MXPA06006614A - Opioid receptor antagonists - Google Patents

Abstract

A compound of the formula (I) wherein the variables X1 to X5, R1 to R7 including R3', E, q, v, y, z, A and B are as described, or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixtures thereof, useful for the treatment, prevention or amelioration of obesity and Related Diseases is disclosed.

Description

ANTAGONISTS OF THE OPIOID RECEIVER FIELD OF THE INVENTION The present invention is in the field of medicinal chemistry. The invention specifically relates to compounds useful as opioid antagonists, methods of treatment, methods of use and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION Three types of opioid receptors, mu, kappa and delta opioid receptors have been reported. Recent evidence points to the interactions between combinations of mu, kappa and / or delta receptor receptor dimers (called heterodimers) that also contribute to opioid activity. Opioid receptors and their normal or lacking regulations have been implicated in disease states that include irritable bowel syndrome, nausea, vomiting, pruritic dermatosis, depression, cigarette and alcohol addiction, sexual dysfunction, stroke and trauma in animals. . Therefore, it is not surprising that the ability to antagonistically bind opioid receptors has been shown to produce relief, preventative and / or treatment effects in animals, including humans afflicted with one or more of these disease states. More recently, certain opioid receptor antagonists have been found to increase energy consumption metabolic, and weight reduction in obese rats while maintaining muscle mass. These findings indicate that an effective opioid antagonist may be useful in the prevention, treatment and / or alleviation of the obesity effect. Considering the percentage of the population that is obese in Western societies, and the indirect cost associated with the treatment of effects and symptoms of obesity and related diseases, one can not overstate the importance of these findings. Although many opioid antagonists have been described, the search continues for alternative and / or improved or more effective antagonists, which have a total benefit to the patient with little or no major side effect. U.S. Patent No. 4,891,379 describes opioid phenylpiperidine antagonists useful for the treatment of diabetes and obesity. In particular, U.S. Patent 4,891,379 describes compound LY 255582 represented by the structure: U.S. Patent No. 4,191,771 also describes compounds useful as opioid antagonists. Also, bicyclic analogs of phenyl piperidine have been prepared and reported as opioid antagonists in Entland, et al. , Biorganic and Medicinal Chemistry Letters 1 1 (2001) 623-626; see also Wentland et al. , Bioorganic and Medicinal Chemistry Letters 1 1 (2001) 1717-1721. Finally, the European Patent publication number EP 1 072592A2 filed on May 18, 2000, describes phenylpiperidine compounds of formula 1 wherein A, D, R1, R2, R3, X and n have the meanings given in the description, which are useful in the prophylaxis and treatment of diseases mediated by opioid receptors such as pruritus. U.S. Patent No. 6,140,352 and related patents describe the compound of formula 1 (1) where the variables X1 r X2, X3 R. , R3, R4, R5 and R6 are as described herein, as beta receptor antagonists Adrenergic useful for the treatment of diabetes and obesity. With respect to these and other descriptions of compounds useful as opioid receptor antagonists, or useful for the treatment of obesity and / or diabetes by other mechanisms, there remains a medical need not covered, for a safe, effective and / or alternative treatment or prophylaxis. of diseases associated with opioid receptors, particularly obesity and related diseases.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a compound of the formula wherein each of X,, X2, X3, X, and X5 are C, CH, or N; as long as ring B does not have more than 2 nitrogen atoms; X is NH or CH2, so that ring A is cyclohexyl, cyclohexenyl, or piperidinyl; E is NH or O; v is 0, 1, 2, or 3; q is 0 or 1, provided that when ring A is cyclohexyl or cyclohexenyl q is 1 and provided that v and q are not simultaneously 0; R and R2 are independently selected from hydrogen, d-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C3-C8 cycloalkyl, alkylaryl d-C.o, heterocyclyl, C? -C10 cycloheterocyclic. C- C8C (O) alkyl dd, - (CH2) n (CO) C3-C8 cycloalkyl, C2-C8CH alkyl (OH) aryl, -CO (O) d-C8 alkyl, -SO2alkyl d-C8, SO2alkylaryl C1-C1 0, SO2alkylheterocyclic d-C8, alkylcycloalkyl d-Cß, - (CH2) nC (O) OR8, - (CH2) nC (O) R8, - (CH2) mC (O) NR8R8 and - (CH2) mNSO2R8; wherein each of the alkyl, alkenyl, cycloalkyl, heterocyclic and aryl groups are optionally substituted with one to five groups independently selected from halo, C -? - C8 haloalkyl, C? -C8 thioalkyl, C -? - C8 alkyl, alkenyl C2-Ca, aryl, alkylaryl dd, -C (O) alkyl d-C8, -SO2alkyl d-C8, -SO2alkylaryl dd, -alkylcycloalkyl d-C8; and wherein R1 and R2 may optionally be combined together to form a heterocycle containing 4, 5, 6 or 7 nitrogen elements, wherein the nitrogen-containing heterocycle may further have substituents selected from the group consisting of amino, C-alkyl C8, C2-C8 alkenyl, C2-C8 alkynyl, aryl, d-C8 alkylaryl, -C (O) d-C8 alkyl, -CO (O) d-C8 alkyl, halo, oxo, d-C8 haloalkyl; R3 and R3 'are each independently selected from hydrogen, d-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, -C1-C8 alkylcycloalkyl, or -C?-C8 alkylaryl; C1-C8 alkylheterocyclic; or R3 and R3 'combine to form a C3-C8 cycloalkyl, C4-C8 cycloalkenyl, or C5-C10 heterocyclic; R 4 and R 5 are each independently selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 alkoxy, d-C 8 thioalkyl, halo, C 1 -C 8 haloalkyl, alkoxyhaloalkyl C? -C8, aryl, -alkylaryl C? -C8, -C (O) alkyl d-C8, or -C (O) OaIquilo d-C8, -alkylamino d-C8, -alkylcycloalkyl C.-C8, - ( CH2) mC (O) C? -C8 alkyl, and (CH2) nNR8R8, wherein each R4 or R5 is attached to its respective ring only to carbon atoms, and wherein y is 0, 1, 2 or 3; and wherein z is 0, 1 or 3; R6 and R7 are each independently selected from hydrogen, C-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -C (O) d-C8 alkyl, hydroxy, C-C8 alkoxy, -SO2alkyl C- C8, SO2alkylaryl d-C8, -SO2alkylheterocyclic d-C8, aryl, -alkylaryl d-C8, cycloalkyl C3-C7, -alkylcycloalkyl d-C6, - (CH2) nC (O) R8, - (CH2) mC (O) NR8R8, and - (CH2) rnNSO2R8; wherein each of the alkyl, alkenyl and aryl groups are optionally substituted with one to five groups independently selected from d-C8 alkyl, C2-C8 alkenyl, aryl, and d-C8 alkylaryl; and wherein R6 and R7 can independently be combined with each other to form a heterocycle containing 4, 5, 6 or 7 nitrogen elements, in which the nitrogen-containing heterocycle can optionally have substituents selected from the group consisting of oxo, -C8, C2-C8 alkenyl, C2-C8 alkynyl, aryl, -D-C8alkylaryl, -C (O) C- C8alkyl, -CO (O) d-C8alkyl, hydroxy, C-C8alkoxy, -alkylamino d-C8, amino, halo, and haloalkyl; R8 is hydrogen, d-C8 alkyl, C2-C8 alkenyl, d-C8 alkylaryl, - C (O) C?-C8 alkyl, or -C (O) O-alkyl d-C8; and wherein n is 0, 1, 2, 3 or 4 and m is 1, 2, or 3; or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixtures of distereomers thereof. The present invention also provides a pharmaceutical formulation comprising a compound of formula I in association with a carrier, diluent and / or excipient. The present invention also relates to a method for the treatment and / or prophylaxis of obesity and related diseases that include eating disorders (bulimia, anorexia nervosa, etc.), diabetes, diabetic complications, diabetic retinopathy, sexual / reproductive disorders, related depression with obesity, anxiety related to obesity, epileptic crisis, hypertension, cerebral hemorrhage, congestive heart failure, sleep disorders, atherosclerosis, stroke, metabolic diseases and symptoms thereof, hyperlipidemia, hypertriglycemia, hyperglycemia, hyperlipoproteinemia, substance abuse, drug overdose, compulsive behavior disorders (such as licking paw in dog), and addictive behaviors such as, for example, gambling addiction and alcoholism, comprising administering a therapeutically effective amount of a compound of formula I or a salt, solvate, enantiomer, racemate, diastereomer or mixtures of diastereomers of the same, pharmaceutically acceptable,. The present invention provides a compound of Formula I useful for the manufacture of a medicament for the treatment, prevention and / or relief of symptoms associated with obesity and related diseases. In another embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixtures thereof, useful as appetite suppressants. In another embodiment, the present invention provides a method for achieving weight loss while maintaining or minimizing loss of lean muscle mass, which comprises administering a compound of formula I or a salt, solvate, enantiomer, racemate, diastereomer or mixtures thereof. pharmaceutically acceptable, to a patient in need thereof. In still another embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixture thereof to a patient in need thereof in combination with another effective therapy for the treatment of Obesity and related disorders.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "obesity" has a commonly understood meaning such as "excessive fat" and includes the clinical designation of being obese as defined in and by the medical literature and support brochures. health organizations public. For example, Dorland's Illustrated Medicinal Dictionary (29th edition, WB Saunders Company, Philadelphia USA.), Defines obesity as "an increase in body weight beyond the limitation of skeletal and physical requirements, as the result of an excessive accumulation of fat in the body. " Because the decision of convenient administration of a compound (s) of the present invention to a patient is made by a qualified physician or qualified nurse, the patient is inherently deemed fit or obese by the managing nurse. As used herein, the term "patient" includes human and non-human animals, such as companion animals (dogs and cats) and livestock animals. The preferred patient for the treatment, alleviation and / or prevention of obesity and Related Diseases, is a human. The terms "treatment" and "treating", as used herein, include their generally accepted meanings, that is, preventing, prohibiting, restricting, alleviating, improving, retarding, stopping or reversing the progress or severity of a pathological condition, or sequel to it, described in this document. The terms "relieve", "prevent", "prevention", "prophylaxis", "prophylactic" and "prevention", are used as used herein interchangeably and refer to reducing the severity of symptoms associated with obesity and related diseases in a patient afflicted therewith or reducing the probability that the container of a compound of formula I will incur in or will develop any of the pathological conditions, or sequelae thereof, described in this document. As used herein, the term "effective amount" is synonymous with "effective dose" and means an amount of a compound of formula I that is sufficient in one or more administrations to prevent, alleviate or treat a condition, or detrimental effect thereof, described herein, or an amount of a compound of formula I that is sufficient to antagonize opioid receptors to achieve the desired result within the scope of the invention. The term "pharmaceutically acceptable" is used herein as an adjective and means substantially non-harmful to the recipient patient. The term "Active Ingredient" as used herein, means a compound of formula 1 or a combination of compounds of formula I or a combination of a compound of formula I and an opioid receptor co-antagonist or a combination of a compound of formula I in addition to another effective anti-obesity, weight loss or anti-diabetic agent (s). The term "formulation", as in pharmaceutical formulation, or "pharmaceutical composition", is proposed to encompass a product comprising the Active Ingredient (as defined above), and the inert ingredient (s) that produce the carrier, or other components of the drug as administered, as well as any product which results, directly or indirectly, of the combination, complex formation or aggregation of any one or more of the active ingredients, or of dissociation of one or more of the active ingredients. Accordingly, the pharmaceutical formulations of the present invention encompass any effective composition made by mixing a compound of the present invention and a pharmaceutical carrier. The pharmaceutical formulations of the present invention also encompass a compound of the formula I and a pharmaceutically acceptable co-antagonist of opioid receptors and other effective therapies useful for the treatment and / or prevention of obesity or Related Diseases. The term "Related Diseases" as used herein refers to such symptoms, diseases or conditions caused by, exacerbated by, induced by or adjuncts to the condition of being obese. Such diseases, conditions and / or symptoms include but are not limited to eating disorders (bulimia, anorexia nervosa, etc.) diabetes, diabetic complications, diabetic retinopathy, sexual / reproductive disorders, depression related to obesity, anxiety related to obesity, crisis epileptic, hypertension, cerebral hemorrhage, congestive heart failure, sleep disorders, atherosclerosis, stroke, metabolic diseases and symptoms thereof, hyperlipidemia, hypertriglycemia, hyperglycemia and hyperlipoproteinemia. As used herein, the terms depression related to obesity and anxiety related to obesity, are conditions of depression and anxiety respectively, which are symptomatic of certain obese patients and possibly carried by the knowledge or the same awareness of the condition of being obese and possibly coupled with the real or perceived notion of acceptance or rejection by a certain individual, individuals or the general public. Depression related to obesity or anxiety can generally be alleviated or treated adjunctively with the underlying condition of being obese or overweight and / or prevented by administration of a compound of formula I. The term "suitable solvent" refers to any solvent, or mixture of solvents, inert to the ongoing reaction that sufficiently solubilizes the reactants to provide a medium within which the desired reaction is effected. The term "mutual solvent" means a solvent that is used to sufficiently dissolve two or more components of a reaction or mixture separately before the reaction or mixing, that is, a solvent common to more than one reagent or components of a mixture . The term "nitrogen-containing heterocycle" refers to an aromatic or non-aromatic monocyclic or bicyclic ring system, which is a 4, 5, 6 or 7 element ring containing 1, 2 or 3 nitrogen atoms in addition to the carbon atoms that complete the ring size, or a combination of 1 nitrogen atom and 1 or 2 atoms selected from oxygen and sulfur in addition to the appropriate number of carbon atoms that complete the size of the ring. A nitrogen-containing heterocycle as used herein can have 0, 1, 2 or 3 double bonds. The term "alkyl d-C8" or "alkyl d-8", refers to, and includes all groups, structural isomers and / or homologs of alkyl groups having from 1 to 8 carbon atoms. When the term d-C8 alkyl precedes or is prefixed by another group, the term d-C8 alkyl only limits the number of carbon atoms in the alkyl component. For example, C 1 -C 8 alkylaryl means an aryl group having a d-C 8 alkyl group substituent, such that the number of carbon atoms in the alkylaryl group d C 8 is effectively the number of carbon atoms in the group aryl plus the number of carbon atoms in the d-C8 alkyl group. Similarly, the term "C 1 -C 8 alkylcycloalkyl" refers to a cycloalkane group having a d-C 8 alkyl substituent, and wherein the full alkylcycloalkane d-C8 group may itself be a substituent attached to either the alkyl group or the cycloalkyl group on a substrate. The definition and use equally applies to other d-C8 homologs such as, for example, d-C, d-C6, etc. In general, and where necessary, a hyphen (-) has been replaced after certain groups to indicate the point of attachment for clarity. However, the absence of a script does not invalidate on the other hand, the obvious position of position (s) of connections known to a person skilled in the art. The term "cycloalkane" or "cycloalkyl" means cycloalkanes having from 3 to 8 carbon atoms, i.e. of cyclopropane to cyclooctane. The term "hal" or "halo", as used herein, refers to a halogen that includes fluorine, chlorine, bromine or iodine. The term "haloalkane" or "haloalkyl" means haloalkanes having from 1 to 8 carbon atoms, and from 1 to 3 halogen atoms permitted by valence considerations. Examples include chloroethyl, trifluoromethyl, 2-chloropropyl, etc. As used herein, the terms "alkenyl" refer to linear or branched carbon atoms having 1 or 2 carbon-carbon double bonds. As used herein, the terms "alkynyl" refer to straight or branched carbon atoms having 1 or 2 triple carbon-carbon bonds. As used herein, the term "alkoxy" refers to the group "O-alkyl", wherein alkyl is as previously defined. The term "aryl" as used herein, refers to compounds or groups having the Huckel electron 4n + 2 pi arranged and include, for example, phenyl, benzyl, naphthyl, tetrahydronaphthyl, benzothiophene, etc. but exclude carbazoles and other tricyclic ring linked structures. As used herein, the term "aroxy" or "aryloxy" refers to the group "O-aryl", wherein aryl is as previously defined.

As used herein, the term "bicyclic fused" means a fused cycloalkane ring system wherein each ring has from 4 to 8 carbon atoms (ie, bicyclic fused C8-C16) and the fused ring system has 0 to 3 carbon atoms of the main bridge. One or both of the fused rings may contain zero or a double bond. Examples of fused bicyclics include but are not limited to, bicyclo [2.2, 1] heptyl, bicyclo [2.2, 1] heptenyl. As used herein, the term "heterocyclic" or "heterocyclyl" or "heterocycle" is used interchangeably and has its usual meaning and includes mono, bi or tricyclic or spirocyclic heterocyclic groups, unless otherwise specified. . Heterocycles as used herein may contain 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur, unless otherwise specified. Examples of heterocyclic groups applicable to the present invention include, but are not limited to pyranyl, pyrazinyl, pyrrolidinyl, azapanyl, azaflorenyl, isoquinolinyl, indollyl, thiophenyl, benzothiophenyl, oxazolyl, morpholinyl, thiomorpholinyl and piperidinyl. Each of the heterocyclic groups can be mono- or di-substituted or as specified with substituents such as alkyl, cycloalkyl, aryl, among others, as defined. In addition, the substitution can be in the 1-position or the heteroatom as in piperazine, pyrrolidine or in a carbon atom or both. As used in this document, the term "group "Protector" refers to a group useful for masking reactive sites in a molecule, to improve the reactivity of another group or to allow reaction at another site or desired sites after which the protecting group can be removed.Protective groups are usually used for protecting or masking groups including, but not limited to, -OH, -NH and -COOH Suitable protecting groups are known to one skilled in the art and are described in Protecting groups in Organic Synthesis, 3rd edition, Greene, TW; Wutus , PGM Eds., John Wiley and Sons, New York, 1999. As used herein, the term "solvate" is a form of the compound of the invention, wherein a crystal or crystals of a compound of the invention have been formed of a stoichiometric or non-stoichiometric amount of the compound of formula I and a solvent Solvant of typical solvation include, for example, water, methanol, ethanol, acetone and dimethylformamide. Where a compound of the invention possesses acidic or basic functional groups, various salts can be formed, which are more water soluble and / or more physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts include, but are not limited to, alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. The salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin.

Included within the definition of pharmaceutically acceptable salts are the addition salts of organic and inorganic base, relatively non-toxic compounds of the present invention, for example, ammonium, quaternary ammonium and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, SM Berge, et al., "Pharmaceutical Salts," _L Phar. Sci., 66: 1-19 (1997)). However, the (the) basic group (s) (s) of the compound of the invention may be reacted with suitable organic and inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitertrato borate, hydrobromide, camsylate, carbonate, clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate, fluoride, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrochloride, hydroxynaphthoate, hydroiodide, isothionate, lactate, lactobionate, laurate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantothenate, phosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate. Preferred salts for the purpose of the invention include the hydrochloride salt, hydrobromide salt, bisulfate salt, methanesulfonic acid salt, p-toluenesulfonic acid salt, bitartrate, acetate salt and citrate. A compound of the invention as illustrated by formula I, can originate as any of its isomers positional, stereochemical isomers or regio-isomers, all of which are objects of the invention. Certain compounds of the invention may possess one or more chiral centers, and thus, may exist in optically active forms. Also, when the compounds contain an alkenyl or alkenylene group, there is a possibility of cis- and trans-isomeric forms of the compounds. The R and S isomers and mixtures thereof, which include racemic mixtures, as well as mixtures of enantiomers or cis- and trans isomers, are contemplated by this invention. Additional asymmetric carbon atoms may be present in a substituent group, such as an alkyl group. All isomers, as well as mixtures thereof, are proposed to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art, using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively, by methods which lead to mixtures of the stereoisomers and Subsequent resolution by known methods. For example, a racemic mixture can be reacted with a single enantiomer of some other compound, i.e., a chiral resolving agent. This changes the racemic form in a mixture of stereoisomers and distereomers, because they have different melting points, different boiling points and different solubilities and can be separated by conventional means, such as crystallization.

International PCT application WO 02/078693 A2 published October 10, 2002, describes compounds of the formula wherein R1 t R2, R3, R4 and X are as described herein, as 5-HT6 receptor antagonists for the treatment of disorders including cognitive disorders, age-related disorders, mood disorders, psychosis, etc. The compounds of the present invention, however, are useful for the treatment and / or prevention of obesity and Related Diseases. The compounds of the present invention also show inhibition of orexigenic effects and are thus useful as appetite suppressants either as a single therapy or as a combination of therapy in conjunction with exercise and another effective appetite suppressant or weight loss medications. The efficacy of certain compounds of the present invention has been demonstrated by their activity or potency in various biological models including, a binding scintillation proximity assay (SPA) and functional GTP-gamma-S GTP assay.

PREFERRED MODALITIES OF THE INVENTION A compound of formula I preferably exists as the free base or a pharmaceutically acceptable salt. More preferred is the hydrochloride salt, bisulfate salt, mesylate or oxalic acid salt of the compound of formula I. Preferred moieties of the compound of formula I include substructures la, Ib, le and Id shown below: (the); (ib); (you); (Id) For the R-i and R2 groups Preferred R1 and R2 groups are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, pentyl, phenyl, naphthyl, benzothiophene and isopropyl. Also preferred are groups R1 and R2 independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, phenyl, each of which is optionally substituted with a group selected from the group consisting of halogen, d-C8 alkyl, d-C8 haloalkyl, d-C8 thioalkyl, d-C8 alkylamino, phenyl, substituted d-C8 phenylalkyl, C4 heterocycle C8 or alkylheterocycle d-C4; or is combined with a selected group of dd alkyl, halogen, C-C8 haloalkyl, d-C8 thioalkyl, C-C8 alkylamino, phenyl, C? -C8 alkylsubstituted phenyl, C4-C8 heterocycle, or C1-C4 alkyl heterocycle for forming a substituted or unsubstituted bicycle or tricycle, and wherein n is preferably 1, 2 or 3. Also preferred are groups R1 and R2 which are combined with each other or with 1 or 2 atoms adjacent to the nitrogen atom for form a selected group of the grypo that consists of each of which is optionally substituted with a group selected from the group consisting of halogen, amino, d-C8 alkyl, C-C8 haloalkyl, d-C8 thioalkyl-C8 alkylamino, phenyl, substituted phenylalkyl, heterocycle C4-C8 or alkylheterocycle-C -.- C4. Preferred R3 and R3 'groups A preferred R3 is hydrogen. A preferred R3 'group is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl and benzyl. Preferred R4 groups A preferred R4 group is selected from the group consisting of hydrogen, halo, d-C5 alkyl, C1-C5 haloalkyl, d-C5 alkoxy, alkylamino d-C5, -N (C-C5 alkyl) 2, -NHalkyl d-C5, alkyl-d-C5N (C1-C5 alkyl) 2, alkyl-d-C5NH-C1-C5 alkyl, phenyl, alkylphenyl-d-C5, alkylcycloalkyl-d-C5, and thioalkyl d-C5. More preferred is an R4 group selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, thiomethyl, phenyl, and benzyl. More preferred is a R4 group selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, propoxy, isopropoxy and benzyl. However, groups R4 and R5 can exist as multiple substituents on their respective ring substrates, a preferred embodiment of the invention involves compounds wherein each of R4 and R5 are independently solely or doubly substituted on their respective ring substrates. Preferred R5 groups A preferred R5 group is selected from the group consisting of hydrogen, halo, d-C5 alkyl, d-C5 haloalkyl, d-C5 alkoxy, alkylamino-C.-D, -N (C1-C5 alkyl) 2, -NHalkyl dd, alkyl-d-C5 N (C1-C5 alkyl) 2, alkyI-d-C5 NHalkyl d-C5, phenyl, alkylphenyl-dd, alkylcycloalkyl-d-C5, and thioalkyl C -? - C5. More preferred is a group R 5 selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, chloro, fluoro, trifluoromethyl, methoxy, ethoxy, thiomethyl, phenyl and benzyl. A more preferred R5 group is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and benzyl. Preferred groups R6 and R7 Groups R6 and R7 independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, pentyl, isopropyl, phenyl and benzyl are preferred. Also preferred are the compounds of formula I, in where R6 and R7 independently combine with each other, and with the nitrogen atom to which they are attached or with 1 or 2 atoms adjacent to the nitrogen atom, to form a nitrogen containing heterocycle containing 4, 5, 6 or 7 elements in which the nitrogen containing heterocycle may optionally have substituents selected from the group consisting of oxo, amino, C---C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, phenyl, C-C8 alkylaryl, -C (O) d-C8 alkyl, -CO ( O) C 1 -C 8 alkyl, hydroxy, C 1 -C 8 alkoxy, halo, and haloalkyl. Preferred values for q q is preferably 0 when ring A is piperidinyl.

P is preferably 1 when ring A is cyclohexyl. Preferred group E A more preferred group E is an oxygen atom (O). Preferred Ring A A preferred ring A is a cyclohexyl or piperidyl. The most preferred ring A is cyclohexyl. Preferred B ring A preferred B ring is a phenyl ring, a pyrazine ring, a pyrimidine ring or a pyridine ring. A more preferred B ring is a phenyl, pyrazine or pyridine ring. Preferred values for v, n and m A preferred value for v is 0, 1 or 2. A preferred value for n is 1, 2 or 3. A preferred value for m is 1 or 2. A preferred compound according to the present invention is a compound selected from the group consisting of: ± 6-. { 4- [2- (tetrahydro-pyran-4-yl) -ethylamino] -cyclohexyloxy} -nicotinamide, ± 6- [4- (3-Methyl-butylamino) -cyclohexyloxy] -nicotinamide ± 6- [4- (2-Thiophene-2-yl-ethylamino) -cyclohexyloxy] -nicotinamide ± 4- [4- (3-Phenyl-propylamino) -cyclohexyloxy] -benzamide T / "a /? S-6- (4-Benzylamino-cyclohexyloxy) -nicotinamide 6- (1-Pyridin-2-ylmethyl-piperidin-4-yloxy) -nicotinamide 6- (1-Cyclopropylmethyl-piperidin-4-yloxy) -nicotinamide 6- [1 - (1 H-l ndol-2-ylmethyl) -piperidin-4-yloxy] -nicotinamide 4- (1-Benzyl-piperidin-4-yloxy) -benzamide 4- [1 - (3-Phenyl-propyl) -piperidin-4-yloxy] -benzamide and a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer or diastereomeric mixture thereof.

PREPARATION OF COMPOUNDS OF THE INVENTION A typical protocol for the preparation of compounds of the invention and intermediates thereof, wherein ring A is an optionally substituted cyclohexyl group, is described in Scheme 1 below. Scheme 1 In accordance with Scheme 1, the starting material 3,3-dimethyl-1,5-diozaspiro [5.5] undecanone (1) and analogs thereof, is reduced in the alcohol 3, 3-Dimethyl-1,5-dioxa-spiro [5.5] undecan-9- corresponding ol (2) by reaction with the boron hydride supported polymer in a methanolic solvent. One skilled in the art is aware that other reducing agents and forms of reduction (by example, without polymer support), can be used to provide compound 2 and analogs thereof. Ketone 1 and analogs thereof can be purchased from chemical distributors such as, for example, Aldrich Chemical Co., ilawaukee, USA. The compound 3, 3-dimethyl-1,5-dioxa-spiro [5.5] undecan-9-ol (2) is then coupled with halo nicotinonitrile or halobenzonitrile or other sources of the B ring, to provide the compound 3 bonded to oxygen or analogs thereof. For example, optionally substituted 4-chloronicotinonitrile is reacted with compound 2 to provide compound 3 bonded to oxygen under basic conditions. The basic conditions include the use of selected bases of inorganic and organic bases. Examples of useful inorganic bases include but are not limited to, potassium carbonate, sodium hydride, sodium carbonate, sodium hydroxide, potassium hydroxide, calcium carbonate and cesium carbonate. Examples of organic bases include but are not limited to, potassium hexamethyl disilazide, n-butyl lithium, hexamethylphosphorous triamide, (HTP), and the like. The basic conditions are complemented by the presence of a solvent, preferably an organic solvent. Preferred organic solvents include protic solvents or polar aprotic solvents. More preferred solvents include dimethylformamide, methanol, dimethylacetamide (DMA), dimethyl sulfoxide. A more preferred basic reaction condition involves the use of potassium carbonate in dimethylacetamide at a temperature of about 60 to 100 ° C. The protective group (dimethylacetal group) of compound 3 is removed by the reaction with an acidic group such as, for example, hydrochloric acid, to provide compound 4. Compound 4 is reductively aminated with a desired amine to provide the 5-amino compound, which is a compound of the invention. Reductive amination can be carried out in two stages or a single stage depending on the spreadability of the intermediate imine. Typically, compound 4 is reacted with a primary or secondary amine (primary amine shown), in methanol as a solvent. Molecular sieves can be added to improve the efficiency of imine formation. In a second step, the reducing agent, typically, sodium borohydride or other hydride reducing agent, is added to the reaction mixture. The progress of the reaction can be monitored by CLD, CLAR, LC-MS or other analytical techniques known to a person skilled in the art, to determine the substantial yield of each step and synchronize them by the addition of the next reagent. The resulting amino nitrile compound 5 is hydrolyzed to the cyano group to provide the primary amide 6. The nitrile hydrolysis is preferably carried out by reaction with hydrogen peroxide and an inorganic base such as sodium carbonate and preferably under pressure. A suitable solvent for performing the above nitrile hydrolysis is DIVISO or DMF. Analogs of compounds 3 and 5 having one or more R substituent groups can be prepared using appropriately substituted starting materials or by interconversion of functionalities susíiíuyeníes. For example, an initial optional substituent group on ring A or B may be appropriately protected and deprotected to achieve the desired final R substitute. Alternatively, an initial substituent may be converted by known reactions of steps 1, 2 or 3 to other desired final substituents. An alternative protocol illustrated in Scheme 2, shows the use of benzamide as the source of ring B. Scheme 2 The use of the amide starting material is particularly preferred for compound of the invention, wherein ring B is the pyridinyl, pyridazinyl, pyrazinyl or pyrimidinyl group. The heterocyclic carboxamide or amide can be introduced as part of the starting material where the appropriate substitute for ring B is commercially available or can be prepared using methods known. For example, the use of pyrazine carboxamide, ida nicotine or substituted analogs thereof, results in substituted derivatives or analogs of compounds of formula 3a or 6a, which are also compounds of the present invention. The primary and secondary amines are useful for reductive amination to convert compound 4a to compound 6a as shown in Scheme 2. Examples of amines useful for reductive amination include but are not limited to, phenethylamine, 3-meityl butylamine, propylamine, isopropylamine, benzylamine and isopentylamine. Compounds prepared by this and other reaction schemes described herein, or known to one skilled in the art, can further be converted to the acid addition salt as shown for example, in Scheme 3. Scheme 3 Scheme 3 shows the preparation of the hydrochloride salt 1 2a, a compound of the invention wherein R 1 R 2 NH is 3-methylbutylamine or another secondary amine group and R 4 and R 5 are both hydrogen. As shown, the starting material 7 is 4-hydroxy piperidine protected at the nitrogen atom using tertiary butoxycarbonyl anhydride (Boc-anhydride). The Boc-protected piperidinol (7) is reacted with a ring B source such as halobenzonitrile, or a haloniconitrile (6-chloro-nicotinonitrile (8) shown) or halopyridazine or carboxamide nitrile thereof as desired. The coupling reaction to form the ether linkage (9) is carried out in the presence of a base such as sodium hydride or sodium carbonate in a suitable solvent such as DMA, DMF or DMSO. The resulting nitrile ether group (9) is then hydrolyzed to form the primary amide. Hydrolysis of the nitrile is carried out in the presence of hydrogen peroxide and a base such as sodium carbonate. The resulting amide 10 is hydrolyzed under acidic conditions to provide the deprotected compound 1 1. The deprotection of the Boc group is better performed using HCl, TFA or HF. The methods for Boc-protection and deprotection are known from one of skill in the art and are described in General Organic chemistry references which include Protecting groups in Organic Synthesis, 3rd edition, Greene, T. W .; Wutus, P.G. M. Eds. , John Wiley and Sons, New York, 1999. Specific procedures can also be found in the experimental section of this document. The free NH piperidinyl group of compound 1 1, it can be reacted with an aldehyde having the alkyl, alkylaryl, cycloalkyl, alkylcycloalkyl, alkylheterocyclic or other desired substituent within the scope of the invention, to provide the desired N-substituted piperidinyl compound. Compound 12 is dissolved in ethanol and a slight excess (for example, 1.0 to 1.5 molar equivalents based on the number of basic sites) of 1 N hydrochloric acid is added at temperatures ranging from about 0 ° C to room temperature. The mixture can be allowed to crystallize for a while with or without cooling, or it can be evaporated to provide the hydrochloride salt, which can be further purified by trituration with a suitable organic solvent such as toluene, hexanes, dieryl ether or mixtures thereof. Alternatively, anhydrous HCl can be pumped into a cold solution of compound 12 until the reaction is complete or the solution is saturated, and the mixture functions properly to provide compound 12a. One skilled in the art is aware of the nuances and varied techniques for preparing, isolating and purifying acid addition salts, and should achieve comparable results using methods appropriate for particular subtraction without undue experimentation. A modified protocol for preparing compounds of the invention is provided in Scheme 4, where the nucleophilic displacement reaction to form the ether linkage is performed toward the end of the synthesis, rather than early.

Scheme 4 According to Scheme 4, the starting material is an appropriately substituted hydroxypiperidine (7), protected in the nitrogen using Boc anhydride. It may be possible to acquire the Boc-protected hydroxy piperidine. The protected Boc hydroxypiperidine 7, is reacted with a ring B source such as 4-fluorobenzonitrile to provide the bound ether compound 9. Other sources of ring B include, for example, phenyl or pyridinecarboxamide, benzonitrile or pyrido-nitrile and analogs thereof. same. Methods to perform the coupling reaction have been previously described. Compound 9 can be hydrolyzed to the amide via the nitrile group, deprived by removing the Boc group as previously described, and finally reducing it to give a composition of the invention. Alternatively, the ether compound 9 can be removed by removing the Boc group to provide the compound 13. The protecting group can be removed by the use of hydrochloric acid or trifluoroacetic acid using procedures known to one of skill in the art. One of skill in the technique is aware that analogously appropriate substances of the compounds of formula 1 3, can be prepared by starting materials appropriately subsumed or condensed therefrom, which can be converted to the desired substitutes. The deprovection of the compound 9 to form the compound 13 is followed by reductive amination to form the N-substituted piperidinyl compound 14. The N -substituted piperidinyl compound 14 is finally hydrolyzed to the nihoryl group to provide the compound 1 5, a compound of the invention. The compounds of formula I where v is 1, can be elaborated following the syneéic scheme described below: Scheme 5 As shown in Scheme 5, the ethyl ester of 4-hydroxy-cyclohexanecarboxylic acid (commercially available from Aldrich Chemical Company, Milwaukee, USA, or other fine chemical suppliers), can be reacted with a source of the B ring, such as halobenzonitrile or haloniconionitrile to form the bound ether product 13. The coupling reaction to form the ether linkage is carried out in the presence of a fal base such as sodium hydrofide or pofasium carbonate in a suitable solvent such as DMA, DMF or DMSO. . The carboxylic acid ester is then selectively reduced to give the corresponding aldehyde 14. This reduction is carried out with hydrides such as, for example, diisobutylammonium hydride (DIBAL-H). The aldehyde 14 is then reductively aminated with the desired amino moiety, to form the amine 15. The nitrile of the amino precursor resulting therefrom is then hydrolyzed to give a compound of the invention 16. Still another pro-isolate for the preparation of compounds of formula I, is shown in Scheme 6. Scheme 6 The aldehyde 14 of Scheme 5 is reacted with methoxymethyldiphenylphosphine oxide or mefoxymethylfiriphenylphosphonium chloride in the presence of a strong base, such as n-buty [lithium, sec-butyl; hexamethyldisilane from plyo or pylium or the like, to provide the vinyl metyl ether 17. The vinyl metyl ether 17 is then hydrolysed under acidic conditions to provide the higher aldehyde 1. The aldehyde 1 8 is then converted to the desired compound 20 of formula I, as shown. and discuss beforehand.

METHODS FOR USING THE INVENTION As stated above, the compounds of the invention are useful in blocking the agonist effect on mu, kappa and / or delta opioid receptors. As such, the present invention also provides a method for blocking a mu, kappa, deli or receptacle combination (heimerodimer) thereof in a mammal comprising administering to said mammal a blocking dose of the receptor of a compound of formula I The term "receptor blocking dose", as used in this document, means an amount of a compound of formula I, necessary to block a mu, kappa, or delia receptor, or combination of receptacle (heimerodimer) thereof, after administration to a mammal that requires blocking of a mu, kappa or delta or combination of receptor (heterodimer) thereof. The compounds of formula I or combinations thereof are effective over a wide range of dosages. For example, dosages per day will normally fall within the inferio of approximately 0.05 to approximately 250 mg / kg of body weight. In the rape of human adults, it is preferred to preserve it from approximately 0.5 to approximately 1000 mg / kg, in single or divided doses. However, it will be understood that the majority of the compiled body will be determined by a specialist, in view of the rellenial circumstances, which include the condition to be treated, the choice of the compound to be administered, the age, weight and individual response of the patient, the severity of the patient's symptoms, and the chosen route of administration. Therefore, the above dosage ranges are not proposed to limit the scope of the invention in any way. The compounds can be administered by a variety of pathways such as the oral, transdermal, subcutaneous, sublingual, intranasal, intramuscular and intravenous routes. A variety of physiological functions have been shown to be subject to, or influenced by mu, kappa or delia recepfores, or combination of receptors (heterodimers) in the brain. As such, the compounds of the present invention are believed to have the ability to eradicate symptoms associated with these receptors or combinations thereof, such as eating disorders, opioid doses, depression, smoking, alcoholism, sexual dysfunction, shock, stroke. , spinal damage and cranial trauma. As such, the present invention also provides methods for treating the above transferences by blocking the effect of agonisias in mu, kappa, delia receptacles or recepfores combination (heimerodimers) thereof. The compounds of the present invention have been found to exhibit excellent activity in an opioid receptor binding assay, which measures the ability of the compounds to block the mu, kappa, delta or combination thereof (heimerodimer) receptor.

Link Test GTP-? A GTP-? Test format was developed? based on SPA, based on previous opioid assays (Emmerson et al., J. Pharm Exp Ther 278, 1221, 1 996; Horng et al., Societe and Neuroscience Abstrais, 434.6, 2000) and muscarinic (DeLapp et al., JPET 289, 946, 1999). Membranes were re-suspended in 20 mM HEPES, 1 00 mM NaCl, 5 mM MgCl 2, 1 mM DTT, and 1 mM EDTA. Fifty (50) mL of GTP -? - [35S], compound, membrane suspension (20 micrograms / well), and SPA beads coated with wheat germ agglutinin (1 mg / well), were added to test plates of 96 cavities of transverse background. GDP (200 mM) was added to the membrane solution prior to addition in the test plates. The plates were sealed and incubated for 4 hours at ambient temperature, then placed in a refrigerator overnight to allow the pellets to sediment. The stability signal at 4 ° C was determined to be > 60 hours The plates were heated to room temperature and coníadas in a Wallac Microbeia esciníilación coníador. For antagonist assays, specific agonists were added to the following concentrations: (MOR) DAMGO 1 micromolar, (DOR) DPDPE 30 nM, (KOR) U69593 300 nM. The Kb were determined by the Cheng-Prusoff equation (see, Cheng and Prusoff, Biochem Pharmacol, 22, 3099, 1973). The results obtained for a representative sample of compounds of the invention in the GTP-S-Link Assay are shown in Fable 1 below.

Table 1 GTP -? - S Bonding Assay of In Vitro Antagonism Compound of the Mu Kappa Delta Example # Kb (uM) Kh (uM) Kb (uM) 1 0.566 0.601 0.819 2 0.594 0.620 0.996 6 > 1,800 0.430 > 7,300 7 1 .785 1 .051 > 7,300 8 > 1,850 0.937 > 7.300 9 1 .120 0.930 > 7,300 1 0 0.453 0.999 1 .965 Linking the Ex-vivo Receptor To link the binding affinity in vitro and the anolygonism-to-efficacy potency and efficacy in vivo, the applicants have developed an ex vivo receptor binding assay in the brain of rabbits. This assay measures the difference in association (binding) of a radioligand of the non-selective opioid receptor of alia affinity (3H-diprenorphine), in brain tissue isolated from animals receiving vehicle with the treatment compound (less 3H-diprenorphine binding = association of major compound with opioid receptors). Studies using the ex vivo receptor binding assay have shown a positive correlation between the activity (potency and duration of activity), which also correlates to 24 hours of efficacy in the diet induced by obese rats.

Methods An ex vivo binding assay of the opioid receptor measures the 3 H-diprenorphine linkage (0.1 -0.4 nM radioligand affinity for mu, delta and kappa receptors) in striatum / nucleus accumbens of rats; a region of the brain that contains a high density of mu, delta and kappa receptors, after oral administration of compounds. Experimentally, a selected dose of 7 mg / kg, p.o of compound or vehicle, is administered to rats. Six hours after administration of the compound, the animals are sacrificed and the striatum / nucleus accumbens is isolated and homogenized in 10 volumes (weight / volume) of binding buffer. The homogenate is then used in a homogenate binding assay using a saturation concentration of 3 H-diprenorphine for 30 minutes. The homogenization and assay are carried out at 4 ° C, to minimize redistribution of the compound in the in vitro binding portion of the assay. The results are reported (Table 2), as a specific link constant Ki in micromolar (uM). Table 2 Assay Kl of Linkage Affinity SPA (uM) Mu Kappa Delta Compound of Example No. 3 0.137 2.561 0.353 4 0.620 > 5,000 2,345 Formulation A compound of the invention is preferably presented in the form of a pharmaceutical formulation comprising a pharmaceutically acceptable carrier, diluent or excipient, and a compound of the invention. Such compositions will range from about 0. 1 percent by weight to about 90.0 percent by weight of the compound of the invention (Active Ingredient). As such, the present invention also provides pharmaceutic formulations comprising a compound of the invention and a pharmaceutically acceptable diluent, diluent or excipient thereof. By making the compositions of the present invention, the active ingredient will usually be mixed with a porfator, or diluted by a porridge, or adjunct with a porler which may run in the form of a capsule, pouch, paper or other container. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, dragees, sachets, seals, elixirs, emulsions, solutions, syrups, suspensions, aerosols (as a solid or in a liquid medium), and gelatin capsules. hard and soft Examples of suitable poisons, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, silicon calcium, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, rubber, gelatin, syrup, methylcellulose, methyl and propylhydroxybenzoates, calcium, magnesium, water and mineral oil. The formulations may also include wetting agents, emulsifying agents and suspension agents, preservatives agents, sweeteners or flavoring agents. The formulations of the invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient, employing procedures well known in the art. For oral administration, the Active Ingredient, a compound of this invention, can be mixed with diluents and diluted and molded in diamonds or enclosed in gelatin capsules. The compositions are preferably formulated in a unit dosage form, each dosage con taining from about 1 to about 500 mg, more usually about 5 to about 300 mg of the Active Ingredient. The term "unit dosage form" refers to physically discrete units suitable as unifarial dosages for human subjects and other mammals, each unit containing a predefined quantity of the calculated active material to produce the desired therapeutic effect, in association with an appropriate pharmaceutical porder. . To more fully illustrate the operation of esía invention, the following formulation examples are provided. The examples are illusory only, and are not intended to limit the scope of the invention. The formulations can be used as an Active Name, any of the compounds of the present invention. FORMULATION 1 Hard gelatin capsules are prepared using the following ingredients: The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities. FORMULATION 2 Capsules that each contain 20 mg of medication, were prepared as follows: The magnesium stearate, magnesium stearate, magnesium stearate and acrylic acid are combined, passed through a U.S. sieve. No. 45 mesh and filled in a hard gelatin capsule.

FORMULATION 3 Capsules that each contain 100 mg of the active ingredient, are elaborated as follows: The old ingredients are mixed uniformly and placed in an empty gelatin capsule. FORMULATION 4 Tablets each containing 10 mg of the active ingredient, are prepared as follows: The active ingredient, starch and cellulose, are passed through a U.S sieve of No. 45 mesh and mixed uniformly. The solution of polyvinylpyrrolidone is mixed with the resulting powders, which are then passed through a U.S. of mesh No. 14. The granule thus produced is dried at 50-60 ° C and passed to fray de yn iammiz U .S. No. 1 8. The sodium carboxymethyl starch, magnesium and falco esarylation, previously passed through a U.S. No. 60 mesh, are then added to the granules, which after mixing, are compressed in a machine of iablefas to give a fable that weighs 1000 mg. FORMULATION 5 A formula of lableía can be prepared using the following ingredients: The components are mixed and compressed to form iableies, each weighing 665 mg. FORMULATION 6 Suspensions that each confers 5 mg of medication per 5 mL of dose, are elaborated as follows: The medication is passed to a doctor from a U.S. No. 45 mesh and mixed with sodium carboxymethylcellulose and syrup, to form a smooth pass. The benzoic acid solution, flavor and color, are diluted with some water and added to the pass with agiíación. Sufficient water is then added to produce the required volume. FORMULATION 7 An aerosol solution is prepared confining the following components: The active compound is mixed with ethanol and the mixture is added to a portion of Propellant 22, cooled to -30 ° C and transferred to a filling device. The required amount is then fed to a stainless steel vessel and further diluted with the propellant resitant quantity. The valve units are then adjusted to the container. Examples Example 1 + 6-. { 4- [2- (Ieirahydro-pyran-4-yl) -erylamino] -cyclohexyloxy} -nicoinamide, Epiapa 1 Preparation of 3,3-dimethy1,5-dioxa-spiro [5.5] undecan-9-ol 3,3-Dimethy1,5-dioxa-spiro [5.5] undecan-9-one (Aldrich, 750 mg, 3.78 mmol) was combined with polymer borohydride (Aldrich, 3026 mg, 7.56 mmol) in methanol (30 mg). mL). The mixture blew away during the night. The reaction mixture was filtered and the filtrate was concentrated. The residue was washed with 0.1 M hydrochloric acid and exfoliated with EOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. Epa 2 Preparation of 6- (3,3-dimethyl-1,5-dioxa-spiro [5.5] undec-9-yloxy) -niconioniolyl A solution of 3,3-dimethy1,5-dioxa-spiro [5.5] undecan-9-ol, (1445 mg, 7.22 mmol) in DMF (2.1 mL) was added to a suspension of sodium hydride. (433 mg, 10.82 mmol) in DMF (8.6 mL). The reaction mixture was allowed to stir at ambient temperature for 1 hour, then heated up while stirring at 50 ° C for 20 min. A solution of 6-chloriconiconifrile (1200 mg) was added by weight., 8.66 mmol) in DMF (4.5 mL). It was coninued by heating at 60 ° C and was stirred during the night. The reaction mixture was concentrated to remove the DMF. The residue was washed with water (1 5 mL) and extracted with EffOAc / hexanes (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (eluent CH 2 Cl 2 / hexanes 2/1) to give 2000 mg (92% yield) of the title compound. Step 3 Preparation of 6- (4-oxo-cyclohexyloxy) -niconioniolyl Hydrochloric acid (1.0 M ac, 20 mL) was combined with a solution of 6- (3,3-dimethy1,5-dioxa-spiro [5.5] undec-9-yloxy) -nicotinonitrile (2000 mg, 6.61 mmol) in acetone (25 mL). It was stirred at ambient temperature for 2 hours, then at 40-50 ° C for 1 hour. The reaction mixture was concentrated. The residue was partitioned between EOAc / hexanes (25 mL) and K2CO3 (aq Sai, 20 mL). The organic layer was washed with water, brine and dried over sodium sulfafo, filtered and concentrated. The residue was treated with EOAc / hexanes (1/4) to give a white solid, which is further purified by flash chromatography (EtOAc / hexanes 1/4) to give 1010 mg (71% yield). yield) as a white solid. Efapa 4 Preparation of 6-. { 4- [2- (Fetrahydro-pyran-4-yl) -erylamino] -cyclohexyloxy} - nicoíinonifrilo, NEA4-A05445-035 The previously obtained 6- (4-oxo-cyclohexyloxy) -nicotinonitrile (200 mg, 0.925 mmol), 2- (teirahydro-pyran-4-yl) -ephilamine (Aldrich, 125 mg, 0.971 mmol) and one tablespoon of Molecular parameters 3A in meianol (4 mL). The reaction mixture was allowed to agitate overnight, and then sodium borohydride (70 mg, 1.85 mmol) was added. The agitation was continued during the night. The reaction mixture was purified by loading onto an SCX column, washing with meianol and eluting with ammonia / mefanol (2.0M). The residue was purified by two insyanine chromosomes (40/1 CH2Cl2 / ammonia in mephanol), to give 199 mg (65%) of the title compound as a pale yellow oil. Step 5 The 6- was combined. { 4- [2- (tetrahydro-pyran-4-yl) -ethylamino] -cyclohexyloxy} -nicoiinoniírilo previously obtained (1 99 mg, 0.604 mmol) and carbonaio de poíasio in DMSO (4 mL). The reaction mixture was cooled to 0 ° C, and then hydrogen peroxide (0.1 81 mL) was added per ml. The reaction mixture was allowed to stir at room temperature for 3 hours. The mixture was tested on water. What was filmed precipitated and redissolved in meianol. Concentrate and purify through an SCX column to give the title compound. Mass spectrum (ion spray): m / z = 348.3 (M + 1); 1 H NMR (CDCl 3): 8.62 (s, 1H), 8.04 (m, 1H), 6.75 (m, 1H), 6.01 (bs, 2H), 5.32 (bs, 1H), 5.07 (m, 1H), 3.97 ( dd, J = 11.0 and 4.0 Hz, 2H), 3.40 (t, J = 11.4 Hz, 2H), 2.73-2.54 (m, 3H), 2.21-2.03 (m, 3H), 1.79-1.28 (m, 12H) . Example 2 + 6- [4- (3-Methy-buylamino) -cyclohexyloxy] -n-coffin amide Using a method similar to Example 1, provided the title compound (199 mg, 96%). Mass speculum (ion spray): m / z = 306.3 (M + 1); 1 H NMR (CDCl 3): 8.66 (s, 1 H), 8.13-8.10 (m, 1 H), 7. 96 (bs, 1H), 7.39 (bs, 1H), 6.81 (m, 1H), 5.17 (s, 1H), 5.00 (m, 1H), 2. 49 (m, 3H), 2.06-1.14 (m, 14H), 0.88 (i, J = 6.6 Hz, 6H). Example 3 + 6- [4- (2-iiophen-2-yl-erylamino) -cyclohexyloxy] -nicofinamide Using a similar method to Example 1, the title compound was provided (203 mg, 87%). Mass spectrum (ion spray): m / z = 346.1 (M + 1); 1 H NMR (CDCl 3): 8.61 (s, 1H), 8.05-8.00 (m, 1H), 7. 17 (m, 1 H), 6.96 (m, 1 H), 6.87 (s, 1 H), 6.98-6.95 (m, 1 H), 6.03 (bs, 2H), 5.31 -5.04 (m, 1 H) , 3.07-2.96 (m, 4H), 2.67-2.55 (m, 1 H), 2.20-2.00 (m, 3H), 1 .78-1 .26 (m, 6H). Example 4 4- [4- (3-phenyl-propylamino) -cyclohexylloxy] -benzamide Step 1 4- (3,3-dimethyl-1,5-dioxa-spiro [5.5] undec-9-yloxy) -benzontromile A solution of 3,3-dimethy1,5-dioxa-spiro [5.5] undecan-9-ol, (NE4-A05445-029, 1377 mg, 6.88 mmol) in DMF (2.0 mL), was added dropwise. a suspension of sodium hydride (412 mg, 10.32 mmol) in DMF (8.0 mL). The reaction mixture was allowed to stir at ambient temperature for 1 hour, then it was heated with stirring at 50 ° C for 20 min. (Min). A solution of 4-fluoro-benzoniiplo (1000 mg, 8.26 mmol) in DMF (4.2 mL) was added by weight. The heating was carried out at 60 ° C and stirred for 2 hours (h). The reaction mixture was concentrated to remove the DMF. The residue was washed with water (15 mL) and extracted with EffOAc / hexanes (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (eluent CH2CI2 / hexanes 2/1) to give xxx mg (xx% yield) of the compound of the extract. Epac 2 4- (4-oxo-cyclohexyloxy) -benzoniiryl Hydrochloric acid (1.0m ac, 20 mL) was combined with an acelline solution (25 mL). It was stirred at room temperature for 2 hours, then at 40-50 ° C for 1 hour. The reaction mixture was concentrated. The residue was partitioned between EtOAc / hex (25 mL) and K2CO3 (sat aq 20 mL). The organic layer was washed with water, brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was triturated with EtOAc / hexanes (1/4) to provide a white solid, which is further purified by insanatose chromatography (EtOAc / hexanes 1/4) to give mg (% yield) as a white solid. Epaque 3 4- (4-oxo-cyclohexyloxy) -benzamide 4- (4-Oxo-cyclohexyloxy) -benzonifril was combined previously obtained (100 mg, 0.464 mmol), K2CO3 (32 mg, 0.232 mmol) in DMSO (23 mL). The reaction mixture was cooled to 0 ° C and hydrogen peroxide (0.1 39 μL) was added. The reaction mixture was allowed to stir for 4 hours at ambient temperature. The reaction mixture was quenched with water (15 mL). Extract with EOAc / 2/1 hex (3 x 20 mL). It was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (20/1 CH2Cl2 / ammonia in 2.0M methanol) to give the title compound (40 mg, 37%). Epa 4 Combined 4- (4-oxo-cyclohexyloxy) -benzamide (20 mg, 0.085 mmol), 3-phenyl-propylamine (1 1 mg, 0.085 mmol), iaceroxyborohydride (23 mg, 0.1 1 1 mmol) and acetic acid (5 μL, 0.085 mmol) in CH2Cl2 (1 mL). He let himself be agitated during the night. It was purified by SCX column (ammonia in 2.0 M meianol). The residue was rinsed with 1/4 EOAc / hexanes to give a white powder (25 mg, 86%). Example 5 rrans-6- (4-benzylamino-cyclohexyloxy) -nicoyinamide EIApa 1 4-benzylamino-cyclohexanol Rrans-4-amino-cyclohexanol (2.0 g, 17.4 mmol) was combined in meianol (75 mL) in a sealed tube, then benzaldehyde (1.85 mL, 18.23 mmol) was added. The reaction mixture was heated to 70 ° C while stirring for 2 hours. The reaction was then allowed to cool down and sodium borohydride (2.46 g, 65.1 mmol) was added in portions. It stirred during the night. The solvent was evaporated to 1/3 of the original volume. The reaction mixture was partitioned between EOAc (50 mL) and water (40 mL). The aqueous layer was extracted again with EtOAc (20 mL). The organic layers were combined and dried over sodium sulfate. It was filtered and concentrated to give the title compound (3.5 g) which will be used direcfamenie in the next step. Ephapa 2 6- (4-benzylamino-cyclohexyloxy) -nicotinonitrile A solution of 4-benzylamino-cyclohexanol (675 mg, 3.28 mmol) in DMF (2 μL) was added by dropwise to a suspension of NaH (196 mg, 4.92 mmol) in DMF (3 mL). It stirred at an instant ambienfe for 45 minutes, then at 50 ° C for 40 additional minutes. A solution of 6-chloro-nicoininoniiril (500 mg, 3.61 mmol) in DMF (1.8 mL) was added by scoring and was stirred overnight at 60 ° C. The reaction mixture was cooled down and the solveny evaporated. The residue was washed with water (10) and extracted with EOAc / hex (2/1, 15 mL). The organic layers were combined and dried over sodium sulfate. They filmed and concentrated. The resulting residue was purified through an SCX column. Furthermore, it was purified by chroma- ography [CH2CI2 / NH3 (2.0 M in mei- tanol) 20/1] to give the compound of the extract (890 mg, 88%). Step 3: K2CO3 (200 mg, 1.44 mmol) was added to a solution of 6- (4-benzylamino-cyclohexyloxy) -nicofinoniyryl (890 mg, 2.89 mmol) in DMFSO (25 mL). The reaction was cooled to 0 ° C and hydrogen peroxide (0.87 mL) was added. The resulfanfe reaction mixture was stirred at ambient temperature for 2 hours. Then the reaction mixture was quenched with water (25 mL) and exujouled with EfOAc (30 mL). Dried over sodium sulfate, filtered and concentrated. The residue was further purified by SCX chromatography to give the title compound (700 mg, 74%). Mass spectrum (ion spray): m / z = 326.0 (M + 1); 1 H NMR (CDCl 3): 8.61 (s, 1 H), 8.04 (m, 1 H), 7.36 (m, 5 H), 6.74 (d, J = 8.8 Hz, 1 H), 5.10 (m, 1 H) , 3.87 (s, 2H), 2.64 (m, 1 H), 2.22-2.07 (m, 4H), 1 .58-1 .33 (m, 4H).

Example 6 6- (1-pyridin-2-ylmethyl-piperidin-4-yloxy) -nicofinamide Epaque 1 4- (5-Cyano-pyridin-2-yloxy) -piperidine-1-carboxylic acid eery-builic acid ester A 4-hydroxy-piperidin-1-carboxylic acid ester solution (1210 mg, 6.01 mmol) in DMF (1.8 mL) was added dropwise to a suspension of NaH (360 mg, 9.02 mmol) in DMF (7.2 mL). It was stirred at room temperature for 45 minutes, then at 50CC for an additional 40 minutes. A solution of 6-chloro-nicoininoniiril (1000 mg, 7.22 mmol) in DMF (3.6 mL) was added by wiping, and it was stirred overnight at 60 ° C. The reaction mixture was cooled down and the solvenle was evaporated. The residue was washed with water (10) and extracted with EOA / hex (2/1, 1 mL). The organic layers were combined and dried over sodium sulfate. They were filified and purified. The resulting residue was purified through an SCX column. It was also purified by chromaphography [CH2CI2 / NH3 (2.0M in meianol) 20/1] for the title compound (1.73 g, 94%).

Epa 2-4- (5-carbamoyl-pyridin-2-yloxy) -piperidine-1-carboxylic acid tert-butyl ester A solution of 4- (5-cyano-pyridin-2-yloxy) -piperidin-1-carboxylic acid eerc-buííl ester (1630 mg, 5.38 mmol) in DMSO (50 mL) with potassium carbonate (371 mg) was combined. 2.69 mmol). The solution was cooled to 0 ° C and hydrogen peroxide (1.61 mL) was slowly added. After 10 minutes, the reaction mixture was stirred at room temperature for 2 hours. Water (25 mL) was added and exiguated twice with CH2Cl2 (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (1669 mg, 97%) as a white solid. Stage 3 Chlorhydrate of 6- (piperidin-4-yloxy) -nicotinamide 4- (5-Carbamoyl-pyridin-2-yloxy) -piperidin-1-carboxylic acid tert -butyl ester (1559 mg, 4.85 mmol) in teirahydrofuran (25 mL) was combined with hydrochloric acid (4.0 M in dioxane, mL). The resulting mixture was agitated for 48 hours. Filtered, the white precipitate was washed with EtOAc (10 mL). The white solid was redissolved in methanol and concentrated to give the title compound (1195 mg, 89%). Eiapa 4 6- (Piperidin-4-yloxy) -nicinoinamide (100 mg, 0.45 mmol) was combined with sodium triacetoxy borohydride (124 mg, 0.59 mmol) and pyridine-2-carbaldehyde (43 μL, 0.45 mmol) in CH 2 Cl 2 (1.5 mL). The reaction mixture was stirred for 3 hours. The reaction mixture was then diluted with CH2Cl2 (5 mL) and washed with NaOH (1M aq, 5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified through SCX chromatography to provide the title compound (83 mg, 59%). Mass spectrum (ion spray): m / z = 313.1 (M + 1); 1 H NMR (DMSO-d 6): 8.67 (ad, J = 2.2 Hz, 1H), 8.50 (m, 1H), 8.12 (dd, J = 2.6 and 8.8 Hz, 1H), 7.98 (bs, 1H), 7.80- 7.76 (m, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.41 (bs, 1H), 7.29-7.26 (m, 1H), 6.84 (d, J = 8.8 Hz, 1H), 5.10 (m , 1H), 3.63 (m, 2H), 2.77-2.74 (m, 2H), 2.35-2.30 (m, 2H), 1.99 (bs, 2H), 1.75-1.69 (m, 2H). Example 7 6- (1-cyclopropylmethyl-piperidin-4-yloxy) -nicoyinamide Using a similar method to Example 6, the compound of the title (89 mg, 72%). Mass spectrum (ion spray): m / z = 276.1 (M + 1); H NMR (DMSO-d6): 8.66 (m, 1H), 8.12 (app.dd, J = 2.2 and 8.3 Hz, 1H), 7.97 (bs, 1H), 7.40 (bs, 1H), 6.84 (app. , J = 8.3Hz, 1H), 5.08-5.03 (m, 1H), 2.82 (bs, 2H), 2.52 (s, 1H), 2.27-2.20 (m, 3H), 1.99 (m, 2H), 1.72 ( m, 2H), 0.86-0.83 (m, 1H), 0.50-0.45 (m, 2H), 0.10-0.07 (m, 2H). Example 8 6- [1- (1H-indol-2-ylmethyl) -piperidin-4-yloxy] -nicoyinamide Using a similar method to Example 6, the compound of the extract was provided (110 mg, 70%). Mass spec (ion spray): m / z 351.1 (M + 1). Example 9 4- (1-benzyl-piperidin-4-yloxy) -benzamide Epaque 1 4- (4-cyano-phenoxy) -piperidine-1-carboxylic acid tert-butyl ester A solution of N-Boc-4-hydroxypiperidine (3-0 g) was added, 14.9 mmol) in DMF (5 mL), to a suspension of sodium hydride (894 mg, 22.4 mmol) in DMF (17 mL). The reaction mixture was stirred while heating at 50 ° C for 45 min. Then, a solution of 4-fluoro-benzonifril (2.16 g, 17.9 mmol) in DMF (5 mL) was added. It was stirred and heated at 50 ° C for 2 hours. It was allowed to cool to ambient temperature and quenched with water (0.5 mL). The DMF was evaporated. The residue was redissolved in EtOAc / hexanes (2/1, 20 mL) and washed with water (3 x 15 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated. Purified by chromatography (20% EtOAc / hexanes and 10% EtOAc / hexanes) to give the title compound (2.32 g, 52%). Stage 2 4- (Piperidin-4-yloxy) -benzoniiryl hydrochloride Acetyl chloride (2.5 mL) was added dropwise to meianol (5.0 mL) at 0 ° C. The resulfanie solution was agitated at 0 ° C for 90 min. Then a solution of 4- (4-cyano-phenoxy) -piperidine-1-carboxylic acid eerc-buílic acid ester (284 mg, 0.94 mmol) in methanol was added. The resulting mixture was stirred for 3 hours. Solvent was evaporated and triturated with diethyl ether to provide the title compound (216 mg, 96%). Stage 3 4- (1-benzyl-piperidin-4-yloxy) -benzoniiryl 4- (Piperidin-4-yloxy) -benzonitrile hydrochloride was combined (64 mg, 0.268 mmol), benzaldehyde (55 μL, 0.536 mmol) and sodium idriaceoxy borohydride (85 mg, 0.402 mmol) in CH2Cl2 (3 mL). He stirred in ambient air during the night. The reaction mixture was diluted with CH 2 Cl 2 (3 mL) and washed with NaOH (1 M ac 5 mL). The organic layer was separated and placed on an SCX column, eluting with ammonia (2.0M in meianol), to provide the title compound (74 mg, 95%). Step 4 4- (1-Benzyl-p -pep'din-4-yloxy) -benzonitrile (74 mg, 0.25 mmol), DMSO (2.5 mL) and potassium carbonate powder (18 mg, 0.13 mmol) were combined. The resulting mixture was cooled to 0 ° C and hydrogen peroxide (76 μL) was added. After the addition, the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with water (2 mL). The precipitate formed was filtered by rinsing with diethyl ether to give the compound of the extract (57 mg, 73%). Mass speculum (ion spray): m / z = 31 1 .1 (M + 1); 1 H NMR (CDCl 3): 7.79 (ad, J = 8.6 Hz, 3H), 7.32-7.21 (m, 5H), 7.14 (bs, 1 H), 6.95 (d, J = 8.6 Hz, 2H), 4.49- 4.42 (m, 1 H), 3.31 (s, 2H), 2.69-2.62 (m, 2H), 2.27-2.19 (m, 2H), 1 .96-1 .89 (m, 2H), 1 .66- 1.56 (m, 2H). Example 10 4- [1 - (3-phenyI-propyl) -piperidin-4-yloxy] -benzamide Stage 1: 4- (4-carbamoyl-phenoxy) -piperidine-1-carboxylic acid eeri-buílic acid ester The 4- (4-cyano-phenoxy) -piperidine-1-carboxylic acid tert-butyl ester, Example 9, step 1, 215 mg, 0.71 mmol) and potassium carbonate (49 mg, 0.36 mmol) in DMSO were combined. (35 mL) at 0 ° C. Then hydrogen peroxide (213 μL) was added dropwise. It was then agitated at room temperature for 1 hour. The reaction was quenched with water (10 mL) and extracted with EtOAc / hexanes (2/1, 3x20 mL). The organic layers were combined, dried over magnesium sulfate, filirado and concentrated to give the compound of the extract. Eyelid 2 Chlorhydrate of 4- (piperidin-4-yloxy) -benzamide Hydrochloric acid (4M in dioxane, 3 mL) was added dropwise to a solution of 4- (4-carbamoyl-phenoxy) -piperidin-1-carboxylic acid eeryc-buyl ester (228 mg, 0.71 mmol) in THF ( 2 mL). It was stirred at ambient temperature for 7 hours (h). The solids were filtered and dried under reduced pressure to give the title compound (180 mg, 99%) as the hydrochloride. Step 3 4- (Piperidin-4-yloxy) -benzamide hydrochloride (102 mg, 0.397 mmol), 3-phenyl-propionaldehyde (106 μL, 0.796 mmol) and triacetoxy borohydride (127 mg, 0.597 mmol) in CH2Cl2 were combined. (3 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with CH2Cl2 (3 mL) and washed with sodium hydroxide (1 N, aq.50 mL). The organic layer was separated and placed on an SCX column directly eluting with ammonia (2.0 in meianol). The resulfant residue was triturated with CH2Cl2 and diethyl ether to give the title compound (63 mg, 47%) as a white solid, mass speculum (ion spray): m / z = 339.1 (m + 1); 1 H NMR (CDCl 3): 7.79 (ad, J = 9.0 Hz, 3 H), 7.28-7.12 (m, 6 H), 6.95 (d, J = 9.0 Hz, 2 H), 4.74-4.40 (m, 1 H), 2.70 -2.63 (bm, 2H), 2.56 (í, J = 7.6 Hz, 2H), 2.31 -2.25 (bm, 2H), 2.22-2.1 5 (bm, 2H), 1 .96-1.89 (bm, 2H) ), 1 .71 (peníet., J = 7.3 Hz, 2H), 1 .63-1 .56 (m, 2H).

Claims (4)

1. CLAIMS 1. A compound of formula (I) characteized because each of X. , X2, X3, X, and X5 is C, CH, or N; as long as ring B does not have more than 2 nickel atoms; X is NH or CH2, so that ring A is cyclohexyl, cyclohexenyl, or piperidinyl; E is NH or O; v is 0, 1, 2, or 3; q is 0 or 1, provided that when ring A is cyclohexyl or cyclohexenyl q is 1 and provided that v and q are not simulinely 0; R1 and R2 are independently selected from hydrogen, d-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C3-C8 cycloalkyl, alkylaryl d-C10, heterocyclic, alkylheterocyclic dC .., alkyl Ci-C8C (O) alkyl d-C8, - (CH2) n (CO) C3-C8 cycloalkyl, C2-C8CH alkyl (OH) aryl, -CO (O) d-C8 alkyl, -SO2alkyl C, -C8, SO2alkylaryl C -? - C10 . SO2alkylheterocyclic d-C8, alkylcycloalkyl d-C8, - (CH2) nC (O) OR8, - (CH2) nC (O) R8, - (CH2) mC (O) NR8R8 and - (CH2) mNSO2R8; wherein each of the alkyl, alkenyl, cycloalkyl, heteroaryl and aryl groups are optionally susíifuidos with one to five independently selected groups of halo, C?-C8 haloalkyl, d-C8 ioalkyl, d-C8 alkyl, C2-C8 alkenyl, aryl, d-C8 alkylaryl, -C (O) d-C8alkyl, -SO2alkyl d -C8, -SO2alkullaryl C -? - C8, -alkylcycloalkyl d-C8; and wherein R1 and R2 may optionally be combined together to form a heterocycle that contains 4, 5, 6 or 7 elements of nihologen, in which the heterocycle containing nihologen may further have substituents selected from the group consisting of amino, alkyl d-C8, C2-C8 alkenyl, C2-C8 alkynyl, aryl, d-C8 alkylaryl, -C (O) C? -C8 alkyl, -CO (O) d-C8 alkyl, halo, oxo, haloalkyl C? C8; R3 and R3 'are each independently selected from hydrogen, C-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, -alkylcycloalkyl d-C8, or -alkylaryl C? -C8; C1-C8 alkyl-cyclic alkyl; or R3 and R3 'combine to form a C3-C8 cycloalkyl, C4-C8 cycloalkenyl, or C5-C6 helerocyclic; R 4 and R 5 are each independently selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 alkoxyalkyl, d-C 8 -alioxy, halo, d-C 8 haloalkyl, α-alkoxyhaloalkyl -C8, aryl, -D-C8alkylaryl, -C (O) C? -C8 alkyl, or -C (O) O-C, -C8 -alkylamino, C? -C8alkylamino, C? -C8alkylcycloalkyl, - ( CH2) mC (O) alkyl dd, and (CH2) nNR8R8, wherein each R4 or R5 is attached to its respective ring only at low carbon, and where y is 0, 1, 2 or 3; and wherein z is 0, 1 or 3; R6 and R7 are each independently selected from hydrogen, d-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -C (O) alkyl
2. C? -C8, hydroxy, C? -C8 alkoxy, -SO2C? -C8alkyl, C2-C8 SO2alkylaryl, dd2-alkylheterocyclic acid, aryl, d-C? Alkylaryl, C3-C7cycloalkyl,? -6-alkylcycloalkyl,? (CH2) nC (O) R8, - (CH2) mC (O) NR8R8, and - (CH2) mNSO2R8; wherein each of the alkyl, alkenyl and aryl groups are optionally substituted with one to five independently selected groups of d-C8 alkyl, C2-C8 alkenyl, aryl, and d-C8 alkylaryl; and wherein R6 and R7 can independently be combined together to form a heterocycle containing 4, 5, 6 or 7 elements of nihologen, in which the nitrogen-containing cyclohexane may optionally have susiiogens selected from the group consisting of oxo, alkyl Cr C8, C2-C8 alkenyl, C2-C8 alkynyl, aryl, -C? -C8 alkylaryl, -C (O) C-alkyl. -C8, -CO (O) C, -C8 alkyl, hydroxy, d-C8 alkoxy, -alkylamino d-C8, amino, halo, and haloalkyl; R8 is hydrogen, d-C8 alkyl, C2-C8 alkenyl, d-C8 alkylaryl, -C (O) d-C8 alkyl, or -C (O) C8-C8alkyl; and wherein n is 0, 1, 2, 3 or 4 and m is 1, 2, or 3; or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomer or mixtures of disherereomers thereof. 2. The compound in accordance with the claim 1, characterized in that ring A is cyclohexyl. 3. A compound according to claim 1, characterized in that ring B is selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine and pyridazine. 4. A compound in accordance with the claim 1, characterized in that ring A is piperidinyl. 5. A compound according to claim 1, characterized in that E is an oxygen atom. 6. A compound according to claim 1, characterized in that y is 0, 1, or 2, and R4 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, meioxy, eioxy, meyilo, efilo, isopropyl, Irifluoromethyl, urea fluoride, phenyl and benzyl. 7. A compound according to claim 1, characterized in that z is 0, 1 or 2, and R5 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, meioxy, eoxy, me yl, ethyl, isopropyl, orifluoromethyl , trifluoromethoxy, phenyl and benzyl. 8. A compound according to claim 1, characterized in that R1 and R2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, and wherein n is 1, 2 or 3. The compound according to claim 1, characterized in that R6 and R7 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, phenyl. 10. A compound according to claim 1, characterized in that E is an oxygen atom, and R6 and R7 are both hydrogen atoms. eleven . A compound according to claim 1, characterized in that v is 1 or 2. 12. A compound according to claim 1, characterized in that v is 1, m is 1, n is 1, and is 0 or 1 and z is O or 1. 13. A characeristic compound because it is selected from the group consisting of: 6-. { 4- [2- (Hydro-pyran-4-yl) -ethylamino] -cyclohexyloxy} -nicofinamide, 6- [4- (3-Methy! -butyamino) -cyclohexyloxyJ-n-cocoynamide 6- [4- (2-Thiophene-2-yl-ethylamino) -cyclohexyloxy] -nicoyinamide 4- [4- (3-Phenyl-propylamino) -cyclohexyloxy] -benzamide
3. RRA /? s-6- (4-Benzylamino-cyclohexyloxy) -nicoxyamide 6- (1-Pyridin-2-ylmethyl-piperidin-4-yloxy) -nicoyinamide 6- (1-Cyclopropylmethyl-piperidin-4-yloxy) -nicotinamide 6- [1- (1 H-lndol-2-ylmethyl) -piperidin-4-yloxy] -nicoin one way 4- (1-Benzyl-piperidin-4-yloxy) -benzamide
4. 4- [1 - (3-Phenyl-propyl) -piperidin-4-yloxy] -benzamide and a salt, solvate, enaniomer, diasphereomer or diastereomeric mixture thereof, pharmaceutically acceptable. 14. A compulsion in accordance with the claim 1, characterized in that the pharmaceutically acceptable salt is the hydrochloride salt, mephsulfonic acid salt, bromhydrate salt, bisulfate salt or salt of tariaric acid. 15. A pharmaceutical composition characterized in that it comprises an ephemeral efficacy of a compound according to claim 1, in association with a porker, diluent and / or excipient. 16. A method for blocking a mu, kappa, delia, or combination thereof (heferodimer) receptor in mammals characterized in that it comprises administering to a mammal that requires blocking of a mu, kappa, delta or combination thereof receptor (heterodimer), a receptor blocking dose of a compound according to claim 1, or a salt, enantiomer, racemafo, mixture of diastereomers or solvate thereof, pharmaceutically acceptable. 1 7. A method for treating and / or preventing diseases related to obesity, characterized in that it includes irritable bowel syndrome, nausea, vomiting, depression related to obesity, anxiety related to obesity, addiction to cigarettes and alcohol, sexual dysfunction, abuse of medications, overdose of drugs, disorders of addictive behavior, meiabolic diseases of compulsions and compulsive symtoms thereof, and stroke, which comprises administering an effective epileptic minimalism of a compound of formula I. 1 8. A method for fraying and / or to prevent obesity and related diseases, characterized in that it comprises administering an effectively epileptic quality of a compound of formula I to a patient in need thereof. 9. A method for suppressing appetite in a patient in need thereof, characterized in that it comprises administering an effective ephedrine quantity of a compound of formula I. 20. A method to effect weight loss in an obese patient, characterized in that it comprises administering an effective amount of a compound of formula I or a salt, solvate, racemate or enaniomer thereof, pharmaceutically acceptable,. twenty-one . A pharmaceutical composition for the framaria and / or relief of symphomas associated with obesity and related diseases, characterized in that it contains as an active ingredient, a compound of formula I according to claim 1.