MC1069A1 - 5-ACETYLSALICYLIC ACID DERIVATIVES AND MEDICINAL PRODUCTS CONTAINING THESE SUBSTANCES - Google Patents

Description

1

The present invention relates to acetylated compounds having medicinal properties, the synthesis of these compounds and their use in medicine.

The Applicant has indeed found that the 5 acetylated compounds of formula I defined below exerted in mammals, and in vitro on mammalian preparations, an inhibitory action on allergic reactions linked to the presence of reaginic antibodies of the type responsible for asthma in humans, and that this effect could be attributed to the suppression of the release of anaphylactic mediators.

In formula I

CH^CO —y_y— OH ( i )

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X denotes a carboxylic group or a salt of that group, an alkoxycarbonyl group whose alkyl portion may have from 1 to 6 carbon atoms, preferably from 1 to 4, or a carboxamide group optionally substituted at nitrogen 20 by one or two alkyl groups each having from 1 to 6 carbon atoms, preferably from 1 to 4, or by an acyl group having from 1 to 7 carbon atoms.

The inhibitory activity of compounds of formula I has been shown (a) by assays using the passive cutaneous anaphylactic response (APC assay) in which the cutaneous reaction produced by the interaction between the intravenously injected specific antigen and the cell-bound reagent antibody, which has been previously injected into the skin of a mammal, is measured (see, for example, Z. Ovary: 30 Fedne Proc. Amc Soc. exp. Biol0 24, 94 (1965))i 0>) by measuring the amount of histamine released by dextran and phosphatidylserine from peritoneal mast cells (see, for example, I. Britc J. Pharmac0 £0 137 (1974) and II. Science 121 1034 (1971)) e"k (°) By the determination of histamine 35 released from ground-up human lung tissue that was passively sensitized in vitro with a reaginic antibody introduced with the homologous antigen (Brc î£ed0 J. £,272 (1968)). The observed anti-allergic action is independent of any inhibitory effect on prostaglantin synthetase. The activity

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compounds of formula I have been shown by the above tests with solutions of the carboxylate anion.

For convenience, compounds of formula I in which X is an alkoxycarbonyl group will be referred to hereafter as "esters" of formula I, and similarly, compounds in which X is a possibly substituted carboxamide group will be called "amides" of formula I, and those in which X designates a salt of the carboxylic group will be called "salts" of formula I. Examples of formula I salts that may be used in pharmacy include ammonium salts, salts of alkali metals such as sodium and potassium, of alkaline earth metals such as magnesium and calcium, as well as salts of organic bases, for example, salts of amines such as triethylamine and diethylaminoethylamine, piperazine, and morpholine. Water-soluble salts are particularly of interest, especially those with a solubility of at least 1 mg/ml.

The anti-allergic activity of salts with the formula I 20 resides in the anion; the nature of the cation does not contribute to its activity, but naturally the cation must be suitable for medical uses.

Pharmaceutically acceptable cations for compounds of formula I include, for example, hydrogen and ammonium cations, alkali metal cations such as sodium and potassium, alkaline earth metal cations such as calcium and magnesium, and organic bases, for example alkylammonium and alkylamine cations such as triethanolamine and diethylaminoethylamine, as well as pipera-zinium and morpholinium cations.

Examples of carboxamide groups with suitable substituents are N-alkyl- and N,N-diallcyl-carboxamide groups whose alkyl portion can have from 1 to 6 carbon atoms, preferably from 1 to 40. Other substituted carboxamide groups are N-acyl-carboxamide groups whose acyl radical has from 1 to 7 carbon atoms, including the benzoyl radical.

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The preparation of compounds of formula I can be carried out by any method known for these compounds and for compounds having an analogous structure, for example by the methods described in the publications Berichte 10, 1776 5 (1897) and ftZî 156 (1914-). They are generally prepared by treating acetylsalicylic acid with a Lewis acid, for example aluminum chloride, or by acetylation of a compound 2-Z-PhOH, Z having the meaning indicated for formula I. The amides, esters, and salts of the acid can be obtained directly by the acetylation method or formed at

starting from the acid, with or without prior isolation thereof

Esters and amides can be prepared by any traditional method including the esterification of the acid or acid chloride with an alkanol or 15-aryl alcohol to form the corresponding alkyl or aryl ester, and the reaction of the acid or acid chloride with ammonia or an amine to obtain the corresponding 15-amide, possibly substituted.

Formula I compounds are of interest for the treatment or prophylaxis of allergic conditions in mammals, such as asthma and other allergic chest conditions, hay fever (allergic rhinitis), conjunctivitis, urticaria, and eczema. They are particularly useful for the treatment of type I hypersensitivity asthma to reaginic mediators (so-called "extrinsic" asthma), as well as so-called "intrinsic" asthma, for which no sensitivity to an extrinsic antigen can be demonstrated.

The importance of a prophylactic or therapeutic dose of a compound of formula I naturally depends on the nature and degree of the allergic condition to be treated, as well as the particular compound chosen and the route of administration. In general, the dose will be between 2 µg and 100 µg per kg of body weight in a mammal.

35 In the case of an allergic condition as defined above, for example allergic asthma, a suitable dose will be 20 µg to 0.5 mg, for example about 0.1 to 0.5 mg of active substance, per kg of body weight of the patient being treated, when the treatment is carried out by administration

pulmonary as described below. In the case of a drug for intravenous administration,

The appropriate doses are 0.2 to 10 mg/kg (preferably 1 to 5 mg)d and in the case of administration by the oral route, the appropriate doses are 1 to 50 mg/kg, preferably 5 to 40 mg/kg, better still, about 10 mg/kg.

If a composition is used for nasal or ocular administration, for example in the treatment of allergic rhinitis, appropriate doses are 0.5 to 1025 mg of a compound of formula I per patient.

The pharmaceutical compositions or medicinal products according to the present invention comprise a compound of formula I as the active ingredient and may also contain a vehicle for pharmaceutical uses, optionally with other ingredients 15 having a therapeutic action0. These medicinal products include compositions for administration by the oral, rectal,

ophthalmic, pulmonary, nasal, dermal, topical or parenteral (hypodermic, intramuscular and intravenous),

but the best route of administration, for a given particular case, depends on the nature and degree of the disease

to be treated, as well as the nature of the active ingredient. These medications can easily be presented in dose units and prepared according to all the well-known methods of pharmacy.

25 These medicinal products for oral administration may be presented in the form of dosing units such as capsules, caplets or tablets, each containing a specified amount of the active substance, in solution or suspension in an aqueous or non-aqueous liquid or in an oil-in-water or water-in-oil emulsion. Each dosing unit will advantageously contain from 50 to 500 mg of the active ingredient.

A particularly interesting form of medication for the treatment of allergic asthma is a composition for administration via the pulmonary route, through the oral cavity, preferably in particles with a diameter of 0.5 to 7 microns, or even better, 1 to 6 microns, containing the active ingredient, which are introduced into the patient's lungs. These compositions are advantageously presented as dry powders for administration using a device.

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for inhalation of powders or self-propelled powder containers, the powder preferably comprising particles containing the active ingredient, of which at least 98% by weight have a diameter greater than 0.5 µm and at least 95% by number have a diameter less than 7 µm. Preferably, at least 95% by weight of the particles will have a diameter greater than 1 µm and at least 90% by number have a diameter less than 6 µm.

The compositions in the form of dry powders 10 will preferably include a fine solid powder as a diluent and will be advantageously presented in pierceable capsules, for example of gelatin.

Self-propellant compositions may provide either a powder or the active ingredient in the form of a solution or suspension. Those providing a powder comprise a liquid propellant with a boiling point below 18°C at atmospheric pressure, which may generally constitute from 50 to 99% of the composition, with the active substance representing from 0.1 to 20% by weight, for example, about 2%. In such compositions, the vehicle may comprise other constituents, in particular a nonionic liquid surfactant or an anionic solid surfactant, or a solid diluent (preferably in particles of the same order of magnitude as those of the active substance), or both. The surfactant may represent up to 20% of the composition's weight, but preferably less than 1%.

Self-propelled compositions in which the active ingredient is in solution comprise, along with the active ingredient, a propellant and a co-solvent, advantageously with an antioxidant stabilizer. The co-solvent may constitute from 5 to 40% of the composition's weight, but preferably less than 20%.

The medicinal products according to the present invention can also be presented in the form of aqueous solutions 35 or diluted alcoholic solutions, optionally sterile solutions, of the active ingredient, intended for use in a nebulizing or atomizing device.

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The medicinal products according to the invention for administration by the parenteral route advantageously comprise sterile aqueous solutions of the active substance, which are preferably isotonic with the blood of the patient to be treated 5 and which advantageously comprise a preservative such as thimerosalate

The following medicinal products for topical use include compositions suitable for administration to the skin, eyes, nose and mouth. The 10 medicinal products intended for use on the skin include lotions and creams containing liquid or semi-solid emulsions.

oil in water or water in oil, as well as ointments, preferably containing 0.2 to 5 / by weight by volume of the active substance. It is good that creams and ointments contain a preservative, for example methyl hydroxybenzoate.

Medicinal products intended for use in the eye include eye drops containing the active ingredient in aqueous or oily solution, and ointments preferably containing 0.2 to 5% by weight by volume of the active substance. The eye drops will advantageously be fungistatic and bacteriostatic and will preferably be prepared in a sterile manner.

Nasal medications 25 include powders, self-propelled compositions, and sprays similar to those described for pulmonary administration but having, when dispersed, somewhat larger particles, on the order of 10 to 200 microns. Other compositions for nasal administration 30 include a coarse powder in particles of 20 to 500 microns, which is taken like snuff, that is, by rapid inhalation through the nostrils using a container held near the nose. Another composition for nasal administration consists 35 of drops containing 0.2 to 5 by weight by volume of the active substance in aqueous or oily solution.

Medicinal products for topical use in the mouth include lozenges containing 10 to 100 mg of the active ingredient in a flavored vehicle, usually of

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sucrose with acacia gum or tragacanth gum, as well as lozenges comprising 10 to 100 mg of the active substance in an inert base such as gelatin and glycerol,

or sucrose and gum arabic.

3 Other ingredients having therapeutic activity, which may be included in the predicates, particularly in the case where these are intended for the treatment of allergic asthma, are for example bronchodilators such as isoprenaline, adrenaline, orciprenaline, isoethanine or their salts of addition with acids tolerated by the body, in particular isoprenaline sulfate, the proportion of the bronchodilator being advantageously from 0.1 to 50% of the weight of the active ingredient present.

Excluded from the scope of the present invention are non-sterile mixtures that are simple solutions or suspensions of known compounds of formula I in solvents or liquids known to be used in the synthesis and isolation of compounds by the methods described above. This invention includes known solutions and suspensions that can be administered to patients for treatment and that also contain at least one other pharmaceutically acceptable ingredient.

In summary, the invention includes, but is not limited to:

2^ 1. The compounds of formula I as they have been

defined above, insofar as these are new products.

2<> The synthesis of these compounds according to all known methods for their preparation as well as for the preparation of compounds having an analogous chemical structure.

3. Medicinal products comprising a compound of formula I with a vehicle for pharmaceutical uses, but excluding known aqueous solutions of sodium 5-acetylsalicylate not containing any other pharmaceutically acceptable ingredient.

4. Sterile injectable compositions comprising a compound of formula I with a vehicle for pharmaceutical uses and preferably a preservative.

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5. Compositions for oral administration, consisting of dose units each containing a determined quantity of a compound of formula I,

with a vehicle for pharmaceutical uses 0 60 A medicinal product containing 5-acetyl-

salicylic in mixture with a vehicle for pharmaceutical uses s o

7. A medicinal product comprising sodium 5-acetylsalicylate mixed with a vehicle for pharmaceutical uses, excluding aqueous solutions not containing any other pharmaceutically acceptable ingredient; 8. The preparation of the above medicinal products by all traditional methods of pharmacy; 9. The use of the compounds and medicinal products above-

15 above for the treatment or prophylaxis of allergic diseases in mammals.

10c Solid or semi-solid medicinal products comprising a compound of formula I in the form of a finely divided solid material with a solid or semi-solid vehicle for 20 pharmaceutical uses.

11. Tablets comprising a compound of formula I

in intimate mixture with a vehicle for pharmaceutical uses.

The following examples illustrate the present invention. 25 EXAMPLE 1 s

Syrup

Sodium salt of 5-acetylsalicylic acid 5*O S

Sucrose 50.0 g

JO Methyl Hydroxybenzoate 0.1 g

Glycerol 10.0 g

flavouring agent q.s.

Purified water per 100.0 ml.

Methyl hydroxybenzoate is dissolved in 35-50 ml of purified water at 80°C. Sucrose is added and dissolved, then the solution is allowed to cool. Glycerol, sodium 5-acetylsalicylate, and flavoring agent are then added along with the remaining water. The resulting syrup contains 250 mg of 5-acetylsalicylic acid in 5 ml.*

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EXAMPLE 2 s

Syrup suspension 5-α-ethylsalicylic acid fine powder 5.0 g

5. Sucrose. 50.0 g

Glycerol 10.0 g

Sodium saccharin 0.1 g

Tragacanth gum powder • 0.3 g

0.3 g of acacia gum powder

10 Methyl Hydroxybenzoate 0.1 g

flavouring agent q.s.

Purified water per 100.0 ml.

Tragacanth gum and acacia gum powders are dispersed in glycerol. This mixture is added to a solution of methyl hydroxybenzoate, sodium saccharin, and sucrose in water. 5-Acetylsalicylic acid is then added and dispersed. Finally, the flavoring agent is added, and the mixture is diluted to the desired volume. EXE3&PLE 3 s 20 Nasal Drops

Sodium salt of 5-acetylsalicylic acid 0.5 g Chlorbutol 0.5 g

Sodium chloride 0.5 g

Distilled water per 100.0 ml. 25 The ingredients are dissolved together in

90% of the required water, then the solution is diluted to the desired volume and filtered. EXAMPLE 4 - s

Eye drops 30 Sodium salt of 5-acetyl-

salicylic 0.5 g

Sodium chloride 0.6 g

Methyl hydroxybenzoate 0.1 g

Phenylethyl alcohol 0.5 ml

35 Distilled water per 100.0 ml.

Dissolve methyl hydroxybenzoate in 90 ml of water at 80°C, allow the solution to cool, then add the other ingredients, dilute the solution to the required volume, and sterilize by filtration.

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EXAMPLE 5 s

Injectable solution

Sodium salt of 5-acetylsalicylic acid 10.0 g

5 Water for injections per 100.0 ml

Chlorocresol 0.1 g.

The sodium salt is dissolved in water and diluted to the required volume. The solution is then sterilized by filtration and aseptically distributed into bottles, which are closed with a suitable rubber stopper and sealed. EXAMPLE 6

Pomma de

α-Acetylsalicylic acid fine powder 5.0 g

15 Soft white paraffin 95.0 g.

The acid is mixed with a little paraffin, and the mixture is triturated to form a smooth paste. This paste is then gradually incorporated into the remaining paraffin, and the resulting ointment is dispensed into metal tubes. 20 EXAMPLE 7

Tablet

5-Acetylsalicylic acid 250 mg

Lactose 100 mg

Starch 60 mg

25 Polyvinyi-pyrrolidone 10 mg

Magnesium stearate 5 mS

30

425 mg.

The acid is mixed with lactose and starch, the mixture is granulated with a solution of polyvinylpyrrolidone in water, then the granules are dried, magnesium stearate is mixed in and the mixture is pressed to form 4-25 mg tablets containing 250 mg of 5-acetylsalicylic acid.

EXAMPLE 8 î 35 Capsule

5-Acetylsalicylic acid 250 mg

Lactose 100 mg

Starch 30 mg.

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The powders are mixed together thoroughly and the mixture is used to fill hard gelatin capsules, each containing 250 mg of 5-acetylsalicylic acid.

EXAMPLE 9 î cj ' Anti-allergic activity

A. By operating on Y/istar rats, suspensions of peritoneal cells containing mast cells are prepared and incubated with a mixture of dextran and phosphatidylserine and the compound to be examined, namely 5-acetylsalicylic acid, following the procedures of Garland, L.G. & Mongar, J.L., Brit. J. Pharmac. £0 137-154 (1974) (see also Goth et al., Science 175 1034-5 (1971)). Then, the released histamine and residual histamine are titrated on the ileum of atropinized guinea pigs according to the method of Boura, A.L.A., Mongar, J.L. & Schill, H0O0 Drit, J. Pharmac., Chemother., 2. 24-30 (1954). Results

The histamine released is expressed as a percentage of the total histamine initially present (released + residual).

with correction for spontaneous release in the absence of

20 dextran and phosphatidylserine. For a concentration of -4

At 10 molars of 5-acetylsalicylic acid, a degree of inhibition of histamine release of 77% is obtained.

B0 The anti-allergic activity of 5-acetylsalicylic acid was studied by oral administration to rats, 25 following the method of Go-ose, J., et al., Immunology, 16, 749 (1969) but modified for a high diluted titer of reaginic antibodies produced according to Orr T.S.Co, et al., Immunology, 20, 185 (1971)-

The following results were obtained:

Dose: mg of medication

Degree of inhibition %

30 per kg of body weight & '

Way

300 oral 60

100 oral 57

35 30 oral 35

10 oral 28.

j^y

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EXAMPLE 10;

5,N-Diac ethylsalicylamide

One gram of 5-acetylsalicylamide is heated under reflux for 2 hours with 10 ml of acetic anhydride, then the solution is evaporated to a small volume at 60°C and 20 ml of ethanol is added. Upon cooling, white needles of 5-acetylsalicylamide are formed, which, after drying,

melt at 117~119°G.

5p-Diacetylsalicylamide is dissolved in 10% aqueous binormal ammonium hydroxide, and concentrated hydrochloric acid is added. 5'N-Diacetylsalicylamide precipitates, is separated by filtration, and recrystallized from ethanol. Melting point 198-200°C. EXAMPLE 11 s 15 5-Acetylsalicylic acid

It is prepared by hydrolysis of the ethyl ester with potassium hydroxide in ethanol for 5 hours. Acidification with concentrated hydrochloric acid gives the desired compound, melting point 218-219°C after recrystallization in ethanol.

EXAMPLE 12 S

5-Acetylsalicylamide

Methyl 5-acetylsalicylate is treated with ammonia, filtered, and the filtrate is acidified with concentrated hydrochloric acid, yielding the desired compound, with a melting point of 228-230°C after recrystallization in ethanol. EXAMPLE 13

5-Ethyl acetylsalicylate

30 Ethyl salicylate is slowly added to a stirred mixture of acetyl chloride and carbon disulfide to which aluminum chloride has been rapidly added. After heating under reflux and removal of the carbon disulfide by distillation, ice-cold water acidified with hydrochloric acid is added, then the oil formed is extracted with ether, the ether extract is washed with water and dried, then the ether is evaporated and the remaining solid matter is crystallized in ethanol, giving the desired compound, melting point 62-64°C.

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EXAMPLE 14:

sodium gi-Aoethylsalicylate

5-Acetylsalicylic acid is dissolved in water containing an equivalent amount of sodium hydroxide, the solution is filtered, and it is evaporated to dryness. The sodium 5-acetylsalicylate thus formed crystallizes in ethanol upon the addition of ether and then melts at 270-275°C, decomposing as it does so. Its infrared spectrum shows strong absorptions at 1359, 1392, 1450, 1587, 1629, and 1670 cm⁻¹.

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Claims (12)

CLAIMS 1 o - Medicinal product having in particular an anti-allergic action, characterized in that it comprises as an active ingredient a compound of formula I below CH-CO (\/) OH (I) in which X denotes a carboxylic group or a salt of that group, an alkoxycarbonyl group whose alkyl portion 10 may have from 1 to 6 carbon atoms, or a carboxamide group optionally substituted on the nitrogen by one or two alkyl radicals each having from 1 to 6 carbon atoms or by an acyl group having from 1 to 7 carbon atoms, with a vehicle for pharmaceutical uses s 0 2.- Medicinal product according to claim 1, characterized in that in the compound of formula I, X is a carboxylic group or a salt of this group, an alkoxycarbonyl group or a carboxamide group optionally substituted on the nitrogen by one or two alkyl radicals each having from 1 to 20 6 carbon atoms. 3o- Medicinal product according to claim 1, wherein the compound of formula 1 is 5-acetylsalicylic acid or a pharmaceutically acceptable salt of this acid. 40- Medicinal product according to any one of claims 1 to 3, wherein the salt is selected from sodium, potassium, ammonium and calcium salts. 5. "Medicinal product according to any one of claims 1 to 4, characterized in that it comprises a dose of a compound of formula I effective for anti-allergic prophylaxis" 60- Medicinal product according to any one of claims 1 to 5> in which the proportion of compound of formula I is suitable for administration to humans at a dose not exceeding 10 mg per kg of body weight, in particular at a dose of 2 to 5 mg per kg. 7- Medicinal product according to any one of claims 1 to 6, presented in the form of separate dosing units, each containing not more than 600 mg of the compound of formula I, in particular not more than 300 mg. 1580- Medicinal product according to any one of claims 1 to 7" presented in the form of tablets, capsules or caplets or "as sterile injectable compositions. 5 indications 1 to 7 days presented in a form suitable for administration by the intrapulmonary route, in which the compound of formula I is in the form of particles of 0.5 to 7 microns in diameter, in particular in the form of a self-propelled composition. 10 10o~ Tablet containing an anti-allergic dose of 5-ethylsalicylic acid or a pharmaceutically acceptable salt of this acid the compounds of formula I defined in claim 1, 15 insofar as these compounds are novel. OBIGIML comprising 16 sheets without cross-references, null words, or added words 9. Medicine according to any of the following claims 11. As new industrial products, 12. 5,N-Diacetylsalicylamide J4'h