SALTS OF AROMATIC SULPHONIC ACIDS

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-lH-dibenz[2,3 :6,7]oxepino[4,5-c]pyrrole and a salt forming agent. Such salts are known. Thus, e.g., 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 antihistamine and antiserotonin activities. The pharmacological profile of trans-5-chloro-2JJaJ2b-tetrahydro-2-methyl-lH- dibenz[2,3 :6,7]oxepino[4,5-c]pyrrole, 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 17-1 123). It has been established that Org 5222, which is trans-5-chloro-2,3,3aJ2b-tetrahydro-2-methyl-lH- dibenz[2,3:6,7]oxepino[4,5-c]pyrrole(Z)-2-butenedio :e (1 : 1), is a very potent dopamine and serotonin antagonist and antihistaminic with potential antipsychotic activity. In view of the compound's utility, it is desired for it to be incorporated into pharmaceutical compositions of all kind and, notably, those that are advantageous with regard to administering to patients suffering from mental disorders. Due to the vary nature of their disease, these patients frequently refuse to take their medicine or simply forget to take it, e.g. as a result of apathy. In view hereof, it is highly desired for compounds such as the above, to be administered in the form of a depot preparation, i.e. a pharmaceutical composition containing a dose of the medicine sufficient for a prolonged time, e.g. several weeks, and which by means of sustained release will perform its desired function to the central nervous system. The known compounds, however, are not very well suitable for use in such depot preparations. The main requirements for such a use are that the compound is crystalline (otherwise the compound will be metastable, due to which it cannot be predicted what, at a certain point in time, the amount of biologically desired compound is) and that it has a low solubility in water. The latter is important for attaining the required sustained release. E.g. 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 controlled sustained release, will be taken up in the patient's blood immediately. The free base (Org 33254) has ' a relatively low solubility of less then 0.1 mg/ml, but is instable. The pamoate (Org 33388) is amorphous, the hemipamoate (Org 39058) is a mixture of amorphous and crystalline material. Further, it is desired that the melting point is not too low (preferably above 80°C), as this may lead to temperature-induced problems when making tablets or granules. For long it has been recognized in the art that there is no reliable way of predicting the influence of a particular salt species on the behaviour of the parent compound, see e.g. J.Pharm.Sci. 66, 1-19, 1977. Salt-forming agents are therefore generally chosen empirically, and also in later literature, e.g. International Journal of Pharmaceutics, 33 (1986) 201-217, it has been recognized that, notably for properties such as hygroscopicity, stability and solubility, it is difficult to select the salt forming agent beforehand. The same holds for the present compounds, all the more since also crystallinity is required. Hence it is an object of the present invention to select a salt-forming agent for the above compound which leads to this pharmacon being substantially water-insoluble, and crystalline. According to the invention the salt-forming agent selected is an aromatic sulphonic acid. Although in principle any pharmaceutically acceptable aromatic sulphonic acid is suitable, some aromatic moieties are clearly preferred. Thus the aromatic moiety may advantageously be of the type having a single phenyl ring. Preferred acids of this type being benzene sulphonic acid and toluene sulphonic acid, the preferred salts of the invention are the besylate and the tosylate. In the alternative, it may be advantageous for the aromatic moiety to be unsubstituted (apart from the sulphonic acid group of course). In this respect not only the besylate is the preferred salt of the invention, but naphthalene sulphonic acid is also a suitable candidate for the acid, resulting in the corresponding napsylate. However, the most preferred salt of the invention is the besylate. 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-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole reference is made to said document. In order to obtain the desired salt, said compound can be dissolved in a suitable solvent, such as ethanol and then be mixed with a solution of the appropriate aromatic sulphonic acid, preferably in the same solvent or in a solvent miscible with the solvent for said compound. The mixture then can be allowed to stand for sufficient time to let the corresponding salt according to the invention crystallize (which occurs spontaneously). If desired the obtained crystals can further undergo conventional washing and drying and/or purifying steps, e.g. simple recrystallization followed by drying. Just as the known maleates, the compositions of the invention are useful in treating mammals, including humans, suffering from all diseases susceptible to treatment by trans- 5-chloro-2J,3aJ2b-tetrahydro-2-methyl-lH-dibenz[2J :6,7]oxepino[4,5-c]pyrrole. These diseases include mental disorders, such as tension, excitation, anxiety, psychosis, and schizophrenia. The compositions may also be used for antidopamine, antihistamine and for antiserotonin related diseases. Hence, the salts of the present invention have a utility as a medicine per se, and they may be administered in any form, although, as described in WO 95/23600, peroral administration may lead to cardiotoxic side-effects. Thus other forms of administration are preferred, e.g. subcutaneous administration, injection, or by means of sublingual or buccal pharmaceutical composition as described in WO 95/23600. All of these single dosage forms of pharmaceutical compositions containing the salt of the present invention comprise one dosage unit of trans-5-chloro-2,3,3a, 12b-tetrahydro-2- methyl-lH-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 of from about 0.03 to 0.50 mg of trans-5-chloro-2,3,3a, 12b-tetrahydro-2- methyl-lH-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole. Any suitable, pharmaceutically acceptable carrier material may be applied, and pharmaceutically acceptable auxiliaries 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 only possible as a result of the present invention, that the salt be administered by means of a depot injection, i.e. at a dose higher than that in a single dosage form. Typical doses for such preparations comprise 10 to 40 mg of the active ingredient. The depot preparations of the present invention in its simplest form may comprise water as a carrier, the low aqueous solubility of the salt of course making it preferable for it to be dispersed rather than dissolved. To facilitate making a stable dispersion, conventional adjuvants may be used, e.g. Tween (surfactant), propylene glycol, lecithin, etc. Other pharmaceutically acceptable carriers are also suitable, e.g. carboxy methyl cellulose, gelatin, poly(vinyl pyrrolidone), or other well-known excipients. For background knowledge of depot 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 sulphonic acid in 15 ml of ethanol was added to a solution of 1.7 g of trans-5-chloro-2,3,3aJ2b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]- oxepino[4,5-c]pyrrole. 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 in vacuo over calcium chloride and potassium hydroxide. Yield: 1.9 g (72%) of trans-5-chloro-2,3,3a, 12b-tetrahydro-2-methyl-lH-dibenz[2,3:6,7]oxepino[4 > 5- cjpyrrole benzene sulphonate (besylate). This salt was found to have a melting point of 227.8°C and a solubility in water measured at 20°C of «1 mg/ml. COMPARATIVE EXAMPLE The procedure of Example 1 was repeated, employing a great many different acids, all known for their suitability as a salt-forming agent for a pharmacon. The results attained are given in the following table: TABLE Salt Form Melting Solubility in water point (°C) (mg/ml) maleate crystalline 141-145 3 fumarate crystalline 185.5-187 1 1 -hydroxy no crystallization - - naphthoate palmitate no crystallization - - pamoate amorphous 230-240 <0.35 hemipamoate amorphous /crystalline 167-168 <0.25 benzoate no crystallization - - 2-hydroxy no crystallization - - benzoate 4-acetyl anύno no crystallization - - benzoate 3-hydroxy-2- no crystallization - - naphthoate 2-methoxy phenyl no crystallization - - acetate Clearly, the aromatic sulphonates of the invention form an exception in combining the desired properties of being crystalline, having a high melting point and displaying such a low solubility in water as to be held water-insoluble. EXAMPLE II The procedure of Example I was repeated, substituting toluene-4-sulphonic acid for benzene sulphonic acid. Thus the corresponding toluene sulphonate (tosylate) was obtained. EXAMPLE III The procedure of Example I was repeated, substituting naphthalene- 1 -sulphonic acid and naphthalene-2-sulphonic acid for benzene sulphonic acid. Thus the corresponding naphthalene sulphonates (napsylates) were obtained.

Claims: Claims: 1. A salt of trans-5-chloro-2J,3aJ2b-tetrahydro-2-methyl-lH-dibenz[2J:6,7]oxepino- [4,5-c]pyrrole and a salt forming agent, characterized in that the salt forming agent is an aromatic sulphonic acid. 2. A salt according to claim 1, characterized in that the aromatic moiety of the aromatic sulphonic acid is a single phenyl ring. 3. A salt according to claim 2, characterized by being the tosylate or besylate. 4. A salt according to claim 1, characterized in that the aromatic moiety of the aromatic sulphonic acid is unsubstituted. 5. A salt according to claim 4, characterized by being the napsylate or besylate. 6. The aromatic sulphonate of trans-5-chloro-2,3,3aJ2b-tetrahydro-2-methyl-lH- dibenz[2,3:6,7]oxepino[4,5-c]pyrrole as a medicine. 7. Trans-5 -chloro-2-methyl-2, 3 ,3 aJ 2b-tetrahydro- 1 H-dibenz[2,3 : 6, 7] oxepino [4,5- cjpyrrole besylate as a medicine. 8. A pharmaceutical composition comprising a salt of trans-5-chloro-2,3,3a,12b-tetra- hydro-2-methyl-lH-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 sulphonate. 9. A pharmaceutical composition according to claim 8, characterized in that the aromatic sulphonate is selected from the group consisting of tosylate, besylate, napsylate, and mixtures thereof. 10. A depot injection preparation comprising an aromatic sulphonate of trans-5-chloro- 2,3,3a, 12b-tetrahydro-2-methyl-lH-dibenz[2,3 :6,7]oxepino[4,5-c]pyrrole and a pharmaceutically acceptable carrier suitable for use in depot injection preparations.

Inventors: HEERES GERARDUS JOHANNES, VAN BAKEL FRANCISCUS HERMANUS, HEERES, GERARDUS, JOHANNES, VAN BAKEL, FRANCISCUS, HERMANUS, ANTONIUS, ADREANA
Applicants: AKZO NOBEL NV, BAKEL FRANCISCUS HERMANUS ANTO, HEERES GERARDUS JOHANNES, AKZO NOBEL N.V., HEERES, GERARDUS, JOHANNES, VAN BAKEL, FRANCISCUS, HERMANUS, ANTONIUS, ADREANA
Application year: 1998
Main classification: C07D491
IPC codes: A61K31, A61P25, A61P43, C07D491