MX2008007199A - Glucocorticoid receptor modulators as antiinflammatory agents - Google Patents

Abstract

The present invention relates to compounds of formula (I) wherein A, X, R1, R2and R3are as defined herein and pharmaceutically acceptable salts thereof. The invention also relates to methods of using the compounds of formula I and pharmaceutical compositions comprising the compounds of formula I.

Description

GLUCOCORTICOID RECEPTOR MODULATORS AS ANTI-INFLAMMATORY AGENTS FIELD OF THE INVENTION This invention relates to oximine and propionamide compounds, and associated compositions and methods of use as therapeutic agents. BACKGROUND OF THE INVENTION Glucocorticoids are an effective treatment for inflammatory diseases such as asthma and rheumatoid arthritis. However, several systemic side effects limit the dose that can be delivered and its long-term usefulness. Side effects include suppression of the hypothalamic-pituitary-adrenal (HPA) axis, osteoporosis, reduced bone growth in young people, behavioral disturbances, and disorders in lipid and glucose metabolism. The glucocorticoid receptor (GR) is a member of a family of genes known as nuclear hormone receptors. After binding their cognate ligands, these receptors are activated and have the ability to regulate transcription both positively and negatively. The detailed mechanism of this regulation, although it is not completely understood, has become increasingly clear. Glucocorticoids can diffuse freely through plasma membranes No. Ref .: 193454 within the cell where they bind to the GR present within the cytoplasm. Once fidos, a conformational change in the receptor causes the release of several chaperone proteins allowing the GR / ligand complex to translocate to the nucleus, specifically dimerize and bind to palindromic DNA sequences in the promoters of regulated genes. The fixed hormone receptor then incorporates a group of proteins known as the coactivator complex. This complex is required to initiate transcription, and works by incorporating both the transcription machinery of the cell and histone acetyltransferases involved in opening the chromatin in the vicinity of the promoter. The transcription of a number of genes containing GRE (acronym in English for glucocorticoid response elements) in its promoters is activated by GR. These include genes involved in gluconeogenesis, intermediary metabolism and the response to stress. In addition to the transcriptional control exercised by GR in GRE, numerous genes, particularly those involved in the response to inflammation, must be controlled by means of alternative mechanisms, since GRE does not appear in the promoters of these genes. The promoters of numerous pro-inflammatory genes do not contain binding sites for the transcription factors NF-kB and AP-1. It has been shown that the GR / ligand complex represses the transcription of genes proinf lamatorios by interacting directly with NF-kB or AP-1 and prevent the increase of transcriptional regulation by transcription factors. In vitro work with GR mutants without the ability to fix DNA showed that GR-mediated transrepression could be genetically disassociated from transactivation. This detachment is further supported by a study in which transgenic mice with introduced gene (knock-in) were generated in which GR in the wild was substituted with a mutant of similar DNA binding domain. These mice did not have the ability to regulate GRE-dependent GR genes such as tyrosine amino transferase (TAT) or genes that are negatively regulated by interaction with a negative GRE, such as pro-opiomelanus-curtain (POMC). In contrast, these mice have the ability to transrepress genes activated by NF-kB or AP-1. Thus, the currently accepted model for a corticosteroid control of inflammation predicts that GR, NFkB and AP-1 interact in a complex regulatory network that leads to the repression of cytosine expression. In accordance with this model, a glucocorticoid modulator that would contain the transrepression activity and lose transactivation activity would have less of the side effects associated with adrenal suppression, behavior alterations, and gluconeogenesis. The anti-inflammatory affectations would be contained.

SUMMARY OF THE INVENTION The present invention relates to compounds of Formula I: wherein A is CH 2 or C = 0 R 1 is H or C 1 -C 6 alkyl; R1 and R3 are each independently H, CF3, N02 or a heteroaryl ring; or R2 and R3 together form a six-membered heterocyclyl ring substituted with 0-2 substituents selected from the group consisting of Ci-Ce alkyl and oxo, with the proviso that when R2 and R3 together form an oxazolinyl ring, A is CH2 X is O or N-OR 4 is H or C 1 -C 6 alkyl; and pharmaceutically acceptable salts thereof. Another aspect of the invention relates to a method for treating an inflammatory disease through the modulation of a glucocorticoid receptor comprising administering to a subject in need thereof a compound of the formula I as defined and pharmaceutically acceptable salts thereof. same. Another aspect of the invention is a composition Pharmaceutical comprising an effective amount of a compound of Formula I as defined above and pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable excipient. All publications cited in this description are incorporated here as a reference in their totalities. DETAILED DESCRIPTION OF THE INVENTION Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It should be noted that, as used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. "Alkyl" means the monovalent linear or branched saturated hydrocarbon portion, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. "Lower alkyl" refers to an alkyl group of one to six carbon atoms, in this case alkyl Ci-Ce. Examples of alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. "Aryl" means a portion of aromatic hydrocarbon monovalent cyclic consisting of an aromatic ring-mono, -bi or tricyclic. The aryl group may be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, optionally substituted phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylene diphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinil, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof. The terms "halo", "halogen" and "halide", which may be used interchangeably, refer to a fluoro, chloro, bromo or substituent iodine. "Haloalkyl" means alkyl according to what is defined herein in which one or more hydrogens have been replaced with the same or different halogen. Exemplary haloalkyls include -CH2C1, -CH2CF, -CH2CC13, perfluoroalkyl (e.g., -CF3), and the like. "Heteroaryl" means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the atoms of remaining ring are C, with the understanding that the coupling point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring can be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, thiazolyl, isothiazolyl., oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, optionally substituted acridinyl and the like, including partially hydrogenated derivatives thereof. "Heterocyclyl" 'means a monovalent saturated portion, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (selected from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are not limited to, piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pirrolidmilo, pirazolidmilo, imidazolinyl, ímidazolidmilo, piridmilo, piridazmilo, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morfolmilo, thiazolidinyl, isotiazolidmilo, qumuclidinilo, quinolinyl, isoquinolmilo, benzimidazolyl, thiadiazolylidinyl, benzotiazolidmilo, benzoazolilidmilo, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, tiamorfolmilo, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dihydroquinolinyl, dihydrisoquinolinyl, tetrahydroquinolinyl, optionally substituted tetrahydropsoquinolyl, and the like. "Optionally substituted", when used in association with "aplo", "phenyl", "heteroaryl", "cyclohexyl" or "heterocyclyl", means an aryl, phenyl, heteroaryl, cyclohexyl or heterocyclyl which is optionally independently substituted with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, oxo, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkyl-ammo, di-alkyla, haloalkyl, haloalkoxy, heteroalkyl, -COR (wherein R is hydrogen, alkyl, phenyl phenylalkyl), (CR 'R ") r -COOR (wherein n is an integer from 0 to 5, R' and R" are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or - (CR'R ") n-CONRaRb (wherein n is an integer from 0 to 5, R 'and R" are independently hydrogen or alkyl, and Ra and Rb are, independently of each other , hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl) "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes what is acceptable for use in veterinary as well as human pharmaceutical use. "Pharmaceutically acceptable salts" of a compound means salts which are pharmaceutically acceptable, as defined herein, and which possess the desired pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic acids such as hydrochloric acid, acid hydrobromic, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, bezenosulfonic acid, benzoic acid, camphor sulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucohethonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxy acid Ethanesulfon? co, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, acid tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; or salts formed when an acidic proton is present in the parent compound whether it is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinated with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, potassium carbonate and sodium hydroxide. Preferred pharmaceutically acceptable salts are the salts formed of acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, potassium, calcium, zinc, and magnesium. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein, of the same acid addition salt.

The term "modulated" means the ability of a molecule to alter the function of a target molecule by, for example, binding to, and stimulating the functional responses of the target molecule. "Modulator" means a molecule that interacts with, and modulates a target molecule. The interactions include, but are not limited to, agonists, antagonists, and the like, as defined herein. "Agonist" means a molecule that interacts with, and improves or increases the function of, a target molecule. As such, the agonists include partial agonists and total agonists. "Antagonist" means a molecule that directly or indirectly inhibits or represses the function of a target molecule. As such, they include partial antagonists and total antagonists. "Disease" and "Disease status" mean any disease, condition, symptom, disorder or indication. "Inflammatory disease" means disease states or indications that are accompanied by inflammatory, allergic, and / or proliferative processes and may include: (i) pulmonary diseases: chronic, obstructive pulmonary diseases of any origin, particularly bronchial asthma and chronic obstructive pulmonary disease (COPD), respiratory distress syndrome (ARDS, for its acronym in English); bronchiectasis, bronchitis of various origins; all forms of restrictive lung diseases, particularly allergic alveolitis; all forms of pulmonary edema, particularly toxic pulmonary edema; all forms of interstitial lung diseases of any origin, for example, radiation pneumonitis; and sarcoidosis and granulomatosis, particularly Boeck's disease. (ii) Rheumatic diseases or autoimmune diseases or joint diseases: all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, and polymyalgia rheumatica; reactive arthritis; rheumatic soft tissue diseases; soft tissue inflammatory diseases of other origins; arthritic symptoms in diseases of degenerative joints (osteoarthritis); traumatic arthritis; collagenosis of any origin, for example, systemic lupus eptematosus, scleroderma, polymyositis, dermatomyositis, Sjogren's syndrome, Still's disease, and Felty's syndrome; (m) Allergic diseases: all forms of allergic reactions, for example, angioneurotic edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock (anaphylaxis), urticaria, angioneurotic edema, and contact dermatitis; (ív) Diseases of vasculitis: panarteritis nodosa, polyarteritis nodosa, temporal arteritis, granulomatosis of egner, giant cell arthritis, erythema nodosum; (v) dermatological diseases: atopic dermatitis, particularly in children; psoriasis; pitiriasis rubra pilaris; erimatoses diseases activated by several harmful agents, for example, radiation, chemicals, parasites, etc .; dermatosis bullosa; diseases of the lichenoid complex; itching (for example, of allergic origin); seborrheic dermatitis, rosacea, pemfigus vulgaris; erythema exudative multiforme; Balamitis, vulvitis, hair loss, as occurs in alopecia areata; and cutaneous T cell lymphomas; (vi) kidney diseases: nephrotic syndrome; and all types of nephritis, for example, glomerulonephritis; (vn) Liver diseases: disintegration of acute liver cells; acute hepatitis of various origins, eg, viral, toxic, drug-induced; and chronically aggressive and / or chronically intermittent hepatitis; (vm) Gastrointestinal diseases: inflammatory bowel diseases, eg, regional enteritis (Crohn's disease), ulcerative colitis; gastritis; Peptic esophagitis (reflux esophagitis); and gastrointestinal enteritis of other origins; for example, non-tropical sprue; (ix) Proctological diseases: anal eczema; fissures hemorrhoids; and idiopathic proctitis; (x) Eye disease: allergic keratitis, uveitis, or iritis; conjunctivitis; blepharitis; optic nerve neuritis; choroiditis; and sympathetic ophthalmia; (xi) Diseases of the ear, nose, and throat area (ENT): allergic rhinitis or hay fever; external otitis; for example, caused by eczema, contact infection, etc .; and otitis media; (xn) Neurological diseases: cerebral edema, particularly tumor related to cerebral edema; multiple sclerosis; acute encephalomyelitis; meningitis; acute spinal cord injury; stroke; and various forms of seizures, for example, spasms with rocking; (xm) Blood diseases: acquired hemolytic anemia, and idiopathic thrombocytopenia; (xiv) Tumor diseases: acute lymphatic leukemia; lymphogranulomatosis, hnfosarcoma; extensive metastasis, particularly in mammary, bronchial, and prostatic carcinoma; (xv) Endocrine diseases: endocrine ophthalmopathy; endocrine orbitopathy; thyrotoxic crisis; DeQuervam thyroiditis, - Hashimoto's thyroiditis; Morbos disease Basedow; granulomatous thyroiditis; lymphomatous struma; and Graves' disease; (xvi) organ and tissue transplants and graft-versus-patient diseases; (xvn) Severe shock states, for example, septic shock, anaphylactic shock, and systemic inflammatory response syndrome (SIRS); (xvm) Substitution therapy in: congenital primary adrenal insufficiency, for example, genitosuprarrenal syndrome; acquired primary adrenal insufficiency, eg, Addison's disease, autoimmune adrenalitis, subsequent infection, tumors, metastasis, etc .; secondary congenital adrenal insufficiency, for example, congenital hypopituitarism; and acquired secondary adrenal insufficiency, for example, subsequent infection, tumors, metastases, etc .; (xix) Pain of inflammatory origin, for example, lumbago; and (xx) several other disease states or conditions including type I diabetes (insulin-dependent diabetes), osteoarthritis, Guillain-Barre syndrome, restenosis followed by percutaneous transluminal coronary angioplasty, Alzheimer's disease, acute and chronic pain, atherosclerosis , reperfusion injury, bone resorption diseases, congestive heart failure, myocardial infarction, thermal wound, injuries secondary to trauma of multiple organs, acute purulent meningitis, necrotizing enterocolitis and syndromes associated with hemodialysis, leukapheresis, and granulocyte transfusion "Subject" means mammals or non-mammals. Mammals means any member of the mammalian class including, but not limited to, humans; non-human primates such as chimpanzees and other species of apes and monkeys; farm animals such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and similar. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject" does not denote a particular age or sex. "Treating" or "treating" a disease state includes: (i) preventing the disease state, in this case causing the clinical symptoms of the disease state that do not develop in a subject that may be exposed to or be predisposed to state of illness, but who has not yet experienced or shown symptoms of the disease state. (i) inhibit the disease state, in this case, stop the development of the disease state or its clinical symptoms, or (ni) alleviate the disease state, in this case, cause a temporary or permanent regression of the disease state or your clinical symptoms The terms "treat", "contact" and "react" when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the product indicated and / or the desired. It should be appreciated that the reaction which produces the indicated and / or the desired product may not necessarily result directly from the combination of two reactants which were initially added, in this case, there could be one or more intermediates which are produced in the mixture that in the end leads to the formation of the indicated product and / or the desired one. In one embodiment the present invention provides a compound of formula I and pharmaceutically acceptable salts thereof wherein A is CH2. In another embodiment, the present invention provides a compound of formula I and pharmaceutically acceptable salts thereof wherein A is C = 0. In one embodiment the present invention provides a combination of formula I and pharmaceutically acceptable salts thereof wherein R 1 is H. In one embodiment, the present invention provides a compound of formula I and pharmaceutically acceptable salts thereof wherein R 2 is H and R3 is CF3, O2 or an optionally substituted five-membered heteroaryl ring. In another embodiment, the present invention provides a compound of formula I and pharmaceutically acceptable salts thereof wherein R2 is H and R3 is an optionally substituted five-membered heteroaryl ring. In yet another embodiment the present invention provides a compound of the formula I and pharmaceutically acceptable salts thereof wherein R2 is H and R3 is an optionally substituted five-membered heteroaryl ring that is in the para position.

In one embodiment the present invention provides a compound of formula I and pharmaceutically acceptable salts thereof wherein R 2 and R 3 together form a six-membered heterocyclyl ring substituted with 2 substituents selected from the group consisting of Ci-Cß alkyl and oxo, with the proviso that when R2 and R3 together form an oxazolinyl ring, A is CH2. In one embodiment the present invention provides a compound of formula I and pharmaceutically acceptable salts thereof wherein X is 0 or N-OR 4, wherein R 4 is H or C 1 -C 6 alkyl. The compounds of Formula (I) wherein A is CH can be prepared by the method set forth in Reaction Scheme I. Reaction Scheme I [I I X-.N0n The intermediate, 1-bromo-3 - [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propan-2-one, of the Formula (II) can be prepared using the starting materials, l-bromo-2- trifluoromethyl-benzene and l-cyclobutylidene-propan-2-one. The reaction of the intermediate compound of the formula (II) with the substituted phenylamines of the formula (III) in a solution of di-iso-propyl ethylamine and dimethylformamide results in the 2-oxo-propylamine compounds of the formula (I). Further reaction with hydroxylamine (with or are alkyl substituents) results in the oxime compounds of the propanone of Formula (I). The reaction scheme 2 establishes the approach that is used to obtain the compounds of the Formula (I) wherein A is C = 0 as defined above. Reaction Scheme 2 2-trif luoromethyl-phenyl acetonitrile was mixed with 1, 2-dibr omopropane to produce the cyclobutanecarbonyl compound, which was then reacted with diisobutyliumium hydride in toluene resulting in the cyclobutanecarbaldehyde intermediate of Formula (IV). This intermediate was then mixed with ethyl ester of diethoxyphosphine-1-ethoxy-acetic acid, followed by two hydrolysis steps to produce 2-oxo-3- [l-2 (trifluoromethyl-phenyl) -cyclobutyl- propionic of the Formula (V). Finally the reaction with the phenylamines of the Formula (III) in the presence of thionyl chloride and dimethyl acetamide results in the propionamide compounds of the Formula (I). In general, the nomenclature used in this Application is based on AUTONOM ™ v.4.0, a computerized Beilstein Institute system for generating the IUPAC systematic nomenclature. The chemical structures shown here were prepared with the use of ISIS® version 2.2. Any open valence appearing on a carbon, oxygen or nitrogen atom in the structures in this description (other than a substitute radical) indicates the presence of a hydrogen. The present invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixtures of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and / or prophylactic ingredients. In general, the compounds of the present invention will be administered in a therapeutically effective amount by any of the modes of administration by agents that perform similar functions. Appropriate dose ranges are typically 1-500 mg daily, such as l-100 mg daily, or 1-130 mg daily, depending on numerous factors such as the severity of the disease to be treated, age and relative health of the patient. subject, the power of the compound used, the route and the form of administration, the indication to which the administration is directed, and the preferences and experience of the medical professional involved. A person skilled in the art of treating such diseases will have the ability, without undue experimentation and with the use of known dosage range methods and the description of this Application, to establish a therapeutically effective amount of the compounds of the present invention. for a certain disease. In general, the compounds of the present invention will be administered as pharmaceutical formulations including those suitable for oral (including buccal and sublingual), rectal, topical, pulmonary, vaginal, or parenteral administration (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) or in a form appropriate for administration by inhalation or insufflation. The preferred manner of administration is generally oral with the use of a convenient daily dosage regimen which can be adjusted in accordance with the degree of affliction. A compound or compounds of the present invention, together with one or more convenient adjuvants, carriers, or diluents may be placed in the form of pharmaceutical unit compositions and dosages. The pharmaceutical unit dosage unit compositions and forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any appropriate effective amount of the active ingredient in proportion to the daily range provided for. Being Employed. The pharmaceutical compositions can be employed as solids, such as filled tablets or capsules, semi-solids, powders, sustained-release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing approximately 1 mg of active ingredient or, more broadly, about 0.01 to about 100 mg, per tablet, are accordingly appropriate representative unit dosage forms. The compounds of the present invention can be formulated in a wide variety of oral administration dosage forms. The pharmaceutical dosage forms and forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. The pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, sachets, suppositories, and granules that can be dispersed. A solid carrier can be one or more substances which also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is generally a finely divided solid which is a mixture with the active component finely divided. In tablets, the active component is generally mixed with the carrier having the necessary binder capacity in appropriate proportions and compacted in the desired shape and size. The powders and tablets preferably contain from about 1% to about 70% of the active compound. The Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, a low melting wax, shortening cocoa, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier, to provide a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, envelopes and pills are included. Tablets, powders, capsules, pills, sachets, and pills can be solid in form for oral administration. Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted in a short time before being used for liquid form preparations. The emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding coloring, flavoring, stabilizing, and thickening agents.

Aqueous suspensions may be prepared by dispersing the active component finely divided in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other sufficiently well-known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. The compounds of the present invention can be formulated for parenteral administration (for example, by injection, for example rapid intravenous injection or continuous infusion) and can have a presentation in unit dose form in ampoules, prefilled syringes, small volume infusion or in multiple dose containers with added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example, solutions in aqueous polyethylene glycol. Examples of carriers, diluents, solvents, oily or non-aqueous vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as agents. of conservation, humidification, emulsion or suspension, stabilization and / or dispersion. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization of the solution for constitution before use with an appropriate vehicle, eg, sterile, pyrogen-free water. The compounds of the present invention can be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. The ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of appropriate thickeners and / or gelation. The lotions can be formulated with an aqueous or oily and will generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Appropriate formulations for topical administration in the mouth include lozenge lozenges which comprise active agents in a flavored base, usually sucrose and acacia or tragacanth; pills comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouth rinses comprising the active ingredient in an appropriate liquid carrier. The compounds of the present invention can be formulated for administration as suppositories. A Low melting point wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into molds of suitable dimension, allowed to cool, and solidified. The compounds of the present invention can be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or powders containing, in addition to the active ingredient, carriers as are known in the art to be appropriate. The compounds of the present invention can be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by convenient means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multiple dose form. In the latter case of a dropper or pipette, this can be obtained by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this can be obtained, for example, by means of a spray pump by dosing spray. The compounds of the present invention can be formulated by aerosol administration, particularly to the respiratory tract and including administration intranasal The compound will generally have a small particle size for example, of the order of five (5) microns or less. Such particle size can be obtained by means known in the art, for example by micronization. The active ingredient is supplied in a pressurized package with an appropriate propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other appropriate gases. The aerosol may also conveniently contain a surfactant such as lecithin. The dose of the drug can be controlled by a metering valve. Alternatively the active ingredients may be supplied in a form of a dry powder, for example, a powder mixture of the compound in an appropriate powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition can be presented in a unit dosage form for example, in capsules, or cartridges of for example, gelatin or paperboard and plastic wrap packaging from which the powder can be administered by means of an inhaler. When desired, the formulations can be prepared with enteric coatings adapted for a sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in subcutaneous drug delivery devices. These delivery systems are convenient when sustained release of the compound is necessary and when it is crucial for a patient in accordance with a treatment regimen. The compounds in transdermal delivery systems are often coupled to a solid support adherent to the skin. The compound of interest can also be combined with a penetration promoter, for example, Azone (1-dodecylazacycloheptane-2-one). Sustained-release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection. Subdermal implants encapsulate the compound in a soluble lipid membrane, for example, silicone rubber, or a biodegradable polymer, for example, polylactic acid. The pharmaceutical preparations preferably have unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form may be a capsule, tablet, sachet, or lozenges themselves, or it may be the appropriate number of any of these in packaged forms. Other acceptable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Representative pharmaceutical formulations containing a compound of the present invention are described in Examples 6-12. EXAMPLES The following preparations and examples are provided to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but simply that they are illustrative and representative of them. The following abbreviations can be used in the examples: EtOAc: ethyl acetate; THF: tetrahydrofuran; RT: room temperature. Example 1: 4-Methyl-6-. { 2-oxo-3 - [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propyl-amino} benzo [d] [1, 2] oxazine-1-one Precursors 1- (2-Trifluoromethyl-phenyl) -cyclobutyl] -propan-2 -one A solution of 2-trifluoromethyl-phenylmagnesium bromide was prepared under a nitrogen atmosphere. from magnesium (1.02 g, 43 mmol) and l-bromo-2- trifluoromethyl-benzene (10.31 g, 46 mmol) in THF and cooled to -5 ° C. Cuprous iodide (3.53 g, 18.5 mmol) was added and the resulting mixture was stirred at -5 ° C for 5 minutes, and then rapidly cooled to -70 ° C. l-Cyclobutylidene-propan-2-one (1.2 g, 11 mmol) was added dropwise added via syringe to the mixture, which was then stirred for 1 hour at -70 ° C and allowed to warm to RT . The reaction mixture was poured into a saturated aqueous ammonium chloride solution and the THF was evaporated in vacuo. The resulting residue was extracted with methylene chloride. The combined organic extracts were concentrated by evaporation in vacuo. The residue was purified by column chromatography on silica gel using a gradual increase in the concentration of the eluent (2% -10% ether-hexane) to yield 5.56 g of the product. XH-NMR (CDC13), 57.63 (dd, 1H), 7.45 (t, 1H), 7.28 (m, 2H), 3.05 (s, 2H) 2.52 (m, 4H), 2.08 (m, 1H), 1.8 ( m, 1H), 1.68 (s, 3H). 1-Bromo-3- [1- (2-trifluoromethyl-1-phenyl) -cyclobutyl] -propan-2 -one To an ice-cooled solution of l- [l- (2-trifluoromethyl-phenyl) -cyclobutyl] -propan- 2-one (2.56 g, 10 mmol) in MeOH (15 ml) was added Br? (0.5 ml, 10 mmol) slowly by means of a syringe. The reaction mixture was stirred for 15 minutes at 0 ° C, after 30 minutes at room temperature. H20 was added to the reaction mixture (15 ml) and the mixture was stirred for 15 minutes at room temperature. The reaction was monitored by TLC, and the TLC showed no starting material left 15 minutes after the addition of H20. The resulting solution was extracted twice with 25% n-hexane in EtOAc. The combined organic extracts were washed twice with a solution of Saturated aqueous NaHC03, dried over sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel with 2% ether-hexane to yield 1.97 g of the product. ^ - MR (CDCI3). d 7.67 (dd, lH), 7.46 (t, lH), 7.32 (t, lH), 7.22 (t, 1H), 3.32 (s, 2H), 3.27 (s, 2H), 2.55 (t, 4H), 2.12 (m, lH), 1.83 (m, 1H) 4-Methyl-6-. { 2-Oxo-3- [1- (2-trifluoromethyl-1-phenyl) -cyclobutyl] -propylamino} -benzo [d-1, 2] oxazine-1-one A solution of 0.35 g (1.04 mmol) of l-bromo-3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propan-2-one, 0.184 g (1.04 mmol) of 6-amino-4-methyl- benzo [d] [1,2] oxazine-1-one and 0.2 ml (1.1 mmol) of di-isopropyl ethylamine in 10 ml of DMF were heated at 80 ° C overnight. The reaction mixture was partitioned between EtOAc and H20. The organic layer was separated, washed twice with H20, dried and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel (10% and 20% EtOAc-hexane) to yield 26 mg of the product. XH-NR (CDC13), d 8.08 (d, lH), 7.67 (dd, lH), 7.38 (dd, 1H), 7.28 (d, 1H), 7.18 (d, lH), 6.71 (dd, 1H) , 6.33 (d, lH), 5.25 (t, 1H), 3.46 (b, 1H), 3.18 (s, 2H), 2.59 (m, 4H), 2.44 (s, 3H), 2.14 (m, 1H), 1.86 (m, 1H). MS (ei): M (+) + H = 431, M + -H = 429 Example 2: Oxime 1- (4-Methyl-l-oxo-lH-benzo [d] [1,2] oxazine-6-ylamino ) -3- [1- (2-trifluoro-methyl-phenyl) -cyclobutyl] -propan-2-one A solution of 29 mg of 4-methyl-6-. { 2-Oxo-3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propylamino} -benzo [d] [1,2] oxazine-1-one in EtOH (8 ml) was treated with 1 ml of 50% NH2OH solution "HCl in H20 and NaOAc (15 mg). The solution was heated under reflux for 2 hours and evaporated. The residue was purified by column chromatography on silica gel (10% -40% EtOAc-hexane) to yield 2 mg of product. Y-NMR (DMSO), d 7.85 (dd, lH), 7.6 (, 1H), 7.52 (d, 1H), 7.32 (tt, 1H), 7.23 (dd, 1H), 6.92 (dd, 2H), 3.69 * (d, 2H), 3. 42 * (d, 2H), 2.78 (s, 2H), 2.55 (m, 4H), 2.37 (s, 3H), 2.0 (m, 1H), 1.75 (m, lH). * two distinguishable maxima for different rotamers, in a 2: 1 ratio. MS (ei): M (+) + H = 446 Example 3: Oxime 1- (3-Oxazol-5-yl-phenylamino) -3- [1- (2-trifluoromethyl-phenyl) -cyclo-butyl] -propan -2 -one Precursors 4-Nitro-N- (3-oxazol-5-yl-phenyl) -benzenesulfonamide A solution of 3-oxazol-5-yl-phenylamine (0.5 g, 3.1 mmol) and 4-nitro-benzenesulfonyl chloride (0.91 g, 4.1 mmol) in pyridine (20 ml) was stirred over the weekend at room temperature. The residue was partitioned between EtOAc and H20. The organic layer was separated, washed twice with H20 and once with the saturated aqueous sodium chloride solution, dried and concentrated by evaporation. The residue was purified by column chromatography on silica gel (5% -15% EtOAc-hexane) to yield 0.63 g of product. XH-NMR (DMSO), d 8.47 (s, lH), 8.39 (d, 2H), 8.04 (d, 2H), 7.67 (s, 1H), 7.48 (m, 2H), 7.38 (t, 1H), 7.1 (d, 1H) MS (ei): M (+) + H = 346 1-Methanesulfonyl-4-nitro-benzene-1- (3-oxazol-5-yl-phenylamino) -3- [1- (2 -trifluoro-methyl-phenyl) -cyclobutyl] -propan-2-one A solution of 0.14 g (0.41 mmol) of 4-nitro-N- (3-oxazol-5-yl-phenyl) -benzenesulfon-amide in 2 ml of DMF under nitrogen was stirred with NaH (15 mg of 60% dispersion of oil, 0.39 mmol) at room temperature for 2 hours. 0.15 g (0.045 mmol) of l-bromo-3- [1- (2-trif luoromethyl-f-enyl) -cyclobutyl] -propan-2-one was added. The mixture was stirred at room temperature overnight. The reaction mixture was paroned between EtOAc and H20. The organic layer was separated, washed twice with H20, dried and concentrated by evaporation. The residue was purified by column chromatography on silica gel (5% -20% EtOAc-hexane) to yield 162 mg of the product as a white solid. XH-NMR (CDC13), d 8.25 (d, 2H), 7.93 (s, lH), 7.71 (d, 2H), 7. 59 (td, 1H), 7.53 (dd, 1H), 7.32 (m, 2H), 7.28 (d, 1H), 7.03 (m, 2H), 6.92 (d, 2H), 3.9 (b, 2H), 3.03 (s, 2H), 2.48 (t, 4H), 2.08 (m, 1H), 1.8 (m, 1H). MS (ei): M (+) + H = 600 1- (3-Oxazol-5-yl-phenylamino) -3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propan-2-one A mixture of 1-methanesulfonyl-4-nitro-benzene-1- (3-oxazol-5-yl-phenylamino) -3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propan-2-one (160 mg, 0.27 mmol), PhSH (0.082 mL, 0.8 mmol), K2C03 (149 mg, 1.08 mmol), MeCN (10 mL) and DMSO (0.25 mL) were heated at reflux for 30 minutes. The reaction mixture was paroned between EtOAc and H20. The organic layer was separated, washed twice with H20, dried and concentrated by evaporation. The residue was purified by column chromatography on silica gel (5% -15% EtOAc-hexane) to yield 43.7 mg of product.

^ -NMR (CDCI3), d 8.27 (d, lH), 7.66 (d, lH), 7.38 (d, 1H), 7.2 (m, 3H), 7.08 (td, 1H), 6.79 (t, 1H), 6.45 (m, 2H), 4.52 (t, 1H), 3.45 (b, 2H), 3.13 (s, 2H), 2.57 (m, 4H), 2.14 (m, 1H), 1.87 (m, 1H). MS (ei): M < +) + H = 415, M < + 1 -H = 413, Oxima 1- (3-Oxazol-5-yl-phenylamino) -3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propan-2 -one was obtained analogously to Example 1 from l- (3-oxazol-5-yl-phenylamino) -3- [1- (2-tri-fluoromethyl-phenyl) -cyclobutyl] -propan-2-one. XH-NMR (CDCl 3), d 7.88 (s, lH), 7.7 (t, lH), 7.05-7052 (m, 5H), 6.98 (m, 1H), 6.67 (m, lH), 6.35 (t, lH ), 3.46 (b, 2H), 2.86 (s, 2H), 2.57 (m, 4H), 2.28 (m, 1H), 2.08 (m, 1H). MS (ei): M (,) + H = 430 Example 4: Oxime 1- (4-Oxazol-5-yl-phenylamino) -3- [1- (2-trifluoromethyl-phenyl) -cyclo-butyl] -propan -2-one Precursors 4-Nitro-N- (4-oxazol-5-yl-phenyl) -benzenesulfonamide was obtained analogously to 4-nitro-N- (3-oxazol-5-yl-phenyl) -benzenesulfonamide with the use of 4-oxazol-5-yl-phenylamine chloride and 4-nitro-benzenesulfonyl.

MS (ei): M'Y 1 = 346 1-Methanesulfonyl-4-nor tro-benzene-1- (4-oxazol-5-yl-phenylamino) -3- [1- (2-trifluoro-methyl-1-phenyl) -cyclobutyl] -propan-2-one was obtained analogously to 1-methanesulfonyl-yl-4-nitro-benzene-1- (3-oxazol-5-yl-phenylamino) -3- [1- (2-trifluoromethyl-phenyl) ) -cyclo-butyl] -propan-2-one with the use of 4-nitro-N- (4-oxazol-5-yl-phenyl) -benzenesulfonamide and 1-bromo-3- [1- (2-trifluoromethyl- phenyl) -cyclobutyl] -propan-2 -one. ^ -NMR (CDC13). d 8.24 (d, 2H), 7.95 (s, lH), 7.69 (d, 2H), 7.27-7.58 (m, 4H), 6.93-7.18 (m, 5H), 3.90 (b, 2H), 3.04 (s) , 2H), 2.48 (m, 4H), 2.10 (m, 1H), 1.81 (m, 1H). MS (ei): M (+) + H = 600 1 - (4-Oxazol-5-yl-phenylamino) -3- [1- (2-trif luoromethyl-phenyl) -cyclobutyl] -propan-2-one was obtained analogously to l- (3-Oxazol-5-yl-phenylamino) -3- [1- (2-trif luoromethyl-phenyl) -cyclobutyl] -propan-2-one. XH-NMR (CDCl 3), d 7.81 (s, lH), 7.63 (t, lH), 7.5 (m, lH), 7.4 (d, 2H), 7.1-7.3 (m, 3H), 6.4 (d, 2H ), 4.53 (b, 1H), 3.42 (b, 2H), 3.12 (s, 2H), 2.57 (m, 4H), 2.13 (m, lH), 1.85 (m, lH). MS (ei): M (+) + H = 415 Oxima 1- (4-Oxazol-5-yl-phenylamino) -3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propan-2-one it was obtained analogously to Oxim 1- (3-Oxazol-5-yl-phenylamino) -3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propan-2-one. XH-NMR (CDC13), d 7.78 (s, lH), 7.68 (t, lH), 7.55 (m, lH), 7.45 (m, 1H), 7.38 (d, 2H), 7.32 (m, 1H), 7.18 (m, 1H), 6.37 (d, 2H), 3.42 (b, 1H), 3.15 * (s, 2H), 2.82 * (s, 2H), 2.52 (, 4H), 2. 22 (m, 1H), 2.05 (m, 1H), 1.81 (m, 2H) * mixture of syn and anti, the ratio is approximately 1: 1. MS (ei): M (+) + H = 430 Example 5: N- (4-Oxazol-5-yl-phenyl) -2-oxo-3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl ] -propionamide Precursors 1- (2-Trifluoromethyl-phenyl) -cyclobutanecarbonitrile A solution of 12.6 g of (2-trifluoromethyl-phenyl) -acetonitrile and 7.6 ml of 1,2-dibromo-propane in 36 ml of ether were slowly added to through a dropping funnel to a suspension of 3.62 g of sodium hydride in 85 ml of DMSO at 0 ° C. After the addition, the ice water bath was allowed to warm to room temperature slowly and the reaction mixture was stirred at room temperature overnight. The reaction was carefully quenched with isopropyl and H20. The suspension became clear. The organic layer was separated, the aqueous layer was extracted twice with ether. The combined organic extracts were combined, dried and concentrated by evaporation in vacuo. The residue was purified by gel column chromatography of silica (EtOAc-hexane 2% -4%) to yield 8.5 g of product as a white solid. XH-NMR (CDCl 3), d 7.72 (dd, lH), 7.58 (t, lH), 7.45 (, lH), 7.33 (d, 1H) 2.92 (m, 2H), 2.71 (m, 2H), 2.54 ( m, lH), 1.96 (m, 1H). 1- (2-trifluoromethyl-phenyl) -cyclobutanecarbaldehyde 50.7 ml of diisobutylaluminium hydride was added dropwise over 2 hours to a solution of 8.5 g of l- (2-trifluoromethyl-phenyl) -cyclobutanecarbonitrile in 85 ml of toluene at 0 ° C. After the addition, the ice water bath was allowed to warm to room temperature slowly and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 200 ml of 5% sulfuric acid in ice water, and stirred for 10 minutes. The mixture was extracted four times with ether. The combined ether extracts were dried and concentrated by evaporation in vacuo. The residue was purified by column chromatography on silica gel (5% EtOAc-hexane) to yield 6.2 g of product. XH-NMR (CDCl 3), d 9.7 (s, lH), 7.68 (d, lH), 7.57 (t, lH), 7.4 (t, 1H), 7.27 (d, 1H), 2.77 (m, 2H), 2.62 (m, 2H), 2.12 (m, IH), 1.87 (m, 1H) 2-Ethoxy-3 - [1 - (2-tri-fluoromethyl-phenyl) -cyclobutyl] -acrylic acid ethyl ester 4.4 ml (11 mmol) of n-butyllithium was added dropwise to a solution of 1.28 ml (9.2 mmol) of diisopropylamine in 25 ml of tetrahydrofuran at 0 ° C and stirred for a further 30 minutes at 0 ° C. Then 1.97 g (7.4 mmol) of phosphonate-ethyl ester (diethoxy-phosphoryl) -ethoxy-acetic acid was added dropwise and stirred for a further 20 minutes at 0 ° C. 1.4 g (6.1 mmol) of 1- (2-trifluoromethyl-phenyl) -cyclobutanecarbaldehyde in 5 ml of tetrahydrofuran was added dropwise at 0 ° C. The ice water bath was allowed to warm to room temperature slowly and the reaction mixture was stirred at room temperature over the course of the weekend. The reaction was quenched with saturated aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate. The ethyl acetate solution was rinsed with saturated aqueous sodium chloride solution, dried and concentrated by evaporation in vacuo. The residue was purified by column chromatography on silica gel (3% EtOAc-hexane) to yield 0.61 g of product. XH-NMR (CDC13), d 6.93-7.61 (m, 3H), 7.27 (q, lH), 6.75 * (d, 1H), 5.77 * (d, 1H), 3.92 (q, 2H), 3.79 (q , 2H), 2.42-2.73 (m, 4H), 2.07 (m, lH), 1.78 (m, 1H), 1.32 (t, 3H), l.ll (t, 3H). * Mix of sin and anti, the ratio is approximately 2: 1. 2-Ethoxy-3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -acrylic acid 4. 6 g of 2-Ethoxy-3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -acrylic acid ethyl ester, 4.3 g of sodium hydroxide, 100 ml of ethanol and 50 ml of water (ethanol-water 2: 1) were mixed and stirred for 2 hours at room temperature. The solvent was evaporated in vacuo, the residue was distributed between water and ethyl acetate, and the solution aqueous was acidified with iN hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate extracts were rinsed with a solution of aqueous sodium chloride, dried and concentrated by evaporation in vacuo. 4.3 g of product were obtained and used for the next reaction without further purification. XH-NMR (CDC13), d 7.629 (d, lH), 7.42 (q, lH), 7.28 (q, lH), 7.18 (t, 1H), 6.87 (b, 1H), 3.97 (q, 2H), 2.55 (m, 4H), 2.12 (m, 1H), 1.85 (m, 1H), 1.17 (t, 3H). 2-0x0-3- [1- (2-Trifluoromethyl-phenyl) -cyclobutyl] -propionic acid 4.6 g of 2-Ethoxy-3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -acrylic acid was stirred in 100 ml of IM of sulfuric acid and 15 ml of concentrated acetic acid in the course of the night at 100 ° C. Water was added, the mixture extracted with ethyl acetate, and the ethyl acetate solution was separated, dried and concentrated by evaporation in vacuo. 4.1 g of the product was obtained as a brown oil. XH-NMR (CDCl 3), d 7.62 (d, lH), 7.42 (t, lH), 7.3 (d, lH), 7.22 (d, 1H), 3.56 (s, 2H), 2.57 (m, 4H), 2.15 (m, lH), 1.85 (m, 1H). MS (ei): M (+) - H = 285 N- (4-Oxazol-2-yl-phenyl) -2-oxo-3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propionamide 0. 052 ml of thionyl chloride were added to a solution of 0.1 g of 2-oxo-3- [l- (2-trifluoromethyl-phenyl) -cyclobutyl] -propionic acid in 2 ml of dimethyl acetamide at -5 ° C , and stirred for 30 minutes at -5 C. Then 56 mg of 4-oxazol-2-yl-phenylamine were added in solid form and stirred for 1 hour at room temperature. Potassium carbonate was added and stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined ethyl acetate extracts were rinsed twice with water, dried and concentrated by evaporation. The residue was purified by column chromatography on silica gel (10% -20% EtOAc-hexane) to yield 63 mg of product. ^ - R (CDC13), d 7.83 (d, 2H), 7.62 (s, lH), 7.15 (s, lH), 6.77 (d, 2H), 3.92 (b, 2H). MS (ei): M (+) + H = 161 Example 6: N- (3-Isoxazol-5-yl-phenyl) -2-oxo-3- [1- (2-trifluoromethyl-phenyl) -cyclo-butyl ] -propionamide was obtained analogously to N- (4-oxazol-5-yl-phenyl) -2-oxo-3- [l- (2-trifluoromethyl-phenyl) -cyclobutyl] -propionamide with the use of 2-oxo-3- acid [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propionic acid and 3-isoxazol-5-yl-phenylamine. XH-NMR (CDCl 3) d 8.62 (s, lH), 8.0 (d, 2H), 7.7 (s, lH), 7.6 (m, 3H), 7. 39 (t, 1H), 7.27 (m, 2H), 3.68 (s, 2H), 2.58 (m, 4H), 2.16 (m, 1H), 1.86 (m, 1H). MS (ei): M! YH = 429, M'- H = 427 Example 7: Formulations Pharmaceutical preparations to be delivered by several routes are formulated according to the standard shown in the following Tables. "Active ingredient" or "Active compound" according to that used in the Tables means one or more of the Compounds of Formula I. Composition for Oral Administration The ingredients are mixed and supplied in capsules condemning approximately 100 mg each; one capsule would approximate a total daily dosage. Composition for Oral Administration The ingredients are combined and granulated with the use of a solvent such as methanol. The formulation is then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tabletting machine. Composition for Oral Administration The ingredients are mixed to form a suspension for oral administration. Parenteral Formulation The active ingredient is dissolved in a portion of the water for injection. A sufficient amount of sodium chloride is then added with stirring to make the solution isotonic. The solution is made to be weighed with the rest of the water for injection, filtered through a 0.2 micron membrane filter and packed under sterile conditions. Suppository Formulation The ingredients are melted together and mixed in a steam bath, and poured into molds containing a total weight of 2.5 g. Topical Formulation The total ingredients, except water, are combined and heated to approximately 60 ° C with stirring. A sufficient amount of water at about 60 ° C is then added with vigorous stirring to emulsify the ingredients, and then enough water was added to about 100 g. Formulations for Nasal Spray Several aqueous suspensions containing from about 0.025-0.5% active compound are prepared as nasal spray formulations. The formulations optionally contain inactive ingredients such as, for example, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, and the like. Hydrochloric acid or sodium hydroxide can be added to adjust the pH. Nasal spray formulations can be supplied by means of a nasal spray dosing pump that typically delivers approximately 50-100 uL of formulation per application. A typical dosing schedule is 2-4 sprays every 4-12 hours. Example 8: Glucocorticoid Receptor Fixation Assay The affinity of glucocorticoid receptor antagonists for the glucocorticoid receptor was determined in competitive binding assays by the ability of the antagonist to compete with tritiated dexamethasone. All steps of the trial were performed on ice in 96-well plates. The fixation buffer contained 10 mM potassium phosphate, pH 7.4, 20 mM Na2Mo, 100 uM EDTA, 2% DMSO, and 5 mM DTT. The human recombinant purified glucocorticoid receptor was used in 1 nM. The compounds evaluated had up to 2% DMSO final concentration. The non-specific binding condition was 1 μM dexamethasone. The radioligand used for the competition assay was 2 nM 3H-Dexamethasone (83 Ci / mmol stock solution). Buffer solutions, compounds or vehicles, GR, and radioligands were incubated at 4 ° C overnight. Unifilter GF / B 96-well filtration plates were treated with 0.5% PEI after incubation. The samples were transferred to the filtration plates by a cell harvester. The filter plates were rinsed five times with 50 mM Tris pH 7.5 and 5 rriM EDTA buffer solution. The samples were dried at 65 ° C for approximately 1 hr. The scintillation fluid was added to the filtration plates in 50 μL / well and 3H cpm were measured in the TopCount scintillation counter. The results of the binding assay of various compounds of the present invention are shown in Table 1. Table 1 Example 9: Transrepression activity: Inhibition of cytokine production in LPS-stimulated human peripheral blood mononuclear cells. Blood is collected from healthy human volunteers by vein puncture in heparinized tubes. The blood is diluted 1: 1 with Dulbecco's phosphate buffer (PBS) and covered over Histopaque-1.077 in 50 ml centrifuge tubes. The tubes are centrifuged at 800 x g for 25 minutes at room temperature. Mononuclear cells at the plasma / Histopaque interface are collected, rinsed three times with PBS, and resuspended at 1 x 106 cells / ml in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS, for its acronym in English) and 100 units / ml penicillin / 100 μg / ml streptomycin. Proportional parts (250 μl) of this cell suspension are preincubated with compounds in various dilutions (the final DMSO concentration is 0.5%) in sterile polypropylene plates for 30 minutes at 37 ° C, 5% C02. LPS is added to 1 ng / ml and the plates are returned to the incubator for an additional 3 hours. Proportional parts of the medium were extracted and frozen at -80 ° C. The levels of cytokine (TNFa, IL6 and IL8) in these samples are determined with the use of BD-Pharmingen OptEIA kits in accordance with the manufacturer's instructions. The C-0 is defined as the concentration of the compound which decreases the production of cytokine in response to 1 ng / ml of LPS at 50% of such in control wells without compounds of the invention. Example 10: Transactivation activity: Tyrosine ammotransferase activity in rat liver cells H4IIE rat hepatoma cells are plated (4 x 10 5 cells / ml in a 24-well plate) in cDMEM with 10% FBS supplements and incubated for 24 hours at 37 ° C, 5% C02. Compounds in several dilutions (final concentration of DMSO is 0.5%) are added and the plates are incubated for an additional 24 hours. The medium is extracted, the cell monolayer is carefully rinsed once with PBS, and 0.2 m] cell lysis buffer is added (10 mM Tris pH 7.5, 10 mM EDTA, 0.25 M sucrose). The plates can be stored at -70 ° C. The cells are used when freezing and thawing 3 times; The lysates are clarified by centrifugation for 5 minutes. 40 μl / well of p-hydroxybenzaldehyde or as standard, control buffer, or proportional parts of lysates are added to a clear 86-well plate. 20 μl / well of TAT buffer (50 mM of KH2P04 pH 7.6, 5 mg / ml of 1 mM BSA of EDTA, 0.1 mM of DTT) are added, followed by 140 μl / well of test mixture (8.2 mM of solution of tyrosine, 0.125 M KH »P04 / 20 mM of a-ketoglutarate 0.3 M pyridoxal 5-phosphate). The reactions are incubated at 37 ° C for 15 minutes, and concluded by the addition of 20 μl / well of 7N KOH, followed by incubation at 37 ° C in the dark by minutes. The product formation is monitored by absorbance at 340 nm, and is expressed as nmoles / min / mg of protein, as calculated from the standard p-hydroxybenzaldehyde curve. The EC ^ o for each compound is defined as the concentration of compound resulting in 50% of the maximum TAT induction for that compound. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (5)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of Formula I: characterized because A is CH? or C = 0 R 1 is H or C 1 -C 6 alkyl; R2 and R3 are each independently H, CF3, N02 or a heteroaryl ring; or R2 and R3 together form a six-membered heterocyclyl ring substituted with 0-2 substituents selected from the group consisting of Ci-Ce alkyl and oxo, with the proviso that when R2 and R3 together form an oxazolinyl ring, A is CH • > X is O or N-OR 4 is H or C 1 -C 6 alkyl; and pharmaceutically acceptable salts thereof. 2. The compound according to claim 1, characterized in that A is CH2 and R1 is H. 3. The compound according to claim 2, characterized in that R2 is selected from the group consisting of oxazolyl, isoxazolyl, oxadiazolyl and tetrazolyl 4 The compound according to claim 2, characterized in that R2 and R3 together form an oxazolinyl ring substituted with 0-2 substituents selected from the group consisting of Ci-C alkyl? . 5. The compound according to claim 1, characterized in that it is selected from the group consisting of: 6-. {
2. 2-H? Drox? Mmo-
3. 3- [1- (2-tpfluoromethyl-phenyl) -cyclobutyl] -propylamino} -4-methyl-benzo [d] [1,2] oxazma-1-one;
4. 4-met? L-6-. { 2 -oxo-3-L 1- (2-tr? Fluoromethyl-phenyl) -cyclobutyl] -propylamino} -benzo [d] [1,2] oxazma-1-one, oxime 1- (4-? soxazol-
5. 5-? l-phenylamino) -3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propan -2 -one, oxime 1- (3? -soxazole-5-? L-phenylammo) -3- [1- (2-tpfluoromethyl-phenyl) -cyclobutyl] -propan-2-one; Oxime 1- (3-oxazol-5-l-phenylammo) -3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propan-2-one; Oxima 1- [3- (lH-tetrazol-5? L) -phenylamino] -3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propan-2 -one, oxime 1- (4-oxazole) 5-? L-phenylammo) -3- [1- (2-tpfluoromethyl-phenyl) -cyclobutyl] -propan-2-one; 2-ethoxy-mmo-N- (4-oxazole-5-l-phenyl) -3- [1- (2-tpfluoromethyl-phenyl) -cyclobutyl] -propionamide, N- (4-? - soxazole-5- L-phenyl) -2-oxo-3- [1- (2-trifluoromethyl- phenyl) -cyclobutyl] -propionamide; N- (3-? Soxazol-5-yl-phenyl) -2-oxo-3- [1- (2-trifluoromethyl-phenyl) -cyclobutyl] -propionamide; and N- (4-oxazol-5-l-phenyl) -2-oxo-3- [1- (2-tr? fluoromethyl-phenyl) -cyclobutyl] -propionamide. 6. A method for treating an inflammatory disease by modulating a glucocorticoid receptor, characterized in that it comprises administering to a subject in need thereof a compound of Formula I according to claim 1 and pharmaceutically acceptable salts thereof. 7. A pharmaceutical composition, characterized in that it comprises an effective amount of a compound of the Formula I according to claim 1 and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient. 8. The use of a compound of Formula I according to claim 1 or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of an inflammatory disease through the modulation of a glucocorticoid receptor.