UA57089C2 - A polymorphic form of 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-triazolo) methylmorpholine as tachykinin RECEPTOR antagonist - Google Patents

Abstract

This invention is concerned with 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-1H,4H-1,2,4-triazolo) methylmorpholine which 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. The instant polymorphic form has advantages over the other known forms 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-triazolo) methylmorpholine in terms of thermodynamic stability and suitability for inclusion in pharmaceutical formulations.

Description

Description of the invention

This invention relates to new polymorphic forms of compound 2 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4 -(3-(5-oxo-1H 4H-1,2,4-triazolo)methylmorpholine.

The present invention also relates to pharmaceutical preparations containing this new polymorphic form of the compound as an active ingredient and to the use of this compound and its preparation in the treatment of certain diseases. 70 The new polymorphic form of this invention is a tachykinin receptor antagonist used in the treatment or prevention of disorders of the central nervous system, inflammatory diseases, pain or migraine, asthma and vomiting.

This polymorphic form has advantages over other known forms of 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phens)ethoxy)-3-(5)-(4-fluoro)phenyl-4 -(3-(5-oxo-1H,4H-1,2,4-triazolo-lo)methylmo 12 rfoline, which consist in thermodynamic stability and in the fact that this form is suitable for inclusion in pharmaceutical preparation forms.

Technical level

Neuropeptide receptors for substance P (neurokinin-1; NK-1) are widespread in the nervous system of mammals (especially in the brain and spinal cord), circulatory system and peripheral tissues (especially in the duodenum and small intestine) and are involved in the regulation of a number of diverse biological processes . This includes the sensory perception of smell, sight, hearing and pain, motor control, gastric motor function, vasodilation, salivation and urination. Substance P (also referred to herein as "BP") is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so named because it exerts a contractile effect on extravascular smooth muscle tissue. Tachykinins differ in a constant sequence with the terminal carboxyl РПе-Х-сиу-И ей-Мей-МН2О. In addition to BP, tachykinins are known (3 mammals include neurokinin A and neurokinin B. In the current nomenclature, receptors for BP, neurokinin

A and neurokinin B are designated as NK-1, NK-2, and NK-3, respectively.

Substance P is a pharmacologically active neuropeptide that is produced in mammals and acts as a vasodilator (vasodilating factor), a depressant, stimulates salivation and creates increased capillary permeability. It is also able to produce both analgesia and hyperalgesia in animals, depending on the dose and the sensitivity of the animal to pain.

Tachykinin receptor antagonists have been considered for pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, morphine withdrawal syndrome, cardiovascular changes, edema such as thermal injury edema, chronic inflammatory diseases such as 39 rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases, including allergic rhinitis, inflammatory bowel diseases, including non-specific ulcerative colitis and Crohn's disease, eye injuries and inflammatory diseases, proliferative vitreoretinopathy, mucositis and bladder dysfunction, including detrusor hyperreflexia bladder "

Moreover, it has been suggested that tachykinin receptor antagonists may be used in the C 50 treatment of the following conditions: depression, dysthymic disorders, chronic airway obstruction, c hypersensitivity such as poison ivy syndrome, vasospastic conditions such as angina and

Reynold's fibrosis and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder syndrome, adduction disorders such as alcoholism, somatic stress-related disorders, neuropathy, neuralgia, disorders associated with immunological activation or suppression, such as systemic lupus erythematosus, ophthalmic diseases, such as conjunctivitis, vernal conjunctivitis, etc., and skin diseases, such as contact dermatitis, atonic dermatitis, urticaria, and others -And eczematoid dermatitis .

Attempts have been made to obtain antagonists of substance P receptors and other tachykinin peptides for more effective treatment of the various diseases and disorders listed above. In particular, in PCT Rybiisayop Mo. MO at 20 94/00440, ERO Rybiysayop Mo, 0 577 394 and PCT Rybiysayop Mo. UUO 95/16679 describes certain compounds of morpholine and thiomorpholine as antagonists of substance P. In particular, compound c 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-( 5)-(4-Fluoro)phenyl-4-(3-(5-oxo-1H 4H-1,2,4-triazolo)methylmorpholine is described as the target compound of example 75 in PCT Rybiysayop Mo. MO 95/16679. This the compound is further identified as a polymorphic form, designated in this description as “Form II.” 29 Of the morphological forms of pharmaceutical compounds, those included in the development may be of interest

GF) of the respective dosage forms, because unless the morphological form remains unchanged during clinical and stability studies, the exact dosage form used or measured cannot be compared from one batch to another. If a pharmaceutical compound is manufactured for use as a medicinal product, it is important to identify the morphological form included in each dosage form in order to be sure that the same forms are used in the manufacturing process and that each dosage form includes the same the same amount of medicine. Therefore, it is necessary to make sure that there is either a single morphological form or some known combinations of morphological forms. In addition, certain morphological forms may exhibit improved thermodynamic stability and may be more suitable than other morphological forms for inclusion in pharmaceutical formulations. In this description, a polymorphic form of a chemical compound has the same chemical essence, but a different crystal structure.

Description of drawings

Figure 1 shows the X-ray powder diffraction pattern of Form I 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4- (3-(5-oxo-1H 4H-1,2,4-triazolo)methylmorpholine.

Figure 2 shows the X-ray powder diffraction pattern of Form I 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl- 4-(3-(5-oxo-1H 4H-1,2,4-triazolo)methylmorpholine.

Detailed description of the invention 70 This invention relates to a new polymorphic form of the compound 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro) phenyl-4-(3-(5-oxo-1H 4H-1,2,4-triazolo)methylmorpholine and the method of obtaining this polymorphic form.

Compound 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo) -1H,4H-1,2,4-triazolo)methylmorpholine has the following structure:

That's it.

AND

With this FI sing

NM. OMN is a tachykinin receptor antagonist used in the treatment of inflammatory diseases, pain or i) migraine, asthma and vomiting.

This particular polymorphic form (designated as "Form I") is superior in properties to other crystalline forms of the compound, as it is more thermodynamically stable than other morphological forms and more suitable for Ge! zo for inclusion in pharmaceutical preparations.

This invention also relates to the method of obtaining Form | so 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo) -3-H,4H-1,2,4-triazolo) o methylmorpholine, which includes: equilibration of Form I and - 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo-1H 4H-1,2,4-triazolo)methylmorpholine in a solvent selected from ethanol, 2-propanol , acetonitrile and isopropyl acetate.

This invention also relates to the method of obtaining Form 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4- (3-(5-oxo-1H 4H-1,2,4-triazolo)methylmorpholine, which includes: "heating the sample in 2-(К)-(1-(К)-(3,5-bis( trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo-1H 4H-1,2,4-triazolo)methylmorpholine of an optional morphological composition to temperatures from 215 to 230"C; and then cooling the sample to ambient temperature.

In particular, heating 2()-Y-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo- 1H,4H-1,2,4-triazolo)methylmorpholine can be carried out in a differential scanning calorimetric cell in an open tank under a nitrogen atmosphere and

Sh- 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo) -1H,4H-1,2,4-triazolo) o methylmorpholine can be heated to a temperature of 215-230 and then cooled to room temperature.

Preferably, the morphological composition of the starting compound is 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3 -(5-oxo-1H 4H-1,2,4-triazolo)methylmo

He)rpholin is Form II.

In addition, the present invention relates to an alternative method, particularly suitable for obtaining

Forms in 2) -(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H- 1,2,4-triazolo)methylmorpholine on an industrial scale, which includes: (F, suspension of 2-(К)-(1-К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3- (5)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine of an optional morphological composition in a methanol/water solution, where the solution preferably has 60 ratio 2/1 (v/v); addition of seed crystals of Form I 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-( 4-fluoro)phenyl-4-(3-(5-oxo-1H 4H-1,2,4-triazolo)methylmorpholine; stirring the obtained mixture at a temperature of about 0 - 50"C for a time sufficient for the formation of 65 Form 2 -(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo-1H) 4H-1,2,4-triazolo)methylmorpholine; and collection of the obtained Form I 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5) -(4-fluoro)phenyl-4-(3-(5-oxo-1H 4H-1,2,4-triazolo)methylmorpholine.

The present invention also relates to a method of obtaining morphologically homogeneous 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl- 4-(3-(5-oxo-1H 4H-1,2,4-triazolo)methylmorpholine, which includes any of the processes described above.

The compound of this invention, a new polymorphic form in 2()AI -(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-( 5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine is a tachykinin receptor antagonist used in the treatment of inflammatory diseases, pain or migraine, asthma and vomiting. Accordingly, the present invention further relates to pharmaceutical preparations, containing this polymorphic form as an active ingredient, and to the use of this polymorphic form and its preparative forms in the treatment of certain diseases.

Form 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo) -1H 4H-1,2,4-triazolo)methylmorpholine is anhydrous and non-hygroscopic and shows a high degree of thermal stability in the solid substance as such and in an aqueous-alcohol solution.

Form II is an anhydrous crystalline material, melting at a temperature of 2547C, which is obtained directly by recrystallization during the chemical synthesis of 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-( 5)-(4-fluoro)phenyl-4-(3-(5-oxo-1H 4H-1,2,4-triazolo)methylmorpholine.

X-ray powder diffraction (XRD)

Research using X-ray powder diffraction is widely used to determine molecular structures, crystallinity, and polymorphism. Diffractograms of powder diffraction of X-rays (PDRI) are recorded on a powder diffractometer RPAirz, model ARYUO 3720, i) equipped with a ZKV X-ray generator (radiation. SiCoa1) and a Mai (Ti) scintillation detector.

Measurements are made from 3" to 45" (2 theta) using a sample stored at room temperature, the results are shown in Fig.1 and Fig.2. Ge")

Form 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-(3-(5-oxo-1H) ,4H-1,2,4-triazolo)methylmorpholine is characterized by an X-ray powder diffraction pattern, which has characteristic reflections at approximately: 12.0, 15.3, 16.6, 17.0, 17.6, 19.4, 20.0, 21.9 23.6, 23.8 and 24.87 (2 theta).

ITS form - 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5 -oxo-1H 4H-1,2,4-triazolo)methylmorpholine is characterized by an X-ray powder diffraction pattern, which has characteristic reflections approximately: 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9 and 24.87 ( 2 theta).

Diffractogram data (PDRP) confirm that both samples have a certain crystalline form. Both Form I and Form II exhibit significant characteristic peaks of crystalline material. "

Differential scanning calorimetry cell (DSC) шщ s Differential scanning calorimetry of Form I 2-(К)-(1-(К)-(3,5 z» bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4 -fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine and Form I! 2-(K)-(1-(K)-(3 ,5-bis(trifluoromethyl)phenylethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine does not show significant differences in their thermal properties.Both phases give thermograms with a single melting endotherm at the same temperature.

In particular, the curve dec Forma

Che 12-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo) -1H,4H-1,2,4-triazolo)methylm oorpholine exhibits a single melting endotherm with a peak temperature of 255.8"С, an extrapolation start temperature of 254.77 and an enthalpy of 105 J/kg. Curve dec of Forms I and 2-(K) -(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo-1H 4H-1, 2,4-triazolo)methylmo

He)rpholine also exhibits a single melting endotherm with a peak temperature of 255.6"C, an extrapolation onset temperature of 254.47, and an enthalpy of 107 J/g.

NMR

Spectra of proton and carbon nuclear magnetic resonance Form | and Forms II did not show any chemical changes in the combination upon conversion from Form II to Form I. iF) Solubility co Solubility of Form I! in 2/1 (v/v) methanol/water at room temperature is 0.9 and 0.1 Tmg/ml. The solubility of form II in 2/1(o6/vol) methanol/water at a temperature of 0"С is 1.3 and 0.2 mg/ml. The solubility ratio is equal to 1.4, which shows that Form I! is a more stable polymorph. Form I is more stable , than Form II by 0.2 kcal/mol.

Steam pressures

The vapor pressure of Form I and Form II at elevated temperatures was the same when studied by the Knudsen effusion method. 65 Studies of antagonism to tachykinin

The compound of this invention, polymorphic Form I

2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo- 1H 4H-1,2,4-triazolo)methylmorpholine is used to antagonize 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 vomiting in mammals with the need for such treatment.Such activity may be demonstrated in a subsequent study.

A. Expression of the receptor in CO5

For the expression of the cloned human neurokinin-1 receptor (NKIR) from the side in CO5, the cDNA for the human NKR is cloned into the expression vector RSOMO, which is obtained from RSOM8 (IMMITKOSEM), inserting the ampicillin-resistant gene (nucleotide 1973-2964 from VGOEZSTYURT ZKU) in the precinct zas II. Transfection of 20 µg of plasmid DNA into millions of CO5 cells is achieved by electroporation in 8000 µl of transfection buffer (135 mM Masi, 1.2 mM

Saii2, 1.2mM Mosi2, 2.4MM K2HROYA4, 0.b6mM KH2ROYA4, 10MM glucose, 10MM NEREZ pH 7.4) at 260 V and 95Ωkf, using IVI SEME2ARREK (IVI, Mem Namep, ST). Cells are incubated in 1095 lethal calf serum, 2 mM glutamine, 100 U/ml penicillin-streptomycin and 9095 Dulbecco's modified medium 7/5 Needle (OMEM) (9IVSO, Sgapa Iziapa, MU) in 590 CO2 at a temperature of 377C for three days before the study for connection

B. Sustained expression in SNO

To obtain a stable cell line expressing the cloned human NKIR, cDNA is subcloned into the pKsSMM vector (IMMITKOSEM). Transfection of 20 μg of plasmid DNA into the CHO cell is achieved by electroporation in 80 μl of transfection buffer with the addition of 0.625 mg/ml of Negivtipd sperm DNA at 300 V and 95 μf using IVI

SEMELARREK (IVI). Transfected cells are incubated in CHO medium (1095 fetal calf serum, 100 U/ml penicillin-streptomycin, 2 mM glutamine, 1/500 hypoxanthinethymidine (ATSS), 9096 IMOM NC medium

VIOBSIEMSEZ, Iepekha, KB), 0.7mg/ml 5418 (SIVSO)|І in 595 СО2 at a temperature of 377"С until the colonies remain visible. Each colony is separated and propagated. Cell clones with the highest number of cells about Human NKR are selected for further use, for example, for drug screening.

C. Research protocol using CO5 or CHO (8)

Studies of the conjugation of human NKIR expressed either in CO5 or in CHO cells are based on the use of 125I-substance P (125I-BP, from OO ROMT, Voziop, MA) in the form of a radioactively labeled ligand, which is compared with unlabeled substance P or any what other ligand for conjugation of human NKR. Gee! zo Single-layer culture of cells of SOC or CHO is dissociated with a non-enzymatic solution (ZRESIAGITM MEOIA, I amaIebtse,

MU) and resuspended in the appropriate volume of binding buffer (50 mM Tris pH 7.5, 5 mM Mpsi2, 150 mM sodium chloride, 0.b04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml ABS, 0.01 mM phosphoramidon) in such a way that about 2000 μl of cell suspension could give rise to about 10,000 pulses (number of pulses per minute) of specific 125I-BP coupling (approximately from 50,000 to 200,000 cells). In the mating study, 200 μl of cells are added to the a test tube containing 20 μl of 1.5 - 2.5 NM 125I-BP and 20 μl of unlabeled substance P or any other compound being tested. The test tubes are incubated at a temperature of 4"C or at room temperature for 1 hour with gentle shaking. Combined radioactive cells are separated from uncombined radioactive cells using a SR/S filter (VKAMOEI, Seipegerigo, MO), which is pre-moistened with 0.195 polyethyleneimine.

The filter is washed with 3 ml of washing buffer (50 mM Tris pH 7.5, 5 mM Maisi2, 150 mM Masi) three times and its radioactivity is determined with a gamma radiation counter. c c Activation of phospholipase C by NCIR can also be measured in CHO cells expressing human NCIR. determination of the accumulation of inositol monophosphate, which is a degradation product of IR. CHO cells are seeded in y? 12-cell tablet with 250,000 cells per cell. After incubation in the CHO medium for 4 days, the cells are loaded with 0.025 μCi/ml of ZH-myoinositol by overnight incubation. Extracellular radioactivity is removed by washing with saline solution with the addition of phosphate buffer. Cells C are added with GCl to a final concentration of 0.1 mM with or without the test compound, and the incubation is continued at 37°C for 15 minutes. Substance P is added to the cells to a final concentration of 0.3 mM for

Sh- activation of the human NCIR. Through ЗОхв. incubation at a temperature of 37"C, the medium is removed and 0.1 M of NOI is added. Each cell is treated with ultrasound at a temperature of 4"C and extracted with SNCI3/methanol (1 : 1). The aqueous 5p phase is applied to 1 ml of an ion-exchange column Yuozheh As 1X8. The column is washed with 0.1 M formic acid and then with 0.025 M ammonium formate-0.1 M formic acid. Inositol monophosphate is eluted with 0.2 M ammonium formate-0.1 M

Ge) formic acid and carry out a quantitative analysis using a beta radiation counter.

The activity of this compound can also be demonstrated with the help of the study described in 1992.

The compound of this invention is of great value in the treatment of a wide range of clinical conditions characterized by the presence of excessive tachykinin activity, in particular, substance P.

F) Thus, for example, excessive activity of tachykinin, and in particular, substance P, occurs in various disorders of the central nervous system. Such disorders include mood disorders, such as depression, or more specifically, depressive disorders, such as episodic or recurrent major nervous disorders and 60 dysthymic disorders, or bipolar disorders, such as bipolar disorder | degree, bipolar disorder II degree and cyclothymic disorders; anxiety such as panic with or without agoraphobia, agoraphobia with a history of panic, certain phobias such as certain fear of animals, obsessive compulsive disorder, stress including post-traumatic stress and acute stress, and general anxiety states; schizophrenia and other psychotic disorders, for example, schizophrenic disorders, schizoaffective disorders, delusional state, short-term psychotic disorders, 65 split psychotic disorders and psychotic disorders with delusions or hallucinations; delirium syndrome, dementia, amnesia and other memory disorders and neurodegenerative disorders such as Alzheimer's disease,

marasmatic dementia or dementia of the Alzheimer type, vascular dementia and other dementias, such as those resulting from HIV infection, head trauma, Parkinson's disease, Huntington's disease,

Pica, Creutzfeldt-Jakob diseases, or which were the result of multiple etiologies; Parkinson's disease and other extrapyramidal movement disorders, such as drug-induced movement disorders, such as neuroleptic parkinsonism, neuroleptic malignant syndrome, neuroleptic acute dystonia, neuroleptic acute akathisia, neuroleptic tardive dyskinesia, and drug-induced postural tremor; disorders associated with the intake of certain substances, arising when using alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, volatile drugs and/or aerosol volatile compounds, nicotine, opium, phenylglycidin derivatives, sedatives, hypnotics , and tranquilizers, where disorders caused by taking these substances include dependence and abuse, intoxication, withdrawal syndrome, intoxication delirium, delirium associated with withdrawal syndrome, persistent dementia, psychotic disorders, mood disorders, anxiety, sexual dysfunction and sleep disorders; epilepsy; Down syndrome; destruction of the myelin layer, such as M5 and A! 5 and other neuropathological disorders, such as peripheral neuropathy, such as diabetic and chemotherapy-induced neuropathy, and shingles neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, and other types of neuralgia; and cerebrovascular disorders resulting from acute or chronic damage to cerebral vessels, such as cerebral infarction, subarachnoid hemorrhage, or cerebral edema.

The action of tachykinin and, in particular, substance P, also takes place in the perception of pain and pain. The compound of the present invention can therefore be used for the prevention and treatment of diseases and conditions in which the dominant factor is pain, including soft tissue damage and peripheral damage, such as acute injuries, osteoarthritis, rheumatoid arthritis, musculoskeletal pain, especially post-traumatic, spinal pain, pain syndrome with simultaneous inflammation of muscle and fascia, headache, episiotomy, and burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, facial pain, such as toothache, abdominal pain, gynecological pain, such as menstrual pain, and labor pain; pain associated with damage to nerves and roots, such as pain associated with disorders of the peripheral nervous system i) such as organ impingement and avulsion of the brachial plexus, amputation, peripheral neuropathies, tic, pain, atypical facial pain, root damage nerves, and araneidism; carcinoma-related pain, often defined as cancer pain; pain in the central nervous system, such as pain caused by damage to the spinal cord or brain stem; pain in the lower back; sciatica; ankylosing spondylitis, gout; and scar pain. co

Tachykinin antagonists and, in particular, substances P, can also be used in the treatment of respiratory diseases, especially those associated with excessive secretion of mucus, such as chronic airway obstruction, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, respiratory distress -syndrome in y-z5 adults and bronchospasm; inflammatory diseases, such as intestinal inflammation, psoriasis, fibrosis, osteoarthritis, rheumatoid arthritis, pruritus and solar erythema; allergic diseases, such as eczema and rhinitis; hypersensitivity, such as "poison ivy" type disease; ophthalmic diseases, such as conjunctivitis, spring conjunctivitis and the like; ophthalmic conditions associated with cell proliferation, such as proliferative vitreoretinopathy; skin diseases such as contact dermatitis, atonic dermatitis, urticaria and other eczematoid diseases. z c Tachykinin ii antagonists, in particular, substance P, can also be used in the treatment of neoplasms, including breast tumors, neuroganglioblastoma, and small cell cancers, such as small cell carcinoma; easy

Tachykinin antagonists, and in particular substance P, can also be used in the treatment of gastrointestinal (GI) disorders, including inflammatory diseases and disorders of the GI tract, such as gastritis, peptic ulcer, gastric cancer, gastric lymphoma, disorders associated with with neural control of internal organs, non-specific ulcerative colitis, Crohn's disease, mucous colitis and vomiting, including acute, delayed

- or premature vomiting, such as vomiting caused by chemotherapy, radiation, toxins, viral or o bacterial infections, pregnancy, vestibular disorders such as pumping,

Vertigo, and Meniere's disease, surgery, migraine, intracranial pressure fluctuations, gastro-oesophageal reflux, heartburn, excessive consumption of food or drink, increased acidity in the stomach, heartburn

Ge) or regurgitation, heartburn, for example, episodic, nocturnal or postprandial heartburn and dyspepsia.

Tachykinin antagonists, and in particular substance P, may also be used in the treatment of a variety of other conditions, including stress-related somatic disorders; reflex sympathetic dystrophy, such as ov bindroma of the shoulder; adverse immunological reactions, such as rejection of transplanted tissues and disorders associated with immunological activation or suppression, such as systemic lupus erythematosus; transudation of plasma, which is

F) as a result of cytokine chemotherapy, bladder function disorders, such as cystitis, bladder detrusor hyperreflexia and urinary incontinence; fibrosis and collagen diseases, such as scleroderma and eosinophilic fascilosis; disorders of blood movement associated with the expansion and narrowing of blood vessels, such as angina, vascular headache, migraine and Reynolds disease; and pain or perception of pain accompanying or associated with any of the above conditions, especially migraine pain transmission.

The compound of this invention is also of value in the treatment of a combination of the above conditions, in particular, in the treatment of concomitant postoperative pain and postoperative nausea and vomiting.

A compound of the present invention is particularly useful in the treatment of emesis, including acute, delayed or premature emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, movement, surgery, migraine and intracranial pressure fluctuations.

More specifically, the compound of this invention is used in the treatment of emesis caused by antineoplastic (cytotoxic) agents, including those commonly used in cancer chemotherapy.

Examples of such chemotherapeutic agents include alkylating agents such as nitrogen ointment, ethyleneimine compound, alkylsulfonates and other alkylating compounds such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example, vinca alkaloids and podophyllotoxin derivatives; and cytotoxic antibiotics.

Specific examples of chemotherapeutic agents are described, for example, in O.9U.5(emag in "Maizea apa Motiypa: 70 Kesepi Kezeagsp apa Siipisai Admapsev", Edv, U. KispagsguK, ebsai,, SKS Rgevzv Ips., Vosa Kaiyop, Riogida, OBA (1991), pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (OTIS), dactinomycin, mechlorethamine (nitrogen ointment), streptozocin, cyclophosphamide, carmustine (VSMO), lomustine (SSMI), doxorubicin (Adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, and chlorambucil 7/5 |KU.Ogaiiia, ei ai., Sapseg Tgteaitepi Kerogov, 68(1) 163- 172 (1984).

The compound of this invention is also used in the treatment of emesis caused by radiation, including radiation therapy, such as in the treatment of cancer, or nausea caused by radiation; and in the treatment of postoperative nausea and vomiting.

For the treatment of certain conditions, it may be desirable to use a compound of this invention in combination with other pharmacologically active agents. It should be understood that the compounds of this invention may be present together with other therapeutic agents in the form of a combined preparation form for simultaneous, separate or sequential use for the relief of emesis. Such combined preparation forms can be, for example, in the form of a double bag.

Another aspect of the present invention is a compound of the present invention in combination with a 5-NTZ antagonist such as ondansetron, granisetron, tropisetron, or zatisetron, or other antiemetic drugs, such as dexamethasone or dopamine antagonists such as metoclopramide. In addition, the compound of this i) invention can be administered in combination with anti-inflammatory corticosteroids, such as dexamethasone. Moreover, the compound of this invention can be administered in combination with chemotherapeutic agents, such as alkylating agents, antimetabolites, mitotic inhibitors or cytotoxic antibiotics, as described above. In general, for Ge!

Any dosage forms of known therapeutic agents available at this time are suitable for use in such combinations. co

When tested on the African ferret model for cisplatin-induced vomiting, described in Fr

EO Taiegzai! ek aiYi., in Eig. IN). rpagtasoi, (1993) 250, K5-Kb, it was found that the compound of this invention attenuates nausea and vomiting caused by cisplatin. A compound of the present invention is also particularly useful in - the treatment of pain or pain perception and/or inflammation and/or disorders associated therewith, such as, for example, neuropathy such as diabetic and chemotherapy-induced neuropathy, post-herpetic and other neuralgias, asthma, osteoarthritis, rheumatoid arthritis, and headache, including migraine, acute or chronic tension-type headache, cluster headache, transient mandibular pain, and maxillary sinus pain.

The present invention also provides a compound of the present invention for use in therapy. "

According to another or alternative aspect, the present invention represents a compound of the present invention for use in the manufacture of medicinal products for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P.;" The present invention also represents a method of treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, where the method includes administering to the patient, if necessary, such

Treatment, reducing the tachykinin amount of a compound of this invention or a composition containing a compound of this invention.

For the treatment of certain conditions, it may be desirable to use a compound of this invention in combination with another pharmacologically active agent. For example, for the treatment of respiratory diseases, such as asthma, the compound of this invention can be used in combination with a bronchodilator, such as a 5p antagonist of the D2-adrenergic receptor or a tachykinin antagonist that acts on NK-2 receptors. Combination of this

The drug of the invention and the bronchodilator can be administered to the patient simultaneously, sequentially or in combination. For the treatment of (Che) conditions requiring antagonism of both neurokinin-1 and neurokinin-2, including disorders associated with airway bronchoconstriction and/or plasma transudation, such as asthma, chronic bronchitis, airway disease, or cystic fibrosis , the compound of this invention can be used in combination with a tachykinin antagonist that acts on neurokinin-2 receptors, or with a tachykinin receptor antagonist that acts on both neurokinin-1 and neurokinin-2 receptors. i) Similarly, a compound of the present invention can be used with leukotriene antagonists, such as the co-antagonist leukotriene 04, such compound being selected from the compounds described in European patents MoMo 0 480 717 and 0 604 114 and in US patents MoMo 4 859 692 and 5 270 324. These combinations are especially useful in the treatment of respiratory diseases such as asthma, chronic bronchitis and cough.

The present invention also provides a method of treating respiratory diseases, such as asthma, which includes administering to a patient, in need of such treatment, an effective amount of a compound of the present invention and an effective amount of a bronchodilator. The present invention also provides a composition containing a compound of the present invention, a bronchodilator and a pharmaceutically acceptable carrier. 65 It should be understood that for the treatment or prevention of migraine, a compound of the present invention may be used in combination with other antimigraine agents such as ergotamines or 5-NTI agonists,

especially sumatriptan or rizatriptan. Also for the treatment of reactive hyperalgesia, the compound of this invention can be used in combination with M-methyl SO-aspartate (MOMA) antagonists, such as dizocilpine. For the treatment or prevention of inflammatory conditions in the lower urinary tract, especially cystitis, the compounds of this invention can be used in combination with an anti-inflammatory agent, such as a bradykinin receptor antagonist. The present invention also includes a composition containing a compound of the present invention, a bronchodilator and a pharmaceutically acceptable carrier.

It should be understood that for the treatment or prevention of pain or sensitivity to pain, the compound of the present invention can be used in combination with other analgesics, such as acetaminophen 7/0 (paracetamol), aspirin and other NSAIDs, in particular, opioid analgesics, especially morphine. Certain anti-inflammatory agents include diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam, and sulindac. Suitable opioid analgesics for use in combination with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, afenanthin, buprenorphine, butorphanol, fentanyl, sufentanil, meperidine, methadone, nalbuphine, propoxyphene, and pentazocine or 7/ 5 their pharmaceutically acceptable salts. Preferred salts of these opioid analgesics include morphine sulfate, morphine hydrochloride, morphine tartrate, codeine phosphate, codeine sulfate, dihydrocodeine bitartrate, diacetylmorphine hydrochloride, hydrocodone bitartrate, hydromorphone hydrochloride, levorphanol tartrate, oxymorphone hydrochloride, afenanthyl hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, fentanyl citrate , meperidine hydrochloride, methadone hydrochloride, nalbuphine hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate (2-naphthalene sulfonic acid (1:1) monohydrate) and pentazocine hydrochloride.

Therefore, a further aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.

In another or alternative aspect of the present invention, there is provided a product containing a compound of the present invention and an analgesic in the form of a preparation form for simultaneous, separate or sequential

Use in the treatment or prevention of pain or susceptibility to pain.

It should be understood that for the treatment or prevention of depression and/or anxiety, the compound of this i) invention may be used in combination with an antidepressant or an anxiolytic agent. Suitable classes of antidepressants for use in the present invention include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, Ge! zo inhibitors of reversible monoamine oxidase, serotonin and norepinephrine reuptake inhibitors, corticotropin-releasing factor (CRE) antagonists, α-adrenoceptor antagonists and atypical antidepressants. co

Another class of antidepressants useful in the present invention are noradrenergic and certain serotonergic (su) antidepressants such as mirtazapine. Suitable examples of norepinephrine reuptake inhibitors include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, v. nortriptyline, reboxetine and protriptyline and their pharmaceutically acceptable salts. Suitable examples of selective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine and sertraline and their pharmaceutically acceptable salts. Suitable examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine, tranylcypromine and selegiline and their pharmaceutically acceptable salts. Suitable examples of reversible monoamine oxidase inhibitors include moclobemide and its pharmaceutically acceptable salts. Suitable examples of serotonin and norepinephrine reuptake inhibitors include venlafaxine and its pharmaceutically acceptable salts. compositions of corticotropin-releasing factor (CRF) antagonists include compositions described in the descriptions of international patents MoMo UMUO 94/13643, UMO 94/13644, MO 94/13661, MOO 94/13676 and MO z 94/13677. Suitable examples of atypical antidepressants include bupropion, lithium, nefazoedone, sibutramine, trazodone and viloxazine and their pharmaceutically acceptable salts. Other antidepressants for use in the present invention include adenozolam, alaproclate, amineptine, amitriptyline/chlordiazepoxide, atipamezole, c azamianserin, bazinaprine, fefuralin, bifemelan, binodaline, bipenamol, brofaromine, bipropion, caroxazone, cericlamine, cyanopramine, cimoxatone, citalopram, clemeprole, clovoxamine, dazepinil, deanol, demexyptyline, - dibenzepine, dothiepine, droxidopa, enefexin, cetazolam, etoperidone, femoxetine, phengabine, fezolamine, o fluotracene, idazoxan, indalpine, indeloxazin, iprindole, levoprotyline, litoxetine, lofepramine, medifoxamine, 5r Mmetapramine, metrolindole , mianserin, milnacipran, minaprine, mirtazapine, montirelin, nebracetam, nefopam, bo nialamide, nomifenzine, norfluoxetine, orotirelin, oxaflozan, pinazepam, pirindol, pisotilin, ritazerin,

Ge) rolipram, cercloremin, cetiptilin, sibutramine, sulbutramine, sulpride, teniloxazine, tozalinone, timoliberine, tianeptine, tiflucarbine, tofenacin, tofizopam, toloxatone, tomoxetine, veralipride, vicvalin, zimelidine and zometapine and their pharmaceutically acceptable salts, St. John's wort, or Nuregisigsi repogaiisht or its ov extract. Preferred antidepressants include selective serotonin reuptake inhibitors, in particular, fluoxetine, fluvoxamine, paroxetine and sertraline and their pharmaceutically acceptable salts.

F) Suitable classes of anxiolytic agents used in the present invention include benzodiazepines and 5-HTTA agonists or antagonists, especially 5-HTTA partial agonists, and corticotropin-releasing factor (CRF) antagonists. In addition to benzodiazepines, other relevant classes of agents for reducing anxiety include non-benzodiazepine sedative-hypnotic drugs such as zolpidem; mood stabilizers such as clobazam, gabapentin, lamotrigine, loreclezole, oxcarbamazepine, stiripentol, and vigabatrin; and barbiturates. Suitable benzodiazepines used in the present invention include alprazolam, chlordisepoxide, clonazepam, chlorazepate, diazepam, galazepam, lorezepam, oxazepam and prazepam, and their pharmaceutically acceptable salts. Suitable examples of 5-HT1A agonists or antagonists useful in the present invention include, in particular, the partial 5-HT1A agonists baspirone, flesinoxan, gepirone, ipsapirone, and pindolol, and their pharmaceutically acceptable salts. Suitable examples of corticotropin-releasing receptor (CRE) antagonists include the compounds described in international patent specifications MoMo U/O 94/13643, MO 94/13644, UMO 94/13661, UMO 94/13676 and MO 94/13677. Another class of anxiolytic agents useful in the present invention are compounds that have muscarinic cholinergic activity. Suitable compounds of this class include muscarinic cholinergic receptor antagonists, such as compounds described in European patents MoMo 0 709 093, 0 709 094 and 0 773 021 and international patent Mo UUO 96/12711.

Another class of agents that reduce anxiety used in the present invention are compounds that act on ion channels. Suitable compounds of this class include carbamazepine, lamotrigine and valproate and their pharmaceutically acceptable salts. 70 Therefore, another aspect of the present invention is a pharmaceutical composition comprising a compound of the present invention and an antidepressant or anxiolytic agent together with at least one pharmaceutically acceptable carrier or excipient.

Suitable antipsychotic agents for use in combination with a compound of the present invention include phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine, and antipsychotic agents of the indolone class. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chloroprothixene and thiothixene. Suitable examples of dibenzazepines include clozapine and olanzapine. An example of butyrophenone is haloperidol. An example of diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone.

Other antipsychotic agents include loxapine, sulpiride, and risperidone. It should be understood that these antipsychotic agents when used in combination with a compound of the present invention may be in the form of a pharmaceutically acceptable salt of chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fluphenazine ethanoate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.

Perphenazine, chlorprothixene, clozapine, olanzapine, haloperidol, pimozide and risperidone are usually used in non-salt form.

Other classes of antipsychotic agents useful in combination with a compound of the present invention i) include dopamine receptor antagonists, particularly dopamine receptor antagonists O2, OZ and O4, and muscarinic receptor agonists. An example of an antagonist of the dopamine receptor OZ is the compound RMO-99194A. An example of a dopamine 04 receptor antagonist is RMO-101387. An example of a muscarinic receptor agonist is dozoxanomeline.

Another class of antipsychotic agents used in combination with a compound of this invention are the 5-HT2A receptor co-antagonists, examples of which include MY 100907 and phananzarine. Also used in combination with the compounds of this invention are serotonin-dopamine antagonists (SODs), which are believed to combine antagonistic action at the 5-HT2A and dopamine receptors, examples of which include olanzapine and z-z5 ziperasidone. yu

Therefore, another aspect of the present invention is a pharmaceutical composition comprising a compound of the present invention and an antipsychotic agent together with at least one pharmaceutically acceptable carrier or excipient.

The compound of this invention and other pharmacologically active agents can be administered to the patient simultaneously, sequentially or in combination. It should be understood that when using the combination of this invention, the compound pt) c of this invention and another pharmacologically active agent can be in the same pharmaceutical. an acceptable carrier and therefore be administered at the same time. They can be in separate pharmaceutical carriers, right?” such as conventional oral dosage forms used simultaneously. The term "combination" is used when the compound is in separate dosage forms and is administered sequentially.

The pharmacological profile of the compound of this invention makes it possible to use it in therapy in small doses, thus minimizing the risk of unwanted side effects.

The compound of this invention can be administered to a patient (animal and human) if such treatment is necessary

Sh- dosage forms that provide optimal pharmacological effect. It should be understood that the doses used in each specific case differ for different patients, which is determined not only by the choice of a specific compound or composition, but also by the method of administration, the nature of the condition being treated, the age and condition of the patient, concomitant treatment or certain diets followed by the patient and other factors,

Ge) which are known to specialists in this area, and the choice of appropriate dosage forms is left to the discretion of the treating therapist.

In the treatment of conditions associated with an excess of tachykinins, appropriate doses are usually from about 0.001 to about 5Omg per kilogram of the patient's body weight per day, and this amount can be administered in a single dose or in multiple doses. Preferably, the dose is from about 0.01 to about 25 mg/kg per day; more preferably from near

F) 0.05 to about 1Omg/kg per day. For example, in the treatment of conditions involving nerve impulse transmission and the sensation of pain, a suitable dose is from about 0.001 to about 25 mg/kg per day, preferably from about 0.005 to about 1 µg/kg per day, and especially from about 0.01 to about bmg/kg per day . The compound can be administered from 1 to 4 times a day, but preferably once or twice a day. In the treatment of vomiting, a suitable dose is from about 0.001 to about 10 mg/kg per day, preferably from about 0.005 to B5 mg/kg per day and especially from about 0.01 to mg/kg per day. The compound can be administered from 1 to 4 times a day, preferably once or twice a day. In the treatment or prevention of disorders of the central nervous system, a suitable dose is from about 0.001 to about 1 Ω/kg per day, preferably from about 0.005 to 5 mg/kg per day and especially from about 0.01 to mg/kg per day. The compound can be administered 65 from 1 to 4 times a day, preferably once or twice a day.

It should be understood that the amount of a compound of the present invention required for use in any treatment depends not only on the particular compound or composition, but also on the route of administration, the nature of the condition being treated, and the age and condition of the patient, and, in the final result is at the discretion of the treating therapist.

The pharmaceutical compositions of this invention can be used in the form of a pharmaceutical preparation form, for example, in a solid, semi-solid or liquid form, which contains one or more compounds of this invention as an active ingredient in a mixture with an organic or inorganic carrier, or a filler suitable for external, enteral or parenteral use. The active ingredient can be combined, for example, with a conventional non-toxic, pharmaceutically acceptable carrier to obtain tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other forms suitable for use. Carriers that may be used include water, glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silicon dioxide, potato starch, urea, and other carriers suitable for use in in the production of preparative forms in solid, semi-solid or liquid form, and auxiliary, stabilizing, thickening and coloring agents can also be used. The active compound is included in the pharmaceutical composition in an amount sufficient to obtain the desired effect on the course or condition of the disease.

To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example, the usual ingredients used in the manufacture of tablets, such as starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or resins. and other pharmaceutical diluents, for example, water, to obtain solid precursors of compositions containing a homogeneous mixture of the compound of this invention or its non-toxic! pharmaceutical acceptable salt. When defining these precursor compositions as homogeneous, it is meant that the active ingredient is uniformly dispersed throughout the composition in such a way that the composition can easily be divided into equally effective unit dosage forms such as tablets, pills and capsules. This solid precursor of the composition is then divided into unit dosage forms of the type described earlier, containing from 0.1 to about 50mg of the active ingredient of this invention. Tablets or pills comprising the new composition may be coated or may be processed to provide sustained-release dosage forms. For example, i) tablets and pills can contain internal dosing and external dosing components, with the latter in the form of a shell around the former. The two components can be separated by a layer that prevents dissolution in the stomach and allows the internal component to pass intact into the duodenum (duzo or delayed excretion. Many materials or coatings can be used for such a layer, which include a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate

Liquid forms for oral administration or injections, in which the new compositions of this invention can be introduced, include an aqueous solution, syrups with appropriate flavorings, aqueous or oily suspensions in. c5 and emulsions with suitable oils such as cottonseed oil, hemp oil, coconut oil or peanut oil, or with solubilizers or emulsifiers suitable for intravenous administration, and with elixirs and similar pharmaceutical carriers. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural resins such as tragacanth, gum arabic, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin. "

Compositions for inhalations or insufflations include solutions and suspensions in pharmaceutical suitable, aqueous pt") with organic solvents or their mixtures and powders. Liquid and solid compositions may contain appropriate pharmaceutically acceptable fillers, such as those indicated above. Preferably, the compositions are administered orally or; nasal respiratory method for local or general action. Compositions in mostly sterile pharmaceutically acceptable solvents can be sprayed using inert gases. Sprayed solutions

May be inhaled directly from the nebulizer or the nebulizer may be attached to a face mask, canopy, or intermittent positive pressure breathing apparatus. Solution, suspension or powder compositions can be administered, preferably orally or nasally, using devices that transmit the composition in an appropriate way. o For the treatment of the clinical conditions and diseases noted above, the compound of this invention may be administered orally, topically, parenterally, by inhalation or rectally in unit dosage forms containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients. The term parenteral administration in

Ge) in this case includes subcutaneous injections, intravenous, intramuscular, intraperitoneal administration or infusion.

Methods of obtaining polymorphic forms of this invention are illustrated in the following examples. The two examples presented below are given for the purpose of illustrating this invention and do not limit its scope.

Example 1

F) (5)-(4-Fluorophenyl)glycine Preparation by chiral synthesis:

Stage A. 3-(«4-Fluorophenyl)acetyl-4-(5)-benzyl-2-oxazolidinone in an oven-dried 1-liter 3-neck flask equipped with a membrane, a nitrogen seal, a thermometer, and a magnetic stirrer with nitrogen and load with a solution of 5.09 g (33.Omol) of 4-fluorophenylacetic acid in 100 ml of anhydrous ether. The solution is cooled to a temperature of -107C and treated with 5.0ml (40.0 mol) of triethylamine followed by 4.30ml (35.00mmol) of trimethylacetyl chloride. A white precipitate will immediately form. The resulting mixture is stirred at a temperature of -107C for 40 minutes, then cooled to a temperature of -7876. 65 An oven-dried 250 ml round-bottom flask equipped with a membrane and a magnetic stirrer is purged with nitrogen and charged with a solution of 5.31 g (30.Omol) 4-(5)-benzyl-2-oxazolidinone in 40 ml of dry THF. The solution is stirred in a dry ice/acetone bath for 10 minutes, then 18.8 ml of a 1.6 M solution of n-butyllithium in hexane is slowly added. After 10 minutes, lithium-treated oxazolidinone solution is added to the mixture in the 3-necked flask through a cannula. The cooling bath is removed from the obtained mixture and the temperature is raised to 0"C. The reaction is stirred with 100 ml of a saturated aqueous solution of ammonium chloride, transferred to a 1-liter flask, and ether and THF are removed in vacuo. The concentrated mixture is distributed between ZOOml of methylene chloride and 5bbml of water and the layers are separated.

The organic layer is washed with 200ml of a 2M aqueous solution of hydrochloric acid, ZOOml of a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 400g of silica gel using C : 206/o06 hexanes/ether as eluent gives 8.95g of an oil which slowly hardens to 7/0 on standing. Recrystallization from 10 : 1 hexanes/ether gave 7.8 g (83906) of the target compound as a white solid, m.p. 64-66"С. Mass spectrum (BBA): t/2 314 (MAN, 10095), 177 (М-АЕСН2СО НН, 8596). 1Н-NMR (400 MHz, СОС13): А 2.76 (dd, 71Н, 9У -13.2, 9.2), 3.26 (dd, 3-13.2, 3.2), 4.16-4.34 (m, 4H), 4.65-4.70 (m, 1H), 7.02-7.33 (m, 9H). Analysis: calculated for C18NIbEMOZ3: C, 69.00; H, 5.15; M, 4.47; P, 6.06; found C, 68.86; H, 5.14; M, 4.48; P, 6.08.

Step B. 3-(5)-Azido-(4-fluorophenyl))acetyl-4-(5)benzyl-2-oxazolidinone Oven-dried 1-liter 3-neck flask equipped with a membrane, a nitrogen seal, a thermometer, and a magnetic stirrer , purged with nitrogen and charged with a solution of 58.Oml of a 1M solution of potassium bis(trimethylsilyl)amide in toluene and 85 ml of THF and cooled to a temperature of -78"C. An oven-dried 250 ml round-bottom flask equipped with a membrane and a magnetic stirrer was purged with nitrogen and charged with the solution 7.20g (23.Ommol)

of 3-(4-fluorophenyl)acetyl-4-(5)-benzyl-2-oxazolidinone in 40 ml of THF. The acyloxazolidinone solution is stirred in a dry ice-acetone bath for 10 minutes, then transferred, through a cannula, to a solution of potassium bis(trimethylsilyl)amide in such a way that the internal temperature of the mixture remains below -707C. The flask from under the acyloxazolidinone is rinsed with 15 ml of THF and rinsed is added through a cannula to the reaction mixture and the resulting mixture is moved at a temperature of -78"C for 30 minutes. An oven-dried 250 ml round-bottomed flask equipped with a membrane and a magnetic stirrer is purged with nitrogen and charged with a solution of 10.89 g (35 mmol) of 2,4,6-triisopropylphenylsulfonyl azide in 4 mmol of THF. The azide solution is stirred in a dry ice/acetone bath for 10 minutes, then it is transferred through a cannula to the reaction mixture in such a way that the internal temperature of the mixture remains below -70°C. After 2 minutes, the reaction is quenched with b.oml of glacial acetic acid, the cooling bath is removed and the mixture is stirred at room temperature for 18 hours. The quenched Ge») and the reaction mixture are partitioned between ZOO ml of ethyl acetate and ZOO ml of saturated aqueous sodium bicarbonate solution. The organic layer is separated, dried over magnesium sulfate and concentrated in vacuo.

Flash chromatography on 500 g of silica gel using 2 : 1 v/v, then 1 : 1 v/v hexanes/methylene chloride as eluent gave 5.45 g (6795) of the target compound as an oil. IR spectrum (pure, cm-1): 2104, 1781, 1702 1nH-NMR (400 MHz, SOC13): dl 2.86 (dd, 1H, 9-13.2, 9.6), 3.40 (dd, 71H, 9U-13.2, 3.2 ), 4.09-4.19 (m, 2H), - 4.62-4.68 (m, 1H), 6.14 (s, 1H), 7.07-7.47 (m, 9H). Analysis: calculated for С18НИ5ЕМ403: С, 61.01; H, 4.27; i am

M, 15.81; E, 5.36; found C, 60.99; H, 4.19; M, 15.80; R, 5.34.

Stage C. (5)-Azido-(4-fluorophenyl)acetic acid

A solution of 5.40 g (15.2 mmol) of 3-(5)-azido-(4-fluorophenyl))acetyl-4-(5)-benzyl-2-oxazolidinone in 200 Oml of Z: « 106/vol THF/water is stirred in an ice bath for 10 minutes. 1.28 g (30.4 mmol) of lithium hydroxide monohydrate is added in one portion and the resulting mixture is stirred cold for 30 minutes. The reaction mixture - c was distributed between 100 ml of methylene chloride and 100 ml of 2595 saturated aqueous solution of sodium bicarbonate and the layers were separated. The aqueous layer is washed with 2 x 100 ml of methylene chloride and acidified to pH 2 with a 2 M aqueous solution of hydrochloric acid. The resulting mixture is extracted with 2 x 100 ml of ethyl acetate; the extracts are combined, washed with 500 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to obtain 2.30 g ( 7790) of the target compound as an oil, which is used in the next step without further purification. IR spectrum (neat, cm-1): 2111, 1724. 1H-NMR (400 MHz, COS13): dl 5.06 (s, 1H), -1 7.08-7.45 (m, 4H), 8.75 (she, 1H).

Stage 0. (5)-(4-Fluorophenyl)glycine (a) Mixture of 2.30g (11.8mmol) (5)-azido-(4-fluorophenyl)acetic acid, 250mg 1095 palladium on carbon catalyst so 50 1 160O0ml Z : 1ob /o06 water/acetic acid is stirred in a hydrogen atmosphere for 18 hours. The reaction mixture is filtered through Celite and the flask and the filter are thoroughly washed with approximately 100 ml C: 1 v/v water/acetic acid. iChe) The filtrate is concentrated in a vacuum to a volume of about 5 Oml. Add 300ml of toluene and concentrate the mixture in vacuo to obtain a solid. The solid substance is suspended in 1:10w/o06 methanol/ether, filtered and dried to obtain 1.99g (10095) of the target compound. T1H-NMR (400 MHz, 020-MaO0): А 3.97 (s, 1H), 6.7 (pr t, 2H, )dE8.8), 7.01 (pr t, 2H, 90-5.6). o Obtaining by repeated dissolution

Stage A". 4-Fluorophenylacetyl chloride is a solution) A solution of 150 g (0.974 mol) of 4-fluorophenylacetic acid and 1 ml of M, M-dimethylformamide in 500 ml of toluene at a temperature of 40 °C is treated with 20 ml of thionyl chloride and heated to a temperature of 407 °C. An additional the amount of thionyl chloride 61.2 ml for more than 1.5 hours. After the addition, the solution is heated at a temperature of 50"C for 1 hour, the solvent is removed under vacuum and the residual oil is distilled under reduced pressure (1.5 mm Hg) to obtain 150.4 g (89.590) of the target compound . T.kip - 68-70.

Stage B'. 2-bromo-2-(4-fluoro)phenylacetic acid methyl ester

A mixture of 150.4 g (0.872 mol) of 4-fluorophenylacetyl chloride and 174.5 g (1.09 mol) of bromine is irradiated at a temperature of 65 °C with a quartz lamp for 5 hours. The reaction mixture is added dropwise to 400 ml of methanol and the solution is stirred for 16 hours. The solvent is removed. in vacuum and the residual oil is distilled under reduced pressure (1.5 mm Hg) to obtain 198.5 g (92905) of the target compound, boiling point - 106-110.

Stage C. Methyl (5)-(4-fluorophenyl)glycine

A solution of 24.7 g (0.1 mol) of 2-bromo-2-(4-fluoro)phenylacetic acid methyl ether and 2.28 g (0.01 mol) of benzyltriethylammonium chloride in 25 ml of methanol is treated with 6.8 g (0.105 mol) of sodium azide and the resulting mixture is stirred for 20 hours at room temperature. The reaction mixture is filtered; the filtrate is diluted

BOml of methanol and hydrogenated in the presence of 0.5 g of 1095 Ra/C at a pressure of 3.515 kg/cm? (50 rvi) for 1 hour. The solution is filtered and the solvent is removed in vacuo.

The residue is distributed between 1095 aqueous solution of sodium carbonate and ethyl acetate. The organic phase 70 is washed with water, a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to obtain 9.8 g of the target compound in the form of an oil.

OSH stage. Methyl ester of (5)-(4-fluorophenyl)glycine

A solution of 58.4 g of (g)-4-fluorophenylglycine methyl ether in 10 ml of 7:1 v/v ethanol/water is mixed with a solution of 28.6 g (0.0799 mol) of O0,0'-(i)-dibenzoyltartaric acid ((i)-DBVK) ( 28.bg, 0.0799mol) in 11Oml 7 : 1v/v 75 ethanol/water and the resulting solution is allowed to stand at room temperature. After the completion of crystallization, ethyl acetate (220 ml) is added and the resulting mixture is cooled to a temperature of -207C and filtered to obtain 32.4 g of (5)-(4-fluorophenyl)glycine methyl ether, (4)-DBVK salt (ei - 93.295). The mother liquors are concentrated in vacuo and the free base is released by partitioning between ethyl acetate and aqueous sodium carbonate. A solution of the free base obtained in this way in 11 Oml 7 : 1 v/v ethanol/water is mixed with a solution of 28.6 g (0.0799 mol) of 20. 9,0'-(-)-dibenzoyltartaric acid (-) (-DBVK) (28.6 bg , 0.0799mol) in 110 ml of 7: T1v/v ethanol/water and the resulting solution is allowed to stand at room temperature. After crystallization is completed, ethyl acetate (22 Oml) is added and the resulting mixture is cooled to a temperature of -207"C and filtered to obtain 47.0 g of (K)-(4-fluorophenyl)glycine methyl ether, (-)-DBVK salt (ei-75.895). Repeat the use of mother liquors and the addition of (i)-DBVK gives the second part 7.4 g of (5)-(4-fluorophenyl)glycinate, (i)-DBVK salt (ei-96.496). Both parts of (5)-amino ester with (39.8 g) combine in 200 ml of 7 : 10 v/v ethanol/water, heat for 30 minutes and cool to room temperature Addition of ethyl acetate, cooling and filtration gives 31.7 g of (5)-(4-fluorophenyl)glycinate, i9) (4) - DBVK salt (ei»9895). Enantiomeric excesses are determined by chiral HPLC (Stom/p-rask CE(yu) 5906 MEON in aq. NSIO4 pH 2, 1.5ml/min 40"C 200nm). A mixture of 17.5 g of (5)-(4-fluorophenyl)glycinate, (14)-DBVK salt and 32 ml of 5.5 M

NSI (32 ml) is heated in a reflux flask for 1.5 hours. The reaction mixture is concentrated under vacuum and the residue is dissolved in 40 ml of water. The aqueous solution is washed with 3x30 ml of ethyl acetate and the layers are separated. The pH of the aqueous layer was adjusted to 7 with ammonium hydroxide and the settled solid was filtered to obtain 7.4 g of the target compound (EI-98.890). at

Example 2 3-(5)-(4-fluorophenyl)-4-benzyl-2-morpholinone -

Stage A. M-Benzyl (5)-(4-fluorophenyl)glycine yu

A solution of 1.87 g (11.05 mmol) of (5)-(4-fluorophenyl)glycine and 1.12 ml (11.1 mmol) of benzaldehyde in 11.1 ml of a 1 M aqueous solution of sodium hydroxide and 1 ml of methanol at room temperature is treated with 165 mg (4.4 mmol) of sodium borohydride. The cooling bath is removed and the resulting mixture is stirred at room temperature for 30 minutes. A second portion of benzaldehyde (1.12 ml (11.1 mmol)) and sodium borohydride (165 mg (4.4 mmol)) was added to the reaction mixture, and stirring was continued for 1.5 hours. The reaction mixture is distributed between 100ml of ether and 5Oml of water and the layers are separated. The aqueous layer is separated and filtered to remove a small amount of insoluble material. The filtrate is acidified to pH 5 with a 2 M aqueous solution of hydrochloric acid and the settled solid substance is filtered, washed with water, then with ether and dried to obtain 1.95 g of the target compound. TIN-NMR (400 MHz, 020 -Maob): А 3.33 (AB sq , 2H, 9-8.4), 3.85 (s, 1H), 6.79-7.16 (m, 4H).

Stage B. 3-(5)-(4-fluorophenyl)-4-benzyl-2-morpholinone with a mixture of 1.95 g (7.5 mmol) of M-benzyl(5)-(4-fluorophenyl)glycine, 3.9 Oml (22.5 mmol ) M,M-diisopropylethylamine, b.BOml (75.O0mmol) of 1,2-dibromoethane and 40ml of M,M-dimethylformamide are stirred at a temperature of 1007 °C for 20 hours (dissolution of all solids occurs during heating). The reaction mixture is then (av) cooled and concentrated in vacuo. The residue is distributed between 25 Oml of ether and 10 Oml of 0.5 M acid potassium sulfate solution and the layers are separated. The organic layer is washed with 100 ml of saturated aqueous bicarbonate solution

Sodium bicarbonate, Х1Х50 ml of water, dried over magnesium sulfate and concentrated in a vacuum. Flash chromatography on 125g (Che) silica gel using C:1v/v hexanes/ether as eluent gave 1.58g (7495) of the target compound as an oil. TN-NMR (400 MHz, SOSIZ): dl 2.65 (dt, 1H, 9-3.2, 12.8), 3.00 (dt, 1H, 9U-12.8, 2.8), 3.16 (d, 1H, 2-13.6), 3.76 ( d, 1H, 9U-13.6), 4.24 (s, 1H), 4.37 (dt, 1H, 9-13.2, 3.2), 4.54 (dt, 1H, 9-2.8, 13.2), 7.07-7.56 (m, 9H) .

Example C o 2-(K)-(3,5-Bis(trifluoromethyl)benzoyloxy)-3-(5)-(4-fluoro)phenyl-4-benzylmorpholine

A solution of 2.67 g (10.0 mmol) of 3-(K)-(4-fluoro)phenyl-4-benzyl-2-morpholino in 40 ml of dry THF is cooled to a temperature of -78°C. The cold solution is treated with 12.5 ml of 1.0 M I -Zeiesigideo, solution in THF, keeping the internal temperature of the reaction below -707"С. The obtained solution is stirred cold for 45 minutes, and the reaction mixture is loaded with 3.0 ml (20.Omol) of 3,5-bis(trifluoromethyl)benzoyl chloride. The resulting yellow mixture is stirred cold for 30 minutes and the reaction is quenched with 5 Oml of a saturated aqueous solution of sodium bicarbonate. The quenched mixture is distributed between 300 ml of ether and 5 ml of water and the layers are separated. The organic layer is dried over magnesium sulfate. The aqueous layer is extracted with 30 Oml of ether; the extract is dried and combined with the original organic phase. The combined organic phases are concentrated in a vacuum. Flash chromatography on 150 g of silica gel with 65 using 37:v/v hexanes/ether as eluent afforded the target compound as a solid (8390 yield). Mass spectrum (BBA): t/7 528 (MAN, 25906), 270 (10095). LN-NMR (400 MHz, SOSIZ, ppt): А 2.50 (dt, 1Н,

93.2, 12.0), 2.96 (pr. d, 1H, 9U-12.0), 2.98 (d, 1H, 1-13.6), 3.74-3.78 (m, 71H), 3.81 (d, 1H, 9-2.8), 3.94 (d, 1H, 9-13.6), 4.19 (dt, 9U-2.0, 12.0), 6.20 (d, 71H, 2-2.8), 6.99 (t, 2H, 9-84), 7.27-7.38 (m, 5H ), 7.52-7.56 (m, 2H), 8.09 (s, 1H), 8.46 (s, 2H).

Example 4

Dimethyltitanocene

A solution of 2.49 g (10.00 mmol) of titanocene dichloride in 50 ml of ether in the dark at room temperature is treated with 17.Bml of a 1.4 M solution of methyllithium in ether, keeping the internal temperature of the reaction below 57"C. The resulting yellow/yellow-hot mixture is stirred at room temperature for 30 minutes and the reaction is quenched by slowly adding 25g of ice to 7/0.The quenched reaction mixture is diluted with 50ml of ether and 25ml of water and the layers are separated.

The organic layer was dried over magnesium sulfate and concentrated in vacuo to give 2.3 g (98905) of the target compound as a light-sensitive solid. Dimethyltitanocene should be stored in the form of a solution in toluene at a temperature of 0"C for at least 2 weeks without visible chemical decomposition. IN-NMR (SOSIS, 200 MHz, ppm): А-0.15 (s, 6Н), 6.06 ( with, 10H).

Example 5 2-(K)-(1-(3,5-Bis(trifluoromethyl)phenyl)ethenyloxy)-3-(5)-(4-fluoro)phenyl-4-benzylmorpholine

A solution of 4.9 mmol of 2-(K)-(3,5-bis(trifluoromethyl)benzoyl-oxy)-3-(5)-(4-fluoro)phenyl-4-benzylmorpholine and 2.50 g (12.Omol)dimethyltitanocene in ZbBml 1: T1ob/o0b THF/toluene is stirred in an oil bath at a temperature of 807C for 16 hours. The reaction mixture is cooled and concentrated in vacuo. Flash chromatography on 150 g of silica gel using C : 1 v/v hexanes/methylene chloride as eluent gave the target compound as a solid (6090 yield). Mass spectrum (BBA): t/2 526 (MAN, 7595), 270 (10090). "H-NMR (400 MHz, SOSIZ, m.d.): 5 2.42 (dt, 9-36, 12.0), 2.90 (pr. d, 1H, 9U-12.0), 2.91 (d, JAN, 9U-13.6 ), 3.62-3.66 (m, 1H), 3.72 (d, -2.6), 3.94 (d, 1H, 9-13.6), 4.09 (dt, 9-24, 12.0, 1H), 4.75 (d, 71H , 9-32), 4.82 (d, 71H, 9-32), 5.32 (d, 4-2.6, 1H), 7.09 (t, 9U-8.8, 2H), 7.24-7.33 (m, 5H), 7.58- 7.62 (m, 2H), 7.80 (s, 1H), 7.90 (s, 2H).

Example 6 2-(K)-(1-(5)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenylmorpholine and about 2-(5)-( 1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenylmorpholine

A mixture of 1.83 g (3.Bmmol) of 2-(K)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(5)-(4-fluoro)phenyl-4-benzylmorpholine and 80 mg of 5 F

The rhodium catalyst on aluminum oxide in 40 ml of absolute ethanol is stirred in a hydrogen atmosphere for 24 hours. The catalyst is filtered through Celite; the reaction flask and the filter are washed with 200 ml of ethyl acetate. co

The filtrate is concentrated in a vacuum and the residue is settled at high pressure (mm Hg, room temperature) "3 to dryness.

The residue is dissolved in 40 ml of isopropanol; add 800 mg of 1095 palladium on charcoal catalyst and stir the resulting mixture in a hydrogen atmosphere for 24 hours. The catalyst is filtered through Celite; the reaction flask and the filter are washed with 200 ml of ethyl acetate. The filtrate is concentrated in a vacuum. Flash chromatography on 50g of silica gel using 2 : 106b/v hexanes/ether, then C : 206/o6 ether/hexanes as eluent gives 283g of 2-(K)-(1-(5)-(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenylmorpholine and 763 mg of 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy) -3-(5)-(4-fluoro)phenylmorpholine, both as oil " (total yield 6895). For 2-(K)-(1-(5)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenylmorpholine: Mass Also spectrum (BBA): t /7 438 (MAN, 6595), 180 (10095). "H-NMR (400 MHz, SOSIZ, ppm): А 1.47 (d, ZN, 9U-6.8), 1.87 c (shs, 1H), 3.03 (dd, 9-2.8, 12.8), 3.17 (dt . , 1H), 4.87 (d, 71H, -2.2), 6.99-7.03 (m, 2H), 7.23-7.27 (m, 2H), 7.63 (s, 2H), 7.66 (s, 1H). For 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenylmorpholine: Mass spectrum (BBA): t/7 438 (MAN, 7596), 180 (10095). "H-NMR (400 MHz, SOSIZ, ppm): A 1.16 (d, 9U-6.8), 1.80 (she, 1 1H), 3.13 (dd, 9-93.2, 12.4), 3.23 (dt, 9 -36, 12.4), Z.bZ(dd, -2.4, 11.2), 4.01 (d, 7H, 9-24), 4.13 (dt, -1 93.2, 12.0), 4.42 (d, 9-24, 1H) , 4.19 (q, 1H, 9U-6.8), 7.04-7.09 (m, 2H), 7.27-7.40 (m, 4H), 7.73 (s, 1H).

Example 7 (ав) 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3- (5-oxo-1,2,4-triazolo)umethylmorph so 50 olin

Stage A. M-Methylcarboxy-2-chloroacetamidrazone and Che) A solution of 5.0 g (66.2 mmol) of chloroacetylnitrile in Zbml of dry methanol is cooled to a temperature of 0"C and treated with 0.105 g (1.9 mmol) of sodium methoxide. The ice bath is removed and the mixture is stirred at room temperature for 30 minutes. 0.11 Oml (1.9 mmol) of acetic acid and then 5.8 g (64.9 mmol) of methyl hydrazine carboxylate are then added to the reaction mixture. After stirring for 30 minutes at room temperature, the suspension is concentrated in vacuo and placed in a high vacuum line overnight to obtain 10, 5g o (9890) of yellow powder, part of which is used in stage C below. ko Stage in 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5 )-(4-fluoro)phenyl-4-(2-(M-methylcarboxyacetamidazo-no)mor 60 folin

A solution of 945 mg (2.3 mmol)2-(K)-(1-(K)-(3,5bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenylmorpholine, 447 mg (2.7 mmol) M-methylcarboxy-2-chloroacetamidrazone and 0.78 ml (4.5 mmol) of M,M-diisopropylethylamine in 17 ml of acetonitrile are stirred at room temperature for 20 hours.

The reaction mixture is concentrated in vacuo and the residue is distributed between 50 ml of methylene chloride and 25 ml of water. 65 The organic layer is separated, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 50 g of silica gel using 50 : 1 : 0.1 methylene chloride/methanol/ammonium hydroxide as eluent gives 1.12 g

(9090) of the target compound as a foam.

Stage (F 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5 -oxo-1,2,4-triazolo)methyl morpholine

Solution 1.01 g (1.8 mmol) 2-(K)-(1-(K)-(3,5-bis((trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4- (2-(M-Methyl-carboxyacetamidazono)morpholine in 15 ml of xylene is heated under reflux for 2 hours. The reaction mixture is cooled and concentrated in vacuo. Flash chromatography on 5Og silica gel using 50 : 1 : 101 methylene chloride/methanol/ammonium hydroxide as an eluent, gives the target compound as a solid 70 "799 yield). Mass spectrum (BBA): t/2 535 (MAN, 10096), 277 (6096). TIN-NMR (400 MHz, SOSIZNSOZOO, m.d. .): A. 1.48 (d, 9U-6.8, ZN), 2.52 (pr. t, 9U-10.4, 1H), 2.85-2.88 (m, 2H), 3.47 (d, 9-2. 8, 1H), 3.63 (d, 9U-14.4, 1H),

Z.7O(dd, 9U-2.0, 11.6, 1H), 4.24 (pr. t, 1H, 9U-10.8), 4.35 (d, 9U-2.8, 1H), 4.91 (KB, 9U-6.8, 1H), 7.07 (pr. t, 2H, 9-84), 7.15 (s, 2H), 7.37-7.40 (m, 2H), 7.65 (s, 1H). Analysis: calculated for С23Н21Е7М403: С, 51.69; H, 3.96; M, 10.48; R, 24.88; found C, 51.74; H, 4.04; M, 10.50; R, 24.59. The sample obtained by this method was further identified as polymorphic Form II. It is characterized by an X-ray powder diffraction pattern with characteristic reflections at approximately: 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9 and 24.87 (2 theta).

Example 8

Dimethyltitanocene

To a well-mixed suspension of titanocene dichloride (Cr2TisSiI2) (249g, 1.0O0mol) in toluene (2.75L), cooled to a temperature of -57C (internal temperature), magnesium methyl chloride (SNZMaSsI) (75Oml, 3.0 M in THF, 2.25 mmol) is added over a period of more than 1 hour, keeping the temperature below 8"C. The obtained orange suspension is kept at a temperature of 0 - 5"C for 1 hour or until the dissolution of insoluble purple

Sr2tTisSiI2. NMR is used to confirm the completion of the reaction (see below), then the reaction mixture is quenched in a solution of 69% aqueous ammonium chloride (700 ml), stored at a temperature of 0-57. The layers are separated and the organic phase is washed with cold water (3 x 575 ml) and saturated saline solution (575 ml), then dried at

Ma2504 (200g). The filtered organic layer is evaporated to 1.5 kg (maintaining an internal temperature of 257C or less). Definition of 95 wt. NMR showed that the solution contains 187 g of product (9090, 12.590 wt. solution in toluene/THF). Typically, the material has a purity greater than 9595, having only traces of the parent material and the monomethyl Fuzo intermediate. The solution is further concentrated to 1.0 kg to obtain 18905 wt. solution in toluene, more suitable for research. However, the presence of a small amount of THF increases the stability of the compound. co

The material is stored in a nitrogen atmosphere in a sealed vessel at room temperature. 1H-NMR Sr2ti((CHZ).: Al o 6.05 (s, 1OH), -0.05 (s, 6H). Sr2tTisk(xSnNaZ): d 6.22 (s, 10H), 0.80 (s, 3H). Sr2tTisSi2: A 6.56 (c, 10H). 13H-NMR

Sr2ti(SNZ)2: A 113.20(Srg), 45.77 (SNZI2). Sr2Tisr(enZ): l 115.86 (Sr2g), 50.37 (SNZ). Sr2TtisSi2g: A 120.18. -

Example 9 (10) 4-Fluoro-o-Cphenylmethyl)amino) benzoacetic acid 4-Fluorobenzaldehyde (7.0 kg, 56.4 mol) is added to a solution of sodium metabisulfite (5.7 bkg, 300.3 mol) in water (50 L) and washed with methanol (5 L ). Add sodium cyanide (2.83Zkg, 57.7mol) and wash with water (Zl). The load is stirred at a temperature of 25"C for 15 minutes, then cooled to a temperature of 8"C. A solution of benzylamine (6.04 kg, 56.4 mol) in methanol (11 l) is added. The load is heated to a temperature of 347C and stirred for 2 hours. Water (2 L) is added and the slurry is extracted with isopropyl acetate (3 L). The organic layer is washed with water (2 x 10 L) followed by washing with a saturated aqueous solution of sodium chloride (10 L), then it is evaporated under reduced pressure to obtain the nitrile compound. The load is dissolved in dimethyl sulfoxide (50 l). Add potassium carbonate (3.27 kg, 23.7 mol) and wash with dimethyl sulfoxide (bl). A solution of hydrogen peroxide in water (30905, 9.43l, 83.2mol) is added and the slurry is stirred at room temperature overnight. 1 The mixture is diluted with water (120 l) and cooled to a temperature of 13"C. The mixture is filtered and the filter is washed with water (50 l). The resulting amide compound is dried on a filter, then mixed in industrial methylated spirit (Zvl). A solution of sodium hydroxide granules is added to the mixture (3.27 kg, 81.75 mol) in water (11 l) and washed with industrial methyl alcohol (bl). After heating in a flask with a reflux condenser (80 "С) for 3.5 o'clock 50 hours, the mixture is distilled to reduce the volume, removing industrial methyl alcohol. The mixture is diluted with water (100 l) and extracted with isopropyl acetate (Zbl). The layers are separated and the aqueous layer is acidified to pH 5-6

Me) with concentrated hydrochloric acid. The settled solid substance is filtered and washed with water (2x1Ol), then

Collect and dry in a vacuum to obtain 12.3 kg (8495 yield from 4-fluorobenzaldehyde) of 4-fluoro-o-Cphenylmethyl)amino|benzeneacetic acid.

Example 10

HF) Methyl ether of 4-fluoro-o-Kphenylmethyl)amino|benzoacetic acid hydrochloride, 4-Fluoro-a-phenylmethyl)amino| benzoacetic acid (12.2 kg, 47.1 mol) is suspended in methanol (37 L), then gaseous hydrogen chloride is passed through the mixture. The resulting suspension is stirred at a temperature of 35 - 45"C for 3 hours, then concentrated to 30 - 35 L by evaporation. Methyl tert-butyl ether 60 (20 L) is added and the mixture is treated with methyl ether of 4-fluoro-o-Cphenylmethyl)amino|benzeneacetic acid hydrochloride. During methyl tert-butyl ether (20 L) is added to the development of the seeded layer. The suspension is allowed to stand for 1 hour, then it is filtered. The filter is washed with methyl tert-butyl ether: methanol (95: 5.8.Ol), then it is dried in a vacuum at a temperature of 307C with obtaining 12.2 kg (8495 yield) of methyl ether of 4-fluoro-o-Cphenylmethyl)amino|benzeneacetic acid hydrochloride. 65 Example 11

Methyl ester of "-amino-4-fluorobenzeneacetic acid

4-fluoro-o-(phenylmethyl)amino|benzeneacetic acid methyl ether hydrochloride (12.2 kg, 39.4 mol) is added to a suspension of 1090 palladium on charcoal (1.2 kg) in isopropanol (50 L). Ammonium formate (5.Okg, 79.4mol) is added and the mixture is heated to a temperature of 5070. The development of the reaction is monitored by HPLC. The mixture is filtered through Nuyo

Ziregsei and the filter are washed with isopropanol (25 l). The filtrate is evaporated to a small volume and washed with isopropyl acetate (50 L). The residue is dissolved in isopropyl acetate (30 L) and washed with 595% aqueous potassium phosphate solution (40 L), followed by washing with saturated aqueous sodium chloride (10 L). The solution is evaporated in a vacuum to obtain 5.79 kg (8790 yield) of racemic methyl ester of o-amino-4-fluorobenzeneacetic acid. 70 HPLC conditions - column: 7 ogra KH-S8, 25 cm x 4.bmm; column temperature 40"С; mobile phase: acetonitrile: 0.19% aqueous phosphoric acid (70: Zbob/rev); flow rate Tml/min; detection: UV at 220nm; approximate retention time: methyl ester of c-amino-4-fluorobenzeneacetic acid : 2.2 minutes; 4-fluoro-o-Cphenylmethyl)amino|benzeneacetic acid methyl ester 2.6 minutes If unreacted 4-fluoro-o-Cphenylmethyl)amino|benzeneacetic acid methyl ester (2290) remains after 1 hour, a second 75 may be used portion of 1095 palladium on charcoal (3300g) suspended in isopropanol (2.0L) followed by the addition of ammonium formate (1.Okg) Heating is then continued until the reaction is complete.

Example 12 (5)-0-Amino-4-fluorobenzeneacetic acid

A solution of the racemic methyl ester of o-amino-4-fluoro-benzeneacetic acid (3.32 kg, 18.2 mol) in 9690 ethanol (Bl) is filtered, then water (500 ml) is added to the filtrate. Then add a solution of di-O-benzoyl-O-tartaric acid (DBVK, 1.32 kg, 3.7 mol) in water-ethanol (1 : 7, 2.8 ml). The crystallizing mixture is cooled to a temperature of 57C and allowed to stand for 1.5 hours. The product is collected by filtration, washed with water:ethanol (1: 7, 1.1 l), dried in air, then dried in a vacuum at a temperature of 50"C to obtain 1.91 kg of methyl ether of o-amino-4-fluorobenzeneacetic acid, DBVK salt (95.890 eu ). with

Solvent (6.bl) is removed from liquids by evaporation under reduced pressure. Benzaldehyde (12 Oml) is added and the solution is stirred and heated to a temperature of 507C for 4 hours. The solution is filtered and the solids are washed with water: ethanol (1:7, 2x150 ml) (chiral HPLC showed that the filtrate contains the racemic methyl ester of o-amino-4-fluorobenzeneacetic acid). A solution of di-O-benzoyl-UO-tartaric acid (439G, b" 20 1.23mol) in water : ethanol (1 : 7, 9bOml) is added to the filtrate, then the mixture is cooled to a temperature of 57C and left for 1.5 hours. The product is collected by filtration, washed with water: ethanol (1: 7, 2xX1.1 l), dried in air, then dried in a vacuum at a temperature of 507°C to obtain 1.05 kg of methyl ether of o-amino-4-fluorobenzeneacetic acid, DBVK salt (95.495 eu). The combined portions of o-amino-4-fluorobenzeneacetic acid methyl ester DBVK salt are 2.96 kg (9595 eu). Re-dissolved o-amino-4-fluorobenzeneacetic acid methyl ether - DBVK salt is distributed between methyl tert-butyl ether (5 L) and 5.5 M hydrochloric acid (6.2 L). The aqueous phase is washed with methyl tert-butyl ether (5 L), then filtered.

Methyl ether of o-amino-4-fluorobenzeneacetic acid DBVK salt (2899g, 29595 ei) is separated between 5.5 M hydrochloric acid (6b.2l) and the second of the methyl tert-butyl ether extracts mentioned above. The aqueous phase is re-extracted with methyl tert-butyl ether (bl) and filtered. Aqueous filtrates are combined and concentrated by slow distillation of the solvent. The mixture is cooled and kept at a temperature of 5 - s for 2 hours. The product is collected by filtration and air-dried for 30 minutes to obtain 4.055 kg/h of (5)-o-amino-4-fluorobenzeneacetic acid hydrochloride (98.790 o.e.i.). ()Recrystallization from 5.5 M hydrochloric acid (Bl) gives hydrochloride of (5)-c-amino-4-fluorobenzeneacetic acid in the form of a wet cake (3.28 kg, 99.895 eu).

This wet cake is heated in a mixture of water (12 liters) and concentrated hydrochloric acid (375 ml). Concentrated aqueous ammonia (1.2 L) and water (4 L) are added, then the mixture is cooled to a temperature of 207C and allowed to stand overnight. The product is collected by filtration, washed with water (bx4l), dried in air, then dried in a vacuum at a temperature of 50"С for 24 hours with the receipt of 1.905 kg of the free base of (5)-α-amino-4-fluorobenzeneacetic acid (299.795 ei, 4895 output from a racemic mixture of methyl o ester of o-amino-4-fluorobenzeneacetic acid.) Chiral HPLC column conditions: Stomprask CE(t), 15 cm x 4.5 mm;

Go! 20 column temperature 40"С; mobile phase; pH 2.0 aqueous perchloric acid: methanol (95: Bob/rev); flow rate Iml/min; detection: UV at 220nm; approximate retention time: (K)- -Amino-4- fluorobenzeneacetic acid: c 2.9 minutes; (5)-o-Amino-4-fluorobenzeneacetic acid 5.6 minutes; (K)-α-Amino-4-fluorobenzeneacetic acid methyl ester 7.7 minutes; (5)-0-Amino-4-methyl ester -fluorobenzeneacetic acid 14.0 minutes 99 Example 13

HF) Sodium salt of (5)-4-fluoro-o-(phenylmethyl)amino|benzene-acetic acid from Solution of (5)-5-Amino-4-fluorobenzoacetic acid (1.00 kg, 5.9 mol) in aqueous sodium hydroxide ( 1 M, 5.91 l) is filtered and added to 1095 palladium on charcoal (25 g). A solution of benzaldehyde (941 g, 8.87 mol) is added and the mixture is stirred in a hydrogen atmosphere (3.515 kg/cm2 (50 rpm)) for 4 hours. The mixture is filtered and the filtrate is evaporated to a residue under vacuum, then washed with ethanol (2x33l). The residue is stirred in boiling ethanol (1.5 l), then cooled to a temperature of 157 "C. The suspension is filtered and the filter is washed with cold ethanol (2 x 500 ml), then dried in a vacuum at a temperature of 5572 to obtain 1.83 Zkg (9295 yield) of the sodium salt (5)- 4-fluoro-2-Cphenylmethyl)amino|benzeneacetic acid. 65 Example 14 (5)-3-(4-Fluorophenyl)-4-(phenylmethyl)-2-morpholinone hydrochloride

The sodium salt of (5)-4-fluoro-o-(phenylmethyl)amino|benzene-acetic acid (850g, 3.02mol) is added to 1,2-dibromoethane (4.85kg, 25.vmol) and diisopropylethylamine (419g, 3.25mol) in dimethylformamide (14.7g). The mixture is heated to a temperature of 907C for 5 hours, then concentrated by distillation in a vacuum with the removal of dimethylformamide. The residue was partitioned between ethyl acetate (3.2 L) and water (3.2 L). The aqueous layer was extracted with a second portion of ethyl acetate (2.Ol). The solution is dried over sodium sulfate, then filtered through a layer of silicon dioxide (1.bkgh. The layer of silicon dioxide is washed with ethyl acetate (8.0 L) and the filtrate is evaporated under vacuum.

The obtained residue is dissolved in a mixture of isopropanol (1.35 l) and ethyl acetate (400 ml), then filtered. A solution of gaseous hydrogen chloride in ethyl acetate (2.4 M, 1.34 L) is added and the suspension is kept in an ice bath for 70 1 hours. The suspension is filtered and the filter is washed with 1:1 isopropanol: ethyl acetate (b00ml), followed by washing with methyl tert-butyl ether (b00ml). The solid substance is dried in a vacuum to obtain 749 g (7795 yield, 9890 e.i.) of (5)-3-(4-fluorophenyl)-4-"phenylmethyl)-2-morpholinone hydrochloride. Conditions of chiral HPLC - column:

Rush! (0)-Dinitrobenzoylphenylglycine (covalent) normal phase, 25 cm x 4.6 mm; column temperature 357; mobile phase: hexane : ethanol (99 : 1 v/v); flow rate Tml/min; detection: UV at 220 nm; approximate retention time 7/5: (k)-3-(4-fluorophenyl)-4-(phenylmethyl)-2-morpholinone: 16 minutes; (5)-3-(4-fluorophenyl)-4-(phenylmethyl)-2-morpholinone 17 minutes.

Example 15

Racemization/separation (cleavage) of 3-(4-fluorophenyl)-4-phenylmethyl-2-morpholino

To a solution of 3-(4-fluorophenyl)-4-phenylmethyl-2-morpholino (i.e. K-benzyl-4-fluorophenyl-1,4-oxazin-2-one)

AOg) in isopropyl acetate (110 ml) at room temperature add a solution of (-)-3-bromocamphor-8-sulfonic acid (-)-ZBKO) (12 g) in acetonitrile (24 ml). Crystallization begins after 2 - 5 minutes. The suspension is stirred for 1 hour at room temperature. Trifluoroacetic acid (7 ml) is added and the mixture is stirred at a temperature of 65"C for 3 days. The mixture is cooled to 0 - 5"C, allowed to stand for 1 hour and the solid is collected, washed with isopropyl acetate and dried in a vacuum at a temperature of 40"C to obtain with

M-benzyl-3-(5)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-3ZBKS salt: yield 17.24g, ei 98.695 (5) isomer. The chiral composition of the remaining liquids is determined as 7990 (K), 2195 (5). The liquids are stirred at a temperature of 6570 o for 3 days, then cooled to a temperature of 0 - 5"C. The solid substance is collected, washed with isopropyl acetate and dried in a vacuum to obtain the next portion of M-benzyl-3-(5)-(4-fluorophenyl) -1,4-oxazin-2-one (--ZBKS salt: yield 0.84g, ei 98.695 (5) isomer. The chiral composition of the remaining liquids is determined as 6490 He»!zo (Kk), Zb9uyu (5). The liquids are evaporated under vacuum and the residue is dissolved in isopropyl acetate (20 ml) containing trifluoroacetic acid (1 ml) and stirred at a temperature of 657°C for 20 hours. The mixture is cooled to a temperature of 0-57°C for 1 hour and the solid is collected, washed with isopropyl acetate and dried in a vacuum to obtain the next portion of M-benzyl-3-(5)-(4-fluorophenyl)-1,4-oxazin-2-one (-)-ZBKS salt: yield 2.2g, ei 99.2956 (5 ) isomer. Total weight of (-)-Z3BKS salt 20.28g, yield 9790. Sample (0.5g) of (-)-ZBKS salt in

Зз5 is left, and the remaining amount is converted back into the free base. The salt is distributed between isopropyl acetate (50 ml) and water (100 ml) containing 0.88 ammonia solution (3 ml). The layers are separated and the aqueous phase is extracted with isopropyl acetate (25 ml). The combined organic phases are washed with water (25 ml). The organic phase is concentrated to a residue and washed with isopropyl acetate Kk! obtaining 3-(5)-(4-fluorophenyl)-4-phenylmethyl-2-morpholino (i.e. M-benzyl-3-(5)-(4-fluorophenyl)-1, 4-oxazin-2-one) in " 70 Forms of the free base: yield 8.7g, 9395 reduction, ei 98.495 (5) isomer. shsh c Another portion of M-benzyl-3-(5)-(4-fluorophenyl)-1,4-okeazin-2-one (-)-ZBKS salt is obtained according to the method described above, except that the following amounts are used and reaction conditions: "" M-benzyl-3-(4-fluorophenyl)-1,4-oxazin-2-one (racemate) (4.96 g), (--3BCS in acetonitrile (1.85 M, 9.4 ml), trifluoroacetic acid (2.1ml) and isopropyl acetate (55ml). The mixture was stirred at 907C for 6 days, then cooled to 0-5°C and dried for an hour. A solid sl M-benzyl-3-(5)-(4-fluorophenyl) -1,4-oxazin-2-one (-)-ZBKS salt was collected and washed with isopropyl acetate (2Oml). - Yield 9.40g (90965); ei 99.69 (5) isomer. The chiral composition of the remaining liquids was determined as 8890 ( K), 1290 (5). o Example 16 (2Bk-cis) /3-(4-fluorophenyl)-4-(phenylmethyl)-2-morpholinyl ether of 3,5-bis(trifluoromethyl)benzoacetic acid

Ge) A stirred suspension of (5)-3-(4-fluorophenyl)-4-(phenyl-methyl)-2-morpholinone hydrochloride (2.3Okg, 7.15mol) in ethyl acetate (22L) is treated with 1095 aqueous sodium bicarbonate (22L). The obtained organic solution is successively washed with 1095 aqueous sodium bicarbonate (11l) and water (2x11l), then dried overnight with 4A molecular sieves (Tl). The solution is evaporated, then washed with tetrahydrofuran (2x3l) to remove traces of ethyl acetate. The obtained free base (5)-3-(4-fluorophenyl)-4-(phenylmethyl)-2-morpholino is dissolved in iF) tetrahydrofuran (19l) and cooled to -757C. I-Selectride (lithium tri-tert-butylborohydride, co 6.74 L, 1.06 M, 7.15 mol) is added to the mixture, keeping the temperature below -70"C. The mixture is allowed to stand for 15 minutes, then 3,5-bis(trifluoromethyl)benzoyl chloride is added (2.57 kg, 9.29 mol), keeping the temperature below -70 "С. The reaction is controlled by HPLC. The reaction was quenched with acetic acid (205 mL) in tetrahydrofuran (800 mL) and the mixture was warmed to room temperature overnight. The solution is concentrated in vacuo and the resulting oil is diluted with hexane (Zbl). The mixture is washed sequentially with water (17L), 1095 aqueous sodium bicarbonate (3x8.bl) and water (2x8.5L), then dried overnight using 4A molecular sieves (1L). Quantitative analysis of the mixture by HPLC showed that it contained 2.44 kg (6595 yield) of (2K-cis)be 3-(4-fluorophenyl)-4-(phenylmethyl)-2-morpholinyl ether 3,5-bis(trifluoromethyl)benzeneacetate acid The mixture is combined with another mixture (2K-cis) 3-(4-fluorophenyl)-4-phenylmethyl)-2-morpholinyl ether

3,5-bis(trifluoromethyl) benzoacetic acid (0.59 kg according to quantitative analysis in 7 liters of hexanes), which is obtained before obtaining the mixture described above. The solutions of the combined mixtures are filtered through a filter with holes of 20 μm, then diluted with hexanes (Ol). A solution of crude (2k-cis) 3-(4-fluorophenyl)-4-"-phenylmethyl)-2-morpholinyl ester of 3,5-bis(trifluoromethyl)benzeneacetic acid (3.0 kg according to quantitative analysis, 5.74 mol) is treated with hydrochloric acid in diethyl ether (9.bl, 1.OM) with obtaining a white precipitate of hydrochloride (2k-cis) 3-(4-fluorophenyl)-4-(phenylmethyl)-2-morpholinyl ether of 3,5-bis(trifluoromethyl)benzeneacetic acid ( hydrochloride is obtained to remove the residue of tri-fluoro-butylborane (from I-Selectride)). The solid substance is collected by filtration, washed with hexane (2x8L), 7/0, then dried in a nitrogen atmosphere. The hydrochloride of the product is decomposed by suspension in a mixture of toluene (Zbl) and 1096 of aqueous sodium bicarbonate (133l). The obtained organic solution is washed with 1095 aqueous sodium bicarbonate (1 L) and water (2 x 18 L). Quantitative analysis of the toluene solution showed that it contained 3.00 kg of (2K-cis) 3-(4-fluorophenyl)-4-(phenylmethyl)-2-morpholinyl ester of 3,5-bis(trifluoromethyl)benzeneacetic acid (8095 by area corrected for toluene). The mixture is stored over 4A molecular sieves (1 l). HPLC conditions - column: 7/5 Zhograh KH-S8, 25cm x 4.bmm; mobile phase: acetonitrile; 0.190 aqueous phosphoric acid (75 : 25 v/v); flow rate 71.bml/min; detection: UV at 220O0nm; approximate retention time: reduced (3)-3-(4-fluorophenyl)-4-(phenylmethyl)-2-morpholinone: 1.6 minutes; (5)-3-(4-fluorophenyl)-4-(phenylmethyl)-2-morpholinone: 3.3 minutes; 3,5-bis(trifluoromethyl)benzoacetic acid (2k-cis)3-(4-fluorophenyl)-4-"-phenylmethyl)-2-morpholinyl ester: 9.2 g Minutes.

Example 17 (2k-cis)-2-((1-(3,5-bis"Trifluoromethyl)phenyl|ethenyl|oxy|-3-(4-fluorophenyl)-4--phenylmethyl)morpholine

A solution of (2k-cis) 3-(4-fluorophenyl)-4-(phenylmethyl)-2-morpholinyl ether of 3,5-bis(trifluoromethyl)benzeneacetic acid in toluene (1.0 kg, 3.02 mol) is evaporated, then purged with nitrogen, tetrahydrofuran (1.bl) is added to the mixture, followed by the addition of a solution of dimethyltitanocene in toluene (8.359795 wt., 1.73 kg of reagent, 8.3 mol) (obtained as described below). The mixture is bubbled with nitrogen for 25 minutes, then i) heated to a temperature of 80"C. The mixture is kept in the dark for 5 hours at a temperature of 807C, then cooled to ambient temperature and kept overnight. The solvent of the mixture is replaced by heptane by vacuum distillation, keeping the temperature below 207 "C (add 126bl of heptane with He! with subsequent distillation of 120l) (the solvent of the reaction mixture is replaced with heptane and the mixture is treated with peroxide with a bicarbonate buffer to precipitate titanium residues). Water (22 L), sodium bicarbonate (2.Okg), then 3095 hydrogen peroxide (3.5 L) are added to the cooled mixture (7"C). The mixture is stirred at room temperature overnight. The phases are separated, and most of the remaining titanium remains in the aqueous phase. The aqueous phase is back-extracted with heptane (Ol) and the combined organic phases are filtered, washed with water (2 x 4 L), then concentrated. The crude product is recrystallized by dissolving it in hot methanol (17 L), cooling it to ambient temperature, then water (1.8 L) is added. The material is separated by filtration at room temperature. The filter is washed with 1095 aqueous methanol (2 L, 0"C), then the solid is dried at ambient temperature in a nitrogen atmosphere (1.45 kg of pure 9490 (2k-cis)- 2-((1-(3,5-bis(trifluoromethyl)phenyl|ethenyl|oxy|-3-(4-fluorophenyl)-4-(phenylmethyl)morpholine). "

The reagent dimethyltitanocene can be obtained in this way. Methyllithium (590 g, 76.9 mol) in a solution of diethyl ether (4.3895 vol/vol, 13.5 kg) is added to a cooled (-8"C) well-stirred suspension of titanocene dichloride (3.3 Bkg, 13.Bmol) in methyl tert- butyl ether (13.4 L), keeping the temperature below 576. y? The resulting suspension is kept at a temperature of 0 - 57"C for 1 hour. The reaction is quenched by adding water (bl), keeping the temperature between 0 and 8"C. The organic phase is washed with cold water (4x3L). Then, in the organic layer, the solvent is replaced with toluene by distillation with the simultaneous addition of toluene (24L), keeping the temperature at 25"C or below Quantitative analysis of 906 wt. using 1H-NMR showed that the solution contains 1.75 kg of dimethyltitanocene (6395 yield, 8.35956 mass solution in toluene). The material is stored in a nitrogen atmosphere at

Sh- at a temperature of 07"C. The development of the reaction is monitored by 1H-NMR (250 MHz, SOSIZ, 1sec delay between pulses). o Ср2Тиме?: А (ррт) 6.05 (с, 1OH), -0.05 (с, 6Н); Ср2ТИСИМе: А 6.22 (s, 1OH), 0.80 (s, ЗН); Ср2ТтисиИ2: А 6.56 (s, 10OH).

The reagent dimethyltitanocene can alternatively be prepared in this way. To a well-mixed suspension of titanocene dichloride (Cr2TiC2) (6.0 g, 24.1 mmol) in toluene (/2 ml), cooled to temperature

He) -BS, add methylmagnesium chloride (SNZMOSI) (19.8g, 19.2ml, ZOM in THF, 57.bmol, 2.4eq) dropwise for more than 10 minutes, keeping the temperature below 5°C. As soon as the magnesium chloride settles, a viscous suspension is obtained. The resulting suspension is kept at a temperature of 0-B"C for 5 minutes, during which the insoluble red Cr2TisSi2 dissolves. NMR analysis of the quenched sample is carried out to confirm the completion of the reaction.

A sample of 0.2 ml is quenched in 1 ml of water and 1 ml of SOSIZ. The chloroform layer is used directly for NMR and F) analysis. Dimethyltitanocene has a resonance at 6.0 ppm. (Cr) group and -0.2 ppm. (SNZ group). The monomethyl co compound has resonances of 0.2 - 0.3 ppm. in the lower part, and titanocene dichloride has a resonance at 6.5 ppm. The reaction is then quenched by adding a solution of 1095 aqueous ammonium chloride (20ml) for more than 20 minutes, keeping the temperature below 10°C. The layers are separated and the organic phase is washed with cold water (3x20ml) and saturated saline (2Oml), then dried over Ma2504 (20g) . The filtered organic layer is concentrated in vacuo to about half the volume. The total weight of the solution is 43g and NMR analysis shows 11.295 wt dimethyltitanocene (4.8g, 96b9o yield). The THF level is 295, however, the presence of a small amount of THF increases the stability of the reagent. The material is stored in a nitrogen atmosphere at a temperature of 0"C. 65 Alternatively, the reagent dimethyltitanocene can be prepared as follows. To a well-stirred cooled suspension of titanocene dichloride (249g, 1.0O0mol) in toluene (2.75L), cooled to temperature

-5"C (internal temperature), add Memas!i (75Oml, 3.OM in THF, 2.25mol) for more than 1 hour, keeping the temperature below 8"C. The obtained yellow-hot suspension is kept at a temperature of 0 - 57"C for 1 hour or until the dissolution of insoluble purple Cr2TisCl2. NMR analysis is carried out to confirm the completion of the reaction (see below), then the reaction mixture is quenched in a solution of 695 aqueous ammonium chloride (7O0Oml), maintaining the temperature 0 - 5"C. The organic phase is washed with cold water (3x575 ml) and saturated saline solution (575 ml), then dried over Ma25054 (220 g). The filtered organic layer is evaporated to 1.5 kg (maintaining an internal temperature of 257C or lower). Quantitative analysis of 96 wt. Using 1H-NMR showed that the solution contains 187g of product (90905, 12.590 mass solution in toluene/THF). Usually the material has a purity greater than 95965, 7/0 having traces of the original material and intermediate monomethyl. The solution can be further concentrated to 1.Okg to obtain 1895 wt. solution in toluene, which facilitates quantitative analysis. However, the presence of a small amount of THF increases the stability of the reagent. The material is stored in a nitrogen atmosphere in a sealed vessel at room temperature. 1H NMR Cr2TiMe2: d Sh5 (c, 6H); Sr2tisSiIMe: A 6.22 (s, 10OH), 0.80 (s, ZN);

Sr2tisSi2: A 6.56 (s, 10H). 13 NMR Srgtimeg2: А 113.20 (Srg), 45.77 (Me2); Sr2tTiSIMe: А 115.86 (Sr2), 50.37 75 (Me); Sr2tisiI2: A 120.18.

HPLC conditions - column: 7 ogra KH-S8, 25 cm x 4.bmm; mobile phase: acetonitrile: 0.1956 aqueous phosphoric acid (65:35v/v); flow rate 1.5ml/min; detection: UV at 220 Ohm; approximate retention time: (2k-cis)-2-((1-(3,5-bis-trifluoromethyl)phenyl|ethenyl|oxy|-3-(4-fluorophenyl)-4-(phenylmethyl)morpholine: 17.2 minutes; (2k-cis) 3-(4-fluorophenyl)-4-(phenylmethyl)-2-morpholinyl ester of 3,5-bis(trifluoromethyl)benzoic acid 18.9 minutes.

Example 18 (2k-cis)-2-((1-I3,5bis((Trifluoromethyl)phenyl|ethenyl|oxy|-3-(4-fluorophenyl)-4-(phenyl-methyl)morpholine

A solution of (2k-cis)3-(4-fluorophenyl)-4-(phenylmethyl)-2-morpholinyl ether of 3,5-bis(trifluoromethyl)benzeneacetic acid (for example, a solution containing SU 4-benzyl-2-(K)- (3,5-bis((trifluoromethyl)bezoyloxy)-3-(5)-(4-fluorophenyl)-1,4-oxa-zine, 2.99 kg, 5.6 b7 mol) in otoluene is evaporated in a 100 L flask. The flask is purged with nitrogen , then tetrahydrofuran (25 L) is added, followed by the addition of a solution of dimethyltitanocene in toluene/THF (12.595 mass, reagent content 4.2 kg, 20.2 mol). The organic solution is bubbled with nitrogen for 25 minutes, then heated to a temperature of 80"C. The reaction mixture is kept in the dark for 4 hours at a temperature of 807C, then cooled to ambient temperature. Methanol (11.bl) and water (1.9L) are added and the mixture is heated to a temperature of 40"C overnight, while titanium precipitates in the form of a green solid After cooling to ambient temperature, the solid substance is removed by filtration, the filter is washed with toluene, and the resulting mother liquor evaporate The crude product is recrystallized by dissolving it in hot methanol (300 ml), cooling it to ambient temperature, and then adding water (3.4 liters) for more than 1 hour. The material is isolated by filtration at a temperature of 0"C, the filter is washed with 1095% aqueous methanol at a temperature of 0"C (2 liters) and the solid substance is dried at room temperature in a nitrogen atmosphere, 2.55 kg are isolated. (2K-cis)-2-((1-(3,5-bis"Trifluoromethyl)phenylethenyl|oxy|-3-(4-fluorophenyl)-4-(phenylmethyl)morpholine (8590).

Example 19 (g k-I2a(KU,Za1|-2-(1-IZ,5-bis("Trifluoromethyl)phenyl|etho-xy|-3-(4-fluorophenyl)morpholine" 4-methylbenzenesulfonate (salt)

Solution of (2K-cis)-2-((1-(3,5-bis(trifluoromethyl)phenyl|ethenyl|oxy|-3-(4-fluorophenyl)-4--phenylmethyl)morpholine) - c (1082g, 94905 purity , 1.94mol) in 1:1 ethyl acetate"ethanol (1 L) is mixed with 1095 palladium on carbon (165 Hg). and The resulting suspension is treated with hydrogen (2.812 kg/cm2 (40 rvi), 20 - 2572) for 12 hours. The reaction is monitored "» by evolution of hydrogen and HPLC. The vessel is purged and the catalyst is removed by filtration. After washing the catalyst 1 : 1 ethyl acetate"ethanol (bl) followed by washing with ethyl acetate (2 l), combined organic phases containing crude 1 (a k-Iha(kU, Za1 |-2-(1-(3,5-bis"Trifluoromethyl)phenyl|ethoxy|-3-(4-fluorophenyl)morpholine, concentrate in vacuum. -1 Get the second portion, starting from 1078g of (2k-cis)-2 -((1-(3,5-bis(trifluoromethyl)phenyl|ethenyl|oxy|-3-(4-fluorophenyl)-4-(phenylmethyl)morpholine (1.9 mol). (ав) Obtained crude (2K-I2a( K),Za1|-2-(1-3,5-bis(Trifluoromethyl)phenyl|ethoxy|-3-(4-fluorophenyl)morpholine 50 is concentrated in vacuum and combined with the first portion. combined portions of crude (g k-I2a(kUza1|-2-(1-IZ,5-bis"Trifluoromethyl)phenyl|ethoxy|-3-(4-fluorophenyl) morpholine are washed with methyl and Che) tert-butyl ether (2x3l) for removal of residues of ethyl acetate and ethanol, then dissolved in methyl tert-butyl ether (3). Quantitative analysis of the solution showed 1348 g (3.0 Omol, 8095 yield) (g of k-I2a(kUZa1|-2-(1-IZ,5-bis("Trifluoromethyl)phenyl|ethoxy|-3-(4-fluorophenyl)morpholine (in as a free base).Alternatively, bOg of vinyl ether, b5O0ml of methyl tert-butyl ether (MTBE) and 18g of 595 Ra on aluminum oxide are mixed with hydrogen under a pressure of 2.812 kg/cm (4 Orzi) at a temperature of 407C for 12 hours. Quantitative o analysis showed 8795 yield with a ratio of diastereomers of 91 : 1. After standing the reaction mixture, the catalyst is removed by filtration through ZoiYika-Rios, then the filtrate is concentrated to 14 Oml.

The first portion is treated with a warm (407) solution of p-toluenesulfonic acid monohydrate (575 g, 3.0 mol) in 60 methyl tert-butyl ether (3.2 l). The salt of p-toluenesulfonic acid (g k-I2a(kU),Za1|-2-(1-IZ,5-bis(Trifluoromethyl)phenyl|ethoxy|-3-(4-fluoro-phenyl)umorpholine) begins to crystallize during addition. The mixture is cooled to ambient temperature and hexane (24 L) is added.

The mixture is allowed to stand for 2 hours, then the product is collected by filtration. The solid substance is washed with 4: 1 hexanes: methyl tert-butyl ether (2x2.5 l), then dried in a nitrogen atmosphere (1761 g (1655 g corrected for 65 purity) (2K-I2a(K),Za1|-2-(1-( 3,5-bis"Trifluoromethyl)phenylethoxy|-3-"4-fluorophenyl)morpholine 4-methylbenzenesulfonate (salt), 94905 wt. 70905 yield). Alternatively, to the second solution add a solution of 16.0 g of p-TZON monohydrate in b4 ml of MTBE at at a temperature of 357C for more than 20 minutes. Tosylate crystallizes in the form of a thick suspension. Then 520 ml of hexanes are added for more than 1 hour, and the suspension is stirred for 2 hours at ambient temperature. The suspension is filtered, washed with 2 x bOml 1 : 4 MTBE:

Hexanes and dried in rarefied air to obtain 51.9 g of tosylate (7595) containing 0.996 of the undesired diastereomer. HPLC conditions - column: 7 ogra KH-S18, 25 cm x 4.bmm; mobile phase: acetonitrile: aqueous 0.005M sodium heptanesulfonate, 0.002M potassium hydrogen phosphate, 0.0005M disodium hydrogen phosphate (75:2506/o6); flow rate 1.Bml/min; detection: UV at 22 Ohm; approximate retention time: (g k-I2a(kU)Za1|-2-(1-IZ,5-bis(Trifluoromethyl)phenyl|ethoxy|-3-(4-fluorophenyl)morpholine: 4.5 minutes; M-benzyl 70 ( g k-Iga(kUZa1|-2-(1-IZ,5-bis"Trifluoromethyl)phenyl|ethoxy|-3-(4-fluorophenyl)morpholine: 25.0 minutes; (2k-cis)-2-((1- (3,5-bis(trifluoromethyl)phenyl|ethenyl|oxy|-3-(4-fluorophenyl)-4--phenylmethyl)morpholine: 30.0 minutes.

HPLC conditions - column: 7 degrees KH-S18, 25cm x 4.bmm; mobile phase: acetonitrile: aqueous 0.005 M sodium heptanesulfonate, 0.002 M potassium hydrogen phosphate, 0.0005 M disodium hydrogen phosphate (60: 40 v/v); flow rate 1.Bml/min; detection: UV at 22 Ohm; approximate retention time: (g k-I2a(KU,Za1|-2-(1-IZ,5-bis((Trifluoromethyl)phenyl|ethoxy|-3-(4-fluorophenyl))morpholine: 9.0 minutes; Diastereomer (g k -I2a(kUZa1|-2-(1-IZ,5-bis("Trifluoromethyl)phenyl|ethoxy|-3-(4-fluorophenyl)morpholine): 11.0 minutes (epimeric in the presence of a methyl group).

Example 20 (g k-I2a(KUZa1|-5-C2-(1-(3,5-bis(trifluoromethyl)phenyl|ethoxy|-3-(4-fluorophenyl)-4-morpholinyl|methyl/-1,2 -didro-ZN-1,2,4-triazol-3-one

Powdered potassium carbonate (682g, 4.9 mol) is added to a solution of (2K-I2a(K),Za1|-2-(1-(3, 5bis(Trifluoromethyl)phenylethoxy|-3--4-fluorophenyl)morpholine 4-methylbenzenesulfonate (salt) (1254g, 2.Omol),

M-methylcarboxy-2-chloroacetamidrazone (375g, 2.2bmol) and dimethylformamide (1Ol). The reaction temperature is maintained in the range from 15 to 25"7C and the mixture is allowed to stand for 2.5 hours. The mixture is diluted 1 : 1 hexane : 100 ml with methyl tert-butyl ether (1Ol) and 10.995 aqueous ammonium chloride (11L). The phases are separated and the aqueous phase back-extract 1:1 hexane:methyl tert-butyl ether (2xvl) and then 1:2 hexane:methyl tert-butyl ether i) (vl). The combined organic phases are washed with water (2x15l), then concentrated in vacuo. The obtained the material is dissolved in xylene (20 L) and heated in a reflux flask (1377 C). The solution is refluxed for 3 hours, then cooled to ambient temperature, during which it crystallizes (g k-I2a(kUZa1| -5-C2-(-3,5-bis(trifluoromethyl)phenylethoxy|-3-(4-fluorophenyl)-4-morpholinyl|methyl/)-1,2-dihydro-

ZH-1,2, 4-triazol-Z-one. The mixture is left overnight, then filtered. The filter is washed with xylene (2 l), and then with hexanes (2 x 2 l), then dried in a vacuum at a temperature of 30°C for three days (696 g, 6390 yield (g k-I2a(kUZa1|-5-C2-(-IZ,5- bis(trifluoromethyl)phenylethoxy|-3-(4-fluorophenyl)-4-morpholinyl|methyl/)-1,2-dihydro-

ZHn-1,2, 4-triazol-3-one, i.e. 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-( 4-fluoro)phenyl-4-(3-(5-oxo-1H 4H-1,2,4-triazolo)methylmorpholine).

Alternatively, the target product is obtained by the following method from the amine T5OH salt (1.90 kg, 3.12 mol),

M-methylcarboxyl-2-chloroacetamidrazone (516.3 g, 3.12 mol), K2SOZ (1.08 kg, 2.5 eq) and DMSO (15.bl). A solution of M-methylcarboxyl-2-chloroacetamidrazone in DMSO (7.8 l) is added to a suspension of amine and powdered K2SOZ in DMSO (7.8 L) at a temperature of 20"C. The first half of the solution is added quickly (with slight cooling in a bath from ice water), then the remaining part is added for more than 1 h? h. After the addition, the reaction is monitored by LC and the reaction mixture is quenched with cold water (15 L) and a solution of methyl tert-butyl ether (MTBE) (30Ol). The organic layer is separated and washed with water, saturated Mansoz, saturated salt solution and H2O (20 L/each wash) respectively. The aqueous layers are back-extracted with MTBE (15 L). c The combined MTBE solutions are concentrated to oil. The resulting crude product is dissolved in xylene (25 L) and diisopropylethylamine (6b.25 L) and heated in a reflux flask (about 135" C) and reaction

Sh- are controlled by ХЖ. It takes 4-6 hours to complete the reaction, the reaction solution is cooled to room temperature overnight and filtered to obtain the target product (expected amount 1.3Zkg, about 8090, usual purity 98.5 Or). The obtained crude product is dissolved in hot methanol (13.ZL), 133g of charcoal is added, then filtered and the coal is washed with hot methanol (3.ZL). Methanol solution

Ge) is cooled to room temperature, then water (7 l) is added drop by drop. After stirring at room temperature for 2 hours. the suspension is filtered to isolate the purified product (i.e. 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4- (3-(5-oxo-1H 4H.-1,2,4-triazolo)methylm ovorpholine) in the form of a white crystalline compound (expected amount 1.20 kg, 9095 reduction, normal purity 99.5 Ado). HPLC conditions - column: 7ogra KH-C8, 25 cm x 4.bmm; mobile phase: (A) acetonitrile, (B) 0.195 aqueous (F) phosphoric acid; linear gradient from 40 : 60 AB to 70 : 30 AB for 10 minutes; flow rate ka 1. Bml/min; detection: UV at 220nm; approximate retention time: alkylated intermediate: 5.7 minutes; -3-(4-Fluorophenyl)-4-morpholinyl|methyl-1,2-dihydro-3 in H-1,2,4-triazol-3Z-one: 8.2 minutes. The sample obtained by this method, further identified as polymorphic

Form II. It is characterized by an X-ray powder diffraction pattern with characteristic reflections 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 65 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-( 5-oxo-1H 4H.-1,2,4-triazolo)methylmorpholine

Form 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo) -1H 4H.-1,2,4-triazolo)methylmorpholine is obtained by swirling Form I 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5 )-(4-fluoro)phenyl-4-(3-(5-oxo-1H 4H.-1,2,4-triazolo)methylmorpholine in isopropyl acetate at a temperature of 25" followed by isolation of the obtained solid substance by filtration.

Similarly, Form 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-( 5-oxo-1H 4H.-1,2,4-triazolo)methylm 7/0 orpholine is obtained by swirling Form I 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy )-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo-1H 4H.-1,2,4-triazolo)methylmorpholine in ethanol, 2-propanol, water, methanol/ water or acetonitrile at a temperature of 25"C with subsequent separation of the obtained solid substance by filtration.

Example 22

Preparation of seed crystals of Form I 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3- (5-oxo-1H 4H.-1,2,4-triazolo)methylm orpholin

Sample Form I 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5 -oxo-1H 4H-1,2,4-triazolo)methylmorpholine is placed in a small aluminum cup and the unsealed cup is placed in a cell for differential scanning calorimetry (0552). The sample is heated from ambient temperature to 230°C, then cooled back to ambient temperature. (4-Fluoro)phenyl-4-(3-(5-oxo-1H 4H.-1,2,4-triazolo)methyl orpholin on an industrial scale.

Example 23 (8)

Preparation of Form I 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5 -oxo-1H 4H.-1,2,4-triazolo)methylmorpholine Hezo 22 liter flask is charged with Form I 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)-phenyl) ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H,-1,2,4-triazolo)methyl co-morpholine (566 g) and 5.7 l of methanol. The mixture is heated in a flask with a reflux condenser (65"C) until all solids dissolve. The solution is cooled to a temperature of 50"7C and about 200 mg of the seed of Form 2-(K)-(1-(K)-(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo-1H 4H.-1,2,4-triazolo)methylmy-orpholine and cooled to a temperature of 45"C, during which a seed layer is formed. The mixture is cooled to a temperature of 267"C with the addition of 2.8 liters of water for more than 1 hour. The mixture is kept at room temperature for 2 hours, then heated to a temperature of 70"7C for 2 hours to complete completion of the transformation of Form I of the material into Form I. The mixture is cooled by draft overnight, then it is cooled to a temperature of 0"C, kept at a temperature of 0"C for 70 minutes, then filtered at a temperature of -376. "

The collected material is dried in a filter tank filled with nitrogen and squeezed dry for 3 pl") to obtain 549 g (9796).

Example 24 ;" Preparation of Form I 2-(K)-(1-(K)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3-(5 -oxo-1H 4H.-1,2,4-triazolo)methylmorpholine with 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)- 3-(5)-(4-fluoro)phenyl-4-(3-(5-oxo-1H4H.-1,2,4-triazolo)

Sh- methylmorpholine (Form II) (14.5 kg) and 158 l of methanol. The mixture is heated to a temperature of 50"C, during which all solid compounds dissolve. Activated carbon (Yuagdo (3-60) (1.5 kg) is added through the upper bottom of the 5-r tank in the form of a suspension in 1 kg of methanol, and the mixture is washed with an additional 2 liters of methanol. The mixture heat with a reflux condenser (6272) and stand for 1 hour. The mixture is cooled to a temperature of 60"C and

Ge) is filtered through a 14" filter 55 zragKieg. After recirculation for 10 minutes, no leaks are visible in the sight glass, so the flow flows back into the reactor. The mixture is then pumped through a sparkler, then through a series of 1Ω and 0.bμ pass filters and, finally , through the receiving tank. The stream is blown forward, then 50 L methanol is jetted into the output reaction vessel. The stream is recirculated for 10 minutes to clean the recirculating stream and to heat it to a temperature above

F) environment. Then it is transferred through filters to the receiving tank. The mixture is then concentrated from about 210 liters to 170 liters by atmospheric distillation. The sample shows the desired concentration, 88g/l (14.9kg, without loss). The mixture is cooled to a temperature of 507C and a seed of pure Form I 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro) is added )phenyl-4-(3-(5-oxo-1H 4H.-1,2,4-triazolo)methylmorpholine. A too light seed layer is formed, and the crystals are barely detectable even at a temperature of 45"C. A thick suspension is resisted at a temperature of 457C for an hour, its appearance changes slightly. The thick suspension is cooled to a temperature of 257C overnight to obtain a suspension of 60.5g/L of dissolved compound 65. The wet cake sample contains only Form I crystals. Then 83.bkg of water (3395 vol. . to methanol) for more than 3 hours below the surface. Samples show 0.195 wt. 030 in the supernatant and all crystals are Form I. The mixture is cooled to 07C over 2 hours. The mixture is then applied to an industrial filter as individual drops. Approximately 15 kg layer washes 2 : 1 MeOH/water are used to wash the vessel, which still contains the remains of prod ktu (probably 500 - 1000g). The remaining 15 kg of sediment is loaded onto the filter through a spray nozzle. Collect 217.8 kg of uterine fluid and wash (0.190 wt. 030). The wet sediment (14.8 kg) is then dried overnight at a temperature of 50"C in a vacuum with a 27.5" 3 0.2 5SEM sweep. After 12 hours, the TG analysis showed 0.09% by mass. the loss The total weight of the compressed mixture is 12.82 kg of the target compound.

Example 25 70 Conventional pharmaceutical compositions containing the compound of this invention

A: Capsules with a dry filler, containing 5 mg of the active ingredient per

Ingredient Quantity per capsule

Active ingredient 5

Lactose 194

Magnesium stearate 1

Capsule (size Mo 1) 200

The active ingredient can be ground to a MobO powder and the lactose and magnesium stearate can be passed through a MobO blotting cloth into the powder. The combined ingredients can then be mixed for 10 minutes and filled into Mo 1 dry gelatin capsules.

A: Tablets

Conventional tablets may contain the active ingredient (5mg), pregelatinized starch OBR (82mg), microcrystalline cellulose (82mg) and magnesium stearate (mg).

Although the present invention has been described and illustrated by certain specific examples, it will be apparent to one skilled in the art that various adaptations, changes, modifications, substitutions, separations and additions may be made to the methods and protocols without departing from the scope of the present invention. For example, depending on the receptivity of the warm-blooded being treated, effective dosage forms other than the dosage forms specified herein may be used for any of the compound combinations described above. Similarly, certain pharmacological responses obtained may vary depending on the particular active compound selected, as well as the presence of pharmaceutical carriers and the type of formulation and route of administration, and (ee) such expected differences or variants of results are consistent with the object and practice of this invention. at

It is intended that the scope of this invention is defined by the claims presented below, and this claim may be interpreted as broadly as appropriate. -

IC c)

Claims (5)

The formula of the invention 1. Polymorphic form of the compound "2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4-fluoro)phenyl-4-(3 -(5-oxo-1H 4H-1,2,4-triazolo)methyl)m 37Z orpholin. c 2. The polymorphic form of claim 1, which essentially has an X-ray powder diffraction pattern with characteristic reflections of approximately 12.0, 15.3, 16.6, 17.0, 17.6, 19.4, 20.0, 21.9, 23.6, 23.8 and 24.87 (2 theta). C. A pharmaceutical composition containing a pharmaceutically acceptable carrier and an effective amount of the polymorph according to item 1. 4. The polymorphic form according to claim 1, which essentially does not contain the compound o 2-(К)-(1-(К)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(5)-(4 -fluoro)phenyl-4-(3-(5-oxo-1H 4H-1,2,4-triazolo)methyl)m-I orpholine with an X-ray powder diffraction pattern with characteristic reflections of approximately 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9 and 24.87 (2 theta). at 5. The pharmaceutical composition according to item C, which contains the polymorphic form of the compound according to claim 2 and essentially does not contain (ee) 50 the polymorphic form of the compound according to claim 4. 3e) Ф) име) 60 b5