MXPA06008410A

MXPA06008410A - Hydroisoindoline tachykinin receptor antagonists

Info

Publication number: MXPA06008410A
Application number: MXPA/A/2006/008410A
Authority: MX
Inventors: Sander G Mills; Jaime Lynn Bunda; Robert J Devita; Jinlong Jiang
Original assignee: Bunda Jaime L; Robert J Devita; Jinlong Jiang; Sander G Mills
Priority date: 2004-01-27
Filing date: 2006-07-26
Publication date: 2006-12-13

Abstract

The present invention is directed to certain hydroisoindoline compounds of formula I which are useful as neurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykinin and in particular substance P. The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, urinary incontinence, depression, and anxiety.

Description

ANTAGONISTS OF THE RECEPTOR mDROISOINDOLINA TAQU1CININA BACKGROUND OF THE INVENTION Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, thus being called the latter because of its immediate contractile action on smooth extravascular muscle tissue. Tachykinins are distinguished by a conserved carboxyterminal sequence. In addition to substance P, mammalian tachykinins include neurokinin A and neurokinin B. The current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin-1 (NK-1), neurokinin-2 (NK- 2), and neurokinin -3 (NK-3), respectively. The tachykinin antagonists, and in particular substance P, are useful in the treatment of clinical conditions which are characterized by the presence of an excess of tachykinin activity, in particular substance P, which includes disorders of the central nervous system, nociception and pain, gastrointestinal disorders, disorders of bladder function and respiratory diseases.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to certain hydroisoindoline compounds which are useful as neurokinin-1 receptor (NK-1) antagonists, and tachykinin inhibitors and in particular substance P. The invention is also involved in pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, urinary incontinence, depression, and anxiety.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds of the formula I: wherein: R1 is selected from the group consisting of: (1) hydrogen, (2) C- | _6 alkyl, which is unsubstituted or substituted by halogen, hydroxyl or phenyl, (3) cyclopentenone, which is unsubstituted or substituted with hydroxyl, or methyl (4) - (CO) - C1-6alkyl, (5) - (CO) -NH2, (6) - (CO) -NHalkyl Ci-6, and (7) - (CO ) -N (Ci -6 alkyl) (Cl-6 alkyl); X is independently selected from the group consisting of: (1) hydrogen, (2) fluorine; and (3) methyl; and pharmaceutically acceptable salts thereof and individual enantiomers and individual diastereomers thereof. One embodiment of the present invention includes compounds of the formula la: wherein R1 and X are defined herein; and pharmaceutically acceptable salts thereof and individual enantiomers and individual diastereomers thereof.

One embodiment of the present invention includes compounds of the formula Ib: wherein R1 and X are defined herein; and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. One embodiment of the present invention includes compounds wherein R "1 is selected from the group consisting of: (1) hydrogen, (2) Ci-3 alkyl, which is unsubstituted or substituted by hydroxyl or phenyl, (3) ) cyclopent-2-en-1-one, which is substituted or unsubstituted with hydroxyl or methyl, (4) - (CO) -alkylCi-3, (5) - (CO) -NH2, (6) - (CO ) -NHalkylCi-3, and (7) - (CO) -N (Ci-3 alkyl) (C 1 -C 3 alkyl) Within this embodiment, the present invention includes compounds wherein R 4 is selected from the group consisting of: (1) hydrogen, (2) methyl, (3) 2-phenylethyl, (4) 2-hydroxyethyl, (5) cyclopent-2-en-1-one, (6) 5-hydroxycyclopent-2-en-1 - ona, (7) 4-hydroxycyclopent-2-en-1 -one, (8) 2-methylcyclopent-2-en-1-one, (9) acetyl, (10) acetamido, (11) methyl-acetamido, and (12) dimethyl acetamido Additionally in this embodiment, the present invention relates to compounds wherein R 1 is hydrogen.Also additionally in this embodiment, the present invention refers to compounds in which R ^ is methyl, 2-phenylethyl or 2-hydroxyethyl. Also additionally in this embodiment, the present invention relates to compounds in which R1 is: which is substituted or unsubstituted with hydroxyl or methyl.

Also additionally in this embodiment, the present invention relates to compounds wherein R 1 is, acetyl, acetamido, methyl-acetamido or dimethyl-acetamido. One embodiment of the present invention includes compounds wherein X is hydrogen. One embodiment of the present invention includes compounds wherein X is fluorine. One embodiment of the present invention includes compounds wherein X is methyl. Specific embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. The compounds of the present invention may contain one or more asymmetric centers and may thus be given as racemates and racemic mixtures, individual enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending on the nature of the various substituents in the molecule. Each such asymmetric center will independently produce two optical isomers and it is desired that all possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention is intended to comprise all such isomeric forms to comprise all such isomeric forms of these compounds. Formula I shows the structure of the class of compounds without preferred stereochemistry. The independent synthesis of these diastereomers or their chromatographic separations can be achieved as is known in the art by appropriate modification of the methodology described herein. Their absolute stereochemistry can be determined by the crystallography of x-rays of crystalline or crystalline intermediate products which are derived, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, the racemic mixtures of the compounds can be separated in such a way that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by the separation of the individual diastereomers by standard methods, such as crystallization or fractional chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives can be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, methods which are well known in the art. Alternatively, any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents or reagents from known configuration by methods well known in the art. There are several acceptable methods of naming the compounds that are discussed in this document. ° "f == t ~ AA X CH3 OXO C0H" 33 For example, the above compound can be called well "(3a / ?, 4ft, 5S, 7af.) Ferc-butyl-5-hydroxy-4-phenylocta dro-2H-isoindole-2-carboxylate "or" urea-butyl (3a, 4R, 5S, 7aR) -5-hydroxy-4-phenyloctahydro-2H-isoindole-2-carboxylate ". The structure of the nucleus can refer generally as octahydroisoindole, hexahydroisoindoline, perhydroisoindoline, hydroisoindoline, or hydroisoindole compounds. As will be appreciated by those skilled in the art, halo or halogen as used herein is meant to include fluoro, chloro, bromo and iodo. Similarly, Ci-6, as in C- | -6 alkyl is defined to identify the group that has 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, so that alkyl of C-i-s includes specifically methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A group in which it is designed so that it is independently substituted with substituents can be independently substituted with multiple amounts of such substituents.

The term "pharmaceutically acceptable salts" refers to salts prepared from non-toxic pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganous, manganous, potassium, sodium, zinc, and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form can exist in more than one crystal structure, and can also be in the form of hydrates. Salts derived from non-toxic organic pharmaceutically acceptable bases include salts of primary, secondary, and tertiary amines, substituted amines including substituted amines that occur naturally, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylene diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylopiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine , methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, the salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isothionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric. , tartaric, p-toluenesulfonic, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of the present invention also include pharmaceutically acceptable salts. Exemplifying the invention is the use of the compounds described in the Examples and in the present document. Specific compounds in the present invention include a compound which is selected from the group consisting of the compounds described in the following Examples and pharmaceutically acceptable salts thereof and individual diastereomers thereof. The compounds of the present invention are useful in the prevention and treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin activity, in particular substance P. Thus, for example, an excess of tachykinin activity, and in particular substance P, is involved in a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, episodic or recurrent single depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia with no history of panic disorders, specific phobias, for example, phobias to specific animals, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophrenic disorders, schizoaffective disorders, delirious disorders, brief psychotic disorders, psychotic division disorders and psychotic disorders with delusions or hallucinations; delirium, dementia, and amnesia and other cognitive or neurodegenerative disorders, such as Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, vascular dementia, and other dementias, eg, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jackob's disease, or due to multiple etiologies; Parkinson's disease and other extrapyramidal movement disorders such as movement disorders due to medication, eg, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, acute neuroleptic-induced dystonia, acute neuroleptic-induced akatisia, neuroleptic-induced tardive dyskinesia, and postural tremor induced by medication; disorders related to substances that arise from the use of alcohol, amphetamines (or substances similar to amphetamines), caffeine, cannabis, cocaine, hallucinogens, inhalers and aerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, hypnotics, and anxiolytics, which disorders related to substances include dependence and abuse, intoxication, abstinence, intoxication delirium, withdrawal delirium, persistent dementia, psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep disorders; epilepsy; Down's Syndrome; demyelination diseases such as MS and ALS and other neuropathological disorders such as peripheral neuropathy, for example diabetic and neuropathy induced by chemotherapy, and posterplegic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgia; and vascular brain disorders due to acute or chronic cerebrovascular damage such as cerebral infarction, subarachnoid hemorrhage or cerebral edema. Tachykinin activity, and in particular substance P, is also involved in nociception and pain. The compounds of the present invention will therefore be of use in the prevention or treatment of diseases and conditions in which pain predominates, including damage to the soft and peripheral tissues, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculoskeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, pain due to episiotomy, and burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, toothache, abdominal pain, gynecological pain, for example, dysmenorrhea, and labor pain; pain associated with nerve and root damage, such as pain associated with peripheral nervous disorders, eg, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, painful tics, atypical facial pain, nerve root pain, and arachnoiditis; pain associated with carcinoma, often referred to as cancerous pain; central nervous system pain, such as pain due to damage to the spinal cord or brainstem; pain of the spinal region of the back; sciatica; ankylosing spondylitis, gout; and pain of scars. Tachykinin antagonists, and in particular substance P, may be of use in the treatment of respiratory diseases, particularly those associated with excess mucous secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, fibrosis. cystic and asthma, respiratory distress syndrome in adults, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; allergies such as eczema and rhinitis; hypersensitivity disorders such as that caused by poison ivy; ophthalmic diseases such conjunctivitis, spring conjunctivitis, and the like; ophthalmic conditions associated with cell proliferation such as proliferative vitreoretinopathy; skin diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis. Tachykinin antagonists, and in particular substance P, can also be used in the treatment of neoplasms, including breast tumors, neuroganglioblastomas and small cell carcinomas such as small cell lung cancer.

Tachykinin antagonists, and in particular substance P, can also be used in the treatment of gastrointestinal (Gl) disorders, including inflammatory disorders and Gl tract diseases such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with control neuronal of viscera, ulcerative colitis, Crohn's disease, irritable bowel syndrome and emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness , dizziness, vertigo and Meniere's disease, surgery, migraine, variations in intracranial pressure, gastroesophageal reflux disease, acid indigestion, too much indulgence with food or drink, heartburn, heartburn or regurgitation, heartburn, for example, episodic, nocturnal or food-induced, and dyspepsia. Tachykinin antagonists, and in particular substance P, can also be used in the treatment of a variety of other conditions including somatic disorders relating to stress; somatic sympathetic dystrophy such as shoulder / hand syndrome; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune potentiation or suppression such as systemic lupus erythematosus; plasma extravasation resulting from chemotherapy with cytokines, disorders of bladder function such as cystitis, hyperreflexia of the bladder detrusor muscle, frequent urination and urinary incontinence, including the prevention or treatment of overactive bladder with symptoms of impulse of urinary incontinence, urgency, and frequency; fibrous and collagen diseases such as scleroderma and eosinophilic fasciolasis; blood flow disorders caused by vasodilation and vasospastic diseases such as angina pectoris, vascular headache, migraine and Reynaud's disease; and pain or nociception attributable to or associated with any of the following conditions, especially the transmission of pain in migraine. The compounds of the present invention are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined postoperative pain and postoperative vomiting and nausea. The compounds of the present invention are particularly useful in the prevention or treatment of emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness. , dizziness, vertigo and Meniere's disease, surgery, migraine, and variations in intracranial pressure. For example, the compounds of the present invention are optionally for use in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeated courses of chemotherapy of moderate or highly emetogenic cancer, including high doses of cisplatin. . Most especially, the compounds of the present invention are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy, and emesis induced by other pharmacological agents, for example, rolipram. Examples of such chemotherapeutic agents include alkylating agents, for example, ethylheneimine compounds, alkylsulfonates and other compounds with an alkylating action such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, folic acid, purine antagonists or pyrimidines; mitotic inhibitors, for example, vinca alkaloids and podophyllotoxin derivatives; and cytotoxic antibiotics. Particular examples of chemotherapeutic agents are described, for example, by D. J. Stewart in Nausea and Vomiting: Recent Research and Clinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Florida, USA (1991) pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine, streptozocin, cyclophosphamide , carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R. J. Gralla et al in Cancer Treatment Reports (1984) 68 (1), 163-172]. A further aspect of the present invention comprises the use of a compound of the present invention to achieve a chronobiological effect (phase shift of circadian rhythm) and alleviate circadian rhythm disorders in a mammal. The present invention is directed further to the use of a compound of the present invention to block the effects of light phase change in a mammal. The present invention further relates to the use of a compound of the present invention or a pharmaceutically acceptable salt thereof, to enhance or improve the quality of sleep as well as to prevent and treat sleep disturbances and sleep disturbances in a mammal. In particular, the present invention provides a method to enhance or improve the quality of sleep by increasing the efficiency of sleep and increasing the duration of sleep. In addition, the present invention provides a method for preventing and treating sleep disorders and sleep disturbances in a mammal which comprises the administration of a compound of the present invention or a pharmaceutically acceptable salt thereof. The present invention is useful for the treatment of sleep disorders, including Sleep Initiation and Maintenance Disorders (insomnia) ("TIMS") which may arise from psychophysiological causes, as a consequence of psychiatric disorders (particularly referred to as anxiety), from the use and abuse of alcohol and drugs (particularly during states of abstinence), childhood onset of TIMS, nocturnal myoclonus, fibromyalgia, muscle pain, sleep apnea and restless legs and non-specific disorders of REM as seen in the aging. Particularly preferred embodiments of the present invention are the treatment of emesis, urinary incontinence, depression or anxiety by administration of the compounds of the present invention to a subject (human or animal) in need of such treatment. The present invention relates to a method for the manufacture of a medicament for antagonizing the effect of substance P at its receptor site or for blocking neurokinin-1 receptors in a mammal comprising combining a compound of the present invention with a pharmaceutical vehicle or diluent. The present invention is further directed to a method for the manufacture of a medicament for the treatment of a physiological disorder associated with an excess of tachykinins in a mammal comprising combining a compound of the present invention with a pharmaceutical carrier or diluent. The present invention also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administering to a patient in need thereof a reduced amount of a tachykinin compound of the present invention or a composition comprising a compound of the present invention. As used herein, the term "treatment" or "treating" refers to the administration of the compounds of the present invention to reduce, ameliorate, or eliminate either the symptoms or the underlying cause of the prominent morbid conditions, in a subject (human or animal) that suffers from that condition or presents clinical indicators of it. The term "prevention" or "prevent" refers to the administration of the compounds of the present invention to reduce, improve, or eliminate the risk or probability of occurrence of the morbid conditions highlighted, in a subject (human or animal) susceptible or predisposed to tcondition. The compounds of this invention are useful for antagonizing tachykinins, in particular substance P in the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory disorders, pain or migraine and asthma in a mammal in need of such treatment. This activity can be demonstrated by the following tests.

Expression of the receptor in COS To express the human receptor cloned neurokinin-1 (NK1R) transiently in COS, the cDNA for the human NK1 R was cloned into the expression vector CMD9p which was derived from pCDM8 (INVITROGEN) by inserting the gene of resistance to ampicillin (nucleotide 1973 to 2964 of BLUESCRIPT SK +) within the Sac II site. Transfection of 20 ug of the DNA plasmid into 10 million COS cells was achieved by electroporation in 800 ul of transfection buffer (135 mM NaCl, 1.2 mM CaCl2, 1.2 mM MgCl2, 2.4 mM K2HPO4, 0.6 mM KH2PO4, 10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and 950 uF using the IBI GENEZAPPER (IBI, New Haven, CT). Cells were incubated in 10% fetal calf serum, 2 mM glutamine, 100U / ml penicillin-streptomycin, and 90% medium DMEM (GIBCO, Grand Island, NY) in 5% CO2 at 37 ° C during three days before the trial.

Stable Expression in CHO To establish a stable cell line expressing the human cloned NK1 R, the cDNA was subcloned into the vector pRcCMV (INVITROGEN). Transfection of 20 ug of the DNA plasmid in the CHO cells was achieved by electroporation in 800 ul of the transfection buffer supplemented with 0.625 mg / ml Herring sperm DNA at 300 V and 950 uF using the IBI GENEZAPPER (IBI). The transfected cells were incubated in CHO medium [10% fetal calf serum, 100 U / ml penicillin-streptomycin, 2 mM glutamine, 1/500 hypoxanthine-thymidine (ATCC), 90% IMDM medium (JRH BIOSCIENCES, Lenexa , KS), 0.7 mg / ml G418 (GIBCO)] in 5% CO2 at 37 ° C until the colonies were visible. Each colony separated and spread. The cell clone with the highest number of human NK1 R was selected for subsequent applications such as drug screening.

Test Protocol using COS or CHO The human NK1 R binding assay expressed well in cells COS or in CHO cells is based on the use of substance P marked with 125 | (125 | -SP, DU PONT, Boston, MA) as a radioactively labeled ligand which competes with unlabeled substance P or any other ligand to bind to human NK1 R. Monolayer cell cultures of COS or CHO cells were dissociated by the non-schematic solution (SPECIALTY MEDIA, Lavallette, NJ) and resuspended in an appropriate volume of binding buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl, 0.04 mg / ml bacitracin, 0.004 mg / ml leupeptin, 0.2 mg / ml BSA, 0.01 mM phosphoramidon) such that 200 ul of the cell suspension provide the appearance of approximately 10,000 cpm of 125 -S -SP specifically bound (approximately 50,000 to 200,000 cells). In the binding assay, 200 ul of cells were added to a tube containing 20 ul of 1.5 to 2.5 nM of 25 | -SP and 20 ul of unlabeled substance P or some other test compound. The tubes were incubated at 4 ° C or at room temperature for 1 hour with gentle shaking. Radioactivity was separated from unbound radioactivity by GF / C filter (BRANDEL, Gaithersburg, MD) which was pre-wetted with 0.1% polyethyloenimine. The filter was washed with 3 ml of wash buffer (50 mM Tris at pH 7.5, 5 mM MnCl2, 150 mM NaCl) three times and its radioactivity was determined by a gamma counter. Activation of phospholipase C by NK1 R can also be measured in CHO cells expressing human NK1 R by determining the accumulation of inositol monophosphate which is a degradation product of IP3. CHO cells were seeded in 12-well plates at 250,000 cells per well. After incubation in CHO medium for 4 days, the cells are loaded with 0.025 uCi / ml 3 H-myoinositol by incubation overnight. The extracellular radioactivity is eliminated by washing with phosphate buffer. LiCl is added to the well at the final concentration of 0.1 mM with or without the test compound, and incubation is continued at 37 ° C for 15 min. Substance P is added to the well at a final concentration of 0.3 nM to activate human NK1 R. After 30 minutes of incubation at 37 ° C, the medium is removed and 0.1 N HCl is added. Each well is sonicated at 4 ° C and is extracted with CHCl3 / methanol (1: 1). The aqueous phase is applied to a 1 ml Dowex AG 1X8 ion exchange column. The column is washed with formic acid 0.1 N followed by 0.025 M format of ammonium-formic acid 0.1 N. Inositol monophosphate was eluted with 0.2 M format of ammonium-formic acid 0.1 N and counter quantified by beta. In particular, the intrinsic antagonistic activities of the tachykinin receptor of the compounds of the present invention can be demonstrated by these assays. The compounds of the following examples have activity in the aforementioned assay in the range of 0.05 nM to 10 μM. The activity of the present compounds can be demonstrated by the assay described by Lei, et al., British J. Farmacol., 105, 261-262 (1992). According to a further or alternative aspect, the present invention provides a compound of the present invention for use as a composition that can be administered to a subject in need of a reduction in the amount of tachykinin or substance P in his body. The term "composition" as used herein is intended to comprise a product that comprises specific ingredients in predetermined amounts or proportions, as well as as some product which results, directly or indirectly, from the combination of the specific ingredients in the specified amounts. This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional vehicle comprising inert ingredients, as well as a product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or of the dissociation of one or more of the ingredients, or of other types of reactions or interactions of one or more of the ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately carrying the active ingredient in association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect in the disease process or condition. Accordingly, the pharmaceutical compositions of the present invention comprise any composition made by administering a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant that the vehicle, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical compositions desired for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and agents. preservatives in order to provide pharmaceutically elegant and palatable preparations. The tablets contain the active ingredient mixed with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulation and disintegration agents, for example, corn starch or alginic acid; binding agents, for example starch, gelatin or gum arabic, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a long period. Compositions for oral use may also be presented as hard gelatine capsules in which the active ingredient was mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules in which the Active ingredients are mixed with water or an oily medium, for example peanut oil, liquid paraffin, or olive oil. The aqueous suspensions contain the active materials mixed with suitable excipients for the preparation of aqueous suspensions. Oily suspensions can be formulated by suspending the active ingredient in a suitable oil. Oil-in-water emulsions can also be used. Dispersible powders and granules suitable for the preparation of an aqueous suspension for the addition of water provide the active ingredient mixed with a dispersing or humidifying agent, suspending agent and one or more preservatives. The pharmaceutical compositions of the present compounds may be in the form of a sterile injectable aqueous or oleaginous suspension. The compounds of the present invention can also be administered in the form of suppositories for rectal administration. For topical use, creams, ointments, gelatins, solutions or suspensions, etc., containing the compounds of the present invention may be employed. The compounds of the present invention can also be formulated for administration by inhalation. The compounds of the present invention can also be administered by a transdermal patch by methods known in the art. Compositions containing compounds of the present invention may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The term "dosage form unit" is taken to mean a single dose in which all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a simple container or packaging with the entire dose contained in it, and does not have to mix together any two or more containers or packages. Typical examples of dosage form units are tablets or capsules for oral administration, single dose vials for injection, or suppositories for rectal administration. This list of dosage unit units is not intended to be limiting in any way, but merely to represent typical examples in the pharmacy techniques of dosage unit units. The compositions containing compounds of the present invention can be presented as a kit, as a result of which two or more components, which may be active or inactive ingredients, vehicles, diluents, and the like, are provided with instructions for the preparation of the current dosage by the patient or person administering the drug to the patient. Such kits may be provided with all the necessary materials contained therein, or may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient. By "pharmaceutically acceptable" is meant the vehicle, diluent or excipient that must be compatible with the other ingredients of the formulation and not deleterious to the recipient.

The terms "administration of" or "administering" a compound should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into the body of the individuals in a therapeutically useful form and in a therapeutically effective amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like; transdermal dosage forms, which include creams, jellies, powders, or patches; oral dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories. The term "therapeutically effective amount" refers to a sufficient amount of the compounds of the present invention, in a suitable composition, and in a suitable dosage form for treating or preventing the morbid conditions highlighted. The compounds of the present invention can be administered in combination with another substance having a complementary effect to the tachykinin and substance P inhibitors of the present invention. Accordingly, in the prevention or treatment of emesis, a compound of the present invention can be used in conjunction with other antiemetic agents, especially 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, palenosetron and zatisetron, a corticosteroid , such as dexamethasone, or GABAß receptor agonists, such as baclofen. Likewise, for the prevention or treatment of migraine 2 A compound of the present invention can be used in conjunction with other antimigraine agents, such as ergotamines or 5HT1 agonists. , especially sumatriptan, naratriptan, zolmatrlptan or rizatriptan. It will be appreciated that for the treatment of depression or anxiety, a compound of the present invention may be used in conjunction with other antidepressant or antianxiety agents, such as norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (s), inhibitors. of monoaminoxidase (MAOI), reversible monoamine oxidase inhibitors (RIMA), serotonin and noradrenaline reuptake inhibitors (SNRI), α-adrenoreceptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists, especially partial agonists of 5- HT-? A, corticotropin releasing factor (CRF) antagonists, and pharmaceutically acceptable salts thereof. For the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention can be used in conjunction with other anorexic agents. It will be appreciated that for the treatment or prevention of pain or nociception or inflammatory diseases, a compound of the present invention can be used in conjunction with an anti-inflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interieucine inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, a nitric oxide inhibitor or an inhibitor of nitric oxide synthesis, an agent not anti-inflammatory steroid, or an anti-inflammatory agent that suppresses cytokines. It will be appreciated that when any combination described herein is used, both the compound of the present invention and the other agent / other active agents will be administered to a patient, within a reasonable period of time. The compounds may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They can be in separate pharmaceutical vehicles such as conventional oral dosage forms which are taken simultaneously. The term "combination" also refers to the case where the compounds are provided in dosage forms prepared and administered sequentially. Thus, by way of example, an active component can be administered as a tablet and then, within a reasonable period of time, the second component can be administered either as an oral dosage form or as an oral dosage form that is dissolves fast By an "oral dissolving formulation fast dissolving" is meant an oral administration form which when placed in the tongue of a patient dissolves in about 10 seconds. By "reasonable period of time" is meant a period of time that is not in excess of about one hour. This is, for example, if the first active component is provided in the form of a tablet, then within one hour, the second active component should be administered, either under the same type of dosage form, or another dosage form which provides effective drug administration. The compounds of this invention can be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimum pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition to be treated, the age and condition of the patient. , concurrent medication or special diets that are followed by the patient, and other factors that those skilled in the art will recognize, with the appropriate dosage being definitely at the discretion of the attending physician. In the treatment of conditions associated with an excess of tachykinins, a dose of an appropriate level of the compounds of the present invention, or pharmaceutically acceptable salts thereof, is from about 0.001 to 50 mg / kg per day, in particular from about 0.01 to about 25 mg / kg, such as from about 0.05 to about 10 mg / kg per day. The dosage range will generally be about 0.5 to 1000 mg per patient per day, which will be administered in single or multiple doses. Preferably, the dosage range will be from about 0.5 mg to 500 mg per patient per day; more preferably about 0.5 mg to 200 mg per patient per day; and even more preferably about 5 mg to 50 mg per patient per day. Specific dosages of the compounds of the present invention, or pharmaceutically acceptable salts thereof, for administration include 1 mg, 5 mg, 10 mg, 30 mg, 100 mg, and 500 mg. Pharmaceutical compositions of the present invention can be provided in a formulation comprising about 0.5 mg for 1000 mg of active ingredient; more preferably comprising about 0.5 mg to 500 mg of active ingredient; or 0.5 mg to 250 mg of active ingredient; or 1 mg to 100 mg of active ingredient. Specific pharmaceutical compositions for the treatment or prevention of excess tachykinins comprise about 1 mg, 5 mg, 10 mg, 30 mg, 100 mg, and 500 mg of active ingredient. Various methods for preparing the compounds of this invention are illustrated in the following Examples. The starting materials and intermediate requirements are in some cases commercially available, or can be prepared according to the methods of the literature or as illustrated in this document. All 1 H NMR spectra were obtained in the instrumentation at a field strength of 400 or 500 MHz.

EXAMPLE 1 (3af?, 4 /? 5S a?) - 5- (1 (S) -r3,5-bis { Trifluoromethyl) phenylethoxy > -4- (4- fluorophenyl) octahydro-1H-isoindol v (3aS.4S, 5 7aS) -5- (1 (S) -r3,5-bis (Trifluoromethyl) pheninetoxy.} -4- (4-fluoro) phenyl) octahydro-1H-isoindole Stage A 2- (4-Fluorophenol) - / V-methoxy -? / - methyl acetamide. To a solution of 16.7 g (108.4 mmole) of (4-fluorophenyl) acetic acid in pure methylene chloride under nitrogen 13.8 g (141.5 mmol) N, O-dimethyl-hydroxylamine, 20 ml triethylamine, 14.2 g (119.3 mmoleses) 4-dimethylaminopyridine (DMAP) and 27 g (140.6 mmoles) EDC were added. The reaction mixture was stirred at RT for 2 hours then transferred to a separatory funnel. The mixture was washed consecutively with aqueous 2N HCl, brine, saturated aqueous NaHCO3 and brine. The organic phase was dried over a drying agent, filtered and the solvent was evaporated under suction, under vacuum to give 21 g of the crude title compound which was used without further purification. 1 H-NMR (CDCl 3): d: 7.26 (2 H, m), 7.02 (2 H, m), 3.77 (2 H, s), 3.65 (3 H, s), 3.21 (3 H, s).

Stage B 1 - . 1- (4-fluorophenyl) but-3-en-2-one To a solution of 220 ml (1.0 M, 220 mmol) of vinylmagnesium bromide in 100 ml of THF, it was added dropwise under a nitrogen atmosphere at 0 °. C a solution of 21 g (106.6 mmoles) 2- (4-fluorophenyl) - / V-methoxy-? -methyl acetamide (step A) in -150 ml of pure ether. The reaction mixture was stirred at 0 ° C for 0.5 hours, then poured slowly into an ice / 2N aqueous HCl mixture. The resulting mixture was diluted with ether and brine, transferred to a separatory funnel and the organic phase was separated. The organic phase was washed with brine, dried over a drying agent, filtered and the solvent was evaporated in vacuo to give 14.2 g of crude title compound which was used without further purification. 1 H-NMR (CDCl 3): d: 7.19 (2 H, m), 7.02 (2 H, t, J = 9.5 Hz), 6.42 (1 H, dd, JT = 14.2 Hz, J2 = 11 Hz). 6.34 (1 H, d, J = 14.2 Hz), 5.86 (1 H, d, J = 11 Hz), 3.87 (2 H, s).

Stage C 1E and 1Z tere -butyl ([1- (4-fluorobenzylidene) prop-2-en-1-ipoxirdimethylsilane To a solution of 104 ml (104.0 mmoles, 1.2 equiv.) Of a 1.0 M solution of potassium tert-butoxide in THF and 100 ml of pure THF under nitrogen atmosphere at -78 ° C was added a solution of 14.2 g (86.6 mmoles, 1 equiv.) Of 1- (4-fluorophenyl) but-3-en-2-one (step B) and 13.0 g (86.6 mmoles) of fer-butylchlorodimethylsilane in 100 ml of pure THF The reaction mixture was stirred at -78 ° C for 6 hours and at RT for 6 hours, then deactivated by the addition of 50 ml of The resulting mixture was warmed to RT, diluted with 150 ml of hexanes, transferred to a separatory funnel and the organic phase was separated.The organic phase was washed with 50 ml of brine, dried over anhydrous magnesium sulfate. , filtered and the solvent was evaporated in vacuo to give 20.5 g of crude title compounds which were used without further purification.1H-NMR (CDCl3): d: 7.52 (2H, m), 6.98 (2 H, m), 6.33 (1 H, dd, J1 = 13.2 Hz, J2 = 8.5 Hz), 5.97 (1 H, s), 5.52 (1 H, d, J = 13.2 Hz), 5.17 (1 H, d, J = 8.5 Hz).

Stage D (3aS, 4R7a) -2-benzyl-5- (rterc-butyl (dimethyl) silinoxy) -4- (4-fluorophenin-3a, 4,7,7a-tetrahydro-1 H-isoindol-1, 3 (2H) -dione and (3a 4S, 7aS) -2-benzyl-5. {((Ferc-butyl (d -methyl) silyl-oxy) -4- (4-fluorophenyl) -3a, 4,7,7a-tetrahydro-1 / - / - isoindol-1,3 (2 / - /) - dione A solution of 15 g (54.0 mmoles, 1 equiv.) Of 1 E and 1Z tert-butyl. [1- (4-fluorobenzylidene) prop-2-en-1-yl] oxy] dimethylosilane (step C) and 12.1 g (64.6 mmol) of N-benzylmaleimide in 150 ml of pure toluene under nitrogen it was heated to reflux for 16 hours, then cooled to RT The solvent was evaporated in vacuo to give 31 g of the crude title compounds which contained the unreacted N-benzylmaleimide and were used without further purification 1 H NMR (CDCl 3 ): d: 7.37-7.26 (3 H, m), 7.22 (2 H, m), 7.00 (2 H, m), 6.78 (2 H, t, J = 8.5 Hz), 5.07 (1 H, t, J = 2.3 Hz), 4.22 (1 H, d, J = 16 Hz), 4.15 (1 H, d, J = 16 Hz), 3.66 (1 H, d, J = 6.5 Hz), 3.52 (1 H, t, J = 7.0 Hz), 3.14 (1 H, m), 2 .87 (1 H, m), 2.68 (1 H, m), 0.92 (1 H, m), 0.78 (9 H, s), 0.11 (3 H, s), -0.1 (3 H, s).

Stage E (3aS.4S, 7aSV2-benzyl-5- (rferc-butyl (dimethyl) silinoxy) -4- (4-fluorophenyl) -2,3,3a, 4,7,7a-hexahydro-1 H-isoindole y (3a 4 7a) -2-benzyl-5- (f.erc-butyl (dimethyl) silyloxy) -4- (4-fluorophenyl) -2,3,3a, 4,7,7a-hexahydro-1 - / - isoindol In a Round bottom flask was added 7.3 g (192.0 mmol, excess) of lithium aluminum hydride in pure ether under nitrogen atmosphere at 0 ° C. A solution of 31 g of the crude intermediate was added dropwise to the resulting mixture. of stage D in 100 ml of dry methylene chloride under nitrogen atmosphere The resulting mixture was stirred at RT for 1 hour, then carefully deactivated at 0 ° C, by dropwise addition of 12 ml of water, then ml of 5.0 N aqueous NaOH The resulting suspension was stirred at RT for 0.5 hour and the solids filtered.The solvent in the filtrate was evaporated in vacuo to give crude title compounds which were used without further purification.

Stage F (3aS, 4S, 7aS) -2-benzyl-4- (4-fluorophenpoctahydro-5H-isoindol-5-one v (3a, 4 7af?) - 2-benzyl-4- (4-fluorophenyl) octahydro- 5 / tf-isoindol-5-one To a solution of intermediate step E in 60 ml of dry acetonitrile under nitrogen atmosphere at RT was added 100 ml (250 mmoles) of a 2.5 M solution of HF in acetonitrile. it was stirred at RT for 16 hours, then it was deactivated at 0 ° C by the dropwise addition of 120 ml of 5.0 N aqueous NaOH. The acetonitrile was evaporated in vacuo and the resulting aqueous mixture was diluted with ether and water. The resulting organic phase was transferred to a separatory funnel and the organic phase was separated The aqueous phase was extracted with an additional portion of ether The combined organic phases were washed with 50 ml of brine, dried over a drying agent, filtered and the The solvent was evaporated in vacuo, the residue was purified by flash column chromatography on silica gel eluting with EtOAc / hexanes (1 / 1) to give 9.0 g of the racemic title compounds. 1 H NMR (CDCl 3): d: 7.27-7.23 (3 H, m), 7.12-7.03 (2 H, m), 3.75 (1 H, d, J = 12.9 Hz), 3.61 (2 H, d, J = 4.8 Hz), 3.61 (1 H, q, J = 14.5 Hz), 2.93 (1 H, t, J = 8.5 Hz) , 2.68-2.52 (3 H, m), 2.43-2.33 (2 H, m), 2.25 (1 H, m), 2.05 (2 H, m).

Stage G (3aS, 4S, 5R7aS) -2-benzyl-4- (4-fluorophenyl) octahydro-1 H-isoindol-5-ol v (3a, 4, 5S, 7af?) - 2-benzyl-4- (4- fluorophenyl) octahydro-1 H-isoindol-5-ol To a solution of the intermediate (9.0 g) of step F under nitrogen atmosphere in dry ether at -78 ° C was added a 1.0 M solution of lithium aluminum hydride (38.3 ml ) in ether. The resulting mixture was stirred at -78 ° C for 0.5 hours, then carefully deactivated by the dropwise addition of water, then aqueous NaOH at 5.0 N. The resulting suspension was stirred at RT for 0.5 hours and the solids filtered. The filtrate solvent was evaporated in vacuo to give the crude title compounds as the major compounds which were used without further purification. 1 H-NMR (CDCl 3): d: 7.38-7.20 (7 H, m), 7.05 (2 H, t, J = 8.5 Hz), 3.75 (2 H, s), 3.75 (1 H, m), 2.8-2.65 (4 H, m), 2.60 (1 H, m), 2.50 (1 H, m), 2.38 (1 H, d, J = 8.1 Hz), 2.21 (1 H, m), 1.95 (1 H, m ), 1.81 (2 H, m), 1.73-1.62 (2 H, m). MS: (MH) + 261.9.

Stage H (3aS, 4S, 5fi, 7aS) -4- (4-fluorophenyl) octahydro-1H-isoindol-5-ol v (3af?, 4 5S, 7a /:?) - 4- (4-fluorophenipoctahydro-1) / - / - isoindol-5-ol The intermediate of step G was hydrogenated at 3.51535 kg / cm2 (50 PSI) of hydrogen above 10% by weight of 10% Pd-C in ethanol for 16 hours at RT. The catalyst was filtered and the filtrate solvent was evaporated in vacuo to give crude title compounds which were used without further purification.

Stage (3aS.4S.5 7aS) -4- (4-fluorophenyl) -5-hydroxyoctahydro-2 / - / - butyl-2-carboxylic acid ferric-butyl ester and (3af?, 4f?, 5S, 7aR) -4- (4-fluorophenyl) -5-hydroxy-octahydro-2-ferrino-2-butyl-2-carboxylic acid ester To a solution of 7.5 g (31.9 mmol) of the intermediate of the H stage in chloride of methylene under nitrogen atmosphere at RT were added 9.0 g (41.5 mmol) of diterbutyl dicarbonate. The resulting mixture was stirred at RT for 16 hours, then the solvent was evaporated in vacuo. The resulting mixture was dissolved in methanol and aqueous NaOH was added at 5.0 N. The resulting mixture was stirred for 2 hours and the methanol was removed in vacuo. The aqueous residue was diluted with EtOAc, transferred to a separatory funnel and the organic phase separated. The aqueous phase was extracted with an additional part of EtOAc. The combined organic phases were washed with 50 ml of brine, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with EtOAc / hexanes (1/4) to give 2.8 g of the racemic title compounds. 1 H NMR (CDCl 3): d: 1 H NMR (CDCl 3): d 1 H NMR (CDCl 3): d 7. 22 (2 H, m), 7.07 (2 H, m), 3.73 (1 H, m), 3.48-3.33 (2 H, m), 3.21-3.10 (2 H, m), 2.51 (1 H, m ), 2.18 (1 H, t, J = 10.7 Hz), 2.25 (1 H, m), 1.98 (1 H, m), 1.97-1.85 (1 H, m), 1.63 (1 H, m), 1.51 -1.40 (1 H, m), 1.49, 1.43 (9 H, two singles). Then the isolate was a minor amount of the cis (less polar) alcohol mixture: (3a /:?, 4f?, 5 /:?, 7af?) - 4- (4-fluorophenol) -5-hydroxyoctahydro- 2H-isoindol-2-carboxylic acid ferric-butyl ester and (3aS, 4S, 5S, 7aS) -4- (4-fluorophenyl) -5-hydroxyoctahydro-2 / - / - isoindol-2-carboxylate ferric acid -butyl. 1 H NMR (CDCl 3): d: 7.25 (2 H, m), 7.05 (2 H, m), 3.95 (1 H, m), 3. 50-3.20 (3 H, m), 3.08, 2.95 (1 H, two doublets, J = 14.3 Hz), 2.77 (1 H, m), 2.65-2.55 (2 H, m), 2.15 (1 H, m ), 1.82 (2 H, m), 1.58 (1 H, m), 1.45, 1.40 (9 H, two singlets).

Stage J (3aS, 4S, 5 7aS) -5- (r3,5-bis (trifluoromethyl) benzoxynoxy) -4- (4-fluorophenyl) octahydro-2H-isoindol-2-carboxylate of fßrc -butyl and (3a /? 4 5SJaf?) - 5- (r3,5-bis (trifluoromethyl) benzoyloxyl-4- (4-fluorophenyl) octahydro-2H-isoindol-2-carboxylic acid-ferricbutyl ester To a solution of 0.09 g (0.26 mmoles) of the intermediate from step I in pure methylene chloride under nitrogen atmosphere at RT were added 0.089 g (0.32 mmol) of 3,5-bis (trifluoromethyl) benzoyl chloride, 0.07 ml of TEA and a The catalytic amount of DMAP The resulting mixture was stirred at RT for 2 hours, then transferred to a separatory funnel, washed with saturated aqueous NaHCO3, aqueous KHSO4, and brine, The combined organic phases were dried over magnesium sulfate, were filtered and the solvent was evaporated in vacuo to provide 0.15 g of crude title compounds which were used without further purification.1H NMR (CDCl3): d: 8.63 (1 H, s), 8.19 (2 H, s), 7.25 (2 H, m), 7.00 (2 H, m), 5.22 (1 H, m), 3.59-3.43 (2 H, m), 3.0-3.20 (2 H, m), 2.83 (1 H, t, J = 12.7 Hz), 2.62 (1 H, m ), 2.43 (1 H, m), 2.20 (1 H, m), 2.02 (1 H, m), 1.90-1.70 (2 H, m), 1.55, 1.47 (9 H, two singlets).

Stage K (3aS, 4S, 7aS) -5 - ((1-f3,5-bis (trifluoromethyl) phenylvinyl) oxy) -4- (4-fluorophenyl) octahydro-2-r7-isoindol-2-carboxylate of * ferc -butyl and (3a 4 5S, 7aR) -5- ( { 1 -f3,5-bis (trifluoromethyl) pheninvinyl) oxy) -4- (4-fluorophenyl) octahydro-2 / - / - isoindol-2 fer-butylcarboxylate To a solution of 0.15 g (0.26 mmol) of the intermediate of step J in dry THF under a nitrogen atmosphere at 0 ° C was added 2 ml of a 0.5 M solution of Tebbe reagent in toluene. The resulting mixture was stirred at 0 ° C for 0.5 hour, then carefully deactivated by the dropwise addition of 0.5 ml of water, then 0.5 ml of 5.0 N aqueous NaOH. The resulting suspension was diluted with ethyl acetate, stirred at RT for 0.5 hour and the solids filtered. The resulting filtrate was stirred with 0.5 ml of 5.0 N aqueous NaOH for 16 hours and the solids filtered through a filter aid pad. The solvent was evaporated in vacuo to give crude title compounds which were used without further purification. 1 H NMR (CDCl 3): d: 7.73 (1 H, s), 7.55 (2 H, s), 7.30-7.18 (2 H, m), 7.03 (2 H, m), 4.67 (1 H, s), 4.37 (1 H, s), 4.25 (1 H, m), 3.55-3.30 (3 H, m), 3.27-3.15 (2 H, m), 2.81 (1 H, t, J = 12.7 Hz), 2.60 (1 H, m), 2.40-30 (2 H, m), 1.98 (1 H, m), 1.83 (1 H, m), 1.55, 1.47 (9 H, two singlets).

Stage L (3aS, 4S, 5 7aS) -5-. { 1 R-r3,5-bis (trifluoromethyl) phenyletoxyl) -4- (4-fluorophenyl) octahydro-2-isoindole-2-carboxylate des-butyl ester and (3a, 4 5S a) -5- ( 1 S-r3,5-bis (trifluoromethyl) pheninetoxy> -4- (4-fluorophenyl) octahydro-2H-isoindol-2-carboxylate ferric-butyl QaS Sd ZaS) -5-. { 1 S - [3,5-bis (trifluoromethyl) phenylethoxy] -4- (4-fluorophenyl) octahydro-2 - / - isoindol-2-carboxylate of fer-butyl and (3a 4 5S, 7af?) -5- (1f? -3,5-bis (trifluoromethyl) fenethoxy) -4- (4-fluorophenyl) octahydro-2H-isoindol-2-carboxylic acid-butyl ester The intermediate of stage G was hydrogenated at 3.51535 kg / cm2 (50 PSI) of hydrogen above 10% by weight of 10% Pd-C in ethanol for 16 hours at RT The catalyst was filtered and the filtrate solvent was evaporated in vacuo to give the title compounds in crude were purified by preparative TLC eluting with EtOAc / hexanes (1/3) to give the two diastereomers, the less polar isomer (the major), 1 H NMR (CDCl 3): d: 7.73 (1 H, s), 7.58 (2 H, s), 7.25 (2 H, m), 7. 10 (2 H, m), 4.05 (1 H, m), 3.23-3.30 (3 H, m), 3.20-3.07 (2 H, m), 2.55 (1 H, t, J = 10.3 Hz), 2.45 (1 H, m), 2.33 (1 H, m), 2.20-1.55 (3 H, m), 1.50, 1.43 (9 H, two singlets), 0.95 (3 H, d, J = 6.9 Hz), 1.0 -0.82 (1 H, m). The minor isomer, 1 H NMR (CDCl 3): d 7.70 (1 H, s), 7.20 (2 H, s). 6.95 (2 H, m), 6.87 (2 H, m), 4.45 (1 H, m), 3.40 (1 H, m), 3.27 (1 H, m), 3.15-3.05 (2 H, m), 2.47 (2 H, t, J = 11.2 Hz), 2.15 (2 H, m), 1.93 (1 H, m), 1.75 (1 H, m), 1.62 (1 H, m), 1.50 (1 H, m), 1.50, 1.45 (9 H, s), 1.30 (3 H, two doublets, J = 6.0 Hz).

Stage M (3a 4 5S, 7aR) -5-. { 1 (S) -r3,5-bis (trifluoromethyl) phenyletoxyl) -4- (4-fluorophenyl) octahydro-1 / - / - isoindol (3aS, 4S, 5R7aS) -5- (1 (RH3,5-b S (trifluoromethyl) phenylethoxy.} -4- (4-fluorophenyl) octahydro-1 / - / - isoindol The less polar major diastereomer of intermediate step L was dissolved in pure methylene chloride and treated with anisole and TFA at RT for 2 hours The solvent was evaporated in vacuo and the residue was taken up in EtOAc The solution was washed with aqueous NaOH, then with brine, dried over drying agent and filtered The solvent was evaporated under vacuum give the crude title compounds: 1 H NMR (CDCl 3): d: 7.77 (1 H, s), 7.60 (2 H, s), 7.28 (2 H, m), 7. 12 (2 H, t, J = 8.2 Hz), 4.07 (1 H, m), 3.35 (1 H, m), 3.22-3.10 (2 H, m), 3.00 (1 H, m), 2.85 (1 H, d, J = 11.3 Hz), 2.65 (1 H, t, J = 11.3 Hz), 2.50 (1 H, m), 2.40 (1 H, m), 1.87-1.68 (2 H, m), 1.53 (1 H, m), 1.30 (1 H, m), 0.95 (3 H, d, J = 6.0 Hz).

EXAMPLE 2 (3aR4 5S.7a /?) - 5-f (1 /?) - 1-r3,5-bis (trifluoromethyl) phenynetoxy > -4- (4- fluorophenyl) -octahydro-1 -isoindole Stage A (3aS, 4S, 5R7aS) -2-benzyl-4- (4-fluorophenyl) octahydro-1 / - / - isoindol-5-ol and (3aR4R5S, 7aR-2-benzyl-4- (4-fluorophenoctahydro- 1 / - / - isoindol-5-ol Starting with 3.5 g of the racemic mixture of (3aS, 4S, 5R 7aS) -2-benzyl-4- (4-fluorophenyl) octahydro-1 H-isoindol-5-ol and (3aR4R5S, 7aR) -2-benzyl-4- (4-fluorophenyl) octa-hydro-1H-isoindol-5-ol (intermediate of Example 1, step G) was separated by chiral HPLC using CHIRACEL AD column eluting with hexanes / EtOH (9/1) to provide the first eluted isomer (3aS, 4S, 5R7aS) -2-benzyl-4- (4-fluorophenyl) octahydro-1 / - / - isoindol-5-ol and the second isomer eluting ( 3aR4R5S, 7a) -2-benzyl-4- (4-fluorophenyl) octahydro-1 / - / - isoindol-5-ol.

Stage B (3aR, 4R, 5S, 7aRV4- (4-fluorophen-p-5-hydroxyoctahydro-2 / - / - isoindol-2-carboxylic acid-ferric) To a solution of 5.36 g (15.8 mmol) of the second isomer eluting ( 3aR4R5S, 7aR) -2-benzyl-4- (4-fluorophenyl) octahydro-1 - / - isoindol-5-ol (intermediate from step A) in 80 ml of EtOH was added 4.31 g (19.7 mmoles) of sodium dicarbonate. difer-butyl and 0.5 g of 10% Pd-C The resulting mixture was hydrogenated at 3.51535 kg / cm2 (50 PSI) of hydrogen for 16 hours at RT The catalyst was filtered and 5 ml of 5.0 N aqueous NaOH was added. The solvent was evaporated in vacuo, the aqueous residue was diluted with EtOAc, transferred to a separatory funnel, washed with brine, dried over a drying agent, filtered and the solvent evaporated in vacuo. purified by flash column chromatography on silica gel eluting with EtOAc / hexanes (1/4) to give the title compound.1H NMR (CDCl3): d: 7.22 (2 H, m), 7.07 (2 H, m), 3.73 (1 H, m), 3.48-3.33 (2 H, m ), 3.21-3.10 (2 H, m), 2.51 (1 H, m), 2.18 (1 H, t, J = 10.7 Hz), 2.25 (1 H, m), 1.98 (1 H, m), 1.97 -1.85 (1 H, m), 1.63 (1 H, m), 1.51-1.40 (1 H, m), 1.49, 1.43 (9 H, two singlets).

Stage C (3aR4R5 $, 7aR) -5- (r3,5-bis (trifluoromethyl) benzoyloxy) -4- (4-fluorophenyl) octahydro-2 / - / - isoindo-2-carboxylic acid-ferricbutyl ester To a solution of 4.75 g (14.0 mmoles) of the intermediate from step B in dry methylene chloride under nitrogen atmosphere at RT was added 4.71 g (17.0 mmoles) of 3,5-bis (trifluoromethyl) benzoyl chloride, 2.4 ml (17.3 mmoles) ) of TEA and a catalytic amount of DMAP. The resulting mixture was stirred at RT for 2 hours, then transferred to a separatory funnel, washed with saturated aqueous NaHCO3 and brine. The combined organic phases were dried over magnesium sulfate, were filtered and the solvent was evaporated in vacuo to provide the crude title compound which was used without further purification. 1 H-NMR (CDCl 3): d: 8.63 (1 H, s), 8.19 (2 H, s), 7.25 (2 H, m), 7.00 (2 H, m), 5.22 (1 H, m), 3.59- 3.33 (2 H, m), 3.30-3.20 (2 H, m), 2.83 (1 H, t, J = 12.7 Hz), 2.62 (1 H, m), 2.43 (1 H, m), 2.20 (1 H, m), 2.02 (1 H, m), 1.90-1.70 (2 H, m), 1.55, 1.47 (9 H, two singlets).

Stage D (3aR4R5S, 7aR-5- ( { 1-r3,5-bis (trifluoromethyl) phenylvinyl) oxy) -4- (4-fluorophenyl) octahydro-2H-isoindole-2-carboxylic acid-ferric-butyl ester solution of 9.5 g (14.0 mmoles) of the intermediate of the stage C in pure THF under nitrogen atmosphere at 0 ° C was added 66 ml (33 mmoles.) Of a 0.5 M solution of Tebbe reagent in toluene. The resulting mixture was stirred at 0 ° C for 2 hours, then carefully deactivated by the dropwise addition of 7.5 ml of water, then 7.5 ml of 5.0 N aqueous NaOH. The resulting suspension was stirred at RT for 0.5 hours and the solids were filtered. The resulting filtrate was stirred with 5 ml of 5.0 N aqueous NaOH for 16 hours and the solids were filtered through a filter aid. The solvent was evaporated in vacuo and the residue was purified by column chromatography eluting with EtOAc / hexanes (1/3) to give the title compound. 1 H NMR (CDCl 3): d: 7.73 (1 H, s), 7.55 (2 H, s), 7.30-7.18 (2 H, m), 7.03 (2 H, m), 4.67 (1 H, s), 4.37 (1 H, s), 4.25 (1 H, m), 3.55-3.30 (3 H, m), 3.27-3.15 (2 H, m), 2.81 (1 H, t, J = 12.7 Hz), 2.60 (1 H, m), 2.40-30 (2 H, m), 1.98 (1 H, m), 1.83 (1 H, m), 1.55, 1.47 (9 H, two singlets).

Stage E (/ 3aR4R5S, 7aR) -5 - ((1S) -1-r3,5-bis (trifluoromethyl) phenyl-1-ethoxy) -4- (4-fluorophenyl) octahydro-2H-isoindol-2-carboxylic acid-ferric-butyl ester and ( 3aR4R5S.7affl-5- { (1R) -1-y3,5-bis (trifluoromethyl) pheninetoxy> 4- (4-fluorophenyl) octahydro-2-isoindol-2-carboxylate tere-butyl A solution of 10.2 g of the crude intermediate from step D in ethanol was hydrogenated at 3.51535 kg / cm2 (50 PSI) of hydrogen over -1 g of 10% Pd-C for 3 hours at RT.The catalyst was filtered and the solvent of the filtrate was evaporated in vacuo to give crude title compounds which were purified by column chromatography eluting with EtOAc / hexanes (2/3) to provide 8.9 g (15.5 mol) of the two diastereomers with the larger diastereomer (S) The mixture was brought into -150 ml of pure THF under a nitrogen atmosphere and treated with 80 ml (80 mmol) of a 1.0 M solution of potassium fer-butoxide in THF.The resulting mixture was heated at 40 ° C. 1 hour, cooled to RT and tempered Pló by adding water. The mixture was diluted with EtOAc, transferred to a separatory funnel, washed with brine, dried over drying agent, filtered and the solvent evaporated in vacuo. The residue was purified by flash column chromatography on that of silica eluting with EtOAc / hexanes (1/3) to give (3aR4R5S, 7aR) -5-. { (1 S) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octa-hydro-2 / - -isoindole-2-carboxylic acid of less polar and the (3aR4R5S, 7aRV-5- { (1R) -1- [3,5- bis (trifluoromethyl) -phenyl] ethoxy] -4- (4-fluorophenyl) octahedron-2H-isoindol-2-carboxylic acid ester, more polar, 1 H-NMR (CDCl 3): d of the less polar isomer: d: 7.73 (1 H, s), 7. 58 (2 H, s), 7.25 (2 H, m), 7.10 (2 H, m), 4.05 (1 H, m), 3.23-3.30 (3 H, m), 3.20-3.07 (2 H, m ), 2.55 (1 H, t, J = 10.3 Hz), 2.45 (1 H, m), 2.33 (1 H, m), 2.20-1.55 (3 H, m), 1.50, 1.43 (9 H, two singlets ), 0.95 (3 H, d, J = 6.9 Hz), 1.0-0.82 (1 H, m). 1 H NMR (CDCl 3): d from the more polar isomer: 7.71 (1 H, s), 7.20 (2 H, s), 6.97 (2 H, m), 6.85 (2 H, m), 4.47 (1 H, m), 3.43-3.03 (4 H, m), 2.47 (2 H, m), 2.15 (2 H, m), 1.92 (1 H, t, J = 10.5 Hz), 1.80-1.57 (3 H, m), 1.50, 1.43 (9 H, two singlets), 1.30 (3 H, d, J = 6.9 Hz ).

Stage F (3aR4R5S.7a) -5 - ((1R-1-r3.5-bis (trifluoromethyl) phenyl-1-ethoxy) 4-hydrochloride salt (4-fluorophenipoctahydro-1 / - / - isoindol) The more polar diastereomer of Step E intermediate (1.5 g, 2.6 mmol) was dissolved in -20 ml of 4 N HCl in dioxane and stirred at RT for 2 hours.The solvent was evaporated in vacuo and the residue was taken up in EtOAc.The solution was washed with aqueous NaOH , then brine, dried over drying agent and filtered.The solvent was evaporated in vacuo to give the crude title compound.HCl treatment in dioxane provided the HCl salt. 1 H NMR (CDCl 3): d: 7.75 (1 H, s), 7.37 (2 H, s), 7.13 (2 H, m), 6. 87 (2 H, t, J = 8.5 Hz), 4.63 (1 H, q, 6.5 Hz), 3.45 (1 H, td, J, = 4 Hz, J2 = 11.9 Hz), 3.17 (1 H, m) , 3.10 (1 H, dd, J, = 6.5 Hz, J2 = 9.5 Hz), 2.90 (1 H, J = 12.7 Hz), 2.57 (2 H, m), 2.47 (1 H, t, J = 9.5 Hz ), 2.25 (1 H, m), 1.98 (2 H, m), 1.68 (1 H, m), 1.10 (3 H, d, 6.5 Hz). MS: (MH) + 475.9.

EXAMPLE 3 f3a?, 4 5S aR) -5-f (1 /?) - 1-r3,5-bisftrifluoromethyl) phenyletoxy > -4- (4- fluorophenyl) -2-methyl-octahydro-1H-isoindole Stage A (3aR4R5S.7a) -5 - ((1?) - 1-r3,5-bis (trifluoromethylphenylethoxy) -4- (4-fluorophenyl) -2-methyloctahydro-1 t'-isoindol To a solution of 30 mg (0.063 mmol) of (3aR4R5S, 7af?) - 5-. {(1 R - [3,5-bis (trifluoromethyl) pheny] ethoxy} -4- (4-fluorophenyl) octahydro-1 H-isoindol (Example 2) -2 ml of methanol were added -20 mg (excess) of aqueous formaldehyde and 40 mg of sodium acetate. The resulting mixture was stirred at RT for 10 minutes, then 20 mg of NaBH was added. The resulting mixture was stirred at RT for 1 hour after the water was added. The methanol was evaporated in vacuo and the residue was extracted with ether (2 x 25 ml). The combined extracts were dried over the drying agent, filtered and the solvent was evaporated in vacuo. The residue was purified by preparative TLC eluting with EtOAc / MeOH (9/1) to give the title compound. 1 H NMR (CDCl 3): d: ppm. 7.68 (1 H, s), 7.23 (2 H, s), 7.02 (2 H, m), 6.87 (2 H, m), 4.45 (1 H, m), 3.27 (1 H,), 2.78-2.65 (2 H, m), 2.57 (2 H, m), 2.45-2.30 (3 H, m), 2.23-2.12 (2 H, m), 1.98 (1 H, m), 1.83-1.68 (2 H, m), 1.30 (3 H, 6.2) MS: (MH) +489.9.

EXAMPLE 4 f3aS, 4S, 5 7aS) -5-U1S) -1-r3,5-bis (trifluoromethyl) pheninetoxy > -4- (4- fluorophenyl) -octahydro-1H-isoindol Stage A (3aS, 4S, 5R7aS) -4- (4-fluorophenyl) -5-hydroxyoctahydro-2H-isoindol-2-carboxylic acid-ferric acid The title compound was prepared from (3aS, 4S, 5R7aS) -2 -benzyl-4- (4-fluorophenyl) octahydro-1-isoindole-5-ol (the first isomer eluting from Example 2 in step A) according to the procedure of example 2, step B). 1 H NMR (CDCl 3): d: 7.22 (2 H, m), 7.07 (2 H, m), 3.73 (1 H, m), 3. 48-3.33 (2 H, m), 3.21-3.10 (2 H, m), 2.51 (1 H, m), 2.18 (1 H, t, J = 10.7 Hz), 2.25 (1 H, m), 1.98 (1 H, m), 1.97-1.85 (1 H, m), 1.63 (1 H, m), 1.51-1.40 (1 H, m), 1.49, 1.43 (9 H, two singlets).

Stage B (3aS, 4S, 5R7aS) -5-. { R3,5-bis (trifluoromethyl) benzoxynoxy) -4- (4-fluorophenyl) octahydro-2 / - / - isoindol-2-carboxylic acid ester of fer-butyl The title compound was prepared from the intermediate of the stage A according to the procedure of example 2, step C. 1 H NMR (CDCl 3): d: 8.63 (1 H, s), 8.19 (2 H, s), 7.25 (2 H, m), 7.00 (2 H, m), 5.22 (1 H, m), 3.59-3.433 (2 H, m) .30-3.20 (2 H, m), 2.83 (1 H, t, J = 12.7 Hz), 2.62 (1 H, m ), 2.43 (1 H, m), 2.20 (1 H, m), 2.02 (1 H, m), 1.90-1.70 (2 H, m), 1.55, 1.47 (9 H, two singlets).

Stage C (3aS, 4S, 5R7aS) -5 - (, (1-f3,5-bis (trifluoromethyl) phenylvinyl) oxy) -4- (4-fluorophenyl) octahydro-2H-isoindol-2-carboxylic acid ferricyl ester The compound titer was prepared from the intermediate of step B according to the procedure of example 2, step D. 1H NMR (CDCl 3): d: 7.73 (1 H, s), 7.55 (2 H, s), 7.30-7.18 (2 H, m), 7.03 (2 H, m), 4.67 (1 H, s), 4.37 (1 H, s), 4.25 (1 H, m), 3.55-3.30 (3 H, m), 3.27-3.15 (2 H, m), 2.81 (1 H, t, J = 12.7 Hz), 2.60 (1 H, m), 2.40-2.30 (2 H, m), 1.98 (1 H, m), 1.83 (1 H , m), 1.55, 1.47 (9 H, two singles).

Stage D (3aS, 4S, 5R, 7aS) -5-. { (1S) -1-y3,5-bis (trifluoromethyl-phenylethyl-4- (4-fluorophenyl) octahydro-2H-isoindol-2-carboxylic acid ferric-butyl ester and (3aS, 4S, 5R7aS) -5- ((1 R-1-f3,5-bis (trifluoromethyl) phenynetoxy) -4- (4-fluorophenyl) octahydro-2 - / - isoindol-2-carboxylic acid ester The title compounds are prepared from the intermediate of step C according to the procedure of example 2, step E. 1 H NMR (CDCl 3): d: the less polar isomer, d: 7.73 (1 H, s), 7.58 (2 H, s) , 7.25 (2 H, m), 7.10 (2 H, m), 4.05 (1 H, m), 3.23-3.30 (3 H, m), 3.20-3.07 (2 H, m), 2.55 (1 H, t, J = 10.3 Hz), 2.45 (1 H, m), 2.33 (1 H, m), 2.20-1.55 (3 H, m), 1.50, 1.43 (9 H, two singlets), 0.95 (3 H, d, J = 6.9 Hz), 1.0-0.82 (1 H, m) 1 H NMR (CDCl 3) of the more polar isomer: 7.71 (1 H, s), 7.20 (2 H, s), 6.97 (2 H, m ), 6.85 (2 H, m), 4.47 (1 H, m), 3.43-3.03 (4 H, m), 2.47 (2 H, m), 2.15 (2 H, m), 1.92 (1 H, t , J = 10.5 Hz), 1.80-1.57 (3 H, m), 1.50, 1.43 (9 H, two singlets), 1.30 (3 H, d, J = 6.9 Hz).

Stage E (3aS, 4S, 5R, 7aSV5- { (1S) -1-r3,5-bis (trifluoromethylphenylethyloxy) -4- (4-fluoro-phenyl) octahydro-1 / - / - isoindol The title compound is prepared from (3aS, 4S, 5R7aS) -5-. {(1 S) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-2 t'-isoindol-2-carboxylic acid-butyl ester (step D) according to the procedure of example 2, stage F. The more polar isomer, 1 H-NMR (CDCl 3): d: 7.68 (1 H, s), 7.20 (2 H, s), 7.05 (2 H, m), 6.87 (2 H, t, J = 8.2 Hz), 4.27 (1 H, m), 3.28 (1 H, m), 3. 20-3.05 (2 H, m), 2.88 (1 H, m), 2.72 (1 H, d, J = 11.7 Hz), 2.58 (1 H, t, J = 11. 9 Hz), 2.40 (1 H, m), 2.20 (1 H, m), 2.10 (1 H, m), 1.92 (1 H, m), 1.83 (1 H, m), 1.60 (1 H, m ), 1.30 (3 H, d, J = 6.0 Hz). MS: (MH) + 475.9.

EXAMPLE 5 3-r (3a 4 5S.7a?) - 5 - ((1R) -1-r3,5-bis (trifluoromethyl) phenynetoxy -4- (4-fluorophenyl) -octahydro-2H-isoindol-2-ill-cyclopentyl -2-in-1-one To a solution of 12.3 mg (0.26 mmol) of (3aR, 4R, 5S, 7aR) -5-. { (1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} 4- (4-fluorophenyl) octahydro-1 -isoindole (Example 2) in -2 ml of pure toluene was added 2.7 mg (0.028 mmol) of cyclopentane-1,3-dione and a catalytic amount (-0.5 mg) of PTSA. The resulting mixture was heated to reflux for 16 hours. The solvent was removed in vacuo and the residue was purified by preparative TLC eluting with EtOAc / MeOH (95/5) to give the title compound. 1 H NMR (CDCl 3): d: 7.73 (1 H, s), 7.20 (2 H, s), 7.03-6.90 (2 H, m), 4.98, 4.80 (1 H, s), 4.50 (1 H, m ), 3.62-3.18 (2 H, m), 3.30-3.18 (3 H, m), 3.15, 2.97 (1 H, d, J = 11.2 Hz), 2.68 (2 H, m), 2.55-2.40 (4 H, m), 2.17 (1 H, m), 2.20 (1 H, m), 2.00 (1 H, m), 1.85 (1 H, m), 1.62 (1 H, m), 1.33 (3 H, d, J = 6.2 Hz). MS: (MH) + 556.0.

EXAMPLE 6 fluorophenyl) -octahydro-1A -isoindole Stage A 4-. { | "fer-butyl (dimethyl) silyloxy] .3- (4-fluorophenyl) cyclohex-4-en-1,2-dicarboxylate diethyl A solution of 37 g (-80% pure, 133.1 mmol, 1 equiv.) of £ 1 and 1Z-ferc-butyl. { [1- (4-fluorobenzylidene) prop-2-en-1-yl] oxy} dimethylosilane (Example 1, step C) and 17 ml (18 g, 104.6 mmol) of diethyl (2E) -but-2-enedioate in 200 ml of xylenes under nitrogen atmosphere was heated at 160 ° C for 5 hours then cooled to RT. The solvent was evaporated in vacuo to give an oil which was used without further purification.

Stage B (1 S, 2S, 3R) -3- (4-fluorophenyl) -4-oxocyclohexane-1-racemic diethyl 1,2-dicarboxylate and (1 R, 2R, 3S) -3- (4-fluorophenyl) -4 diethyl-1-cyclohexane-1,2-dicarboxylate To a solution of the above intermediate in 30 ml of acetonitrile under nitrogen atmosphere at RT in a plastic reaction flask was added 200 ml (500 mmol) of a 2.5 M solution of HF in acetonitrile. The resulting mixture was stirred at RT for 24 hr. The reaction mixture was added to a mixture of 125 ml of 5.0 N aqueous NaOH and 100 g of ice, then it was stirred at RT for 5 minutes. The resulting mixture was diluted with 300 ml of ether. The resulting mixture was transferred to a separatory funnel and the organic phase was separated. The aqueous phase was saturated with NaCl when extracted with an additional portion of ether. The combined organic layer was washed with brine, dried over another drying agent, filtered and the solvent was evaporated in vacuo to give 40.8 g of the title compound. 1 H NMR (CDCl 3): d: 7.10 (2 H, m), 7.05 (2 H, m), 4.23-4.15 (2 H, m), 3.90-3.80 (3 H, m), 3.32 (1 H, td , J-, = 13.0 Hz, J2 = 4.0 Hz), 3.21 (1 H, t, J = 12.9 Hz), 2.68 (2 H, m), 2.55 (1 H, m), 2.07 (1 H, m) , 1.30 (3 H, t, J = 7.2 Hz), 0.85 (3 H, t, J = 7.2 Hz).

Stage C (1S, 2S, 3R4S) -3- (4-fluorophenyl) -4-hydroxycyclohexane-1, 2-dicarboxylic racemate of diethyl and (1 R, 2R, 3S, 4R) -3- (4-fluorophenyl) -4 diethyl 1-hydroxycyclohexane-1,2-dicarboxylate To a solution 40.2 g (119.3 mmol) of the intermediate from step B in 150 ml of ethanol under a nitrogen atmosphere at -78 ° C was added 4.1 g (108.5 mmol) of powder NaBH4. The resulting mixture was stirred at -78 ° C for 0.5 hours, then at RT for 2 hours. The reaction mixture was carefully quenched by the addition of 30 ml of water and carefully acidified with 2N aqueous HCl., then the solvent was evaporated in vacuo. The residue was dissolved in ether, transferred to a separatory funnel, washed with saturated aqueous NaHCO3 and brine, dried over a drying agent, filtered and the solvent evaporated in vacuo to give crude title compounds which will be purified in the next stage. 1 H-NMR (CDCl 3): d: 7.25 (2 H, m), 7.05 (2 H, t, J = 8.2 Hz), 4.20- 4.05 (2 H, m), 3.85-3.72 (3 H, m), 2.85 (2 H, m), 2.70 (1 H, t, J = 7.8 Hz), 2.25 (2 H, m), 1.70 (1 H, m), 1.60 (1 H, m), 1.25 (3 H, t , J = 7.2 Hz), 0.85 (3 H, t, J = 7.2 Hz).

Stage D (1S, 2S.3R, 4S) -3- (4-fluorophenylV4-hydroxycyclohexane-1,2-diethyl dicarboxylate Starting with 21 g of the racemic mixture of (1S, 2S, 3R, 4S) -3- (4- fluorophenyl) -4-hydroxycyclohexane-1,2-dicarboxylate diethyl ester and (1R, 2R, 3S, 4R) -3- (4-fluorophenyl) -4-hydroxycyclohexane-1,2-dicarboxylate diethyl ester (step C) is separated by chiral preparative HPLC using CHIRACEL AD column eluting with heptanes / i-PrOH (9/1) to provide 9.09 g of the desired isomer eluting first (1S, 2S, 3R, 4S) -3- (4-fluorophenyl) 4-hydroxycyclohexane-1,2-dicarboxylate diethyl ester.

Stage E (I SVI-rS.d-bisftrifluoromethylphenylethyl ^^^ - trichloroethanimidoate A solution of 25.82 g (100 mmol) of (1 S) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol in 200 ml of pure diethyl ether under a nitrogen atmosphere, it was cooled in a water / ice bath 3 ml of pure DBU (20 mmol, 0.2 equiv) were added to the reaction flask, then the mixture was stirred at 0 ° C for 10 minutes. drop 15 ml (150 mmol, 1.5 equiv.) of trichloroacetonitrile for 15 min.The reaction was stirred at 0 ° C for 2 hours, during which time it became bright yellow.The volatiles were removed under vacuum using a cold bath (<35 ° C) to give a mobile pale brown liquid which was purified by column chromatography on silica gel (7.62 cm X 25.4 cm pad) in two batches eluting with hexanes / EtOAc (9/1) after with hexanes / EtOAc (4/1) The fractions produced were combined and the solvent was removed in vacuo to give 37.5 g of the title compound in the form of a pale yellow oil. 1 H NMR (CDCl 3): d: 1.74 (3 H, d, J = 6.5 Hz), 6.07 (1 H, q, J = 6.5 Hz), 7.82 (1 H, s), 7.86 (2 H, s), 8.40 (1 H, br. S) ppm.

Stage F (1S, 2S.3R4S) -4 - ((1R) -1-r3.5-bis (trifluoromethyl) pheninetoxy.] -3- (4-fluorophen-1-cyclohexane-1,2-dicarboxylate diethyl) solution of 9.09 g (26.9 mmol) of the first isomer eluting (1S, 2S, 3R, 4S) -3- (4-fluorophenyl) -4-hydroxycyclohexane-1,2-dicarboxylate diethyl ester (step D) and 21.5 g (53.5 mmol) of (1 S) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl-2,2,2-trichloroethanimidoate (step E) in 250 ml of cyclohexane / 1,2-chloroethane (3 / 1) under nitrogen atmosphere at -5 ° C 0.51 ml (3.58 mmol) of 54% HBF 4 in ether was added.The reaction mixture was stirred at -5 ° C-0 ° C for 2 hours, then diluted with ether The mixture was washed with saturated aqueous NaHCO3 The organic phase was dried over a drying agent, filtered and the solvent was evaporated in vacuo The residue was purified by flash column chromatography on silica gel eluting with EtOAc / hexanes (1H NMR (CDCl3)? / 4) to give 9.2 g of the title compound as an oil.1H-NMR (CDCl3): d: d: 7.70 (1 H, s), 7.20 (2 H, s), 7.00 (2 H, m), 6. 85 (2 H, t, J = 8.5 Hz), 4.43 (1 H, q, J = 6.0 Hz), 4.20-4.10 (2 H, m), 3.80-3.73 (2 H, m), 3.36 (1 H , m), 2.90-2.76 (2 H, m), 2.40 (1 H, m), 2.28 (1 H, m), 1.63-1.55 (2 H, m), 1.33 (3 H, d, J = 6.0 Hz), 1.25 (3 H, t, J = 7.2 Hz), 0.82 (3 H, t, J = 7.2 Hz). The unreacted starting alcohol could be recovered by purging the column with EtOAc and reusing it in the previous reaction.

Stage G r (1 S.2R3R4S) -4-. { (1 R) -1-r3,5-bis (trifluoromethyl) phenetoxyl-3- (4-fluorophenyl) cyclohexane-1,2-diyl-1-dimethanol To a solution of 9.2 g (15.9 mmol) of (1 S, 2S, 3R4S) -4-. { (1 R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -3- (4-fluorophenyl) cyclohexane-1,2-d-diethylcarboxylate (step F) in 100 mL THF under nitrogen atmosphere at RT was added 2 g (112.4 mmol, excess) of LiBH4 powder. The resulting mixture was heated at 68 ° C for 2 hours, then cooled to RT. The reaction mixture was carefully warmed by the addition of 30 ml of water, then extracted with EtOAc. The combined organic extracts were dried over drying agent, filtered and the solvent was evaporated in vacuo to give 7.5 g of the crude title compound as an oil which was used without further purification. 1 H NMR (CDCl 3): d: 7.70 (1 H, s), 7.20 (2 H, s), 7.00 (2 H, m), 6. 87 (2 H, t, J = 8.2 Hz), 4.20 (1 H, q, J = 6.0 Hz), 3.78 (1 H, m), 3.67 (1 H, m), 3.52 (1 H, m), 3.30-3.20 (2 H, m), 2.58 (1 H, t, J = 11.9 Hz), 2.32 (1 H, m), 1.87 (1 H, m), 1.65 (1 H, m), 1.58-1.35 (3 H, m), 1.30 (3 H, t, J = 6.0 Hz).

Stage H r (1S, 2R3R4S) -4 - ((1R) -1-f3,5-bis (trifluoromethyl) phentopexy) -3- (4-fluorophenyl) cyclohexane-1,2-diyldi (methylene) dimethanesulfonate To a solution of 1.82 g (3.7 mmol) [(1 S, 2R3R4S) -4-. { (1 R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -3- (4-fluorophenyl) cyclohexane-1,2-diyl] dimethanol (step G) in 50 ml of methylene chloride cooled to -5 ° C in an ice / salt bath was added 1.0 ml (3.5 equiv.) Of methanesulfonyl chloride; 2.1 ml (4 equiv.) Of TEA and 44 mg (0.1 equiv.) Of DMAP. The reaction mixture was stirred at -5 ° C for 30 minutes and then quenched at that temperature by the addition of 20 ml of saturated aqueous NaHCO3. The mixture was heated to RT. The organic phase was separated and the aqueous phase was extracted with an additional 50 ml of methylene chloride. The combined organic layer was washed with 20 ml of 2N aqueous HCl, 30 ml. of saturated aqueous NaHCO3, brine, dried over MgSO drying agent, filtered and the solvent was evaporated in vacuo to give the title compound as an oil which was used without further purification.

Stage (3aR, 4R, 5S, 7aS) -2-benzyl-5-. { (1 RV1-r3.5-bis (trifluoromethyl) phenylethoxy.} -4- (4-fluorophenyl) octahydro-1 - / - isoindol In a pressurized tube, a solution of [(1S, 2R3R, 4S) -4-. { (1 R) -1 - [3,5-bis (trifluoromethyl) phenyl] ethoxy} -3- (4-fluorophenyl) cyclohexane-1,2-diyl] di (methylene) dimethanesulfonate (step H) in -20 ml of ethanol and 1.2 ml (-3 equiv.) Of benzylamine. The pressurized tube was sealed and heated to 150 ° C in an oil bath for 3 hours. The tube was cooled to RT and opened. The resulting mixture was transferred to a round bottom flask and the solvent was removed in vacuo. The residue was diluted with 100 ml of EtOAc, washed with 20 ml of 5N aqueous NaOH, dried over MgSO drying agent, filtered and the solvent evaporated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with EtOAc to give 1.6 g of the title compound. 1 H-NMR (CDCl 3): d: 7.35-7.20 (5 H, m), 7.50 (2 H, s), 6.97 (2 H, m), 6.85 (2 H, t, J = 8.2 Hz), 4.42 (1 H, t, J = 6.0 Hz), 3.75 (2 H, d, J = 13.4 Hz), 3.50 (2 H, d, J = 13.4 Hz), 3.30 (1 H, m), 2.96 (1 H, m), 2.52 (3 H, m), 2. 19 (2 H, m), 1.98 (1 H, m), 1.97 (1 H, m), 1.86 (2 H, m), 1.57 (1 H, m), 1.33 (3 H, t, J = 6.0 Hz), 1.30 (1 H, m). MS: (MH) + 566.0.

Stage J (3aR, 4R5S, 7aS) -5 - ((1R) -1-r3,5-b1s (trifluoromethyl) feninetoxi> -4- (4-fluorophenyl) octahydro-1 / - / - isoindol To one solution of (3aR, 4R5S, 7aS) -2-benzyl-5- { (1) -1- [3,5-bis (trifluoromethyl) -phenyl] ethoxy} -4- (4-fluorophenyl) ) octahydro-1 - / - isoindol (step H) in -50 ml EtOH 0.2 g (20% by weight) of 10% Pd (OH) 2-C was added The reaction mixture was hydrogenated at 3.51535 kg / cm 2 (50 PSI) for 16 hours at RT The catalyst was filtered and the filtrate solvent was evaporated in vacuo to give the title compound.1H NMR (CDCl3): d: 7.70 (1 H, s), 7.20 (2 H, s), 6.95 (2 H, m), 6. 87 (2 H, t, J = 8.5 Hz), 4.42 (1 H, q, J = 6.5 Hz), 3.55 (1 H, m), 3.30 (1 H, m), 3.10-2.95 (2 H, m ), 2.83 (1 H, m), 2.70 (1 H, m), 2.52 (1 H, m), 2.40 (1 H, m), 2.10 (1 H, m), 1.97 (2 H, m), 1.80 (1 H, m), 1.33 (3 H, d, J = 6.2 Hz). MS: (MH) + 476.1.

EXAMPLE 7 3-r (3aR4R5S aS) -5 - ((1) -1-f3,5-bis (trifluoromethyl) phenytoxy) -4- (4-fluorophenyl) -octahydro-2f -isoindole-2-incyclopentyl- 2-en-1-one To a solution of 0.73 g (1.5 mmol) of (3aR, 4R, 5S, 7aS) -5- { (1R) -1 - [3, 5-bis (tri-fluoromethyl) phenyl] ethoxy.} -4- (4-fluorophenyl) octahydro-1 / - / - isoindol (Example 6) in -25 ml of dry toluene was added 0.166 g (1.7 mmol) of cyclopentane-1,3-dione and 0.03 g (0.15 mmol) of PTSA The resulting mixture was refluxed for 2 hrs.The solvent was removed in vacuo and the residue was purified by preparative TLC eluting with CHCl3 / 2N NH3 in MeOH (9/1) to provide 0.49 g of the title compound The compound could be further purified by HLPC on CHIRACEL AD column eluting with hexanes / EtOH (9/1) The compound could be crystallized (mp = 216.5-217.5 ° C) from hexanes / EtOAc or hexanes / EtOH 1 H NMR CDCl 3: d: 7.71 (1 H, s), 7.23 (2 H, s), 7.00 (2 H, m), 6.93 (2 H, t, J = 8.2 Hz), 4.89, 4.48 (1 H, s), 4.47 (1 H, m) , 3.71, 3.48 (1 H, m), 3.35 (1 H, m), 3.28-3.17 (1 H, m), 2.95 (1 H, m), 2.95, 2.81 (1 H, m), 2.68 (2 H, m), 2.45 (2 H, m), 2.37 (2 H, m), 2.15 (1 H, m), 1.93 (2 H, m), 1.60 (1 H, m), 1.38 (1 H, m), 1.36 (3 H, t, J = 6.0 Hz).

MS: (MH) + 556.0. EXAMPLE 8 (3aR4R5S aS) -r) - (1R) -1-r3,5-bis (trifluoromethyl) phenyl-1-yl > -4- (4- fluorofenH) -A / -methyl-octohydro-2-t-tsoindol-2-carboxamide To a solution of -20 mg (0.042 mmol) of (3aR4R, 5S, 7aS) -5-. { (1 R) -1 - [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (4-fluorophenyl) octahydro-1 H-isoindole (Example 6) in 2 ml of pure methylene chloride at RT was added several drops of methylisocyanate. The resulting mixture was stirred at RT for 2 hours. Several drops of 2 N aqueous NaOH were added to the reaction mixture. The organic phase was separated, dried over the drying agent, filtered and the solvent removed in vacuo. The residue was purified by a TLC preparation that eluted with EtOAc and the highest band product was isolated. The residue was taken up in EtOAc and the solids filtered. The filtrate solvent was removed in vacuo to provide the title compound. 1 H NMR (CDCl 3): d: 7.71 (1 H, s), 7.23 (2 H, s), 6.98 (2 H, m), 6. 85 (2 H, m), 4.45 (1 H, m), 4.00 (1 H, m), 3.68 (1 H, m), 3.36 (1 H, m), 3.08 (1 H, m), 2.93 ( 1 H, m), 2.77 (3 H, s), 2.55 (1 H, m), 2.45 (1 H, m), 2.10 (1 H, d, J = 12.5 Hz), 2.00-1.70 (2 H, m), 1.70-1.50 (1 H, m), 1.30 (1 H, m), 1.30 (3 H, d, J = 6.0 Hz). MS: (MH) + 533.5.

EXAMPLE 9 3-r (3aR4R5S aS) -5 - ((1 /?) - 1-r3,5-bis (trifluoromethyl) phenytoxy) -4- (4-fluoropheniD-octahydro _ / tMsoindol-2-ip-5 -hydroxycyclopent-2-en-1-one To a solution of 20 mg (0.07 mmol) of 3 - [(3aR4R5S, 7aS) -5-. { (1 R) -1- [3,5-bis (trifluoromethyl) pheny] ethoxy} -4- (4-fluorophenyl) octahydro-2 - / - isoindol-2-yl] cyclopent-2-en-1-one (Example 7) and 170 mg (0.39 mmol) MoOPH in -2 ml of pure THF under a nitrogen atmosphere at -78 ° C, 0.076 ml (0.15 mmol) of 2.0 M solution of KHMDS was added. The resulting mixture was stirred at -78 ° C for 2 hours; then warming by the addition of saturated aqueous NH 4 Cl. The mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over the drying agent and filtered. The residue was purified by a preparative TLC eluting with CHCl3 / 2N NH3 in MeOH (9/1) to give the title compound as a mixture of diastereomers. 1 H NMR (CDCl 3): d: 7.71 (1 H, s), 7.23 (2 H, s), 7.00 (2 H, m), 6. 93 (2 H, t, J = 8.2 Hz), 4.85, 4.71 (1 H, s), 4.47 (1 H, m), 4.20 (1 H, m), 3.80-3.65 (1 H, m), 3.37 (1 H, m), 3.25-3.08 (1 H, m), 3.10-2.80 (3 H, m), 2.58 (1 H, m), 2.50-2.30 (1 H, m), 2.15 (1 H, m), 1.95 (2 H, m), 1.35 (3 H, d, J = 6.0 Hz). MS: (MH) + 572.5. The diastereomers were separated by HPLC or CHIRACEL AS column eluting with hexanes / EtOH (85/15) to provide the individual diastereomers.

EXAMPLE 10 3-r (3aR4R5S aS) -5-f (1R) -1-r3,5-bis (trifluoromethyl) pheninetoxy) -4- (4-fluorophenyl) -octahydro-2r / -isoindole-2-in-4-hydroxycyclopent -2-in-1-one Stage A 4-f (3aR4R5S, 7aS) -5 - ((1R) -1-r3,5-bis- (trifluoromethyl) phenyl-1-ethoxy-4- (4-fluorophenyl) octahydro-2 / - / - isoindole 2-cyclopent-4-ene-1, 3-dione The title compound was prepared from (3aR, 4R, 5S, 7aS) -5- { (1) -1 - [3, 5-bis ( trifluoromethyl) phenyl] ethoxy.} -4- (4-fluorophenyl) octahydro-1 / - / - isoindol (Example 6) and cyclopentane-1, 2,4-trione according to the procedure of Example 7. MS: ( MH) + 570.0 Stage B 3-F (3aR4R5S.7aS) -5 - ((1 R) -1-f3,5-bis (trifluoromethyl) feninetox!) -4- (4-fluorophenyl) -octah-dr-2 / - / - soindol -2-il1-4-hydroxycyclopent-2-en-1-one The title compound is prepared as a mixture of diastereomers of the intermediate of step A according to the procedure of Example 6, step C (NaBH4 in methanol). 1 H NMR (CDCl 3): rotamers; d: 7.71 (1 H, s), 7.23 (2 H, s), 7.00 (2 H, m), 6.93 (2 H, t, J = 8.2 Hz), 4.88-4.65 (2 H, m), 4.46 (1 H, m), 4.07 (0.5 H, m), 3.83 (0.5 H , m), 3.55 (1 H, m), 3.35 (1 H, m), 3.28 (1 H, m), 2.97 (2 H, m), 2.92 (1 H, m), 2.58 (1 H, m ), 2.43 (1 H, m), 2.25 (1 H, m), 2.13 (1 H, m), 2.05 - 1.85 (2 H, m), 1.70 - 1.55 (2 H, m), 1.30 (3 H , 2d, J = 6.0 Hz). MS: (MH) + 572.5 The diastereomers were separated by HPLC on CHIRACEL OD column eluting with hexanes / EtOH (85/15) to provide the individual diastereomers.

EXAMPLE 11 3-r (3aR4R5S aS) -5-f (1R) -1-r3,5-bis (trifluoromethyl) phenylethoxy > -4- (2- methylphenyl) -octahydro-2W-isoindol-2-cyclopent-2-en-1-one Stage A 2- (2-methylphenyl) -? / - methoxy- / V-methylacetamide The title compound was prepared from 2- (methylphenyl) acetic acid according to the procedure for Example 1, Step A. 1H NMR (CDCl 3): d: 7.23 (4 H, m), 3.83 (2 H, s), 3.65 (3 H, s), 3.28 (3 H, s), 2.36 (3 H, s).

Stage B 1 - . 1- (2-methylphenyl) but-3-en-2-one The title compound was prepared from the intermediate of the stage A according to the procedure of Example 1, step B. 1 H NMR (CDCl 3): d: 7.24 - 7.11 (4 H, m), 6.42 (1 H, dd, = = 14.2 Hz, J2 = 11 Hz). 6.34 (1 H, d, J = 14.2 Hz), 5.81 (1 H, d, J = 11 Hz), 3.90 (2 H, s) 2.26 (3 H, s).

Stage C 1 _ and 1Z ferc-butyl. { [1- (2-methylbenzylidene) prop-2-en-1-yl-1oxi} dimethylsilane The title compound was prepared from the intermediate of step B according to the procedure of Example 1, step C. 1 H-NMR (CDCl 3): d: 7.22-7.07 (4 H, m), 6.40 (1 H, dd , ^ = 13.2 Hz, J2 = 8.5 Hz), 5.85 (1 H, s), 5.54 (1 H, d, J = 13.2 Hz), 5.19 (1 H, d, J = 8.5 Hz) 2.28 (3 H, s).

Stage D 4-. { Diethyl rferc-butyl (dimethyl) silyl-oxoyl-3- (2-methylphenyl) cyclohex-4-en-1,2-dicarboxylate The title compound was prepared from the intermediate of step C according to the procedure of Example 6, Stage A and was used without further purification.

Stage E (1S, 2S, 3R) -3- (2-methylphenyl) -4-oxocyclohexane-1,2-diethyl carboxylate and (1R, 2R, 3S) -3- (2-methylphenyl) -4-oxocyclohexan-1 , Racemic diethyl 2-dicarboxylate The title compounds were prepared from the intermediate of step D according to the procedure of Example 6, step B. 1 H-NMR (CDCl 3): d: 7.26-7.90 (4 H, m), 4.23-4.12 (2 H, m), 3. 90-3.80 (3 H, m), 3.32 (1 H, td, J-, = 13.0 Hz, J2 = 4.0 Hz), 3.28 (1 H, t, J = 13 Hz), 2.67 (2 H, m) , 2.50 (1 H, m), 2.24 (3 H, s), 2.09 (1 H, m), 1.25 (3 H, t, J = 7.2 Hz), 0.83 (3 H, t, J = 7.2 Hz) .

Stage F (1S, 2S, 3R4S) -3- (2-methylphenin-4-hydroxycyclohexan-1,2-diethyl carboxylate and pR2R3S, 4R) -3- (2-methylphenyl) -4-hydroxycyclohexan Racemic diethyl-1, 2-dicarboxylate The title compounds were prepared from the intermediate of step E according to the procedure of Example 6, step C. 1 H-NMR (CDCl 3): d: 7.20-7.10 (4 H, m) , 4.15-4.07 (2 H, m), 3. 88-3.66 (3 H, m), 3.09 (1 H, t), 2.83 (2 H, m), 2.30 (3 H, s), 2.24 - 2.15 (2 H, m), 1.68 (1 H, m ), 1.57 (1 H, m), 1.25 (3 H, t, J = 7.2 Hz), 0.83 (3 H, t, J = 7.2 Hz), Stage G (1 S.2S, 3R4S) -3- (2-methylphenyl) -4-hydroxycyclohexan-1,2-diethyl dicarboxylate The racemic mixture of (1 S, 2S, 3R4S) -3- (2-methylphenyl) -4-hydroxycyclohexan -1, 2-diethyl dicarboxylate and (1, 2R, 3S, 4R) -3- (2-methylphenyl) -4-hydroxycyclohexan-1,2-d-diethylcarboxylate (step F) was separated by HPLC chiral preparative using CHIRACEL AD column eluting with heptanes / i-PrOH (9/1) to provide the desired first isomer eluting (1 S, 2S, 3R, 4S) -3- (2-methyl-phenyl) -4- diethyl hydroxycyclohexane-1,2-dicarboxylate according to the procedure of Example 6, Step D.

Stage H (1S, 2S, 3R4S) -4 - ((1R) -1 -r3,5-bis (trifluoromethyl) phenylmethoxy) -3- (2-methylphenyl) cyclohexane-1,2-dicarboxylate diethyl compound The title was prepared from the first isomer eluting (1S, 2S, 3R, 4S) -3- (2-methylphenyl) -4-hydroxycyclohexan-1,2-dicarboxylate diethyl ester (step G) and (1S) - 1- [3,5-bis (trifluoromethyl] -phenyl] ethyl-2,2,2-trichloroethanimidoate (Example 6, step E) according to the process of Example 6, step F. 1 H NMR (CDCl 3): d: 7.65 (1 H, s), 7.15 (2 H, s), 7.08 - 6.92 (4 H, m), 4.25 (1 H, q, J = 6.0 Hz), 4.20-4.10 (2 H, m), 3.85-3.66 (2 H, m), 3.42 (1 H, m), 3.21 (1 H, t), 2.90-2.79 (2 H, m), 2.35 (1 H, m), 2.25 (1 H, m), 2.22 (3 H, s), 1.69-1.56 (2 H, m), 1.30 (3 H, d, J = 6.0 Hz), 1.23 (3 H , t, J = 7.2 Hz), 0.77 (3 H, t, J = 7.2 Hz). The unreacted starting alcohol can be recovered by purging the column with a flow of EtOH and reusing it in the previous reaction.

Stage f (1 S, 2R3R4S) -4 - ((: R) -1-r3,5-bis (trifluoromethyl) phenylethoxy.) -3- (2-methylphenyl) cyclohexane-1,2-diyl-1-dimethanol The title compound is prepared from the intermediate of step H according to the procedure of Example 6, step G. 1 H NMR (CDCl 3): d: 7.64 (1 H, s), 7.16 (2 H, s), 7.04 - 6.91 (4 H , m), 4.24 (1 H, q, J = 6.0 Hz), 3.74 (1 H, m), 3.60 (1 H, m), 3.48 (1 H, m), 3.35-3.20 (2 H, m) , 2.90 - 2.70 (2 H, m), 2.26 (1 H, m), 2.21 (3 H, s), 1.85 (1 H, m), 1.62 (1 H, m), 1.56-1.42 (3 H, m), 1.28 (3 H, t, J = 6.0 Hz). 7 Stage J [(1S, 2R3R4S) -4-. { (1 R) -1-r3,5-bis-1,3-fluoromethyl) -phenylHytoxy) -3- (2-methylphenyl) -cyclohexane-1,2-di-di (methylene) dimethanesulfonate The title compound was prepared from Intermediate of the Stage I according to the procedure of Example 6, step H and was used without further purification.

Stage K (3aR4R, 5S, 7aS) -2-Benzyl-5 - ((1R) -1-r3,5-bis (trifluoromethyl) phenyl] ethoxy) -4- (2-methylphenyl) octahydro-1H-isoindole The compound title was prepared from the intermediate of step J and benzylamine according to the procedure of Example 6, step I. 1 H NMR (CDCl 3): d: 7.64 (1 H, s), 7.32-7.25 (5 H, m) , 7.18 (2 H, s), 7.04 - 6.97 (4 H, m), 4.25 (1 H, q, J = 6.0 Hz), 3.75 (1 H, d, J = 13.4 Hz), 3.65 (1 H, d, J = 13.4 Hz), 3.40 (1 H, m), 2.90 (2 H, m), 2.54 - 2.30 (4 H, m), 2.22 (3 H, s), 2.02 - 1.85 (3 H, m ), 1.61 (1 H, m), 1.33 (3 H, t, J = 6.0 Hz), 1.30 (1 H, m).

Stage L (3aR4R, 5S, 7aS) -5 - ((1R) -1-r3,5-bis (trifluoromethyl) phenyl-1-yl) -4- (2-methylphenyl) octahydro-1/7-isoindole The title compound was prepared at from the intermediate stage K according to the procedure of Example 6, step J. 1 H NMR (CDCl 3): d: 7.64 (1 H, s), 7.18 (2 H, s), 7.04 - 6.97 (4 H, m), 4.25 (1 H, q, J = 6.5 Hz), 3.40 (1 H, m), 3.25 (1 H, m), 2.90-2.75 (2 H, m), 2.63 (1 H, t), 2.44 (1 H, t ), 2.35 (1 H, m), 2.22 (3 H, s), 2.05 (1 H, m), 1.86 -1.72 (2 H, m), 1.61 (1 H, m), 1.33 - 1.20 (5 H , m).

Stage M 3-r (3aR4R5S, 7aS) -5 - ((1R) -1-33,5-β '(trifluoromethyl) feninetox!) -4- (2-methylphenyl) -octahydro-2 / - / - isoindol-2 -p-cyclopent-2-en-1-one The title compound was prepared from (3aR, 4R, 5S, 7aS) -5-. { (1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy} -4- (2-methylphenyl) octahydro-1 - / - isoindol (step L) and cyclopentane-1,3-dione according to the procedure of Example 7. 1 H NMR (CDCl 3): rotamers d: 7.64 (1 H, s ), 7.18 (2 H, s), 7.04 -6.97 (4 H, m), 4.74, 4.53 (1 H, s), 4.42 (1 H, m), 3.68, 3.43 (1 H, m), 3.50 ( 1 H, m), 3.06 (1 H, m), 2.93 (2 H, m), 2.86, 2.76 (1 H, m), 2.57 (1 H, m), 2.40 (2 H, m), 2.28 ( 3 H, s), 2.20 (1 H, m), 2.17 (1 H, m), 2.10 - 1.94 (3 H, m), 1.58 (1 H, m), 1.40 (1 H, m), 1.28 ( 3 H, d, J = 6.0 Hz).

MS: (MH) + 552.43 Using procedures essentially comparable to those described above, the compounds of the following examples were prepared.

Using procedures essentially comparable to those described above, the compounds of the following examples were prepared.

Although the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols can be made without departing from the spirit and scope of the invention.

Claims

NOVELTY OF THE INVENTION
A compound of the formula I: wherein: R1 is selected from the group consisting of: (1) hydrogen, (2) Ci-6 alkyl, which is unsubstituted or substituted by halogen, hydroxyl or phenyl, (3) cyclopentenone, which is unsubstituted or substituted with hydroxyl, or methyl (4) - (CO) - C- | -6 alkyl, (5) - (CO) -NH2, (6) - (CO) -NHalkyl C? _6, and (7) - ( CO) -N (C- | 6 alkyl) (C- | 6 alkyl); X is independently selected from the group consisting of: (1) hydrogen, (2) fluorine, and (3) methyl; and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. 2. The compound according to claim 1 of the formula la:
Ja and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. 3. The compound according to claim 1 of formula Ib:
Jb and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. 4. The compound according to claim 1, further characterized in that R1 is selected from the group consisting of: (1) hydrogen, (2) methyl, (3) 2-phenylethyl, (4) 2-hydroxyethyl, (5) ) cyclopent-2-en-1-one, (6) 5-hydroxycyclopent-2-en-1-one, (7) 4-hydroxycyclopent-2-en-1-one, (8) 2-methylcyclopent-2 en-1-one, (9) acetyl, (10) acetamido, (11) methyl-acetamido, and (12) dimethyl-acetamido. 5. The compound according to claim 1, further characterized in that X is hydrogen.
6. The compound according to claim 1, further characterized in that X is fluorine.
7. A compound which is selected from the group consisting of: and pharmaceutically acceptable salts thereof.
8. - A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
9. A method for preparing a medicament for antagonizing the effect of substance P in its receptor site or for blocking neurokinin-1 receptors in a mammal comprising combining a compound of the present invention or a pharmaceutically salt acceptable with a pharmaceutical vehicle or diluent.
10. A method for the preparation of a medicament for the treatment of a physiological disorder associated with an excess of tachykinins in a mammal comprising combining a compound of the present invention or a pharmaceutically acceptable salt thereof with a carrier or diluent. pharmacist.