MXPA01006789A - 3,3-biarylpiperidine and 2,2-biarylmorpholine derivatives - Google Patents

Abstract

The present invention relates to compounds of formula (I), wherein Z1, Z2, X, Q, R1, R2 and R3 are defined as in the specification, pharmaceutical compositions containing such compounds, the use of such compounds to treat neurological and gastrointestinal disorders.

Description

DERIVATIVES OF 3.3-BIARILPIPERIDINA AND 2,2-BIARILMORFOLINA BACKGROUND OF THE INVENTION This invention relates to 3,3-biarylpiperidine and 2,2-biarylmorpholine derivatives which have utility as ligands for opioid receptors. In the study of opioid biochemistry, a variety of endogenous opioid compounds and non-endogenous opioid compounds have been identified. This effort has led to significant research to understand the mechanism of action of the opioid drug, particularly in those that refer to opioid receptors of differentiated and cellular tissue. Opioid drugs are typically classified by their binding selectivity with respect to differentiated and cellular tissue receptors to which a specific drug species binds as a ligand. These receptors include mu (μ), delta (d) and kappa (K) receptors. At least three subtypes of opioid receptors are described (mu, delta, and kappa), and documented in the scientific literature. The three receptors are present in the central and peripheral nervous systems of many species, including man. The activation of delta receptors produces antinociception in rodents and can produce analgesia in humans, as well as influencing the mobility of the gastrointestinal tract.

(See Burks, T.F. (1995) in "The Pharmacology of Opioid Peptides," edited by Tseng, L.F., Harwood Academic Publishers).

Well-known narcotic opioids, such as morphine and its analogs, are selective for the mu opioid receptor. Mu receptors mediate analgesia, respiratory depression and inhibition of the gastrointestinal tract. Kappa receptors mediate analgesia and sedation. The existence of the delta opioid receptor is a relatively recent discovery that was a consequence of the isolation and characterization of endogenous enkephalin peptides, which are ligands for the delta receptor. Research over the past decade has produced significant information about the delta receptor, but a clear picture of its function has not yet emerged. The delta receptors mediate analgesia, but do not appear to inhibit intestinal passage in the characteristic form of mu receptors. The patent of E.U.A. 4,816,586, which was issued on March 28, 1989, of P.S. Portoghese, refers to various delta opioid receptor antagonists. These compounds are described as possessing a unique antagonist profile of the opioid receptor, and include compounds that are highly selective for the delta opioid receptor. The patent of E.U.A. 4,518,711, which was issued May 21, 1985, by V. J. Hruby et al., Describes cyclic analogues, conformationally of enkephalins. These compounds include both delta receptor agonists and antagonists, and are said to induce pharmacological and therapeutic effects such as analgesia in the case of agonist species of such compounds. It is suggested that the agonist species of the The compounds described are useful in the treatment of schizophrenia, Alzheimer's disease, and respiratory and cardiovascular functions. S. Goenechea, et al., In "Investigation of the Biotransformation of Meclozine in the Human Body", J. Clin. Chem. Clin. Biochem., 1988, 26 (2), 105-15, describes the oral administration of a polyarylpiperizine compound in a study of meclozine metabolism in human patients. In "Plasma Levéis, Biotransformation and Excretion of Oxatomide in Rats, Dogs, and Man", Xenobiotica, 1984, 15 (6). 445-62, Meuldermans, W., et al., Refers to a metabolic study of plasma levels, biotransformation and excretion of oxatomide. T. Iwamoto, et al., In "Effects of KB-2796, to New Calcium Antagonist, and Other Diphenylpiperazines on [3H] nitrendipine Binding", Jpn. J. Pharmacol., 1988, 48 (2), 241-7, describes the effect of a polyarylpiperazine as a calcium antagonist. K. Natsuka, et al. in "Synthesis an Structure Activity RelationShips of 1 -Substituted 4- (1, 2-Diphenylethyl) Piperazine Derivates Having Narcotic Agonist and Antagonist Activity "J. Med. Chem, 1987, 30 (10), 1779-1787, describes racemates and enantiomers of 4- [-] derivatives. 1- (substituted) 2- (3-hydroxyphenyl) -1-phenylethyl] -piperazine The European patent application No. 458,160, published on November 27, 1991, refers to certain substituted diphenylmethane derivatives as analgesic and anti-inflammatory agents, including that the bridge methylene group (linking two phenyl moieties) is substituted on the methylene carbon with a piperidinyl or piperazinyl group South African patent application No. 8604522, which was published on December 12, 1986, refers to certain compounds amino-substituted heterocyclics aryl-alkylene and arylalkyl N-substituted, including piperidine derivatives, such as cardiovascular, antihistaminic, and antisecretory agents European Patent Application No. 133,323 , published on February 20, 1985, refers to certain diphenylmethyl piperazine compounds as non-sedating antihistamines. There is a continuing need in the art for improved opioid compounds, particularly compounds that are free from the addictive nature and other adverse side effects of conventional opiates such as morphine and fetidine. The applicant has discovered a new class of derivatives of 3,3-biarylpiperidine and morpholine which are potent and selective opioid delta ligands, and are useful for the treatment of rejection of organ transplants and skin grafts, non-somatic pain, stroke, cerebral ischaemia, shock, brain trauma, spinal trauma spinal, cerebral edema, Hodgkin's disease, Sjogren's disease, systemic lupus erythematosus, gastrointestinal disorders such as gastritis, functional bowel disease, irritable bowel syndrome, functional diarrhea, functional distension, non-ulcerogenic dyspepsia and other disorders of mobility or secretion, and emesis, acute pain, chronic pain, neurogenic pain, non-somatic pain, allergy, respiratory disorders such as asthma, cough and apnea, inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis and inflammatory bowel disease, urogenital duct disorders such as incontinence urinary, hypoxia (for example, perinatal hypoxia), neuron damage to the hypoglycemic, dependencies and addictions of chemical compounds (for example, dependence or addiction to opiates, benzodiazepines, cocaine, nicotine, ethanol), drug or alcohol withdrawal syndrome, and brain deficits after surgery and cardiac bypass grafting.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to compounds of the formula wherein R1 is hydrogen, (C0-C8) alkoxy-alkyl (CrC8) -, wherein the total number of carbon atoms is eight or less, aryl, aryl-alkyl (CrC8) -, heteroaryl, heteroaryl- (C -? - C8) -, heterocyclic, heterocyclic-alkyl (C? -C8), cycloalkyl (C3-C7) -, or (C3-C7) -cycloalkyl-alkyl (C? -8) alkyl, wherein said aryl and the aryl moiety of said aryl-alkyl (C? -8) -are independently selected from phenyl and naphthyl, and wherein said heteroaryl and the heteroaryl moiety of said heteroaryl-alkyl (C? -C8) -are independently selected from pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, cabazolyl, 1, 2,5-thiadiazolyl, quinazoninyl, pyridazinyl, pyrazinyl, cinolinyl, phthalazinyl, quinoxalinyl, xanthinyl , hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolyl, oxadiazole ilo, isoxazolyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyridinyl, and pyrimidinyl; and wherein said heterocyclic and the heterocyclic moiety of said heterocyclic-alkyl (CrC8) - are selected from monocyclic or bicyclic non-aromatic saturated or unsaturated ring systems, said monocyclic ring systems containing from four to seven carbon atoms in the ring, one to three of which may be optionally replaced by O, N or S, and containing said bicyclic ring systems of seven to twelve carbon atoms in the ring, one to four of which may be optionally replaced by O, N or S; and any of the aryl, heteroaryl or heterocyclic radicals of R being optionally substituted with one to three substituents, preferably with one or two substituents, independently selected from halo (ie, chloro, fluoro, bromo or iodo), alkyl (C? -C6) optionally substituted with one to seven (preferably with zero to four) fluorine, phenyl, benzyl, hydroxyl, acetyl, amino, cyano, nitro, alkoxy (C? -C6), alkyl (C? -C6) amino atoms and [alkyl] any of the alkyl moieties in R1 (eg, the alkyl moieties of the alkyl, alkoxy or alkylamino groups) being optionally substituted with one to seven (preferably with zero to four) fluorine atoms; R2 is hydrogen, aryl, heteroaryl, heterocyclic, SO2R4, COR4, CONR5R6, COOR4, or C (OH) R5R6, wherein R4, R5 and R6 are independently defined, as R1 is defined above, or R5 and R6 together with the carbon or nitrogen to which both are attached, form a saturated ring of three to seven members containing from zero to three selected heterocarbons, independently of O, N and S, and said aryl, heteroaryl, and heterocyclic being defined as such terms are defined above in the definition of R1 and any of the aryl, heteroaryl residues may be and R 2 heterocyclic are optionally substituted with one to two substituents, independently selected from halo (ie, chloro, fluoride, bromine or iodine), (C) Cs alkyl optionally substituted with one to seven (preferably with zero to four) fluorine, phenyl, benzyl, hydroxyl, acetyl amino, cyano, nitro, alkoxy (C C6) optionally substituted with one to seven (preferably with zero to four) fluorine atoms, alkyl (Cyclamine and [alkyl (C? C6)] 2a? T? No; R3 is hydroxyl, -NHSO2R7, -C (OH) R7R8, -OC (= O) R7, fluorine or-CONHR7, wherein R7 and R8 are the same or different and are selected of hydrogen, alkyl (C- | -C4), alkoxy (CC) and alkoxy (CrC4) -alkyl (CrC4), having a total of four or fewer carbon atoms, and in which any of the alkyl residues of R7 and R8 may optionally be substituted with one to seven (preferably with zero to four) fluorine atoms; Q is oxygen or CH2; X is CH or N; and Z1 and Z2 are independently selected from hydrogen, halo and alkyl (C5); With the proviso that there are no two adjacent ring oxygen atoms and there is no oxygen atom of the ring adjacent either to a ring nitrogen atom or to a ring sulfur atom in any of the heterocyclic or heteroaryl moieties of formula I; and pharmaceutically acceptable salts of such compounds. Preferred compounds of formula I include those in which Q is CH2. Other preferred compounds of formula I are those in which X is CH. Other preferred compounds of formula I are those in which R3 is OH, CONH2, or fluoro. Other preferred compounds of formula I are those wherein R2 is selected from C (OH) (C2H6) 2, CON (C2H6) 2, CONCH3 (C2H6) and the following cyclic groups: (a) (b) (c) (d) (e) (f) Other preferred compounds of formula I are those in which Z1 and Z2 are independently selected from hydrogen and fluorine. Other preferred compounds of formula I are those in which R 1 is selected from allyl, cyclopropylmethyl, methyl, 2,2,2-trifluoromethyl, methallyl, isopropyl, 2-pyrimidinyl and Examples of other embodiments of the present invention are the following: Compounds of the formula I wherein Q is oxygen and X is CH; compounds of the formula I in which Q is oxygen and X is N; compounds of the formula I in which Q is oxygen, X is CH and R3 is OH, CONH2, or fluoro; compounds of the formula I in which Q is oxygen and X is N; compounds of formula I wherein Q is CH2, X is N, and R3 is OH, CONH2, or fluoro; compounds of formula I wherein Q is CH2, X is N, R3 is OH, CONH2 > or fluoro, and R2 is selected from C (OH) (C2H6) 2 and one of the cyclic groups (a) - (f) drawn above; and compounds of the formula I wherein Q is oxygen, X is CH and R3 is OH, CONH2, or fluoro; compounds of the formula I in which Q is oxygen, X is NH, R3 is OH, CONH2, or fluoro, and R2 is selected from C (OH) (C2H6) 2, CON (C2H6) 2 and one of the cyclic groups (a) - (f) drawn previously; compounds of the formula I in which Q is oxygen, X is CH, R3 is OH, CONH2, or fluoro, Z1 and Z2 are independently selected from hydrogen and fluoro, and R1 is selected from allyl, cyclopropylmethyl, methyl, , 2,2-trifluoroethyl, methallyl, isopropyl, 2-pyridinyl, 2-pyrimidinyl and a cyclic group (g) shown above, and compounds of formula I wherein Q is oxygen, X is NH, R3 is OH, CONH2 , or fluoro, Z1 and Z2 are selected, independently, of hydrogen and fluoro, and R 1 is selected from allyl, cyclopropylmethyl, methyl, methallyl, isopropyl, 2-pyridinyl, 2-pyrimidinyl and a cyclic group (g) shown above. The compounds of formula I and their pharmaceutically acceptable salts are opioid receptor ligands, and are useful in the treatment of a variety of neurological and gastrointestinal disorders. Examples of disorders that can be treated with the compounds of formula I and their pharmaceutically acceptable salts are rejection in organ transplants and skin grafts, epilepsy, chronic pain, neurogenic pain, non-somatic pain, stroke, cerebral ischemia, shock, cerebral trauma, spinal cord trauma, cerebral edema, Hodgkin's disease, Sjogren's disease, systemic lupus erythematosus, gastrointestinal disorders such as gastritis, functional bowel disease, irritable bowel syndrome, functional diarrhea, functional distension, non-ulcerogenic dyspepsia and others disorders of mobility or secretion, and emesis, acute pain, chronic pain, neurogenic pain, non-somatic pain, allergy, respiratory disorders such as asthma, cough and apnea, inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis and inflammatory bowel disease, disorders of the urogenital duct such as urinary incontinence, hi poxia (for example, perinatal hypoxia), hypoglycemic neuronal damage, dependencies and addictions of chemical compounds (for example, dependence or addiction to opiates, benzodiazepines, cocaine, nicotine or ethanol), drug or alcohol withdrawal syndrome, and subsequent brain deficits to the surgery and graft of cardiac bypass. The present invention also relates to the acid addition salts and pharmaceutically acceptable base addition salts of the compounds of formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the above-mentioned base compounds of this invention are those which form non-toxic acid addition salts, ie, salts containing pharmaceutically acceptable anions, such as the salts of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, t-toluenesulfonate and pamoate [ie, 1,1'-methylene-bis- (2-hydroxy-3- naphtoate)]. The chemical bases which are used as reactants for preparing the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula I. Such non-toxic base salts include those which are obtained from pharmaceutically cations acceptable such as sodium, potassium, calcium and magnesium, etc. The present invention also relates to the pharmaceutically acceptable base addition salts of the compounds of formula I. These salts are all prepared by conventional techniques. The chemical bases which are used as reactants for preparing the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula I. Such non-toxic base salts include those which are obtained from pharmaceutically cations acceptable such as sodium, potassium, calcium and magnesium, etc. For a study on pharmaceutically acceptable salts, see Berge and cok, J. Pharm. Sci., 66, 1-19 (1977). This invention also relates to a pharmaceutical composition for treating a disorder or condition, which treatment or prevention can be effected or facilitated by modulating (ie, increasing or decreasing) the binding to opioid receptors in a mammal, including the human being, which comprises an amount of a compound of formula I, or a pharmaceutically effective salt thereof, which is effective to treat such disorder or condition, and a pharmaceutically acceptable vehicle.

This invention also relates to a method for treating a disorder or condition, which treatment or prevention can be effected or facilitated by modulating the binding to opioid receptors in a mammal, which comprises administering to a mammal in need of such treatment an amount of a compound of formula I, or a pharmaceutically effective salt thereof, which is effective to treat such disorder or condition. This invention also relates to a pharmaceutical composition for treating a disorder or condition selected from inflammatory diseases such as arthritis (e.g., rheumatoid arthritis and osteoarthritis), psoriasis, asthma or inflammatory bowel disease, respiratory function disorders such as asthma, cough and apnea, allergies, gastrointestinal disorders such as gastritis, functional bowel disease, irritable bowel syndrome, functional diarrhea, functional distension, functional pain, non-ulcerogenic dyspepsia and other disorders of mobility or secretion, and emesis, stroke, shock, cerebral edema , cerebral trauma, spinal cord trauma, cerebral ischemia, cerebral deficits after surgery and cardiac bypass graft, disorders of the urogenital tract such as urinary incontinence, dependencies and additions to chemical compounds (ie addictions or dependencies to alcohol, opioids , benzodiazepines, nicotine, heroin na or cocaine), chronic pain, non-somatic pain, acute pain and neurogenic pain, systemic lupus erythematosus, Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organ transplants and skin grafts in a mammal, including a human being, comprising an effective amount, modulating the neurotransmission of glutamate, a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. This invention also relates to a method for treating a selected state of inflammatory diseases such as arthritis, psoriasis, asthma, or inflammatory bowel disease, disorders of respiratory function such as asthma, cough and apnea, allergies, gastrointestinal disorders such as gastritis, functional bowel disease, irritable bowel syndrome, functional diarrhea, functional distension, functional pain, non-ulcerogenic dyspepsia and other disorders of mobility or secretion, and emesis, stroke, shock, cerebral edema, cerebral trauma, spinal cord trauma, ischemia cerebral, cerebral deficits after surgery and graft of cardiac bypass, disorders of the urogenital tract such as urinary incontinence, dependencies and addictions to chemical compounds (for example, addictions or dependencies to alcohol, opiates, benzodiazepines, nicotine, heroin or cocaine), pain chronic, non-somatic pain, acute pain and neurog pain Enico, systemic lupus erythematosus, Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organ transplants and skin grafts, in a mammal, which comprises administering to said mammal, including a human, an effective amount, modulating the binding to the opioid receptor, a compound of formula I, or a pharmaceutically acceptable salt thereof.

This invention also relates to a pharmaceutical composition for treating a disorder or condition, the treatment of which can be effected or facilitated by modulating the binding to opioid receptors in a mammal, including a human, comprising an effective amount, modulating the binding to the opioid receptor, a compound of formula I, or a pharmaceutically effective salt thereof, and a pharmaceutically acceptable carrier. This invention also relates to a method for treating a disorder or condition, which treatment or prevention can be effected or facilitated by modulating in a mammal, including a human, which comprises administering to said mammal, an effective, modulatory amount of the binding to the mammal. opioid receptor, of a compound of formula I, or a pharmaceutically acceptable salt thereof. This invention also relates to a method for treating a selected state of inflammatory diseases such as arthritis, psoriasis, asthma, or inflammatory bowel disease, disorders of respiratory function such as asthma, cough and apnea, allergies, gastrointestinal disorders such as gastritis, functional bowel disease, irritable bowel syndrome, functional diarrhea, functional distension, functional pain, non-ulcerogenic dyspepsia and other disorders of mobility or secretion, and emesis, stroke, shock, cerebral edema, brain trauma, spinal cord trauma, ischemia cerebral, cerebral deficits after surgery and graft of cardiac bypass, disorders of the urogenital tract such as urinary incontinence, dependencies and addictions to chemical compounds (for example, addictions or dependencies to alcohol, opiates, benzodiazepines, nicotine or cocaine), chronic pain, non-somatic pain, acute pain and neurogenic pain, l systemic erythematosus, Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organ transplants and skin grafts, in a mammal, which comprises administering to a mammal, in need of such treatment, an amount of a compound of formula I which is effective to treat such state. This invention also relates to a pharmaceutical composition for treating a selected state of inflammatory diseases such as arthritis, psoriasis, asthma, or inflammatory instestinal disease, disorders of respiratory function such as asthma, cough and apnea, allergies, gastrointestinal disorders such as gastritis. , functional intestinal disease, irritable bowel syndrome, functional diarrhea, functional distension, functional pain, non-ulcerogenic dyspepsia and other disorders of mobility or secretion, and emesis, stroke, shock cerebral edema, cerebral trauma, spinal cord trauma, ischemia cerebral, cerebral deficits after surgery and graft of cardiac bypass, disorders of the urogenital tract such as urinary incontinence, dependencies and addictions to chemical compounds (ie, addictions or dependencies to alcohol, opiates benzodiazepines, nicotine, heroin or cocaine), chronic pain , non-somatic pain, ague pain and neurogenic pain, systemic lupus erythematosus, Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organ transplants and skin grafts, in a mammal, comprising an amount of a compound of formula I which is effective in treating such a condition, and a pharmaceutically acceptable vehicle. Unless indicated otherwise, the alkyl groups referred to herein, thus the alkyl moieties of other groups referred to herein (e.g., alkoxy) may be linear or branched, and may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or they may be linear or branched and may contain cyclic moieties. The term "alkoxy", as used herein, means "O-alkyl", wherein "alkyl" is as defined above. The term "alkylene", as used herein, means an alkyl group having two available linking sites (i.e., -alkyl-, wherein alkyl is as defined above.The term "treating", as used herein it refers to investing, alleviating, inhibiting progress, or preventing the disorder or condition to which that term applies, and one or more symptoms of such disorder or condition. "treatment", as used herein, refers to treating, being "treating" as defined immediately above. Unless indicated otherwise, "halo" and "halogen", as used herein, refer to fluorine, bromine, chlorine or iodine. The compounds of formula I can have chiral Ppp centers and therefore can exist in different enantiomeric and diastereomeric forms. This invention relates to all optical isomers and all other stereoisomers of compound of formula I and to all racemic mixtures and others thereof, and to all pharmaceutical compositions and methods of treatment defined above that contain or employ such isomers or mixtures. Formula I above also includes compounds labeled with radioisotopes which are identical to those drawn in formula I, but which differ in the fact that one more atom is substituted by an atom having an atomic mass or mass number different from the mass atomic or mass number usually found in nature. Examples of isotope that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36CI, respectively. Certain compounds labeled with radioisotopes of the present invention, for example, those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and / or substrate tissue distribution assays. Particularly preferred are the tritiated isotopes, ie, 3H, and carbon-14, i.e., 14C, for their ease of preparation and detection ability, in addition the replacement with heavier isotopes such as deuterium, i.e., 3H can produce certain therapeutic advantages resulting from increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and, therefore, may be preferred in some circumstances. The compounds of formula I labeled with radioisotopes of this invention can generally be prepared by carrying out the procedures described in the schemes and / or examples below, substituting a readily available radioisotope-labeled reagent for a reagent not labeled with radioisotopes.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula I can be prepared according to the methods illustrated in schemes 1-9 and set forth below. In the following reaction and exposure schemes, except as otherwise indicated, X, Q, Y, Z, Z2, R1, R2, R3, R4, R5, R6, R7, and R8, and structural formula I, they are as defined above. Scheme I illustrates a method for the preparation of compounds with the general formula I, wherein R 3 is alkoxy (C Cß) or fluorine, R 2 is CONR 5 R 6, Y is a carbon, Q is carbon, X is carbon and R 1 is as is defined above with the proviso that it is not attached to the piperidine nitrogen is a secondary alkyl carbon or an aryl group. Referring to scheme 1, a bromobenzene derivative of formula 0, in which R3 is methoxy or fluorine, is cooled to -70 ° C in dry tetrahydrofuran, and then a solution of n-butyllithium is added thereto. The resulting solution is then treated with N-benzylpiperidin-3-one and the solution is allowed to warm to room temperature to produce the corresponding compound 1.

Alternatively, the benzene derivative of formula 0 in tetrahydrurofuran can be treated with magnesium at a temperature of about 0 ° C to the reflux temperature, preferably started at room temperatures for about 3 hours, and then heating to reflux and allowing the reaction proceeds for another hour, after which N-benzylpiperidin-3-one is added to the mixture. The resulting solution is then stirred at a temperature ranging from about 0 ° C to the reflux temperature, preferably at about room temperature, to produce the corresponding compound of formula 1. The compound of formula 1, produced by any of the foregoing methods, in dichloromethane, is then treated with phenol and aluminum chloride or another Lewis acid (eg, zinc chloride, boron trifluoride etherate) and the resulting solution is stirred at a temperature which ranges from about 0 ° C to the reflux temperature, preferably at about the reflux temperature, to produce the corresponding phenolic derivative, of formula 2. The compound of formula 2 is then treated with trifluoromethanesulfonic anhydride or other suitable reagent such as N-phenyltrifluoromethanesulfonamide, in the presence of a base such as pyridine, triethylamine, or trialkylamine, an alkali metal hydride or an alkali metal carbonate, to form the trifluoromethane sulfonate ester of formula 3. This reaction is typically carried out in dichloromethane a a temperature ranging from about 0 ° C to the reflux temperature, preferably at about the temperature a environment The compound of formula 3 is placed under a carbon monoxide atmosphere at a pressure ranging from about 96,526 kPa to 0.689 MPa, in a solution of dimethyl sulfoxide and a lower alkanol, such as methanol or ethanol, with a suitable trialkylamine base (e.g., triethylamine) and palladium acetate with 1,3-bis (diphenylphosphino) propane (DPPP), 1,3-bis (diphenylphosphino) -ferrocene (DPPF) or other suitable palladium ligand. Other palladium catalysts such as bis (triphenylphosphine) palladium dichloride can also be used. This reaction is carried out at temperatures ranging from about 20 ° C to 100 ° C. The treatment of the ester of formula 4 with an aluminum amide of a primary or secondary amine, for example, diethylamine, in a solvent such as dichloroethane or toluene, at a temperature ranging from about 20 ° C to about the temperature of reflux, preferably at about the reflux temperature, produces the corresponding amide of formula 5. Variations in the nature of the R1 group of the piperidine nitrogen can be effected in the following manner, as illustrated by the process steps (5- > 6-> 7) in scheme 1. The compound of formula 5 is placed under a hydrogen atmosphere at pressures ranging from about 96,526 kPa to 0.689 MPa, in ethanol or other solvent such as acetic acid or methanol, to produce the corresponding compound of formula 6. This reaction is carried out typically at a temperature of about 0 ° C to about the reflux temperature, preferably at about the reflux temperature, preferably at about room temperature. The treatment of the compound of formula 6 with a sodium aldehyde and triacetoxyborohydride or other reducing agent (for example, sodium borohydride or sodium cyanoborohydride), in 1,2-dichloromethane dichloromethane or another suitable solvent such as methanol, ethanol or toluene, at a temperature ranging from about 0 ° C to 100 ° C, preferably at about room temperature produces the desired compound of formula 7.

SCHEME 1 (Me = methyl) R10 = CrC6 alkyl) SCHEME 1 CONTINUED (R1 = CH2RX) Compounds of formula I in which R1 is a group that binds to the piperidine nitrogen via an aryl moiety or a primary or secondary alkyl moiety, can be prepared by treating the corresponding compound of formula 6 with an alkylating agent or aryl of formula R1X, wherein X is a leaving group such as chlorine, bromine, iodine, triflate (Otf), mesylate (Oms) or tosylate (Ots), and sodium or potassium carbonate or other alkali metal carbonate or bicarbonate in a solvent such as dimethylformamide, dichloromethane or 1,2-dichloromethane, at a temperature ranging from about 20 ° C to 100 ° C, as shown below in scheme 2.

SCHEME 2 The compounds of general formula 1, wherein R 3 is hydroxyl, can be prepared by deprotecting the corresponding alkyl ether of formula 7 (wherein R 10 is alkyl (Ci-Cß)) with boron tribromide in dichloromethane, or with hydrobromic acid aqueous and acetic acid, or with sodium ethanethiolate in dimethylformamide, at a temperature ranging from about 0 ° C to the reflux temperature, as shown in scheme 3. Ambient temperature is preferred when boron tribromide is used, the reflux temperature is preferred when using hydrobromic acid / acetic acid; and about 100 ° C to about 120 ° C is preferred when sodium ethane-methoxide is used.

SCHEME 3 The carboxamide of formula 12 can be obtained by conversion of the phenol of formula 9 to a triflate ester of formula 10 by addition of triflic anhydride in the presence of a base such as pyridine, or a trialkylamine base such as triethylamine, and in the presence of dimethylaminopyridine in a solvent such as methylene chloride, at a temperature ranging from -40 ° C to the reflux temperature, preferably at 0 ° C. The triflate ester of formula 10 is then converted to the nitrile of formula 11 by treatment with zinc cyanide and a palladium catalyst, such as tetrakis (triphenylphosphine) palladium, in a solvent such as dimethylformamide, or toluene, at a temperature of from about 0 ° C to about the reflux temperature, preferably at about the reflux temperature. The nitrile of formula 11 can be converted into the carboxamide of formula 12 by treatment with hydrogen peroxide and sodium carbonate in ethanol, at a temperature ranging from 0 ° C around the reflux temperature, preferably to about room temperature . PPP SCHEME 4 The compounds of general formula? wherein R is methoxy, hydroxy or fluorine and R 2 is an aromatic or heteroaromatic moiety (referred to in scheme 5 as compounds of formula 14) can be prepared by organometallic coupling of a compound of formula 3 with an aryl and heteroarylboronic acid, wherein the aryl and heteroaryl are defined as in the definitions of R1 and R2, in a solvent such as ethanol or toluene, in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) -palladium and an alkylamine base (e.g. , triethylamine) or an alkali metal carbonate base, as shown below in Scheme 5. This reaction is generally carried out at a temperature from about room temperature to about reflux temperature, preferably about 50 ° C. the reflux temperature.

SCHEME 5 (R3 = O-alkyl (C, -C6), OH or F) The compounds of general formula 1 in which R3 is fluoro or methoxy and R2 is a carbinol such as diethylcarbinol (referred to in scheme 6 as a compound of formula I j) can be prepared, as illustrated in scheme 6, by treatment of the ester of formula 4 with an alkyl lithium or an alkyl Grignard reagent, in a solvent such as ether or tetrahydrofuran, at a temperature ranging from about -78 ° C to about reflux temperature, preferably starting at room temperature environment and heating to around the reflux temperature.

SCHEME 6 (R3 = O-alkyl (C C6) or F) (R3 = O-alkyl (C ^ Cg) or F) The compounds of formula 14 (scheme 5) and 15 (scheme 6) can be converted to the analogous compounds, wherein R3 = CONH2, using the procedures illustrated in schemes 3 and 4 and described above to synthesize carboxamides of formula 12. The compounds of general formula 16 can be prepared, as illustrated in scheme 7, by treatment of the phenol of formula 9 with acid chloride, in the presence of pyridine or a trialkylamine such as triethylamine in dichloromethane, tetrahydrofuran or other suitable solvent, a temperature ranging from about -78 ° C to about the reflux temperature, preferably at about room temperature.

SCHEME 7 16 Scheme 8 illustrates a method for preparing compounds of the general formula 1 wherein Q is oxygen, R3 is methoxy, hydroxyl, R2 is CONH5R6 and R1 is as defined above. Referring to scheme 8, a bromobenzene derivative of formula 17, in which R3 is methoxy or fluorine, is cooled to -70 ° C in dry tetrahydrofuran, and treated with a solution of n-butyllithium. The resulting solution is then treated with an appropriately substituted arylaldehyde of formula Ij ^ and the solution is allowed to warm to room temperature to produce the corresponding compound of formula 19. Alternatively, the benzene derivative of formula 17 in tetrahydrofuran can be treated with magnesium a a temperature of about 0 ° C to the reflux temperature, preferably starting at room temperature for about 3 hours, and then heating to reflux and allowing the reaction to proceed for about another hour, after which the arylaldehyde is added of formula 18 to the mixture. The resulting solution is then stirred at a temperature ranging from about 0 ° C to the reflux temperature, preferably at about room temperature, to produce the corresponding compound of formula 19. The compounds of formula 20 can be prepared using a oxidation is Swern. Thus, a solution of trifluoroacetic anhydride in methylene chloride is treated with DEMO at a temperature of about -78 ° C at about room temperature, preferably at -78 ° C, and to this mixture is added a solution of the compound of formula 19 in methylene chloride, followed by the addition of a trialkylamine base such as triethylamine. The mixture is allowed to warm to room temperature to produce the corresponding compound of formula 20. As an alternative, the compounds of formula 20 can be prepared by oxidation of the compound of formula 19 by addition of pyridinium dichromate, in a solvent such as methylene chloride, at a temperature of about -78 ° C at about reflux temperature, preferably at around room temperature. The compounds of formula 20 can be converted to compounds of formula 21 by the addition of trimethylsilyl cyanide in the presence of zinc iodide in a solvent such as methylene chloride, at a temperature of about -78 ° C at about the temperature of refluxing, preferably at about room temperature, followed by treatment of the intermediate cyanohydrin with lithium aluminum hydride or another metal hydride source such as diisobutylaluminum hydride, in a solvent such as methylene chloride, at a temperature of about -78 ° C at about reflux temperature, preferably at 0 ° C. The treatment of a compound of formula 21 with a trialkylamine base such as triethylamine and chloroacetyl chloride in a solvent such as toluene or tetrahydrofuran, at a temperature ranging from about -40 ° C to about the reflux temperature, preferably at 0 ° C, produces the corresponding compound having the formula 22. The subsequent treatment of a diluted solution of the resulting compound of formula 22 in a solvent such as tetrahydrofuran or toluene with metal alkoxides, preferably potassium t-butoxide, at a temperature which ranges from -40 ° C to around the reflux temperature, preferably at about room temperature, gives the corresponding derivative of formula 23. The reaction of the derivative of formula 23 with lithium aluminum hydride or other hydride source metal such as dibutylaluminum hydride, in a solvent such as methylene chloride, at a temperature of about -78 ° C. at 0 ° C, gives the corresponding compound of formula 24. When R1 is not bonded to the morpholino nitrogen on a secondary alkyl carbon or an aryl group, the R1 group can be added to the morpholino nitrogen of the compound of formula 24 by reacting such compound with a sodium triacetoxyborohydride aldehyde or other reducing agent (for example, sodium borohydride or sodium cyanoborohydride), in dichloromethane, 1,2-dichloroethane or another suitable solvent such as methanol, ethanol or toluene, at a temperature that fluctuates from about 0 ° C to 100 ° C, preferably at about room temperature. This reaction produces the desired compound of formula 25. When R1 is attached to the morpholino nitrogen via an aryl moiety or a primary or secondary alkyl moiety, it can be added to the compound of formula 24 using the procedure illustrated in scheme 2 and described above. Compounds of formula 24 can be produced by alkylation or heteroarylation of the corresponding compound of formula 24 using conditions identical to those described above for the preparation of compounds of formula 7, scheme 2. The compound of formula 25 is placed under a monoxide carbon at a pressure ranging from about 96,526 kPa to 0,689 MPa, in a solution of dimethyl sulfoxide and a lower alkanol, such as methanol or ethanol, with a suitable trialkylamine base (e.g., triethylamine) and palladium acetate with 1, 3-bis (diphenylphosphino) propane (DPPP) or other suitable palladium ligand, to produce the desired compound of formula 26. Other suitable palladium catalysts may also be used, such as bis (triphenylphosphine) palladium dichloride. This reaction can be carried out at temperatures ranging from about 20 ° C to 100 ° C, preferably at about 70 ° C. The treatment of the ester of formula 26 with an aluminum amide of a primary or secondary amide, for example, diethylamine, in a solvent such as dichloroethane or toluene, at a temperature ranging from about 20 ° C to about the temperature of Reflux, preferably at about reflux temperature, produces the corresponding amide of formula 27. Compounds of formula d ^ in which R3 is hydroxyl, can be prepared by deprotecting the corresponding alkyl ethers of formula 27 (wherein R3 is OR10 and R10 is alkyl (C? -C6)) with boron tribromide in dichloromethane, or with aqueous hydrobromic acid and acetic acid, or with sodium ethanethiolate in dimethylformamide, at a temperature ranging from about 0 ° C to about reflux temperature, as shown in scheme 3. Ambient temperature is preferred when boron tribromide is used; the reflux temperature is preferred when hydrobromic acid / acetic acid is used; and about 100 ° C to about 120 ° C is preferred when sodium ethane-methoxide is used.

SCHEME 8 2. LAH, THF 20 SCHEME 8 CONTINUED R * CHO, NaBH (OAc) 3 26 CH C 25 (R1 = CH2Rx) 27 28 The compounds of formula 25 can be converted into the corresponding compounds in which the bromine substituent is replaced by an aromatic or heteroaromatic substituent using the procedure illustrated in scheme 5 and discussed above. The compounds of formula 26 can be converted to the corresponding compounds wherein R2 is -C (OH) R5R6 better than -COOR7 using the procedure described above as illustrated in scheme 6. The compounds of formula 28 can be converted into derivatives to form the corresponding compounds wherein R3 is -CONH2 and -OC (= 0) R7 using the procedures described above and illustrated in schemes 4 and 7, respectively, to prepare compounds of formulas Yl (scheme 4) and 6 (scheme 7). Scheme 9 illustrates a method for the preparation of compounds with the general formula i wherein X is nitrogen, R3 is methoxy, hydroxyl, R2 is CONR5R6 and R1 is as defined above. Referring to scheme 9, the compounds of formula 3_1 can be obtained by treatment of phenylacetonitrile derivatives of formula 29 with sodium hydride and a 2-bromopyridine or 2-halopyridine derivative of formula 30 in dimethylforde or in another suitable solvent such as tetrahydrofuran. , or a temperature of about 0 ° C to about the reflux temperature, preferably at about 60 ° C. The treatment of compound of formula 3_1 with sodium hydride in dimethylforde or in another suitable solvent such as tetrahydrofuran, at a temperature of about 0 ° C to about reflux temperature, preferably at 60 ° C, followed by treatment with a Alkylating agent such as 1-bromo-3-chloropropane, at a temperature of about 0 ° C to about the reflux temperature, preferably at about 60 ° C, produces the corresponding compounds of formula 32. The reduction of the cyano group of the compounds of formula 32 with a reducing agent such as diisobutylaluminum hydride or another source of reducing metal hydride such as lithium aluminum hydride, in a solvent such as methylene chloride, at a temperature of about -78 ° C to around the reflux temperature, preferably at -78 ° C, and gradually heating to room temperature, gives the corresponding compounds of formula 33 after stirring vigorous in a saturated aqueous Rochelle salt solution. When R1 is not bound to the piperidine nitrogen on a secondary alkyl carbon or an aryl moiety, the compounds of formula 33 can be converted to the corresponding compounds of formula 34 by reacting them with a sodium aldehyde and triacetoxyborohydride or other reducing agent (e.g. , sodium borohydride or sodium cyanoborohydride), in dichloromethane, 1,2-dichloroethane or other suitable solvent such as methanol, ethanol, or toluene, at a temperature ranging from about 0 ° C to about 100 ° C, preferably at around room temperature. When R1 is attached to the piperidine nitrogen via an aryl moiety or a primary or secondary alkyl carbon, the compounds of formula 34 can be produced by alkylation or heteroarylation of compounds of general formula 33 using conditions identical to those described for the preparation of formula 7, in scheme 2. The compounds of formula 34 are placed under an atmosphere of carbon monoxide at a pressure ranging from about 96,526 kPa to 0,689 MPa, in a solution of dimethyl sulfoxide and a lower alkanol, such as methanol or ethane, with a suitable trialkylamine base (e.g., triethylamine) and palladium acetate with 1,3-bis (diphenylphosphino) propane (DPPP) or other suitable palladium ligand. Other suitable palladium catalysts, such as bis (triphenylphosphine) palladium dichloride, can also be used. This reaction, which is typically carried out at temperatures ranging from about 20 ° C to 100 ° C, produces the desired compound of formula 35. The treatment of the ester of formula 35 with an aluminum amide of a primary or secondary amine, by example, diethylamine, in a solvent such as dichloroethane or toluene, at a temperature ranging from about 20 ° C to about the reflux temperature, preferably at about the reflux temperature, produces the corresponding amide of formula 36. compounds of formula 37, wherein R3 is hydroxyl, can be prepared by deprotecting the corresponding alkyl esters of formula 36 (wherein R3 is OR10 and R10 is (C6C6) alkyl) with boron tribromide in dichloromethane, or with acid aqueous hydrobromic acid and acetic acid, or with sodium ethanethiolate in dimethylformamide, at a temperature ranging from about 0 ° C to around the reflux temperature, as shown in scheme 3. The temperature is preferred. environment when the boron tribromide is used, the reflux temperature is used when bromidic acid / acetic acid is used; and about 100 ° C to about 120 ° C is preferred when sodium ethane-methoxide is used.

SCHEME 9 29 H2CI2 32 33 34 RxCOH, Na (OAc) 3BH CH C (R1 = CH2R <) SCHEME 9 CONTINUED 34 35 The compounds of formula 34 can be converted to the corresponding compounds in which the bromine substituent is replaced by an aromatic or heteroaromatic substituent using the procedure illustrated in Scheme 5 and discussed above. The compounds of formula 35 can be converted into the corresponding compounds wherein R2 is -C (OH) R5R6 better than -COOR7 using the procedure described above and illustrated in scheme 6. The compounds of formula 37 can be converted into derivatives for forming the corresponding compounds wherein R3 is -CONH2 and -OC (= O) R7 using the procedures described above and illustrated in schemes 4 and 7, respectively, to prepare compounds of formulas 12 (scheme 4) and 16 (scheme 7) ). Scheme 10 illustrates a method for the preparation of compounds with the general formula I wherein R3 is NHSO2R7. Referring to scheme 10, the phenol of formula 38 is converted to triflate 39 by the procedures illustrated in schemes 1 and 4 and described above, after which the triflate is transformed into the ester of formula 40 can then be converted into the carboxylic acid of formula 4J_ by hydrolyzing it with lithium hydroxide in a water / THF solution at about room temperature. Treatment of the resulting carboxylic acid of formula 41 with diphenylphosphoryl azide and triethylamine in a tert-butanol solvent at about reflux temperature yields the corresponding tert-butyl carbamate of formula 42. The acid treatment of carbamate of formula 42 with trifluoroacetic acid in methylene chloride produces the corresponding aniline of formula 43. The aniline 43 can then be reacted with sulfonyl chloride, in the presence of a base such as pyridine or triethylamine, to produce the desired sulfonamide of formula I. This reaction is carried preferably in a polar solvent such as methylene chloride, dichloroethane or THF, at a temperature of 0 ° C to about the reflux temperature of the solvent. 39 38 40 41 42 43 Ppp The preferred method for making compounds of formula I in which R3 is OH, NHS02R7, C (OH) R7R8, or C (= 0) NHR7, is to make the analogous compounds in which R3 is O-alkyl (Ci-Cβ ) and then converting them into derivatives using standard methods well known in the art and illustrated in the foregoing schemes. The starting materials used in the systems 1-9 processes are commercially obtained, known in the literature, or are readily obtainable from commercially available or known compounds using methods that are well known in the art or are described above. Unless indicated otherwise, the pressure of each of the above reactions is not critical. Generally, the reactions will be carried out at a pressure of about 101, 325 to about 303,975 kPa, preferably at room temperature (about 101, 325 kPa). The preparation of other compounds of formula I not specifically described in the above experimental section can be achieved using combinations of the reactions described above, which will be apparent to those skilled in the art. The compounds of formula I which are basic in nature, are capable of forming a wide variety of different salts with various inorganic and organic acids. The acids that can be used to prepare the pharmaceutically acceptable acid addition skids of the base compounds of this invention are those which form non-toxic acid addition salts, ie, salts containing pharmaceutically acceptable anions, such as the salts of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e. 1, 1'-methyl-bis- (2-hydroxy-3-naphthoate)]. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of formula I, from the reaction mixture, as a pharmaceutically unacceptable salt and then simply convert to the latter again to the free base compound by treatment with an alkaline reagent, and subsequently converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as metal or ethanol . With careful evaporation of the solvent, the desired solid salt is obtained. The compounds of formula I which are acidic by nature are capable of forming base salts with various pharmacologically acceptable cations. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents for preparing the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the base compounds of formula I. Such non-toxic base salts include those which are obtained from cations pharmaceutically acceptable such as sodium, potassium, calcium and magnesium, etc. These salts can be easily prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmaceutically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing together lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide, and then evaporating the resulting solution to dryness in the same manner as before. In any case, stoichiometric amounts of the reagents are preferably employed in order to ensure completion of the reaction and maximum yield of the desired final product. The compounds of formula I and the pharmaceutically acceptable salts thereof (hereinafter also collectively referred to as "the active compounds of the invention") are useful for the treatment of neurodegenerartive deficits, induced by psychotropics and drugs or alcohol, and are ligands. powerful of the opioid receptor. The active compounds of the invention can therefore be used in the treatment of disorders and conditions, such as those listed above, which can be treated by modulating the binding to the opioid receptor. The ability of the compounds of formula I to bind to the various opioid receptors, and their functional activity in such receptors, can be determined as described below. The delta opioid receptor binding can be determined using methods well known in the art, such as those referred by Lei Fang et al. J. Pharm. Exp. Ther., 268, 1994, 836-846 and Contreras et al., Brain Research, 604, 1993, 160-164. In the description of the binding and functional assays that follow, the following abbreviations and terminology are used. DAMGO is [D-Ala2, N-MePhe4, Gly5-ol] enkephalin. U69593 is ((5a, 7a, 8b) - (+) - N-methyl-N- (7- [1-pyrrolidinyl] -1-oxa-spiro [4.5] dec-8-yl) -benzenacetamide). SNC-80 is (+) - 4- [a ((2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-methoxybenzyl] -N, N-diethylbenzamide. Nor-BNI is nor-binaltorphimine. CTOP is 1, 2-dithia-5,8,11, 14,17-pentaazacycloheicosane and the cyclic peptide derivative DPDPE is [D-en 2, D-Pen 5] enkephalin). [3H] -DAMGO, [3H] -U69593, norBNI, and CTOP are all commercially available from DuPont, Amersham International, RBI and DuPont, Amersham intematíonal, RBI and DDuPont, respectively. [3 H] -SNC80 was prepared by Amersham international. The opioid receptor (mu and kappa) receptor binding assays can be carried out in preparations of guinea pig brain membranes. Binding assays can be carried out at 25 ° C for 60 minutes in 50 mM Tris buffer (pH 7.4). [3H] -DAMGO (2 nM) and [3H] -U69.593 (2 nM) can be used to mark isotopically the mu and kappa receptor binding sites, respectively. The protein concentration can be approximately 200 μg / well. The non-specific binding can be defined with 10 μM naloxone. The delta receptor binding assays can be carried out on a stable line of CHO cells expressing the human delta receptor. The binding assay can be carried out at 25 ° C for 120 minutes in 50 mM Tris buffer (pH 7.4). [3H] -SNC-80 can be used to isotopically label the delta receptor binding sites. The protein concentration can be approximately 12.5 μg / well. The non-specific binding can be defined with naltrexone 10 μM. The binding reaction can be terminated by rapid filtration through glass fiber filters, and the samples can be washed with buffer Tris (pH 7.4) 50 mM cooled with ice. The agonist activity in delta, mu and kappa opioid receptors can be determined as follows. The opioid activity (delta, mu and kappa) is studied, as described below, in two isolated tissues, the mouse vas deferens (MVD) (d) and the myenteric plexus of the guinea pig with attached longitudinal muscle (GPMP) (μ Y K). MVD (race DC1, Charles River, 25-35 g) was suspended in 15 ml of baths for organs containing Kreb's buffer without Mg ++ of the following composition (mM): NaCl, 119; KCl, 4.7; NaHCO3, 25; KH2PO4, 1.2; CaCl2, 2.5 and glucose, 11. The buffer is gasified with 95% O2 and 5% CO2.

The tissues are suspended between platinum electrodes, attached to an isometric transducer with a voltage of 500 mg, and are stimulated with pulses of 0.03 Hz pulse width of 1 msec at the supraximal voltage. The IC2 values are determined by regression analysis of the response concentration curves for the inhibition of electrically induced contractions in the presence of 300 mM of the mu-selective CTOP antogonist. This test is a measure of d agonism. Myenteric guinea pig plexuses (Porcellus breed, male, 450-500 g, Dunkin Hartley) are suspended, with longitudinal muscle segments attached, in Kreb buffer with 1 g of tension, and stimulated with pulses of 0.1 Hz pulse width of 1 msec to the supra maximum voltage. The mu functional activity is determined in the presence of 10 nM nor-BNI with 1 μM of the mu selective agonist, DAMGO, added to the bath at the end of the experiment to define a maximum response. This test is an average of the mu agonist. Functional kappa activity is determined in the presence of 1 μM CTOP with 1 μM of the selective kappa agonist U-69.593 added at the end of the experiment, to define a maximum response. All inhibitions of the contraction height for the test compounds are expressed as a percentage of the inhibition otenida with the standard agonist, and the corresponding IC50 values are determined. The following procedure can be used to determine the activity of the therapeutic agents of this invention as agonists and as delta opioid receptor antagonists.

Cell culture: Chinese hamster ovarian cells, expressing the human delta opioid receptor, are passed twice a day in Hamis F-12 medium with L-glutamine containing 10% fetal bovine serum and 450 μg / ml of hygromycin. The cells are prepared for tests, 3 days before the experiment. 15 ml of 0.05% trypsin / EDTA are added to a confluent triple flask, swirled and decanted to rinse. 15 ml of 0.05% trypsin / EDTA are added again, and the flask is placed in an incubator at 37 ° C for 2 minutes. The cells are removed from the flask by tilting, and the supernatant is poured out into a 50 ml tube. 30 ml of the medium is then added to the flask to stop the action of the trypsin, and then decanted in a 50 ml tube. The tube is centrifuged for 5 minutes at 1,000 rpm, the medium is decanted, and the pellet is suspended again in 10 ml of the medium. Viability of the cells is assayed using trypan blue, the cells are counted and plated onto 96-well poly-D-lysine coated plates at a density of 7,500 cells / well. Test plate antagonist cells, plated 3 days before assay, are rinsed twice in PBS. The plates are placed in a 37 ° C water bath. 50 μl of assay buffer (PBS, 1 mg / ml dextrose, 5 mM MgCl 2, 30 mM HEPES, 66.7 μg / ml IBMX) are then added to the designated wells. Fifty microliters of the appropriate drug is then added to the designated wells, and is timed for 1 minute. Fifty microliters of 10 μM forskolin + 0.4 nM DPDPE are then added (the final assay concentration is 5 μM forskolin, 0.2 nM DPDPE) to the designated wells, and is monitored for 15 minutes. The reaction is stopped by the addition of 10 μl of 6N perchloric acid to all wells. To neutralize, add 13 μl of 5N KOH to all wells, and to stabilize, add 12 μl of Tris 2M, pH 7.4, to all wells. Mix by shaking in an orbital shaker for 10 minutes, and centrifuge in mode 7 for 10 minutes. Aliquots are placed on 3H plates. Agonist test plate The cells, plated 3 days before the test, are rinsed twice with PBS. The plates are placed in a 37 ° C water bath. then 50 μl of assay buffer (PBS, 1 mg / ml dextrose, 5 mM MgCl 2, 30 mM HEPES, 66.7 μg / ml IBMX) is added to the designated wells. Fifty microliters of the appropriate drug + 10 μM forskolin are then added (the final assay concentration is 10 μM forskolin (the final assay concentration is 5 μM forskolin) at all wells, and the sample is monitored for 15 minutes. add 10 μl of 6N perchloric acid to all wells, to neutralize, add 13 μl of 5N KOH to all wells, and to stabilize, add 12 μl of 2M Tris, pH 7.4, to all wells. shaking on an orbital shaker for 10 minutes, and centrifuged in mode 7 for 10 minutes Aliquots are placed on 3H plates.These test plates are placed in the 3H cAMP Amersham binding kit, overnight, and are cultured on GF / B filters previously soaked in PEI 0.5% with a Skatron using 50 mM Tris HCl, pH 7.4, at 4 ° C. The filters can be air dried overnight, then placed in bags with betaplate scintillation cocktail, and they are counted in a or betaplate for 60 sec per sample. The data can be analyzed using Excel. The compositions of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. In this way. The active compounds of the invention can be formulated for oral, buccal, transdermal (eg, patch), intranasal, parenteral (eg, intravenous, intramuscular or subcutaneous) or rectal, or in a suitable or subcutaneous form) or rectal administration , or in a form suitable for administration by inhalation or insufflation. For oral administration, the pharmaceutical compositions can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (eg, pregela corn starch-Ppp stained, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (for example), lactose, microcrystalline cellulose or calcium phosphate); lubricants (for example), magnesium stearate, talc or silica): disintegrants (for example), potato starch glycolate or sodium starch glycolate); or wetting agents (for example), sodium laurisulfate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (for example, lecithin or gum arabic); non-aqueous vehicles (for example), almond oil; oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates, or sorbic acid). For buccal administration, the composition may take the form of tablets or tablets formulated in conventional manner. The active compounds of the invention can be formulated for parenteral administration by injection, including the use of conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, for example, sterile, pyrogen-free water, before use. The active compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides. For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently released in the form of a solution or suspension from a pump spray container that is tightened or pumped by the patient, or as an aerosol spray presentation. from a pressure vessel or a nebulizer, with the use of a suitable propellant, e.g., dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dose unit can be determined by providing a valve to release a measured quantity. The pressure vessel or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, of gelatin) for use in an inhaler or insufflator can be formulated containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. In general, an oral or intravenous, therapeutically effective dose of the compounds of formula (I) and their salts ranges from about 0.001 to 50 mg / kg of body weight of the patient to be treated, preferably 0.1 to 20 mg / kg. The compounds of formula (I) and their salts can also be administered by intravenous infusion, at a dose ranging from about 0.001-10 mg / kg / h.

The tablets or capsules of the compounds can be administered singly, or two or more at a time, as appropriate. It is also possible to administer the compounds in delayed-release formulations. The doctor will determine the actual dose that will be the most appropriate for an individual patient, and that will vary with the age, weight and response of the particular patient. The above doses are examples of the middle case. Of course, there may be individual circumstances in which higher or lower dose ranges are needed, and such ranges are within the scope of this invention. Alternatively, the compounds of formula (I) can be administered by inhalation or in the form of a suppository or pessary, or they can be applied topically in the form of a lotion, solution, cream, ointment or fine powder. An alternative means for transdermal administration is through the use of a skin patch. For example, they can be incorporated into a cream comprising an aqueous emulsion of polyethylene glycols or liquid paraffin. They may also be incorporated, at a concentration between 1 to 10% by weight, into an ointment comprising a white wax or white soft paraffin base together with stabilizing agents or preservatives, as required. The following examples illustrate the preparation of the compounds of the present invention. The commercial reagents were used without further purification. All NMR data were recorded at 250, 300 or 400 MHz in deuterochloroform, unless otherwise specified, and are given in parts per million (or), and are referenced to the deuterium stabilization signal of the solvent of the sample. All non-aqueous reactions were carried out in dry glassware with dry solvents under an inert atmosphere for convenience and to maximize yields. All reactions were shaken with a magnetic stir bar, unless otherwise stated. All mass spectra were obtained using chemical impact conditions, unless stated otherwise. At room or laboratory temperature it refers to 20-25 ° C.

EXAMPLE 1 N, N-diethyl-4-r3- (3-methoxyphenyl) -piperidin-3-ip-benzamide A. 1. Benzyl-3- (3-methoxy-phenyl) -piperidin-3-ol It was added to a suspension of magnesium (7.8 g, 325 mmol) in THF (120 ml) at room temperature under an atmosphere of Nitrogen, a solution of 3-bromoanisole (37.5 ml, 296 mmole) in THF (60 ml) for 10 min. The resulting mixture was stirred at 50 ° C for 4 hours, and cooled to room temperature. A solution of N-benzyl-3-piperidinone (30.0 g, 159 mmol) in THF (50 ml) was added to the mixture. The reaction was stirred at room temperature for 10 hours. The mixture was poured slowly into ice-water (100 ml), and the aqueous layer was washed with EtOAc (3 x 50 ml). The combined organic extracts were dried (MgSO) and concentrated. The crude residue was purified by flash chromatography with hexane / EtOAc (3: 1) to give 38.4 g of 1-benzyl-3- (3-methoxyphenyl) -piperidin-3-ol. 1 H NMR (400 MHz, CDCl 3) or 7.31-7.20 (comp. 6H), 7.09 (s, 1 H), 7.01 (d, 1 H), 6.79 (d, 1 H), 4.01-3.96 (br, 1 H ), 3.79 (s, 3H), 3.58 (s, 2H), 2.91 (d, 1 H), 2.74 (d, 1 H), 2.32 (d, 1 H), 2.09-1.82 (comp 2H), 1.81 -1.61 (comp 3H). MS (M + 1) 298.2.

B. 2-1-Benzyl-3- (3-methoxy-phenol) -piperidin-3-n-phenol. Phenol (16.7 g, 178 mmol) was added to a solution of 1-benzyl-3- (3-methoxyphenyl) ) -piperidin-3-ol (17.6 g, 73.1 mmol) (CH2) 2 CI2 (200 mL), followed by the portionwise addition (highly exothermic) of Alcl3 (23.3 g, 178 mmol). The reaction mixture was heated to reflux for 2 hours.

The mixture was cooled to room temperature, and slowly poured into a mixture of crushed ice (50 ml) and aq NH4OH. to 30% (120 ml). The mixture was stirred vigorously for 20 minutes, and then filtered through celite.

The celite cake was washed with CH 2 Cl 2 (200 ml). The organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 (3 x 100 ml). The combined organic layers were dried (MgSO) and concentrated. The crude residue was purified by flash chromatography with hexanes / EtOAc (1: 1) to give 16.3 g of 4- [1-benzyl-3- (3-methoxy-phenyl) -piperidin-3-yl] -phenol. 1 H NMR (400 MHz, CDCl 3) or 7.39-7.21 (comp, 5H), 7.19-7.05 (comp, 3H), 6.84 (s, 1 H), 6.79 (d, 1 H), 6.67-6.61 (comp, 3H) ), 3.73 (s, 3H), 3.50 (s, 2H), 2.86-2.79 (comp, 2H), 2.45-2.38 (comp, 2H), 2.21-2.19 (comp, 2H), 1.60-1.51 (comp, 2H) ); MS (M + 1) 374.2.

C. Trifluoromethanesulfonic acid 4- [1-benzyl-3- (3-methoxyphenyl) -piper-dine-3-phenyl) pyridine (3.37 ml, 41.7 mmol) was added to a suspension of 4- [1- benzyl-3- (3-methoxyphenyl) -piperidin-3-yl] -phenol (10.4 g, 27.8 mmol) in CH2Cl2 (60 ml) at 0 ° C, followed by the dropwise addition of anhydride Triflic (5.62 ml, 27.8 ml) for 5 minutes. The reaction mixture was stirred at 0 ° C for 1 hour, and at room temperature for 2 hours. The solution was then cooled to 0 ° C, and 40 ml of cold saturated aqueous NaHCO3 was added. The organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 (3 x 50 ml). The combined organic layers were dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography with hexanes / EtOAc (4: 1) to give 9.81 g of trifluoromethanesulfonic acid 4- [1-benzyl-3- (3-methoxyphenyl) -piperidin-3-yl] -phenyl ester. 1 H NMR (400 MHz, CDCl 3) or 7.39-7.22 (comp, 7H), 7.15 (t, 1 H), 7.09 (d, 2H), 6.76-6.67 (comp, 3H), 3.72 (s, 3H), 3.52 -3.49 (comp, 2H), 3.08-2.91 (m, 1 H), 2.72-2.60 (m, 1 H), 2.59-2.49 (m, 1 H), 2.41-2.29 (m, 1 H), 2.23- 2.19 (comp, 2H), 1.61-1.41 (comp, 2H), MS (M + 1) 506.1. [? 4- [1-Benzyl-3- (3-methoxyphenyl) -piperidin-3-yl] -benzoic acid methyl ester DEMO (18 ml) and triethylamine (21 ml, 151 mmol) were added to a solution of 4-ester. Trifluoromethanesulfonic acid [1-benzyl-3- (3-methoxyphenyl) -piperidin-3-yl] -phenyl acid (12.9 g, 25.4 mmol) in a Parr pressure bottle in MeOH (39 mL). Palladium acetate (3.99 g, 17.8 mmol) and 1,3-bis (diphenylphosphonium) propane (5.25 g, 12.3 mmol) were added to the reaction mixture. The reaction mixture is stirred under 275, 790 Kpa of CO at 70 ° C for 4 hours. The reaction mixture was cooled to room temperature, and diethyl ether (600 ml) was diluted. The ether layer was washed with water (5 x 60 ml), dried (MgSO) and concentrated. The crude residue was purified by flash chromatography with hexanes / EtOAc (3: 1) to give 9.82 g of 4- [1-benzyl-3- (3-methoxyphenyl) -piperidin-3-yl] -benzoic acid methyl ester 1 H NMR (400 MHz, CDCI3) or 7.87 (d, 2H), 7.41-7.20 (comp, 7H), 7.12 (t, 1 H), 6.77 (s, 1 H), 6.73 (d, 1 H), 6.66 (d , 1 H), 3.86 (s, 3H), 3.71 (s, 3H), 3.51 (s, 2H), 3.05 (br, 1 H), 2.68 (br, 1 H), 2.55 (br, 1 H), 2.41-2.24 (comp, 2H), 2.22-2.18 (m, 1 H), 1.61-1.42 (comp, 2H); MS (M + 1) 416.3.

E 4-Ri-Benzyl-3- (3-methoxyphenyl) -piperidin-3-in-N, N-diethyl-benzamide Trimethylaluminum (39.8 ml, 79.6 mmol, 2M in hexanes) was added dropwise to a solution of diethylamine. (8.21 mL, 79.6 mmol) in CH2CICH2CI 820 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. A solution of 4- [1-benzyl-3- (3-methoxyphenyl) -piperidin-3-yl] -benzoic acid methyl ester (6.0 g, 14.5 mmol) in (CH2) 2 Cl2 (6 mL) was added. , and the reaction mixture was heated to reflux for 14 hours (h). The solution was then cooled to 0 ° C, and sat aqueous sodium bicarbonate was added dropwise. (NaHCO3) (15 ml). The mixture was filtered through celite. The celite cake was washed with CH 2 Cl 2 (40 ml). The organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 (3 x 30 ml). The combined organic layers were dried over magnesium sulfate (MgSO) and concentrated. The crude residue was purified by flash chromatography with ethyl acetate (EtOAc) to give 6.57 g of 4- [1-benzyl-3- (3-methoxyphenyl) -piperidin-3-yl] -N, N-diethyl-benzamide. 1 H NMR (400 MHz, CDCl 3) or 7.41-7.20 (comp, 9H), 7.14 (t, 1 H), 6.82 (s, 1 H), 6.75 (d, 1 H), 6.66 (d, 1 H), 3.73 ( s, 3H), 3.68-3.51 (comp, 2H), 3.50 (s, 2H), 3.32-3.21 (comp, 2H), 2.98-2.89 (m, 1 H), 2.82-2.74 (m, 1 H), 2.65-2.59 (m, 1 H), 2.56-2.32 (comp, 2H), 2.29-2.19 (comp, 3H), 1.57-1.49 (comp, 1 H), 1.23-1.10 (comp, 3H), 1.09-1.04 (comp, 2H); MS (M + 1) 457.3.

F. N, N-diethyl-4- [3- (3-methoxy-phenyl) -piperidin-3-benzamide Palladium hydroxide (Pd (OH) 2) (10% on carbon, 0.04 g) was added to a solution of 4- [1-Benzyl-3- (3-methoxyphenyl) -piperidin-3-yl] -N, N-diethyl-benzamide (8 ml) in a bottle under pressure Parr. The reaction mixture was stirred under 344,737 Kpa of H2 for 20 hours. The reaction mixture was filtered through celite. The celite cake was washed with EtOAc. N, N-diethyl-4- [3- (3-methoxyphenyl) -piperidin-3-yl] -benzamide as the acetate salt. H NMR (400 MHz, CDCI3) or 7.39-7.17 (comp, 5H), 6.84-6.61 (comp, 3H), 3.74 (s, 3H), 3.73-3.60 (comp, 2H), 3.57-3.41 (comp, 2H) ), 3.38-3.14 (comp, 2H), 3.11-2.89 (comp, 2H), 2.48-2.26 (comp, 2H), 1.81-1.66 (comp, 2H), 1.21-1.70 (comp, 3H), 1.06-0.99 (comp, 3H); MS (M + 1) 367.4. The following compounds were prepared using the procedure set forth above in Example 1, starting with a compound analogous to the title compound of Example 1A, wherein R3 is fluoro or methoxy, and adding the appropriate amine reagent in the procedure of Example 1 AND. 4- [1-Benzyl-3- (3-methoxyphenyl) -p -peridin-3-yN-ethyl-N-methyl-benzamide 1 H NMR (400 MHz, CDCl 3) or 7.31 (d, 4 H), 6.82 (s, 1 H), 6.76 (d, 2H), 6.67 (dd, 1 H), 3.71 (s, 3H), 3.53 (br, 1 H), 3.50 (s, 2H), 3.27 (br, 1 H), 2.25-2.21 (comp, 2H); MS (M + 1) 4.43. 4- [1-Benzyl-3- (3-fluoro-5-methoxyphenyl) -p -peridin-3-yl-1-N, N-diethyl-benzamide PPP Rmn 1H (400 MHz, CDCl 3) d 7.33- 7.29 (comp, 4H), 7.25-7.21 (comp, 5H), 6.59 (s, 1 H), 6.54 (d, 1 H9, 6.39 (dt, 1 H), 3.69 (s, 3H), 3.54-3.45 ( comp, 4H), 3.24 (br, 2H), 2.80 (br, 2H), MS (M + 1) 475.3. 4-Ri-Benzyl-3- (3-methoxy-phenin-piperidin-3-yl-N- (2,2,2-trifluoroethylene-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.64 (d, 2H), 6.76-6.66 (comp, 3H), 6. 30 (br, 1 H), 4.11-4.07 (comp, 2H), 3.51 (s, 2H), 2.24-2.19 (comp.1 H); MS (M + 1) 483.3.

EXAMPLE 2 General procedure for the reductive alkylation of N, N, diethyl-4- [3- (3-methoxyphenyl) -piperidin-3-n-benzamide The aldehyde (1.2 equivalents) was added to a solution of N, N-diethyl-4- [3- (3-methoxyphenyl) -piperidin-3-yl] -benzamide (1 equivalent) in methylene chloride (CH2Cl2) (0.4M), followed by the addition of acetic acid (1.2 equivalents) and NaBH (OAc) 3 (1.5 equivalents). The reaction mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between equal volumes of CH2Cl2 and sat. Aqueous sodium bicarbonate. (NaHCO3). The organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 (3 x). The combined organic layers were dried (MgSO4) and concentrated. Purification by flash chromatography gave the desired tertiary amines with yields ranging from 60-95%. The following compounds were prepared using a procedure similar to that of Example 2, starting with a diaryl-substituted pyridine in which R3 is fluoro or methoxy and R2 is the appropriate amide group. 4-f1-Cyclopropylmethyl-3- (3-methoxyphenyl) -pyridin-3-yNN, N-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.34 (d, 2H), 7.24 ( dd, 2H), 7.13 (t, 1 H), 6.91 (s, 1 H), 6.84 (d, 1 H), 6.66 (d, 1 H), 3.71 (s, 3 H), 3.48 (br, 2 H), 3.25 (br, 2H), 3.05-2.80 (comp; 2H), 2.48 (br, 2H), 2.29-2.20 (comp, 4H), 1.60-1.50 (comp, 2H), 1.23 (br, 3H), 1.08 (br , 3H), 1.00-0.92 (comp, 1 H), 0.52 (d, 2H), 0. 12 (d, 2H); MS (M + 1) 421.3. 4- [1-Cyclopropylmethyl-3- (3-methoxyphenyl) -piperidin-3-yl-N, N-diisopropyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.31 (d, 2 H), 5.92 (s, 1 H), 6.85 (d, 1 H), 6.67 (d, 1 H), 2.48 (br, 2H), 2.25 (d, 4H), 1.02-0.93 Q (comp, 1 H), 0.90-0.80 (comp, 2H), 0.53 (d, 2H), 0.12 (d, 2H); MS (M + 1) 449.3. . { 4- [1-Cyclopropylmethyl-3- (3-methoxyphenyl) -p -peridin-3-ill-phenyl] - (3,4-dihydro-1 H -isoquinolin-2-yl) -methanone 1H NMR (400 MHz, CDCI3) d 7.37 (q, 4H), 6.91 (s, 1 H), 6.84 (d, 1 H), 6.69 (d, 1 H), 3.74 (s, 3H), 2.94-2.80 (comp, 4H ), 2.47 (br, 1 H), 2.28 (br, 4h), 0.55 (d 2H), 0.15 (br, 2H); MS (M + 1) 421.3. . { 4-Ri-Cyclopropylmethyl-3- (3-methoxy-phenol) -piperidin-3-y-phenol) -piperidin-1-yl-methanone 1 H-NMR (400 MHz, CDCl 3) d 7.35 (d, 2H), 7.15 (t, 1 H), 6.92 (s, 1 H), 6.84 (d, 1 H), 6.67 (d, 1 H), 3.74 (s, 3H), 3.66-3.60 (comp, 2H) , 3.40-3.34 (comp, 2H), 2.25 (d, 4H), 0.53 (d, 2H), 0.12 (d, 2H); MS (M + 1) 433.3. . { 4- [1-Cyclopropylmethyl-3- (3-methoxyphenyl) -piperidin-3-1-phenol-morpholin-4-yl-methanone 1 H-NMR (400 MHz, CDCl 3) d 7.39 (d, 2H) , 7.27 (d, 2H), 6.90 (s, 1 H), 6.83 (d, 1 H), 6.68 (d, 1 H), 2.25 (d, 4 H), 0.53 (d, 2 H), 0.12 (d, 2 H); MS (M + 1) 435.3.

N, N-Dethyl-4- [1-ethyl-3- (3-methoxy-phenol) -piperidin-3-yl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.32 (d, 2 H), 6.89 (s, 1 H), 6.82 (d, 1 H), 6.67 (dd, 1 H), 3.74 (s, 3H), 3.50 (br, 2H), 2.42 (q, 4H), 2.25-2.22 (comp, H); MS (M + 1) 395.2.

EXAMPLE 3 Alkylation of N, N-diethyl-4-r3- (3-methoxy-phenyl) -piperidin-3-p-benzamide Potassium carbonate (K2CO3) (3-10 equivalents) and the alkyl or heteroaryl halide (1-5 equivalents) were added to a solution of N, N-diethyl-4- [3- (3-methoxyphenyl) - piperidin-3-yl] -benzamide (1 equivalent) in DMF (0.5m). The reaction mixture was stirred at 60-120 ° C for 3-16 hours. The mixture was then cooled to room temperature, and filtered. The filtrate was diluted with diethyl ether, and the ether layer was washed with brine. The organic phase was dried (MgSO) and concentrated. Purification by flash chromatography gave the desired amines with yields ranging from 30-85%. The following compounds were prepared using a procedure analogous to that of Example 3, starting from the appropriate amide group.

N, N-Dietl-4- [3- (3-methoxyphenyl) -1-pyrimidin-2-ylpperidin-3-yn-benzamide 1 H-NMR (400 MHz, CDCl 3) d 8.35 (d , 2H), 7.33 (d, 2H), 7.23 (d, 2H), 7.14 (t, 1 H), 6.91 (s, 1 H), 6.86 (d, 1 H), 6.68 (dd 1 H), 6.49 (t, 1 H), 4.29 (q, 2H), 3.87-3.80 (comp, 1 H), 3.76-3.69 (comp, 1 H), 3.67 (s, 3H), 3.49 (br, 2H), 3.21 (br, 2H), 2.51-247 (comp; 2H), 1.62 (br, 2H), 1.18 (br, 3H) 1.06 (br, 3H); MS (M + 1) 445.4.

NN-Dietl-4-r3- (3-methoxyphenyl) -3,4,5,6-tetrahydro-2H- [1, 2'-bipyridin-3-yl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 8.24 -8.22 (comp, 1 H), 7.33 (d, 2H), 6.92 (s, 1 H), 6.86 (d, 1 H), 6.69 (dd, 2H), 4.10 (q, 2H), 3.23 (br, 2H), 2.45 (br 2H); MS (M + 1) 444.2. 4-Ri-Benzooxazol-2-yl-3- (3-methoxy-phenyl) -p -peridin-3-yl-N, N-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.41 (d, 1 H), 7.04 (t, 1 H), 6.90-6.86 (comp, 2H), 6.71 (dd, 1 H), 4.18 (br, 2H), 3.49 (br, 2H), 2.51-2.45 (comp, 2H) ), 1.69 (br, 2H); MS (M + 1) 484.4.

N, N-Dietl-4-f1- (5-fluoro-pyrimidin-2-yl) -3- (3-methoxyphenyl) -piperidin-3-yl-benzamide 1 H-NMR (400 MHz, CDCl 3 ) d 8.23- (s, 2H), 7.15 (t, 1 H), 7.90-7.84 (comp, 2H), 6.69 (dd, 1 H), 4.23 (q, 2H), 3.49 (br, 2H), 2.48-2.45 (comp, 2H), 1.62-1.67 (comp, 2H); MS (M + 1) 463.3. 4-p-Allyl-3- (3-methoxyphenyl) -piperidin-3-ip-N, N-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.29 (d, 2H), 7.23 (d, 2H), 7.12 (t, 1 H), 6.86 (s, 1 H), 5.99-5.89 (comp, 1 H), 5.19-5.13 (comp, 2H), 3.70 (s, 3H), .48 (br, 2H), 2.98 (d, 2H), 2.44 (br, 2H), 2.24-2.19 (comp, 2H); MS (M + 1) 07.3.

EXAMPLE 4 Deprotection of methyl aryl ethers A solution of boron tribromide (1-5 equivalents) in CH 2 Cl 2 (1.0M) was added dropwise to a solution of methyl ether (1 equivalent) in CH 2 Cl 2 (0.4M) at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 hour, warmed to room temperature, and stirred for an additional 4-6 hours. The mixture was quenched with slow addition of water, and brought to pH 8 with saturated water / ammonium hydroxide solution (NH OH). The aqueous layer was washed with CH2Cl2. The organic phase was dried (MgSO4) and concentrated. Purification by flash chromatography gave the desired phenols with performance ranging from 60-95%. Alternatively, the methyl ethers were deprotected with sodium hydride and ethanethiol in dimethylformamide (DMF) as follows: Ethanethiol (10 equivalents) was added dropwise to a suspension of sodium hydride (NaH) (10 equivalents) in DMF ( 0.2M) at room temperature. The mixture was stirred 5 minutes. A solution of the methyl ether (1 equivalent) in DMF (0.2M) was added to the reaction mixture. The mixture was heated at 120 ° C for 10-16 hours. The reaction was cooled to room temperature, and quenched with water. The mixture was diluted with diethyl ether, and the organic layer was washed with brine. The organic phase was dried (MgSO4) and concentrated. Purification by flash chromatography gave the desired phenols with yields ranging from 60-95%.

The following compounds were prepared using a procedure similar to that of Example 4. 4- [1-Benzyl-3- (3-hydroxyphenyl) -p -peridin-3-yNN, N-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.31-7.29 (comp, 4H), 7.28 -7.19 (comp, 5H), 7.03 (t, 1 H), 6.72 (d, 1 H), 6.62 (s, 1 H), 6.57 (dt, 1 H), 3.58-3.42 (comp, 4H), 3.47 (s, 2H), 3.25 (br, 2H), 2.88 (br, 1 H), 2.72 (br, 1 H), 2.49 (br, 1 H), 2.38 (br, 1 H), 2.25-1.95 (comp , 2H), 1.59-1.42 (comp, 2H), 1.20 (br, 3H), 1.09 (br, 3H); MS (M + 1) 443.3.

NN-Diethyl-4-f3- (3-hydroxy-phenyl) -p-perpent-3-n-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.31-7.14 (comp, 9H), 7.79 (d, 1 HOUR), 6. 70 (s, 1 H), 6.57 (dd, 1 H), 3.49 (br, 2H), 2.93 (br, 1 H), 2.66-2.60 (comp, 2H), 2. 66-2.17 (comp, 2H), 1.20 (br, 3H); MS (M + 1) 471.2. 4- [1-Cyclopropylmethyl-3- (3-hydroxyphenyl) -pyridin-3-yNN, N-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.32 (d, 2H), 7.02 (t, 1 H), 6.80 (d, 1 H), 6.53 (d, 1 H), 3.50 (br, 2H), 2.42 (br, 1 H), 1.56-1.51 (comp, 2H), 1.00-0.90 (comp, 1 H), 0.51 (d, 2H); MS (M + 1) 407.1 NN-Diethyl-4-r3- (3-hydroxyphenyl) -1-thiazol-2-methyl-piperidin-3-yl-1-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.68 ( d, H), 7.07 (t, 1 H), 6.80 6.75 (comp, 2H) 6.61 (dd, 1 H), 6.40 (br, 1 H), 3.51 (br, 2H), 2.54 (comp, 2H), 2.21 (br, 2H), 1.60-1.50 (comp, 2H); MS (M + 1) 450.2 4-Ri-Cyclohex-3-en-methyl-3- (3-hydroxyphenyl) -piperidin-3-yl-1-N, N-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.32 (d, 2H), 7.05 (t, 1 H), 6.81 (d, 1 H), 6.74 (d, 1 H), 6.58 (dd, 1 H), 3.50 (br, 2H), 1.89-1.80 (comp, 2H) , 1.70-1.63 (comp, 1 H), 1.54-1.42 (comp, 2H) 1.20 (br, 3H); MS (M + 1) 447.2 4- [1-Butyl-3- (3-hydroxyphenyl-piperidin-3-yNN, N-dethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.30 (d, 2H), 7.05 (t, 1 H), 6.80 (d, 1 H), 6.70 (s, 1 H), 6.56 (dd, 1 H), 3.50 (br, 2H), 2.93 (br, 1 H), 2.69 (br , 1 H), 2.35-2.30 (comp, 3H), 1.54-1.42 (comp, 5H), 0.91 (t, 3H), MS (M + 1) 409.3 NN-Diethyl-4-f3- (3-hydroxyphenyl) -1- (1H-imidazol-2-ylmethyl) -piper-dine-3-ip-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.17- 7.12 (comp, 4H), 6.87 (s, 2H), 6. 65 (d, 1 H), 6.52 (d, 1 H), 3.53 (br, 2H), 3.27-3.15 (comp, 4H), 2.60-250 (comp, 2H), 1.46 (br, 2H); MS (M + 1) 433.3 N, N-Diethyl-4-r3- (3-hydroxyphenyl) -1-propyl-piperidin-3-yn-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.31 (d, 2H), 7.04 (t, 1 H), 6.80 (d, 1 H), 6.71 (s, 1 H), 6.56 (dd, 1 H), 3.50 (br, 2H), 2.49 (br, 1 H), 2.20 (br, 2H), 1.62- 1.50 (comp, 4H) 0.90 (t, 3H), MS (M + 1) 395.3 NN-Diethyl-4-r3- (3-hydroxyphenyl) -1- (3-methylbutyl) -piperidin-3-yl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.331 (d, 2H), 7.04 (t, 1 H), 6.80 (d, 1H), 6.69 (s, 1H), 6.55 (dd, 1 H), 3.50 (br, 2H), 2.51 (br, 1 H), 2.39-2.24 (comp, 3H), 1.10 (br, 3H), 0.90 (d, 6H); MS (M + 1) 423.3 (4-Ri-Cyclopropylmethyl-3- (3-hydroxyphenip-pyridin-3-yl-1-piperidin-1-yl-methanone 1 H-NMR (400 MHz, CDCl 3) d 7.33-7.30 (comp, 2H) , 7.07 (t, 1 H), 6.80 (d, 1 H), 6.76 (s, 1 H), 6.61 (dd, 1 H), 3.65 (br, 2H), 3.33 (br, 2H), 2.37 (d , 2H), 2.24 (br, 2H), 1.05-0.94 (comp, 1H) 0.55 (d, 2H), 0.15 (d, 2H), MS (M + 1) 419.3 4-f1-Allyl-3- (3-hydroxyphenyl) -p -peridin-3-yNN, N-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.28 (comp, 2H), 7.04 (t, 1 H), 6.78 (d, 1 H), 6.68 (s, 1 H), 6.56 (dd, 1 H), 6.00-5.89 (comp, 1 H), 5.18 (d, 1 H), 5.15 (s, 1 H) 3.5 ( br, 2H), 2.50 (br 1 H), 2.39 (br, 1 H), 160-1.47 (comp, 2H); MS (M + 1) 393.2 NN-Detyl-4-f3- (3-hydroxyphenyl) -1-thiophen-3-ylmethyl-piperidin-3-yn-benzamide 1 H-NMR ( 400 MHz, CDCI3) d 7.09-7.05 (comp, 2H), 7.01 (t, 1 H), 6.70 (d, 1 H) 6.65 (s, 1 H), 6.56 (dd, 1 H), 3.49 (br, 4H), 2.37 (br, 1 H), 2.18 (br, 2H), 1.58-1.44 (comp, 2H); MS (M + 1) 449.3 4-f1-Acetyl-3- (3-hydroxy-phenyl) -piperidin-3-in-NN-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.28-720 (comp, 4H), 7.07 (t, 1 H), 6.84 (s, 1H), 6.72 (dd, 1H), 6.66 (dd, 1H), 4.18 (d, 1H), 3.85 (d, 1 H), 3.21 (br, 2H), 2.04 (s, 3H) 1.59-1.47 (comp, 2H); MS (M + 1) 395.2 4-RI-But-2-enyl-3- (3-hydroxyphenyl) -piperidin-3-yl-N, N-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.28 (d, 2H), 7.04 (t, 1 H), 6.78 (d, 1 H), 6.67 (s, 1 H), 6.55 (dd, 1 H), 5.60-5.57 (comp, 2H), 3.50 (br, 2H), 2.36 ( br, 1 H), 2.21 (br, 2H) 1.60-1.46 (comp, 2H), MS (M + 1) 407.3 4-f1-Cyclopropylmethyl-3- (4-fluoro-3-hydroxyphenyl) -piperidin-3-yl-1-N, N-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.30 (d, 2H), 6.98 (d , 1 H), 6.92 (dd, 1 H), 6.77 (s, 1 H), 3.51 (br, 2H), 2.27 (br, 2H), 1.54 (br, 2H), 0.55 (d, 2H); MS (M + 1) 425.5 4-f1-Cyclopropyl-methyl-3- (3-hydroxyphenyl) -piperidin-3-yNN, N-dethyl-benzamide H-NMR (400 MHz, CDCl 3 ) d 7.33 (d, 2H), 7.04 (t, 1 H), 6.81 (d, 1 H), 6.70 (s, 1 H), 6.54 (dd, 1H), 3.05 (s, 3H), 2.41 (br , H), 1.60-1.46 (comp, 2H), 0.51 (dd, 2H); MS (M + 1) 379.1 NN-Diethyl-4-r3- (3-hydroxyphenyl) -1- (3,4,4-trifluorobut-3-enyl) -piperidin-3-yl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.31-7.29 (comp, 4H), 7.28-7.19 (comp, 5H), 7.03 (t, 1 H), 6.72 (d, 1 H), 6.62 (s, 1 H), 6.57 (dt, 1 H), 3.50 (comp, 2H), 3.47 (s, 2H), 3.25 (br, 2H), 2.88 (br, 1 H), 2.72 (br, 1 H), 2.49 (br, 1 H), 2.38 (br, 1 H), 2.20 (comp, 2H), 1.51 (comp, 2H), 1.20 (br, 3H), 1.09 (br, 3H); EM (M + 1) 443.3 4-p-Cyclopropylmethyl-3- (3-hydroxyphenyl) -piperidin-3-yl-1-N-ethyl-N-methyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.33 (d, 2H), 7.05 (t , 1H), 6.82 (d, 1 H), 6.72 (s, 1 H), 6.56 (d, 1 H), 2.42 (br, 1 H), 2.32-1.17 (comp 4H), 1.62-1.48 (comp 2H), 0.53 (dd, 2H); MS (M + 1) 393.1.

NN-Dietl-4-f3- (3-hydroxyphenyl-1- (2-oxobutyn-piperidin-3-yl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.33-7.26 (comp.l H), 7.05 (t, 1 H), 6.73 (d, 1 H), 3.50 (br, 2H), 3.15-3.05 (comp 1 H), 2.24 (br, 1 H), 2.11 (d, 4H), EM ( M + 1) 423.1. 4- [1-Benzyl-3- (3-fluoro-5-hydroxy-phenyl) -piperidin-3-yl] -N, N-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 6.49 ( d, 1 H), 6.38 (s, 1 H), 6.29 (dt, 1 H), 3.49 (comp 2H), 3.45 (comp 2H), 3.25 (br, 2H); MS (M + 1) 461.3. 4- [1-Cyclopropylmethyl-3- (3-fluoro-5-hydroxyphenyl) piperidin-3-yl-1-N, N-dimethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.29-7.27 (comp 2H), 7.23-7.20 (comp. 2H), 6.59 (d, 1 H), 6.45 (s, 1H), 6.23 (dt, 1 H), 3.50 (br, 2H), 3.26 (br, 2H), 2.24 (d, 2H), 2.15 (br, 2H), 0.52 (comp 2H), 0.10 (comp 2H), 2.40 (br, 1 H), 2.24 (comp 2H), 1.53 (comp 2H), 1.20 (br, 3H), 1.10 (br, 3H); MS (M + 1) 425.3.

N, N-Diethyl-4-f3- (3-fluoro-5-hydroxyphenyl) -1-propyl-piperidin-3-yn-benzamide 1 H-NMR (400 MHz, CDCl 3) d 6.57 (d, 1 H), 6.43 (s, 1 H), 6.25 (dt, 1 H), 3.50 (br, 2H), 3.25 (br, 2H), 2.41 (br, 2H), 2.41 (br, 2H) , 2.27 (t, 2H), 2.13 (br, 1H); MS (M + 1) 413.3.

NN-diethyl-4- [1- (5-fluoropyrimidin-2-yl) -3- (3-hydroxyphenyl) -1-propyl-piperidin-3-in-benzamide 1 H-NMR (400 MHz, CDCl 3) d 8.22 (s) , 2H), 7.30-7.27 (comp 2H), 7. 05 (t, 1 H), 6.83 (d, 1 H), 6.74 (t, 1 H), 4.21 (q, 2H), 3.82-3.75 (comp 1 H), 3.65-3.59 (comp 2H), 3.49 (br, 2H), 2.41 (comp.2H); MS (M + 1) 449.3.

N, Nd-ethyl-4- [3- (3-hydroxyphenyl) -1-pyrimidin-2-yl-piperidin-3-yl-1-benzamide 1 H-NMR (400 MHz, CDCl 3) d 8.34 (s, 2H), 7.05 (comp 1 H), 6.81 (d, 2H), 6.55 (d, 2H), 3.82 (comp 1 H), 3.72 (comp 1 H), 2.43 (br, 2H); MS (M + 1) 431.3. (4- [1-Cyclopropylmethyl-3- (3-hydroxy-phenyl) -piperidin-3-yl] -phenyl) - (3,4-dihydro-1 H-isoquinolin-2-yl) - methanone 1 H NMR (400 MHz, CDCl 3) d 7.28 (d, 2 H), 7.05 (t, 1 H), 6.75 (d, 1 H), 6.72 (s, 1 H), 6.59 (dd, 1 H), 6.07 (br, 1 H), 3.50 (br, 2H), 3.13 (d, 1 H), 2.79-2.63 (comp 1 H), 2.18 (br, 2H), 1.21 (br, 3H); MS (M + 1) 435.3.

N, N-Diethyl-4- [3- (3-hydroxyphenyl) -1- (2.2.2-trifluoroethyl) -pyridin-3-yl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.38 (d, 2H), 7.27-7.19 (comp.H4H), 7. 17 (t, 1 H), 6.74 (s, 1 H), 6.60 (dd, 1 H), 2.38-2.20 (comp 4H), 1.57 (br, 2H), 0.54 (d, 2H); MS (M + 1) 435.3.

EXAMPLE 5 4-Ri-Benzyl-3- (carboxaminophenyl) -piperidin-3-1-N-diethyl-benzamide A. Ester 3- trifluoromethanesulfonic acid 3- [1-benzyl-3- (4-diethylcarbamoylphenol) -piperidin-3-phenyl ester. Pyridine (0.25 ml, 3.12 mmol) was added to a solution of 4- [1-benzyl] 3- (3-hydroxyphenyl) -piperidin-3-yl] -N, N-diethyl-benzamide (0.92 g, 2.08 mmol) in CH2Cl2 (15 mL) at 0 ° C, followed by dropwise addition of triflic anhydride (0.52 ml, 3.61 mmol) for 5 minutes. The reaction mixture was stirred at 0 ° C for 1 hour, and at room temperature for 2 hours. The solution was then cooled to 0 ° C, and 15 ml of cold saturated aqueous NaHCO3 was added. The organic layer was separated, and the aqueous layer was washed with CH2Cl2 (3x20 ml). The combined organic layers were dried (MgSO) and concentrated. The crude residue was purified by flash chromatography with hexanes / EtOAc (4: 1) to give 0.50 g of trifluoromethanesulfonic acid 3- [1-benzyl-3- (4-diethylcarbamoylphenyl) -piperidin-3-yl] -phenyl ester. 1 H NMR (400 MHz, CDCl 3) d 7.39-7.18 (comp 12H), 7.04-6.99 (m, 1 H), 3.60-3.39 (comp 4H), 3.35-3.28 (comp 2H), 3.06-2.87 ( m, 1 H), 2.68-2.44 (comp 2H), 2.38-2.25 (m, 1 H), 2.23-1.96 (comp 2H), 1.64-1.39 (comp 2H), 1.25-1.11 (comp. ), 1.10-0.09 (comp 3H); MS (M + 1) 575.2.

B. 4-1-Benzyl-3- (3-cyanopheniD-piperidin-3-p-N, N-d-ethyl-benzamide) Zinc cyanide (0.057 g, 0.49 mmol) and tetrakis were added. (triphenylphosphine) palladium (0.16 g, 0.14 mmol) to a solution of trifluoromethanesulfonic acid 3- (1-benzyl-3- (4-diethylcarbamoylphenyl) -piperidin-3-yl] -phenyl ester (0.40 g, 0.69 mmol ) in DMF (8 ml). The reaction was stirred under a nitrogen atmosphere at 90 ° C for 5 hours. The mixture was cooled to room temperature and diluted with diethyl ether (30 ml). The organic layer was washed with brine (5x10 ml), dried (MgSO) and concentrated. Purification with hexanes / EtOAc (1: 1) gave 0.28 g of 4- [1-benzyl-3- (3-cyanophenyl) -piperidin-3-yl] -N, N-diethyl-benzamide. 1 H NMR (400 MHz, CDCl 3) d 7.66 (s, 1 H), 7.69-7.20 (comp.10H), 7.15-7.13 (comp.2H), 3.60-3.38 (comp.4H), 3.31-3.19 (comp. 2H), 3.09-2.94 (m, 1 H), 2.8-2.45 (comp 2H), 2.22-2.17 (comp 3H), 1.71-1.61 (m, 1 H), 1.28-1.16 (comp 3H), 1.17-1.08 (comp 3H); MS (M + 1) 452.2.

B. 4-Ri-benzyl-3- (3-carboxaminophenyl) -piperidin-3-irj-N, N-dethyl-benzamide. Aqueous 3N Na2CO3 (3.25 mL) and 30% aqueous H2O2 (0.88 mL) were added. to a solution of 4- [1-benzyl-3- (3-cyanophenyl) -piperidin-3-yl] -N, N-diethyl-benzamide (0.50 g, 1.11 mmol) in 85 ml ethanol). The reaction mixture was stirred at room temperature for 8 hours. The mixture was diluted with water (2 ml), and the aqueous layer was washed with CH2Cl2 (3x10 ml). The organic layer was dried (MgSO4) and concentrated. The residue was purified by flash chromatography with CH2Cl2 / methanol (MeOH) (10: 1) to give 0.42 mg of 4- [1-benzyl-3- (3-carboxaminophenyl) -piperidin-3-yl] -N, N-dimethyl. -benzamida. 1 H NMR (400 MHz, CDCl 3) d 7.80 (s, 1 H), 7.56 (d, 1 H), 7.40-7.16. (comp 11 H), 5.99 (br, 1 H), 5.59 (br, 1 H), 3.59-3.39 (comp 4H), 3.34-3.18 (comp 2H), 3.06-2.88 (m, 1 H), 2.81-2.62 (m, 1 H), 2.41-2.27 (m, 1 H), 2.25-2.17 (comp 3H), 2.58-2.41 (comp 2H), 1.28-1.18 (comp.2H), 1.17-1.00 (comp. 3H); MS (M + 1) 470.3.

The following examples were prepared by methods similar to those described above in example 5. 4- [1- (2,2,2-trifluoroethyl) -3- (3-carboxaminophenyl) -p- peridn-3-yNN, N-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.93 (s, 1H), 7.64-7.61 (m, 1H), 6.24 (br, 1H), 3.56-3.42 (comp.2H), 2.62 (t, 1H), 1.18-1.10 (comp.3H); MS (M + 1) 462.3.

N, Nd-ethyl-4-f3- (3-carboxamnphenyl) -1-tiazol-2-ylmethyl-piperidin-3-yl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 8.15 (s, 1H), 7.72 (d, 1H), 7.68-7.65 (m, 1H), 5.93 (br, 1H), 2.77-2.67 (comp.2H), 1.08 (comp.3H); MS (M + 1) 477.3.

N, N-Diethyl-4-p-furan-2-methyl-3- (3-carboxaminophenyl) -p- peridn-3-iri-benzamide 1 H NMR (400 MHz, CDCl 3) d 7.92 (s) , 1H), 7.61 (d, 1H), 6.23 (br, 1H), 3.27-3.21 (comp.2H), 1.18-1.01 (comp.3H); MS (M + 1) 460.3.

EXAMPLE 6 1-Cyclopropylmethyl-3- (methoxyphenyl) -3- (4-thiophen-2-ylphenyl) -piperidine 2-Thiophaboric acid (0.052 g, 0.5 mmol) and sodium carbonate (0.037 g, 0.29 mmol) and tetrakis (triphenylphosphine) palladium (0.02 g, 0.5 mmol) were added to a solution of 4- [1-cyclopropylmethyl-3-ester. Trifluoromethanesulfonic acid (3-methoxy-phenyl) -piperidin-3-yl] -phenyl acid (0.1 g, 0.2 mmol) in ethanol (4.5 ml) and water (0.5 ml). The reaction mixture was heated to reflux for 2 hours. The mixture was then filtered, and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography with hexanes / EtOAc (3: 1) to give 0.08 g of 1-cyclopropylmethyl-3- (3-methoxyphenyl-3- (4-thiophen-2-ylphenyl) -piperidine) 1 H NMR (400 MHz , CDCI3) d 7.49 (d, 2H), 7.35 (d, 2H), 7.22-7.06 (comp. 3H), 7.05-7.00 (m, 1 H), 6.96 (s, 1 H), 6.89 (d, 1 H), 6.70-6.67 (m, 1 H), 3.76 (s, 3H), 3.17-2.82 (comp.2H), 2.61-2.39 (comp.2H), 2.27-2.18 (comp.4H), 1.62-1.39 (comp 3H), 0.60-0.45 (comp 2H), 0.18-0.11 (comp 2H), MS (M + 1) 404.2.

EXAMPLE 7 3- (4-f1-Allyl-3- (3-methoxy-phenyl) -piperidin-3-yl-phenyl) -pentan-3-ol Ethylmagnesium bromide (1 M in tert-butymethyl ether, 6.8 mL, 46.8 mmol) was added to a solution of 4- [1- allylmethyl-3- (3-methoxyphenyl) -piperidin-3-yl] - methyl ester. Benzoic acid (1.71 g, 4.68 mmol) in THF (30 ml) at 0 ° C. The ice bath was removed, and the reaction was stirred at room temperature for 1 hour. The mixture was quenched with slow addition of water (15 ml). The aqueous layer was washed with diethyl ether (3x30 ml). The combined extracts were dried (MgSO) and concentrated giving 1.67 g (91%) of 3-. { 4- [1-allyl-3- (3-methoxyphenyl) -piperidin-3-yl] -phenyl} -pentan-3-ol 1 H NMR (400 MHz, CDCl 3) d 7.23-7.20 (Compound 5H), 7.15 (t, 1 H), 6. 85-6.84 (comp 2H), 6.66 (dd, 1 H), 6.01-5.92 (m, 1 H), 5.20 (s, 1 H), 5.17-5.14 (m, 1 H), 3.71 (s, 3H), 3.04-2.95 (comp.2H), 2.88-2.72 (comp.2H), 2.50-2.40 (comp.2H), 2.27-2.21 (comp.2H), 1.83-1.71 (comp.4H), 1.57-1.49 (comp. 2H), 0.71 (dt, 6H); MS (M + 1) 394.3. The following compounds were prepared by a procedure analogous to that of Example 4 for the deprotection of the methyl ethers. 3-. { 1-Allyl-3- [4- (1-ethyl-1-hydroxypropyl) -phenyll-3-yl) -phenol 1 H-NMR (400 MHz, CDCl 3) d 7.21 (s, 5H), 7.09 (t, 1 H), 6.84 (d, 1 H), 6.73 (s, 1 H), 6.55 (dd, 1 H), 6.02-5.92 (m, 1 H), 5.20-5.14 (comp 2H), 3. 07-2.96 (comp 2H), 2.88-2.82 (comp, 2H), 2.50-2.40 (comp 2H), 2.25-2.20 (comp 2H), 1.82-1.72 (comp 4H), 1.65 (br, 1 H), 1.61-1.52 (comp 2H), 0.71 (t, 6H); MS (M + 1) 380.3. 3-l3-l4- (1-ethyl-1-hydroxypropyl) -phenyl-1 - (2,2,2-trifluoroetin-piperidin-3-in-phenol 1 H NMR (400 MHz, CDCl 3) d 6.84 (dd, 1 H) , 6.79 (t, 1 H), 4.97 (br, 1 H), 2.23-2.20 (comp 2H), 0.72 (t, 6H), EM (M + 1) 422.2. 3-. { 3- [4- (1-ethyl-1-hydroxypropyl) phenin-3,4,5,6-tetrahydro-2H-ri. 2'-1-bipyridinyl-3-ylMenol 1 H-NMR (400 MHz, CDCl 3) d 8.17-8.16 (m, 1 H), 7.07 (t, 1 H), 6.71 (d, 1 H), 4.25 (d, 1 H), 3.96 (d, 1 H), 2.47-2.35 (comp 2H); MS (M + 1) 417.3. 3-. { 1-cyclopropylmethyl-3-f4- (1-ethyl-1-hydroxypropyl) phenylpiperidin-3-yl) -phenol 1 H NMR (400 MHz, CDCl 3) d 7.10 (t, 1 H), 6.80 (d, 1 H ), 6.64 (d, 1 H), 2.32 (br, 1 H), 2.24 (br, 1 H), 0.58 (d, 2H); MS (M + 1) 394.4. The following compounds were prepared using the procedure of Example 7, followed by the conversion of R3 = OH to R3 = CONH2, according to the procedure of Example 5. 3- (1-Allyl-3-yl- (1-ethyl-1-hydroxypropyl) -phenyl] -piperidin-3-yl-l-benzamide 1 H NMR (400 MHz, CDCl 3) d 7.83 (s, 1 H) , 7.54 (d, 1H), 7.40 (d, 1H), 7.30 (t, 1H), 7.24-7.15 (comp, 4H), 6.06-5.94 (comp, 2H), 5.56 (br, 1H), . 21-5.16 (comp.2H), 3.00 (d, 2H), 2.69 (br, 1H), 2.56 (br, 1H), 2.42-2.28 (comp, 2H), 2.27-2.20 (m, 1H), 1.82- 1.70 (comp, 4H), 1.64 (br, 1H), 1.60-1.42 (comp, 2H), 0.71 (dt, 6H); MS (M + 1) 407.3. 3- (3-l4- (1-ethyl-1-hydroxypropyl-phenyl) -3,4,5,6-tetrahydro-2H-1,2,2-bipyridin-3-yl.} - benzamide 1 H-NMR (400 MHz, CDCI3) d 8.22 (d, 1H), 8.11 (s, 1H), 7.31 (t, 1H), 2.63-2.57 (comp, 2H), 2.52-2.39 (comp.2H), 0.69 (t, 6H) MS (M + 1) 444.3. 3- (3-R4- (1-ethyl-1-hydroxypropiophenin-1 - (2,2,2-trifluoromethyl) -p.per.din-3-yl) -benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.95 (s, 1H), 7.23 (d, 2H), 7.15 (d, 2H), 5.62 (br, 1H), 2.86 (d, 2H), 2.60-2.54 (m, 1H), 0.71 (t, 6H); MS (M + 1) 431.3.

EXAMPLE 8 3- (1-Cyclopropylmethyl-3-P-tolyl-piperidin-3-yl) -phenyl ester of propionic acid DMAP (18 mg, 0.15 mmol), triethylamine (0.071 ml, 0. 52 mmole) and propionyl chloride (0.038 ml, 0.45 mmole) to a solution of 3- (1-cyclopropylmethyl-3-p-tolyl-p, pperid-3-yl) -phenol (65 mg, 0.15 mmoles) in CH2CI2 (2 ml) at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The reaction was partitioned between 5 ml of CH2Cl2 and 5 ml of saturated aqueous NaHCO3. The aqueous layer was washed with CH2Cl2 (3x5 ml), dried over Na2SO and concentrated. Purification by flash chromatography with hexanes / EtOAc (1: 1) gave 58 mg of propionic acid 3- (1-cyclopropylmethyl-3-p-tolyl-piperidin-3-yl) -phenyl ester. 1 H NMR (400 MHz, CDCl 3) d 7.33 (d, 2H), 7.26-7.19 (comp, 3H), 7.16-7.03 (comp, 2H), 6.89-6.86 (m, 1 H), 3.59-3.43 (comp. 2H), 3.35-3.19 (comp.2H), 2.59-2.53 (q, 2H), 2.52-2.41 (comp, 2H), 2.27-2.18 (comp, 4H), 1.57-1.44 (comp, 2H), 1.31- 1.19 (t, 3H), 1.18-1.09 (comp, 3H), 1.08-1.01 (comp, 3H), 1.00-0.91 (m, 1 H), 0.59-0.49 (comp 2H), 0.19-0.11 (comp, 1 HOUR); MS (M + 1) 463.3. The following compound was prepared using a procedure similar to that of Example 8. 1 H NMR (400 MHz, CDCl 3) d 7.36-7.29 (comp, 2H), 7.10-7.02 (comp, 2H), 6.89-6.85 (m, 1 H), 3.01-2.82 (comp 2H), 2.82-2.75 ( m, 1 H), 1.28 (d, 3H); MS (M + 1) 477.3.

EXAMPLE 9 4-r4-Cyclopropylmethyl-2- (3-hydroxyphenyl) -morpholin-2-in-N, N-diethylbenzamide A. (4-Bromophenyl) - (3-methoxyphenyl) -methanol A solution of bromoanisole was added dropwise.

Ppp (9.1 ml, 71.4 mmol) in THF (30 ml) at room temperature to a magnesium suspension (2.4 g., 100 mmol) in THF (20 ml). The reaction mixture was stirred at room temperature for 2 h, and at 60 ° C for 2 h. The mixture was cooled to room temperature, and a solution of 4-bromobenzaldehyde (13.2 g, 71.4 mmol) was added over 5 minutes. The reaction mixture was stirred at room temperature for 3 hours, and quenched by the addition of aqueous saturated ammonium chloride (NH4CI) (30 ml). The aqueous layer was washed with ether (3x40 ml), dried over Na2SO4 and concentrated. Purification by flash chromatography with hexanes / EtOAc (10: 1) gave 16.95 g of (4-bromophenyl) - (3-methoxyphenyl) -methanol. 1 H NMR (400 MHz, CDCl 3) d 7.46-7.41 (comp 2H), 7.27-7.18 (comp, 3H), 6.91-6.87 (comp, 2H), 6.81-6.78 (m, 1 H), 5.73 (s, 1 H), 3.76 (s, 3H); MS (M + 1) 2.94.2 B (4-Bromophenyl) - (3-methoxyphenyl) -methanone A solution of trifluoroacetic acid (TFAA) (12.12 ml, 86.0 mmol) in CH2Cl2 (50 ml) was added during 5 min. A DEMO solution (8.13 ml, 114.7 mmol) ) in CH2CI2 (80 ml) at -78 ° C. the mixture was stirred for 20 min, a solution of (4-bromophenyl) - (3-methoxyphenyl) -methanol (16.8 g, 57.4 mmol) in CH2Cl (50 mL) was added dropwise over 5 min. The reaction mixture was stirred at -78 ° C for 30 min, and Et3N (24.0 mL, 172 mmol) was added. The mixture was stirred at -78 ° C for an additional 30 min, and at room temperature for 1 h. The CH2CI layer was washed with brine (3x30 ml), dried over Na2SO4 and concentrated. Purification with hexanes / EtOAc (10: 1) gave 16.0 (4-bromophenyl) - (3-methoxyphenyl) -methanone. 1 H NMR (400 MHz, CDCl 3) d 7.67-7.66 (comp 2H), 7.64-7.60 (comp, 2H), 7.37 (m, 1 H), 7.34-7.27 (comp, 2H), 7.14-7.11 (m, 1 H), 3.84 (s, 3H).

C. 2-Amino-1 - (4-bromopheniD-1 (3-methoxyphenyl) -ethanol Znl2 (0.15 g, 0.47 mmol) was added to a solution of (4-bromophenyl) - (3-methoxyphenyl) -methanone (2.06 g, 7.07 mmol) in CH2CI2 (3.5 ml) at room temperature, followed by the addition of TEMCN (4.29 ml, 32.2 mmol) The reaction mixture was stirred at room temperature for 3 h, and quenched by the addition of brine ( 20 ml) The aqueous layer was washed with CH2Cl2 (3x30 ml), and the combined organic extracts were dried over Na2SO and concentrated to give an oil.The resulting oil was dissolved in THF (7 ml), and the solution was added. drop exhausted to a solution of lithium aluminum hydride (LAH) in THF (1 M, 8.13 ml) at 0 ° C. The mixture was stirred at 0 ° C. for 1 h, and at room temperature for 1 h. (1.5 ml) to the solution, followed by the addition of 15% aqueous sodium hydroxide (NaOH) (1.5 ml) and H2O (4.5 ml) The mixture was filtered through celite, and the celite was washed with EtOAc (twenty ml) The filtrate was dried over MgSO4 and concentrated. Purification by flash chromatography with CH2Cl2 / MeOH (20: 1) gave 2.1 g of 2-amino-1- (4-bromophenyl) -1-3 (3-methoxyphenyl) -ethanol. 1 H NMR (400 MHz, CDCl 3) d 7.44-7.40, (comp 2H), 7.33-7.26 (comp, 2H), 7.24-7.20 (m, 1 H), 7.01-6.99 (m, 1 H), 6.97- 6.94 (m, 1 H), 3.77 (s, 3H), 3.47-3.35 (comp 2H), 3.29-3.24 (comp, 2H); MS (M + 1) 304.1, 306.1.

D. N-f2- (4-Bromophenyl) -2-hydorxy-2- (3-methoxyphenyl) -eti-11-chloroacetamide. Triethylamine (0.41 ml, 3.07 mmol) was added to a solution of 2-amino- 1- (4-bromophenyl) -1- (3-methoxyphenyl) -ethanol (0.94 g, 2.92 mmol) in toluene (10 ml) at 0 ° C. A solution of chloroacetyl chloride (0.23 ml, 2.92 mmol) in toluene (1 ml) was added to the reaction mixture, and the reaction was stirred at 0 ° C for 30 min and at room temperature for 1 h. Cold water (10 ml) was added to the reaction, and the mixture was stirred for 10 min. EtOAc (20 ml) was added and the layers were separated. The aqueous layer was washed with EtOAc (2x20 ml), and the combined organic extracts were dried over MgSO4 and concentrated. Purification by flash chromatography with hexanes / EtOAc (4: 1) gave 1.08 g of N- [2- (4-bromophenyl) -2-hydroxy-2- (3-methoxyphenyl) -ethyl] -2-chloroacetamide. 1 H NMR (400 MHz, CDCl 3) d 7.45-7.41 (comp, 2H), 7.29-7.20 (comp, 3H, 6.97-6.96 (m, 1 H), 6.93-6.90 (m, 1 H), 6.86-6.85 ( m, 1 H), 6.85-6.79 (m, 1 H), 4.14-3.98 (comp, 2H), 3.95 (s, 2H), 3.77 (s, 3H), MS (M + 1) 380.0, 382.0.

E. 6- (4-BromophenD-6- (3-methoxyphenyl) -morpholin-3-one t-BuOK (4.54 g, 40.5 mmol) was added to a solution of N- [2- (4-bromophenyl) -2-hydroxy-2- (3-methoxyphenyl) -ethyl] -2-chloroacetamide (3.67 g, 9.2 mmol) in benzene (205 ml) at room temperature The reaction mixture was stirred at room temperature for 2 h. Water (40 ml) was added and the mixture and the aqueous layer was washed with CH2Cl2 (2x50 ml) The combined organic extracts were dried over MgSO4 and concentrated.Purification by flash chromatography with hexanes / EtOAc (3: 1) gave 3.34 g of 6- (4-bromophenyl) -6- (3-methoxyphenyl) -morpholin-3-one. 1 H NMR (400 MHz, CDCl 3) d 7.46-7.41 (comp, 2H), 7.27-7.17 (comp 2H), 6.89-670 (comp, 3H), 6.69 (br, 1H), 4.10 (s, 2H), 3.93-3.80 (comp, 2H), 3.76 (s, 3H); MS (M + 1) 362.1, 364.1.

F. 2- (4-Bromophenyl) -2- (3-methoxy-phenol) -morpholine A solution of 6- (4-bromophenyl) - (3-methoxyphenyl) -morpholin-3-one (3.34 g, 9.23) was added. mmoles) in THF (15 ml) was added to a solution of LAH in THF (1M, 13.9 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h, and at room temperature for 16 h. H2O (6.2 ml) was added to the mixture followed by the addition of 15% aqueous NaOH (6.2 ml) and H2O (7 ml). The mixture was filtered through celite, and the celite was washed with EtOAc (50 ml). The filtrate was dried over MgSO 4 and concentrated to give 2.82 g of 2- (4-bromophenyl) -2- (3-methoxyphenyl) -morpholine. 1 H NMR (400 MHz, CDCl 3) d 7.43-7.36 (comp, 2H), 7.33-7.20 (comp, 3H), 6.98-6.82 (comp, 2H), 6.78-6.75 (m, 1 H), 3.76 (s, 3H), 3.68-3.69 (comp, 2H), 3.45-3.29 (comp, 2H), 2.93-2.88 (comp, 2H); MS (M + 1) 348.01, 350.0.

G. 2- (4-Bromophenip-4-cyclopropylmethyl-2- (3-methoxyphenyl) -morpholine Prepared by methods similar to those described in examples 2 and 3. 1 H-NMR (400 MHz, CDCl 3) d 7.42-7.38 (comp , 2H), 7.30-7.18 (comp, 3H), 7.08-6.97 (m, 1 H), 6.96-6.84 (m, 1 H), 6.79-6.71 (m, 1 H), 3.76 (s, 3H), 3.75-3.61 (comp, 2H), 3.15-2.88 (comp, 2H), 2.59-2.51 (comp, 2H), 2.29-2.19 (comp, 2H), 1.01-0.84 (m, 1 H), 0.50-0.49 ( comp, 2H), 0.18-0.11 (comp, 2H), MS (M + 1) 402.0, 404.0.

H. 4-l4-Cyclopropylmethyl-2- (3-methoxyphenyl) -morpholin-2-yl-benzoic acid methyl ester Prepared by a procedure similar to that described in example ID. 1 H NMR (400 MHz, CDCl 3) d 7.94 (d, 2 H), 7.48 (d, 2 H), 7.21-7.18. (m, 1 H), 6.98 (s, 1 H), 6.91 (d, 1 H), 6.74 (dd, 1 H), 3.87 (s, 3H), 3.75 (s, 3H), 3.74-3.63 (comp , 2H), 3.09-2.92 (comp, 2H), 2.56-2.48 (comp, 2H), 2.31-2.18 (comp, 2H), 0.98-0.88 (m, 1 H), 0.59-0.51 (comp, 2H), 0.14-0.10 (comp, 1 H); MS (M + 1) 382.1.

I. 4- [4-Cyclopropylmethyl-2- (3-methoxyphenyl) -morpholin-2-in-N, N-diethyl-benzamide Prepared by a method similar to that described in Example 1 E. 1 H NMR (400 MHz , CDCI3) d 7.40 (d, 1H), 7.28 (d, 2H), 7.23-7.18 (m, 1 H), 7.06-6.98 (m, 1 H), 6.93 (d, 1H), 6.75 (dd. H), 3.76 (s, 3H), 3.75-3.76 (comp, 2H), 3.55-3.49 (comp, 2H), 3.32-3.19 (comp, 2H), 3.16-3.02 (m, 1 H), 2.99-2.84 (m, 1 H), 2.58-2.43 (comp, 2H), 2.34-2.26 (m, 1 H), 2.25-2.18 (m, 1 H), 1.26-1.17 (comp, 3H), 1.16-1.04 (comp , 3H), 0.99-0.90 8m, 1 H), 0.59-0.51 (comp, 2H), 0.14-0.10 (comp, 2H); MS (M + 1) 423.3.

J. 4- [4-Cyclopropylmethyl-2- (3-hydroxyphenyl) -morpholin-2-yl-N, N-diethyl-benzamide Prepared by a method similar to that described in Example 4 1H-NMR (400 MHz, CDCl 3) d 7.38 (d, 1 H), 7.26 (d, 2H), 7.23-7.06 (m, 1 H), 6.91 (d, 1 H), 6.82 (s, 1 H), 6.61 (dd, 1 H), 3.79-3.63 (comp, 2H), 3.59-3.42 (comp, 2H), 3.35 -3.19 (comp, 2H), 3.08-2.83 (comp, 2H), 2.61-2.44 (comp, 2H), 2.32-2.18 (comp, 2H), 1.29-1.19 (comp, 3H), 1.18-1.01 (comp, 3H), 0.99-0.89 (m, 1 H), 0.59-0.49 (comp, 2H), 0.15-0.10 (comp, 2H); MS (M + 1) 409.1. The following examples were prepared by procedures described above in Example 9. 4- [4-Allyl-2- (3-hydroxyphenyl) -morpholin-2-yNN, N-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 6.81 (s, 1 H), 6.02 -5.83 (m, 25 1H), . 29-5.16 (comp, 2H), 3.04-2.98 (comp, 2H), 2.58-2.43 (comp, 2H); MS (M + 1) 395.3. 4- [4-Benzyl-2- (3-hydroxyphenyl) -morpholin-2-yl-1-N, N-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.13-7.06 (m, 1 H), 6.81-6.75 (comp, 2H), 6.67 (d, 1 H), 3.79-3.61 (comp, 2H), 3.32-3.18 (comp, 2H); MS (M + 1) 445.3. The following compound was prepared by the procedure of Example 9 and subsequent conversion of R3 = OH to R3 = CONH2, according to the procedure of Example 5. 4-f4-Cyclopropylmethyl-2- (3-carboxaminophenyl) -morpholin-2-yl-1-N, N-diethyl-benzamide 1 H-NMR (400 MHz, CDCl 3) d 7.91 (s, 1 H), 7.70-7.61 ( comp, 2H), 3.81-3.63 (comp, 2H), 0.61-0.44 (comp, 2H), 0.21-0.15 (comp, 2H); MS (M + 1) 436.3.

EXAMPLE 10 A. (5-Bromopyridin-2-yl) - (3-methoxyphenyl) -acetonic acid. 3-methoxyphenylacetonitrile (8.0 g., 54.3 mmol) was added to a suspension of 60% sodium hydride washed with hexane (2.65, 66.0 mmol) in DMF (30 ml) at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 min. A solution of 2,5-dibropyridine (15.45 g, 65.2 mmol) in DMF (20 ml) was added, and the reaction was stirred at room temperature for 20 min and at 50 ° C for 30 min. H2O (20 ml) and Et20 (200 ml) were added. The organic layer was washed with brine (5x50 ml), dried over Na2SO and concentrated. Purification by flash chromatography with hexanes / EtOAc (10: 1) gave 10.6 g of (5-bromopyridin-2-yl) - (3-methoxyphenyl) -acetonitrile. 1 H NMR (400 MHz, CDCl 3) d 8.63 (s, 1 H), 7.80 (dd, 1 H), 7.27 (comp, 2H), 6.98 (d, 1 H), 6.87 (s, 1 H), 6.84 ( m, 1 H), 5.28 (s, 1 H), 5.23 (s, 3H); MS (M + 1) 303.0, 305.0 B. 2- (5-Bromopyridin-2-yl) -5-chloro-2- (3-methoxyphenyl) -pentanonitrile A solution of (5-bromopyridin-2-yl) - (3-methoxidenil) was added. ) -acetonitrile (1.75 g, 5.76 mmol) to a suspension of 60% sodium hydride washed with hexane (0.35, 8.6 mmol) in DMF (2 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 min, and at room temperature for 1 h. 1-Bromo-3-chloropropane (0.69 ml, 6.91 mmol) was added, and the mixture was stirred at room temperature for 4 h. H2O (5 ml) was added to the reaction mixture, Et20, and the organic layer was washed with brine (5x5 ml), dried over Na2SO4 and concentrated. Purification by flash chromatography with hexanes / EtOAc (10: 1) yielded 1.81 g of 2- (5-bromopyridin-2-yl) -5-chloro-2- (3-methoxyphenyl) -pentanenitrile. 1 H NMR (400 MHz, CDCl 3) d 8.65 8 s, 1 H), 7.76 (dd, 1 H), 7.36 (d, 1 H), 7.27-7.21 (m, 1 H), 7.03 (d, 1 H), 6.98 (s, 1 H), 6.82 (dd, 1 H), 4.77 (s, 3H), 3.55 (t, 2H), 2.79-2.70 (comp, 1 H), 2.62-2.52 (comp, 1 H), 1.89-1.79 (comp, 2H); MS (M + 1) 378.8, 380.8.

C. 5-Bromo-3 '- (3-methoxyphenyl) -1', 2 ', 3', 4 ', 5', 6'-hexahydro-r2,3'-bipyridinyl DIBAL in CH2Cl2 (1M, 3.2 ml) to a solution of 2- (5-bromopyridin-2-yl) -5-chloro-2- (3-methoxyphenyl) -pentanenitrile (0.54 g, 1.43 mmol) in CH2Cl2 (3 ml) at -78 ° C. . The reaction mixture was stirred at -78 ° C for 1 h, and at room temperature for 4 h. The solution was poured into a saturated aqueous solution of Rochelle's salt (10 ml), and the resulting mixture was stirred vigorously for 16 h. The aqueous layer was washed with CH2Cl2 (3x10 ml), and the combined extracts were dried over Na2SO4, and concentrated. Purification by flash chromatography with CH 2 Cl 2 / MeOH (10: 1) yielded 0.36 g of 5-bromo-3 3-methoxy-phenyl) -1 ', 2', 3 ', 4', 5 ', 6'-hexahydro- [2,3 '] bipyridinyl. 1 H NMR (400 MHz, CDCl 3) d 8.62 (s, 1H), 7.63 (dd, 1H), 7.24-7.18 (m, 1H), 6.91 (d, 1H), 6.81-6.67 (comp, 3H), 3.96- 3.90 (m, 1H), 3.75 (s, 3H), 3.09-3.00 (comp, 2H), 2.81-2.74 (m, 1H), 2.54-2.48 (m, 1H), 2.41-2.34 (m, 1H), 1.64-1.60 (m, 1H), 1.38-1.31 (M, 1H); MS (M + 1) 347.1, 349.1.

D. 5-Bromo-1'-benzyl-3 '. (3-methoxy-phenyl) -1', 2 ', 3'.4'.5'.6'-hexahydro-r2,3'1-bipyridinyl Prepared by methods similar to those described in examples 2 and 3. 1 H NMR (400 MHz, CDCl 3) d 8.55 (s, 1H), 7.62 (dd, 1H), 7.42-7.21 (comp, 6H), 7.20-7.12 (m, 1H), 7.01 (d, 1H), 6.81- 6.74 (m, 1H), 6.67 (dd, 1H), 3.78 (s, 3H), 3.59-3.41 (comp, 2H), 3.20-3.12 (m, 1H), 2.81-2.25 (comp, 4H), 2.18- 2.04 (m, 1H), 1.62-1.41 (comp, 2H); MS (M + 1) 437.2, 439.3.

E. Methyl ester of 1 '-benzyl-3' - (3-methoxyphenyl) -1'.2 ', 3'.4'.5', 6'-hexahydro- [2,3'-1-pyridinyl-5 -carboxylic Prepared by a method similar to that of Example 1D. 1 H NMR (400 MHz, CDCl 3) d 9.10 (s, 1H), 8.10 (dd, 1H), 7.41-7.01 (comp, 7H), 6.81-6.77 (comp, 2H), 6.67 (dd, 1H), 3.90 ( s, 3H), 3.70 (s, 3H), 3.61-3.42 (comp, 2H), 3.25-3.15 (m, 1H), 2.85-2.75 (comp, 2H), 2.61-2.53 (m, 1H), 2.41- 2.38 (m, 1H), 2.20-2.12 (m, 1H), 1.62-1.55 (comp, 2H); MS (M + 1) 417.2.

F. Diethylamide of 1'-benzyl-3 '- (3-methoxyphenyl) -1', 2'.3'.4'.5 ', 6'-hexahydro-r2,3'-bipyridinyl-5 -carboxylic Prepared by a method similar to that of Example 1E. 1 H NMR (400 MHz, CDCl 3) d 8.53 (s, 1H), 7.55 (dd, 1H), 7.38-7.21 (comp, 5H), 7.18-7.09 (comp, 2H), 6.83.6.78 (comp, 2H), 6.68-6.62 (m, 1H), 3.71 (s, 3H), 3.60-3.42 (comp, 4H), 3.38-3.22 (comp, 2H), 3.18-3.07 (m, 1H), 2.92-2.82 (m, 1H) ), 2.65-2.61 (m, 1H), 2.58-2.40 (comp, 2H), 2.18-2.03 (m, 1H), 1.64-1.43 (comp, 2H), 1.34-1.10 (comp Ppp 6H); MS (M + 1) 449.3.

G. 1'-Benzyl-3 '- (3-hydroxy-phenyl) -1'.2'.3', 4 ', 5', 6'-hexahydro-f2.3'lbp acid diethylamide Ridinyl-5-carboxylic acid Prepared by a method similar to that of Example 4. 1 H NMR (400 MHz, CDCl 3) d 8.53 (s, 1 H), 7.55 (d, 1 H), 7.40-7.21 (comp, 5H), 7.19-7.08 (m, 1H), 7.03-6.89 (m, 1H), 6.77-6.62 (comp, 2H), 6.58-6.52 (m, 1H), 3.60-3.42 (comp, 4H) , 3.36-3.22 (comp, 2H), 3.18-3.04 (m, 1H), 2. 82-2.78 (m, 1H), 2.71-2.26 (comp, 3H), 2.18-2.03 (m, 1H), 1.62-1.44 (comp, 2H), 1.35-1.10 (comp, 6H): MS (M + 1) 444.2.

The following compounds were prepared by methods similar to those described in example 10.

Diethylamide of 1 '- (5-lfuoro-pyrimidin-2-yl) -3' - (3-hydroxyphenyl) -1 '.2'.3, .4'.5'.6'-hexahydro-r2 .3'-1-bipyridinyl-5-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 8.20 (s, 2 H), 4.57 (d, 1 H), 4.17 (d, 1 H); MS (M + 1) 450.3. 3 '- (3-Hydroxyphenyl) -pyrimidin-2-yl-1', 2'.3 ', 4', 5'.6'-hexahydro-r2,3'lbipyridinyl acid diethylamide -5-carboxylic acid 1 H NMR (400 MHz, CDCl 3) d 8.33 (s, 2 H), 6.49 (d, 2 H), 4.57 (d, 1 H), 4.17 (d, 1 H); MS (M + 1) 432.3. 1'-Cyclopropylmethyl-3 '- (3-hydroxyphenyl) -1'.2'.3'.4'.5, .6'-hexahydro-r2,3'lbpyridinyl-5-carboxylic acid diethylamide 1 H NMR (400 MHz, CDCl 3) d 7.58 (dd, 1 H), 1.01-0.84 (m, 1 H), .57-0.49 (comp, 2H), 0.17-0.11 (comp, 2H); MS (M + 1) 408.4. 3 '- (3-Hydroxyphen-1'-propyl-1'.2'.3'.4'.5'.6'-hexahydro- [2,3'-1-bipyridinyl-5-carboxylic acid 1H-NMR (400 MHz, CDCl 3) d 6.78 (s, 1H), 6.62 (d, 1H), 2.20-2.12 (m, 1H), 1.16-0.99 (comp, 3H), MS (M + 1) 396.4. 3 '- (3-Hydroxyphenyl) -1'-pentyl-1'.2'.3'.4'.5'.6'-hexahydro-r2,3'1-bipyridinyl-5-carboxylic acid diethylamide RMN 1H (400 MHz, CDCl 3) d 2.60-2.40 (comp, 4H), 1.41-1.10 (comp, 8H), 0.87 (t, 3H); MS (M + 1) 424.3. 3 '- (3-Hydroxyphen-1'-isobutyl-1', 2 ', 3', 4'.5'.6'-hexahydro-r2,3'lbpyridinyl-5-diethylamide -carboxylic NMR 1H (400 MHz, CDCl 3) d 7.58 (dd, 1H), 6.82 (s, 1H), 3.31-3.23 (comp, 2H), 1.00-0.70 (comp, 6H); MS (M + 1) 410.3 . 3 '- (3-Hydroxyphenyl) -1'-propyl-3', 4 ', 5', 6'-tetrahydro-2'H-f2.1 '; 3'.2"1-pyridin-5" - diethylamide - 1 H NMR carboxylic acid (400 MHz, CDCl 3) d 9.02 (s, 1H), 8.29 (d, 1H), 7.39-7.34 (m, 1H), 6.87 (br, 1H); MS (M + 1) 431.3. 3 '- (3-Hydroxyphenip-1' - (2-methylbutyl) - ', 2', 3 ', 4', 5'.6'-hexahydro-f2.3'1-bipyridinyl-5-diethylamide carboxylic 1 H NMR (400 MHz, CDCl 3) d 8.53-8.50 (m, 1 H), 6.83 (s, 1 H), .92-2.64 (comp, 2H), 1.17-1.09 (comp, 3H); MS (M +1) 424.4.

Claims (34)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula wherein R1 is hydrogen, (C0-C8) alkoxy-(C-? - C8) alkyl-, wherein the total number of carbon atoms is eight or less, aryl, aryl-alkyl (C? -8) - (heteroaryl, heteroarylalkyl (CrC8) -, heterocyclic, heterocyclic-C8 alkyl), cycloalkyl (C3-C7) -, or (C3-C7) cycloalkyl-alkyl (C? -8), wherein said aryl and the aryl moiety of said aryl-achenyl (C? -C8) - are independently selected from phenyl and naphthyl, and wherein said heteroaryl and the heteroaryl moiety of said heteroaryl (C -? - C8) alkyl are independently selected from pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, cabazolyl, 1, 2,5-thiadiazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinolinyl, phthalazinyl, quinoxalinyl, xanthinyl , hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolyl, oxadiazo lyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyridinyl, and pyrimidinyl; and wherein said heterocyclic and the heterocyclic moiety of said heterocyclic alkyl (C -? - C8) - are selected from saturated or unsaturated monocyclic or bicyclic ring systems, said monocyclic ring systems containing from four to seven carbon atoms. carbon in the ring, one to three of which may be optionally replaced by O, N or S; and any of the aryl, heteroaryl or heterocyclic moieties of R1 being optionally substituted with one to three substituents, preferably with one to two substituents, independently selected from halo (ie, chloro, fluoro, bromo or iodo), alkyl (C-) ? -C6) optionally substituted with one to seven (preferably with zero to four) fluorine, phenyl, benzyl, hydroxyl, a cetyl, amino, cyano, nitro, alkoxy (Ci-Cß), alkyl (C-Cinylamino and [alkyl] atoms) (Ci-C6)] 2-amino, and any of the alkyl residues in R1 (for example, the alkyl residues of the alkyl, alkoxy or alkylamino groups) being optionally substituted with one to seven (preferably with zero to four) fluorine atoms R2 is hydrogen, aryl, heteroaryl, heterocyclic, SO2R4, COR4, CONR5R6, COOR4, or C (OH) R5R6, wherein R4, R5 and R6 are independently defined as R1 as defined above, or R5 and R6, together with the carbon or nitrogen to which both are bound, form a saturated ring of three to seven members containing from zero to three heterocarbons independently selected from O, N and S, said aryl, heteroaryl, and heterocyclic being defined as such terms are defined above in the definition of R1, and any of the aryl, heteroaryl and heterocyclic R2 moieties are optionally substituted with one to three substituents, preferably with one to two substituents, independently selected from halo (ie, chloro, fluoro, bromo or iodo), C6 alkyl) optionally substituted with one to seven (preferably with zero to four) fluorine, phenyl, benzyl, hydroxyl, acetyl, amino, cyano, nitro, (C? -C6) alkoxy optionally substituted with one to seven (preferably with zero to four) fluorine atoms , alkyl (CrCßJamino and [alkyl (C6C6)] 2 a; R3 is hydroxyl, -NHSO2R7, -C (OH) R7R8, -OC (= O) R7, fluoro or -CO, wherein R7 and R8 are identical or different and are selected from hydrogen, alkyl (Cr C), alkoxy (C -? - C) and (C? -C) alkoxy-alkyl (C? -C), having a total of four or fewer carbon atoms, and in which any of the alkyl moieties of R7 and R8 can optionally being substituted with one to seven (preferably with zero to four) fluorine atoms; Q is oxygen or CH2; X is CH or N; and Z1 and Z2 are independently selected from hydrogen, halo, and alkyl (C-1-C5); with the proviso that there are not two adjacent ring oxygen atoms and there is no oxygen atom of the adjacent ring either to a ring nitrogen atom or to a ring sulfur atom, in any of the heterocyclic moieties or heteroaryl of formula I; or a pharmaceutically acceptable salt of such compound.

2. A compound according to claim 1, wherein Q is CH2.

3. A compound according to claim 1, wherein X is CH.

4. A compound according to claim 1, wherein X is CN.

5. - A compound according to claim 1, wherein Q is oxygen.

6. A compound according to claim 1, wherein R3 is OH, CONH2, or fluoro.

A compound according to claim 1, wherein R2 is selected from C (OH) (C2H6) 2, CONCH3 (CH2CH3), CON (C2H6) 2 and the following cyclic groups. (a) (b) (c) (d) (e) (f)

8. A compound according to claim 2, wherein X is CH.

9. A compound according to claim 2, wherein X is N.

10. A compound according to claim 6, wherein Q is CH2 and X is CH.

11. A compound according to claim 7, wherein Q is CH2 and X is CH.

12. A compound according to claim 6, wherein Q is CH2 and X is CH.

13. A compound according to claim 7, wherein Q is CH2 and X is N.

14. A pharmaceutical composition for treating a disorder or condition selected from inflammatory diseases such as arthritis, psoriasis, asthma, or inflammatory bowel disease, disorders of respiratory function such as asthma, cough and apnea, allergies, gastrointestinal disorders such as gastritis, functional bowel disease, irritable bowel syndrome, functional diarrhea, functional distension, functional pain, non-ulcerogenic dyspepsia and other disorders of mobility or secretion , and emesis, stroke, shock, cerebral edema, brain trauma, spinal cord trauma, cerebral ischemia, cerebral deficits after surgery and cardiac bypass graft, disorders of the urogenital tract such as urinary incontinence, dependencies and additions, to chemical compounds (for example, addictions or dependencies to alcohol, opiates, benzodiazepines, nicotine, heroin na or cocaine), chronic pain, non-somatic pain, acute pain and neurogenic pain, systemic lupus erythematosus, Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organ transplants and skin grafts in a mammal, comprising an effective amount of a compound according to claim 1, which is effective to treat disorder or condition, and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition for treating a disorder or condition, the treatment or prevention of which can be effected or facilitated by modulating the binding to opioid receptors in a mammal, comprising an amount of a compound according to claim 1, which is effective to treat such a disorder or condition, and a pharmaceutically acceptable vehicle.

16. A pharmaceutical composition for treating a disorder or selected state of inflammatory diseases such as arthritis, psoriasis, asthma, or inflammatory bowel disease, disorders of respiratory function such as asthma, cough and apnea, allergies, gastrointestinal disorders such as gastritis, functional bowel disease, irritable bowel syndrome, functional diarrhea, functional distension, functional pain, non-ulcerogenic dyspepsia and other disorders of mobility or secretion, and emesis, stroke, shock, cerebral edema, spinal cord trauma, cerebral ischemia, deficits brain injuries after cardiac bypass surgery and graft, urogenital tract disorders such as urinary incontinence, dependencies and addictions to chemical compounds (for example, addictions or dependencies to alcohol, opiates, benzodiazepines, nicotine, heroin or cocaine), chronic pain, pain not somatic, acute pain and neurogenic pain, lupus erythema systemic matose, Hodgkin's disease, Sjogren's disease, epilepsy and rejection in transplantation of organs and skin grafts in a mammal, comprising an effective amount, modulating the binding to the opioid receptor, of a compound according to claim 1, and a pharmaceutically acceptable vehicle.

17. A pharmaceutical composition for treating a disorder or condition, the treatment or prevention of which can be effected or facilitated by modulating the binding to opioid receptors in a mammal, comprising an effective amount, modulating the binding to the opioid receptor, a compound according to claim 1, and a pharmaceutically acceptable vehicle.

18. The use of an effective opioid receptor binding modulator amount of a compound according to claim 1 for the manufacture of a medicament for treating a disorder or condition selected from inflammatory diseases such as arthritis, psoriasis, asthma, or inflammatory bowel disease, respiratory function disorders such as asthma, cough and apnea, allergies, gastrointestinal disorders such as gastritis, functional bowel disease, irritable bowel syndrome, functional diarrhea, functional distension, functional pain, non-ulcerogenic dyspepsia and other disorders of mobility or secretion, and emesis, applejía, shock, cerebral edema, cerebral trauma, spinal cord trauma, cerebral ischemia, cerebral deficits after surgery and cardiac bypass graft, disorders of the urogenital tract such as urinary incotinence, dependencies and addictions to chemical compounds (for example, addictions or dependencies aa alcohol, opioids, benzodiazepines, nicotine, heroin or cocaine), chronic pain, non-somatic pain, acute pain and neurogenic pain, systemic lupus erythematosus, Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organ transplants and skin grafts in a mammal.

19. The use of an effective amount, modulator of the binding to the opioid receptor, of a compound according to claim 1 for the manufacture of a medicament for treating a disorder or condition whose treatment or prevention can be carried out or facilitated by modulating the union to opioid receptors in a mammal.

20. - The use of a compound of the formula wherein R1 is hydrogen, (C0-C8) - alkoxy, in the total number of carbon atoms is eight or less, aryl, aryl-alkyl (CrC8) -, heteroaryl, heteroarylalkyl (CrC8) -, heterocyclic, heterocyclic- alkyl (CrC8), cycloalkyl (C3-C7) -, or (C3-C7) cycloalkyl-alkyl (CrC8), wherein said aryl and the aryl moiety of said aryl-alkyl (C? -8) -select, independently , of phenyl and naphthyl, and wherein said heteroaryl and the heteroaryl moiety of said heteroaryl (C? -C8) alkyl are independently selected from pyrazinyl, benzofuranyl, quinoline, isoquinolyl, benzothienyl, isobenzofuranyl, pyrazolyl, indolyl, isoindolyl , benzimidazolyl, purinyl, cabazolyl, 1, 2,5-thiadiazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracil, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolyl , oxadiazolyl, isoxazolyl, thiazolyl, isotiaz olyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyridinyl, and pyrimidinyl; and wherein said heterocyclic and the heterocyclic moiety of said heterocyclic-C (C8) alkyl- are selected from monocyclic or non-aromatic saturated or unsaturated bicyclic ring systems, said monocyclic ring systems containing from four to seven carbon atoms in the ring, one to three of which may optionally be replaced by O, N or S, and containing said bicyclic ring systems of seven to twelve carbon atoms in the ring, one to four of which may be optionally replaced by O , N or S; and any of the aryl, heteroaryl or heterocyclic radicals of R1 being optionally substituted with one to three substituents, preferably with one or two substituents, independently selected from halo (ie, chloro fluoro, bromo or iodo), alkyl (C6) optionally substituted with one to seven (preferably with zero to four) fluorine, phenyl, benzyl, hydroxyl, acetyl, amino, cyano, nitro, alkoxy, (C? -C6), alkyl (C Ce) amino and [alkyl ( CrC6)] 2amino, and any of the alkyl moieties in R1 (for example, the alkyl moieties of the alkyl, alkoxy, or alkylamino groups) being optionally substituted with one to seven (preferably with zero to four fluorine atoms; R2 is hydrogen, aryl, heteroaryl, heterocyclic, SO2R4, COR4, CONR5R6, COOR4, or C (OH) R5R6, wherein R4, R5 and R6 are independently defined as R1 as defined above, or R5 and R6, together with the carbon or nitrogen to which both are bound, form a saturated ring of three to seven members containing from zero to three heterocarbons independently selected from O, N, and S, and said aryl, heteroaryl, and heterocyclic being defined as such terms are defined above in the definition of R1, and can be of the aryl, heteroaryl and heterocyclic R2 moieties are optionally substituted with one to three substituents, preferably with one to two substituents, independently selected from halo (ie, chloro fluoro, bromo or iodo), optionally substituted (Ci-Cβ) alkyl with one to seven (preferably with zero to four) fluorine, phenyl, benzyl, hydroxyl, acetyl, amino, cyano, nitro, alkoxy, (C? -C6) optionally substituted with one to seven (preferably with zero to four) atoms fluorine atoms, alkyl (C C6) amino and [alkyl (d-Ce ^ amino; R3 is hydroxyl, -NHSO2R7, -C (OH) R7R8, -OC (= O) R7, fluoro or -CONHR7, wherein R7 and R8 are the same or different and are selected from hydrogen, alkyl (CrC4), alkoxy ( C? -C4) and (C? -C4) alkoxy-alkyl (CrC4), having a total of four or fewer carbon atoms, and wherein any of the alkyl moieties of R7 and R8 may be optionally substituted with each other seven (preferably with zero to four) fluorine atoms; Q is oxygen or CH2; X is CH or N; and Z1 and Z2 are independently selected from hydrogen, halo, and (C1-C5) alkyl; with the proviso that there are not two adjacent ring oxygen atoms and there is no oxygen atom of the adjacent ring either to a ring nitrogen atom or to a ring sulfur atom, in any of the heterocyclic moieties or heteroaryl of formula I, or a pharmaceutically acceptable salt of such compound for the manufacture of a medicament for treating a disorder or condition.

21. Use of a compound according to claim 20, wherein Q in said compound is CH2.

22. Use of a compound according to claim 20, wherein X in said compound is CH.

23. - Use of a compound according to claim 20, wherein X in said compound is N.

24.- Use of a compound according to claim 20, wherein Q in said compound is oxygen.

25. Use of a compound according to claim 20, wherein R3 in said compound is OH, CONH2, or fluoro.

26. Use of a compound according to claim 20, wherein R2 in said compound is selected from C (OH) (C2H6) 2 CONCH3 (CH2CH3), CON (C2H6) 2 and the following cyclic groups: (a) (b) (c) (d) (e) (f)

27. - Use of a compound according to claim 21, wherein X in said compound is CH.

28. Use of a compound according to claim 21, wherein X in said compound is N.

29.- Use of a compound according to claim 25, wherein Q in said compound is CH2 and X is CH.

30. Use of a compound according to claim 26, wherein Q in said compound is CH2 and X is CH.

31. Use of a compound according to claim 25, wherein Q in said compound is CH2 and X is N.

32. - Use of a compound according to claim 26, wherein Q in said compound is CH2 and X is N.

33.- The use according to claim 22, wherein the disorder or condition is selected from inflammatory diseases such as arthritis, psoriasis, asthma, or inflammatory bowel disease, disorders of respiratory function such as asthma, cough and apnea, allergies, gastrointestinal disorders such as gastritis, functional bowel disease, irritable bowel syndrome, functional diarrhea, functional distension, functional pain, dyspepsia not ulcerogenic and other disorders of mobility or secretion, and emesis, stroke, shock, cerebral edema, brain trauma, spinal cord trauma, cerebral ischemia, post-surgery cerebral deficits and cardiac bypass graft, disorders of the urogenital tract such as incontinence urinary, dependencies and addictions to chemical compounds (for example, addictions or dependencies to alcohol, opiates, benzod iazepines, nicotine, heroin or cocaine), chronic pain, non-somatic pain, acute pain and neurogenic pain, systemic lupus erythematosus, Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organ transplants and skin grafts in a mammal.

34. The use according to claim 22, wherein the treatment of the disorder or condition can be effected or facilitated by modulating the binding to opioid receptors in a mammal.