SK70993A3 - Salts of 4-amino-3-acylquionoline derivative and their use as inhibitors of gastric acid secretion - Google Patents

Abstract

A compound of structure (I) in the form of a salt, a process for its preparation and pharmaceutical compositions comprising such a salt and its use in therapy.

Description

Field of the invention

The present invention relates to a salt of a 4-amino-3-acylquinoline derivative and to pharmaceutical compositions containing the same which are useful as inhibitors of gastric juice secretion.

BACKGROUND OF THE INVENTION

Quinoline derivatives capable of inhibiting gastric acid secretion are known. For example, EP 330 485 discloses a series of 4-amino-3-acylquinoline derivatives in which the quinoline is substituted at the 8-position with, for example, hydroxyalkyl and hydroxyalkoxy groups.

It has been shown that the compounds described in said patent dissolve poorly in water and, as a result, the potentially poor bioavailability of these compounds in vivo, and thus also the low and hardly reproducible level of therapeutic effect, is potentially low.

It has now been found that the problem of poor solubility can be overcome by using these compounds in the form of salts of a particular type. In addition, it is important to consider various factors in addition to physical properties, such as good solubility, for example when selecting these substances for therapeutic purposes.

Compounds with the desired level of activity and sufficient duration of action must be used. It has been shown that one of the compounds described in European Patent Specification no. 330 485, in the form of its certain salts, not only has the desired physical properties, for example sufficient solubility, but also has a sufficiently strong effect and a sufficiently long duration of action. Thus, the salts can be advantageously used for therapeutic purposes.

SUMMARY OF THE INVENTION

The present invention provides the salts of the 4-amino-3-acylquinoline of the novel derivative of formula (I)

(CH ₂ ) ₂ CH ₃

O _{(CH2) 2} OH (I), the salts may be formed by reacting a compound of formula I with a strong acid.

The term strong acid in this application means an acid with a pKa of less than 4.0. The nature of such acids is readily apparent to those skilled in the art, for example some inorganic acids such as δ hydrochloric acid and sulfonic acids such as alkylsulfonic acids such as methanesulfonic acid.

Particularly preferred salts of the invention are those formed by reaction with hydrochloric or methanesulfonic acid, i.e. 3-butyryl-4- (2-methyl-phenylamino) -8- (2-hydroxy-ethoxy) -quinoline hydrochloride and 3-butyryl-4. - (2-methylphenylamino) -8- (2-hydroxyethoxyquinoline mesylate).

The salts of the invention, in particular the above hydrochloride and mesylate, have an exceptionally fast dissolution rate as compared to the dissolution of the free base of Formula I. Therefore, where the free base has non-reproducible bioavailability due to the slow dissolution rate in vivo, it is believed that the salts of the invention will, due to their rapid solubility, have reproducible bioavailability and hence a greater effect at a given dose, making them suitable for medical use in humans.

The disclosed salts can be used to treat diseases of the stomach and intestinal tract in mammals, particularly humans. Use is possible, for example, in gastric and duodenal ulcers, in aspiratory pneumonia and in the Zol 1 inger-El1 ison syndrome. In addition, the salts can be used to treat other disorders where it is preferable to suppress gastric acid secretion, for example in patients with a history of alcoholism and in patients with gastroesophageal reflux (GERD).

For therapeutic use, these salts may be administered in the form of standard pharmaceutical compositions comprising said salts and a pharmaceutically acceptable carrier. Accordingly, the present invention provides pharmaceutical compositions which contain, as an active ingredient, the aforementioned salts together with a pharmaceutical carrier and which are intended for the treatment of the aforementioned diseases.

The salts of the present invention can be formulated into the same types of pharmaceutical compositions as those disclosed in European Patent Application Ser. 330 485.

Suitable daily dosages for an adult patient may be, for example, in the range of 1 to 1000 mg, preferably in the range of 1 to 500 mg, in the case of oral, subcutaneous or intramuscular administration, in the range of 0.1 to 100, preferably 0.1 up to 25 mg, wherein the salts are administered in unit doses of 1 to 4 times daily.

The salts may also be administered together with other active ingredients such as anacids, for example magnesium carbonate, magnesium hydroxide or aluminum hydroxide, with non-steroidal anti-inflammatory agents, with stereo-acting agents, with nitrite-binding agents or with other agents, used to treat gastric ulcers, such as prostanoids or β 1 -receptor antagonists, such as cimetidine.

The preparation of the salts according to the invention will be explained in the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

3-Butyryl-4- (2-methylphenylamino) -8- (2-hydroxyethoxy) -quinoline can be prepared as described in European Patent Application Ser. EP 330,485.

In the preparation of 3-butyryl-4- (2-methylphenylamino) -8- (2-hydroxyethoxy) quinoline hydrochloride 3-butyryl-4- (2-methylphenyl amino) -8- (2-hydroxyethoxy) quinoline is suspended in 100 ml of methanol at room temperature and then concentrated hydrochloric acid are added slowly until a clear solution is formed, then the solvent is evaporated. The residue is dissolved twice in 2-propanol and evaporated again and then recrystallized from a mixture of 2-propanol and ether to give 9.7 g of the title salt, m.p. 214-215 ° C.

Analysis for ^C 22 ^H 24 ^N 2 ° 3. HCl. 0.2 H ₂ 0 requires C 65.32, H 6.33, N 6.93% found C 65.50, H 6.21, N 6.88%

Example 2

Preparation of 3-butyryl-4- (2-methyl-phenyl-amino) -8- (2-hydroxy-ethoxy) -quinoline nmesylate g 3-butyryl-4- (2-methyl-phenyl-amino) -8- (2-hydroxy-ethoxy) The quinoline is suspended in 400 ml of ethyl acetate, the suspension is heated to 50 [deg.] C. and then 16.3 g of methanesulfonic acid are added with vigorous stirring. As the reaction mixture cools, the desired salt crystallizes, which salt is filtered off and washed with ethyl acetate to give 50.1 g of the title salt, m.p. 83-85 ° C.

Analysis for C 24 2 £ ^{Η Ν 2θ3} 'CH4O3S. calculated C 57.73, H 6.32, N 5.85% found C 57.78, H 6.28, N 5.84%.

Claims (8)

- 6 PATENT CLAIMS 1. Salts of a 4-amino-3-acylquinoline derivative of formula I (I) obtainable by reacting a compound of formula I with a strong acid. A salt according to claim 1, 3-butyryl-4- (2-methylphenylamino) 8- (2-hydroxyethoxy) quinoline hydrochloride. The salt of claim 1, 3-butyryl-4- (2-methylphenylamino) 8- (2-hydroxyethoxy) quinolysyl acetate. 4. A process for the production of a salt according to claim 1, wherein the compound of formula I is reacted with a strong acid. 5. A pharmaceutical composition for the treatment of gastric ulcers and for inhibiting gastric acid secretion, characterized in that it comprises, as its active ingredient, a salt according to claim 1 together with a pharmaceutically acceptable carrier. 6. A pharmaceutical composition according to claim 5 comprising 3-butyryl-4- (2-methylphenyl amino) -8- (2-hydroxyethoxy) quinoline hydrochloride and a pharmaceutically acceptable carrier. The salt of claim 1 for use in therapy. 8. 3-Butyryl-4- (2-methylphenylamino) -8- (2-hydroxyethoxy) quinoline hydrochloride for use in therapy.