Patent Application
20110039901
The present invention concerns a process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one of formula:
in all its stereochemical configurations, a co-crystal obtained by said process comprising 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and fumaric acid, and its use for the treatment of mood disorders, disorders of anxiety, depression, convulsive conditions, in the improvement of learning ability, in the reversal of amnesia, in resolving abstinence syndrome from medicaments and drugs.
The compound rel-(3R,3aS,7aS)-3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one, also known as BTG 1640, is described in international patent application WO93/17004 and belongs to a new family of psychoactive agents.
According to this document, the compound BTG 1640 is prepared as a yellow oil then salified as a hydrochloride salt.
Said preparation, which comprises the use of an oily free base for forming the hydrochloride salt, requires a complicated crystallization and purification stage for obtaining a pharmaceutical grade salt.
Thus, there is still a need for a BTG 1640 compound in crystalline form which is easy to prepare, i.e. that does not require difficult and lengthy crystallizations and hence can be easily scaled-up to industrial levels.
The object of the present invention is therefore to provide the compound BTG 1640 in crystalline form which responds to the need for an industrially scalable process.
Since the hydrochloride salt of BTG 1640 not only had preparation problems, but it was also unstable at temperatures above 30° C., the inventors of the present invention have turned their attention to alternative preparations to BTG 1640 hydrochloride.
The aforementioned object was hence attained through the selection of fumaric acid and the selection of reaction solvent(s).
The invention therefore concerns a process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one which comprises the step of reacting 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one with fumaric acid in one or more solvents, wherein at least one solvent is a solvent having a carbon atom number of from 3 to 6, said solvent being non-halogenated and having a dielectric constant ∈ in the range from 4 to 25.
In a preferred aspect, the invention concerns a process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one which comprises the step of reacting 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one with fumaric acid in a 2:1 molar ratio, in one or more solvents, wherein at least one solvent is a solvent having a carbon atom number of from 3 to 6, said solvent being non-halogenated and having a dielectric constant ∈ in the range from 4 to 25.
The inventors of the present invention have surprisingly found that the crystalline form compound of BTG 1640 obtained by the process of the invention is a co-crystal.
Another aspect of the invention, therefore, concerns a co-crystal comprising 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and fumaric acid.
In a further aspect of the invention, the co-crystal comprising 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and fumaric acid is used as a medicament.
In yet a further aspect of the invention, the co-crystal comprising 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and fumaric acid is used for the manufacture of a medicament for treating mood disorders, disorders of anxiety, depression, convulsive conditions, in the improvement of learning ability, in the reversal of amnesia, in resolving abstinence syndrome from medicaments and drugs.
The characteristics and advantages of the invention will be evident from the detailed description that follows and from the accompanying figures, in which:
The invention therefore concerns a process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one which comprises the step of reacting 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one with fumaric acid in one or more solvents, wherein at least one solvent is a solvent having a carbon atom number of from 3 to 6, said solvent being non-halogenated and having a dielectric constant ∈ in the range from 4 to 25.
The reaction between 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one and fumaric acid takes place in the presence of one or more solvents. In this respect, the inventors of the present invention have shown that they have obtained a compound in crystalline form by means of a process suitable for industrial scale-up, through the selection of at least one reaction solvent according to specific physical and structural characteristics.
Said reaction solvent is hence a non-halogenated solvent, having a carbon atom number of from 3 to 6 and having a dielectric constant ∈ in the range from 4 to 25.
The at least one solvent of the invention is preferably selected from the group consisting of diethylether, t-butyl-methyl-ether (MTBE), 1,2-dimethoxyethane, tetrahydrofuran (THF), diisopropylether, 4-methyl-2-pentanone, 2-methoxyethanol, 2-butanol, 2-methyl-1-propanol, 2-propanol, 2-butanone, 1-propanol, 1-butanol, acetone.
In the most preferred embodiment of the invention the at least one reaction solvent is selected from the group consisting of t-butyl-methyl-ether (MTBE), tetrahydrofuran (THF), 1-butanol, acetone. In said embodiment, advantageously, the yield of the crystalline form compound is in the range from 70% to 99%.
Advantageously, by using at least one solvent of the invention selected from the group consisting of t-butyl-methyl-ether (MTBE), tetrahydrofuran (THF), 1-butanol, acetone, the reaction between BTG 1640 and fumaric acid can be conducted with decidedly moderate amounts of solvents, i.e. a ratio of solvent volume/mmol of reacting fumaric acid in the range from 2 to 13, and preferably in the range from 2.8 to 12.2.
In a preferred aspect, the invention concerns a process for preparing a crystalline form compound of 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one which comprises the step of reacting 3-benzyl-2-methyl-2,3,3a,4,5,6,7,7a-octahydrobenzo[d]isoxazol-4-one with fumaric acid in a 2:1 molar ratio, in one or more solvents, wherein at least one solvent is a solvent having a carbon atom number of from 3 to 6, said solvent being non-halogenated and having a dielectric constant ∈ in the range from 4 to 25.
In the process of the invention fumaric acid is hence reacted with the BTG 1640 free base, preferably in a 1:2 ratio.
Preferably in the process of the invention fumaric acid is added under reflux to the solution consisting of the BTG 1640 free base dissolved in one or more solvents, said reflux conditions being maintained until a clear solution is obtained. The solution is then cooled to a temperature in the range from room temperature to −25° C. for a time varying from 3 to 24 hours.
Advantageously, if the at least one reaction solvent is methyl-t-butyl-ether (MTBE) or 1-butanol, yields higher than 70% can be obtained even at room temperature.
The compound in crystalline form which separates as a colourless compound can be optionally subjected to further purification cycles according to the known art techniques. The mother waters can possibly be evaporated and subjected to prolonged cooling with the aim of recovering more of the BTG 1640 and fumaric acid compound in crystalline form.
The compound in crystalline form which separates from the process of the invention is a co-crystal comprising fumaric acid and BTG 1640 free base.
As it will be demonstrated in the experimental part, the co-crystal of the invention is a crystalline molecular complex, i.e. a combination of the two molecules BTG 1640 and fumaric acid spatially disposed to create a single crystalline form.
The co-crystal of the invention was characterized by X-ray diffractometry carried out on both the powders and the single crystal.
X-ray powder diffractometry was used to obtain the observed experimental diffractogram shown in
More specifically, the diffractogram relating to the co-crystal of the invention exhibits characteristic peaks at the following diffractometer angles:
5.79°2θ
9.89°2θ
10.93°2θ
17.27°2θ
19.50°2θ
22.23°2θ
From the X-ray diffractometry on the single crystal, information on the structure and on the interatomic distances of the molecules involved was obtained, which confirmed the fact that the crystalline solid is a co-crystal consisting of two molecules of BTG 1640 and one of fumaric acid. Calculations on the data obtained from the diffraction analysis on the single crystal of BTG 1640 and fumaric acid co-crystal, have generated the calculated experimental diffractogram being devoid of any of the imperfections and background noise typical of microcrystalline powders. The calculated experimental diffractogram is given in is
According to the invention, the co-crystal is therefore obtained by a simple procedure, easily scalable to industrial levels and avoiding the use of lengthy and costly crystallization and purification steps, to obtain high yields of a stable pharmaceutical grade crystalline form.
The co-crystal comprising BTG 1640 and fumaric acid of the invention can be used as a medicament.
It can then be combined with a pharmaceutically acceptable carrier and, optionally, with suitable excipients, to obtain pharmaceutical compositions. The term “pharmaceutically acceptable carrier” includes solvents, diluents and the like which are used in the administration of the co-crystals of the invention.
Said pharmaceutical compositions can be parenterally, orally or topically administered.
Compositions of the present invention suitable for oral administration will be conveniently in the form of discrete units such as tablets, capsules, cachets, as powders or granules, or as a suspension in a liquid.
More preferably, the compositions of the invention for oral administration will be in the form of tablets.
The tablets will preferably comprise an amount from 1 to 100 mg, even more preferably from 1 to 50 mg, of the co-crystal comprising fumaric acid and BTG 1640.
Preferably the tablets will contain from 1.9% to 41.1% by weight of the co-crystal comprising BTG 1640 and fumaric acid and even more preferably the co-crystal comprising BTG 1640 and fumaric acid will constitute from 2.2% to 36% of the total tablet weight.
The tablets could also contain suitable excipients of common pharmaceutical use such as pre-gelatinized starch, microcrystalline cellulose, sodium starch glycolate, talc, lactose, magnesium stearate, sucrose, stearic acid, mannitol.
Compositions for parenteral administration will conveniently comprise sterile preparations.
Preparations for parenteral administration will preferably comprise an amount from 0.1 to 100 mg of co-crystal comprising fumaric acid and BTG 1640.
Compositions for topical administration will be conveniently in the form of creams, pastes, poultices, oils, ointments, emulsions, foams, gels, drops, aqueous solutions, spray solutions and transdermal patches.
Preparations for topical administration will preferably comprise an amount from 1 to 100 mg of co-crystal comprising fumaric acid and BTG 1640.
The co-crystal of the invention can be used for the production of a medicament for the treatment of mood disorders, disorders of anxiety, depression, convulsive conditions, in the improvement of learning ability, in the reversal of amnesia, in resolving abstinence syndrome from medicaments and drugs.
The invention will now be described in greater detail in the following examples, given by way of non-limiting illustration of the invention, relative to the process of the invention and to the characterization of the co-crystal obtained by the process.
0.8035 g of BTG 1640 free base (3.28 mmol) were placed in a 50 ml flask containing 10 ml of acetone; 0.190 g (1.64 mmol) of anhydrous fumaric acid were then added under reflux to the solution thus obtained. Reflux conditions were maintained until a clear solution was obtained. After cooling for 15 hours at a temperature of −20° C., the BTG 1640 and fumaric acid co-crystal separated from the solution (melting point between 110 and 120° C.) with a yield of 80%.
0.8036 g of BTG 1640 free base (3.28 mmol) were placed in a 50 ml flask containing 20 ml of tert-butylmethylether (MTBE); 0.190 g (1.64 mmol) of anhydrous fumaric acid were then added under reflux to the solution thus obtained. Reflux conditions were maintained until a clear solution was obtained.
After cooling for 15 hours at a temperature of −20° C., the BTG 1640 and fumaric acid co-crystal separated from the solution (melting point between 110 and 120° C.) with a yield of 92%.
0.8036 g of BTG 1640 free base (3.28 mmol) were placed in a 50 ml flask containing 20 ml of tert-butylmethylether (MTBE); 0.190 g (1.64 mmol) of anhydrous fumaric acid were then added under reflux to the solution thus obtained. Reflux conditions were maintained until a clear solution was obtained.
After cooling for 15 hours at a temperature of 4° C., the BTG 1640 and fumaric acid co-crystal separated from the solution (melting point between 110 and 120° C.) with a yield of 80%.
0.8035 g of BTG 1640 free base (3.28 mmol) were placed in a 50 ml flask containing 20 ml of tert-butylmethylether (MTBE); 0.190 g (1.64 mmol) of anhydrous fumaric acid were then added under reflux to the solution thus obtained. Reflux conditions were maintained until a clear solution was obtained. After cooling for 15 hours at room temperature, the BTG 1640 and fumaric acid co-crystal separated from the solution (melting point between 110 and 120° C.) with a yield of 73%.
0.624 g of BTG 1640 free base (2.54 mmol) were placed in a 100 ml flask containing 60 ml of diisopropylether; 0.147 g (1.27 mmol) of anhydrous fumaric acid were then added under reflux to the solution thus obtained. Reflux conditions were maintained until a clear solution was obtained. After cooling for 5 hours at a temperature of −20° C., the BTG 1640 and fumaric acid co-crystal separated from the solution (melting point between 110 and 120° C.) with a yield of 74%.
0.624 g of BTG 1640 free base (2.54 mmol) were placed in a 100 ml flask is containing 60 ml of diisopropylether; 0.294 g (2.54 mmol) of anhydrous fumaric acid were then added under reflux to the solution thus obtained. Reflux conditions were maintained for 2 hours after which the undissolved fumaric acid was separated by filtration. The clear solution was cooled for 5 hours at a temperature of −20° C., and the BTG 1640 and fumaric acid co-crystal (melting point between 110 and 120° C.) separated with a yield of 74%.
0.703 g of BTG 1640 free base (2.87 mmol) were placed in a 100 ml flask containing 60 ml of diisopropylether; 0.294 g (2.54 mmol) of anhydrous fumaric acid were then added under reflux to the solution thus obtained. Reflux conditions were maintained for 2 hours after which the undissolved fumaric acid was separated by filtration. The clear solution was cooled for 5 hours at a temperature of −20° C., and the BTG 1640 and fumaric acid co-crystal (melting point between 110 and 120° C.) separated with a yield of 75%.
From examples 5-7 the inventors of the present invention have shown there is no advantage in terms of yield by operating under conditions where one or other of the reagents is in excess, i.e. under conditions in which the molar ratio of BTG 1640 to fumaric acid is other than 2:1.
Advantageously in the process of the present invention the reagents BTG 1640 and fumaric acid will hence be reacted respectively in the stoichiometric ratio of about 2:1.
0.854 g of BTG 1640 free base (3.48 mmol) were placed in a 50 ml flask containing 10 ml of tetrahydrofuran; 0.202 g (1.74 mmol) of anhydrous fumaric acid were then added under reflux to the solution thus obtained. Reflux conditions were maintained until a clear solution was obtained. After cooling for 15 hours at a temperature of −20° C., the BTG 1640 and fumaric acid co-crystal separated from the solution (melting point between 110 and 120° C.) with a yield of 71%.
0.820 g of BTG 1640 free base (3.34 mmol) were placed in a 50 ml flask containing 10 ml of 1-butanol; 0.194 g (1.67 mmol) of anhydrous fumaric acid were then added under reflux to the solution thus obtained. Reflux conditions were maintained until a clear solution was obtained. After cooling for 4 hours at a temperature of −20° C., the BTG 1640 and fumaric acid co-crystal separated from the solution (melting point between 110 and 120° C.) with a yield of 99%.
The co-crystal obtained in example 1 was analysed to determine its structure. Specifically the colourless needle crystal of example 1, being 0.2×0.2×0.3 mm in size, was mounted on a glass fibre in a random orientation. The crystallographic data were collected at room temperature using a Nonius CAD-4 diffractometer, Mo-kβ radiation, α=0.71073 Å, with a graphite monochromator.
The cell parameters and an orientation matrix for data collection were obtained by the least-squares method using the setting angles of 25 reflections in the range 7°<θ<15°.
The space group was determined by means of the XPREP programme. The spacial group was P21/c. The structure was solved by direct methods and refined using the full-matrix least-squares method on F2 with the SHELX-97 programme.
The crystallographic data obtained are summarized in Table 2 below.
The results of the crystallographic analysis have demonstrated that in samples of the substance obtained in example 1, there is no transfer of hydrogen between the fumaric acid carboxyl groups and the nitrogen atom of the BTG 1640 free base confirming that the compound of the invention is a co-crystal of fumaric acid and BTG 1640.
An X-ray powder diffractogram was obtained from the same sample as example 10 by the X'Pert Pro analytical automated diffractometer equipped with X'Celerator, CuKα, using glass sample holders and 150 mg of substance, setting the voltage and amperage to 40 kV and 40 mA respectively. The programme used for collecting data was set to obtain the data within the 2 theta range from 3° to 40°.
The observed experimental diffractogram is shown in
The peaks are given in table 1 below:
The same analyses as in examples 10 and 11 were carried out on the samples obtained from preparative examples 2-9. The obtained results are in agreement with the results given in examples 10 and 11, confirming the fact that all the preparative conditions of examples 1-9 have resulted in the BTG 1640 and fumaric acid co-crystal according to the invention.
The process of the invention, being simple and of immediate industrial scale-up, has hence provided a new crystalline form which is a co-crystal comprising BTG 1640 and fumaric acid.
| Number | Date | Country | Kind |
|---|---|---|---|
| 08425287.3 | Apr 2008 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2009/054860 | 4/23/2009 | WO | 00 | 10/21/2010 |
