MXPA99010901A - Salts of aromatic sulphonic acids - Google Patents

Abstract

The invention is a salt of the CNS-depressant trans-5- chloro-2,3,3a,12b-tetrahydro-2- methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole and a salt-forming agent, the latter being an aromatic sulphonic acid. The disclosed salt, preferably the besylate, has favourable properties. Thus it has the required insolubility and crytallinity in order to be suitable for use in depot injection preparations.

Description

SALTS OF AROMATIC SULPHONIC ACIDS The invention pertains to a salt of the compound trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz [2,3: 6,7] oxepino [4,5-c] pyrrole and a salt forming agent. Such salts are known. Thus, for example, the maleate of the above compound (Org 5222), as well as the preparation thereof, has been described in US 4, 145,434, the disclosure of which is incorporated herein by reference. The compound is described as having CNS depressant activity and anti-serotonin and antihistamine activities. The pharmacological profile of trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz [2,3: 6,7] oxepino [4,5-c] pyrrol , its kinetics and metabolism, as well as the first safety and efficacy studies in human volunteers and in schizophrenic patients were reviewed by De Boer et al. (Drugs of the Future 1993, 18 (12), 1 1 1 7-1 123). It has been established that Org 5222, which is trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz [2,3: 6,7] oxepino [4,5-c ] pyrrole (Z) -2-butenodiate (1: 1), is a very potent dopamine and serotonin antagonist, and antistamy only with potential antipsychotic activity. In view of the utility of the compound, it is desired that it be incorporated into pharmaceutical compositions of all types and, remarkably, those which are advantageous with respect to administering to patients suffering from mental disorders. Due to the varied nature of their illnesses, these patients often refuse to take their medicine or simply forget to take it, for example, as a result. { of apathy. In view of this, compounds such as the foregoing are highly desirable to be administered in the form of a depot preparation, ie, a pharmaceutical composition containing a dose of the drug sufficient for a prolonged time, eg, several weeks, and which, by means of sustained release, will perform its desired function for the central nervous system. However, the known compounds are not very suitable for use in such depot preparations. The main requirements for such use are that the compound is crystalline (otherwise the compound will be metastable, due to which it can not be predicted what is the amount of biologically desired compound at a certain time), and that it has a low solubility in water . The latter is important to achieve the sustained release required. For example, the maleate, (the (Z) -2-butenedioate Org 5222), which is crystalline, has a solubility of 3 mg / ml (21 ° C), which means that also higher doses, intended for Sustained controlled release, will be captured in the patient's blood immediately. The free base (org 33254) has a relatively low solubility of less than 0.1 mg / ml, but is unstable. The pamoate (Org 33388) is amorphous, the hemipamoate (Org 39058) is a mixture of amorphous and crystalline material. Additionally, it is desired that the melting point is not too low (preferably before 80 ° C), since it can lead to temperature-induced problems when making tablets or granules.

It has long been recognized in the art that there is no reliable way to predict the influence of a particular salt species on the behavior of the parent compound, see for example, J. Pharm. Sci. 66, 1 -1 9, 1 977. Consequently, the salt-forming agents are chosen empirically, and furthermore, in later literature, for example, International Journal of Pharmaceutics, 33 (1986 ) 201 -217, it has been recognized that, notably for properties such as hydroscopicity, stability and solubility, it is difficult to select the salt forming agent in advance. The same applies to the present compounds, the more since crystallinity is also required. Hence, an object of the present invention is to select a salt-forming agent for the above compound, which leads to this drug being substantially insoluble in water and crystalline. According to the invention, the selected salt-forming agent is an aromatic sulfonic acid. Although in principle any pharmaceutically acceptable aromatic sulfonic acid is suitable, some aromatic portions are clearly preferred. In this way, the aromatic portion may advantageously be of the type having a simple phenyl ring, the preferred salts of the invention being besylate and tosylate. In the alternative, it may be advantageous if the aromatic portion is unsubstituted (apart from the sulfonic acid group, of course). In this regard, not only the besylate is the preferred salt of the invention, but also the sulfonic acid of naphthalene is a suitable candidate for the acid, resulting in the corresponding napsylate. However, the most preferred salt of the invention is besilate. The salts of the present invention can be prepared analogously to those described in US 4, 145,434. For the preparation of the compound trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz [2,3: 6,7] oxepino [4,5-c] pyrrole, it is reference to said document. In order to obtain the desired salt, said compound can be dissolved in a suitable solvent, such as ethanol and then it can be mixed with a suitable solution of the aromatic sulfonic acid, preferably in the same solvent or in a solvent miscible with the solvent for said compound. The mixture can then be allowed to remain for a sufficient time to leave the corresponding salt according to the invention to crystallize (which occurs spontaneously). If desired, the crystals obtained can further undergo conventional steps of washing and drying and / or purification, for example, simple recrystallization followed by drying. Just like the known maleates, the compositions of the invention are useful for treating mammals, including humans, that suffer from all diseases susceptible to treatment by trans-5-chloro-2,3,3a, 1 2b-tetrahydro-2- methyl-1 H-dibenz [2, 3: 6,7] oxepin [4, 5-c] pyrrole. These diseases include mental disorders, such as tension, excitement, anxiety, psychosis and schizophrenia. The compositions can also be used for antidopamine, antihistamine and for diseases related to antiserotonin.

Thus, the salts of the present invention have utility as a medicine per se, and can be administered in any form, although, as described in WO 95/23600, peroral administration can lead to cardiotoxic side effects. Thus, other forms of administration are preferred, for example, subcutaneous administration, injection, or by means of a sublingual or buccal pharmaceutical composition as described in WO 95/23600. All these simple dosage forms of pharmaceutical compositions containing the salt of the present invention comprise a dosage unit of trans-5-chloro-2, 3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz (2, 3: 6,7] oxepino [4,5-c] pyrrole as an active ingredient A dosage unit may contain between 0.005 mg and 15 mg of the active ingredient Preferably, the dosage unit contains from about 0.03 to 0.50 mg of trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz (2,3: 6,7] oxepino [4,5-c] pyrrole Any pharmaceutically carrier material can be applied acceptable, suitable, and pharmaceutically acceptable auxiliaries can be added All of these pharmaceutically acceptable excipients, such as carriers and auxiliaries, are known to the person skilled in the art and do not require elucidation here, it is preferred, and is only possible as a result of the present invention, that the salt be administered by means of a reservoir injection, that is, at a higher dose than that in a simple dosage form. Normal doses for such preparations comprise 10 to 40 mg of the active ingredient. The deposit preparations of the present invention in their simplest form can comprise water as a carrier, preferably making the low aqueous solubility of the salt that is dispersed rather than dissolved. To facilitate making a stable dispersion, conventional auxiliaries can be used, for example, Tween (surfactant), propylene glycol, lecithin, etc. Other pharmaceutically acceptable carriers are also suitable, for example, carboxy methyl cellulose, gelatin, poly (vinyl pyrrolidone), or other well-known excipients. For support knowledge of deposit preparations reference is made to Leiberman, Rieger, Bunker, Pharmaceutical Dosage Forms: Disperse System. Volume 2. The invention is further illustrated with reference to the following examples.

EXAMPLE I A solution of 940 mg of benzene sulfonic acid in 15 ml of ethanol was added to a solution of 1.7 g of trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1. H-dibenz (2,3: 6,7] oxepino [4,5-c] pyrrole The crystallization occurred and the crystals obtained were collected and recrystallized from 75 ml of boiling ethanol, after cooling to 20 ° C. , the crystals were collected and dried under vacuum over calcium chloride and potassium hydroxide Yield: 1.9 g (72%) of trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl- 1 H-dibenz (2, 3: 6, 7) oxepino [4,5-c] pyrrole benzene sulfonate (besylate) This salt was found to have a melting point of 227.8 ° C and a solubility in water measured at 20 ° C. ° C of «1 mg / ml.

COMPARATIVE EXAMPLE The procedure of Example 1 was repeated, employing a large amount of different acids, all known for their convenience as a salt-forming agent for a drug. The results achieved are given in the following table: TABLE Sal Form Melt Solubility Point (° C) water (mg / ml) Crystalline Maleate 141 -145 3 Crystalline Fumarate 18.5-187 1 1 -hydroxy naphthoate Without crystallization - - Palmitate Without crystallization - - Amorphous Pamoate 130-240 < o .: Amorphous / crystalline Hemipamoate 167-168 < 0 .: Benzoate No crystallization - - 2-hydroxy benzoate No crystallization - - 4-acetyl amino No crystallization - -benzoate 3-hydroxy-2-naphthoate No crystallization _ _ 2-methoxy phenyl acetate No crystallization Clearly, the aromatic sulfonates of the invention form an exception in the combination of the desired properties of being crystalline, have a high melting point and exhibit such low water solubility as to be maintained insoluble in water.

EXAMPLE I I The procedure of Example I was repeated, replacing toluene-4-sulfonic acid with benzene sulfonic acid. In this way, the corresponding toluene sulfonate (tosylate) was obtained.

EXAMPLE 1 The procedure of Example I was repeated, substituting naphthalene-1-sulfonic acid and naphthalene-2-sulfonic acid for benzene sulfonic acid. In this manner, the corresponding naphthalene sulfonates (napsylates) were obtained.

Claims (9)

REIVI NDICATIONS

1 . A salt of trans-5-chloro-2, 3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz (2,3: 6,7] oxepino [4,5-c] pyrrole and a forming agent of salt, characterized in that the salt-forming agent is an aromatic sulfonic acid

2. A salt according to claim 1, characterized in that the aromatic portion of the aromatic sulfonic acid is a simple phenyl ring

3. A salt according to claim 2, characterized in that it is tosylate or besylate

4. A salt according to claim 1, characterized in that the aromatic portion of the aromatic sulfonic acid is unsubstituted

5. A salt according to claim 4, characterized in that it is Napsylate or besylate

6. The aromatic sulfonate of trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz (2,3: 6,7] oxepino [4,5-c ] pyrrole as a medicine

7. Trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz (2,3: 6,7] oxepino [4,5-c] besilate ] pyrrole as a medicine

8. A pharmaceutical composition comprising a a salt of trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz (2,3: 6,7] oxepino [4,5-c] pyrrole as a medicinally active compound and a pharmaceutically acceptable carrier, characterized in that the salt is an aromatic sulfonate.

9. A pharmaceutical composition according to claim 8, characterized in that the aromatic sulfonate is selected from the group consisting of tosylate, besylate, napsylate and mixtures thereof. 1 0. A depot injection preparation comprising an aromatic sulfonate of trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz (2,3: 6,7] oxepino [4 , 5-c] pyrrole and a pharmaceutically acceptable carrier suitable for use in depot injection preparations.