A CHROMOGLYCIC ACID DERIVATIVE AND PROCESS FOR THE PREPARATION THEREOF

Abstract: A derivative of chromoglycic acid having the formula The process for the preparation thereof is based on the reaction of chromoglycic acid, or a salt thereof, with benzidamine in a polar solvent.

Description: The invention relates to a chromoglycic acid derivative, particularly dibenzidamine chromoglycate having the structural formula (I) The invention also relates to a process for the preparation of said derivative. The said process is characterised by reacting chromoglycic acid or an alkali salt thereof with benzidamine in the free base or strong acid salt form thereof, in a polar solvent. Preferably the salt is the hydrochloride and the said solvent is water, a low molecular weight alcohol or acetone. The reaction temperature may reach the boiling point of the solvent. Benzidamine is an amine, the full name of which is N,N-dimethyl-3-((1-(phenylmethyl)-1H-indazol-3-yl)oxy)-1-propanamine, which may give acid addition salts with strong acids such as the one to be found in commerce, the hydrochloride. Chromoglycic acid is 1,3-bis(2-carboxy-4-oxo-5-chromenyloxy)-2-propanol acid, also available in commerce or in sodium salt form. Disodium chromoglycate has been described (Vidal Dictionary, 1987) as having anti-asthmatic properties, preventing the release of chemical anaphylaxis mediators by stabilisation of the mast cell membrane where it inhibits the intracellular penetration of Ca⁺². Benzydamine has been described (Vidal Dictionary, 1987) as a non-steroidal anti-inflammatory drug having anti-inflammatory and antialgic activity and beneficial effects by way of the reduction of the vascular permeability, reduction of the edema in the exudative reactions and reduction of the inflammatory pain. Furthermore, Azuma et al. ( Shika Kiso Igakkai Zasshi, 26 , 1347, 1984) have described that benzydamine has a weak effect in the IgE-mediated PCA when compared with disodium chromoglycate and other NSAID's. Nevertheless, no potentiation of effects between both classes of compounds has been shown. The derivative obtained affords advantages over other salts of chromoglycic acid or of benzidamine, on sharing in one same structure membrane stabilising and anti-inflammatory properties respectively, thereby potentiating the antiinflammatory effect of benzidamine in immunity diseases, which does not occur in other chromoglycic acid or benzidamine derivatives. With the use of the product obtained, inflammatory, immunity and allergy processes, covering a wide range of diseases may be treated, with a multiple action not described up to date. The local tolerance has been studied in the rat, after topical application of the derivative, the product being observed to be well tolerated. For therapeutic use, benzidamine chromoglycate may be administered topically, orally, via rectum or parenterally. The active ingredient, dibenzidamine chromoglycate, according to the form of administration, will be found in an effective amount, depending on the necessary amounts of chromoglycic acid and benzidamine. Preferably, the dose levels will range from 100 to 1500 mg. When the reaction medium is an organic solvent, any alkali or ammonium chloride formed is removed by filtration and the salt is obtained by evaporation of the organic solvent. When the medium is aqueous, the salt is obtained by decantation. The salt is obtained in the form of an ambar coloured oil, which solidifies on subsequent removal of the solvent. To facilitate the understanding, certain embodiments of the process are described hereinafter. Example 1 A solution of 58.7 g of benzidamine hydrochloride in 300 ml of water was added slowly over a solution of 43.5 g of disodium chromoglycate in 400 ml of water. After stirring for one hour an ambar coloured oil was drawn off which, after decantation and drying gave 76.0 g of a very pale yellow powder. U.V. (methanol) : lambda max : 222 and 312 nm I.R. (KBr) : 3400, 2500, 1640, 1600, 1530, 1480, 1350, 1300, 1120, 1050, 880, 810, 740 and 700 cm⁻¹ Elementary analysis : Calculated (%) for C₆₁H₆₂N₆O₁₃: C : 67.39; H : 5.75; N : 7.73 Found: C : 67.09; H : 5.96; N : 7.76 Example 2 A suspension of 93.9 g of benzidamine hydrochloride and 69.6 g of disodium chromoglycate in 400 ml of methanol was heated to reflux. After two hours at reflux, the sodium chloride formed was removed by filtration. The methanol was removed in vacuo and 135.4 g of a fine powder similar to that of the previous Example was obtained.

Claims: A chromoglycic acid derivative having the structural formula I: A process for the preparation of a chromoglycic acid derivative, having the structural formula I characterised by reacting chromoglycic acid or an alkali salt thereof with benzidamine in free base or strong acid salt form in a polar solvent. The process of claim 2, characterised in that said salt is the hydrochloride. The process of claim 2 characterised in that said polar solvent is water, a low molecular weight alcohol or acetone.

Inventors: BUXADE VINAS, ANTONIO, Buxadé Vinas, Antonio
Applicants: LABORATORIOS VINAS S.A.
Application year: 1988
Main classification: C07D405
IPC codes: A61K31, A61P29, C07D231, A61P37, C07D311