MXPA99012067A

MXPA99012067A - Polymorphic form of the tachykinin receptor antagonist 2-(r)-(1-(r) -(3,5-bis(trifluoromethyl) phenyl)ethoxy)-3-(s)-(4-fluoro) phenyl-4-(3-5 (-oxo-1h,4h-1,2,4,-triazolo) methylmorpholine

Info

Publication number: MXPA99012067A
Application number: MXPA/A/1999/012067A
Authority: MX
Inventors: Crocker Louis; Mccauley James
Original assignee: Crocker Louis; Mccauley James; Merck & Co Inc
Priority date: 1997-07-02
Filing date: 1999-12-17
Publication date: 2001-12-04

Abstract

Estáinvención se refiere a una forma polimórfica novedosa del compuesto 2-(R)-(1-(R)-(3,5-bis(trifluorometil)-fenil)-etoxi )3-(S)-(4-flucro)-fenil-4-(3-5(-oxo-IH,4H-1,2,4-tr iazolo)metilmorfolina que es un antagonists de receptor de taquiquininaútil en el tratamiento prevención de transtornos del sistema nervioso central, enfermedades inflamatorias, dolor o migraña, asma y emesis;la presente forma polimórfica tiene ventajas sobre las otras formas conocidas de 2-(R)-(l-(R)-(3,5-bis(trifluorometil)-fenil)-etoxi )3-(S)-(4-fluoro)fenil-4-(3-5(-oxo-lH,4H-1,2,4-tri azolo)metilmorfolina en cuanto a estabilidad termodinámica y adaptabilidad para incluirse en formulaciones farmacéuticas.

Description

POL1MORPHIC FORM PE 2- (R) - (1- (RH3.5-BIS (TRIFLUOROMETHYL) - FENILi-ETOXl) -3- (S) - (4-FLUORO) PHENYL 4- (3-5 (-OXO-1 H.4H-1.2.4- TRIAZOLO? METHYLMORFOLINE WHICH IS AN ANTAGONIST OF TAQUIQUININE RECEIVER DESCRIPTIVE MEMORY This invention relates to a novel polymorphic form of the compound: 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) ) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine The present invention also relates to pharmaceutical compositions comprising this novel polymorphic form of the compound as an ingredient Active and the use of the compound and its formulations in the treatment of certain disorders The novel polymorphic form of this invention is a tachykinin receptor antagonist, useful in the treatment or prevention of disorders of the central nervous system, inflammatory diseases, pain or migraine , asthma and emesis This polymorphic form has advantages over other known forms of 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxyl) -3- (S) - ( 4-fluoro) phenyl-4- (3- (5-oxo-1 H.4H-1, 2,4-triazole) methylmorpholine, in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations.

BACKGROUND OF THE INVENTION Neuropeptides receptors of substance P (neurokinin-1; NK-1) are widely distributed through the nervous system of mammals (especially in the brain and spinal ganglia), the circulatory system and peripheral tissues (especially duodenum and jejunum), where they play a regulatory role in a number of different biological processes. These include olfactory, visual, auditory and pain sensory perception, movement control, gastric motility, vasodilation, salivation and urination. Substance P (also called here "SP") is a naturally occurring undecapeptide, which belongs to the tachykinin family of peptides, the latter named for its rapid contractile action in extravascular tissue of smooth muscle. The tachykinins are distinguished by a conserved carboxyl terminal sequence Phe-X-Cly-Leu-Met-NH2. In addition to SP, known mammalian tachykinins include neurokinin A and neurokinin B The current nomenclature designates the SP receptors, neurokinin A and neurokinin B as NK-1, NK-2 and NK3, respectively. Substance P is a pharmacologically active neuropeptide produced in mammals and acts as a vasodilator, depressant, stimulator of salivation and producing increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on the dose and response to animal pain.

We have reviewed the evidence on the usefulness of tachykinin receptor antagonists in pain, headaches especially migraine, Alzheimer's disease, multiple sclerosis, cardiovascular changes, edema such as edema caused by thermal damage, chronic inflammatory diseases such as arthritis rheumatoid, asthmatic / bronchial hyperreactivity and other respiratory diseases, including allergic rhinitis, inflammatory bowel diseases, including ulcerative colitis and Chrohn's disease, eye damage and inflammatory eye diseases, proliferative vitreoretinopathy, irritable bowel syndrome and impaired function of the bladder, including cystitis and hyperreflex voiding of the bladder. In addition, it has been suggested that tachykinin receptor antagonists have utility in the following disorders: depression, dysthymic disorders, chronic obstructive airway disease, hypersensitivity disorders such as poison ivy (Rhus toxicodendron), vasospastic diseases such as angina and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder / hand syndrome, addiction disorders such as alcoholismsomatic disorders related to stress, neuropathy, neuralgia, disorders related to the increase or immunological suppression such as lupus erythomatosus, ophthalmic diseases such as conjunctivitis, vernal conjunctivitis and the like and cutaneous diseases such as contract dermatitis, atopic dermatitis, urticaria and others eczematoid dermatitis. Attempts have been made to provide antagonists for the substance P receptors and other tachykinin peptides to more effectively treat the various disorders and diseases mentioned above. In particular, PCT Publication No. WO 94/00440. EPO Publication No. 0.577.394 and PCT Specification No. WO 95/16679 disclose certain morpholine and thiomorpholine compounds as antagonists of the substance P. In particular, the compound 2- (R) - (1-R) - ( 3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1,2,4- 0 triazole) methylmorpholine is described as the title compound in Example 75 of PCT Publication No. WO 95/16679. This compound was subsequently identified as the polymorph form designated herein as "Form M". The morphological forms of the pharmaceutical compounds may be of interest to interested in the development of a suitable dosage form, since if the morphological form is not kept constant during clinical and stability studies, the exact dose used or measured may not be comparable from one batch to another. produces a pharmaceutical product to use it, it is important to recognize the morphological form delivered in each dosage form To ensure that the production procedure uses the same form and that the same dosage form is included in each dosage. Therefore, it is imperative to ensure that a single morphological form or some known combination of morphological forms is present. In addition, certain morphological forms they may exhibit enhanced thermodynamic stability and may be more suitable than other morphological forms for inclusion in pharmaceutical formulations. As used herein, a polymorphic form of a chemical compound is the same chemical entity, but with a different crystal arrangement.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray diffraction pattern of the powder of Form 1 of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- ( S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine Figure 2 is a powder X-ray diffraction pattern of Form II of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new polymorphic form of the compound 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine and the process for preparing it The compound 2- (R) - (1 -R) - (3,5 Bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine has the structure: M * which is a tachykinin receptor antagonist, useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis. This particular polymorphic form (designated here as "Form I") has superior properties over other crystalline forms of the compound, in that it is more thermodynamically stable than other morphological forms and is more suitable for inclusion in pharmaceutical formulations. The present invention also relates to a process for the preparation of Form I of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine, which comprises: - balancing Form II of 2- (R) - (1- R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H.4H-1, 2, 4-triazole) methylmorpholine in a solvent selected from ethanol, 2-propanol, acetonitrile and isopropyl acetate The present invention further relates to a process for the preparation of Form I 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H.4H-1, 2,4- triazole) methylmorpholine, which comprises: - heating a sample of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine of optional morphological composition, in a temperature range between 215 and 230 ° C, and then - allow the sample return to the room temperature. In particular, the heating of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3 - (5-oxo-1 H.4H-1, 2,4-triazole) methylmorpholine can be carried out in an open tray under a nitrogen atmosphere, heating the 2- (R) - (1-R) - (3,5- bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine at a temperature at 215-230 ° C and then cooled to room temperature Preferably, the morphological composition of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- ( S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine is initially Form II In addition, the present invention relates to a process alternative, particularly useful for the preparation of Form I and 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) ) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine, on a larger scale, comprising: suspending 2- (R) - (1 -R) - (3 , 5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4- f luoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine of optional morphological composition in methanol / water solution, preferably in ratio 2/1 (v / v); - add seed crystals of Form I of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (SH4-fluoro) phenyl-4- (3 - (5-oxo-1 H.4H-1, 2,4-triazole) methylmorpholine: - stir the resulting mixture, between 0 to 50 ° C, for a sufficient period to produce Form I of 2- (R ) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H -1, 2,4-triazole) methylmorpholine; and - collecting the resulting Form I from 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine Similarly, the present invention is also directed to a process for the preparation of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H.4H-1, 2,4-triazole ) morphologically homogeneous methylmorpholine, which comprises any of the above-mentioned processes The compound of this invention, the novel polymorphic form of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine, is a receptor antagonist of tachykinins useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis. Therefore, the present invention is further directed to pharmaceutical formulations comprising this polymorphic form as an active ingredient and the use of this polymorphic form and its formulations in the treatment of certain disorders. Form I of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- ( 5-oxo-1 H, 4H-1, 2,4-triazole) Methylmorpholine is anhydrous and non-hygroscopic and exhibits a high degree of thermal stability as a pure solid and in hydro-alcoholic solution Form II 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H- 1, 2,4-triazole) methylmorpholine is an anhydrous crystalline material that melts at 254 ° C, which is obtained directly from recrystallization in the chemical synthesis of 2- (R) - (1-R) - (3,5 Bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine.

Diffraction of X-Rays to Dust (XRPD) Diffraction studies of X-rays to dust have been widely used to elucidate molecular structures, crystallinity and polymorphism. X-ray powder diffraction patterns were recorded using a Philips model APD 3720 powder diffractometer, equipped with a 3 Kw X-ray generator (CUKal radiation) and a Nal (Time) scintillation detector. The measurements were made from 3o to 45 ° (2 theta), with the sample at room temperature, which are presented in Figure 1 and Figure 2. Form I of 2- (R) - (1-R) - (3,5-bis (tpfluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1) 2, 4-triazole) methylmorpholine was characterized by a diffraction pattern of X-rays to the powder with key reflections at: 12.0; 15.3; 16.6; 17.0; 17.6; 19.4; 20.0; 21.9; 23.6; 23.8 and 24.8 ° (2 theta) approximately. Form II of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenol) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H.4H-1, 2,4-triazole) methylmorpholine was characterized by a diffraction pattern of X-rays to the powder, with key reflections to: 12.6, 16.7, 17.1, 17.2; 18.0; 20.1; 20.6; 21.1; 22.8; 23.9 and 24.8 ° (2 theta) approximately These XRPD patterns confirm that both samples are distinct crystalline forms, both Form I and Form II exhibit intense peaks, characteristic of material crystalline.

Differential Scanning Calorimetric Cell [DSCj The differential scanning calorimetry of Form I of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine and of Form II 2- (R) - (1-R) - (3 , 5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine they did not show significant differences in their thermal behavior, both phases produced thermograms with a single melting endotherm at the same temperature, in particular, the DSC curve of Form I of 2- (R) - (1-R) - (3, 5- bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-5-triazole) methylmorpholine exhibited a single fusion endotherm, with a peak temperature of 255.8 ° C, an extrapolated temperature of start of 254.7 ° C and an enthalpy of 105J / g.The DSC curve of Form II of 2- (R) - (1- R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenol-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methyl Morpholine also exhibited a single melting endotherm with a peak temperature of 255.6 ° C, an extrapolated temperature of onset of 254.4 ° C and an enthalpy of 107 J / g.

NMR The proton and 15 carbon magnetic resonance spectra of Form I and Form II did not indicate chemical changes in the compound, converting it from Form II to Form I.

Solubility The solubility of Form I in methanol / water 2/1 (v / v) at 0 ° C determined that it was 0.9 ± 0.1 mg / molecule. The solubility of Form II in methanol / water 2/1 (v / v) at 0 ° C was determined to be 1.3 ± 0.2 mg / molecule. The ratio of the solubilities is 1.4, which indicates that Form I is the more stable polymorph. Form I is more stable than form II by 0.2 kcal / mol.

Steam Pressures The vapor pressures of Form I and Form II at elevated temperatures were similar when examined by Knudsen effusion techniques.

ANATOGONISM TEST OF THE TAQUIQUININE The Compound of this invention, Polymorphic Form I 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl -4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine is useful for antagonizing tachykinins, in particular, substance P and neurokinin A, in the treatment of gastrointestinal disorders , disorders of the central nervous system, inflammatory diseases, pain or migraine, asthma and emesis, in mammals in need of such treatment.This activity can be demonstrated by the following test.

A. Expression of the receptor in COS To express the human neurokinin-1 receptor, cloned (NK1 R) transiently in COS, the human NK1 R cDNA was cloned into the expression vector pCDM9, which was derived from pCDM8 (INVITROGEN) by inserting the ampicillin resistance gene (nucleotides 1973 to 2964 of ^ - "^^^ i ^ fffffrfi-ifil BLUESCRIPT SK +) within the Sac II site Transfection of 20 ug of plasmid DNA into 10 million COS cells was achieved by electroporation in 800 ul transfection buffer (135 mM of NaCl, 1.2 mM of CaCl2, 1.2 mM MgCl2> 2.4 mM of K2HPO4, 0.6 mM of KH2PO4, 10 mM of glucose, 10 mM of HEPES at pH 7.4) at 260 V and 950 uF, using the GENEZAPPER IBI (IBI, New Haven, CT) Cells were incubated in 10% fetal calf serum, 2 mM glutamine, 100 U / ml penicillin-streptomycin and 90% DMEM medium (GIBCO, Grand Island, NY) in 5% CO2 , at 37 ° C for three days before the agglomeration test.

B. Stable Expression in CHO To establish a stable cell line expressing the cloned human NK1 R, the cDNA was sub-cloned into the vector pRcCMV (INVITROGEN). Transfection of 20 ug of plasmid DNA into CHO cells was achieved by electroporation in 800 ul of transfection buffer supplemented with 0.625 mg / sardine sperm DN DN at 300 V and 950 uf, using the GENEZAPPER IBI (IBI). Transfected cells were incubated in CHO medium [10% fetal calf serum, 100 U / ml penicillin-streptomycin, 2 mM glutamine, 1/500 hypoxanthine-thymidine (ATCC), 90% IMDM medium (JRH BIOSCIENCES, Lenexa, KS), 0.7 mg / molecule of G418 (GIBCO)] in 5% CO2 at 37 ° C until the colonies became visible. Each colony separated and spread. The cell clone with the highest number of human NK1 R was selected for the sub-applications, such as drug isolation. c. Test Protocol Using COS or CHO The agglomeration test of NK1 R expressed both in cells COS as in CHO cells is based on the use of 125 I-substance P (125 I-SP, from DUPONT, Boston, MA) as a radioactively labeled ligand, which competes with the unlabeled substance P, or any other ligand, for agglomerate with the human NK1 R. Cultures of COS or CHO monolayer cells were dissociated with the non-enzymatic solution (SPECIALTY MEDIA, Lavallette, NJ) and re-suspended in an appropriate volume of agglomeration buffer (50 mM Tris at pH 7.5, 5 mM MnCl2, 150 mM of NaCl, 0.04 mg / ml of bacitrin, 0.004 mg / ml of leupeptin, 0.2 mg / ml of BSA, 0.01 mM of phosphoramidon) so that 200 ul of cell suspension gave rise to about 10,000 cpm of specific agglomeration 125l- Sp (approximately 50,000 to 200,000 cells). In the agglomeration test, 200 ul of cells was added to a tube containing 20 ul of 125 I-substance P 1.5 at 2.5 nM and 20 ul of unlabeled substance P, or any other test compound. The tubes were incubated at 4 ° C or at room temperature for 1 hour, with gentle shaking. The agglomerated radioactivity was separated from the non-agglomerated radioactivity by a GF / C filter (BRANDEL, Gaithersburg, MD) which had been pre-moistened with 0.1% polyethylenimine. The filter was washed with 3 ml of wash buffer (50 mM Tris pH 7.5, 5 mM of MnCl2, 150 mM NaCl), three times and its radioactivity was determined with a gamma counter. Activation of phospholipase C by NK1 R can also be measured in CHO cells expressing human NK1 R, determining the accumulation of inositol monophosphate, which is a product of IP3 degradation. CHO cells are seeded in 12-well plates at 250,000 cells per well. After incubation in CHO medium for 4 days, the cells are loaded with 0.025 uCi / ml of 3 H-myoinositol by incubation overnight. The extracellular radioactivity was removed by washing it with phosphate buffered saline. LiCl is added to the well at a final concentration of 0.1 mM, with or without the test compound, the incubation being continued at 37 ° C for 15 minutes. Substance P is added to the well at a final concentration of 0.3 nM, to activate the human NK1 R. After 30 minutes of incubation at 37 ° C, the medium is removed and 0.1 N HCl is added. Each well is sonicated at 4 ° C and extracted with CHCl 3 / methanol (1: 1). The aqueous phase is applied to a 1 ml Dowex AG 1X8 ion exchange column. The column is washed with 0.1 N formic acid, followed by 0.025 M ammonium formate - 0.1 N formic acid. Inositol monophosphate is eluted with 0.2 M ammonium formate / 0.1 N formic acid and quantified with a beta counter. The activity of the present compound can also be demonstrated by the assay described by Lei et al. British J. Pharmacol., 105, 261-262 (1992).

The compound of the present invention is valuable in the treatment of a wide variety of clinical conditions, which are characterized by the presence of an excess of activity of tachykinin, in particular, the substance P. Thus, for example, an excess of activity of tachykinin, and in particular substance P, is implicated in a variety of disorders of the central nervous system. Such disorders include behavioral disorders, such as depression or, more particularly, depressive disorders, for example, major depressive disorders of single or recurrent episodes, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder, with or without agoraphobia, agoraphobia with no history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, tension disorders including post-traumatic disorder , acute tension disorder and generalized anxiety disorders, schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, illusory disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with illusions or hallucinations; delirium, dementia, amnesia and other cognitive or neurodegenerative disorders, such as Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, vascular dementia and other dementias, for example, those due to HIV disease, brain trauma, Parkinson's disease , Huntington's disease, • & **? J jt ¿& ~ - * '. - > Pick's disease, Creutzfeld-Jakob disease, or due to multiple etiologies; Parkinson's disease and other extrapyramidal movement disorders, such as movement disorders induced by remedies, for example, neuroleptically induced parkinsonism, neuroleptic malignant syndrome, acute neuroleptically induced dystonia, acute neuroleptically induced akatisia, neuroleptically induced tardive dyskinesia, and posturally induced postural remedies disorders related to substances derived from the use of alcohol, amphetamines (or substances of the amphetamine type), caffeine, marijuana, cocaine, hallucinogens, inhalants, aerosol propellants, nicotine, opioids, phenylglycine derivatives, sedatives, hypnotics and anxiolytics, Substance-related disorders include dependence and abuse, intoxication, abandonment, intoxication delirium, persistent dementia, psychotic disorders, behavioral disorders, anxiety disorder, sexual dysfunction, and sleep disorders; epilepsy; Down's Syndrome; demyelinating diseases such as MS and ALS and other neuropathological disorders such as peripheral neuropathy, for example, diabetic neuropathy or chemotherapy-induced. Post-herpetic neuralgia, trigeminal, segmental or intercostal neuralgia and other neuralgia; and cerebral vascular disorders due to acute or chronic damage such as cerebral infarction, sub-arachnoid hemorrhage or cerebral edema. The activity of tachykinin and, in particular, the substance P, is also related to involuntary nerve discharges and pain. The compound of the present invention, therefore, will be used in the prevention or treatment of diseases or conditions in which pain predominates, including damage to the soft tissues and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, pain muscle-skeletal, particularly after trauma, spinal pain, myofascial pain syndromes, headache, episiotomy pain and burns; deep and visceral pains, such as cardiac pain, muscle pain, eye pain, orofacial pain, for example, toothache, abdominal pain, gynecological pain, for example, dysmenorrhea and labor pain, pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, eg, nerve compression and brachial plexus avulsions, amputation, peripheral neuropathies, painful tic, atypical facial pain, damage to the nerve root and arachnoiditis, pain associated with carcinoma, often designated as cancer pain; central nervous system pain, such as pain due to damage to the spinal cord or brainstem; Pain in the back side of the back; sciatica; ankylosing spondylitis, gout and scarring pains. Tachykinin antagonists, and in particular substance P, may be useful in the treatment of respiratory diseases, particularly those associated with an excess of mucus secretion, such as chronic obstructive airway disease, bronchopneumonia, chronic bronchitis, fibrosis. cystic and asthma, respiratory distress syndrome in adults and bronchospasm; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, rheumatoid arthritis, pruritus and sunburns; allergies such i as eczema and rhinitis; hypersensitivity disorders such as poison ivy, ophthalmic diseases such as conjunctivitis, vernal conjunctivitis and the like; ophthalmic conditions associated with proliferation of cells such as vitreoretinopathy, cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematous dermatitis. Tachykinin antagonists and, in particular, substance P may also be useful in the treatment of neoplasms, including breast tumors, neuroganglioblastomas and small cell carcinomas such as small cell cancer of the pulp. Tachykinin antagonists and, in particular, substance P may also be useful in the treatment of gastrointestinal (Gl) disorders, including inflammatory disorders and diseases of the Gl tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with neuronal control of viscera, ulcerative colitis, irritable bowel syndrome and emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy , radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, eg dizziness caused by movement, vertigo, fainting and Meniere's disease, surgery, migraine, variations in intracranial pressure, gastro-esophageal reflux disease, acid indigestion, overindulgence in food or drink, heartburn, regurgitation , Ardencies for example, episodic, nocturnal or food-induced ardencies and dyspepsia. Tachykinin antagonists and, in particular, substance P may also be useful in the treatment of a variety of other conditions including somatic disorders related to tension; sympathetic dystrophy reflects such as hand / shoulder syndrome; adverse immune reactions such as rejection of transplanted tissues and disorders related to augmentation or suppression such as systemic lupus erythematosus, plasma extravasation resulting from chemotherapy with cytokines, disorders of bladder function such as cystitis, hyperreflexive emptying of the bladder and incontinence; fibrosis and collagen diseases such as scleroderma and eosinophilic fascioliasis; blood flow disorders caused by vasodilatation and vasospastic diseases such as angina, vascular headache, migraine and Reynaud's disease and pain associated with any of the above conditions, especially pain transmission in migraine. The compound of the present invention is also useful in the treatment of a combination of the above conditions, in particular in the treatment of combined postoperative pain and postoperative nausea and vomiting. The compound of the present invention is particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, movement, surgery, migraine and variations of the intracranial pressure. Most especially, the compound of the present invention is for use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy. Examples of such chemotherapeutic agents include alkylating agents for example, nitrogen mustards, ethyleneimine compounds, alkylsulfonates and other compounds with alkylating action such as nitrosoureas, cisplatin and dicarbazine, antimetabolites, eg, folic acid, purine antagonists, pyrimidine; mitotic inhibitors, for example, vinca alkaloids and podophyllotoxin derivatives and cytotoxic antibiotics. Particular examples of chemotherapeutic agents are described, for example, by D.J. Stewart in "Nausea and Vomiting: Recent Research and Clinical Advances" Eds. J. Kucharczyk et al., CRC Press Inc., Boca Raton, Florida, USA (1991), pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (mustard nitrogen), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etopside, metrotrexate, 5-fluorouracil, vlinblastine, vincristine, bleomycin and chlorambucil [RJ Gralla et al., Cancer Treatment Reports, 68 (1), 163-172 (1984)].

The compound of the present invention is also useful in the treatment of radiation induced emesis including radiation therapy such as in the treatment of cancer, or radiation sickness and in the treatment of postoperative nausea or vomiting. For the treatment of certain conditions it may be desirable to employ the compound of the present invention in conjunction with another pharmacologically active agent. It will be understood that the compound of the present invention can be presented together with another therapeutic agent, such as a combined preparation, to be used simultaneously, separately or sequentially in the relief of emesis. Such combined preparations can be, for example, in the form of twin containers. A further aspect of the present invention comprises the compound of the present invention in combination with a t-HT3 antagonist, such as odansetron, granisetron, tropisetron or zatisetron or other anti-emetic drugs, for example, dexamethasone or a dopamine antagonist such as like metoclopramide. Additionally, the compound of the present invention can be administered in combination with an anti-inflammatory costicosteroid, such as dexamethasone. Moreover, the compound of the present invention can be administered in combination with a chemotherapeutic agent such as an alkylating agent, antimetabolite, mitotic inhibodor or cytotoxic antibiotic, as described above. In general, the currently available dosage forms of the known therapeutic agents are suitable for use in such combinations.

When tested in the ferret model, for emesis induced by cisplatin, as described by F.D. Tattersall et al., Eur. J. Pharmacol., (1993) 250, R5-R6, the compound of the present invention was found to attenuate the nausea and vomiting induced by cisplatin. The compound of the present invention is also particularly useful in the treatment of involuntary pain or nerve discharge and / or inflammation and disorders associated with them, such as, for example, neuropathy, such as that induced by diabetes and chemotherapy, postherpetic neuralgia and others, asthma. , osteoarthritis, rheumatoid arthritis and headache, including migraine, acute or chronic tension headache, temporomandibular pain headache and maxillary sinus pain. The present invention further provides the compound of the present invention for use in therapy. According to a further or alternative aspect, the present invention provides the compound of the present invention for use in the manufacture of a medicament for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially the substance P. The present invention it also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administering to a patient in need thereof, a reducing amount of the compound of the present invention, or a composition comprising the compound of the present invention. For the treatment of certain conditions it may be desirable to employ a compound according to the present invention, in conjunction with another pharmacologically active agent. For example, for the treatment of respiratory diseases such as asthma, the compound of the present invention can be used in conjunction with a bronchodilator, such as the β2-adrenergic receptor antagonist or the tachykinin antagonist acting at the NK-2 receptors. The compound of the present invention and the bronchodilator can be administered to a patient simultaneously, sequentially or in combination. For the treatment of conditions that require antagonism of both, neurokinin-1 and neurokinin-2, including disorders associated with bronchoconstriction and / or extravasation of plasma in the airways, such as asthma, chronic bronchitis, airway diseases or cystic fibrosis, the compound of the present invention can be used in conjunction with a tachykinin antagonist that acts on neurokinin-2 receptors, or with a tachykinin receptor antagonist that acts on both the neurokinin-1 and the neurokinin receptors -2. Similarly, the compound of the present invention can be used with leukotriene antagonists, such as leukotriene D antagonist, such as a compound selected from those described in the specification of European Patent Nos. 0 480 717 and 0 604 114 and üiB ^ ^ Éi ^ in U.S. Patents Nos. 4,859,692 and 5,270,324. This combination is particularly useful in the treatment of respiratory diseases such as asthma, chronic bronchitis and cough. The present invention, therefore, provides a method for the treatment of respiratory diseases, such as asthma, which method comprises administering to a patient in need thereof, an effective amount of the compound of the present invention and an effective amount of a bronchodilator The present invention also provides a composition comprising the compound of the present invention, a bronchodilator and a pharmaceutically acceptable carrier. It will be understood that for the treatment or prevention of migraine, the compound of the present invention can be used in conjunction with other anti-migraine agents, such as ergotamines or 5HT? especially sumatriptan or rizatriptan. Similarly, for the treatment of behavioral hyperalgesia, the compound of the present invention can be used in conjunction with an N-methyl-D-aspartate (NMDA) antagonist, such as dizocipine. For the treatment or prevention of inflammatory conditions in the lower urinary tract, especially cystitis, the compound of the present invention can be used in conjunction with an anti-inflammatory agent such as the bradykinin receptor antagonist. The present invention also provides a composition comprising the compound of the present invention, a bronchodilator and a pharmaceutically acceptable carrier.

It will be understood that for the treatment or prevention of pain or involuntary nerve discharges, the compound of the present invention can be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs and, particularly, opioid analgesics, especially morphine. Specific anti-inflammatory agents include diclofenac, ibuprofen, indmetacin, ketroprofen, naproxen, piroxicam and sulindac. Opioid analgesics suitable for use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetyl morphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, afenanthyl, buprenorphine, butorphanol, fentanyl, sufentanil, meperidine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof. Preferred salts of these opioid analgesics include morphine sulfate, morphine hydrochloride, morphine tartrate, codeine phosphate, codeine sulfate, dihydrocodeine bismatrate, hydromorphone hydrochloride, levorphanol tartrate, oxymorphone hydrochloride, phenanthyl hydrochloride, hydrochloride buprenorphine, butorphanol tartrate, phenanthyl citrate, meperidine hydrochloride, methadone hydrochloride, nalbuphine hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate (2-naphthalenesulfonic acid monohydrate (1: 1)) and pentazocine hydrochloride. Therefore, in a further aspect of the present invention, a pharmaceutical composition comprising the compound of the invention is provided. present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient. In a further, alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an analgesic, such as a combined preparation, for simultaneous, separate or sequential use in the treatment or prevention of pain or discharges. Involuntary nervous Additionally, it will be understood that for the treatment or prevention of depression and / or anxiety, the compound of the present invention can be used in combination with an antidepressant or anti-anxiety agent. Suitable classes of antidepressant agents for use in the present invention include: norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, reversible monoamine oxidase inhibitors, serotonin and noradrenaline reuptake inhibitors, corticotropin-releasing factor (CRF) antagonists, α-adrenoceptor antagonists and atypical antidepressants. "Another class of antidepressant agent, for use in the present invention are specific noradrenergic and serotonergic antidepressants, Examples of suitable norepinephrine reuptake inhibitors include amitripdiline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, macrotiline, nortriptyline, reboxetine and protriptyline and the pharmaceutically acceptable salts thereof. Serotonin reuptake includes fluoxetine, fluvoxamine, paroxetine and sertraline and the pharmaceutically acceptable salts thereof Suitable examples of monoamine oxidase inhibitors include isocarboxacid, phenelzine, tranylcypromaine and selegiline and the pharmaceutically acceptable salts thereof. Suitable examples of reversible monoamine oxidase inhibitors include moclobemide and the pharmaceutically acceptable salts thereof. Suitable examples of serotonin and noradrenaline reuptake inhibitors include venlafaxine and pharmaceutically acceptable salts thereof. Suitable examples of corticotropin releasing factor (CRF) antagonists include those compounds described in the Descriptive Specifications of International Patent Nos. WO 94/13643, WO 94/13661, WO 94/13644, WO 94/13676 and WO 94 / 13677. Suitable examples of atypical antidepressants include bupropion, lithium, nefazoedone, sibutramine, trazodone and viloxazine and the pharmaceutically acceptable salts thereof. Other antidepressants for use in the present invention include adinozolam, alaproclate, amineptine, the combination amitriptyline / clordiazepoxide, atipamezole, azamianserin, bazinaprine, fefuraline, bifemelane, binodaline, bipenamol, brofaromine, bupropion, caroxazone, cericlamine, cyanopramine, cimoxanthone, citalopram, clemeprol , clovoxamine, desapenyl, deanol, demexiptiline, dibenzepine, dotiepina, droxidropa, enefexina, setazolam, etoperidone, femoxetina, fengabina, fezolamine, fluotracen, idazoxan, indalpina, indeloxazina, iprindole, levoprotilina, litoxetina, lofepramina, medifoxammina, ^ ^ ^ ^ ^ JSjte faith? ? Or metapramin, metralindol, mianserin, milnacipran, minaprine, mirtazapine, montirelin, nebracetam, nefopam, nialamide, nomifensin, norfluoxetine, orotrelin, oxaflozane, pinazepam, pyrindole, pizotiline, ritaserin, rolipram, serchloremin, setiptilin, sibutramine, sulbutiamine, sulpride , tenyloxazine, thozalinone, thymoliberin, thianeptin, tiflucarbin, tofenacin, tofisopam, toloxatone, tomoxetine, veralipride, viqualine, zimelidine and zometapine and the pharmaceutically acceptable salts thereof and the herb St. John's wort (Hypericum perforaturm) or extracts thereof. Antidepressant agents include selective inhibitors of serotonin rake, in particular, fluoxetine, fluvoxamine, paroxetine and sertraline and the pharmaceutically acceptable salts thereof. Suitable classes of anti-anxiety agents for use in the present invention include benzodiazepines and 5-HTIA agonists or antagonists, especially the partial agonists of 5-HT1A and the corticotropin-releasing factor (CFR) antagonists. In addition to benzodiazepines, other suitable classes of anti-anxiety agents are sedative-hypnotic non-benzodiazepine drugs, such as zolpidem; behavioral stabilizing drugs such as clobazam, gabapentin, lamotrigine, loreclezole, oxcarbamzepine, stripentol and vigabatrin; and the barbiturates. Benzodizepins suitable for use in the present invention include alprazolam, clordizepoxide, clonazepam, clorazepate, diazepam, halazepam, lorezepam, oxazepam and prazepam and the pharmaceutically acceptable salts thereof. Examples of 5-HT A agonists or antagonists for use in the present invention include, in particular, the partial agonists of 5-HT1A, buspirone, flesinoxan, gepirone, ipsapirone, and pindolol and the pharmaceutically acceptable salts thereof. Suitable examples of corticotropin-releasing factor (CRF) antagonists include those compounds described in the Descriptive Memoirs Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677. . Another class of anti-anxiety agents for use in the present invention are compounds that have cholinergic muscarinic activity. Suitable compounds of this class include muscarinic cholinergic receptor m 1 antagonists, such as those compounds described in the Descriptive Specifications of European Patent Nos. 0 709 093, 0 709 094 and 0 773 021 and in International Patent Specification No. WO 96/12711. Another class of anti-anxiety agent for use in the present invention are compounds that act on ion channels. Suitable compounds of this class include carbamazepine, lamotrigine and vaproate and the pharmaceutically acceptable salts thereof. Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of the present invention and a surfactant or anti-anxiety agent, together with at least one pharmaceutically acceptable carrier or excipient. Suitable anti-psychotic agents to be used in combination with the compound of the present invention include the classes of phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indole of anti-psychotic agents. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. Suitable examples of dibenzazepines include clozapine and olanzapine. An example of butyrophenone is haloperidol. An example of fifenylbutylpiperidine is pimozide. An example of indole is molindolone. Other anti-psychotic agents include loxapine, sulpride and rispepdone. It will be understood that anti-psychotic agents, when used in combination with the compound of the present invention may be in the form of a pharmaceutically acceptable salt., for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenozine maleate, fluphenazine hydrochloride, flupfenazine enatate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate, and hydrochloride molindona. Perphenazine, chlorprothixene, clozapine, olanzapine, haloperidol, pimozide and risperidone are commonly used in the form of non-salt. Other classes of anti-psychotic agents to be used in combination with the compound of the present invention include dopamine receptor antagonists, especially the D2, D3 and D4 receptor antagonists, and m1 muscarinic receptor agonists. An example of a dopamine D3 receptor antagonist is compound PNU-99194A m1. An example of a dopamine D4 receptor antagonist is the compound H ^^^ l ¡¡¡¡¡¡¡^^^ j PNU-101387. An example of muscarinic receptor agonist m1 is xanomelin. Another class of anti-psychotic agent to be used in combination with the compound of the present invention are the 5-HT1A receptor antagonists, examples of which include MDL100907 and fananserin. Also to be used in combination with the compound of the present invention are the serotonin dopamine antagonists (SDAs) which are believed to combine the activity of 5-HT-? A receptor agonists and dopamine, examples of which include olanzapine and ziperasidone . Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of the present invention and an anti-psychotic agent, together with at least one pharmaceutically acceptable carrier or excipient. The compound of the present invention and the other pharmacologically active agent can be administered to a patient simultaneously, sequentially or in combination. It will be understood that when a combination of the present invention is used, the compound of the present invention and the other pharmacologically active agent can be in the same pharmaceutically acceptable carrier and, therefore, can be administered simultaneously. They can be in separate pharmaceutical vechicles, such as conventional oral dosage forms, which are taken simultaneously. The term "combination" further refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. The pharmacological profile of the compound of the present invention offers the opportunity for use in therapy at low doses, thus minimizing the risk of undesirable side effects. The compound of the present invention can be administered to patients (animals and humans) in need of such treatment, in dosages that provide optimum pharmaceutical efficiency. It will be understood that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition to be treated, the age and condition of the patient. , concurrent medication or special diets followed by the patient and other factors that those trained in the art will recognize, with the appropriate dose being dictated by the attending physician. In the treatment of a condition associated with an excess of tachykinins, an appropriate dosage level will be, in general, from 0.001 to 50 mg per kilogram of the patient's live weight, per day, which can be administered in single or multiple doses. Preferably, the dosage level will be between 0.01 to 25 mg / kg per day; more preferably around 0.05 to 10 mg / kg per day. For example, in the treatment of conditions that encompass the neurotransmission of pain sensations, a suitable dosage level is around 0.001 to 25 mg / kg per ^ A ^ l ^ X * ^^ h ^. ^ Day, preferably, from 0.005 to 10 mg / kg per day and, especially, from 0.01 to 5 mg / kg per day. A compound can be administered in the regimen 1 to 4 times daily, preferably once or twice daily. In the treatment of emesis, a suitable dosage level is from 0.001 to 10 mg / kg per day, preferably, from 0.005 to 5 mg / kg / day and, especially, from 0.01 to 1 mg / kg per day. The compound can be administered in a regimen of 1 to 4 times daily, preferably once or twice daily. In the treatment or prevention of a central nervous system disorder, a suitable dosage level is from 0.001 to 10 mg / kg per day, preferably, from 0.005 to 5 mg / kg per day and, especially, from 0.01 to 1 mg / day. kg per day. The compound can be administered in a regimen of 1 to 4 times daily, preferably once or twice daily. It will be understood that the amount of the compound of the present invention, required for use in any treatment will vary, not only with the particular compounds or composition selected, but also with the route of administration, the nature of the condition to be treated and the age and condition of the patient and, ultimately, will be at the discretion of the attending physician. The pharmaceutical compositions of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semi-solid or liquid form, which contains one or more of the compounds of the present invention, as an active ingredient, in admixture with a vehicle organic or inorganic, or suitable excipient for external, inert or parenteral applications. The active ingredient may be mixed, for example, with non-toxic, pharmaceutically acceptable carriers, customary for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and any other form of suitable use. The vehicles that can be used are water, glucose, lactose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other suitable vehicles for the manufacturing of preparations in solid, semi-solid or liquid form and, in addition, additional stabilizing agents, thickeners and dyes and perfumes. The active ingredient of the compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect in the disease process or condition. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example, conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums of other pharmaceutical diluents, e.g., water, to form a preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. By referring to such preformulation compositions as homogeneous, it means that the active ingredient is evenly distributed in the composition, so that it can be easily subdivided into equally effective dosage forms, such as tablets, pills and capsules. This solid preformulation composition is subdivided into dosage forms of the above-mentioned type, containing from 0.1 to 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated and compounded in some other way, to provide a dosage form with the advantages of a prolonged action. For example, the tablet or pill can comprise an internal dosing component and an external one, the latter in the form of a wrapping of the former. The two components can be separated for an enteric layer which serves to resist disintegration in the stomach and allows the internal component to pass intact to the duodenum or have delayed release. A variety of materials can be used for these enteric layers or coatings, such materials include an amount of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate. Liquid forms in which the novel compositions of the present invention can be incorporated by oral or injection administration include aqueous solution, suitably flavored syrups, aqueous and oily suspensions and emulsions with suitable oils such as cotton nuggets, sesame oil, oil of coconut or peanut, or with a suitable solubilizing or emulsifying agent for intravenous use, as well as elixirs and similar pharmaceutical vehicles. Dispersing or suspending agents suitable for aqueous suspensions include gums f ^ j? ^. synthetic and natural, such as tragacanth gum, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin. Compositions for inhalation or insufflation include solutions or suspensions in pharmaceutically acceptable solvents, aqueous or orthoanic solvents, or mixtures thereof and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients, as discussed above. Preferably, the compositions are administered orally or nasally, to have local or systemic effects. Preferably, the compositions in sterile, pharmaceutically acceptable solvents can be nebulized by inert gases. The nebulized solutions can be breathed directly from the nebulizer device, or it can be connected to a face mask, tent or an intermittent, positive-pressure breathing machine. The solutions, suspensions or powder compositions can be administered orally or nasally, preferably from devices that deliver the formulation in an appropriate manner. For the treatment of clinical conditions and the aforementioned diseases, the compound of the present invention can be administered orally, topically, parenterally, by inhalation of aspersion, or rectally in formulations containing conventional, non-toxic, pharmaceutically acceptable vehicles and aids. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular or intramuscular injections or infusion techniques.

The methods for preparing the polymorphic forms of this invention are illustrated in the following Examples. The following Examples are given for the purpose of illustrating the present invention and should not be construed as limitations on the scope or spirit of the present invention.

EXAMPLE 1 (S) - (4-fluorophenyl) qyline Via Sintensis Quiral. Step A: 3- (4-fluorophenyl) acetit-4- (S) -benzyl-2-oxazotidonone A 1-liter, three-neck flask, oven dried, equipped with a partition, nitrogen inlet, thermometer and a magnetic stir bar, rinsed with nitrogen and charged with a solution of 5.09 g (33.0 mmol) of 4-fluorophenylacetic acid in 100 ml of anhydrous ether. The solution was cooled to -100 ° C and treated with 5.60 ml (40.0 mmol) of triethylamine, followed by 4.30 ml (35.0 mmol) of trimethylacetyl chloride. A white precipitate formed immediately. The resulting mixture was stirred at -10 ° C for 40 minutes and then cooled to -78 ° C. A 250 ml round bottom flask, oven dried, equipped with a partition and a magnetic stir bar, rinsed with nitrogen, was charged with a solution of 5.31 g (30.0 mmol) of 4- (S) -benzyl-2. -oxazolidinone in 40 ml of dry THF. The solution was stirred in a dry ice / acetone bath for 10 minutes and then 18.8 ml of a 1.6M n-butyl lithium solution in hexanes was slowly added. After 10 minutes, the lithiated solution of oxazolidinone was added via cannula to the three-necked flask mixture. The cooling bath was removed from the mixture and the temperature was allowed to rise to 0 ° C. The reaction was warmed with 100 mL of saturated aqueous solution of ammonium chloride, transferred to a 1 L flask and the ether and THF were removed in vacuo. The concentrated mixture was partitioned in 300 ml of methylene chloride and 50 ml of water and the layers were separated. The organic layer was washed with 200 ml of 2N hydrochloric acid aqueous solution, 300 ml of saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate and a vacuum was concentrated. Flash chromatography on 400 g of silica gel, using hexanes / ether 3: 3 v / v as eluent, gave 8.95 g of an oil which solidified slowly at rest. Recrystallization from hexanes / ether 10: 1 gave 7.89 g (83%) of the title compound, as a white solid, melting point 64-66 ° C. Mass Spectrum (FAB): m / Z 314 (M + H, 100%), 177 (M-ArCH2CO + H, 85%). 1 H NMR (400 MHz, CDCl 3): d 2.76 (dd, 1 H, J = 13.2, 9.2), 3.26 (dd, J = 13.2, 3.2), 4.16-4.34 (m, 4H), 4.65-4.70 (m, 1 H), 7.02-7.33 (m, 9H). Analysis: calculated for C18H? 6FNO3: C, 60.00; H, 5.15; N, 4.47; F, 6.06. Found: C, 68.86; H, 5.14; N, 4.48; F, 6.08.

Step B: 3 - ((S) -azido- (4-fluorophenyl) acetyl-4- (S) -benzyl-2-oxazolidinone A 1-liter, three-necked, oven-dried flask, equipped with a partition, inlet of nitrogen, thermometer and a magnetic stir bar, rinsed with nitrogen and charged with a solution of 58.0 ml of 1 M potassium bis (trimethylsilyl) amide solution in toluene and 85 ml of THF and cooled to -78 ° C A 250 ml round bottom flask, oven dried and equipped with a partition and a magnetic stir bar was rinsed with nitrogen and charged with a solution of 7.20 g (23.0 mmol) of 3- (4-fluorophenyl) acetyl. -4- (S) -benzyl-2-oxazolidinone in 40 ml of THF The acyl oxazolidinone solution was stirred in a dry ice / acetone bath for 10 minutes and then transferred, via cannula, to the bis ( trimethylsilyl) amide of potassium, at a rate such that the internal temperature of the mixture was kept below -70 ° C. The acyl oxazolidinone flask was rinsed with 15 ml of THF and the rinse was added, via cannula, to the reaction mixture; The resulting mixture was stirred at -78 ° C for 30 minutes. A 250 ml round bottom flask, oven dried, equipped with a partition and a magnetic stir bar was rinsed with nitrogen and charged with a solution of 10.89 g (35.0 mmol) of 2,4,6-trisopropylphenylsulfonyl azide. in 40 ml of THF. The azide solution was stirred in a dry ice / acetone bath for 10 minutes and then transferred via cannula, to the reaction mixture, at a rate such that the internal temperature of the mixture remained below -70 ° C. . After 2 minutes, the reaction was warmed with 6.0 ml of glacial acetic acid, the cooling bath was stirred and the mixture was stirred at room temperature for 18 hours. The warm reaction mixture was partitioned between 300 ml of ethyl acetate and 300 ml of 50% saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 500 g of silica gel using hexanes / methyl chloride, first 2: 1 v / v and then 1: 1 v / v, as eluent gave 5.45 g (67%) of the title compound, as an oil. IR spectrum (pure, cm "1): 2104, 1781, 1702. 1 H NMR (400 MHz, CDCl 3): d 2.86 (dd, 1 H, J = 13.2, 9.6), 3.40 (dd, J = 13.2, 3.2) , 4.09-4.19 (m, 2H), 4.62-4.68 (m, 1 H), 6.14 (s, 1 H), 7.07-7.47 (m, 9H) Analysis: Calculated for C, 61.01; H, 4.27; N 15.81, F, 5.36, Found: C, 60.99, H, 4.19, N, 15.80, F, 5.34.

Step C: Acid (S) -azido- (4-fluorophenyl) acetic A solution of 5.40 g (15.2 mmol) of 3 - ((S) -azido- (4-fluorophenyl)) acetyl-4- (S) -benzyl -2-oxazolidinone in 200 ml of THF / water 3: 1 v / v was stirred in an ice bath for 10 minutes. 1.28 g (30.4 mmol) of lithium hydroxide monohydrate was added in one portion and the resulting mixture was stirred cold for 30 minutes. The reaction mixture was partitioned between 100 ml of methylene chloride and 100 ml of 25% saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was washed with 2 x 100 ml of methylene chloride and acidified to pH 2 with aqueous 2N hydrochloric acid solution. The resulting mixture was extracted with 2 x 100 ml of ethyl acetate; the extracts were combined, washed with 50 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 2.30 g (77%) of the title compound as an oil, which was used in the next step without further purification. IR spectrum (pure, cm-1): 2111, 1724. 1 H NMR (400 MHz, CDCl 3): d 5.06 (s, 1 H), 7.08-7.45 (m, 4H), 8.75 (br s, 1 H).

Step D: (SH4-fluorophenyl) qlycine A mixture of 2.30 g (11.8 mmol) of (S) -zido- (4-fluorophenyl) acetic acid, 250 mg of 10% palladium on charcoal catalyst and 160 ml of water / acetic acid 3: 1 v / v under a hydrogen atmosphere, for 18 hours. The reaction mixture was filtered through Celite and the flask and filter cake were rinsed well with -11 water / acetic acid 3: 1 v / v. The filtrate was concentrated in vacuo to about 50 ml in volume. 30 ml of toluene was added and the mixture was concentrated to give a solid. The solid was suspended in methanol / ether 1: 1 v / v, filtered and dried to give 1.99 g (100%) of the title compound. 1 H NMR (400 MHz, D 2 O + NAOD): d 3.97 (s, 1 H), 6.77 (app t, 2 H, J = 8.8), 701 (app t, 2 H, J = 5.6).

Via Resolution: Step A ': 4-fluorophenylacetyl chloride A solution of 150 g (0.974 mmol) of 4-fluorophenyl acetic acid and 1 ml of N, N-dimethylformamide in 500 ml of toluene, at 40 ° C, was treated with 20 ml of thionyl chloride and heated to 40 ° C. 61.2 ml of additional thionyl chloride was added dropwise over 1.5 hours. After the addition, the solution was heated at 50 ° C for 1 hour, the solvent was removed in vacuo and the residual oil was distilled under reduced pressure (1.5 mm Hg) to give 150.4 g (89.5%) of the title compound, Boiling point 68-70 ° C.

Step B: Methyl-2-bromo-2- (4-fluoro) phenylacetate A mixture of 150.4 g (0.872 mmol) of 4-fluorophenylacetyl chloride and 174.5 g (1.09 mmol) of bromine was irradiated at 40-50 ° C with a quartz lamp for 5 hours. The reaction mixture was added dropwise to 400 ml of methanol and the solution was stirred for 16 hours. The solvent was removed in vacuo and the residual oil was distilled under reduced pressure (1.5 mm Hg) to give 198.5 g (92%) of the title compound, boiling point 106-110 ° C.

Step C methyl (± M4-fluorophenyl) qlycine A solution of 24.7 g (0.1 mole) of methyl-2-bromo-2- (4-fluoro) phenylacetate and 2.28 g (0.01 mole) of benzyltriethylammonium chloride in 25 ml of methanol it was treated with 6.8 g (0.105 mol) of sodium azide and the resulting mixture was stirred for 20 hours at room temperature. The reaction mixture was filtered; the filtrate was diluted with 50 ml of methanol and hydrogenated in the presence of 0.5 g of 10% Pd / C at 3.51 kg / cm2 (50 psi) for 1 hour. The solution was filtered and the solvent removed in vacuo. The residue was partitioned between 10% saturated aqueous sodium carbonate solution and ethyl acetate. The organic phase was washed with water, saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 9.8 g of the title compound as an oil. 3 »xt¡¿3báb **» i < .

Step D ': methylene (SM4-fluorophenyl) qlycinate A solution of 58.4 g of methyl (±) -4-fluorophenylglycinate in 110 ml of ethanol / water 7: 1 v / v was mixed with a solution of 28.6 g (0.0799). mol) of 0.0 '- (+) - d -benzoyltartaric acid ((+) - DBT) (28.6 g), 0.0799 mol) in 110 ml of ethanol / water 7: 1 v / v and the resulting solution was allowed to stand at room temperature ambient. Ethyl acetate (220 ml) was added after completion of the crystallization and the resulting mixture was cooled to -20 ° C, filtered to give 32.4 g of methyl (S) - (4-fluorophenyl) glycinate, salt (+) - DBT (ee = 93.2%). The mother liquors were concentrated in vacuo and the free base was liberated by dividing it between ethyl acetate and aqueous sodium carbonate solution. A solution of the free base, thus obtained, in 110 ml of ethanol / water 7: 1 v / v was mixed with a solution of 28.6 g (0.0799 mol) of 0.0 '- (-) - dibenzoyltartaric acid ((-) - DBT) (28.6 g, 0.0799 mol) in 110 ml of ethanol / GUA 7: 1 v / v and the resulting solution was allowed to stand at room temperature. Ethyl acetate (220 ml) was added after the crystallization was complete and the resulting mixture was cooled to -20 ° C and filtered to give 47.0 g of methyl ®- (4-fluorophenyl) glycinate, salt (-) - DBT (ee = 75.8%). The recycling of the mother liquors and the addition of (+) - DBT gave a second crop of 7.4 g of (S) - (4-fluorophenyl) glycinate, salt (+) - DBT (ee = 96.4%): The two harvests of the (S) -amino ester (39.8 g) were combined in 200 ml of ethanol / water 7: 1 v / v, heated for 30 minutes and cooled to room temperature. Addition of ethyl acetate, cooling and filtration yielded 31.7 g of (S) - (4-fluorophenyl) glycinate, salt (+) - DBT (ee> 98%).

H- HT I rjj aS = »^ ..

The enantiomeric excess was determined by chiral HPLC (Crownpack CR (+) 5% MeOH in aqueous HCIO4, at pH 2, 1.5 ml / minute, 40 ° C, 200 nm). A mixture of 17.5 g of (S) - (4-fluorophenyl) glycinate, salt (+) - DBT and 32 ml of 5.5 N HCl (32 ml) was heated at reflux for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in 40 ml of water. The aqueous solution was washed with 3 x 30 ml of ethyl acetate and the layers were separated. The pH of the aqueous layer was adjusted to 7 using ammonium hydroxide and the solid precipitate was filtered to give 7.4 g of the title compound (ee = 98.8%).

EXAMPLE 2 3- (S) - (4-fluorophenyl) -4-benzyl-2-morpholinone Step A: N-benzyl (SM4-fluorophenyl) glycine A solution of 1.87 g (11.05 mmol) of (S) - (4- fluorophenyl) -glycine and 1.12 ml (11.1 mmol) of benzaldehyde in 11.1 ml of 1N aqueous sodium hydroxide solution and 11 ml of methanol, at 0 ° C was treated with 165 mg (4.4 mmol) of sodium borohydride. The cooling bath was removed and the resulting mixture was stirred at room temperature for 30 minutes. Second portions of benzaldehyde (1.12 ml, 11.1 mmol) and sodium borohydride (165 mg, 4.4 mmol) were added to the reaction mixture and stirring was continued for 1.5 hours. The reaction mixture was partitioned between 100 ml of ether and 50 ml of water and the layers were separated. The aqueous layer was separated and filtered to remove a small amount of insoluble material. The filtrate was acidified to pH 5 with 2N aqueous hydrochloric acid solution and the solid which had precipitated was filtered, rinsed well with water, then ether and dried to give 1.95 g of the title compound. 1 H NMR (400 MHz, D 2 O + NaOD): d 3.33 (AB q, 2 H, J = 8.4), 3.85 (s, 1 H), 6.79-7.16 (m, 4 H).

Step B: 3- (S) - (4-fluorophenyl) -4-benzyl-2-morpholinone A mixture of 1.95 g (7.5 mmol) of N-benzyl (S) - (4-fluorophenyl) glycine, 3.90 ml (22.5 mmol) of N, N-diisopropyl-ethylamine, 6.50 ml (75.0 mmol) of 1,2-dibromomethane and 40 ml of N, N-dimethylformamide was stirred at 100 ° C for 20 hours (dissolution of all solids occurred during the heating). The reaction mixture was cooled and concentrated in vacuo. The residue was divided between 250 ml of ether and 100 ml of 0.5 N potassium hydrogen sulfate solution and the layers were separated. The organic layer was washed with 100 ml of saturated aqueous sodium bicarbonate solution, 3 x 150 ml of water, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 125 g of silica gel using hexanes / ether 3: 1 v / v as eluent afforded 1.58 g (74%) of the title compound as an oil. 1 H NMR (400 MHz, CDCl 3): d 2.65 (dt, 1 H, J = 3.2, 12.8), 3.00 (d, 1 H), J = 12.8, 2.8), 3.16 (d, 1 H, J = 13.6) , 3.76 (d, 1 H, J = 13.6), 4.24 (s, 1 H), 4.37 (dt, 1 H, J = 13.2, 3.2), 4.54 (dt, 1 H, J = 2.8, 13.2), 7.07 -7.56 (m, 9H).

EXAMPLE 3 2- (R) - (3,5-bis (trifluoromethyl) benzoyloxy) -3- (S) - (4-fluoro) phenyl-4-benzylmorpholine A solution of 2.67 g (10.0 mmol) of 3- (R) - (4-fluoro) -phenyl-4-benzyl-2-morpholinone in 40 ml of dry THF was cooled to -78 ° C. The cold solution was treated with 12.5 ml of 1.0 M L-Selectride®, solution in THF, keeping the internal reaction temperature below -70 ° C. The resulting solution was stirred cold for 45 minutes and the reaction was charged with 3.60 ml (20.0 mmol) of 3,5-bis (trifluoromethyl) benzoyl chloride. The resulting yellow mixture was stirred cold for 30 minutes and the reaction was warmed with 50 ml of saturated aqueous sodium bicarbonate solution. The warm mixture was partitioned between 300 ml of ether and 50 ml of water and the layers were separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 300 ml of ether, the extract was dried and combined with the original organic layer. The combined organic layers were concentrated in vacuo. Flash chromatography on 150 g of silica gel, using hexanes / ether 37: 3 v / v as eluent, afforded the title compound as a solid (83% yield). Mass Spectrum (FAB) m / Z 528 (M + H, 25%), 270 (100%). 1H NMR CDCl 3 MHz, ppm): d 2.50 (dt, J = 3.2, 12.0 1 H), 2.96 (d app, J = 12.9, 1 H), 2.98 (d, J = 13.6 , 1 H), 3.74-3.78 (m, 1 H), 3.81 (d, J = 2.8, 1 H), 3.94 (d, J = 13.6, 1 H), 4.19 (dt, J = 2 , 0.12.0), 6.20 (d, J = 2.8, 1 H), 6.99 (t, J = 8.4, 2H), 7.27-7.38 (m, 5H), 7.52-7.56 (m, 2H), 8.09 (s, 1 H), 7.46 (s, 2H).

EXAMPLE 4 Dimethyl titanocene A solution of 2.49 g (10.0 mmol) of titanocene dichloride in 50 ml of ether was treated, in the dark, at 0 ° C, with 17.5 ml of 1.4 M methyl lithium solution, in ether, maintaining the internal temperature below 5 ° C. The resulting yellow / orange mixture was stirred at room temperature for 30 minutes and the reaction was warmed by slowly adding 25 g of ice. The quenched reaction mixture was diluted with 50 ml of ether and 25 ml of water and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 2.03 g (98%) of the title compound as a light sensitive solid. The dimethyl titanocene can be stored as a solution in toluene, at 0 ° C, for at least 2 weeks without apparent chemical degradation. 1 H NMR (CDC, 200 MHz, ppm): d-0.15 (s, 6H), 6.06 (s, 10H).

EXAMPLE 5 2- (RW1- (3,5-bis (trifluoromethylphenyl) ethenyloxy) -3- (S (4-fluoro) -phenyl-4-benzylmorpholine A solution of 4.9 mmol of 2- (R) - (1- (3,5-bis (trifluorometii) phenyl) ethenyloxy) -3- (S) - (4-fluoro) -phenyl-4-benzylmorpholine and 2.50 g ( 12.0 mmol) of dimethyl titanocene, in 35 ml of THF / toluene 1: 1 v / v, was stirred in an oil bath at 80 ° C for 16 hours. The reaction mixture was cooled and concentrated in vacuo. Flash chromatography on 150 g of silica gel, using hexanes / methylene chloride 3: 1 v / v as eluent gave the title compound as a solid (60% yield). Mass Spectrum (FAB): m / z 526 (M + H, 75%), 270 (100%). 1 H NMR (CDCl 3, 400 MHz, ppm): d 2.42 (dt, J = 3.6, 12.0), 2.90 (app d, J = 12.0, 1 H), 2.91 (d, J = 13, 6, 1 H), 3.62-3.66 (m, 1 H), 3.72 (d, J = 2.6), 3.94 (d, J = 13.6, 1H), 4.09 (dt, J = 2.4, 12.0, 1 H), 4.75 (d, J = 3.2, 1 H), 4.82 (d, J = 3.2, 1H), 5.32 (d, J = 2.6, 1 H), 7.09 (t, J = 8.8, 2H), 7.24-7.62 (m, 2H), 7.80 (s, 1 H), 7.90 (s, 2H).

EXAMPLE 6 2-fRH1- (S) - (3.5-bis (trifluoromet? Nfen? Netoxy) -3- (S) - (4-fluoro) fen? Lmor folin v 2- (SH1- (RV (3.5-bis ( trifluoromethyl-phenytoxy) -3- (SH4-fluoro) phenyl morpholine A mixture of 1.83 g (3.5 mmol) of 2- (R) - (1- (S) - (3,5-bis (trifluoromethyl) phenyl) ethenyloxy) -3- (S) - (4-fluoro) phen? L-4-benzylmorpholine and 800 mg of 5% rhodium catalyst in alumina, in 40 ml of absolute ethanol, was stirred under a hydrogen atmosphere for 24 hours. The catalyst was filtered on a pad of Celite; The reaction flask and the filter cake were rinsed with 200 ml of ethyl acetate. The filtrate was concentrated in vacuo and the residue was subjected to high vacuum (1 mm Hg, at room temperature) to dryness.

The residue was redissolved in 40 ml of isopropanol; 800 mg of palladium-on-carbon catalyst was added and the resulting mixture was stirred under a hydrogen atmosphere for 24 hours. The catalyst was filtered on a pad of Celite; the reaction flask and the cake were rinsed with 200 ml of ethyl acetate. The filtrate was concentrated in vacuo. Chromatography on 50 g of silica gel using hexanes / ether 2: 1 v / v, then ether / hexanes 3: 2 v / v as eluents yielded 283 mg of 2- (R) - (1- (S) - (3 , 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenolmorpholine and 763 mg of 2- (R) - (3,5-bis (trifluoromethyl) phenol ( ethoxy) -3- (S) - (4-fluoro) phenyl morpholine, both as oil (total yield = 68%). For 2- (R) - (1- (S) - (3,5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl morpholine: Mass Spectrum (FAB) m / Z 438 (M + H, 65%), 180 (100%). 1 N NMR (CDCl 3 , 400 MHz, ppm) - d 1.47 (d, J = 6.8, 3H), 187 (br s, 1 H), 3.03 (dd, J = 2.8, 12.8), 3.17 (dt, J = 4.0, 12.4, 1 H), 3.43-3.47 (m, 1 H), 3.80 (dt, J = 3.2, 11, 6), 4.10 (d, J = 2.2, 1 H), 4.70 (q, J = 6.8, 1H), 4.87 (d, J = 2.2, 1 H), 6.99-7.03 (m, 2H), 7.23-7.27 (m, 2H), 7.63 (s, 2H), 7.66 (s, 1 H). For 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4 -flour) phenylmorpholine: Mass Spectrum (FAB) m / Z 438 (M + H, 75%), 180 (100%). 1 H NMR (CDCl 3, 400 MHz, ppm): d 1.16 (d, J = 6, 8) 180 (br s, 1 H), 3.13 ((dd, J = 3.2, 12.4), 3.23 (dt, J = 3.6, 12.4), 3.63 (dd, 2.4, 11, 2), 4.01 (d, J = 2.4, 1 H), 4.13 (dt, J = 3.2, 12.0), 4.42 (d, J = 2.4, 1 H), 4.19 (q, J = 6.8, 1 H), 7.04-7.09 (m, 2H), 7.27-7.40 (m, 4H), 4.73 (s, 1 H).

EXAMPLE 7 2- (R) - (1- (R) -3,5-bis (trifluoromethinophenoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1) , 2,4-tr? Azo) methylmorpholine Step A: N-methylcarboxy-2-chloroacetamidrazone A solution of 5.0 g (66.2 mmol) of chloroacetonitrile in 35 ml of dry methanol was cooled to 0 ° C and treated with 0.105 g (1.9 mmol) of sodium methoxide. The ice bath was stirred and the mixture was allowed to stir at room temperature for 30 minutes. Then, 0.110 ml (1.9 mmol) of acetic acid and then 5.8 g (64.9 mmol) of methyl hydrazinecarboxylate were added to the reaction. After stirring 30 minutes at room temperature, the suspension was concentrated in vacuo and placed on the high vacuum line overnight to give 10.5 g (98%) of yellow powder, a portion of which was used in the Step C, below.

Step B: 2- (RH1- (R) -3.5-b1s (trifluoromethylphenol) -3- (SH4-fluoro) phenyl-4- (2- (N-methylcarboxyl) -acetamidrazone) morpholine A solution of 945 mg (2.3 mmol) of 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl morpholine, 447 mg (2.7 mmol) of N-methylcarboxy-2-chloroacetamidrazone and 0.78 ml (4.5 mmol) of N, N-diisopropylethylamine in 17 ml of acetonitrile was stirred at room temperature for 20 hours.The reaction was concentrated in vacuo and the residue was partitioned between 50 ml of methylene chloride and 25 ml of water, the organic layer was separated, dried over magnesium sulfate and concentrated in vacuo, flash chromatography on 50 g of silica gel, using methylene chloride. methanol / ammonium hydroxide 50: 1: 0.1 as eluent produced 1.12 h 890%) of the title compound as a foam.

Step C: 2- (RH1- (RH3,5-bis (trifluoromethylphenyl) ethoxy) -3- (SH4-fluoro) phenyl-4- (3- (5-0X0-1, 2,4-triazole) methyl -morpholine A solution of 1.01 g (1.8 mmol) of 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) phenyl) ethoxy) -3- (S) - (4-fluoro) Phenyl-4- (2- (N-methylcarboxy-acetamidrazone) morpholine in 15 ml of xylenes, the reflux was heated for 2 hours.The reaction was cooled and concentrated in vacuo.Short chromatography on 50 g of silica gel, using chloride of methyl / methanol / ammonium hydroxide 50: 1: 0.1 as eluent, afforded the title compound as a solid (70% yield) Mass Spectrum (FAB) m / Z 535 (M + H, 100%) 277 (60%) .1H NMR (CDCI3 + CD3OD, 400 MHz, ppm) d 1.48 (d, J = 6.8, 3H), 2.52- (app t, J = 10.4, 1 H), 2.85 -2.88 (m, 2H), 3.47 (d, J = 2.8, 1 H), 3.63 (d, J = 14.4, 1 H), 3.70 (dd, J = 2.0, 11, 6, 1 H), 4.24 (app t, J = 10.8, 1 H), 4.35 (d, J = 2.8, 1 H), 4.91 (q, J = 6.8, 1 H), 7.07 (app t, J = 8.4, 2H), 7.15 (s, 2H), 7.37-7.40 (m, 2H9, 7.65 (s, 1 H) Analysis Calculated for C23H2? F7N4? 3: C, 51.69M H, 3.96; N, 10.48; F, 24.88. Found: C, 51.74; H, 4.04; N, 10.50; F, 24.59. A sample prepared for this process was subsequently identified as the polymorphic Form II. It was characterized by a diffraction pattern of X-rays to dust with key reflections to * * ... -j.Afifa. ha ha? . approximately: 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9 and 24.8 ° (2 theta).

EXAMPLE 8 Dimethyl titanocene To a well-stirred suspension of titanocene dichloride (Cp2TiCl2) (249 g, 1.00 mol) in toluene (2.75 I), cooled to -5 ° C (internal temperature) was added methyl magnesium chloride (CH3MgCI) (750 ml. , 3.0 M in THF, 2.25 mol), for 1 hour, keeping the temperature below 8 ° C. The resulting orange suspension was allowed to stand for 1 hour at 0.5 ° C, or until the insoluble purple Cp2TiCl2 was dissolved. An NMR was taken to confirm the end of the reaction (see below) and then warmed up in an aqueous solution of 6% ammonium chloride (700 ml), maintained at 0-5 ° C. The layers were separated and the organic phase was washed with cold water (3 x 575 ml) and brine (575 ml), then dried with Na 2 SO 4 8220 g). The filtered organic layer was evaporated up to 1.5 kg (maintaining an internal temperature of 25 ° C or lower). The percentage weight test by 1 H NMR showed that the solution contained 187 g of the product (90%, 12.5%, by weight, of toluene / THF solution). Typically, the material was more than 95% pure, with only traces of the initial material and monomethyl intermediate. The solution can be further concentrated to 1 kg, giving an 18% solution, by weight, in toluene, allowing an easier test. However, the presence The amount of a small amount of THF increases the stability of the compound. The material was stored under nitrogen in a sealed jug, at 0 ° C. 1 H NMR Cp2Ti (CH3) 2: d 6.05 (s, 10H), -0.05 (s, 6H). Cp2Ti (CH3): d 6.22 (s, 10H), 0.80 (s, 3H) ,. Cp2TiCI2: d 6.56 (s, 10H). 13 C NMR Cp2Ti (CH3) 2: d 113.20 (Cp2), 45.77 ((CH3) 2). CP2TiCICH3: d 115.86 (Cp2), 50.37 (CH3). Cp2TiCI2: d 120.18.

EXAMPLE 9 4-Fluoro-a - [(phenylmethyl) amidobenzene acetic acid 4-Fluorobenzaldehyde (7.0 kg) was added, 56.4 moles) to a solution of sodium metabisulfite (5.6 kg, 30.3 moles) in water (50 L) and rinsed with methanol (5 L). Sodium cyanide (2.83 kg, 57.7 moles) was added and rinsed with water (3 I). The preparation was stirred at 25 ° C for 15 minutes before cooling to 8 ° C. A solution of benzylamine (6.04 kg, 56.3 moles) in methanol (11 L) was added. The batch was heated to 34 ° C and stirred for two hours. Water (23 L) was added and the batch was extracted with isopropyl acetate (30 L). The organic layer was washed with water (2 x 10 L) followed by saturated aqueous sodium chloride solution (10 L), then evaporated under reduced pressure to give a nitrile compound. The batch was dissolved in dimethyl sulfoxide (50 I). Potassium carbonate (3.27 kg, 23.7 moles) was added and rinsed with dimethylsulfoxide (6 I). Hydrogen peroxide solution in water (30%, 9.43 I, 83.2 moles) was added and stirred at room temperature overnight. The batch was diluted with water (120 I) and cooled to • 35 13 ° C. The batch was filtered and the filter cake was washed with water (50 L). The resulting amide compound was dried on the filter and then suspended in a methylated industrial spirit (38 I). A solution of sodium hydroxide in pellets (3.27 kg, 81.75 moles) in water (11 I) was added and rinsed with methylated industrial spirit 86 I). After heating the reflux (80 ° C) for 3.5 hours, the batch was distilled at low volume, stirring the methylated industrial spirits. The batch was diluted with water (100 L) and extracted with isopropyl acetate 830 I). The layers were separated and the aqueous layer was acidified to pH 5-6 with concentrated hydrochloric acid. The precipitated solid was filtered and washed with water (2 x 10 l), then collected and dried under vacuum to give 12.3 kg (84% yield from 4-fluorobensaldehyde) of 4-fluoro-a [(phenylmethyl) amino] ] benzenacetic.

EXAMPLE 10 4-Fluoro-a - [(phenyl, ethyl) amino-1-benzeneacetic acid methyl ester hydrochloride The 4-fluoro-a [(phenylmethyl) amino] benzenacetic acid (12.2 kg, 47.1 mole) was suspended in methanol (37 L) and then a mixture of hydrogen chloride was added to the mixture. The resulting suspension was stirred at 34-35 ° C for 3 hours, then concentrated to 30-35 I by distillation. Methyl-f-butyl ether (20 L) was added and the batch was seeded with 4-fluoro-a - [(phenylmethyl) amino] benzeneacetic acid methyl ester hydrochloride. After the development of seed bed, methyl-1-butyl ether (20 I) was added. The suspension was allowed to stand for 1 hour and then filtered. The filter cake was washed with methyl-1-butyl ether-methanol (95: 5, 8.0 I), then dried under vacuum at 30 ° C to give 12.2 kg (84% yield) of 4-methyl ester hydrochloride. fluoro-a [(phenylmethyl) amino] benzenacetic.

EXAMPLE 11 Methyl ester of a-amino-4-fluorobenzenacetic acid 4-Fluoro-a [(phenylmethyl) amino] benzenacetic acid methyl ester hydrochloride (12.2 kg, 39.4 moles) was added to a 10% palladium-on-carbon suspension (1.2 kg) in isopropanol (50 I). Ammonium formate (5.0 kg, 79.4 moles) was added and the batch heated to 50 ° C. The progress of Hyflo Supercel and the filter cake was washed with isopropanol (25 I). The filtrate was evaporated at low volume and washed with isorpopyl acetate (50 I). The residue was dissolved in isopropyl acetate (30 L) and washed with 5% aqueous potassium phosphate (40 L), followed by saturated aqueous sodium chloride solution (10 mL). The solution was evaporated under vacuum to give 5.79 kg. (87% yield) of racemic methyl ester of a-amino-4-fluorobenzenacetic acid. HPLC conditions- Column: Zorbax Rx-C8, 25 cm x 4.6 mm; column temperature: 40 ° C; mobile phase: acetonitrile: 0.1% aqueous phosphoric acid (70.30 v / v /); flow rate: 1 ml / minute; detection: UV at 220 nm; Approximate retention times: a-amino-4-4-fluorobenzeneacetic acid methyl ester: mü gD ^ gm ^ 2.2 minutes; methyl ester of 4-fluoro-a - [(phenylmethyl) amino] benzenacetic acid: 2.6 minutes. If methyl ester of 4-fluoro-a [(phenylmethyl) amino] -benzeneacetic acid (> 2%) remains after 1 hour, a second charge of 10% placode-on-carbon (300 g) suspended in isopropanol can be made (2.0 I), followed by ammonium format (1.0 kg). Continue heating until the reaction is complete.

EXAMPLE 12 (S) - α-amino-4-fluorobenzeneacetic acid A racemic methyl ester solution of a-amino-4-fluorobenecentric acid (3.32 kg, 18.2 moles) in 96% ethanol (5 L) was filtered and water (500 ml) was added. Then, a solution of di-O-benzoyl-D-tartaric acid (CBT, 1.32 kg, moles) in water: ethanol (1: 7, 2.86 I) was added. The recrystallization mixture was cooled to 5 ° C and allowed to stand for 1.5 hours. The product was collected by filtration, washed with water: ethanol (1: 7, 1.1 I), air-dried, then under vacuum at 50 ° C, to give 1.91 kg of a-amino-4-methyl ester Fluorobenzeneacetic, DBT salt (95.8% ee). The solvent (6.6 I) was removed from the liquors by evaporation, under reduced pressure. Benzaldehyde (120 ml) was added and the solution was stirred and heated at 50 ° C for 4 hours. The solution was filtered and the solids were washed with water: ethanol (1: 7.2 x 150 ml) (chiral HPLC showed that the filtrate contained racemic methyl ester of a-amino-4-fluorobenzeneacetic acid). A solution of di-O-benzoyl-D-tartaric acid (439 g, 1.23 moles) in water: ethanol / 1: 7, 960 ml) was added to the filtrate, which was cooled to 5 ° C and allowed to stand for 1.5 hours The product was collected by filtration, washed with water: ethanol (1: 7.2 x 1.1 L), dried in the air, then under vacuum at 50 ° C to give 1.05 kg of methyl ester of the a-acid. amino-4-fluorobenzeneacetic, DBT salt (95.4% ee). The combined yield of a-amino-4-fluorobenzeneacetic acid methyl ester, DBT salt was 2.96 kg (95% ee). The methyl ester of a-amino-4-fluorobenzenacetic acid, DBT resolved salt was divided between methyl-t-butyl ether (5 I) and hydrochloric acid 5.5 M (6.2 I). The aqueous phase was washed with methyl-t-butyl ether (5 I) and then dried. The methyl ester of a-amino-4-fluorobenzenic acid, DBT salt (2899 g, >95% ee) was divided between 5.5 M hydrochloric acid (6.2 I) and the second methyl-T-butyl ether extract above. The aqueous phase was re-extracted with methyl-t-butyl ether (5 L) and filtered. The aqueous filtrates were combined and concentrated by slow distillation of the solvent. The preparation was cooled and allowed to stand for 2 hours at 5 ° C. The product was collected by filtration and air-dried for 30 minutes to give 4-055 kg of (S) -α-amino-4-fluorobenzeneacetic acid hydrochloride salt (98.7% ee) (1). Recrystallization from 5.5 M hydrochloric acid (5 I) gave the hydrochloride salt of (S) -α-amino-4-fluorobenzenacetic acid, as a wet cake (3.28 kg, 99.8% ee). This wet cake was heated in a mixture of water (12 I) and concentrated hydrochloric acid (375 ml). Then concentrated aqueous ammonia (1.2 I) and water (4 I) were added, then the batch was cooled to 20 ° C and allowed to stand overnight. The product was collected by filtration, washed with water (6 x 4 l), dried in air, then under vacuum at 50 ° C for 24 hours, for 1905 kg of free base of the (S) -amino-amino acid. 4-fluorobenzeneacetic (> 99.7% ee, 48% yield from the racemic methyl ester of a-amino-4-fluorobenzeneacetic acid). Chiral HPLC conditions: Column: Crownpak CR (+), 15 cm x 4.5 mm; column temperature: 40 ° C; mobile phase: pH 2.0 aqueous perchloric acid: methanol (95: 5 v / v) flow rate: 1 ml / minute; detection: UV at 220 nm; approximate retention times: (R) -α-amino-4-fluorobenzenacetic acid: 2.9 minutes; (S) -α-amino-4-fluorobenzeneacetic acid: 5.6 minutes; methyl ester of (R) -α-amino-4-fluorobenzeneacetic acid: 7.7 minutes; methyl ester of (S) -α-amino-4-fluorobenzeneacetic acid: 14.0 minutes.

EXAMPLE 13 Sodium salt of (S) -4-fluoro-af (phenylmethyl) amino-1-benzeneacetate A solution of (S) -α-amino-4-fluorobenzeneacetic acid (1.00 kg, 5.91 mol) in 1 M aqueous sodium hydroxide, 5.91 I) was filtered and 25 g of 10% palladium-on-charcoal was added. . A solution of benzaldehyde (941 g, 8.87 mol) was added and the preparation was stirred under hydrogen (3.5 kg / cm2) (50 psi) for 4 hours. The preparation was filtered and the filtrate was evaporated to the residue under vacuum, and then washed with ethanol (3 x 3 I). The residue was suspended in boiling ethanol (1.5 L) and then cooled to ° C. The suspension was filtered and the cake was washed with cold ethanol (2 x 500 ml), then dried under vacuum at 55 ° C, to give 1.83 kg (92% yield of sodium salt of (S) -4-fluoro- a [(phenylmethyl) amino] -benzene acetate.

EXAMPLE 14 (S) -3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinone hydrochloride Sodium salt of (S) -4-fluoro-a - [(phenylmethyl) -aminojbenzeacetate (850 g, 3.02 moles) was added to 1,2-dibromoethane (4.85 kg, 25.8 moles) and diisopropylethylamine (419 g, 3.25 moles) in dimethylformamide (14.7 I). The preparation was heated at 90 ° C for 5 hours, then concentrated by vacuum distillation to remove the dimethylformamide. The residue was partitioned between ethyl acetate (3.2 I) and water (3.2 I). The aqueous layer was extracted with a second portion of ethyl acetate. The solution was dried over sodium sulfate, then filtered through a silica pad (1.6 kg). The silica pad was rinsed with ethyl acetate (8.0 I) and the filtrate was evaporated under vacuum. The resulting residue was dissolved in a mixture of isopropanol (1.35 I) and ethyl acetate (400 ml) and then filtered. A solution of hydrogen chloride gas in ethyl acetate (2.44 M, 1.34 I) was added and the suspension was allowed to stand in an ice bath for 1 hour. The suspension was filtered and the cake was washed with isopropanol: ethyl acetate 1: 1 (600 ml), followed by methyl-t-butyl (600 ml). The solid was dried under vacuum to give 749 g (77% yield, 98% ee) of (S) -3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinone hydrochloride. Terms ^ fflrTTpyifiTItt chiral HPLC: Column: (D) -dinitro-benzoylphenyl-glycine (covalent) chiral normal phase, 25 cm x 4.6 mm; column temperature: 35 ° C; mobile phase: hexane: ethanol (99: 1 v / v); flow rate: 1 ml / minute; detection: UV at 200 nm; Approximate retention times: (R) -3- (4-fluorophenyl) -4- (phenylmethyl-2-morpholinone: 17 minutes.

EXAMPLE 15 Racemization / Resolution of 3- (4-fluorophenyl) -4-phenylmethyl) -2-morpholinone It was added to a solution of 3- (4-fluorophenyl) -4-phenylmethyl-2-morpholinone (for example, N-benzyl-4-fluorophenyl-1,4-oxazin-2-one) (10 g) in sodium acetate. 110 ml), at room temperature, a solution of (-) - 3-bromocamphor-8-sulfonic acid ((-) - 3BCS) (12 g) in acetonitrile (24 ml). The crystallization was used after 2-3 minutes. The suspension was stirred for 1 hour at room temperature. Trifluoroacetic acid (7 ml) was added and the mixture was stirred at 65 ° C for 3 days. The mixture was cooled to 0-5 ° C, allowed to stand for 1 hour and the solid collected, washed with isopropyl acetate and dried in vacuo to give an additional batch of (-) - 3BCS n-benzyl salt -3-3 (S) - (4-fluorophenyl) -1,4-oxazin-2-one: yield 0.84 g 98.6% ee of the (S) isomer. The chiral composition of the remaining liquors was determined to be 64% (R), 36% (S). The liquors were stripped in vacuo and the residue was dissolved in isopropyl acetate (20 ml) containing trifluoroacetic acid (1 ml) and stirred at 65 ° C for 20 hours. The mixture was cooled to 0-5 ° C for 1 hour and the solid was collected, washed with isopropyl acetate and dried in vacuo to give an additional batch of salt (-) - 3BCS of N-benzyl-3- ( S) - (4-fluorophenyl) -1,4-oxazin-2-one: yield 2.2 g, 99.2% ee of the (S) isomer. Total weight of salt (-) - 3BCS: 20.28 g, 97% yield. A sample of the salt (-) - 3BCS (0.5 g) was retained and the rest was converted back to the free base. The salt was partitioned between isopropyl acetate (50 ml) and water (100 ml) containing 0.88 ammonium solution (3 ml). The layers were separated and the aqueous phase was extracted with isopropyl acetate (25 ml). The combined organic phases were washed with water (25 ml). The organic phase was concentrated to the residue and rinsed with isopropyl acetate to give 3- (S) - (4-fluorophenyl) -4-phenylmethyl-2-morpholinone (e.g., N-benzyl-3- (S) - (4-fluorophenyl) -1,4-oxazin-2-one) as free base: yield 8.7 g, recovery 93%, 98.4 ee of the (S) isomer. An additional batch of the salt (-) - 3BCS of N-benzyl-3- (S) - (4-fluorophenyl) -1,4-oxazin-2-one) was prepared substantially according to the previous method, except that the following were used Amounts and reaction conditions: (racemate) of N-benzyl-3- (4-fluorophenyl) -1,4-oxazin-2-one (4.96 g); (-) - 3BCS in acetonitrile (1.85 M, 9.4 ml); trifluoroacetic acid (2.1 ml) and isopropyl acetate (55 ml). The mixture was stirred at 90 ° C for 6 days and then cooled to 0-5 ° C and allowed to stand for 1 hour. The solid (-) - 3BCS salt of N-benzyl-3- (S) - (4-fluorophenyl-1,4-oxazin-2-one) was collected and washed with isopropyl acetate (20 ml) Yield: 9.40 g ( 90%), 99.6% ee of the isomer (S).

The chiral composition of the remaining liquors was determined as 88% (R) and 12% (S).

EXAMPLE 16 5 Ester 3- (4-fluorophenyl) -4- (2R-cis) -3.5-bis (trifluoromethyl) benzenacetic acid (phenylmethyl-2-morpholinyl) ester A suspension of (S) -3- (4-fluorophenyl) -4- (phenylmethyl) 2-morpholinone hydrochloride (2.30 kg, 7.15 mol) in ethyl acetate (22 I) was added. treated with 10% aqueous sodium bicarbonate (22 I). The resulting organic solution was washed sequentially with 10% aqueous sodium bicarbonate (11 L) and water (2 x 11 L) and then dried overnight with 4A molecular sieves (1 L). The solution was evaporated and then washed with tetrahydrofuran (2 x 3 I) to remove traces of ethyl acetate. The free base The resulting (S) -3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinone was dissolved in tetrahydrofuran (19 L) and cooled to -75 ° C. L-Selectride (lithium tri- sec-butylborohydride, 6.74 I, 1.06 M, 7.15 mol) was added to the batch, maintaining the temperature below -70 ° C. It was allowed to stand for 15 minutes, to then add 3.5-bis- (triloforomethyl) benzoyl chloride (2.57 kg, 9.29 moles), keeping the temperature below -70 ° C. The reaction was monitored by HPLC. The reaction was quenched with acetic acid (250 ml) in tetrahydrofuran (800 ml) and the preparation was allowed to warm to room temperature overnight. The solution was concentrated in vacuum and oil sfet ^ 2_í "r..H¡-. *" .yfSt. rs ... rute-sm was diluted with hexanes (36 I). The preparation was washed sequentially with water (17 I) 10% aqueous sodium bicarbonate (3 x 8.5 I) and water 2 x 8.5 I), then dried overnight using 4A molecular sieves (1 I). The preparation was assayed by HPLC, showing that it contained 2.44 kg (65% yield) of 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl ester of (2R-cis) -3.5-bis (trifluoromethyl) -benzeneacetic. This preparation was combined with another preparation of 3- (4-fluoropropyl) -4- (phenylmethyl) -2-morpholinyl ester of (2R-cis) -3,5-bis (trifluoromethyl) -benzeneacetic acid (0.59 kg to the test in 7 I of haxanes) that had been prepared just before I today. The solutions of the combined batches were filtered through a 20 μm in-line filter and then diluted with hexanes (9 I). The crude solution of (2R-cis) -3,5-bis (trifluoromethyl) -benzeneacetic acid ester (3.03 kg to the test, 5.74 moles) was treated with the crude solution of 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl ester. hydrochloric acid in diethyl ether (9.6 I, 1.0 M) to give a white precipitate of the hydrochloride salt of the 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl ester of (2R-cis) -3.5-bis ( trifluoromethyl) -benzeneacetic (the hydrochloride salt was formed to remove the residue of tri-sec-butyl boride (from L-Selectride) .The solid was collected by filtration, washed with hexanes (2 x 8 I), then dried under nitrogen The hydrochloride salt of the product was broken by suspending it in a mixture of toluene (36 I) and 10% aqueous sodium bicarbonate (13 I) and water (2 x 18 I.) The toluene solution showed the test that contained 3.00 kg of (2R-cis) -3,5-bis (trifluoromethyl) -benzeneacetic acid 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl ester (80% area, corrected for toluene). tanda ** ß »* U¡ k ** i¿? 6 &* - stored on molecular meshes of 4 (1 I). HPLC conditions: Column: Zorbax RX-C8, 25 cm x 4.6 mm; mobile phase: acetonitrile: 0.1% aqueous phosphoric acid (75:25, v / v); I will assess flow: 1.5 ml / minute; detection: UV at 220 nm; approximate retention times: (S) -3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinone reduced: 1.6 minutes; (S) -3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinone: 3.3 minutes; 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl ester of (2R-cis) -3,5-bis (trifluoromethyl) benzeneacetic acid: 9.2 minutes.

EXAMPLE 17 (2-cis) -2-rf1-r3.5-bis (trifluoromethyl) phenyl-1-quinoline-3- (4-fluorophenyl) -4- (phenylmethyl) morpholine A solution of 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl ester of (2R-cis) -3,5-bis (trifluoromethyl) benzeneacetic acid (1.60 kg), 3.02 moles) in toluene, evaporated, then purged with nitrogen. Tetrahydrofuran (1.6 I) was added followed by a solution of dimethyl titanocene in toluene (8.35%, by weight, 1.73 kg of reagent, 8.31 moles) (prepared as described below). The preparation was sprinkled with nitrogen for 25 minutes, then heated to 80 ° C. The preparation was allowed to stand in the dark for 5 hours at 80 ° C, then cooled to room temperature and allowed to stand overnight. To the preparation the solvent was changed to heptane by vacuum distillation, keeping the temperature below 20 ° C (126 I of heptane added with concomitant distillation of 120 I) - •. * (To the reaction mixture was changed the solvent and treated with peroxide buffered with bicarbonate to precipitate the titanium residues). Water (22 I), sodium bicarbonate (2.0 kg), then 30% hydrogen peroxide (3.5 I) was added to the cooled mixture (7 ° C). The preparation was stirred at room temperature overnight. The phases were divided, in that most of the titanium residue remained in the aqueous phase. The aqueous phase was re-extracted with heptane (101) and the combined organic phases were filtered, washed with water (2 x 4 I) and then concentrated. The crude product was recrystallized by dissolving it in hot methanol (17 I), cooling it to room temperature, then adding water (1.8 I), the material was isolated by filtration at 0 ° C), then the solid was dried at room temperature under nitrogen ( 1.45 kg of (2R-cys) -2 - [[1- [3,5-bis (trifluoromethyl) phenyl] ethenyl] oxyl-3- (4-fluorophenyl) -4- (phenylmethyl) morpholine) 94% pure, in weight. The dimethyl titanocene reagent can be prepared as follows. Methyl lithium (590 g, 26.9 moles) in a solution of diethyl ether (4.38% w / w, 13.5 kg) is added to a well-stirred, cooled suspension (-8 ° C) of titanocene dichloride (3.35 kg, 13.5 moles). ) in methyl-5-butyl ether (13.4 I), keeping the temperature below 5 ° C. The resulting suspension was allowed to stand at 0-5 ° C for 1 hour. The reaction is added by adding water (8 I) maintaining the temperature between 0 and 8 ° C. The organic phase is washed with cold water (4 x 3 I). To the organic layer the solvent is changed to toluene by distillation with concomitant addition of toluene (24 I), maintaining the temperature at 25 ° C or less. The 1H NMR weight percent test showed that the solution contained 1.75 kg of dimethyl titanocene (63% yield, 8.35%, by weight, in toluene solution). The material was stored under nitrogen at 0 ° C. The progress of the reaction was followed by 1 H NMR (250 MHz, CDCl 3, 10 seconds was delayed between pulses). Cp2TMeMe2: d 6.56 (2, 10H). Alternatively, the dimethyl titanocene reagent can be prepared as follows. To a well stirred suspension of titanocene dichloride (Cp2TiCl2) (6.0 g, 24.1 mmol) in toluene (72 ml9, cooled to 5 ° C) was added dropwise dimethyl magnesium chloride (CHsMgCI) / 18.7 gm 19.2 ml, 3.0 M in THF, 57.6 moles, 2.4 equivalents) for 10 minutes, keeping the temperature below 5 ° C. A viscous suspension formed as the magnesium chloride precipitated. The resulting suspension was allowed to stand at 0-5 ° C for 50 minutes, during which time red, insoluble Cp2TiCl2 was dissolved. An NMR assay was taken from a warm sample to confirm the termination of the reaction. A 0.2 ml sample was tempered in 1 ml of water and 1 ml of CDCI3. The chloroform layer was used directly for the NJR analysis. The dimethyl tiocene has resonances at 6.0 ppm (group Cp) and -0.2 ppm (group CH3). The monomethyl compound has resonances at 0.2-0.3 ppm downfield and the titanocene dichloride has resonance at 6.5 ppm. The reaction was then quenched by the addition of a 10% aqueous ammonium chloride solution (20 ml) for 10 minutes, keeping the temperature below 10 ° C. The layers were separated and the organic phase was washed with cold water (3 x 20 ml) and brine (20 ml), then was separated with Na 2 SO 4 (20 g). The filtered organic layer was concentrated under vacuum to about half the volume. The total weight of the solution was 43 g and the NMR analysis showed 11.2%, by weight, of dimethyl titanocene (4.8 g, 96% yield). The THF level was 2%, however, the presence of a small amount of THF increases the stability of the reagent. The material was stored under nitrogen at 0 ° C. Alternatively, the dimethyl titanocene reagent can be prepared as follows. To a well stirred suspension of titanocene dichloride (246 g, 1.00 mol) in toluene (2.75 I), cooled to -5 ° C (internal temperature) was added MeMgCI (750 ml, 3.0 M in THF, 2.25 moles) for 1 hour. hour, keeping the temperature below 8 ° C. The resulting orange suspension is allowed to stand at 0-5 ° C for 1 hour, or until the purple, insoluble Cp2TiCl2 has dissolved. An NMR is taken to confirm the reaction term (see below), then the reaction is warmed up in a solution of 6% aqueous ammonia chloride (700 ml), maintained at 0-5 ° C. The organic phase was washed with cold water (3 x 575 ml) and brine (575 ml), then dried with Na 2 S 4 (220 g). The filtered organic layer was evaporated at 1.5 kg (maintaining an internal temperature of 25 ° C or less). The weight percent test by 1H NMR showed that the solution contained 187 g of the product (90%, 12.5%, by weight, of toluene / THF solution). Typically, the material was more than 95% pure, with only traces of the initial material and monomethyl intermediate. The solution can be further concentrated to 1.0 kg, giving a solution in toluene with 18% and allowing an easier test. However, the presence of a small amount of THF increases the stability of the reagent. The material was stored under nitrogen in a sealed jug, at 0 ° C. 1H NMR Cp2TiMe2: d 6.05 (s, 10H), -0.05 (s, 6H.Cp2TiMe2 d 6.22 (s, 10H, 0.80 (s, 3H9, Cp2TiCl2: d 6.56 (s, 10H). 13C NMR Cp2TiMe2: d 113.20 ( Cp2), 45.77 (Me2) .Cp2TiCIMe: d 115.86 (Cp2), 50.37 Me, Cp2TiCI2: d 120.18 HPLC conditions: Column: Zorbax RX-C8, 25 cm x 4.6 mm, mobile phase: acetonitrile: aqueous phosphoric acid 0.1% (65:35, v / v); flow rate: 1.5 ml / minute; UV detection at 220 nm; approximate retention times (2R-cis) -2 - [[1-3.5-bis (trifluoromethyl) -phenyl] ethenyl] oxyl] -3- (4-fluorophenyl) -4- (phenylmethyl) -morpholine: 17.2 minutes; 3- (4-fluorophenyl) -4- (phenylmethyl) -2-morpholinyl ester of (2R-cis) -3,5-bis (trifluoromethyl) benzenoetic acid: 18.9 minutes.

EXAMPLE 18 (2R-cs) -2-fp-f3,5-bis (trifluoromethyl) -pheninetenyloxy1-3- (4-fluorophenyl) -4- (phenylmethi-morpholine) A solution in toluene of 3- (4-fluorophenyl) -4-phenylmethyl) -2-morpholinyl ester of (2R-cis) -3,5-bis (trifluoromethyl) -benzeneacetic acid was evaporated into a 100-mL flask. for example, (4-benzyl-2- (R) -3,5-bis (trifluoromethyl) benzyloxy) -3- (S) - (4-fluorophenyl) -1,4-oxazine] dissolved in toluene, which contained 2.99 kg, 5.67 mmoles). The flask was purged with nitrogen, then tetrahydrofuran (25 I) was added, followed by a solution of dimethyl titanocene in tolueneTHF (12.5%, by weight, containing ".i kg reagent, 20.2 mmol), The orange solution was sprinkled with nitrogen for 25 minutes and then warmed to 80 ° C. The reaction was allowed to stand in the dark for 4 hours at 80 ° C., then cooled to room temperature, methanol (11.6 l) and water (1.9 l) were added. ) and the mixture was heated at 40 ° C overnight, precipitating the titanium residues as a green solid.After cooling to room temperature, the solid was removed by filtration, the filter cake was washed with toluene and the mother liquors The resulting product was evaporated, the crude product was recrystallized by dissolving in hot methanol (30 L), cooling it to room temperature and then adding water (3.4 L) for 3 hours.The material was isolated via filtration at 0 ° C, the filter cake was filtered off. washed with methanol 10% bear, at 0 ° C (2 I) and the solid was dried at room temperature, under nitrogen, giving 2.25 kg of (2R-cis) -2 - [[1- [3,5-bis (trifluoromethyl)] phenyl] ethenyl] oxyl] -3- (4-fluorophenyl) -4- (phenylmethyl) -morpholine (85%) isolated.

EXAMPLE 19 4-Methylbenzenesulfonate salt of f2- (R-r2a (R *), 3a1l-2- [1-r3,5-bis (trifluoromethyl) phenylethoxy1-3- (4-fluorophenyl) morpholine A solution of (2R-cis) -2 - [[1- [3,5-bis (trifluoromethyl) -phenyl] ethenyl] oxy] -3- (4-fluorophenyl) -4- (phenylmethyl) morpholine (1.082 g 94% pure, 1.94 moles) in ethyl acetate: ethanol 1: 1 (13 I) was mixed with 10% palladium-on-charcoal (165 g).

The resulting suspension was treated with hydrogen (2.81 kg / cm2 (40 psi), 20-25 ° C) for 12 hours. The reaction was monitored by absorption with hydrogen and HPLC. The vessel was ventilated and the catalyst was removed by filtration. After washing the catalyst with ethyl acetate: ethanol 1: 1 (6 I) followed by ethyl acetate (2 I), the combined organic phases containing the (2R- [2a (R *), 3a]] - 2- [1- [3,5-bis (trifluoromethyl) -phenyl] ethoxy] -3- (4-fluorophenyl) -morpholine was concentrated in vacuo. A second batch was prepared, initiated with 1078 g of (2 R-). cis) -2 - [[1- [3,5-bis (trifluoromethyl) -phenyl] ethenyl] oxy] -3- (4-fluorophenyl) -4- (phenylmethyl) morpholine (1.93 mol). [2R- [ 2a (R *), 3a]] - 2- [1 - [3,5-bis (trifluoromethyl) -phenyl] ethoxy] 3-3 (fluorophenyl) -morpholine resulting was concentrated in vacuo and combined with the first batch The combined runs of (2R- [2a (R *), 3a]] - 2- [1- [3,5-bis (trifluoromethyl) phenyl] ethoxy] -3- (4-fluorophenyl) -morpholine were rinsed with methyl-t-butyl ether (2 x 3 I) to remove ethyl acetate and residual ethanol, then dissolved in methyl-t-butyl ether (3 I) The solution was tested and showed to contain 1348 g (3.09 moles) , 80% yield of [2R- [2a (R *), 3a]] - 2 - [1- [3,5-bis (trifluoromethyl) -phenyl] ethoxy] -3- (4-fluorophenyl) -morpholine (as the free base). Alternatively, 60 g of vinyl ether, 650 ml of methyl t-butyl ether (MTBE) and 18 g of 50% Pd on alumina, under hydrogen at 2.81 kg / cm2 (40 psi) of pressure, were stirred at 40. ° C for 12 hours. The yield to the test was 87%, with relation 19.9 of diastereomers. At the end of the reaction, the catalyst was removed by filtration through Solka-Floc, after the filtrate was concentrated to 140 ml.

The first batch was treated with a hot (40 ° C) solution of p-toluenesulfonic acid monohydrate (575 g, 3.03 mol) in methyl-t-butyl ether (3.2 I). The p-toluenesulfonic acid salt of [2-R- [2a (R *), 3a]] - 2- [1- [3,5-bis (trifluoromethyl) phenyl] ethoxy] -3- (4-fluorophenyl) -morpholine began to crystallize during the addition. The batch was cooled to room temperature and hexane (24 I) was added. The batch was allowed to stand for 2 hours, then the product was collected by filtration. The solid was washed with hexane: methyl-t-butyl ether (2 x 2.5 I), then dried under nitrogen (1761 g corrected for purity) of 4-methylbenzenesulfonate salt of [2R- [2a (R *), 3a] ] -2- [1 - [3,5-bis (trifluoromethyl) -phenyl] ethoxy] -3- (4-fluorophenyl) -morpholine, 94% pure, 70% yield. Alternatively, a solution of 6.0 g of p-TsOH monohydrate in 64 ml of MTBE, at 35 ° C, was added to the second solution over a period of 20 minutes. The tosylate salt crystallized as a slurry. Then, 520 ml of hexane was added over 1 hour and the suspension was stirred 2 hours at room temperature. The suspension was filtered, washed with 2 x 60 ml of MTBE: hexanes 1: 4 and dried by suction of air to give 51.9 g of tosylate salt (75% yield) containing 0.9% of the undesired diastereomer. HPLC conditions: Zorbax column RX-C18, 25 cm x 4.6n mm; mobile phase: acetonitrile: sodium heptanesulfonate, 0.005M, potassium diacid, 0.002, phosphate, sodium acid 0.0005M (75:25, v / v); flow rate: 1.5 ml / minute, detection: UV at 220 nm; approximate retention times: [2R- [2a (R *), 3a]] - 2- [1- [3,5-bis (trifluoromethyl) phenyl] -ethoxy] 3- (4-fluorophenyl) morpholine: 4.5 minutes; N-benzyl [2R- [2a (R *), 3a]] - 2- [1- [3,5-bis (trifluoromethyl) phenyl] -ethoxy] 3- (4-fluorophenyl) morpholine: 25.0 minutes; (2R-cis) -2 - [[1- [3,5-bis (trifluoromethyl) -phenyl] ethene] oxy] -3- (4-fluorophenyl) -4- (phenylmethyl) morpholine: 30 minutes . HPLC conditions: Column Zorbax RX-C18, 25 CM X 4.6 mm; mobile phase: acetonitrile: 0.005M sodium heptanesulfonate, 0.002M potassium diacid phosphate, 0.0005 M disodium hydrogen phosphate (60:40, v / v); flow rate 1.5 ml / min; detection: UV at 220 nm; approximate retention times: [2R- [2a (R *), 3a]] - 2- [1 - [3,5-bis (trifluoromethyl) phenyl] -ethoxy] 3- (4-fluorophenyl) morpholine: 9.0 minutes; Diastereoisomer of [2R- [2a (R *), 3a]] - 2- [1- [3,5-bis (trifluoromethyl) phenyl] -ethoxy] 3- (4-fluorophen? L) morpholine: 11.0 minutes (epimeric in the methyl group).

EXAMPLE 20 f2R-r2a (R *), 3an-5-ff2-ri- [3,5-bis (trifluoromethyl) phenn-ethoxyl3- (4-fluorophenin-4-morpholinylmethyl-1, 2-dihydro-3H, 1, 2,4-triazol-3-one Powdered potassium carbonate (682 g, 4.93 mol) was added to a solution of 4-methylbenzenesulfonate salt of [2R- [2a (R *), 3a]] - 2- [1- [3,5-bs ( trifluoromethyl) phenyl] ethoxy] 3- (4-fluorophenyl) morpholine (1254 g, 2.06 mol), N-methylcarboxy-2-chloroacetamidrazone (375 g, 2.26 mol) and dimethylformamide (10 I). The reaction was maintained between 15 and 25 ° C and allowed to stand for 2.5 hours. The batch was diluted with hexane: methyl-t-butyl ether 1: 1 (10 I) and 10.9% aqueous ammonium chloride (11 I). The phases were partitioned and the aqueous phase was re-extracted with hexane: methyl-t-butyl ether 1: 1 (2 X 8 I) followed by hexane: methyl-t-butyl ether 1: 2 (8 I). The combined organic phases were washed with water (2 x 15 I), then concentrated in vacuo. The resulting material was dissolved in xylenes (20 I) and heated to reflux (137 ° C). The solution was refluxed for 3 hours, then cooled to room temperature, whereupon [2R- [2a (R *), 3a]] - 5 - [[2- [1 - [3,5-] bis (trifluoromethyl) phenyl] ethoxy] 3- (4-fluorophenyl) -4-morpholinyl] methyl] -1,2-dihydro-3-H-1, 2,4-triazol-3-one. The batch was allowed to stand overnight and then filtered. The filter cake was washed with xylenes (2 I), then with hexanes (2 x 2 I), then dried under vacuum at 30 ° C for 3 days (696 g, 63% yield of [2R- [2a ( R *), 3a]] - 5- [2- [1- [3,5-bis (trifluoromethyl) phenyl-ethoxy] 3- (4-fluorophenyl) -4-morpholinyl] methyl] -1,2-dihydro- 3H, 1, 2,4-triazol-3-one, for example, 2- (R) - (1-R) -3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - ( 4-fluoro) phenyl) -4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine). Alternatively, the title compound can be prepared as follows from the amine salt of TsOH (1.90 kg, 3.12 moles); N-methylcarboxyl-2-chloroacetamidrazone (516.3 g, 3.12 moles); K2CO3 (1.08 kg, 2.5 equivalents) and DMSO (15.6 I). To a suspension of amine salt and K2CO3 powder in DMSO (7.8 I) at 20 ° C is added a solution of N-methylcarboxyl-2-chloroacetamidrazone in DMSO (7.8 I). The first half of the solution is added quickly, (with slight cooling in an ice bath) then the remaining half is added during a period of 1 hour. After the addition, the reaction is checked by LC and treated with cold water (15 I), and the solution of methyl t-butyl ether (MTBE) (30 I). The organic layer is separated and washed with water, saturated NaHCO3, brine and water (20 I each), respectively. The aqueous layers are re-extracted with additional MTBE (15 I).

The combined MTBE solution is concentrated to an oil. The resulting crude product is dissolved in xylene (25 I) and diisopropylamine (6.25 I) and heated to reflux (~ 135 ° C); the reaction is monitored by LC. The reaction takes 4-6 hours to complete; the reaction solution is cooled to room temperature overnight and filtered to obtain the title product (1.33 kg, -80%, typical purity 98.5% A can be expected). The resulting crude product is dissolved in hot methanol (13.3 I), 133 g wood charcoal is added, then it is filtered and the charcoal is washed with hot methanol (3.3 I). The methanol solution is cooled to room temperature and then water is added dropwise. After stirring at room temperature for 2 hours, the suspension is filtered to isolate the purified product (for example 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine) as a white crystalline compound (1.20 kg can be expected, 90% recovery, typical purity 99.5% A). HPLC conditions: Column: Zorbax RX-C8, 25 cm x 4.6 mm; mobile phase: (A) acetonitrile, (B) 0.1% aqueous phosphoric acid; linear gradient: 40:60 A: B until 70:30 A: B in 10 minutes; flow rate: 1.5 ml / minute; detection: UV at 220 nm; approximate retention times: rented intermediary: 5.7 minutes; [2R- [2a (R *), 3a]] - 5 - [[2- [1- [3,5-bis (trifluoromethyl) phenyl] -ethoxy] -3- (4-fluorophenyl) -4-morpholinyl] methyl] -1,2-dihydro-3H-1, 2,4-triazol-3-one: 8.2 minutes. A sample prepared by this procedure was subsequently identified as polymorphic form II. It was characterized by the diffraction pattern of the X-rays to the powder, with key reflections at approximately: 12.6, 16.7, 17.1, 17.2, -18.0, 20.1, 20.6, 21 , 1, 22.8, 23.9 and 24.8 ° (2 theta).

EXAMPLE 21 Preparation of Form I of 2- (RH1-R) - (3,5-bis (trifluoromethyl) -phenoxyethoxy) -3- (SH4-fluoro) phenyl-4- (3- ( 5-oxo-1 H, 4H-1, 2,4-triazo-methylmorpholine Form I of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- ( 5-oxo-1 H.4H-1, 2,4-tr? Azole) methylmorpholine was prepared by forming a vortex with the form II of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) ) -phenyl) etox?) - 3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine in isopropyl acetate a 25 ° C, followed by isolation of the resulting solid by filtration.Similarly, Form I of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) - 3- ( S) - (4-fluoro) phenol-4- (3- (5-oxo-1H, 4H-1, 2,4-triazole) methylmorpholine was also prepared by forming a vortex with form II of 2- ( R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-trizol) methylmorpholine in ethanol, 2-propanol, water, methanol / water mixtures or acetonitrile at 25 ° C, followed by isolation of the resulting solid by filtration.

EXAMPLE 22 Preparation of seed crystals of Form I from 2- (R) - (1-R) - (3,5-bis (trifluoromethylMennetene) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1.2.4- triazoDmethylmorpholine A Form II sample of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3 - (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine was placed in a small aluminum tray and, unsealed, placed in a Differential Scanning Calorimetric Cell (DSC) instrument. from room temperature to 230 ° C, then cooled again to room temperature.The resulting solid is suitable for use as seed crystals in the large scale preparation of Form I of 2- (R) - (1- R) - (3,5-bis (trifluoromethyl) -phen?) Ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H- 1, 2,4-triazole) methylmorpholine.

EXAMPLE 23 Preparation of Form I of 2- (RM1-R) - (3.5-b1s (trifluoromethyl) -pheniOethoxO-3- (SH4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H -1.2.4-triazole) methylmorpholine A 22 liter flask was charged with form I of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (SH4-fluoro) phenyl-4 - (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine (566 g) and 5.7 liters of methanol The mixture was heated to reflux (65 ° C) whereupon Solubilized all the solids The solution was left or cooling to 50 ° C and plating with approximately 200 mg of Form I of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5, oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine, allowing it to cool to 45 ° C, whereby the seed bed was formed. The mixture was cooled to 26 ° C and 2.8 liters of water was added over a period of 1 hour.The mixture was allowed to stand at room temperature for 2 hours, then heated at 70 ° C for 2 hours, to ensure the Complete conversion of all material from form II to form I. The mixture was allowed to cool overnight, then cooled to 0 ° C, allowed to stand at 0 ° C for 70 minutes, then filtered at -3 ° C. The collected material was dried in a nitrogen-coated filtration vessel overnight and packed dry to give 549 g (97%).

EXAMPLE 24 Preparation of Form I of 2- (R) - (1-R) - (3,5-bis (trifluoromethyl-phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- ( 3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine A reaction vessel, pilot scale, was charged with 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine (form II) (14.5 kg) and 158 liters of methanol The mixture was heated to 50 ° C , in which all the compound had dissolved, Activated carbon (Darco G60) (1.5 kg) was added via gate, as a suspension in 6 kg of methanol and rinsed with an additional two liters of methanol. at reflux (62 ° C) and allowed to stand for 1 hour. *** & < * ** & - - ** batch at 60 ° C and filtered through a 355.6 mm (14") SS foam filter After recycling for 10 minutes, no change was observed in the sight glass, so that the recycling line was emptied, emptying it to the reactor. The batch was pumped through the filter, then through a 10μ and 6μ in-line filter assembly and finally into a reception tank. The line was blown forward and then 50 I of methanol was added to the initial reaction vessel, as a rinse. The rinse was recycled for 10 minutes, to clean the recycling line and to heat the environment on the product. Then, it was transferred forward through the filters to the receiving container. Then the batch was concentrated from around -210 liters to 170 liters, by atmospheric distillation. One sample showed the desired concentration, 88 g / l (14.9 kg, no losses). The batch was cooled to 50 ° C and seeded with 300 g of pure form I, 2- (R) - (1-R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H.4H-1, 2,4-triazole) methylmorpholine. An extremely light seed bed was formed and the crystals could hardly be distinguished , still at 45 ° C. The light suspension was allowed to stand at 45 ° C for 1 hour and still showed little change in its appearance, it was allowed to stand at 25 ° C overnight, resulting in a suspension with 60.5 g. One sample of the wet cake indicated only crystals of Form I. Then 83.6 kg of water (33% of the volume of methanol) were added for 3 hours by the sub-surface loading line. they indicated 0.1%, by weight 030 in the supernatant, with all the crystals of form I. The batch was cooled to 0 ° C - «for 2 hours. The batch was discharged to a large-scale filter, at one time. Approximately 15 kg of MeOH / water 2: 1 was used for washing the cake to wash the container, leaving the product still retained (possibly 500-1,000 g). The remaining 15 kg of cake was loaded into the filter by means of a spray nozzle. 217.8 kg of mother liquors and washes were collected (0.1%, by weight 030). The wet cake (14.8 kg) was dried overnight at 50 ° C under a vacuum of approximately 71 cm Hg with a sweep of 0.2 SCFM. After 12 hours, the TG analysis showed a 0.0% weight loss. The total weight of the packaged batch was 12.82 kg of the title compound.

EXAMPLE 25 Typical pharmaceutical compositions containing the compound of the invention A: Dry-filled capsules containing 5 mq of active ingredient per capsule Ingredient Quantity per capsule (mq) Active ingredient 5 Lactose 194 Magnesium stearate 1 Capsule (Size No. 1) 200 The active ingredient can be reduced to powder No. 60 and the lactose and the magnesium stearate can then be passed through a No. 60 blotting cloth on the powder. The combined ingredients can be mixed for about 10 minutes to fill gelatin capsules No. 1.

B: Tablets A typical tablet will contain the active ingredient (5 mg), pre-gelatinized starch USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg). Although the invention has been described and illustrated with reference to certain particular modalities thereof, those trained in the art will understand that various adaptations, changes, modifications, substitutions, deletions or additions to the processes and protocols can be made without departing from the spirit and scope. of the invention. For example, effective dosages other than those set forth herein may be applicable, as a consequence of variations in the response of the treated mammal, to any of the indications of the compound of the invention indicated above. Similarly, the specific pharmacological responses observed may vary according to and depending on the particular compound selected or the presence of pharmaceutical carriers, as well as the type of formulation and mode of administration employed and, such expected variations, or differences in results are contemplated in accordance to the objects and practices of the present invention. Therefore, it is intended that * 8t, ""? "", The invention is defined by the scope of the claims and that such claims are interpreted as widely as is reasonable.

Claims

NOVELTY OF THE INVENTION CLAIMS 1. A polymorphic form characterized in that it consists of the compound 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4 fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine, which is designated form I. 2.- The polymorphic form of claim 1, essentially characterized by a diffraction pattern of X-rays to powder with 10 key reflections at approximately: 12.0, 15.3, 16.6, 17.0, 17.6, 19.4, 20.0, 21, 9, 23 , 6, 23.8 and 24.8 ° (2 theta) 3.- A pharmaceutical composition characterized in that it comprises a pharmaceutically acceptable carrier and an effective amount of the polymorphic form of claim 1. 4.- The use of the polymorphic form of the compound of claim 1, for the manufacture of a medicament for antagonizing the effect of substance P at its receptor site for blocking neurokinin-1 receptors in a mammal. polymorphic of the compound of Claim 1, for the manufacture of a medicament for treating or preventing a condition selected from the group consisting of: diabetic neuropathy; peripheral neuropathy; neuropathy related to AIDS; neuropathy induced with chemotherapy; and neuralgia, in a mammal. ^ "^. ^ ^ Al ^ ^ .. ^^ .. ^. * - -., ^. ^^^^^^^. ^^^^ 6. - The use of the polymorphic form of the compound of claim 1, for the manufacture of a medicament for treating or preventing emesis in a mammal. 7. The use of the polymorphic form of the compound of claim 1, for the manufacture of a medicament for treating or preventing a disorder of the central nervous system in a mammal. 8. The use of the polymorphic form of the compound of claim 1, for the manufacture of a medicament for treating or preventing depression in a mammal. 9. The use of the polymorphic form of the compound of claim 1, in combination with an antidepressant agent, for the manufacture of a medicament for treating or preventing depression in a mammal. 10. The use of the polymorphic form of the compound of claim 1, for the manufacture of a medicament for treating or preventing anxiety in a mammal. 11. The use of the polymorphic form of the compound of claim 1, in combination with an anti-anxiety agent, for the manufacture of a medicament for treating or preventing anxiety in a mammal. 12. The use of the polymorphic form of the compound of claim 1, for the manufacture of a medicament for treating or preventing schizophrenia in a mammal. 13. The use of the polymorphic form of the compound of claim 1, in combination with an antipsychotic agent, for the manufacture of a medicament for treating or preventing schizophrenia in a mammal. 14. A process for the preparation of Form I of 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4- fluoro) phenyl-4- (3- (5-Qxo-1H, 4H-1, 2,4-triazole) methylmorpholine, characterized in that it comprises: balancing form II of 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1H, 4H-1, 2,4-triazole) methylmorpholine in a solvent which is selected from: ethanol, 2-propanol, acetonitrile and isopropyl acetate 15. A product produced by the process of claim 14. 16. A process for the preparation of Form I of - (R) - (1- (RH3,5-bis (trifluoromethyl) -phenyl) et QXi) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H -1, 2,4-triazole) methylmorpholine, characterized in that it comprises: heating a sample of 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) -phenyl) etQxi) -3- ( S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmroline of optional morphological composition at a temperature range of 215 to 230 ° C; and return then the sample at room temperature. 17. The process of claim 16, characterized in that the morphological composition of 2- (R) - (1- (R) - (3,5-bis (trifluQromethyl) -phenyl) etQxi) -3- (S) - (4-FluQro) phenyl-4- (3- (5-oxQ-1H, 4H-1,2,4-triazQl) methylmorpholine is initial form II. 18. - A procedure for the preparation of Form I of 2- (R) - (1- (R) - (3,5-bis (tpfluQromethyl) -phenyl) etQXi) -3- (S) - (4-fluQro) phenyl-4- (3- (5-Qxo-1H, 4H-1, 2,4-triazl) methylmorpholine, characterized in that it comprises: suspending 2- (R) - (1- (R) - (3,5- bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-Qxo-1 H, 4H-1,2,4-triazole) methylmarpholine of morphological composition optionally in a methanol / water solution, add seed crystals of form I of 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy-3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazl) methylpyridine, stir the resulting mixture at 0-50 ° C for a sufficient period to cause formation of the form I of 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) -phenyl) etQxi) -3- (S) - (4-fluoro) phenyl-4- (3 - (5-oxQ-1H, 4H-1,2,4-triazole) methylmroline, and collecting the resulting form I from 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) - phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmethroline. claim 18, characterized in that the morphological composition of 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (SH4-fluoro) phenyl-4- (3- (5-QXQ-1 H, 4H-1, 2,4-triazole) methylmorpholine initial is form II. 20, -A product produced by the process of claim 19. 21.- A polymorphic form of the compound 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) - 3- (S) - (4-fluQra) phenyl-4- (3- (5-oxQ-1H, 4H-1,2,4-triazQl) methylmethroline, characterized by a powder X-ray diffraction pattern with reflections key to approximately: 12.0, 15.3, 16.6, 17.0, 17.6, 19.4, 20.0, 21, 9, 23.6, 23.8 and 24.8 ° ( 2 theta) which is substantially free of a polymeric form of the compound 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - ( 4-fluoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine characterized by a powder X-ray diffraction pattern with key reflections at approximately 12.6 , 17.1 17.2, 18.0, 20.1, 20.6, 21, 1, 22.8, 23.9 and 24.8 ° (2 theta) 22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a polymeric form of the compound 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-f) luoro) phenyl-4- (3- (5-oxo-1 H, 4H-1, 2,4-triazole) methylmorpholine characterized by a powder X-ray diffraction pattern with key reflections at approximately 12.0, 15, 3, 16.6, 17.0, 17.6, 19.4, 20.0, 21, 9, 23.6, 23.8 and 24.8 ° (2 theta) which is substantially free of a polymeric form of the compound 2- (R) - (1- (R) - (3,5-bis (trifluoromethyl) -phenyl) ethoxy) -3- (S) - (4-fluoro) phenyl-4- (3- (5 -oxo-1 H.4H-1, 2,4-triazole) methylmorpholine characterized by a powder X-ray diffraction pattern with key reflections at approximately 12.6, 16.7, 17.1, 17.2, 18 , 0, 20.1, 20.6, 21, 1, 22.8, 23.9 and 24.8 ° (2 theta).