagulation slope and a tendency of the latency time to increase.

   With respect to DPA, the inhibition is significant. A decrease in the percentage of maximum coagulation and in the slope of coagulation are observed.

   D. Therapeutic application Having been assured, by studies of the subacute and chronic toxicity on two species of animals, of the perfect tolerance of 1,1dimethylprop-2-ynylamine acetyl-salicylate, progression is made to clinical tests on volunteers. The active compound is used, in particular in the field of treatment for rheumatism, various algias and in cardiovascular therapeutics, especially in thrombosis cases.

   The treatment is implemented by means of suitable pharmaceutical compositions in the form of powders and injectable solutions.

   When administered orally, the active compound has the properties of acetyl-salicylic acid: it is analgesic, anti-inflammatory and anti-pyretic. Its gastric tolerance is studied particularly both from the clinical point of view and from the point of view or rigorous controls, such as gastroscopy, fibroscopy and bioscopy, investigated from bleeding in the digestive tract using traditional chemical tests or by marking the red blood corpuscles.

   When administered parenterally, the use of the soluble form is an important advantage as regards efficiency and 1,1 -dimethylprop-2- ynylamine acetyl-salicylate is useful in the treatment of various algias and in cardiovascular therapeutics because of its anti-coagulation action.

   WHAT WE CLAIM IS: 1. 1,1-Dimethylprop-2-ynylamine acetylsalicylate.
2. 2. A process for preparing the compound according to claim 1, which comprises reacting acetyl-salicylic acid with 3-amino-3-methylbut-l-yne in solution, and isolating the product formed.
3. 3. A process according to claim 2, wherein the product is isolated by lyophilisation.
4. 4. A process according to claim 2, carried out substantially as described in Example 1 or Example 2 herein.
5. 5. The compound according to claim 1 whenever obtained by a process according to any one of claims 2 to 4.
6. 6. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 in admixture or conjunction with a pharmaceutically suitable carrier.
7. 7. A composition according to claim 6 which is in solid form and wherein the active ingredient is lyophilised.