MX2008003257A - Sustained-release formulation comprising a glucuronate salt of a piperazine compound and uses thereof - Google Patents

Abstract

The present invention provides pharmaceutical compositions comprising a glucuronate salt of a piperazine compound, useful as a modulation of one or more GPCRs. In general, this salt form, and pharmaceutically acceptable compositions thereof, is useful for treating or lessening the severity of a variety of diseases or disorders including Parkinson's disease, stress/anxiety, Alzheimer's disease, Huntington's disease, panic disorders, obsessive compulsive disorder, eating disorders, drug addiction, social phobias, aggression or agitation, migraine, scleroderma and Raynaud's phenomenon, emesis, a Gl tract disorder related to the regulation of peristalsis, RLS, or prolactin secretion arising from tumours of the pituitary gland.

Description

SUSTAINED RELEASE FORMULATION COMPRISING SALT GLUCURONATE OF A COMPOUND OF PIPERAZINE AND USES OF THE SAME CROSS REFERENCE WITH RELATED APPLICATION This application claims the priority benefit of United States Provisional Patent Application 60 / 716,066, filed on September 12, 2005, the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION The present invention provides salt forms, and compositions thereof, useful as modulators of one or more GPCRs.

BACKGROUND OF THE INVENTION The family of G-protein coupled receptors (GPCRs) is the most extensive known family of genes, representing more than 1% of the human genome, and encompasses a wide range of biological functions (including several autocrine, paracrine and endocrine processes) . The GPCR superfamily is also the family of genes most exploited by the pharmaceutical industry for the development of therapeutic compounds. GPCRs have been classified into rhodopsin-like GPCRs, secretin-like GPCRs, cAMP receptors, fungal-coupled mating pheromone receptors, and the family of metabotropic glutamate receptors. The rhodopsin-like GPCRs themselves represent an extensive family of proteins that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with the guanine nucleotide binding proteins (G). Although their activating ligands vary widely in structure and character, the amino acid sequences of rhodopsin-like GPCRs are very similar and are presumed to adopt a common structural framework comprising 7 alpha-helices that extend through the membrane and are coupled to G proteins within the cell that dissociate from the receptor by binding to an agonist and initiate or inhibit the signaling mechanisms of second messengers. See: Lander et al. Nature 409: 860 (2001); Basic and clinical pharmacology, 8th Ed., Katzung. USA: The McGraw Hill Companies, Inc. (2001). The rhodopsin-like GPCR family includes several classes of receptors that are distributed in a variety of ways throughout the central nervous system (CNS) and many peripheral sites and have been implicated in a variety of CNS and neuropsychiatric conditions. Included within these receptors are dopamine ("D") receptors, and 6 of 7 major subtypes of serotonin receptors (5-hydroxytryptamine, "5HT") (the receptors of subtypes 5 ???, 2, and 4? 7 are GPCRs whereas 5HT3 subtype receptors are Na + / K + ion channels dependent on ligands). Dopamine neurons in the central nervous system of vertebrates are involved in the initiation and execution of movement, the maintenance of emotional stability, and the regulation of pituitary function. The binding of dopamine to the extracellular binding groove of the D receptors activates the G proteins - the D- and D5 receptor subtypes ("D-like") are linked to stimulatory G proteins, while the subtypes of receptors 2- 4 ("D2-like") are linked to inhibitory G proteins, D2-type receptors are found throughout the brain and in smooth muscle and presynaptic nerve terminals and have an inhibitory effect on neurotransmission when they are linked to an agonist Specifically, D2 receptors are abundant and disseminated in the striatum, the limbic system, the thalamus, the hypothalamus, and the pituitary gland.) Antagonists bound to D2 receptors inhibit the binding of agonists and thus prevent the inhibition of Descending signaling mechanisms: D2 receptor antagonists are used in the treatment of psychosis (eg, schizophrenia, mania, psychotic depression and depression). bipolar disorder), and show utility for short-term sedation in aggression or agitation (eg, amisulpride, clozapine, haloperidol, nemonapride, pimozide, remoxipride, spiperone, sulpiride) and may be useful for treating drug addictions, while the agonists of the D2 receptor are used in the treatment of Parkinson's disease and to suppress the secretion of prolactin generated by tumors of the pituitary gland (eg, apomorphine, bromocriptine, dihydroergotamine, piribedil, quinpirol), and to treat the syndrome of the legs restless (RLS; for example, pramipexole, ropinirole). See: Basic and clinical pharmacology, 8th Ed., Katzung. USA: The McGraw Hill Companies, Inc. (2001); Pharmacology, 4th Ed., Rang et al. Edinburgh, United Kingdom: Harcourt Publishers Ltd. (2001); Sedvall et al. The Lancet, 346: 743-749, (1995); Hietala. The Lancet, 346: 1 130-1 131 (1995); Kemppainen et al. Eur J Neurosci., 18: 149-154 (2003). 5-Hydroxytryptamine is ubiquitous in plants and animals. It is a neurotransmitter and local hormone important in the CNS and intestine, and is involved in a wide range of physiological and pathophysiological pathways. The binding of 5-hydroxytryptamine to the extracellular binding groove of 5-HT receptors activates G-proteins - it is known that subtype receptors 5HT! they are linked to inhibitory G proteins, while subtypes 2, 4, 6 and 7 are linked to stimulatory G proteins. Of these, it is known that the receptors of subtypes 51-1 ^ (at least 5 are known) are found first of all in the brain and in the cerebral blood vessels where they mediate the inhibition and neural vasoconstriction. Specific agonists to 5HTi receptors are used in the treatment of migraine (eg, sumatriptan) and in stress / anxiety treatment (eg, buspirone), whereas antagonists have been recommended in the treatment of psychosis (eg, spiperone, methiotepine). In addition, the regulation of subtype 5 receptors ??? It has been implicated in drug addiction, Alzheimer's disease, Parkinson's disease, depression, emesis and eating disorders. The 5HT2 subtype receptors (at least 3 are known) are found along the CNS and in many peripheral sites where they produce excitatory neuronal effects and on the smooth muscle. Antagonists of 5HT2 receptors are used in migraine therapy (eg, metisergide) and have shown potential in the treatment of scleroderma and Raynaud's phenomenon (eg, ketanserin). It is known that 5HT3 receptors occur primarily in the peripheral nervous system and antagonists are used as antiemetics (eg, ondansetron, tropisetron). 5HT4 receptors are found in the brain, as well as in the heart, bladder and gastrointestinal tract (Gl). Within the Gl tract, they produce neuronal excitation and mediate the effect of 5HT during the stimulation of peristalsis. Specific 5HT4 receptor antagonists are used to treat Gl disorders (eg, metoclopramide). The receptors of subtypes 5 (at least 5 are known), 6 and 7 of 5HT are also found throughout the CNS and may be potential targets for small molecule drugs. In particular, the 5HT7 subtype receptor has been implicated in depression, psychosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, migraine, stress / anxiety, eating disorders and emesis. See: Basic and clinical pharmacology, 8th Ed., Katzung. USA: The McGraw Hill Companies, Inc. (2001); Pharmacology, 4th Ed., Rang et al. Edinburgh, United Kingdom: Harcourt Publishers Ltd. (2001); Kleven et al. European Journal of Pharmacology, 281: 219-228 (1995); Pat. United States No. 5,162,375; Leone et al. Neuro Report, 9: 2605-2608 (1998); Pat. United States No. 4,771, 053; WO 01/52855; De Vry et al. European Journal of Pharmacology, 357: 1-8 (1998); Wolff et al. European Journal of Pharmacology, 340: 217-220 (1997); Alfieri et al. British Journal of Cancer, 72: 1013-1015 (1995); Wolff et al., Pharmacology Biochemistry and Behavior, 52: 571-575 (1995); Lucot. European Journal of Pharmacology, 253: 53-60 (1997); U.S. Patent No. 5,824,680; U.S. Patent No. 4,687,772; Rasmussen et al. Annual Reports in Medicinal Chemistry, 30: 1-9 (1995); WO 00/16777; U.S. Patent No. 4,438.1 19; Millan, Journal of Pharmacology and Experimental Therapeutics, 295: 853-861 (2000); WO 93/04681; Miyamoto, et al. Current Opinion in CPNS Investigational Drugs, 2:25 (2000); Hagger, et al. Biol. Psychiatry, 34: 702 (1993); Sharma et al. J. Clin. Psychopharmacol., 18: 128 (1998); Lee et al. J. Clin. Psychiatry, 55:82 (1994); Fujii, et al. J. Neuropsychiatry Clin. Neurosci., 9: 240 (1997); Mason et al. Eur. J. Pharmacol., 221: 397 (1992); Newman-Tancredi et al. Neuropharmacology, 35: 119, (1996); Sumiyoshi er al. J. Clin. Pharmacol., 20: 386 (2000); Carli et al. Eur. J. Neurosci., 10: 221 (1998); Meneses er al. Neurobiol. Learn. Mem., 71: 207 (1999); and Glennon er al. Neuroscience and Behavioral Reviews, 14: 3547 (1990). The action of 5HT at the synapse concludes by its Na + / K + mediated reuptake through the presynaptic membrane. 5HT reuptake inhibitors are used in the treatment of depression, stress / anxiety, panic disorders, obsessive-compulsive disorder, eating disorders and social phobias, (eg, citalopram, clomipramine, fluoxetine, fluvoxamine, indatralin, zimelidine) and may be useful in the treatment of migraine, psychosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, drug addiction, eating disorders, scleroderma and Raynaud's phenomenon, Gl tract disorders related to the regulation of peristalsis, and / or emesis. See: Basic and clinical pharmacology, 8th Ed., Katzung. USA: The McGraw Hill Companies, Inc. (2001); Pharmacology, 4th Ed., Rang er a /. Edinburgh, United Kingdom: Harcourt Publishers Ltd. (2001); Masson et al. Pharm. Rev. 51: 439 (1999); and in addition, the references of the preceding paragraphs. Accordingly, it would be desirable to provide compounds that modulate the GPCRs in a form suitable for administration to a patient in need of treatment for any of the disorders mentioned above. In particular, it would be desirable for said compounds to exhibit additional characteristics such as good solubility, stability and ease of formulation, etc.

BRIEF DESCRIPTION OF THE INVENTION It has been discovered that the novel salt forms of the present invention, and compositions thereof, are useful as modulators of one or more GPCRs and exhibit desirable characteristics for that. In general, these salt forms, and pharmaceutically acceptable compositions thereof, are useful for treating or decreasing the severity of a variety of diseases or disorders including, but not limited to, Parkinson's disease, psychosis (eg, schizophrenia, mania, psychotic depression, bipolar disorder), depression, stress / anxiety, Alzheimer's disease, Huntington's disease, panic disorder, obsessive-compulsive disorder, eating disorders, drug addiction, social phs, aggression or agitation, migraine, scleroderma, phenomenon of Raynaud, emesis, gastrointestinal tract disorders related to the regulation of peristalsis, RLS, or prolactin secretion generated by tumors of the pituitary gland.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 and table A depict the powder X-ray diffraction pattern for Form I of compound 2. Figure 2 represents the 1 H NMR spectrum of compound 2.

Figure 3 represents the 13C NMR spectrum of the compound 2. Figure 4 represents the spectrum of ?? NMR of compound 1. Figure 5 represents the powder X-ray diffraction pattern for Form I of compound 2. Figure 6 represents the DSC pattern for Form I of compound 2. Figure 7 represents the diffraction pattern X-ray powder for amorphous compound 2. Figure 8 represents the DSC pattern for amorphous compound 2. Figure 9 represents the powder X-ray diffraction pattern for Hydrate I of compound 2. Figure 10 represents the DSC pattern for Hydrate I of compound 2. Figure 1 1 represents the powder X-ray diffraction pattern for Hydrate II of compound 2. Figure 12 represents the DSC patterns for Hydrate I (upper sweep) and Hydrate II (lower sweep) of compound 2. Figure 13 represents the powder X-ray diffraction pattern for the methanolate of compound 2. Figure 14 represents the powder X-ray diffraction pattern for the compound Ethanolate I 2.

Figure 15 represents the powder X-ray diffraction pattern for Ethanolate II from compound 2. Figure 16 represents the DSC pattern for Ethanolate II from compound 2. Figure 17 represents the powder X-ray diffraction pattern for Isopropanolate I (+ DMF) of compound 2. Figure 18 represents the DSC pattern for Isopropanolate I (+ DMF) of compound 2. Figure 19 represents the powder X-ray diffraction pattern for Isopropanolate II of compound 2. Figure 20 represents the DSC pattern for Isopropanolate II of compound 2. Figure 21 represents the dust X-ray diffraction pattern for Acetonate of compound 2.

DETAILED DESCRIPTION OF THE INVENTION General description of certain aspects of the invention International patent application number PCT / EP / 00/08190 (International Publication Number WO 01/14330) discloses various indole-containing piperazine derivatives, which include compound 1 (8-. { 4- [3- (5-fluoro-1 H -indol-3-yl) -propyl] -piperazin-1-yl] -2-methyl-4H-benzo [1,4] oxazin-3-one , presented), which exhibit antagonist activity at the D2 receptors and inhibitory activity against the reuptake of 5HT in therapeutic models.

Additionally, compound 1 is active in therapeutic models that are sensitive to relevant antipsychotics, antidepressants and anxiolytics for clinical use, as well as in Parkinson's disease. Accordingly, compound 1 is useful for treating Parkinson's disease, psychosis (eg, schizophrenia, mania, psychotic depression, bipolar disorder), depression, stress / anxiety, panic disorders, Alzheimer's disease, obsessive-compulsive disorder, eating disorders, drug addiction, social phobias, aggression or agitation, migraine, scleroderma and Raynaud's phenomenon, emesis, gastrointestinal tract disorders related to the regulation of peristalsis, RLS, and to suppress prolactin secretion generated by tumors of the pituitary gland. In addition, compound 1 has a low propensity to induce catalepsy in rodents and is therefore less prone to induce extrapyramidal side effects than currently existing antipsychotics. See: WO 01/14330; van der Heyden and Bradford. Behav. Brain Res. 31: 61 (1988); van der Poel er a /. Psychopharmacology, 97: 147 (1989); and Ungerstedt. Acta Physiol. Scand. 82: (suppl 367) 69 (1971). It would be desirable to provide a salt form of compound 1 which, compared to compound 1, imparts characteristics such as improved aqueous solubility, stability and ease of formulation. In particular, the improved aqueous solubility would be advantageous by the provision of an improved solution in the Gl tract, thereby improving absorption and bioavailability. The improved bioavailability would allow a lower dose, which could produce fewer adverse effects Gl such as nausea or emesis. The lower dosage could also allow the development of a smaller dosage form (eg, tablet, capsule) which would be beneficial from the point of view of the drug process and would increase patient adherence (i.e., patients prefer to ingest tablets or smaller capsules). In addition, a once-a-day dosage form would also increase the patient's adherence over a multiple dose, which is an important consideration for the relevant patient population such as individuals suffering from schizophrenia or other psychoses. Accordingly, the present invention provides the glucuronate salt of compound 1 in a form suitable for extended release formulation, which would have the added benefits of reducing the adverse effects of the upper Gl tract such as nausea or emesis by limiting the amount of drug there released and avoiding receptors in the upper Gl tract that are responsible for such effects.

According to one embodiment, the present invention provides a glucuronate salt of compound 1, represented by compound 2: 2 Those of ordinary skill in the art will appreciate that glucuronic acid and compound 1 are ionically bound to form compound 2. It is contemplated that compound 2 can exist in a variety of physical forms. For example, compound 2 can exist in the form of solution, suspension, or in solid form. In certain embodiments, compound 2 is in solid form. When compound 2 is in solid form, said compound may be amorphous, crystalline, or mixtures thereof. The solid forms for exemplifying are described in more detail below. As used herein, notwithstanding the structure of compound 2 depicted above, the phrase "glucuronic acid salt," and related terms, refers to the salt of D-glucuronic acid, the salt of L-glucuronic acid, the salt of DL-glucuronic acid, or mixtures thereof. In certain embodiments, compound 2 is the salt of D-glucuronic acid. In other embodiments, compound 2 is the salt of D-glucuronic acid substantially free of the salt of L-glucuronic acid, where "substantially free" means that the compound does not contain a significant amount of the salt of L-glucuronic acid. . In certain embodiments, at least about 95% by weight of compound 2 is present as the salt of D-glucuronic acid. In still other embodiments of the invention, at least about 99% by weight of compound 2 is present as the salt of D-glucuronic acid. Those of ordinary skill in the art will recognize that glucuronic acid may exist in the cyclic form, as depicted above, or in an open ring form.Therefore, the present invention contemplates that the glucuronate salt, compound 2, includes the salt forms of the cyclic glucuronic acid and the salt forms of the ring-opened glucuronic acid In other embodiments, the present invention provides the compound 2 substantially free of impurities. As used herein, the term "substantially free of impurities" means The compound does not contain a significant amount of foreign matter, such foreign matter may include excess glucuronic acid, excess of compound 1, residual solvents, or any other impurity that may result from the preparation and / or isolation of compound 2. In certain embodiments, is present, at least about 95% by weight of compound 2. In In other embodiments of the invention, at least about 99% by weight of compound 2 is present.

According to one embodiment, the compound 2 is present in an amount of at least about 97, 97.5, 98, 98.5, 99, 99.5, 99.8% by weight where the percentages are based on the total weight of the composition. According to another embodiment, compound 2 contains no more than about 2.0% per HPLC area of total organic impurities and, in certain embodiments, no more than about 1.5% per HPLC area of total organic impurities relative to the total area of the HPLC chromatogram. In other embodiments, compound 2 contains no more than about 0.6% per HPLC area of any individual impurity, and, in certain embodiments, no more than about 0.5% per HPLC area of any single impurity, relative to the total area of the chromatogram. of HPLC. The structure depicted for compound 2 is also intended to include all isomeric (e.g., enantiomeric or conformational) forms of the structure. For example, the R and S configurations in the stereogenic carbon are included in this invention. Therefore, the individual stereochemical isomers as well as the enantiomeric and conformational mixtures of the present compound are within the scope of the invention. further, all tautomeric forms of compound 2 are within the scope of the present invention. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the compounds having the present structure are within the scope of this invention, except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by carbon enriched in 13C or 14C.

Solid forms of compound 2: It has been found that compound 2 can exist in a variety of solid forms. Said forms include pure crystalline forms, also called polymorphs, solvates, hydrates and amorphous. All of said forms are contemplated within the present invention. In certain embodiments, the present invention provides compound 2 as a mixture of one or more solid forms selected from polymorphs, solvates, hydrates and amorphous of compound 2. As used herein, the term "polymorph" refers to different structures crystalline (of unsolvated forms) where a compound can crystallize. As used herein, the term "solvate" refers to a crystalline form where a stoichiometric or non-stoichiometric amount of solvent is incorporated into the crystal structure. Similarly, the term "hydrate" refers to a crystalline form where a stoichiometric or non-stoichiometric amount of water is incorporated into the crystal structure. In certain embodiments, compound 2 is a crystalline solid. In other embodiments, compound 2 is a crystalline solid substantially free of amorphous compound 2. As used herein, the term "substantially free of amorphous compound 2" means that the compound does not contain a significant amount of amorphous compound 2. In certain embodiments, at least about 95% by weight of the compound 2 is present. In still other embodiments of the invention, at least about 99% by weight of the crystalline compound 2 is present. In certain embodiments, compound 2 is a pure crystalline form and thus has no water or solvent incorporated in the crystal structure. It has been found that compound 2 can exist in at least two distinct pure, or polymorphic, crystalline forms. Two of said polymorphic forms are referred to herein as Form I and Form II. In certain embodiments, the present invention provides Form I of compound 2. According to one aspect, Form I of compound 2 has a powder X-ray diffraction pattern substantially similar to that shown in Figure 1 and Table A or Figure 5. According to another embodiment, Form I of compound 2 is characterized by having one or more peaks in its powder X-ray diffraction pattern selected from those at about 1 7.5, 22.5, 19.9, 3.9, and 12.2 degrees 2 -theta. As used herein, the term "approximately", when used in reference to a value in 2-theta degrees refers to the indicated value ± 0.1 degrees 2-theta. The methods for preparing Form I of compound 2 are described below.

TABLE A PEAK SEARCH REPORT (5 PEAKS, MAX P / N = 23.1) [98 Glucuronate.RAW] Glucuronic 98 PEAK: 35-pt / Parabolic Filter, Threshold = 9.0, Cut = 0.1%, BG = 3 / 1.0, Peak Superior = Top In other embodiments, the present invention provides Form II of compound 2. According to another embodiment, Form II of compound 2 has a characteristic peak in its powder X-ray diffraction pattern selected from those at approximately 18.7 degrees 2 theta. The methods for preparing Form II of compound 2 are described below. According to another embodiment, the present invention provides compound 2 as an amorphous solid. The powder X-ray diffraction pattern of amorphous compound 2 is depicted in Figure 7. Amorphous solids are well known to those of ordinary skill in the art and are typically prepared by methods such as lyophilization, melting and precipitation. supercritical fluid, among others. Other methods for preparing amorphous compound 2 are described below. It has been found that compound 2 can exist in at least two hydrate forms. The two hydrate forms are referred to herein as Hydrate I and Hydrate II. In certain modalities, the present invention provides the Hydrate I of compound 2. According to one embodiment, Hydrate I is characterized by having one or more peaks in its powder X-ray diffraction pattern selected from those at approximately 9.49, 16.40 and 17.61 degrees 2-theta. According to one aspect, the Hydrate I of compound 2 has a powder X-ray diffraction pattern substantially similar to that shown in Figure 9. The methods for preparing Hydrate I of compound 2 are described below. Table 1 a Next, it shows the X-ray diffraction peaks observed for Hydrate I of compound 2 where each value is expressed in 2-theta degrees.

TABLE 1 Observed X-ray diffraction peaks for Hydrate I of compound 2 In certain embodiments, the present invention provides Hydrate II of compound 2. According to one embodiment, Hydrate I is characterized by having one or more peaks in its powder X-ray diffraction pattern selected from those at about 8,252, 10,015. , 16.51 1 and 24.42 degrees 2-theta. According to one aspect, the Hydrate II of compound 2 has a powder X-ray diffraction pattern substantially similar to that shown in Figure 1 1. The methods for preparing Hydrate II of compound 2 are described below. Table 2 below it shows the X-ray diffraction peaks observed for Hydrate II of compound 2 where each value is expressed in 2-theta degrees.

TABLE 2 Observed X-ray diffraction peaks for Hydrate II of compound 2 It has been found that compound 2 can exist in a variety of solvated crystal forms. In certain embodiments, the present invention provides a crystalline methanolate of the compound 2. According to one aspect, the methanolate of the compound 2 has a powder X-ray diffraction pattern substantially similar to that shown in Figure 13. According to an embodiment , the methanolate of compound 2 is characterized by having one or more peaks in its powder X-ray diffraction pattern selected from those at approximately 1 1 .048, 15.21 1, 17.363, 1 9.047 and 22.897 degrees 2-theta. The methods for preparing the methanolate of compound 2 are described below. Table 3 below shows the observed X-ray diffraction peaks for the methanolate of compound 2 where each value is expressed in 2-theta degrees.

TABLE 3 Observed X-ray diffraction peaks for the methanolate of compound 2 In other embodiments, the crystalline compound 2 is provided as an ethanolate. Two ethanolate forms of compound 2 have been identified. According to one aspect, the crystalline ethanolate of compound 2 is Etholate I and has a powder X-ray diffraction pattern substantially similar to that shown in Figure 14. According to another embodiment , the ethanolate of compound 2 is characterized by having one or more peaks in its powder X-ray diffraction pattern selected from those at about 8.32, 9.81, 16.56, 20.88 and 24.47 degrees 2-theta. The methods for preparing Ethanolate I from compound 2 are described below. Table 4 below shows the X-ray diffraction peaks observed for Ethanolate I from compound 2 where each value is expressed in 2-theta degrees.

TABLE 4 Observed X-ray diffraction peaks for Ethanolate I of compound 2 In certain embodiments, the crystalline ethanolate of compound 2 is Ethanolate II and has a powder X-ray diffraction pattern substantially similar to that shown in Figure 15. According to another embodiment, Ethanolate II of compound 2 is characterized by having one or more peaks in their powder X-ray diffraction pattern selected from those at approximately 15.09 and 16.9 degrees 2-theta. The methods for preparing Ethanolate II from compound 2 are described below. Table 5 below shows the observed X-ray diffraction peaks for Ethanolate II of compound 2 where each value is expressed in 2-theta degrees.

TABLE 5 Observed X-ray diffraction peaks for Ethanolate II of compound 2 In other embodiments, crystalline compound 2 is provided as an isopropanolate of compound 2. Two isopropanolate forms of compound 2 have been identified. According to one aspect, the crystalline isopropanolate of compound 2 is isopropanolate I, which contains DMF. According to one aspect the Isopropanolate I of compound 2 has a powder X-ray diffraction pattern substantially similar to that shown in Figure 17 and / or a DSC pattern as depicted in Figure 18. According to another embodiment, the Isopropanolate I of compound 2 is characterized by having one or more peaks in its powder X-ray diffraction pattern selected from those at about 6.59, 13.23, 16.55 and 23.31 degrees 2-theta. The methods for preparing the Isopropanolate I of compound 2 are described below.

Table 6 below shows the X-ray diffraction peaks observed for Isopropanolate I (+ DMF) of compound 2 where each value is expressed in 2-theta degrees.

TABLE 6 Observed X-ray diffraction peaks for Isopropanolate I (+ DMF) of compound 2 According to another aspect, the crystalline isopropanolate of compound 2 is Isopropanolate II, which does not contain DMF. According to one aspect the Isopropanolate II of compound 2 has a powder X-ray diffraction pattern substantially similar to that shown in Figure 19. According to another embodiment, Isopropanolate II of compound 2 is characterized by having one or more peaks. in their powder X-ray diffraction pattern selected from those at approximately 3.79, 15.54 and 23.32 degrees 2-theta. The methods for preparing the Isopropanolate II of compound 2 are described below.

Table 7 below shows the X-ray diffraction peaks observed for Isopropanolate II of compound 2 where each value is expressed in 2-theta degrees.

TABLE 7 Observed X-ray diffraction peaks for Isopropanolate II of compound 2 In other embodiments, the crystalline compound 2 is provided as an acetonate. According to one aspect, the Acetonate of compound 2 has a powder X-ray diffraction pattern substantially similar to that shown in Figure 21. According to another embodiment, the Acetonate of compound 2 is characterized by having one or more peaks in its powder X-ray diffraction pattern selected from those at approximately 1 1, 0, 15, 15, 47 and 20.81 degrees 2-theta. The methods for preparing the Acetonate of compound 2 are described below.

Table 8 below shows the X-ray diffraction peaks observed for Acetonate of compound 2 where each value is expressed in 2-theta degrees.

TABLE 8 Observed X-ray diffraction peaks for Acetonate of compound 2 In certain embodiments, the present invention provides Form I of compound 2 comprising one or more additional solid forms of compound 2. In other embodiments, the present invention provides Form I of compound 2 comprising one or more of Form II, a hydrate of compound 2, a solvate of compound 2 or amorphous compound 2.

General methods for providing compound 2: Compound 1 is prepared according to the methods described in detail in PCT publication number WO 01/14330, the contents of which are incorporated herein by reference. Another aspect of the present invention provides a method for preparing compound 2: comprising the steps of: providing compound 1: combining compound 1 with glucuronic acid in an appropriate solvent; and, optionally, isolating compound 2. A suitable solvent can solubilize one or more of the reaction components, or, alternatively, the appropriate solvent can facilitate the agitation of a suspension of one or more of the components of the reaction. Examples of suitable solvents useful in the present invention are a protic solvent, a polar aprotic solvent or mixtures thereof. In certain embodiments, suitable solvents include an ether, an ester, an alcohol, a ketone or mixtures thereof. In certain embodiments, the appropriate solvent is methanol, ethanol, isopropanol or acetone where said solvent is anhydrous or in combination with water or heptane. In other embodiments, suitable solvents include tetrahydrofuran, dimethylformamide, dimethisulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol and acetonitrile. In another embodiment, the appropriate solvent is anhydrous ethanol. According to another embodiment, the present invention provides a method for preparing compound 2: comprising the steps of: combining compound 1: with an appropriate solvent and heat to form a solution thereof; add glucuronic acid to said solution; and, optionally, isolating compound 2. As described above in a general manner, compound 1 is dissolved in an appropriate solvent, optionally with heat. In certain embodiments, compound 1 is dissolved at about 60 ° C. In other embodiments, compound 1 is dissolved at about 40 ° C. In still other embodiments, compound 1 is dissolved at a temperature between about 40 ° C and about 60 ° C. In still other embodiments, compound 1 is dissolved in an appropriate solvent at the boiling temperature of the solvent. In other embodiments, compound 1 dissolves without heat. In certain embodiments, the solution of compound 1 is filtered prior to the addition of glucuronic acid. In other embodiments, the solution of compound 1 is not filtered prior to the addition of glucuronic acid. In certain embodiments, where the solution of compound 1 is heated to any temperature between about 40 ° C and about 60 ° C, the solution is subsequently cooled to any lower temperature which is between about 20 ° C and about 40 ° C prior to the addition of glucuronic acid. In certain embodiments, where the solution of compound 1 is heated to any temperature between about 40 ° C and about 60 ° C, the solution is not subsequently cooled to any lower temperature prior to the addition of glucuronic acid. In certain embodiments, about 1 equivalent of glucuronic acid is added to compound 1 to give compound 2. In other embodiments, less than 1 equivalent of glucuronic acid is added to compound 1 to give compound 2. In still other embodiments, it is added to compound 1 more than 1 equivalent of glucuronic acid to give compound 2. In other embodiments, compound 1 is added from about 1.0 to about 1.2 equivalents of glucuronic acid to give compound 2. In still other embodiments, it is added to the compound 1 about 0.9 to about 1.1 equivalents of glucuronic acid to give compound 2. In another embodiment, about 0.99 to about 1.01 equivalents of glucuronic acid is added to compound 1 to give compound 2. It will be appreciated that glucuronic acid can be added to the mixture of compound 1 and a suitable solvent in any appropriate form. For example, glucuronic acid can be added in solid form or as a solution or suspension in an appropriate solvent. The appropriate solvent can be the same appropriate solvent that is combined with the compound 1 or can be a different solvent. According to one embodiment, the glucuronic acid is added in solid form. In certain embodiments, glucuronic acid is combined with an appropriate solvent prior to addition to compound 1. According to another embodiment, glucuronic acid is added as a solution in an appropriate solvent. In other embodiments, the appropriate solvent where the glucuronic acid is dissolved is a polar protic solvent or a polar aprotic solvent. Such solvents include alcohols, ethers and ketones. Examples of said solvents include water, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol and acetonitrile. In certain embodiments, the appropriate solvent is selected from those mentioned above and is anhydrous. According to one embodiment, glucuronic acid dissolves in water. In certain embodiments, the resulting mixture containing the compound 2 is cooled. In certain embodiments where the mixture containing the compound 2 is heated to more than about 20 ° C, the solution is allowed to cool to about 20 ° C. In other embodiments, the mixture containing compound 2 is cooled to less than 20 ° C. In certain embodiments, compound 2 precipitates from the mixture.

In another embodiment, compound 2 crystallizes from the mixture. In other embodiments, compound 2 crystallizes from the solution followed by seeding crystals in solution (ie, by adding crystals of compound 2 to the solution). The crystalline or amorphous compound 2 can be precipitated from the reaction mixture or generated by removing part or all of the solvent by methods such as evaporation, distillation, filtration (eg nanofiltration, ultrafiltration), reverse osmosis, absorption and reaction, by the addition of an anti-solvent such as heptane, by cold or by different combinations of these methods. As described above in a general manner, compound 2 is optionally isolated. It will be appreciated that compound 2 can be isolated by any suitable physical means, known to those of ordinary skill in the art. In certain embodiments, the precipitated solid compound 2 is separated from the supernatant by filtration. In other embodiments, the precipitated solid compound 2 is separated from the supernatant by decanting the supernatant. In certain embodiments, the solid compound 2 is separated from the supernatant by filtration. In certain embodiments, the isolated compound 2 is air dried.

In other embodiments, the isolated compound 2 is dried under reduced pressure, optionally at elevated temperature. According to another embodiment, the present invention provides a method for preparing compound 2: 2 comprising the steps of: combining compound 1: 1 appropriate solvent and heat to form a solution add an aqueous solution of glucuronic acid to said solution; and, optionally, isolating compound 2. In certain embodiments, the method for preparing compound 2 further comprises the step of distilling the reaction mixture. According to another aspect of the present invention, the reaction mixture is distilled while adding additional solvent in order to decrease the water content. In other embodiments, the method for preparing compound 2 further comprises the step of cooling the resulting suspension comprising compound 2 and isolating compound 2 by appropriate physical means. According to one embodiment, the molar ratio of glucuronic acid to compound 1 obtained is from about 0.5 to about 1.0. In other embodiments, the ratio of glucuronic acid to compound 1 obtained is between about 0.8 and about 2.0. In certain embodiments, the ratio is between about 0.9 and about 1.2. In other embodiments, the ratio is between about 0.94 and about 1.06. In still other modalities, the ratio is between approximately 0.94 and approximately 0.95.

Uses of compounds and compositions acceptable for pharmaceutical use As discussed above, the present invention provides compound 2 which is useful as modulator of D receptors, 5HT receptors, 5HT reuptake and prostaglandin synthesis and shows utility in clinically relevant models for psychosis, depression, stress / anxiety and Parkinson's disease. In certain embodiments, the present compound is useful as a modulator of one or more of the D2 receptor subtypes, 5HT reuptake or prostaglandin synthesis. In other embodiments, the present compound is useful for the treatment of psychosis, depression, stress / anxiety and Parkinson's disease. Accordingly, in another aspect of the present invention, acceptable compositions for pharmaceutical use are provided, wherein these compositions comprise compound 2 and optionally a carrier, adjuvant or vehicle acceptable for pharmaceutical use. In certain embodiments, these compositions optionally comprise one or more additional therapeutic agents. As described above, the pharmaceutical acceptable compositions of the present invention additionally comprise a carrier, adjuvant or vehicle acceptable for pharmaceutical use, which, as used herein, includes any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening agents or emulsifiers, preservatives , solid binders, lubricants and the like, according to that appropriate for the particular dosage form desired. Disclosed in Remington's Pharmaceutical Sciences, 16th Ed, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) various vehicles used in the formulation of pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the salts of the invention, such that it produces any undesired biological effect or otherwise detrimentally interacts with any other component of the composition acceptable for pharmaceutical use, its use is contemplated as within the scope of this invention. Some examples of materials that can serve as acceptable carriers for pharmaceutical use include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, such as human serum albumin, pH regulating substances such as phosphates. , glycine, sorbic acid or potassium sorbate, mixtures of partial glycerides of saturated vegetable acid grades, water, salts or electrolytes, such as protamine sulfate, monohydric disodium phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica colloidal, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; jelly; talcum powder; excipients such as cocoa butter and wax for suppositories; oils such as peanut oil, cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; pH buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate pH regulator solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and flavoring agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator.

In yet another aspect, a method is provided for treating or decreasing the severity of a disorder associated with the modulation of D receptors, 5HT receptors, 5HT reuptake and prostaglandin synthesis, and / or to treat or decrease the severity of psychosis, depression, stress / anxiety and / or Parkinson's disease, comprising the administration of an effective amount of compound 2 or a pharmaceutically acceptable composition thereof, to a subject in need thereof. In certain embodiments of the present invention an "effective amount" of the compound or composition acceptable for pharmaceutical use is that amount effective to treat or decrease the severity of a disorder associated with the modulation of D receptors, 5HT receptors, 5HT reuptake and synthesis. of prostaglandin, and / or to treat or decrease the severity of psychosis, depression, stress / anxiety and / or Parkinson's disease. In other embodiments, an "effective amount" of a compound is an amount that acts as a modulator of one or more D receptors, 5HT receptors, 5HT reuptake and prostaglandin synthesis. An "effective amount" of a compound can achieve a desired therapeutic and / or prophylactic effect, such as an amount that results in the prevention of, or a decrease in, symptoms associated with, a disease associated with one or more of the D receptor, 5HT receptor, reuptake of 5HT and modulation of prostaglandin synthesis, and / or with psychosis, depression, stress / anxiety and / or Parkinson's disease.

The compounds and compositions, according to the method of the present invention, can be administered using any amount and any effective route of administration to treat or decrease the severity of a disorder associated with the modulation of one or more of the D receptors, receptors of 5HT, reuptake of 5HT and synthesis of prostaglandin, and / or to treat or reduce the severity of psychosis, depression, stress / anxiety and / or Parkinson's disease. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, its mode of administration and the like. The salt of the invention is preferably formulated in unit dosage form (eg, as a tablet, capsule or vial) for ease of administration and uniformity of dosage. The term "unit dosage form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily use of the salts and compositions of the present invention will be decided by the attending physician within the scope of medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity thereof; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration and level of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidence with the specific compound employed and similar factors well known in the medical art. The term "patient", as used herein, means an animal, preferably a mammal and more preferably a human. The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, nasally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powders, ointments or drops), buccal or the like, depending on the severity of the infection being treated. In certain embodiments, the salts of the invention may be administered orally or parenterally at dosage levels of from about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg., body weight of the subject per day, one or more times a day, to obtain the desired therapeutic effect. Liquid dosage forms for oral or nasal administration include, but are not limited to, emulsions, microemulsions, solutions, suspensions, aerosols, gels, syrups and elixirs acceptable for pharmaceutical use. In addition to the active salts, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor bean and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acids and mixtures thereof. In addition to the inert diluents, the oral compositions may also include adjuvants such as wetting, emulsifying and suspending agents, sweetening, flavoring and flavoring agents. Aerosol formulations typically comprise a solution or fine suspension of the active substance in an aqueous or non-aqueous solvent acceptable for physiological use and are generally presented in individual or multi-dose quantities in sterile form in a sealed container, which can take the form of a cartridge or allow recharge for use with an atomizer device. Alternatively, the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser equipped with a fixed dose valve which is discarded after the contents of the container are exhausted. When the dosage form comprises an aerosol dispenser, it will contain an acceptable propellant for pharmaceutical use. The aerosol dosage forms can also take the form of a pump atomizer. Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using appropriate dispersing agents or humectants and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion, in a non-toxic diluent or solvent acceptable for parenteral use, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed is water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly employed as a solvent or suspending medium. For this purpose, any soft fixed oil may be used, including mono or synthetic diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacteria retainer filter or by the incorporation of sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. Advantageously, compound 2, as described herein, has improved water solubility. Accordingly, the present compound is useful for intravascular and intramuscular administration. Without wishing to embrace any particular theory, it is presumed that the increased solubility of compound 2 would allow a smaller injection volume resulting in less pain and discomfort for the patient. Accordingly, the present invention also relates to an injectable formulation for intravascular or intramuscular administration. In order to prolong the effect of a compound of the present invention, it is often desirable to delay the absorption of the subcutaneous or intramuscular injection compound. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. Then, the level of absorption of the compound depends on its level of dissolution that can depend on the size of the crystal and its crystalline form. Alternatively, the delayed absorption of a compound administered parenterally is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are prepared by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the nature of the particular polymer employed, the release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. Typical parenteral compositions consist of a solution or suspension of the compound or salt acceptable for physiological use in a sterile aqueous or non-aqueous carrier or oil acceptable for parenteral use, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with an appropriate solvent prior to administration. Compositions for rectal or vaginal administration are conveniently presented in the form of suppositories, pessaries, vaginal tablets, foams or enemas. Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the salts of this invention with suitable non-irritating excipients or vehicles such as cocoa butter, polyethylene glycol or wax suppositories that are solid at room temperature but liquid at body temperature and therefore melt in the rectal or vaginal cavity and release the active compound. Dosage forms for oral administration include capsules, tablets, pills, powders and granules. In said solid dosage forms, the active compound is mixed with at least one inert excipient or carrier, acceptable for pharmaceutical use such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidinone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, starch of potato or tapioca, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium salts, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, pol solid ethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form can also comprise pH regulating agents. Compositions suitable for buccal or sublingual administration include tablets, orally dissolving tablets and lozenges, wherein the active component is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin. Solid compositions of similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. These may optionally contain opacifying agents and may also be part of a composition that releases the active components only or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedded compositions that can be used include polymeric substances and waxes. Solid compositions of similar type can also be used as fillers in soft and hard gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

Compound 2 can also exist in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulating art. In said solid dosage forms, the compound 2 can be mixed with at least one inert diluent such as sucrose, lactose or starch. Said dosage forms may also comprise, as is normal in the art, additional substances other than inert diluents, e.g., compression lubricants and other processing aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms can also comprise buffering agents. These may optionally contain opacifying agents and may also be part of a composition that releases the active components only or, preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedded compositions that can be used include polymeric substances and waxes. Compositions for oral administration can be designed to protect the active component against degradation as it passes through the alimentary tract, for example by an outer coating of the formulation on a tablet or capsule.

In another embodiment, compound 2 is provided in an extended release (or "delayed" or "sustained") composition. This delayed release composition comprises compound 2 in combination with a delayed release component. This composition allows the selective release of compound 2 in the lower gastrointestinal tract; for example in the small intestine, the large intestine, the colon and / or the rectum. In certain embodiments the delayed release composition comprises compound 2 and further comprises an enteric or pH dependent coating such as cellulose acetate phthalates and other phthalates (eg, polyvinyl acetate phthalate, methacrylates (Eudragits)). Alternatively, the delayed release composition provides controlled release to the small intestine and / or the colon by the provision of pH sensitive methacrylate coatings, pH sensitive polymeric microspheres or polymers that undergo degradation by hydrolysis. The delayed release composition can be formulated with hydrophobic or gelling excipients or coatings. Colonic administration can also be provided by coatings that are digested by bacterial enzymes such as amylose or pectin, by pH-dependent polymers, by a hydrogel plug that swells over time (Pulsincap), by time-dependent hydrogel coatings and / or by acrylic acid bound to coatings with azoaromatic bonds. In certain embodiments, the sustained release compositions of the present invention comprise hypromellose, microcrystalline cellulose and a lubricant. The mixture of compound 2, hypromellose and microcrystalline cellulose can be formulated into a tablet or capsule for oral administration. In certain embodiments, the mixture is granulated and pressed into tablets. In other embodiments, the delayed release compositions of the present invention are provided in a multiparticulate formulation. A mixture of compound 2 and a suitable polymer is granulated to form pellets that are coated. In certain embodiments, the pellets are coated with a non-functional sealing coating. In other embodiments, the pellets are first coated with a non-functional sealing coating and then coated with a functional coating. As used herein the term "non-functional coating" is a coating that affects the rate of drug release. Examples of a non-functional coating include hydroxypropyl cellulose, hypromellose or polyvinyl alcohol. In certain embodiments, the non-functional coating is Opadry® Clear, which contains hydroxypropyl methylcellulose and polyethylene glycol. As used herein the term "functional coating" is a coating that affects the rate of release of the drug from the dosage form. Examples of a functional coating include ethylcellulose and polymethacrylate derivatives (Eudragits). Accordingly, another embodiment provides a multiparticulate formulation comprising a pellet core comprising compound 2, a nonfunctional seal coating and a functional seal coating. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with an acceptable carrier for pharmaceutical use and any necessary preservative or pH regulator as required. Ophthalmic formulation, ear drops and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled administration of a compound to the organism. Said dosage forms can be prepared by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The level can be controlled by the provision of a level controlling membrane or by dispersing the compound in a polymer or gel matrix. The compositions may contain from 0.1% to 99% (w / w), preferably from 0.1-60% (w / w), more preferably from 0.2-20% by weight and more preferably from 0.25 to 12% (p. / p) of compound 2, depending on the method of administration.

As described above in general form, the salts of the present invention are useful as modulators of one or more of the D receptors, 5HT receptors, 5HT reuptake and prostaglandin synthesis and thus the invention also refers to a method for treat (eg, palliative, curative, prophylactic) a disease or disorder associated with the modulation of one or more of the D receptors, 5HT receptors, 5HT reuptake and prostaglandin synthesis. In one embodiment, compound 2 is a modulator of one or more of the D receptors, 5HT receptors, 5HT reuptake and prostaglandin synthesis and thus, without wishing to encompass any particular theory, the present compound and the compositions are particularly useful to treat or decrease the severity of a disease, condition or disorder where it is involved in the disease, condition or disorder, the modulation of one or more of the D receptors, 5HT receptors, 5HT reuptake and prostaglandin synthesis. When modulation of one or more of the D receptors, 5HT receptors, 5HT reuptake and prostaglandin synthesis is involved in a particular disease, condition or disorder, the disease, condition or disorder may be referred to as "receptor-mediated disease". D, 5HT receptor, reuptake of 5HT and synthesis of prostaglandin "or symptom of disease. In certain embodiments, the salts and compositions of the present invention provide a method of treating or decreasing the severity of one or more disorders including, but not limited to, Parkinson's disease, psychosis (eg, schizophrenia, mania, psychotic depression, bipolar disorder), depression, stress / anxiety, Alzheimer's disease, Huntington's disease, panic disorder, obsessive-compulsive disorder, eating disorders, drug addiction, social phobias, aggression or agitation, migraine, scleroderma and Raynaud's phenomenon, emesis, Gastrointestinal tract disorders related to the regulation of peristalsis, RLS and secretion of prolactin from tumors of the pituitary gland where said method comprises administering to a patient a compound 2 or a composition thereof. It will also be appreciated that the compounds and compositions acceptable for pharmaceutical use of the present invention can be used in combination therapies, which means that compound 2 and compositions thereof can be administered concurrently with, prior to or subsequent to, one or more of other desired medical or therapeutic procedures. In the particular combination of therapies (therapeutic or procedures) to be used in a combination regimen, the compatibility of the desired therapies and / or procedures and the therapeutic effects to be obtained will be taken into account. It will also be appreciated that the therapies employed may obtain a desired effect for the same disorder (e.g., a compound of the invention may be administered concurrently with another agent used to treat the same disorder) or may obtain different effects (e.g., control of any adverse effect). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are referred to as "appropriate for the disease or condition being treated." The amount of additional therapeutic agent present in the compositions of this invention will not be greater than the amount that would normally be administered in a composition comprising that therapeutic agent as the sole active agent. In certain embodiments, the amount of additional therapeutic agent in the disclosed compositions herein will range from about 50% to 100% of the amount normally present in a composition comprising that therapeutic agent as the sole therapeutically active agent. Another aspect of the invention refers to the modulating activity of D receptors, 5HT receptors, 5HT reuptake and prostaglandin synthesis in a biological sample or a patient, which method comprises administering a patient with or contacting said sample. biological with compound 2 or a composition thereof. The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof. Modulation of the activity of D receptors, 5HT receptors, 5HT reuptake and prostaglandin synthesis in a biological sample is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, biological assays. The amount of compound 2 effective to treat a disorder such as those discussed above depends on the nature and severity of the disorder treated and the weight of the patient in need thereof. However, an individual dosage unit for a 70 kg adult will usually contain 0.01 to 100 mg, for example 0.1 to 50 mg, preferably 0.5 to 16 mg of the compound of the invention per day. The unit doses may be administered one or more times a day, for example, 2, 3 or 4 times a day, usually 1 to 3 times a day, more preferably 1 or 2 times a day. It will be appreciated that the dosage levels set forth above provide a guide for the administration of compound 2 to an adult. The amount to be administered to, for example, an infant or a baby can be determined by a general practitioner or by someone skilled in the art and can be less than or equal to the amount administered to an adult. The unit dose is preferably provided in the form of a capsule or a tablet. All the preferred features of each of the aspects of the invention apply to all those other aspects by changing what corresponds. In order that the invention described herein be fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

EXAMPLES General procedures X-ray powder diffraction patterns were obtained in a Rigaku Miniflex Diffraction System (Rigaku MSC Inc.). The dust samples were placed on a polished silicon sample holder for zero background. A standard 0.45 kW copper focus X-ray tube equipped with a Ni? ß filter with scanning at 2 degrees / minute from 3.00 to 40.00 2-theta degrees was used as the X-ray source. The processing of the data was done using a Jade 6.0 software. Nuclear Magnetic Resonance spectra of protons (1 H NMR) were obtained on a Bruker spectrometer model Avance DRX-500 MHz RNM, equipped with a 5mm QNP probe. Approximately 5-25 mg of each compound was dissolved in 0.6 ml of DMSO-d6 (99.9% D), containing 0.05% TMS as an internal reference. The 1H NMR spectra were recorded at 500.133 MHz, using a 30 degree pulse, with a pulse delay of 20 seconds, 32k data points, 64 readings. An exponential window function was applied with a line widening from 0.3 Hz to 16k data points to process data without filling with zero and the TMS was referred to as 0.00 ppm. The 13C quantitative NMR was obtained at 125.7 MHz, using "inverted gated decoupling", a 30-degree pulse and a delay of 8 seconds. The DSC data were obtained in a Differential Scanning Calorimeter TA Q1000. The instrument heated the sample from 40 ° C to 200 ° C at 10 ° C / min with a nitrogen purge of 50 ml / min.

EXAMPLE 1 Preparation of compound 2 (Form I) Compound 1 (500 mg) was suspended in 20 ml anhydrous ethanol and heated to 60 ° C to obtain a clear solution. The solution was filtered through a 0.45 μ? T filter. and cooled to 40 ° C. To this solution, 275 mg of glucuronic acid (1.2 equivalents) were added. A thin white suspension was obtained. The suspension was cooled to 20 ° C and stirred with a magnetic stirrer for 16 hours. The suspension was filtered and the resulting solid phase was air dried at room temperature and analyzed by X-ray diffraction (see Figure 1 and Table A) and optical microscopy and found to be crystalline compound 2. Figure 2 represents the 1H NMR spectrum obtained for compound 2. Figure 3 represents the 13C RNM spectrum obtained for compound 2 and Figure 4 represents the 1H NMR spectrum obtained for compound 1.

EXAMPLE 2 Preparation of compound 2 (Form I) by reactive distillation of ethanol / water D-glucuronic acid (4.6 g) was added in 25 ml of water and dissolved at room temperature. Compound 1 (10 g) was added in 320 ml of anhydrous ethanol and heated to 50-70 ° C to obtain a clear solution. The prepared solution of acid and glucuronic water (1 eq) was added to the solution of free base and ethanol solution. The solution remained clear and then cooled naturally to room temperature and stirred for 16 hours. The resulting solution was distilled in azeotropic form at 78 ° C. Approximately 400 ml total of anhydrous ethanol, 200 ml every 0.5 hour during the distillation were added back to the solution. A white solid precipitated during the distillation. The distillation was stopped once 600 ml of solution were distilled and 150 ml of white suspension was left. The suspension was filtered and dried overnight at 50 ° C under vacuum to give compound 2. The final product (12 g, yield 84%) was crystalline and was characterized by X-ray powder diffraction (Figure 5) and DSC (Figure 6). Table 9 below shows the observed X-ray diffraction peaks for Form I of compound 2 where each value is expressed in 2-theta degrees.

TABLE 9 X-ray diffraction peaks observed for compound 2 (Form I) 2-Theta 12,158 14,460 15,541 16,399 17,599 19,204 20,018 22,340 23,296 25,740 29,658 EXAMPLE 3 Preparation of compound 2 (Form I) by heterogeneous reaction in ethanol Compound 1 (500 mg) was dissolved in 70 ml of anhydrous ethanol at room temperature. 230 mg of glucuronic acid (1.0 eq) was added to the free base solution to form a suspension. The suspension is stirred for 16 hours at room temperature and then filtered. The solid phase dried under vacuum at 50 ° C to give compound 2. The final product (235 mg, 32.2% yield) was characterized by X-ray diffraction, DSC and RNM spectroscopy.

EXAMPLE 4 Preparation of compound 2 (Form I) by heterogeneous reaction at 60 ° C in ethanol Compound 1 (400 mg) was suspended in 13 ml anhydrous ethanol and heated to 60 ° C to obtain a clear solution. The solution was filtered through a 0.45 μ? T filter. and cooled to 40 ° C. 202 mg of glucuronic acid (1.1 equivalents) were added to this solution. A clear white suspension was obtained. The suspension was cooled to 20 ° C and stirred with a magnetic stirrer for 16 hours. The suspension was filtered and the resulting solid phase (224 mg, 38%) was air-dried at 50 ° C under vacuum.

EXAMPLE 5 General method for preparing compound 2 (Form I) Add 25.3 kg of ethanol to 1 kg of compound 1 and heat the mixture to 60 ° C. Add 2 kg of water to 0.46 kg of glucuronic acid; Stir to allow the dissolution of all the acid in water. Add the glucuronic acid solution to the free base solution. Verify transparent solution. Cool the solution to 50 ° C. Filter the reaction solution at 50 ° C through a filter 0.5 μ? T ?. Cool the reaction solution to 24 ° C and stir slowly for 16 hours. Heat the reaction solution at 78 ° C to begin distillation. Distil 15.8 kg of solution, add 15.8 kg of ethanol, distill 1 5.8 kg of solution, add 15.8 kg of ethanol and finally distill 20 I of solution. (60 I distillates, 40 I aggregates, volume of remaining solution 15.5 I). Cool the reaction at 20 ° C in 1 hour and maintain the reaction at 20 ° C for 1 hour. Filter the mother liquor and wash the cake twice with 4.0 kg (8 kg total) of ethanol. Dry the cake at 50 ° C under vacuum for 12 hours.

EXAMPLE 6 Alternative method for preparing compound 2 (Form I) from acetonitrile In another method for preparing Form I, the amorphous compound 2 was suspended in acetonitrile at room temperature for three days. The amorphous solid was transformed into the pure crystalline form of compound 2 (Form I).

EXAMPLE 7 Preparation of amorphous compound 2 Method A 0.92 g of D-glucuronic acid in water of 5 ml was added and dissolved at room temperature. 2 g of free base SLV-314 (32797-94-01) was added in 20 ml acetone and heated to 40-50 ° C to obtain a clear solution. The prepared solution of water and glucuronic acid (1 eq) was added to this solution and stirred. The solution remained clear and then cooled naturally to room temperature and stirred for 16 hours. The resulting solution was distilled at ~ 56 ° C. 50 ml of acetone were added back to the solution at two intervals during the distillation. Some white solids appeared briefly during distillation and then dissolved. The distillation was stopped after 35 ml of solution were distilled and 35 ml of clear solution was left. The solvent was evaporated in a dryer at 50 ° C under vacuum generating a light brown dry amorphous solid, which was characterized by X-ray powder diffraction (Figure 7) and DSC (Figure 8).

Method B Compound 2 was dissolved in 32 volumes of ethanol and 4 volumes of water at elevated temperature. The solvent was evaporated at atmospheric pressure by heat at reflux temperature. A gel was produced. The gel was dried under vacuum and 50 ° C. An amorphous solid was produced.

EXAMPLE 8 Preparation of compound 2 (Form II) Form I of compound 2 becomes Form II upon suspension of Form I in a variety of solvents. This transformation occurs over time at room temperature or at elevated temperature.

Form I was resuspended in toluene, acetone, tBME, acetonitrile or isopropyl acetate at room temperature or 50 ° C for one to two weeks. It has been found that the elevated temperature facilitated the transformation. Formation of Form II was monitored by the characteristic peak at 18.7 degrees two-theta in the powder X-ray diffraction pattern.

EXAMPLE 9 Preparation of Hydrate I of compound 2 Form I of compound 2 was resuspended in water for more than 2 weeks at room temperature or 50 ° C. The total transformation was very slow to obtain the title compound as a mixture of Form I and Hydrate I characterized by X-ray diffraction of powder crystal and DSC. See Figures 9 and 10.

EXAMPLE 10 Preparation of Hydrate II of compound 2 The amorphous compound 2 was dissolved in 6 volumes of water at room temperature and the compound was allowed to crystallize at room temperature. The resulting suspension was stirred until the next day and the title compound was collected by filtration and characterized by X-ray diffraction of powder crystal and DSC. See Figures 1 1 and 12, respectively.

EXAMPLE 11 Preparation of solvates of compound 2 Methanolate The amorphous compound 2 was dissolved in 6 volumes of methanol at room temperature and the compound was allowed to crystallize at room temperature. The resulting mixture was stirred until the next day and the solid methanolate was collected by filtration. See Figure 13. It was discovered that the methanolate is unstable under drying and was transformed to Form I.

Ethanolate Compound 1 was dissolved in 32 volumes of 1 J1 ethanol at elevated temperature. A stoichiometric amount of glucuronic acid, dissolved in 3-4 volumes of water, was added immediately. The nucleation began immediately. The resulting mixture was stirred on ice for 30 minutes then left overnight without stirring. The title compound was collected by filtration and characterized by its powder crystal X-ray diffraction as that of Ethanolate I. See Figures 14. Ethanolate I was converted to Form I after drying. Alternatively, a second ethanolate of compound 2, Ethanolate II, was prepared by dissolving the amorphous compound 2 in 6 volumes of 1 J1 ethanol (ethanol-ethyl acetate). The mixture was stirred until the next day and Ethanolate II was collected by filtration. Figure 15 represents the dust X-ray diffraction pattern of Ethanolate II and Figure 16 represents the DCS of Ethanolate II.

Isopropanolate Compound 2 was dissolved in 10 volumes of DMF at room temperature. 60 volumes of IPA were added for 10 minutes. The resulting mixture was stirred for 30 minutes. The compound Isopropanolate I was collected by filtration and characterized by X-ray diffraction of powder crystal and DSC. See Figures 17 and 18. The wet filter cake showed Isopropanolate + DMF. The drying of the sample destroyed the structure to amorphous compound containing solvent. Alternatively, a second isopropanolate, Isopropanolate II, of compound 2 was prepared by suspension of the amorphous compound 2 in IPA at room temperature for 2 or 3 days. See Figures 19 and 20, which represent the powder X-ray diffraction pattern and the DSC plot, respectively.

Acetonate Compound 1 was dissolved in 32 volumes of acetone at elevated temperature. A stoichiometric amount of glucuronic acid, dissolved in 3-4 volumes of water, was added immediately. The nucleation began immediately. The resulting mixture was stirred on ice for 30 minutes then left overnight without stirring. The title compound was collected by filtration. Figure 21 depicts the dust X-ray diffraction pattern of Acetonate. Acetonate of compound 2 was converted to Form I after drying.

EXAMPLE 12 The integrations of glucuronic acid signals were compared with the single peak of compound 1 (Figure 4) to obtain the molar ratio of glucuronic acid to compound 1. The observed acid to 1 ratio ranged from 0.94 to 0.95. The comparative equilibrium solubilities of the hydrochloride, hydrobromide and glucuronate salts of compound 1 are listed in Table 10.

TABLE 10 Comparative equilibrium solubilities of compound 1 salts EXAMPLE 12 Preparation of extended release formulations Formulation A An extended release formulation of compound 2 (30% w / w), microcrystalline cellulose (29% w / w), hypromellose (40% w / w) and magnesium stearate (1% w / w) was prepared by the combination of compound 2, a portion of the microcrystalline cellulose, hypromellose and some magnesium stearate and then dry granulation of the mixture by roller reduction. Then, the resulting compacts were classified by size by grinding and / or sieving. The remaining microcrystalline cellulose is combined and the granulation is lubricated with the remaining magnesium stearate and compressed into tablets.

Formulation B Another example of an extended release dosage form is a multiparticulate formulation with a core comprised of compound 2 (70% w / w) and microcrystalline cellulose (30% w / w). The core is prepared by combining the components and granulating them with water in a planetary mixer. Then, using the Nica® System, the resulting wet mass is extruded through a 1.0 mm sieve. Then, the extrudates are transferred to the spheronizer and rotated at about 700 rpm until obtaining spherical pellets, approximately 2-3 minutes. Then, the wet pellets are dried in a fluid bed dryer at a moisture level of 2-5%. The dried pellets are passed through an 18 mesh screen to remove pellets exceeded in size. The pellets are then coated with a sealing coating comprising Opadry® Clear (5% w / w) and water (95% w / w). This is carried out firstly by adjusting the fluid bed apparatus with a Wurster column and a lower nozzle spray system, then applying the Opadry® seal coating at an inlet temperature of approximately 60 ° C, a spray level. of coating solution of 5-10 grams / min, atomization pressure of 1-2 bar. The desired product temperature is 38-43 ° C. After an increase of approximately 2% by weight of the sealing coating is achieved, an ethylcellulose coating can be applied. This coating comprises Surelease® (aqueous dispersion of ethylcellulose, 25% solids, 5% w / w) and water (95% w / w) and is applied similarly to the sealing coating up to a weight increase of 3-8% . After applying the ethylcellulose coating, the pellets are dried for an additional 5-10 minutes. Then, the pellets are removed and sieved through an 18 mesh screen to remove agglomerates and oversized particles.

Claims (13)

NOVELTY OF THE INVENTION CLAIMS

1 .- A sustained release composition comprising compound 2:

2. - The composition according to claim 1, further characterized in that said composition comprises hypromellose, microcrystalline cellulose and a lubricant.

3. The composition according to claim 1, further characterized in that said composition is compressed into a tablet.

4. - A multiparticulate formulation comprising a pellet core comprising compound 2: a non-functional sealing coating and a functional sealing coating.

5. The use of a composition of claim 1, for the manufacture of a medicament useful for treating, or decreasing the severity of, one or more disorders selected from Parkinson's disease, psychoses including schizophrenia, mania, psychotic depression, bipolar disorder, depression, stress / anxiety, Alzheimer's disease, Huntington's disease, panic disorder, obsessive-compulsive disorder, an eating disorder, drug addiction, social phobias, aggression or agitation, migraine, scleroderma, Raynaud's phenomenon, emesis, a disorder of the Gastrointestinal tract related to the regulation of peristalsis, RLS or prolactin secretion generated by tumors of the pituitary gland in a patient.

6. - The use as claimed in claim 5, wherein said disorder is Parkinson's disease.

7. - The use as claimed in claim 5, wherein said disorder is a psychosis selected from schizophrenia, mania, psychotic depression and bipolar disorder.

8. - The use as claimed in claim 5, wherein said disorder is depression, stress / anxiety, panic disorder, obsessive-compulsive disorder, an eating disorder, drug addiction or social phobia.

9. - The use as claimed in claim 5, wherein said disorder is aggression or agitation.

10. - The use as claimed in claim 5, wherein said disorder is Alzheimer's disease, Huntington's disease, migraine, scleroderma, Raynaud's phenomenon, emesis, a gastrointestinal tract disorder related to the regulation of peristalsis , RLS or secretion of prolactin generated by tumors of the pituitary gland.

11. The composition according to claim 1, further characterized in that it comprises Form I of compound 2 and one or more additional solid forms of compound 2.

12. The composition according to claim 11, further characterized in that it comprises the Form I of compound 2 and one or more of Form II, a hydrate of compound 2, a solvate of compound 2, or amorphous compound 2.

13. - The use of a compound 2: for the preparation of a medicament in the form of a sustained release composition useful for treating, or decreasing the severity of, one or more disorders selected from Parkinson's disease, psychosis including schizophrenia, mania, psychotic depression, bipolar disorder, depression, stress / anxiety , Alzheimer's disease, Huntington's disease, panic disorder, obsessive-compulsive disorder, an eating disorder, drug addiction, social phobias, aggression or agitation, migraine, scleroderma, Raynaud's phenomenon, emesis, a gastrointestinal tract disorder related to regulation of peristalsis, RLS or secretion of prolactin generated by tumors of the pituitary gland.