MXPA00008362A - 2-arylethyl-(piperidin-4-ylmethyl)amine derivatives as muscarinic receptor antagonists - Google Patents

Abstract

This invention relates to muscarinic receptor antagonists compounds of formula (I) and to their pharmaceutically acceptable salts, individual isomers or to a racemic or non-racemic mixture;to pharmaceutical compositions containing them, and to methods for their use as therapeutic agents.

Description

DERIVATIVES OF 2-iü --ETXL- (PZP-5RZPZN-4-Zl-METZL) AMZtP- AS ANTAGONISTS OF THE MPSCARXNXCO RECEIVER BACKGROUND OF THE INVENTION The present invention relates to the compounds of formula wherein R1 is each, independently, hydrogen, alkyl, alkyloxy, halogen, haloalkyl, or amino; R2 is each, independently: (1) alkyl, (2) alkyloxy, (3) halogen, (4) haloalkyl, (5) nitro, (6) heterocyclyl, optionally substituted with oxo, REF .: 122461 (7) -0 (CH2) pX, wherein p is 0-6 and X is independently selected from haloalkyl or aryl, (11) -NR6C3R% (12) -NR6CSNRR8, (13) -NR6S02R9, (14) -NR6S02NR7R8, (15) -SR9, (16) -SOR9, (17) -S02R9, (18) -S02NRRβ; or R1 and R2 taken together with the ring to which they are attached to form a 5 or 6 membered monocyclic, saturated or unsaturated ring, optionally containing 0, 1 or 2 heteroatoms selected, independently from each other, between nitrogen, oxygen or sulfur; R3 and. "Are each, independently of each other, lower alkyl, alkenyl or cycloalkyl; R5 is each independently: (1) hydrogen, (2) -COR ', (3) -COOR7, (4) -CONR7R \ (5) -C0 (CH2) "C0R ', (6) -C0 (CH2)" S02Rs, (7) -C0 (CH2) nC0NR7R \ (8) -CO (CH2) n? 02NR7R \ (9> -CO (CH2) nNR6CORs, (10) -C0 (CH2) nNR6S02R \ (11) -C0 (CH2) "NRsC0NR7R \ (12) -C0 (CH2)" NRsS02NR7R \ (13) -CSR5, (14) -CSNR7R8, (15) -S02R9, (16) -S02NR7R ", (17) -S02 (CH2) nNR6S02Rs, or (18) -S02NR '(CH2) nC00R7; wherein n is 1-6; R6 and R7 are each, independently of each other, hydrogen or lower alkyl; R8 is each, independently, hydrogen, lower alkyl, cycloalkyl, aryl or heteroaryl; R9 is each, independently: (1) alkyl (2) cycloalkyl, (3) arylalkyl, () aryl, unsubstituted or mono-, di- or trisubstituted aryl, the substituents being independently selected from lower alkyl, alkyloxy, halogen, haloalkyl, cyano, nitro, -C0NR7Rβ, -COR7, -COOR7, - NR7R8, -NCOR9, -S02R9, -S02NR7R8 or -0 (CH2) pX, wherein p is 0-6 and X is haloalkyl or aryl, (5) heterocyclyl, optionally substituted with one or two substituents, selected from lower alkyl, hydroxy, hydroxyalkyl, oxo, -COR7, or -COOR7, or (6) heteroaryl, optionally substituted by one or two substituents, selected from lower alkyl, alkyloxy, halogen, haloalkyl, cyano, nitro, -CONR7R, -COR7, -COOR7, -NR7R8, -NCOR9, -S02R9, -S02NR7R8, or 0 (CH2) pX, wherein p is 0-6 and X is haloalkyl or aryl; and to an individual isomer or to a racemic or non-racemic mixture of isomers, or to a pharmaceutically acceptable salt thereof. The compounds of the present invention are muscarinic receptor antagonists. Muscarinic receptor antagonists prevent the effects of acetylcholine by blocking its binding to muscarinic cholinoreceptors at neuroeffector sites on smooth muscle, cardiac muscle, and glandular cells; in ganglia peripherals; and in the central nervous system, and predominantly have been used to inhibit the effects of parasympathetic nervous system activity. In this way, muscarinic receptor antagonists achieve far-reaching physiological effects, and drugs that interact selectively with muscarinic receptors have a broad spectrum of therapeutic applications. For example, muscarinic receptor antagonists have been employed in the treatment of various disorders in the gastrointestinal tract, genitourinary tract, respiratory tract, cardiovascular system, central nervous system, and have been shown to be useful in anesthesiology and ophthalmology. Muscarinic receptor antagonists have been shown to be useful in the treatment of various gastrointestinal disorders, including a wide variety of conditions involving increased spasticity or motility of the gastrointestinal tract, for example diarrhea. These agents can reduce tone and motility if conditions are due to excessive smooth muscle muscle contractions. Muscarinic receptor antagonists have been shown to be useful in the treatment of disorders of the genitourinary tract. These agents have proven to be J of low intravesical pressure, increase the capacity of the bladder, and reduce the frequency of contractions of the urinary bladder, by antagonizing the parasympathetic control of this organ. Muscarinic receptor antagonists have been shown to be useful in the treatment of various disorders of the respiratory tract, particularly including those conditions that reduce secretion in both the upper and lower respiratory tract, and induce bronchial dilation. These agents can have beneficial effects when airway obstruction is associated, for example, with chronic bronchitis, chronic lung obstructive disease, bronchial asthma or emphysema. Muscarinic receptor antagonists have been shown to be useful in the treatment of various cardiovascular disorders, for example, including those conditions where excessive vagal tone causes sinusal or nodal bradycardia. Muscarinic receptor antagonists have been shown to be useful in the treatment of central nervous system disorders. These agents have been shown to be effective in previous dystonias or parkinsonian symptoms and have been highly effective in preventing movement sickness (motion sickness).

Muscarinic receptor antagonists have proved to be useful in anesthesiology, particularly for the inhibition of excessive saliva formation and respiratory tract secretions induced by the administration of general anesthetic agents, and their concomitant bronchodilator action. They have also proven to be useful in ophthalmology to produce mydriasis and cycloplegia when applied locally to the eye. These and other therapeutic uses are described in The Pharmacological Basis of Therapeutics by Goodman & Gillman, ninth edition, McGraw-Hill, New York, 1996; chapter 7, pages 148-160. Certain piperidinaminic compounds have been set as an example in the chemical patent literature. For example, US Patent Nos. 5,310,743; 5,541,195; and 5,646,144 (Schilling et al.) describe derivatives of 1-acyl-N- (2-chlorophenyl) ethyl-4-piperidinamine having antagonist properties of the substance P. Other derivatives of piperidine are described in US Patent No. 5,286,735 (Bonnaud and Bigg) as useful as ligands of the serotonergic receptor and for the treatment of anxiety or depression; U.S. Patent No. 5,089,507 (Vechietti et al.) for the treatment of painful conditions or hyponatremic disease; the published European patent application No. EP 532 398 (assigned to Synthelabo) for the treatment of psychosis, anxiety, hypertension and migraine; and the published PCT application No. WO 97/10212 (issued to Neurosearc A / S) for the treatment of stroke, anoxia, ischemia, migraine, psychosis, epilepsy or other seizure disorders. The subject of the present invention are the compounds of formula I and the pharmaceutically acceptable salts thereof, the racemic mixtures and their corresponding enantiomers, the preparation of the compounds mentioned above, the medicaments containing them and their preparation, as well as the use of these compounds mentioned above, in the control or prevention of diseases, especially diseases and disorders of the type described above, or in the preparation of the corresponding medicaments. Unless otherwise indicated, the following terms used in the specification and claims have the meanings set forth below: "Alkyl" means a monovalent radical of saturated hydrocarbons, branched or unbranched, of one to twelve carbon atoms inclusive , as p. ex. methyl, ethyl, propyl, 1-ethylpropyl, 2-propyl, butyl, tert-butyl, n-octyl, n-nonyl, and the like.

"Lower alkyl" means an alkyl radical of one to six carbon atoms inclusive. "Alkyloxy" means the group -O-R wherein R is alkyl as defined above. "Cycloalkyl" means a saturated monovalent carbocyclic radical having from three to fourteen carbon atoms inclusive, p. ex. cyclopropylmethyl, cyclopropylethyl, cyclobutyl, 3-ethylcyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. "Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms inclusive, or a branched monovalent hydrocarbon radical of three to six carbon atoms inclusive, containing a double bond, such as ethenyl, allyl, -propenyl, 2-butenyl, and the like. "Halogen" means fluorine, chlorine, bromine or iodine.

"Haloalkyl" means alkyl as defined above, substituted with one, two or three halogen atoms as defined above in any position, such as p. ex. 1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloromethyl, and the like. "Hydroxyalkyl" means alkyl substituted with 1, 2 or 3 hydroxy groups, such as p. ex. hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, 1,3-dihydroxybutyl, and the like. "Aryl" means a monocyclic aromatic ring or a bicyclic or tricyclic ring system of 9 to 14 members, in which at least one ring is aromatic in nature. Examples of aryl radicals include but are not limited to, phenyl, naphthyl, biphenyl, diphenylmethyl, 9H-fluorenyl, indanyl, and the like. "Arylalkyl" means the radical RaRb- in which Ra is aryl as defined above, and R is alkyl as defined above, for example, benzyl, phenylethyl, 3-phenylpropyl, and the like. "Heteroaryl" means a monocyclic aromatic ring of a 9 to 14 membered bicyclic ring system, wherein at least one ring is aromatic in nature and includes heterocycles having one, two or three heteroatoms within the ring, chosen from nitrogen , oxygen and sulfur. Examples of heteroaryl radicals include but are not limited to, furyl, 3,3-dimethyl-2,3-dihydrobenzofuryl, benzofuryl, 2,3-dihydrobenzofuryl, pyranyl, benzo [1,3] dioxyl, 2,3-dihydrobenzotl, 4] dioxinyl, indolyl, 2,3-dihydroindolyl, pyridyl, pyrazolyl, pyrazinyl, quinolyl, 1,2,3,4-tetrahydroquinolyl, isoquinolyl, 1,2,3,4- tetrahydroisoquinolyl, pyrrolyl, imidazolyl, 1,2,3,4-tetrahydro [1, 5] naphthyridinyl, 2H-3, -dihydrobenzo [l,] oxazine, thienyl, benzo [b] thienyl, and the like. "Heterocyclyl" means a saturated monovalent carbocyclic radical having five, six or seven ring atoms, of which one or two are selected from nitrogen, oxygen or sulfur. Examples of heterocyclyl radicals include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, piperadinyl, piperazinyl, morpholino, thiomorpholino, 1,1-dioxo-thiomorpholino, imidazolidinyl, pyrrolidinyl, pyrrolidin-2-one, pyrrolidin-2,3-dione. , and similar. "Amino protecting group" or "N-protecting group" means a protection group that refers to those organic groups intended to protect the nitrogen atom against undesired reactions during the different processes of the synthesis, and includes benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), trifluoroacetyl and the like, although not limited thereto. It is preferred to use BOC or CBZ as the amino-protecting group because of its relatively easy elimination, for example by means of mild acids in the case of BOC, eg trifluoroacetic acid or hydrochloric acid in ethyl acetate; or by catalytic hydrogenation in the case of CBZ. "Optional" or "optionally" means that the event or circumstance described below may take place although not necessarily, and that the description includes examples in which the event or circumstance takes place and examples in which it does not take place. For example, "optionally substituted aryl" means that the aryl portion may or may not be substituted, and that the description includes both the substituted aryl and the unsubstituted aryl. "Inert organic solvent" or "inert solvent" means an inert solvent under the reaction conditions described in conjunction therewith, and include, for example, benzene, toluene, acetonitrile, tetrahydrofuran, chloroform (CHC13), methylene chloride or dichloromethane ( CH2C12), diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine and the like. Unless otherwise specified, the solvents used in the reactions of the present invention are inert solvents. The compounds of this invention may have one or several asymmetric centers; these compounds can therefore be produced as mixtures of stereoisomers or as isolated or purified individual stereoisomers (R) - or (S) -. The individual enantiomers can be obtained by separating a racemic or non-racemic mixture from an intermediate product at some appropriate stage of the synthesis, and then continuing the synthesis so that the chirality is preserved, or by separating the compound of formula I by conventional means. Individual enantiomers as well as racemic or non-racemic mixtures thereof are within the scope of the present invention, and it is intended that all of them be represented by the structures of this specification unless otherwise specifically indicated. The use of the symbol "(R)" or "(S)" preceding a substituent indicates an absolute stereochemistry of this substituent according to the Cahn-Ingold-Prelog rules (Cahn et al., Angew., Chem., Inter., Ed. 5, 385, Errata 511, Cahn et al., Angew, Chem. 1966, 78, 413, Cahn and Ingold J. Chem. Soc. (London) 1951, 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116). A "pharmaceutically acceptable carrier" means a carrier that is useful for preparing a pharmaceutical composition, and is generally compatible with the other ingredients of the composition, is not detrimental to the recipient, is not undesirable neither biologically nor by any other cause, and including a support that is acceptable for use in veterinary medicine as well as for pharmaceutical and human use. A "pharmaceutically acceptable carrier" as used in the I specification and claims, includes both one and several of this type of supports. A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that has the desired pharmacological activity of the parent compound. These salts include: 10 (1) Acid addition salts, formed with inorganic acids such as p. ex. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as p. ex. acetic acid, propionic acid, hexanoic acid, cyclopentanpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid; citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-en-l-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, acid trimethylacetic, tert-butyl-acetic acid, lauryl-sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mondnic acid, and the like; or (2) the salts that are formed when an acidic proton present in the original compound is replaced by a metal ion p. ex. an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or it is coordinated with an organic basis such as p. ex. ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. Preferred pharmaceutically acceptable salts are the salts formed from hydrochloric acid, phosphoric acid, trifluoroacetic acid, and dibenzoyl-L-tartaric acid. "Mammal" includes humans and all domestic and wild animals, including without limitation, cows, horses, pigs, sheep, goats, dogs, cats and the like. The "treatment" of a disease includes: (1) The prevention of the disease, that is, the cause of the clinical symptoms of the disease does not develop in a mammal that may be exposed or predisposed to the disease, but still has not experienced or presented symptoms of the disease, (2) Inhibition of the disease, that is, the interruption of the development of the disease or its clinical symptoms, or (3) The relief of the disease, that is, causing a regression of the disease or its clinical symptoms. A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for the treatment of a disease, is sufficient to effect this treatment of the disease. The "therapeutically effective amount" will vary depending on the compound and the state of the disease to be treated, the severity of the disease treated, the age and relative health of the subject, the route and manner of administration, the criteria of the physician who attends, and other factors. The naming and numbering of the compounds of this invention is indicated below: In general, the nomenclature used in the present application is based on the AutoNom method, a computerized system of the Beilstein Institute for the generation of the systematic nomenclature of the IUPAC. However, as a consequence of a strict observance of these rules, a substantial change of the names will be obtained by changing only a simple substituent, for which the compounds have been named so as to maintain the consistency of the nomenclature for the basic structure of the molecule. For example, a compound of formula I wherein R 1 is hydrogen, R 2 is trifluoromethyl, R 3 is methyl, R 4 is cyclopropylmethyl, and R 5 is methanesulfonic, is named N- [2- (4-trifluorophenyl) -l-methylethyl] -N-cyclopropylmethyl- (1-methanesulfonylpiperidin-4-ylmethyl-sheet.

For example, a compound of formula I wherein R1 and R2 taken together with the ring to which they are attached, form 2,3-dihydrobenzofuran-5-yl, R3 is methyl, R4 is ethyl, and R5 is dimethylaminocarbonyl, receives the name of N- [2- (2, 3-dihydrobenzofuran-5-yl) -1-methylethyl] -N-ethyl- [1- (dimethylaminocarbonyl) -piperidin-4-ylmethyl] amine. For example, a compound of formula I wherein R 1 is hydrogen, R 2 is 4-methoxyphenylcarbonylamino, R 3 is methyl, R 4 is propyl, and R 5 is morpholine-4-carbonyl, is called N-. { 2- [3- (4-methoxyphenylcarbonylamino) phenyl] -l-methylethyl] -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine. Among the family of compounds of the present invention, certain compounds of formula I are preferred. For example, preferred compounds of formula I include those in which R3 and R4 are each, independently of each other, lower alkyl or cycloalkyl; more preferably R3 and R4 are each, independently of each other, methyl, ethyl, propyl, isopropyl or cyclopropylmethyl; and still more preferably R3 is methyl and R4 is ethyl, propyl, isopropyl or cyclopropylmethyl. Within this category, a preferred group comprises the compounds wherein R5 is -S02R9, wherein R9 is alkyl, more preferably methyl, ethyl or propyl, and still more preferably, methyl; wherein R is -COR 9, wherein R 9 is heterocyclyl or heteroalyl, more preferably morpholino, piperidinyl or 1,2,3,4-tetrahydro [1,5] naphthyridinyl; wherein R5 is -CONR7R8, wherein R7 and R8 are each, independently of each other, lower alkyl, more preferably methyl, ethyl or propyl; wherein R5 is -CO (CH2) nNR6S02R6, wherein n is 1-6, R6 is hydrogen and R9 is lower alkyl, R9 is more preferably methyl, ethyl, or propyl. Another preferred group includes the compounds wherein R1 and R2 are taken together with the ring to which they are attached to form a saturated or unsaturated 5 or 6 membered monocyclic ring, optionally containing 0, 1 or 2 heteroatoms selected, independently from each other, between nitrogen, oxygen or sulfur, and in which the ring is unsubstituted or optionally mono or disubstituted with lower alkyl or oxo; more preferably R1 and R2 taken together with the ring to which they are attached to form a saturated 5 or 6 membered monocyclic ring optionally containing 0, 1 or 2 oxygen heteroatoms; most preferably R1 and R2 taken together with the ring to which they are attached to form indanyl, 2,3-dihydrobenzofuran-5-yl, 2,3- dihydrobenzofuran-6-yl, 3,3-dimethyl-2,3-dihydrobenzofuran-6-yl, or 2,3-dihydrobenzo [1,4] dioxin-6-yl. Another preferred group includes the compounds wherein R 1 is hydrogen and R 2 is alkyloxy, haloalkyl or halogen; more preferably R2 is methoxy, ethoxy, trifluoromethyl, chlorine or fluorine; or wherein R2 is -NRdC0R9 wherein R6 is hydrogen and R9 is aryl, unsubstituted or mono, di or trisubstituted with lower alkyl, alkyloxy, halogen or haloalkyl; more preferably R7 is hydrogen and R9 is phenyl, unsubstituted or mono, di or trisubstituted with methyl, ethyl, methoxy, ethoxy, chloro or trifluoromethyl. Another preferred group includes the pharmaceutically acceptable salts of the compounds of the present invention wherein the salts are formed from hydrochloric acid, phosphoric acid, dibenzoyl-L-tartaric acid; more preferably the salts are formed from hydrochloric acid or phosphoric acid. Examples of the particularly preferred compounds are: N- [2 - (2,3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- (1-methanesulfonyl-piperidin-4-methylmethyl) amine; N- [2- (2, 3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-propyl- (1-methanesulfonyl-pipe idin-4-ylmethyl) amine, -N- [2- (2, 3 -dihydrobenzofuran-6-yl) -l-methylethyl] -N-propyl- [1- (morpholin-4-carbonyl) -piperidin-4-ylmethyl] amine; N- [2- (2, 3-dihydrobenzofuran-6-yl) -l-methylethyl] -N-cyclopropylmethyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl) amine, - N- [2 - (2,3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- [1- (morpholine-4-carbonyl) -piperidin-methyl-ethyl] amine; N- [2- (2,3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine; N- [2- (2,3-dihydrobenzo [1,4] ioxin-6-yl) -l-methylethyl] -N-et l- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine , - (S) -N-. { 3- [4- ( { [2- (2, 3-dihydrobenzofuran-5-yl) -1-methylethyl] ethyl-amino} methyl) -piperidin-1-yl] -3-oxopropyl) methanesulfonamide , - N - [2- (indan-5-yl) -l-methylethyl] -N-ethyl-time-tansulfonyl-piperidin-ylmethyl) -amine, -N- 12 - (indan-5-yl) -l-methylethyl] -N-propyl- (1-methanesulfonylpiperidin-4-ylme-yl) -amine, - N- [2- (3,3-dime-li-, 3-dihydrobenzofuran-6-yl) -l-methylethyl] -N-ethyl - [1- (morphine-4-carbonyl) -pi-eridin-4-methylethyl] -N-ethyl- [1- (morpholine-4-carbonyl) -piperidin-4-ylmethyl-jimine, - N- [2- ( 3, 3-dimethyl-2,3-dihydrobenzofuran-6-yl) -1-methylethyl] -N-ethyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine, - N- [2- (4-methoxyphenyl) - l-methylethyl] -N-ethyl- [1- (dimethylaminocarbonyl) -piperidin-4-ylmethyl] amine; N- [2- (3-trifluoromethyl-phenyl) -l-methylethyl] -N-ethyl- [1- (dimethylaminocarbonyl) -piperidin-4-ylmethyl] -amine; N- [2- (3-trifluoromethyl-phenyl) -l-methylethyl] -N-ethyl- [1- (piperidin-1-carbonyl) -piperidin-4-ylmethyl] -amine; N- [2- (4-trifluoromethyl-phenyl) -l-methylethyl] -N-ethyl- [1- (piperidin-1-carbonyl) -piperidin-4-ylmethyl] -amine, - N- [2- (4-trifluoromethyl-phenyl) -l-methylethyl] -N-ethyl- [1- (dimethylamino-carbonyl) -piperidin-4-ylmethyl] amine; N- [2- (3-trifluoromethyl-phenyl) -l-methylethyl] -N-ethyl- [1- (morpholin-carbonyl) -piperidin-4-ylmethyl] -amine, - N- [2- (3-triflucromethyl-phenyl) - 1-methylethyl] -N-ethyl- [1- (1,2,3,4-tetrahydro [1,5] aftiridin-1-carbonyl) piperidin-4-ylmethyl] amine; N- [2- (3-Chlorophenyl) -l-methylethyl] -N-ethyl- [1- (piperidin-1-carbonyl) -piperidin-4-ylmethyl] amine; N- [2- (3-trifluoromethyl-phenyl) -l-methylethyl] -N-propyl- [1- (morpholin-4-carbonyl) -piperidin-4-ylmethyl] -amine; N- [2 - [3- (4-methoxyphenylcarbonylamino) phenyl] -1-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylme] amine, -and N-. { 2- [3- (4-methylphenylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine.

The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods already known in the art, for example, by the process described below, which comprises: a) reduction of a compound of the formula: with a reducing agent to obtain a compound of formula: the b) deprotection of a compound of formula: to give a compound of formula the or c) reaction of a compound of formula 4 with a compound of formula Or 23 to obtain a compound of formula Ó d) reaction of a compound of formula the with a compound of formula to obtain a compound of formula or e) substitution of the H atom at position 1 of the piperidine ring of formula the With the groups described for R5 or f) modification of one or more substituents R1 -R5 within the definitions given above, and if desired, conversion of the compound obtained, into a pharmaceutically acceptable acid addition salt. The starting materials and reagents used in the preparation of these compounds can be either purchased from commercial suppliers such as Aldrich Chemical Co., or prepared by methods known to those skilled in the art, following the procedures described in references as p. ex. Fieser and Fieser's Reagents for Organic Synthesis ("Reagents for organic synthesis, by Fieser and Fieser"), Wiley &Sons: New York, 1991, volumes 1-15, Rodd's Chemistry of Carbon Compounds ("Chemistry of carbon compounds ", by Rodd), Elsevier Science Publishers, 1989, volumes 1-5 and supplements, and Organic Reactions (" Organic Reactions "), Wiley 4 Sons: New York, 1991, volumes 1-40 These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications can be made to these schemes, which will be suggested by one skilled in the art with reference to this description.

The starting materials * and the intermediates of the reaction can be isolated and purified if desired, using conventional techniques comprising, but not limited to, filtration, distillation, crystallization, chromatography and the like. Such materials can be characterized using conventional means including physical constants and spectral data. Unless specified otherwise, the reactions described herein take place at atmospheric pressure and in a temperature range from about -78 ° C to about 150 ° C, more preferably from about 0 ° C to about 125 ° C. C, and still more preferably at about room temperature, e.g. ex. approximately 20 ° C. In general, the compounds of formula I are prepared by reacting an aldehyde (piperidine-4-carboxaldehyde) with an amine substituted at R 4, under normal conditions of reductive amination, to form the corresponding ethyl-piperidin-4-ylmethyl amines, or by acylation of a substituted amine in R 4 under normal acylation conditions, followed by a reduction. Schemes A and B describe methods for generating the substituted amines in R4 and piperidine-4-carboxaldehydes, respectively. The schemes C to K describe methods for generate the compounds of Fimula I with different variants of R5. The schemes L to P describe methods for generating the compounds of formula I with different variants of R2. Scheme A Scheme A describes the methods for the preparation of a compound of formula I from the corresponding substituted amine in R 4 of formula _4, wherein R 1, R 2, R 3 and R 4 are as defined in the summary of the invention . Route (a) Route (aa) Route (b) Route (c) In the route (a), an amine _4 substituted in R4 can be prepared from the corresponding aldehyde 1 by methods known to a person skilled in the art. The aldehyde 1 can be purchased commercially or can be synthesized by a person skilled in the art. A nitrostyrene 2 can be prepared by reacting the corresponding aldehyde 1 with a nitroalkane under the conditions of the noevenagel or Henry reaction, for example, as described by Hass and Riley in Chem. Reviews 1943, 22,406. A primary amine _3 can be prepared by reducing the nitrostyrene 2 to obtain a saturated amine. Suitable reducing conditions include lithium aluminum hydride in diethyl ether or tetrahydrofuran or borane / sodium borohydride in tetrahydrofuran. An amine _4 substituted in R4 can be prepared by reaction of the compound 3 with an aldehyde R4CH0 under reductive amination conditions; or with an acylating agent R4C (0) L wherein L is a leaving group, such as chlorine, followed by a reduction; or with an alkylating agent R 4 L, wherein L is a leaving group such as chlorine, under alkylation conditions. In the route (aa), a ketone 7 can be prepared, for example, from a bromine compound 5. A bromine compound 5 is converted into a reactant organometallic, for example a Grignard reagent, by methods already known in the art. The reaction takes place in the presence of a metal such as magnesium, zinc or aluminum, preferably magnesium, and an activating agent such as 1,2-dibromoethane. Suitable inert organic solvents for the reaction include tetrahydrofuran, benzene, toluene and the like, preferably tetrahydrofuran. An alkene compound 6 is prepared by the attachment of an organometallic compound with an alkenyl halide, for example 3-bromo-2-methylpropene. The ketone is formed by oxidation of the alkene compound 6, for example, by ozonolysis, followed by a treatment with a reducing agent such as thiourea, dimethyl sulfide, trimethyl phosphite, preferably thiourea. The reaction takes place in a mixture of suitable organic solvents such as dichloromethane and methanol. Alternatively, a ketone 7 can be commercially purchased, or it can be synthesized by a person skilled in the art, for example, as described by Stoemer and Stroh in Chemischer Berichte. { "Chemical Reports") 1935, 68, 2112. Alternatively, in the route (b), an amine 4 substituted in R 4 or its enantiomerically pure isomers can be prepared, from the corresponding ketone 7 by methods described in the chemical literature, for example, by Nichols et al, in J. Med. Chem. 1973, 16, 480-483; J. Med. Chem. 1986, 29, 2009-2015; and J. Med. Chem. 1991, 34, 1662-1668. A compound 8 wherein W is a removable chiral auxiliary group, is formed by reaction of a corresponding ketone 1_ with a chiral auxiliary such as 1-phenylethylamine or 1- (2-naphthalenyl) ethylamine under reducing conditions. Suitable reducing conditions include, for example, hydrogen and a hydrogenation catalyst such as Raney nickel, platinum or palladium catalysts (eg Pt02 or Pd / C), or other reducing agents such as sodium cyanoborohydride, triacetoxyborohydride of sodium, sodium borohydride, and the like Suitable solvents for sodium cyanoborohydride include alcohol solvents such as methanol or ethanol, preferably ethanol Suitable solvents for sodium triacetoxyborohydride include aprotic organic solvents such as tetrahydrofuran , acetonitrile or dichloroethane A compound 9 substituted at R4 is prepared by treating an amine compound _3 with an aldehyde under reductive amination conditions, an acylating agent followed by a reduction, or an alkylating agent.

An amine _4 substituted in R4 is prepared by eliminating the chiral auxiliary group W of compound 9 by catalytic hydrogenolysis. Suitable catalytic hydrogenolysis conditions include a platinum or palladium catalyst, in the presence of hydrogen donors, for example ammonium formate. Suitable solvents for the reaction include alcohol solvents such as methanol or ethanol. Alternatively, in the route (c), an amine _4 substituted in R4 can be prepared from the corresponding ketone 7 by methods generally known in the chemical literature. Ketone 7 is reacted with a primary amine R 4 NH 2, such as ethylamine under conditions of a reductive amination reaction. Reductive amination procedures are described in the chemical literature. For example, Magid, A. et al., In J. Org. Chem. 1996, 61, 3849-386 discloses a method that uses sodium triacetoxyborohydride as a reducing agent; and Borch, R. et al., in J. Am. Chem. Soc. 1971, 93, 2897-2904 discloses a method that uses sodium cyanoborohydride as a reducing agent. Examples of preparations of a compound of formula 7 using the reaction conditions described in scheme A, route (aa), are given in "preparation 1"; a compound of formula 4 described in routes (b) and (c) is given in preparations 2 and 3", respectively Scheme B Scheme B describes a method of preparing a compound of formula I from the corresponding piperiain-4-carboxaldehydes of formula 13 or 17 where P is an amino-protective group Route (a) Route { B) 11 15 or 12 15 13 17 The piperidinecarboxylic acid _10, the N-protected activated derivative 12, and the piperidinecarboxylic acid ester _14 can be purchased commercially or can be synthesized by a person skilled in the art.

In route (a), a N, ____! -protected piperidine-4-carboxylic acid, in which P is an amino-protecting group, is prepared by joining a suitable amino-protecting group such as benzyl, tert-butoxycarbonyl ( BOC) or carbobenzyloxy (CBZ) to 4-piperidinecarboxylic acid 10 by methods already known to those skilled in the art. Suitable solvents for the reaction include dichloromethane, dichloroethane, xylenes, and the like. An N-protected activated derivative _12, wherein L is a leaving group such as N-methoxy-N-methylamino, is prepared by treatment of compound 1_1 with N, 0-dimethylhydroxylamine hydrochloride by methods known to the person skilled in the art. the specialty.

An N-protected piperidine-4-carboxaldehyde is prepared by treatment of compound 1_2 with a reducing agent such as lithium aluminum hydride., aluminum and sodium hydride or diisobutylaluminum hydride. Suitable solvents for the reaction include aprotic organic solvents such as diethyl ether, dioxane, tetrahydrofuran, and the like. Alternatively, in the route (b), an N-substituted 4-piperidinecarboxylic acid ester, 15, is prepared by treatment of the compound _1_4 with a sulfonylating agent R5S02L or an acylating agent R5C0L wherein L is a leaving group such as a halogen, preferably chlorine. The reaction is carried out in the presence of a base, for example, triethylamine in a suitable inert organic solvent such as dichloromethane, dichloroethane, carbon disulfide, and the like, preferably dichloromethane.

A N-16 substituted 4-hydroxymethylpiperidine is prepared by treating the compound _______ with a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, lithium tribohydride, preferably lithium aluminum hydride. Inert organic solvents suitable for the reaction include aprotic organic solvents such as diethyl ether, dioxane, tetrahydrofuran, and the like.

A piperidine-4-carboxaldehyde substituted at N, 17, is prepared by treatment of 4-hydroxymethylpiperidine _______ with an oxidizing agent such as dimethyl sulfoxide in an oxidizing agent such as dimethyl sulfoxide in the presence of oxalyl chloride. Suitable solvents for the reaction include inert organic solvents such as halogenated hydrocarbons, for example dichloromethane or dichloroethane. Examples of preparations of compounds of formula _13 and _17 using the reaction conditions described in Scheme B are listed in "Preparations 4 and 5", respectively. Scheme C Scheme C, in general, describes the methods for the preparation of a compound of formula I wherein R5 is hydrogen. This compound is designated as a compound of formula la.

Route (a) -S Route (b) In the route (a), an N-protected piperidin-4-carboxamide 1_8, wherein P is an amino-protecting group, preferably the CBZ, is prepared by reaction of a substituted 4-amine in R4, with an activated derivative. under acylation conditions, where L is chlorine. The reaction takes place in the presence of a base such as aqueous potassium carbonate or aqueous sodium carbonate. Suitable solvents for the reaction include inert organic solvents such as dichloromethane, dichloroethane, toluene or ethyl acetate, preferably toluene.

A piperidine-4-carboxamide 19 is prepared by removal of the N-protecting group from compound 18. When the N-protecting group is CBZ, compound 19 is prepared under hydrogenation conditions such as p. ex. Raney nickel or a platinum or palladium catalyst in alcoholic solvents such as methanol or ethanol. When the N-protecting group is the BOC, the compound _______ is prepared by treatment with a strong organic acid such as trifluoroacetic acid in an inert organic solvent such as halogenated hydrocarbons, for example dichloromethane or dichloroethane, preferably dichloromethane. A compound of formula la, is prepared by treatment of compound 1_9, with a reducing agent such as lithium aluminum hydride, diborane, and the like, preferably lithium aluminum hydride. The reaction takes place at the reflux temperature in an inert organic solvent such as diethyl ether, dioxane, tetrahydrofuran and the like, preferably tetrahydrofuran. Alternatively, an N-protected piperidin-4-ylmethyl amine 20 is prepared in the route (b), in which P is preferably BOC, by reaction of a substituted 4-amine in R4, with a piperidin-4-carboxaldehyde 13, under reaction conditions of a reductive amination. The The reaction takes place in the presence of a reducing agent such as triacetoxyborohydride. Suitable solvents for the reaction are inert organic solvents such as halogenated hydrocarbons, for example, dichloromethane or dichloroethane, preferably dichloroethane. A compound of formula I is prepared by deprotection of compound _20 in the presence of a strong organic acid such as trifluoroacetic acid. The reaction takes place at room temperature. Suitable solvents for the reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane and the like, preferably dichloromethane.

Examples of preparations of a compound of formula which use the reaction conditions described in Scheme C are given in example 1. Scheme D Scheme D describes an alternative method of preparing a compound of formula I wherein R5 is hydrogen . This compound is designated as a compound of formula la. twenty Ketone 7 can be prepared as described above in Scheme A, path (aa). A N-protected 4-aminomethylpiperidine 2_1, in which P is an amino-protecting group, particularly BOC, is prepared by the method described by Prugh, J.D. in Synth. Commun. 1922, 22, 2357-2360. An amine 22, protected in N, is prepared by the binding of the ketone 1_ to the compound 21 under conditions of reductive amination. The reaction takes place in the presence of a reducing agent such as sodium cyanoborohydride. Suitable solvents for the reaction are alcohol solvents such as methanol or ethanol. An amine 20 substituted in R 4 is prepared by reaction of compound 22 with an aldehyde R 4 CHO in reductive amination conditions in the presence of a reducing agent such as sodium triacetoxyborohydride. Suitable solvents for the reaction include inert organic solvents such as dichloromethane, dichloroethane, tetrahydrofuran or acetonitrile. A compound of formula la is prepared by eliminating the N-protecting group, from compound 20. When the N-protecting group is CBZ, compound 20 is prepared under hydrogenation conditions such as Raney nickel or a platinum catalyst. or palladium, in alcoholic solvents such as methanol or ethanol. When the N-protecting group is the BOC, the compound 20 is prepared by treatment with a strong organic acid such as trifluoroacetic acid in an inert organic solvent such as dichloromethane or dichloroethane, preferably dichloromethane. The reaction takes place at room temperature. Examples of preparations of a compound of formula la, which use the reaction conditions described in Scheme D, are given in example 2. Scheme E Scheme E describes an alternative method of preparing a compound of formula I wherein R5 is -COR9 or -CSR9. This compound is designated as a compound of formula Ib.

Route (a) Route (b) In route (a), a compound of formula Ib is prepared by reaction of a substituted 4-amine in R 4, with a piperidine-4-carboxaldehyde 23 under the conditions of reductive amination, described in example C. Alternatively, in the route (b), a compound of formula Ib is prepared by reaction of a compound of formula la with an acylating reagent R9C (0) L / R9C (S) L, wherein L is a leaving group, in particular, chlorine. The reaction is carried out in the presence of a base such as aqueous sodium carbonate or aqueous potassium carbonate, in an inert organic solvent such as aromatic hydrocarbons, for example toluene, benzene and the like. Examples of preparations of a compound of formula Ib using the reaction conditions described in Scheme E are given in example 3. Scheme F Scheme F describes an alternative method for the preparation of a compound of formula I, wherein R 5 is -CONR7R8 or -CSNR7R8. This compound is designated as a compound of formula _______. Route (a) Route (b) Route (c) R »NCO / RBNCS Route (d) In route (a), a compound of formula _______ is prepared by reacting a compound of formula Ia with phosgene or a compound equivalent to phosgene such as tpfosgen, followed by a treatment with a primary or secondary amine. The reaction takes place at room temperature. Suitable solvents include the aprotic organic solvents such as diethyl ether, dioxane, tetrahydrofuran, and the like. Alternatively, in the route (b), a compound of the formula _______ is prepared by reacting a compound of the formula la with a carbamyl halide / thiocarbamyl. The reaction takes place in the presence of a base, such as triethylamine, at room temperature. The solvents suitable include halogenated hydrocarbons such as dichloroethane or dichloromethane. Alternatively, in the route (c) a compound of the formula le is prepared, by reaction of a compound of the formula _______ with an isocyanate / isothiocyanate in an aprotic organic solvent such as diethyl ether, tetrahydrofuran, toluene and the like. Alternatively, in route (d), a compound of formula _______ is prepared by reaction of a compound of formula _______ with an aqueous solution of a cyanate / thiocyanate salt such as cyanate / potassium thiocyanate or cyanate / sodium thiocyanate in the conditions of a Wohler reaction. The reaction takes place at reflux temperature. Examples of preparations of a compound of formula I using the reaction conditions described in Scheme F are given in example 4. Scheme G Scheme G describes an alternative method of preparing a compound of formula I wherein R 5 is -COOR7. This compound is designated as a compound of formula Id.

Id A compound of formula Id can be prepared by reacting a compound of formula I_a with an acylating agent R70C (0) C1. The reaction takes place in the presence of a base such as triethylamine at room temperature. Suitable solvents for the reaction include halogenated hydrocarbons such as dichloroethane, dichloromethane, and the like. An example of preparation of a compound of formula Ld using the reaction conditions described in Scheme G is given in example 5. Scheme H Scheme H describes a method for the preparation of a compound of formula I, wherein R 5 is -C0 (CH2) nNR6S02R9 or -C0 (CH2) nNR6C0R9, wherein R6 is hydrogen. This compound is designated as a compound of formula le.

An N-protected compound of formula 2 is prepared by reacting a compound of formula I with an N-protected amino acid in the presence of a peptide-binding reagent such as carbonyldiimidazole. The reaction takes place at room temperature. Suitable solvents for the reaction include halogenated hydrocarbons such as dichloromethane or dichloroethane. An unprotected compound of formula 25 is prepared by treating compound 2_4 with a strong organic acid such as trifluoroacetic acid at room temperature when the amino-protecting group is BOC; or using the hydrogenation conditions when the amino-protective group is CBZ. A compound of formula I is prepared by reacting a compound with a sulfonyl halide or acyl halide in the presence of a base, such as diisopropylethylamine. Suitable solvents for the reaction include halogenated organic solvents such as dichloromethane, dichloroethane, and the like. An example of preparation of a compound of formula _______ using the reaction conditions described in Scheme H, is given in example 6. Scheme I Scheme I describes an alternative method for the preparation of a compound of formula I wherein R 5 is -S02R9. This compound is designated as a compound of formula If. Route (a) Route (b) 27 28 Route (c) I * + L-SO.R9 In route (a), a compound of formula If is prepared by reaction of a substituted 4-amine in R4 with a piperidine-4-carboxaldehyde 26, and using the reductive amination conditions described in Scheme C. Alternatively, in the route (b) a carboxamide 28 is prepared by reaction of a substituted 4-amine in R 4 with an activated derivative 27 wherein L is a leaving group, particularly chloro, in the presence of a base such as triethylamine. Suitable solvents for the reaction include dichloromethane, dichloroethane or pyridine. A compound of formula If is prepared by treating compound 28 with a reducing agent such as lithium aluminum hydride or diborane. The reaction takes place at a temperature around 0 ° C in an inert atmosphere. Suitable solvents for the reaction include aprotic organic solvents such as diethyl ether, dioxane or tetrahydrofuran.

Alternatively, in the route (c), a compound of the formula If is prepared by reacting a compound of the formula la with a sulfonyl halide R9S02L wherein L is a leaving group, particularly chloro. The sulfonyl halides can be purchased commercially or can be prepared by methods such as those described by Langer, R.F. in Can. J. Chem. 1983, 61, 1583-1592; Aveta, R. et al., In Gazetta Chimica Italiana ("Italian Chemical Magazine") 1986, 116, 694-652; King, J.F. and Hillhouse, J.H. in Can. J. Chem. 1976, 498; and Szymonifka, M.J. and Heck. J.V. in Tetrahedron Lett. 1989, 2860-2872. The reaction takes place in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane, dichloroethane and the like. An example of preparation of a compound of formula If using the conditions of the reaction described in Scheme I, is given in example 7. Scheme J Scheme J describes an alternative method for the preparation of a compound of formula I, wherein R5 is -S02NRR8 or -S02NR6 (CH2) nC00R7. These compounds are designated as a compound of formula Ig_ and formula Ig 'respectively.

A sulfonylated compound 29 is prepared by reaction of a compound of formula Ia with chlorosulfonic acid followed by phosphorus pentachloride. The reaction takes place in the presence of a base such as triethylamine. Suitable solvents for the reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, and the like. A compound of formula _______ is prepared by reaction of compound 29 with a primary or secondary amine. The reaction takes place in the presence of a base such as diisopropylethylamine. Suitable solvents for the reaction include aprotic solvents such as tetrahydrofuran, methylene chloride and the like. Optionally, a compound of formula _______ 'can be prepared by reaction of a compound 29 with a amino acid The reaction takes place at the reflux temperature in the presence of alkylsilyl cyanide. Suitable solvents for the reaction include polar aprotic solvents such as acetonitrile, tetrahydrofuran and the like. Examples of preparations of a compound of formula _______ or formula Ij 'using the conditions of the reaction described in Scheme J are given in example 8. Scheme K Scheme K describes an alternative method for the preparation of a compound of formula I wherein R5 is -S02 (CH2) 2NR6S02R9, wherein R6 is hydrogen. This compound is designated as a compound of formula Ih.

A vinyl sulfonamide compound _______ is prepared by reaction of a compound of formula I with a sulfonylating agent such as 2-chloroethylsulfonyl chloride in a suitable solvent such as dichloromethane or dichloroethane. A compound of formula Ih is prepared by reaction of compound 30 with a sulfonamide H2NS02R9 in presence of a strong base such as sodium hydride. Suitable solvents for the reaction include polar aprotic solvents such as tetrahydrofuran or dimethylformamide. Examples of preparations of a compound of formula _______, which use the conditions of the reaction described in Scheme K, are given in example 9. Scheme L Scheme L describes an alternative method for the preparation of a compound of formula I wherein R2 is -NR6COR9 wherein R6 is hydrogen. This compound is designated as a compound of formula I. Route (a) Ij Route (b) R'COOH Ij Route (c) 17 In general, the aniline compounds of formula li or formula 9__ can be prepared by reduction of the nitro group to an amino group using the conditions of the reaction described in scheme A.

In route (a), a compound of formula _______ can be prepared by reacting the aniline of formula Ii with an acylating reagent R9C (0) L, wherein L is a leaving group, in particular chlorine, and using the conditions of The reaction described in Scheme E. Alternatively, in the route (b), a compound of the formula _______ can be prepared by the attachment of a compound of the formula _______ with a carboxylic acid derivative R9COOH in the presence of a binding reagent such as N, N'-carbonyl-diimidazole (CDI), dicyclohexyl-carbodiimide (DCC) or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI). The reaction occurs in conjunction with an additive such as 1-hydroxybenzotriazole hydrate. Suitable solvents for the reaction include aprotic organic solvents such as tetrahydrofuran, N, -dimethylformamide, and the like. Alternatively, in the route (c), a compound of the formula ______ is prepared by removing the auxiliary chiral group W of the compound 9"using the reaction conditions described in scheme A, path (b). The compound of formula _______ is prepared by the reaction of the amine if_ with a piperidin-4-carboxaldehyde 1_7, and using the reductive amination conditions described in scheme C, route (b).

Examples of preparations of compounds of formula Ij, using the reaction conditions described in Scheme L, are given in example 10. Scheme M Scheme M describes the methods for the preparation of a compound of formula I, wherein R2 is - NR6C0NR7R8 or -NR6C? NR7R8, wherein R6 is hydrogen. This compound is designated as a compound of formula Ik. Route (a) O (S) RWNCSNH-, R5 R «R NC0NH L? X ^ NR'R »R3 I Route RßR'NCSNH- .R5 RßR'NCONH RSNCO / RßNCS R3 Ik Route (c) In route (a), a compound of formula Ik is prepared by reaction of an aniline compound of formula Ii with a carbamyl / thiocarbamyl halide, and employing the reaction conditions described in scheme F, route (b). Alternatively, in the route (b), a compound of the formula _______ is prepared by reacting an aniline compound of the formula I_i with an isocyanate / isothiocyanate, and using the reaction conditions described in scheme F, route (c). Alternatively, in route (c), a compound of formula _______ is prepared by reacting an aniline compound of formula _______ with an aqueous solution of a cyanate / thiocyanate salt, such as potassium cyanate / thiocyanate, and using the conditions of reaction described in scheme F, route (d). Examples of preparations of compounds of formula _______ using the reaction conditions described in Scheme M, are given in example 11. Scheme N Scheme N describes a method for the preparation of a compound of formula I, wherein R2 is -NR6S02R9 , where R6 is hydrogen. This compound is designated as a compound of formula II.

A compound of formula II can be prepared by reacting an aniline compound of formula I_i with a sulfonylating agent R9S02L, wherein L is a leaving group, in particular chlorine, and employing the reaction conditions described in scheme I, route (c). Examples of preparations of compounds of formula II using the reaction conditions described in Scheme N are given in example 12. Scheme O Scheme O describes a method for the preparation of a compound of formula I, wherein R2 is -NR6S02NR7R8, where R6 is hydrogen. This compound is designated as a compound of formula Im.

Ii A compound of formula Im can be prepared by reaction of an aniline compound of formula VII with a sulfonylating agent of R8R7NS02L, wherein L is a leaving group, in particular chlorine, and employing the reaction conditions described in Scheme J. Examples of preparations of compounds of formula Im, using the reaction conditions described in Scheme 0, are given in example 13. Scheme P Scheme P describes a method for the preparation of a compound of formula I, wherein R2 is - NR7Rβ, wherein R7 and R8 are each, methyl. This compound is designated as a compound of formula In.

T- A compound of formula In can be prepared by reacting an aniline compound of formula Ii with formic acid and formaldehyde under reducing methylation conditions, for example under Eschhweiler-Clarke conditions. The reaction takes place at a temperature around 50-120 ° C.

The examples ife preparations of compounds of formula In, using the reaction conditions described in Scheme P, are given in example 14. General utility Muscarinic receptors stimulate the cellular actions of acetylcholine in the central nervous system and in peripheral tissues innervated by the parasympathetic nervous system (Caufield, MF Pharmacol., Ther. 1993, 58, 319-379). Muscarinic receptors play a key role in the regulatory function of smooth muscle in the lower urogenital, gastrointestinal and respiratory tracts (Eglen, R.M. et al., Pharmacol, Rev. 1996, 48, 531-565). Accordingly, muscarinic receptor antagonists, such as those described in the invention, are useful for the treatment of conditions that can be improved by blocking muscarinic receptors. Such conditions include diseases and disorders associated with impaired motility and / or smooth muscle tone of the gastrointestinal tract, genitourinary tract and respiratory tract. Gastrointestinal tract disorders treatable with the compounds of this invention specifically include irritable bowel syndrome, diverticular disease, achalasia, disorders of the gastrointestinal hypermotility, and diarrhea; disorders of the genitourinary tract treatable with compounds of this invention specifically include the overactive bladder (and its symptoms such as urgency, frequency and instinctual incontinence) and stress incontinence; Respiratory tract disorders treatable with the compounds of this invention specifically include chronic obstructive pulmonary disease, asthma and pulmonary fibrosis. Additionally, since muscarinic receptors in the heart play a key role in the regulation of breast rhythm, it should be expected that the compounds of the present invention would be useful in the treatment of various forms of bradyarrhythmias including sinus bradycardia. As muscarinic receptors play an important role in the stimulation of synaptic transmission in the central nervous system, one would expect that the present compounds would be useful in the treatment of nervous system disorders including Parkinson's disease, Alzheimer's disease, and the disease of movement. Finally, the compounds of the present invention would also be useful in anesthesia, for example as pre-anesthetic medication, and in ophthalmology to produce mydriasis and cycloplegia.

Assays The compounds of this invention are muscarinic receptor antagonists. The muscarinic receptor affinity of the test compounds can be determined by an in vitro receptor binding assay, which utilizes a cell membrane preparation from Chinese hamster ovary cells that express recombinant human muscarinic receptors (my - m5), and is described in more detail in example 16. The properties of the muscarinic antagonist of the test compounds can be identified by an in vivo test by determining the inhibitory activity against the contraction of the bladder stimulated by the receptor muscarinic, and saliva secretion in anesthetized rats, and is described in more detail in Example 17. The properties of the muscarinic antagonist of the test compounds can be identified by an in vivo assay by determining the inhibitory activity against the contraction of the bladder stimulated by the muscarinic receptor, and the secretion of saliva in anesthetized dogs, and is described in more detail in Example 18.

Administration and Pharmaceutical Composition The invention includes a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt or a derivative thereof together with one or more "pharmaceutically acceptable carriers, and optionally other therapeutic and / or prophylactic ingredients. , the compounds of this invention will be administered in a therapeutically effective amount by any of the administration modalities for agents having similar characteristics.The suitable dosage ranges are from 1 to 500 mg daily, preferably from 1 to 100 mg daily, and more preferably from 1 to 30 mg daily, depending on numerous "factors such as p. ex. the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and administration method, the indication to which the administration is directed, and the preferences and experience of the physician involved . An expert in the art of treating these diseases will be able, without undue experimentation and depending on the personal knowledge and description of this application, to ascertain the amount therapeutically effective of the compounds of this invention for a certain disease. In general, the compounds of this invention will be administered as pharmaceutical formulations including those that are suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral administration (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous), or in a form suitable for administration by inhalation or insufflation. The preferred mode of administration is oral administration using a convenient daily dosage regimen, which can be adjusted according to the severity of the condition. The compounds of the invention, together with a conventional adjuvant, vehicle or diluent, can be placed in the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and dosage unit forms may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage form may contain any suitable effective amount of the active ingredient provided with the intended daily dosage range, which will be used. The pharmaceutical composition can be used in solid form, such as tablets or filled capsules, serffijBolids, powders, extended-release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing one (1) milligram of active ingredient or more generally, 0.01 to one hundred (100) milligrams, per tablet, according to the suitably representative unit dosage forms. The compounds of the present invention can be formulated in a wide variety of dosage forms for oral administration. The pharmaceutical compositions and dosage forms may comprise the compounds of the invention or their pharmaceutically acceptable salts as the active component. The pharmaceutically acceptable vehicles can be solid or liquid. Solid form preparations include powders, pills, capsules, wafers, suppositories and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, agents for the disintegration of tablets, or an encapsulating material. In powders, the vehicle is a finely divided solid which is a mixture with the finely divided active component. In the tablets, the active component is mixed with the vehicle having the necessary binding capacity in suitable proportions and compressed into the desired shape and size. The powders and tablets preferably contain from one to about seventy percent active component. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting point wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with an encapsulating material as a carrier providing a capsule in which the active component, with or without vehicles, is surrounded by a vehicle which is associated therewith. Similarly, wafers and pills are included. The tablets, powders, capsules, pills, wafers and lozenges can also be solid forms suitable for oral administration. Other forms suitable for oral administration include preparations in liquid form, including emulsions, syrups, aqueous solutions, aqueous suspensions, or solid form preparations to convert shortly before use, into ready-to-use preparations. liquid The emulsions can be prepared in the form of a solution, with aqueous solutions of propylene glycol or they can contain in their composition, emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, preservatives and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspension agents. Solid form preparations include solutions, suspensions and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, natural and artificial sweeteners, dispersants, thickeners, solubilizing agents, and the like. The compounds of the present invention can be formulated for parenteral administration (eg, by injection, eg injection in the boto or continuous infusion), and can be presented in unit dosage form in ampoules, pre-filled syringes, small volume infusion. 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, for example, solutions in aqueous polyethylene glycol. Examples of carriers, diluents, solvents or vehicles, oily or non-aqueous, include propylene glycol, polyethylene glycol, vegetable oils (eg olive oil) and injectable organic esters (eg ethyl oleate) and may contain of formulation such as preservatives, wetting agents, emulsifiers, for suspensions, stabilizers and / or dispersants. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of a sterile solid or by lyophilization of a solution to be reconstituted before use with a suitable vehicle, e.g. ex. sterile water, free of pyrogens. The compounds of the present invention can be formulated for topical administration to the epidermis, in the form of ointments, creams or lotions, or as a transdermal patch. The ointments and creams can, for example, be formulated with an aqueous or oily base, with the addition of an appropriate thickener and / or gelling agents. The lotions may be formulated with an aqueous or oily base and generally contain also one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. The formulations suitable for topical administration in the mouth include the lozenges containing active agents in an aromatic base, usually sucrose and acacia or tragacanth; the tablets containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and oral elixirs containing the active ingredient in a suitable liquid vehicle. The compounds of the present invention can be formulated for administration as suppositories. A low melting point wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component dispersed homogeneously, for example, by stirring. The homogenously melted mixture is then poured into molds of suitable size, and allowed to cool and solidify. The compounds of the present invention can be formulated for vaginal administration. Pessaries, cushions, creams, gels, pastes, foams or spray solutions, containing in addition to the active ingredient, the appropriate vehicles used in the specialty. The compounds of the present invention can be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dripper, pipette or spray. The formulations can be elaborated in unitary form or as multidose. In the case of a dripper or a pipette, this can be achieved by the patient administering an appropriate, predetermined volume of solution or suspension. In the case of a sprayer this can be achieved, for example, by means of an atomized spray measuring pump. The compounds of the present invention can be formulated for aerosol administration, particularly for the respiratory tract and including intranasal administration. The compound will generally have a small particle size, for example of the order of 5 microns or less. Said particle size can be obtained by means already known in the art, for example, by comminution. The active ingredient is supplied in a pressurized container with a suitable propellant such as chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may also conveniently contain a surfactant such as lecithin. The dose of drug can be controlled by a metering valve. Alternatively, the active ingredients may be supplied in dry powder form, for example with a powder mixture of the compound in a suitable powder base, such as lactose, starch. starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder vehicle will form a gel in the nasal cavity. The composition of the powder can be presented in the form of a unit dose for example in capsules or cartridges of p. ex. gelatin or vesicles from which the powder can be administered by means of an inhaler. If desired, the formulations can be prepared with enteric coatings adapted for administration of the active ingredient in prolonged or controlled release. The pharmaceutical preparations are preferably unit dosage forms. In this form, the preparation is subdivided into unit doses containing the appropriate quantities of the active component. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation, such as tablets, capsules and powders packed in ampoules or ampoules. Likewise the unit dosage form can be a capsule, tablet, wafer or lozenge itself, or it can be the appropriate number of any of these in a packaged form. Other suitable pharmaceutical vehicles and their formulations are described in Remington: The Science and Practice of Pharmacy ("Science and Practice of Pharmacy") 1995, edited by E.W. Martin, Mack Publishing Company, 19"edition, Easton, Pa. Representative pharmaceutical formulations containing a compound of the present invention are described in Example 15.

EXAMPLES The following preparations and examples are described to enable those skilled in the art to better understand and practice the present invention. They should not be considered as limiting the scope of the invention, but simply as illustrative and representative of them.

PREPARATION 1 Preparation of a compound of formula 7 as described in scheme A A. 5- (2-Methylallyl) -2,3-dihydrobenzofuran A solution of 5-bromo-2,3-dihydrobenzofuran (50 grams, 0.251 mole) and 1,2-dibromoethane (2.2 ml) in tetrahydrofuran (250 ml) was added dropwise to a stirred suspension of magnesium swarf (7.5 grams, 0.31 atom-grams) in tetrahydrofuran (50 ml) over a period of 5 minutes. During the addition, the reaction temperature was maintained at 30 ° C. The solution was cooled in an ice-water bath and 3-bromo-2-methylpropene was added all at once, after stirring overnight, the The reaction was carried out with 2% hydrochloric acid and the mixture was extracted with ether, evaporation of the solvent gave 5- (2-methylallyl) -2,3-dihydrobenzofuran as an oil (43.4 grams, 99%). B. 1- (2,3-dihydrobenzofuran-5-yl) Dropan-2-one A solution of 5- (2-methylallyl) -2, 3-dihydrobenzofuran (58 grams, 0.333 moles) and pyridine (27 ml) in methylene chloride (450 ml) and methanol (150 ml) was cooled in a dry ice / acetone bath and an ozone stream passed therethrough for 1.0 hours.Thourea (18 grams, 0.24 moles) was added and the mixture was added. The resulting precipitate was filtered and the mother liquor evaporated to give an oil which was distilled under reduced pressure to give 1- (2,3-dihydrobenzofuran-5-yl) propan-2-one (32 grams, 54%), e.g. 110 ° C 120 mT. PREPARATION 2 Preparation of a compound of formula 4 as described in scheme A The compound of formula is prepared using the procedures described by Nichols et al. in J. Med. Chem. 1973, 16, 80-433; J. Med. Chem. 1986, 29, 2009-2015; and J. Med. Chem. 1991, 34, 1662-1668. A. ÍS hydrochloride, S) -N- f2 - (2,3-dihydrobenzo-uran-5-yl) -1-methyl-ethyl-1-phenylethylamine (?) - (-) -1-phenylethylamine (17.5 ml, 0.136 moles) was added ) to a stirred solution of 1- (2,3-dihydro-benzofuran-5-yl) -propan-2-one (32 grams, 0.18 moles) in benzene (300 ml) and heated at reflux for 4 hours with separation of water. The solution was evaporated to obtain an oil, and the resulting imine was dissolved in ethanol (300 ml).

Activated Raney nickel was added as catalyst (6 grams), and the mixture was hydrogenated at 50 psi for 24 hours. The catalyst was removed by filtration and the solution was acidified with 1.0 M hydrogen chloride in ether. The salt was filtered and dried to obtain (S, S) -N- [2- (2, 3-dihydrobenzofuran-5-yl) -l-methylethyl] -1-phenylethylamine hydrochloride (26 grams), m.p. 151 ° C.

B. (S. S) -N- f 2 - (2-dihydrobenzofuran-5-yl) -1-methylethyl-N-ethyl- (1-phenylethyl) amine Sodium triacetoxyborohydride (26 grams, 0.123 moles) was added to a suspension of (S, S) -N- [2- (2, 3-dihydrobenzofuran-5-yl) -l-methylethyl] -1-phenylethylamine hydrochloride (26 grams, 0.08 moles) in dichloroethane (300 ml) and triethylamine (11.5 ml). After stirring for 5 minutes, acetaldehyde (.8 ml, 0.086 mole) was added and the mixture was stirred for 2 more hours. Sodium carbonate 5% (400 ml) was added and the mixture was extracted with methylene chloride. Evaporation of the solvent gave (S, S) -N- [2- (2, 3-dihydro-benzofuran-5-yl) -l-methylethyl] -N-ethyl- (1-phenylethyl) amine in the form of a oil (23 grams, 91%), M * 309. C. (S) -N-f2- (2,3-dihydrobenzofuran-5-yl) -1-methyl-ethyl-ethylamine A mixture of (S, S) - N- [2- (2, 3-dihydrobenzofuran-5-yl) -1-methylethyl] -N-ethyl- (1-phenylethyl) amine (2 grams, 0.074 moles) and ammonium formate (30 grams, 0.48 moles) and 10% palladium on charcoal (3.7 grams) in ethanol (300 ml) was heated at reflux for 24 hours. The mixture was filtered and the solvent was evaporated obtaining a residue which was partitioned between 5% sodium hydroxide and ether. Evaporation of the organic phase gave (S) -N- [2- (2,3-dihydrobenzofuran-5-yl) -l-methylethyl] ethylamine in the form of an oil (1 gram, 92%), M * 205.

PREPARATION 3 An alternative preparation of a compound of formula 4, as described in the scheme AA T2- (l-methyl-2 - (3-nitrophenyl) ethylamine hydrochloride Combine in dichloromethane (50 ml) the l- (3 -n? tro-phenyl) ropan-2 -one (1.44 grams, 8 mmolee), ethylamine hydrochloride (0.42 gram, 8 mmol), and triethylamine (11 ml, 11 mmol) The mixture was stirred under nitrogen at room temperature for 30 minutes, then sodium triacetoxyborohydride (2.5 grams, 11.7 mmolee) was added in one portion, the mixture was stirred under nitrogen for 18 hours, an additional amount of ethylamine hydrochloride was added. (0.4 gram) After a further 18 hours, the mixture was diluted with ethyl ether, washed with 10% sodium hydroxide solution (50 ml), dried with anhydrous magnesium sulfate and the solvent removed. vacuum was obtained, oil was dissolved in methanol, acidified with acid 1M hydrochloric acid in ether and the salt was precipitated by a subsequent addition of ether. The re-emerging solid was filtered and air dried to obtain [2- (l-methyl-2- (3-nitrophenyl) ethyl] ethylamine hydrochloride (1.4 grams, 85%), mp 173-175 ° C, M * H 208 B. [2 - (4-Bromophenyl) -1-methylethyl ethylamine hydrochloride A mixture of 1- (4-bromophenyl) propan-2-one (5 grams, 23.5 mmol), ethylamine hydrochloride (19 grams, 0.23 moles) and eodium cyanoborohydride i.2. 22 grams, 0.035 moles) in methanol (100 ml) was stirred at 22 ° C for 16 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between 1.0 N sodium hydroxide (25 ml) and ethyl ether (60 ml). The organic phase was dried (anhydrous magnesium eulfate) and concentrated under reduced pressure. The base oil was converted to the eal of the hydrochloride and recrystallized from ethanol / ethyl ether to obtain [2- (4-bromophenyl) -l-methylethyl] ethylamine hydrochloride (3.8 grams, 58%), m.p. 175 - 176 ° C. C. Similarly, substituting 1- (4-bromophenyl) propan-2-one or 1- (3-nitrophenyl) propan-2-one, with other ketones and optionally replacing ethylamine with other amine, and following procedures described above in preparation 3B, the following compounds of formula 4 were prepared: [2- (2-fluorophenyl) -l-methylethyl] ethylamine hydrochloride, mp 146 ° C; (S) [2- (4-Chlorophenyl) -1-methylethyl] -ro-p-pillnine hydrochloride, m.p. 184-185 ° C; (R) [2 - (3-trifluoromethylphenyl) -1-methyl- hydrochloride ethyl] propylamine, m.p. 180-181 ° C; [2- (2, 3-Dihydrobenzo [1,4] dioxin-6-yl) -1-methylethylj-ropylamine hydrochloride, m.p. 151-152 ° C. PREPARATION 4 Preparation of a compound of formula 13. as described in Scheme B A. 1- (tert-Butoxycarbonyl) piperidine-4-carbo-xylic acid To a piperidine-4-carboxylic acid solution (10 grams, 0.08 molee) in 3N-eodium hydroxide (52 ml), water (48 ml), and dioxane (100 ml), di-tert-butyl dicarbonate (18.6 grams, 0.085 mole) and magnesium oxide (3.4 grams, 0.05 mole) were added. 084 molee). The mixture was stirred at room temperature for 16 h. The mixture was filtered and the filtrate was acidified with sodium bieulfate and extracted with dichloromethane. The organic layer was dried with magnesium sulfate and concentrated to reduced pressure to obtain l- (tert-butoxycarbonyl) piperidine-4-carboxylic acid in the form of a white colored solid (17.7 g, 99%). B- 1- (tert-butoxycarbonyl) pioeridin-4- (N-methoxy-N-methyl) -carboxamide To a solution of 1- (tert-butoxycarbonyl) pipe-ridine-4-carboxylic acid (17.7 grams, , 08 mol) in dichloromethane (00 ml) was added N, 0-dimethyl-hydroxylamine hydrochloride (9.2 grams, 0.094 moles), diisopropylethyl- amine (12.17 grams, 0.094 mole), dicyclohexylcarbodiimide (16.2 grams, 0.079 moles) and dimethylaminopyridine (4.8 grams, 0.048 mole). The mixture was stirred at room temperature for 16 h. The insoluble solid was removed by filtration, and the filtrate was concentrated at reduced pressure to obtain a residue which was purified by flash chromatography on silica gel eluting with 40% ethyl acetate in hexane to obtain 1- (tert-butoxycarbonyl) pipet. Ridin-4- (N-methoxy-N-methyl) -carboxamide in the form of an oil (17.51 grams, 82%), M * H 273. C. 1- (tere-butoxycarbonyl) piperidin-4-carboxaldehyde A cold solution of 1- (tert-butoxycarbonyl) piperidin-4- (N-methoxy-N-methyl) -carboxamide (7.0 grams, 0.026 moles) in anhydrous tetrahydrofuran (50 ml) was added lithium aluminum hydride (2.5 grams, 0.066 mole) in portions, at 0 ° C. The reaction mixture was stirred for 30 minutes and then ethyl ether (100 ml) was added, followed by 20% citric acid (100 ml). Stirring was continued for an additional 30 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl ether. The combined organic extract was washed with sodium bicarbonate, water, citric acid 10%, and water, dried with eodium eulfate and concentrated to reduced pressure, yielding 1- (tert-butoxycarbonyl) piperidine. 4-carboxaldehyde, in the form of an oil (5.02 grams, 92%), M * H = 213.

PREPARATION 5 Preparation of a compound of formula 17 as described in Scheme B A. L-Methanesulfonyl-pyridine-4-carboxylic acid ethyl ester A solution of methanesulfonyl chloride (28 ml, 0.36 mole) in dichloromethane (50 ml. ) was added dropwise to a solution of the ethyl ester of piperidin-4-carboxylic acid (50 gram, 0.32 mole) and triethylamine (53 ml, 0.38 mole) in dichloromethane (350 ml) at 0 ° C. The reaction mixture was stirred at 0-5 ° C for 3 h. The solution was washed with 2 x 100 ml of water, dried (anhydrous magnesium sulfate) and concentrated to reduced pressure. The solid residue was triturated with 100 ml of ethyl ether, collected by filtration and extracted to obtain 1-methanesulfonyl-piperidine-4-carboxylic acid ethyl ester (68 grams, 90%), m.p. 91 - 92 ° C. B. 1-Methanesulfonylpiperidin-4-methanol A solution of 1.0 M lithium aluminum hydride (200 ml, 0.2 moles) in tetrahydrofuran was added dropwise to a solution of the ethyl ester of 1-methanesulfonyl-piperidin-4 carboxylic (68 grams, 0.29 moles) in tetrahydrofuran (500 ml) at about + 5 ° C. The reaction mixture was stirred at 5-10 ° C for 15 minutes. Water (10 ml) was added dropwise and the mixture was filtered. The filtrate was concentrated under reduced pressure and triturated with ethyl ether 50% -hexane (100 ml). The white recyclable solid was collected by obtaining l-methanesulfonylpiperidin-4-methanol.p.m. 96 97 ° C. C. 1-methanesulfonylDiperidin-4-carboxaldehyde A solution of dimethyl eulfoxide (39 g, 0.55 mol) in dichloromethane (300 ml) was added slowly to an oxalyl chloride solution (22.7 ml, 0.264 mole) in dichloromethane. (700 ml) at -60 ° C. After 10 minutes a solution of l-methanesulfonylpiperidin-4-methanol (46 grams, 0.238 mol) in dichloromethane (500 ml) was slowly added. After 30 minutes at -60 ° C, triethylamine (167 ml) was added. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (1.2 liters) and water (200 ml). The organic phase was dried (anhydrous magnesium eulfate) and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / hexane to obtain 1-methanesulfonyl-piperidm-4-carboxaldehyde (34 grams), m.p. 97 ° C. D. Similarly, substituting the methanesulfonyl chloride with other chlorides, and following the procedures described supra in Preparation 5A, the following compounds of formula 17: 1- (morpholine-4-carbonyl) piperidin-4 were prepared. -carboxaldehyde, pf 78-79 ° C, and l- (cyclohexanecarbonyl) piperidine-4-carboxaldehyde. M * 223.

EXAMPLE 1 Preparation of the formula compueetoe as described in Scheme C Route (a) 1A. N- (2- (4-M -toxhoxyphenyl) -l-methylethyl-N-ethyl- (piperidin-4-ylmethyl) amine dihydrochloride, hemihydrate To a mixture of N- [2- (4-methoxyphenyl) -1- hydrochloride methylethyl] ethylamine (2.0 gram, 8.71 mole) and sodium carbonate (3 2 gram, 30 moles) in toluene (75 ml) and water (50 ml), was added dropwise to a 1-benzyloxycarbonylpiperidine chloride solution 4-carbonyl (2.67 grams, 9.5 moles) in toluene (25 ml) The reaction mixture was stirred at 22 ° C. for 16 h.The mixture was diluted with ethyl acetate (100 ml), the organic phase was dried ( magnesium anhydrous eulfate) and concentrated under reduced pressure, the residue was subjected to flash column chromatography on silica gel eluted with 30% ethyl acetate in hexane. N- [2- (4- methoxyphenyl) -l-methylethyl] -N-ethyl- [1- (benzyloxycarbonyl) piperidin-4-ylcarbonyl] amine, in the form of an oil, (3.5 grams, 95%); M * H 439. A mixture of N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- [1- (benzyloxycarbonyl) piperidin-4-ylcarbonyl] amine (3.5 grams, 8.3 mmol) and 10% palladium on charcoal (0.7 gram) in ethanol (40 ml) was hydrogenated at 22 ° C and 50 pei. for 2.5 hours. The catalyst was removed by filtration and the filtrate Concentrated at reduced pressure to obtain N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (piperidin-4-ylcarbonyl) amine in the form of a syrup (2.11 grams).84%), M * 305. A solution of lithium aluminum hydride (30 mmole) in tetrahydrofuran (120 ml) was heated to reflux. A solution of N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (piperidin-4-ylcarbopyl) amine (7.8 grams, 25.6 mmol) in tetrahydrofuran (40 ml) was added dropwise. After 30 minutes, an excess of water at 22 ° C was added. The mixture was filtered and the filtrate concentrated to reduced pressure obtaining N- [2- (4-me-toxyphenyl) -l-methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine, which was added as the hydrochloride salt from acetonitrile (7.0 gram, 75%), mp 144 - 146 ° C, M * H 405. IB. In a similar manner, replacing N- [2- (4-methoxyphenyl) -l-methylethyl] ethyl'-amine hydrochloride with (?) -N- [2- (4-methoxyphenyl) -l-methylethyl] hydrochloride] ethylamine, and following the procedure described above in Example IA, prepared (S) -N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine, M * H 291. Route (b) 1C. ÍS) -N- Í2- (2,3-dihydrobenzofuran-5-yl) -1-methylethyl-N-ethyl- (pyoeridin-4-ylmethyl) -amine To a solution of (S) -N- [2- (2, 3-dihydrobenzofuran-5-yl) -l-methylethyl] -ethylamine (2.38 grams, 11.6 mmolee) and l- (tert-butoxycarbonyl) piperidine-4-carboxaldehyde (2.47 grams, 11.6 mmolee) in dichloroethane (20 m!), triacetoxyboron was added Sodium hydride (3 67 grams, 17.4 mmol) The reaction mixture was stirred for 16 hours at room temperature. The solvent was removed at reduced pressure and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with water, dried with potassium carbonate and concentrated at reduced pressure to obtain a residue which was purified by flash chromatography on silica gel using 30% ethyl acetate in hexane. The appropriate fractions were combined and concentrated to obtain (S) -N- [2- (2, 3-d? h? drobenzofuran-5-? l) -1-meth? l-ethyl] -N-ethyl- [1- (tert-butoxycarbonyl) p? pepdm-4-? lmet? l] gun in the form of an oil (3.78 g, 82%), M * H 403 A (S) -N- [2- (2, 3-d? h? drobenzofuran-5 -? l) -1-met? let? l] -N-ethyl- [1- (tert-butox? carbon? l) p? per? d? n-4-? lmet? l] amine (3 78 grams 9 mole), 20% trifluoroacetic acid (50 ml) was added in dichloromethane. The solution was stirred at room temperature for 4 hours. The solution was concentrated under reduced pressure and the residue was partitioned between dichloromethane and eodium hydroxide. The organic layer was washed with water, dried with potassium carbonate and concentrated to give (S) -N- [2- (2 , -d? h? drobenzofuran-5-? l) -1-met? let? l] -N-ethyl- (pipendm-4-methylmethyl sheet, in the form of an oil (2 42 grams, 85%), M * H 303 EXAMPLE 2 An alternative preparation of the compound of the formula as described in Scheme D 2A. N- \ 2- (4-methoxyphenyl) -l-methylethyl] -N-prooyl-1- (tert-butoxycarbonyl) -piperidin-4-ylmethyl amine A solution of eodium cyanoborohydride (1.07 gram, 17 mmolee) , 4-aminomethyl-1- (tert-butoxycarbonyl) piperidine (3.0 gram, 14.3 moles) and 1- (4-methoxyphenyl) propan-2-one (2.35 grams, 14.31 mmolee) in methanol (50 ml) was stirred at 22 ° C] 0 for 17 hours. The mixture was concentrated at reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase (anhydrous magnesium sulfate) was concentrated under reduced pressure to obtain N- [2- (4-methoxyphenyl) -l-methylethyl] - [1- (tere-butoxycarbonyl) piperidin-4-ylmethyl] amine, 5 in the form of an oil (4.28 grams, 82%); hydrochloride p.f. 198-199 ° C (methanol / ethyl acetate), M * H 391. A mixture of N- [2- (4-methoxyphenyl) -l-methylethyl] - [1- (tert-butoxycarbonyl) piperidin-methyl)] amine (0-87 grams, 2.4 mmol), propionic aldehyde (0.2 mL, 2.5 mmol) and tri-0-edoxy acetoxyborohydride (0.763 grams, 3.6 mmol) in 1,2-dichloroethane (25 mL) was stirred at 22 ° C. for 16 hours. The mixture was concentrated under reduced pressure and the reagent was distributed between 100 m! of ethyl ether and 25 ml of 10% aqueous eodium carbonate. The organic phase was concentrated (anhydrous magnesium sulfate) and concentrated, and subjected to flash chromatography on silica gel 230-240 mesh eluting with ethyl acetate. % ethyl / hexane. The product fractions were concentrated under reduced pressure to obtain N- [2- (4-methoxyphenyl) -l-methylethyl] -N-propyl- [1- (tert-butoxycarbonylpiperidin-4-ylmethyl) amine, in the form of a syrup (0.93 grams, 95%), M * H 405. 2B. Similarly, replacing propionic aldehyde with acetaldehyde and following the procedure described above in Example A, N- [2- (4-methoxyphenyl) -1-methylethyl] -N-ethyl- [1- ( tert-butoxycarbonyl) piperidin-4-ylmethyl] -amine. EXAMPLE 3 Preparation of compound of formula Ib as described in Scheme E Route (a) 3A. Dibenzoyl-L-tartrate N-22- (4-fluoro-phenyl) -1-methyl-ethyl-N-ethyl- fl-cyclohexancarbonyl) piperidin-4-ylmethyl amine A mixture of N- [2- (4 - fluorophenyl) -l-methylethyl] -ethylamine (0 5 gram, 2.76 mmolee), 1- (cyclohexanecarbonyl) piperidine-4-carboxaldehyde (0.616 grams, 2.76 mmol), and sodium triacetoxy borohydride (0.88 grams, 4.15 mmolee ) in 1,2-dichloroethane (20 ml) was stirred for 16 hours. The solution was concentrated under reduced pressure and the residue was partitioned between 1.0N sodium hydroxide (20 m) and ethyl acetate (50 ml). The organic phase was dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The product was obtained as salt from dibenzoyl-L-tartrate with ethyl ether, obtaining di-benzoyl-L-tartrate hemihydrate, of N- [2- (4-fluorophenyl) -1-rr.e-tilethyl] -N-ethyl- [1- (cyclohexanecarbonyl ) iperidin-4-ylmethyl] amine, (1.9 gram, 92%), p, .f. 121 - 123 ° C. 3B. Similarly, substituting N- [2- (4-fluoro-phenyl) -l-methylethyl] -ethylamine for other compounds of formula 4, optionally substituting 1- (cyclohexanecarbonyl) pi-peridin-carboxaldehyde with other compounds of Formula 23, and following the procedures described above in Example 3A, the following compounds of formula Ib were prepared: N- [2 - (3-phenoxyphenyl-1-methylethyl] -N-ethyl- [l-cyclohexanecarbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 463; N- [2- (4-methoxyphenyl-1-methylethyl] -N-butyl- [l-cyclohexanecarbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 429; Dibenzoyl-L-tartrate hemihydrate N- [2- (3,4-dichloro-phenyl-1-methylethyl] -N-ethyl- [l-cyclohexanecarbonyl) piperidin-4-ylmethyl] amine,, M * H 439; Dibenzoyl-L-tartrate N- [2- (3-chlorophenyl) -1-methylethyl] -N-ethyl- [1-cyclohexanecarbonyl) piperidin-4-ylmethyl] amine hemihydrate, M * H 405; Dibenzoyl-L-tartrate N- [2- (4-trifluoromethylphenyl) -1-methylethyl] -N-ethyl- [1- cyclohexanecarbonyl) piperidin-4-ylmethyl] amine M * H 439 hemihydrate; N- [2- (2,3-Dihydrobenzo [1,4] dioxin-6-yl) -1-methylethyl] -N-ethyl- [1-cyclohexanecarbonyl) iperidin-4-ylmethyl] amine hydrochloride, M * H 429; Dibenzoyl-L-tartrate hemihydrate, of N- [2- (4-methoxyphenii) -l-methylethyl] -N-ethyl- [1- (morpholino-carbonyl) piperidin-4-ylmethyl] amine, M * H 404; Dibenzoyl-L-tartrate hemihydrate, N-. { 2- [4- (2, 2, 2-tri-fluoroethoxy) phenyl] -l-methylethyl} -N-propyl- [1-cyclohexane-carbonyl) piperidin-4-ylmethyl] amine, M * H 483; Dibenzoyl-L-tartrate hemihydrate, N-. { 2- [4- (2, 2, 2-tri-f-luoroethoxy) phenyl] -l-methylethyl} -N-ethyl- [1-cyclohexanecarbonyl) piperidin-4-ylmethyl] amine, M * H 483; Dibenzoyl-L-tartrate hemihydrate, N- [2- (4-phenoxyphenyl) -l-methylethyl] -N-ethyl- [1-cyclohexanecarbonyl) piperidin-4-ylmethyl] amine, M * H 463; N- [2- (2,3-Dihydrobenzo [1,4] dioxin-6-yl) -l-methylethyl] -N-ethyl- [1- (morpholinocarbonyl) piperidin-limemethyl chloride, M * H 432; N- [2- (3-trifluoromethylf enyl) -l-methylethyl] -N-ethyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 442; N- [2- (3-chlorophenyl) -1-methylethyl] -N-ethyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 408; N- [2- (3-chlorofenyl) -l-methylethyl] -N-cyclo-propylmethyl- [1- (morpholinyl-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 434; N- [2- (3-nitrophenyl) -l-methylethyl] -N-pro-pil- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M? 419; N- [2- (3-Aminophenyl) -l-methylethyl] -N-propyl- [l- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 403; N- [2- (3-trifluoromethylphenyl) -1-methyl-ethyl] -N-propyl- [1- (morpholino-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 456; N- [2- (2, 3-dihydrobenzofuran-6-yl) -1-methylethyl] -N-ethyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 416; N- [2- (2,3-dihydrobenzofuran-6-yl) -1-methylethyl] -N-propyl- [1- (morpholino-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 430; N- [2- (2,3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- [1- (morphine-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 416; (S) -N- [2 - (2,3-dihydrobenzofuran-5-yl) -1-methylethyl] -N-ethyl- [1- (morphine-4-carbonyl) piperidin-4-yl ethyl ] amine, [a] D2s + 15 ° (c 1.0 CHC1.), M * H 416; N- [2- (2, 3-dihydrobenzofuran-5-yl) -1-me-t-lethyl] -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 429; N- [2- (3-Oxo-4H-benzo [1,4] oxazin-6-yl) -1-methylethyl] -N-propyl- [1- (morphine-4-carbonyl) piperidin-4-hydrochloride -ylmethyl sheet, M * H 459; N- [2- (4-Nitrophenyl) -l-methylethyl] -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 433; (S) -N- [2- (3-Nitrophenyl) -l-methylethyl] -N-ethyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 419; Hydrochloride and N- [2- (3, 3-dimethyl-2,3-dihydrobenzofuran-6-yl) -l-methylethyl] -N-ethyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl ] amina, pf 203-204 ° C, and (S) -N- [2- (2, 2-dimethyl-2, 3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- [1-] hydrochloride (morpholin-4-carbo-n? l) piperidin-4-ylmethyl] amine, M * H 444. Route (b) 3C. Di-p-toluyl-L-tartrate N-> 2- (4-methoxy-phenyl) -1-methylethine-N-ethyl- fl- (cyclohexanecarbonyl) pyoeridin-4-methyl-amine hydrate A solution of N- [2] - (4-methoxyphenyl) -l-methylethyl] -N-ethyl- [1- (tert-butyloxycarbonyl) piperidin-4-ylmethyl] amine (0.28 grams, 0.72 mol) in trifluoroacetic acid (5 m) was concentrated under reduced pressure. The residue was mixed with 10% aqueous sodium carbonate (15 ml), toluene (10 ml) and cyclohexane-carbonyl chloride (0.134 ml, 1.0 mmolee). The mixture was reacted at 22 ° C for 15 hours and extracted with ethyl acetate (25 ml). The organic phase was dried (anhydrous magnesium eulfate) and concentrated under reduced pressure. The product was isolated as the di-p-toluyl-L-tartrate salt to give the di- p-toluyl-L-tartrate hydrate of N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- [1- (cyclohexanecarbonyl) piperidin-4-ylmethyl] amine, (0.29 grams, 51%), m.p. 119-120 ° C, M * H 401. 3D. (S) -N- 12- (4-methoxyphenyl) -1-methyl-ethyl-N-ethyl- fl- (cyclohexanecarbonyl) pyoeridin-4-ylmethine amine hydrochloride A mixture of (S) -N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine (1.54 gram, 5.3 mmolee) and eodium carbonate (1.6 gram, 15 mmolee) in toluene (50 rr!) And water (30 ml), cyclohexanecarbonyl chloride (0.74 ml, 5 5 mmol) was added. After 16 hours, the reaction mixture was extracted with ethyl acetate (100 ml), the organic fae was dried (Magnesium eulfate anhydrous) and concentrated at reduced pressure. The product was isolated as the hydrochloride eal with ethyl acetate / ethyl ether to obtain (S) -N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- [1- (cyclohexyl) hydrochloride. hexancarbonyl) piperidin-4-ylmethyl] amine (1.25 grar.oe, 54%), m.p. 159 - 160 ° C. 3E. In a similar manner, replacing the (S) -N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine, with other compounds of the formula, optionally substituting the chloride of cyclohexanecarbonyl with other carbonyl chlorides, and following the procedures described above in the 3D example, the following compounds of formula Ib were prepared: N- [2- (4-methoxyphenyl) -1-methylethyl) dibenzoyl-L-tartrate hydrate ] -N-ethyl- (l-iobutyrylpiperidin-4-ylmethyl) amine, mp 119 -. 119 - 120 ° C ethyl ether); Dibenzoyl-L-tartrate hemihydrate, of N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- [1- (cyclopentanecarbonyl) piperidin-4-ylmethyl] amine, m.p. 121-123 ° C (ethyl ether); Dibenzoyl-L-tartrate hemihydrate, N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- [l- (tet rahydropyran-4-carbo-nyl) piperidin-4-ylmethyl] amine pf 116-118 ° C (ethyl ether); Dibenzoyl-L-tartrate hemihydrate, of N- [2- (4-methoxyphenyl) -1-methylethyl] -N-ethyl- (l-acetyl-iperidin-4-ylmethyl) amine m.p. 114-115 ° C (ethyl ether), - N- [2- (4-methoxyphenyl) -1-methylethyl] -N-ethyl- [1- (dif-enylmethylcarbonyl) piperidin-4-ylmethyl dibenzoyl-L-tartrate hydrate ] amine,; M * H 485; Dibenzoyl-L-tartrate hydrate of N- [2- (3-trifluoromethyl-phenyl) -l-methylethyl] -N-ethyl- [1- (cyclohexanecarbonyl) piperidin-4-ylmethyl-sheet, M * H 439; N- [2- (2,3-Dihydrobenzo [1,4] dioxin-6-yl) -1-methylethyl] -N-ethyl- [1- (tetrahydropyran-4-carbonyl) piperidin-4-ylmethyl] hydrochloride] amine, M * H 431; Dibenzoyl-L-tartrate N- [2- (2, 3-dihydrobenzoyl hydrate [1,4] dioxin-6-yl) -1-methylethyl] -N-ethyl- [1- (tetrahydropyran-4-carbonyl) piperidin-4-ylmethyl] mine, M * H 431; N- [2- (3-trifluoromethylphenyl) -1-methyl-ethyl] -N-ethyl- [1- (tetrahydropyran-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 441; N- [2- (3-chlorophenyl) -l-methylethyl] -N-ethyl- [1- (tetrahydropyran-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 407, - N- Hydrochloride [2- (2, 3-dihydrobenzofuran-6-yl) -1-methylethyl] -N-cyclopropylmethyl- [1- (tet rahydropyran-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 442; N- [2- (2, 3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-cyclopropylmethyl- [1- (tetrahydropyran-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M "H 442 N- [2- (4-nitrophenyl) -l-methylethyl] -N-propyl- [1- (tert-butoxycarbonyl) piperidin-4-ylmethyl] amine hydrochloride, M? 420; N- [2] -hydrochloride - (4-nitrofenyl) -l-methylethyl] -N-propyl- [1- (piperidin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 431; N- [2- (4- nitro? f enyl) -1-methylethyl] -N-propyl- [1- (l-trifluoroacetylpyridin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 527; N- [2- (2-trifluoroacetate] , 3-dihydrobenzofuran-5-yl) -1-methylethyl] -N-ethyl- [1- (2-hydroxy-1-ylcarbonyl) piperidin-4-ylmethyl] amine, M * H 451; N-,. 2- [3- (4-tert-Butyl) butylcarbonylamino) phenyl] -l-methylethyl.} - N -propyl- [1- (4-methanesulfonyl phenyl -carbonyl) piperidin-4-ylmethyl) amine, M * H 632; N-. {2- [3- (4-tert-Butylphenylcarbonyl-ammo) phenyl] -l-melethyl trifluoroacetate} - N-propyl- [1] - (f uran -2 -carbo- nil) iperidin-4-ylmethyl] amine, M * H 544; N- trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl - [1- (ethoxycarbonyl) piperidin-4-ylmethyl] amine, M * H 550; N- trifluoroacetate. { 2- [3- (4-tert-Butylf-enylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (pyridine-4-car-bonyl) piperidin-4-ylmethyl] amine, M * H 555; N- trifluoroacetate. { 2- [3- (4-tert-Butylf-enylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (tert-butylcarbonyl) piperidin-4-ylmethyl] amine, M * H 534; N- trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (cyclone ex-ilcar-bonyl) piperidin-4-ylmethyl] amine, M * H 560; N- trifluoroacetate. { 2- [3- (4-tert-Butylf-enylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (pyridin-3-carbonyl) piperidin-4-ylmethyl] amine, M * H 555; N- trifluoroacetate. { 2- [3- (4-tert-Butylf-enylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1-acetylpiperidin-4-ylmethyl] amine, M * H 492; N- trifluoroacetate. { 2- [3- (4-tert-Butylf-enylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (ethylcarbonyl) piperidin-4-ylmethyl] amine, M * H 506; N- trifluoroacetate. { 2- [3- (4-tert-Butylf-enylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (2-methylphenylcarbonyl) piperidin-4-ylmethyl] amine, M * H 568; N- trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (cyclobutylcarbo-nil) piperidin-4-ylmethyl] amine, M * H 532; N- trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (4-cyanophenylcarbo-nyl) piperidin-4-ylmethyl] amine, M * H 579; N- trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (ie, butylcarbo-nyl) piperidin-4-ylmethyl] amine, M * H 534; and N- Trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (ioxazole-5 -carbonyl) piperidin-4-ylmethyl] amine, M * H 545. EXAMPLE 4 Preparation of compound of formula I as described in Route (a) 4A. N- [2- (4-methoxyphenyl-1-methylethyl-N-ethyl- fl- (pyrrolidin-1-carbonyl) pyoeridin-4-ylmethyl amine dibenzoyl-L-tartrate.) To a 2 M phosgene solution toluene (2.0 ml, 4 mmol) in ethyl ether (20 ml) was added a solution of N- [2- (4-methoxyphenyl-1-methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine] (0.23 grams, 0.79 mmoles) in ethyl ether (0 ml) After 30 minutes, the precipitate was collected by filtration and dried in vacuo to obtain N- [2- (4-methoxyphenyl-1-hydrochloride. methyethyl] -N-ethyl- (l-chlorocarbon? lp? pepd? n-?? lmet? l) amine (0 238 grams, 77%), mp 144-145 ° CA a suspension of N- [2] hydrochloride - (4-methox? Phen? II -methylethyl] -N-ethyl- (l-chlorocarbon? Lp? Per? D? N-4-? Lmec? L) amine (0 1 gram, 0 257 mmol) in ethyl ether (10 mL), pyrrolidine (0 mL, 1.2 mmol) was added. The mixture was stirred at 22 ° C for 15 hours. The mixture was stirred with 10% aqueous eodium carbonate (10 mL), the organic phase was dried (anhydrous magnesium sulfate) and concentrated under reduced pressure The residue was subjected to flash column chromatography on silica gel eluting with ethyl acetate The product was isolated as dibenzoyl-L-tartrate with ethyl ether by taking dibenzoyl L-tartrate N- [2- (4-methox? phen? ll-met? let? l] - N-ethyl- [1- (p? rrol? d? nl-carbon? l) p? per? d? n hydrate -4-? Lmet? L] amine, (0 087 gram, 45%), mp 110 - 112 ° C 4B Similarly, replacing the N- [2- (4-methox? -phen? 1-met ? let? l] -N-ethyl- (p? per? d? n-4-? lm et? l) amine by other compounds of formula la, optionally substituting pyrro-lidma for other amines, and following the procedures described above in example 4A, the following compounds of the formula Dibenzoyl-L-tartrate hydrate were prepared from S) -N- [2- (4-methox? Fe-nil) -1-met? Let? L] -N-et l- [1- (3-h? Drox? -p? Rrol? Dm-1 -carbo-n? l) p? pepd? n-4-? lmet? l] amine, mp 101-102 ° C, Dibenzoyl-L-tartrate N- [2- (4-methox? phen? l) hydrate 1-methylethyl] -N-ethyl- [1- (4-tert-butoxycarbon lp? Perazm-l- carbonyl) piperidin-4-ylmethyl] amine, m.p. 108-109'C, M-H503; N- [2- (3-trifluoromethyl-phenyl) -l-methylethyl] -N-ethyl- [1- (2-hydroxymethylpi-eridin-1-carbonyl! Piperidin-4-ylmethyl] amine hydrochloride, M * H 470; (S) -N- [2- (3-chlorophenyl) -l-methylethyl] -N-ethyl- [1- (pyrrolidin-1-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, K 'K 392. Route (b) 4C Dibenzoyl-L-tartrate hemihydrate of N- f2- (4-methoxyphenyl) -1-methylethyl-N-ethyl- fl- (diisooropylamino-carbonyl) piperidin-4-ylmethyl 1-amine One N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine hydrochloride (0.205 grams, 0.564 mmol), triethylamine (0.5 ml, 3.6 mmol) and chloride of diisopropylcarbamyl (0.115 grams, 0.7 mmol) in dichloromethane (25 ml) was stirred at 22 ° C. for 15 hours.The residue obtained after concentrating under reduced pressure was partitioned between 5% aqueous sodium carbonate and ethyl ether. free obtained from the organic phase eeca (anhydrous magnesium sulfate) and concentrated, it became the salt of dibenzoyl-L-tartrate obtaining dibenzoyl-L-tartrate hemihydrate, of N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- [1- (diisopropylaminocarbonyl) piperidin-4-ylmethyl] amine, ( 0.3 grams, 69%), mp 105-106 ° C. 4D. In a similar manner, substituting N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (piperidin-4-ylmethyl] amine for other compounds of formula la, optionally substituting diieopropylcarbamyl chloride for another carbamyl chloride, and following the procedures described above in Example 4C, the following compounds of the formula were prepared: N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- [1] hydrochloride - idimethylaminocarbonyl) piperidin-4-ylmethyl] amine, M * K 362.

Dibenzoyl-L-tartrate N- [2- (4-r.ethoxyphenyl) -l-methylethyl] -N-ethyl- [1- (dimethylarninocarbonyl) piperidin-4-ylmethyl] amine hemihydrate,, M * H 362. N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (l-propanoylpiperidin-4-ylmethyl) amine dibenzoyl-L-tartrate, mp. 106-107 ° C, - H 347; N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- [1- (isopropyl-aminocarbonyl) piperidin-4-ylmethyl] amine, m.p. 123-124 ° C; N- [2- (3-trifluoromethylphenyl) -1-methylethyl] -N-ethyl- [1- (dimethylaminocarbonyl) piperidin-4-ylmethyl] amine dibenzoyl-L-tartrate, M * H 400; N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- [1- (di-8-ylaminocarbonyl) piperidin-4-yl-methyl] amine hydrochloride, m.p. 68 -70 ° C; N- [2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -l-methylethyl] -N-ethyl- [1- (diethylaminocarbonyl) iperidin-4-hydrochloride lmethyl] amine, M * H 418, N- [2- (2, 3-d? h? drobenzo [1,4] d? oxm-6-? l) - 1-met? let? l] - N-ethyl- [1- (dimethylaminocarbonyl) p? Per? Dm-4-ylmethyl] amine, M * H 390, N- Dibenzoyl-L-tartrate. { 2- [4- (2, 2, 2-tr? Fluoroethoxy?) Phen l] -l-met let? L} -N-propyl- [1- (dimethylammocarbonyl) p? Per? Dm-4-? Lmethyl] amine, M * H 444, Dibenzoyl-L-tartrate N-. { 2- [4- (2, 2, 2-tr? Fluoroethoxy?) F enyl] -l-met? Let? L} -N-et? L- [1- (d? Met? Nocarbon? L) p? Per? Dm-? -ylmethyl] amine, M * H 430, Dibenzoyl-L-tartrate of N- [2- ( 4-methox? F enyl) -1-mst? L-ethyl] -N-propyl- [1- (dimethylammocarbonyl) piper idin- 4-yl ethyl] amine, mp 109-110 ° C, N-Chlorohydrate [2- (3-tr? Fluoromet? Lfeml) -1- et? L-ethyl] -N-ethyl- [1- (p? Per? D? Nl-carbon? L) p? Per? D? N- 4-? Lmet? L) amine, M * H 440, N- [2- (3-tpfluoromet? Lfen? L) -l-ethylethyl] -N-ethyl- [1- (p? Dibenzoyl-L-tartrate. per? dm-1-carbon? l) p? er? dm-4-ylmethyl] amine, M * H 440, N- [2- (3-chloromet? lf enyl) -1-dibenzo-l-tartrate -thylethyl] -N-ethyl- [1- (dimethylammocarbonyl) p? per? dm-4-lmethyl] amine, M * H 366, Dibenzoyl-L-tartrate of N- [2- (4-tpfluoromet? lf eml ) -1-methylethyl] -N-ethyl- [1- (p? Per? Dm-1-carbon? L) p? Per? Dm-4-ylmethyl] amine, M * H 440, Dibenzoyl-L-tartrate of N- [2- (4-tpfluoromet? Lfen l) -1-methylethyl] -N-ethyl- [1- (dimethylaminocarbonyl) p? Per? Dm-4-ylmethyl] amine, M * H 400, N- [2- (4-methox? Phen? L) -1-met? Let? L] -N-ethyl- [1- (tert-butyl-am? Nocarbon? L) prper? Dm-4 -? lmet? l] am? na, m 96 - 97 ° C, Dic) N- [2- (3-tr? Fluoromet? Lfen? L) -1-meth? L-ethyl] -N-ethyl- [1- (p? R? D? N-3-met? lam? nocarbon? l) p? pend? n-4-ylmethyl] amine, M * H 463, N- [2- (3-tr? f luoromethylphenyl) -1-met? l-et l] -N-hydrochloride -et? l- [l- (1, 2,3,4-tetrahydro [l, 5] naft? r_d? nl-carbon? l) p? per? dm-4? lmet? l] amine, M "H 486, N- [2- (3-chlorophemethyl) -1-met? Let? L] -N-ethyl- [1- (p? Per? D? Nl-carbon? L) p? Per hydrochloride ? dm-4-? lmet? l] amine, M * H 406, N- [2- (3-tnfluoromet? lf enyl) -1-met? le 111] -N-e 111 - [1 - ( 1 2, 3, 4 - etr ah i dr och ino 1 in - 1 -carbon? L) p? Per? D? N-4-? Lmet? L] ami ^ a, M "H 488, N-Hydrochloride [2- (3-trifluoromethyl-enyl) -1-ret-1-ethyl] -N-ethyl- [1- (3,4-d? -hydroquinoline-2H-benzo [1,4] oxaz? n-4-carbon? l) p? per? d? n-4-? lmet? l] amine, M * H 490, and N- [2- (3-tr? f luoromethylphenyl) -1- hydrochloride methy1-ethyl] -N-ethyl- [1- (2-met? lcarbox? lp? per? d? nl-carbon? l) p? per? dm-4-? lmet? l] am? na, M * H 498, N- Dihydrochloride. { 2- [3- (4-tert-butyl) in lcarbonylamine) fyl] -1-met? Let? L} -N-propyl- [1- (4-met? Lp? Peraz? N-1-carbon? L) p? Per? D -4-? Lmet? L] amine, mp 182 - 183 ° C, M * H 576, N- hydrochloride. { 2- [3- (4-tert-Butylphenylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- [l-thiomorpholine-4-carbonyl) piperidin-4-ylmethyl] amine, m.p. 137-138 ° C, M * H 579; N- trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (diethylminocarbonyl) piperidin-4-ylmethyl] amine, M * H 549; N- trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl - [1- (dimethyl-amino-carbonyl) piperidin-4-ylmethyl] -amine, M * H 521; N- trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (diieopropylamino-carbonyl) piperidin-4-ylmethyl] amine, M * H 577; and N- Trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (phenylamino or -carbonyl) piperidin-4-ylmethyl] amine, - M * H 569. Route (c) 4E. N-> 2- (4-methoxy-enyl) -1-methylethyl-1-N-ethyl-ritmethyl-laminocarboryl) pyoeridin-4-ylme in amine To a solution of N- [2- (4-methoxyphenyl) -l -methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine (0.23 gram, 0.79 mmolee) in ethyl ether (10 ml) was added methyl isocyanate (0.2 ml, 3. 4 mmoles). After 1.0 hour at 22 ° C, the solution was concentrated under reduced pressure and the residue was recrystallized from ethyl ether / hexane to obtain N- [2- (4-methoxyphenyl) -1-methylethyl] -N-ethyl- [1 - (Methylaminocarbonyl) piperidin-4-ylmethyl] amine (0.249 grams, 91%), mp 97-98 ° C. 4F. Similarly, substituting N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (piperidin-4-ylmethyl), by other compounds of formula la, optionally by substituting methyl isocyanate for other isocyanates, and following the procedures described above in Example 4E, the following compounds of the formula were prepared: N- [2- (3-chlorophenyl) -l-methylethyl] -N-ethyl dibenzoyl-L-tartrate - [1- (isopropyl-aminocarbonyl) piperidin-methylmethyl] amine, M * H 380; N- [2- (3-chlorophenyl) -1-methyl-ethyl] -N-ethyl- Dibenzoyl-L-tartrate [1- (cyclohexylaminocarbonyl) piperidin-4-ylmethyl] amine, M * H 420; N- [2- (4-methoxyphenyl) -1-methyl-ethyl] -N-ethyl- [1-] dibenzoyl-L-tartrate (methylaminothiocarbonyl) piperidin-4-ylmethyl] amine, M * H 364; N- { 2- [3- (4-tere-buyl-phenyl-carbonylamino) -phenyl] -1-methylethyl} -N-propyl- [1- (tert-butylaminocarbonyl) piperidin-4-ylmethyl] amine, mp 155-160 ° CM 'H 549; N-. {2- [3- (4-tert-butyl) trifluoroacetate enylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (tere-butylamino -carbonyl) piperidin-4-ylmethyl] amine, M * H 549; N- trifluoroacetate. { 2- [3- (4-tert-Butylf-enylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (i eopropylamino -carboml) piperidin-4-ylmethyl] amine, M "H 535; N- trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (methylaminocarbonyl) piperidin-4-ylmethyl] mine, M * H 507; Route (d) 4G. N- f2- (4-methoxyphenyl) -l-methylethyl-N-ethyl- (1-aminocarbonyl-piperidin-4-methylmethyl) A mixture of N- [2- (4-methoxyphenyl) -1-methylethyl] - hydrochloride N-ethyl- (piperidin-4-ylmethyl) amine, (0.42 grams, 1.16 mmoles) and potassium cyanate (1.5 grams, 18.5 thrones) in water (5 ml) was heated to reflux for about 20 minutes. The white solid that formed after cooling was collected and recrystallized from chloroform / hexane to obtain N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (1-aminocarbonyl-piperidin-4-ylmethyl) ) amine (0.3 grams, 77%), mp 104 - 105 ° C. 4H. Dibenzoyl-L-tartrate hydrate of N- f2- (4-methoxyphenyl) -l-methylethyl-N-ethyl- fl- (4-acetylPJperazin-1-carbonyl) piperidin-4-methylmethyl amine A solution of N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- [1- (4-tert-butoxycarbonylpiperazin-1-ylcarboniUpiperidin-4-ylmethyl] amine (0.325 grams, 0.65 mmol) in trifluoroacetic acid (2.0 ml. ) was kept at 22 ° C for 45 minutes.The solution was concentrated under reduced pressure, the residue was partitioned between iodo hydroxide and ethyl ether.The dry organic phase (anhydrous magnesium sulfate) was concentrated at reduced pressure. dissolved in a mixture of pyridine (5 ml) and acetic anhydride (1.0 ml) and the eeolution maintained at 22 ° C for 15 h. The solution was concentrated under reduced pressure and the residue was partitioned between 0.5 N sodium hydroxide and ethyl ether. The organic phase was dried (anhydrous magnesium sulfate) and concentrated. The product was isolated as a dibenzoyl-L-tartrate salt with ethyl ether to obtain N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- [1- (4-dibenzoyl-L-tartrate hydrate. -acetylpi erazin-1-carbonyl) piperidin-4-ylmethyl] amine, (0.13 grams, 26%), mp 117 - 119 ° C, M * H 445. 41. Similarly, replacing N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine hydrochloride, with other compounds of formula J_a, and following the procedures described above in Example 4H, the following compounds of the formula le were prepared: N-. {2- [3- (4-tert-butylphenylcarbonylamino) phenyl] -1-methylethyl} -N-propyl- (1-) carbamoylpi? eridin-4-ylmethyl) amine, mp 182 - 183 ° C, M * H 493; and N-. {2- [3- (4-tert-butylphenylcarbonylamino) phenyl] -l-methylethyl hydrochloride .}. N-propyl- ([1- (1, l-dioxo-thiomorpholine-4-carbonyl) piperidin-4-ylmethyl) amine, M "H 611. EXAMPLE 5 Preparation of compounds of formula Id as described in the G scheme 5A. Dibenzoyl-L-tartrate of N- f2- (4-methoxyphenyl) -1-methyl-ethyl-N-ethyl- fl- (isopropyloxycarbonyl) PIDeridin-4-ylmethyl amine To a mixture of N- [2- (4-hydrochloride -methoxyphenyl) -1- methylethyl] -N-ethyl- (piperidin-4-ylmethyl] amine, (0.2 grams, 0.55 mmol) and triethylamine (0.4 ml, 2.9 mmol) in dichloromethane (10 ml), isopropyl chloroformate was added 1.0 M (0.83 mL, 0.83 mmol) in toluene The reaction mixture was stirred at 22 ° C for 16 hours, and then concentrated under reduced pressure The residue was partitioned between ethyl acetate (20 μL) and sodium bicarbonate. aqueous solution at 5% (20 ml) The dry organic phase (anhydrous magnesium eulfate) was concentrated under reduced pressure and the residue was subjected to iristant column chromatography on silica gel eluting with 1% methanol in chloroform containing 0.5% of ammonium hydroxide The product was isolated as an eal of dibenzoyl-L-tartrate (ethyl ether) obtaining dibenzoyl-L-tartrate d and N- [2- (4-methoxyphenyl) -1-methylethyl] -N-ethyl- [1- (isopropyloxycarbonyl) piperidin-4-ylmethylamine (0.345 grams, 85%), m.p. 96-98 ° C, M * H 377. 5B. Similarly, replacing N- [2- (4-methoxyphenyl) -1-methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine hydrochloride, by other compounds of formula la and isopropyl chloroformate by others chloroformiatoe, and following the procedures described above in example 5A, the following compounds of formula Id were prepared: N- trifluoroacetate. { 2 - [3- (4-tert-Butylf-enylcarbonyl-amino) phenyl] -α-methylethyl} -N-? Ropil- [l- (ethoxycarbonyl) piperidin-4-ylmethyl] amine, M * H 522. EXAMPLE 6 Preparation of a compound of formula I as described in scheme H 6A. (S) -N- (3- f4- ([f2- (2,3-dihydrobenzofuran-5-yl) -1-methylethyl-ethylaminolmethyl) -piperidin-1-ill-3-oxopropyl) methanesulfonamide To a solution of N -terc-butoxycarbonyl-ß-alar.ina (0.31 grams, 1.65 mmol) in dichloromethane (5 ml) was added N, N'-carbonyldiimidazole (0.3 grams, 1.85 mmol). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a solution of (S) -N- [2- (2,3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- (? Iperidin-4-ylmethyl) plate (0.5 grams, 1.65 mmol) in dichloromethane (2 ml) The reaction mixture was stirred for 16 hours, the solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with 2% methanol in dichloromethane containing 0.1% hydroxide. The appropriate fractions were combined and concentrated to give (S) -3-tert-butoxycarbonylamino-l- [4- ( { [2- (2,3-di-hydrobenzofuran-5-yl) -1 -methylethyl] -ethylaminojmethyl) -piperidin-1-yl] propan-1-one, in the form of a solid (0.76 grams, 97%).

To (S) -3-tert-butoxycarbonylamino-l- [4- ( { [2- (2, 3-dihydrobenzofuran-5-yl) -l-methylethyl] ethylaminojmethyl) -piperidin-1-yl ] propan-1-one (0.76 grams, 1.60 mmol) was added 20% tri-fluorouracetic acid (20 ml). The reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane and 1 N sodium hydroxide. The organic layer was washed with water, dried with potassium carbonate and concentrated to give the (S) -3-amino-1- [4- ( { [2- (2,3-dihydrobenzofuran-5-yl) -1-methyl-ethyl-ethylamino-methyl) -piperidin-1-yl] -propan-1-one, in the form of an oil (0.59 grams) , 99%), M * H 373. To (S) -3-amino-1- [4- ( { [2- (2, 3-dihydrobenzofuran-5-yl) -l-methylethyl] ethylamino} methyl) piperidin-1-yl] propan-1-one, (0.4 grams, 1.07 mmol) and diisopropylethylamine (0.21 grams, 1.62 mmol) in dichloromethane (10 ml) at 0 ° C methanesulfonyl chloride (0.16 grams) , 1.39 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was washed with water, dried with potassium carbonate and concentrated to obtain a residue which was purified by flash crapatography on silica gel, using 3% methanol in dichloromethane containing 0 1% ammonium hydroxide. The appropriate fractions were combined and evaporated obtaining (S) -N-. { 3- [4- ( { [2- (2, 3-dihydrobenzofuran-5-yl) -l-methylethyl] -ethylaminojmethyl) -piperidin-1-yl] -3-oxopropyl} methanesulfon-amide, in the form of an oil (0.32 grams, 66%), M * H 452.

Analysis in% of the hydrochloride eal found: C, 51.83, -H, 7.38; N, 7.87; Theory: C, 51.82; H, 7.56; N, 7.88. 6B. Similarly, substituting (S) -N- [2- (2, 3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine with other compounds of formula , optionally substituting the methanesulfonyl chloride with other chlorae, and following the procedures described above in Example 6A, the following compounds of the formula: N- Hydrochloride were prepared. { 1- [4- ( { [2- (3-trifluoromethylphenyl) -1-methylethyl] ethylamins.} methyl) piperidin-1-yl] -3-oxo-propyljmetane sulfonamide, M * H 478; N- hydrochloride. { l- [4- ( { [2- (3-trifluoromethylphenyl) -1-methylethyl] ethylaminojmethyl) piperidin-1-yl] -3 -oxo-propyl} -N-methyl-methanesulfonamide, M * H 492; N- hydrochloride. { l- [4- ( { [2- (3-trifluoromethyl-enyl) -1-methylethyl] -ethylamino} methyl) piperidin-1-yl] -3-oxo-propyl} -N, N-dimethyl-methanesulfonamide, M * H 507; Hydrochloride of (S) -N-. { 1- [4- ( { [2- (3-trifluoromethylphenyl) -1-methylethyl] ethylaminojmethyl) piperidin-1-yl] -3-oxo-propyl-4-methylphenylsulfonamide, M * H 554; N- hydrochloride. { l- [4- ( { [2- (3-trifluoromethyl) enyl) -1-methylethyl] ethylamino} methyl) piperidine-1-carbonyl] -2-methanesulfonyl-ethyl-methane sulfonamide, M * H 571; Hydrochloride of (S) -N-. { 1- [4- ( { [2- (3-chlorophenyl) -l-methylethyl] ethylaminojmethyl) iperidine-1-carbonyl] -3-methanesulfonyl-propyl} -methansulfonamide, M * H 536; Hydrochloride of (S) -N-. { 1- [4- ( { [2- (3-chlorophenyl) -1-methyl-ethyl] ethylamino} methyl) piperidine-1-carbonyl] -3-methanesulfinyl-propyl} -metanesulfonamide, M * H 520; Hydrochloride of (S) -N-. { 1- [4- ( { [2- (3-chlorophenyl) -l-methylethyl] ethylamino.} methyl) piperidine-1-carbonyl] -3-methanesulfonyl-propyl} -methansulfonamide, M * H 536; and (?) -N- hydrochloride. { 2- [4- ( { [2- (2,3-dihydrobenzofuran-5-yl) -l-methylethyl] ethylamino} methyl) piperidin-1-yl] -1,1-dimethyl-2-oxo -ethyl-J-methanesulfonamide, M * H 466. EXAMPLE 7 Preparation of compounds of formula VII as disclosed in Scheme I Route (a) 7A. (S) -N- f2- (2, 3-dihydrobenzofuran-5-yl) -l-methylethyl-Ne il- (1-methanesulfonyl-piperidin-4-ylmethyl) amine The (S) -N- [2 - (2,3-dihydrobenzofuran-5-yl) -1-methylethyl] ethylamine (24 grams, 0.117 moles) in dichloroethane (300 ml), and eiodic triacetoxyborohydride (37.2 grams, 0.176 moles) was added. After stirring for 5 minutes N-methanesulfonyl-piperidine-4-carboxaldehyde (22.4 grams, 0.117 moles) was added, and the mixture was stirred for a further 2 hours. HE added 5% sodium carbonate (600 ml) and the mixture was extracted with dichloromethane. Evaporation of the solvent provided an oil which was recrystallized from ether to obtain (S) -N- [2- (2,3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- (1-methanesulfonylpiperidine). 4-ylmethyl) amine (28 grams, 63%), mp 99-101 ° C. 7B. (S) -N- f2- (2, 3-dihydrobenzofuran-5-yl) -l-methylethyl-N-ethyl- (1-methansulphyl-piperidin-4-ylmethyl) amine hydrochloride The (?) - was dissolved N- [2- (2, -dihydrobenzofuran-5-yl) -1-methylethyl] -N-ethyl- (1-methanesulfonyl-piperidin-4-ylmethyl) amine (0.9 l3 grams, 2.4 mmol) in hot methanol (20 mL). ml). To this solution was added 1.0 M hydrogen chloride in ethyl ether (2.5 ml). The solvent was removed under reduced pressure. The residue was dissolved in hot 2-butanone (.0 ml). After 15 hours at 22 ° C, the crystals were collected and dried under vacuum to obtain (S) -N- [2- (2,3-dihydro-benzofuran-5-yl) -1-methyl-ethyl] -hydrochloride] N-ethyl- (1-methanesulfonyl-p? Peridin-4-ylmethyl) amine (0.99 grams, 99%), m.p. 112-114 ° C, M "H 381. 7C Phosphate of (S) -N-> 2- (2,3-dihydrobenzofuran-5-yl) -1-methylethyl-N-ethyl- (l-methanesulfonyl-piperidin-4-) ilmethyl) amine The (S) -N- [2- (2,3-dihydrobenzofuran-5-yl) -1-methylethyl] -N-ethyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine was dissolved (0.4 grams, 1.05 moles) in hot 10% aqueous ethanol (10 ml). To this solution 85% phosphoric acid (0.122 grams, 1.06 mmol) was added. The solution was kept at 22 ° C for 16 hours. The deposited crystals were collected and dried in vacuo at 70 ° C to obtain (S) -N- [2- (2,3-dihydro-benzofuran-5-yl) -l-methylethyl] -N-ethyl- phosphate. (1-methanesulfonyl-piperidin-4-ylmethyl) amine (0.454 grams, 97%), mp 209 -210 ° C. 7D. Similarly, substituting (S) -N- [2- (2,3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine for other compounds of formula 4 , optionally substituting the methanesulfonyl chloride with other chlorides, and following the procedures described above in examples 7A, 7B or 7C, the following compounds of the formula If were prepared: Dibenzoyl-L-tartrate N- hydrate. { 2- [4- (2, 2, 2-trifluo-roe oxy) phenyl] -l-methylethyl} -N-propyl- (1-methanesulfonyl-piperidin-methylmethyl) amine, M * H 451; N- [2- (3-trifluoromethylphenyl) -l-methylethyl] -N-ethyl- (l-methanesulfonyl-piperidin-4-ylmethyl) amine hydrochloride, M * H 407; (S) -N- [2- (3-Trifluoromethyl-phenyl) -l-methylethyl] -N-ethyl- (1-methanesulfonyl-piperidin-phenylmethyl) hydrochloride, [c *] D2s + 10.2 ° (c 1.0 CH. OH); M * H 407; (R) -N- [2- (3-trifluoromethylphenyl) -l-methylethyl] -N-ethyl- (1-methanesulfonyl-piperidin-4-ylmethyl) amine hydrochloride, a] D "- 8.86 ° (c 1.0 CH30H); M * H 407; Dibenzoyl-L-tartrate N- [2- (3-triflusromethyl-phenyl) -l-methylethyl] -N-ethyl- (1-methanesulfonyl-piperidin-4-ylmethyl) amine hydrate, M * H 407; N- [2- (2,3-Dihydrobenzo [1,] dioxin-5-yl) -l-methylethyl] -N-ethyl- (l-methanesulfonyl-piperidin-4-ylmethyl) amine hydrochloride, M * H 397; (S) -N- [2- (2,3-Dihydrobenzo [1,4] dioxin-6-yl) -l-methylethyl] -N-ethyl- (1-methansulfonylpiperidin-4-ylmethyl) lamellar hydrochloride, [ a] D2S + 11.2 ° (c 1.0 CH, 0H); M * H 397; Dibenzoyl-L-tartrate hydrate of N- [2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -l -methylethyl] -N-ethyl- (1- me ansulfonyl-piperidin-4-ylmethyl) amine, M * H 397; Dibenzoyl-L-tartrate hydrate of N- [2- (3-trifluoromethyl-phenyl) -l- methylethyl] -N-ethyl- (1-methansulfonylpiperidin-4-ylmethyl) amine, M * H 407; N- [2- (3-chlorofenyl) -l-methylethyl] -N-ethyl- (l-) hydrochloride methanesulfonylpiperidin-4-ylmethyl) amine, M * H 373; (S) -N- [2- (3-chlorofenyl) -l-methylethyl] -N-ethyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride , [a] DS + 11.2 ° (c 1.36 CH30H), M * H 373; (R) -N- [2- (3-chlorofenyl) -l-methylethyl] -N-ethyl- (l-methanesulfonylpiperidin) hydrochloride -4-ylmethyl) amine, [cv] D25-9.4 ° (c 0.42 CH30H), M * H 373; N- [2- (3-amino-eul-onyl-4-methoxy-enyl) -1-methylethyl] -N-hydrochloride] -propyl- [1- (tert-but oxycarbonyl) piperidin-4-ylmethyl] amine, M * H 484; Hydrochloride? N- [2- (3-nitrophenyl) -l-methylethyl] -N-pro-pyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine, M * H 384; N- [2- (3-aminosulfonyl-4-methoxyphenyl) -1-methylethyl] -N-propyl- (l-methanesulfonyl-piperidin-4-ylmethyl) amine hydrochloride, M * H 462; i- (R) -N- [2- (2, 3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- (1-methanesulfonyl-pi? eridin-4-ylmethyl) amine (28 gram, 63%), [a] ,, 25 - 9 ° (CIO CH.OH); M * H 381; N- [2- (2,3-Dihydrobenzofuran-5-yl) -l-methylethyl] -N-cyclopropylmethyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, M * H 407; N- [2- (2, 3-dihydrobenzofuran-5-yl) -1-methylethyl] -N-propyl- (1-methanesulfonyl-piperidin-4-ylmethyl) amine hydrochloride, M 'H 395; (S) -N- [2- (2, 3-Dihydrobenzofuran-5-yl) -1-methylethyl] -N-propyl- (1-methanesulfonyl-piparidin-4-ylmethyl) amine hydrochloride, M * H 395; N- [2- (Benzo [1,3] dioxol-5-yl) -l-methylethyl] -N-ethyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, M * H 383; N- [2- (2,3-Dihydrobenzo [1,4] dioxin-6-yl) -l-methylethyl] -N-ieopropyl- (1-methanesulfonyl-piperidin-4-ylmethyl) amine hydrochloride, M * H 411; N- [2- (2, 3-dihydrobenzofuran-6-yl) -l-methylethyl] -N-propyl- (1-methanesulfonyl-piperidin-4-ylmethyl) amine hydrochloride, M-H 395; N- [2- (2, 3-dihydrobenzofuran-6-yl) -l-methylethyl] -N-ethyl- (l-methanesulfonyl-piperidin-4-ylmethyl) amine hydrochloride, M * H 381; N- [2- (2, 3-dihydrobenzofuran-6-yl) -l-methylethyl] -N-cyclopropylmethyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, M * H 407; N- [2- (3-Oxo-4H-benzo [1,4] oxazin-6-yl) -1-methylethyl] -N-ethyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, M * H 424.1; N- [2- (4-Methylthiophenyl) -l-methylethyl] -N-ethyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, m.p. 71-72 ° C; N- [2- (Indan-5-yl) -l-methylethyl] -N-cyclopropylmethyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, M * H405; N- [2- (Indan-5-yl) -l-methylethyl] -N-ethyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, M * H 379; N- [2- (Indan-5-yl) -l-methylethyl] -N-propyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, M * H 393; (S) -N- [2- (3, 4-dimethoxyphenyl) -l-methyl-ethyl] -N-ethyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, M * H 399; N- [2- (4-Nitrophenyl) -l-methylethyl] -N-propyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, M * H 398; N-12- (3, 3-dimethyl-2,3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, m.p. 67-69 ° C; N- [2- (3-Nitrophenyl) -l-methylethyl] -N-ethyl- (1-methanesulfonylpiperidin-4-ylmethyl plate, M * H 384; Hydrochloride of (S) -N- [2- (2, 2 -dimethyl-2, 3-dihydrobenzo-furan-5-yl) -l-methylethyl] -N-ethyl- (1-methanesulfonylpiperidin-4-ylmethyl (amine, M * H 409; N- [2- (benzofuran -5-yl) -l-methylethyl] -N-ethyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine, M * H 379; N- [2- (5,6,7,8-tetrahydronaphthalen-2-yl) -1-methylethyl] -N-ethyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, M "H 393; Hydrochloride ? e N- [2- (naphthalen-2-yl) -l-methylethyl] -N-ethyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine, M * H 389; N- [2- (Chroman-6-yl) -l-methylethyl] -N-ethyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, M * H 395. Route (b) 7E. Alternative preparation of the hydrochloride e (S) -N-f2- (2,3-dihydrobenzofuran-5-yl) -l-methylethyl-N-ethyl- (1-methanesulfonylPYperidin-4-ylmethyl) A solution of chloride of l- methanesulfonylpiperidine-4-carbonyl, in dichloromethane (10 ml) was added to a suspension of (S) -N- [2- (2,3-dihydrobenzofuran-5-yl) -1-methylethyl] -ethylamine hydrochloride (1.21 grams) , 5 mmol) in dichloromethane (10 ml). The mixture was cooled to O'C, and criethylamine was added dropwise (1.7 ml, 12 mmoles). When the addition was complete, the mixture was warmed to room temperature and stirred for about 1 hour. Saturated ammonium chloride was added (20 ml) and the separated organic layer was extracted once with dichloromethane (20 ml). The combined organic layers were washed with IN hydrochloric acid (25 ml), saturated sodium bicarbonate (25 ml), dried with magnesium eulfate and concentrated to give (S) -N- [2- (2,3-dihydrobenzofuran-5-yl) -1-methylethyl] -N-ethyl- (l) -metanesulfonylpiperidin-4-ylcarbonyl) amine, in the form of a whitish foam (2.21 g). A solution of (S) -N- [2- (2, 3-dihydrobenzofuran-5-yl) -1-methylethyl] -N-ethyl- (1-methanesulfonylpiperidin-4-ylcarbonyl) amine (2.21 g, 5 mmol) in tetrahydrofuran (5 ml), was added dropwise to a suspension of lithium aluminum hydride (0.38 g, 10 moles) in tetrahydrofuran (10 ml) at 0 ° C, under nitrogen . The mixture was heated to reflux temperature for 2 hours and cooled to room temperature. Water (380 ml) was added dropwise to the mixture, followed by 15% sodium hydroxide (380 ml) and additional water (1550 μl). The mixture was stirred at room temperature for approximately 15 minutes and filtered. The filtrate was washed and rinsed with dichloromethane. Evaporation of the solvent provided a colorless oil that solidified upon standing. Recrystallization with ethyl acetate / hexanes (1: 1) gave the (S) -N- [2- (2,3-dihi- drobenzofuran-5-yl) -l-methylethyl] -N-ethyl- (1-methanesulfonyl-piperidin-4-ylmethyl) amine in the form of colorless crystals (1.02 g). Route (c) 7F. Dibenzoyl-L-tartrate of N-f2- (-methoxyphenyl) -l-methylethyl-N-ethyl- (l-isopropylsulfonylPYPeridin-4-ylmethyl) amine To a mixture of N- [2- (4-methoxyphenyl) hydrochloride - 1-Methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine (0.2 grams, 0.55 mmol) in dichloromethane (10 ml), triethylamine (0.4 ml, 3 mmol) and isopropylsulfonyl chloride (0.1 ml, 0.89 g. mmoles). The reaction mixture was stirred at 22 ° C for 16 hours. The residue was concentrated under reduced pressure and partitioned between ethyl acetate and 5% sodium bicarbonate solution. The dried organic phase (anhydrous magnesium sulfate) was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel eluting with 50% ethyl acetate / hexane containing 0.5% ammonium hydroxide. The product was obtained as a dibenzoyl-L-tartrate salt, obtaining N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (1-ieopropyle-sulfonylpiperidin-4-ylmethyl) dibenzoyl-L-tartrate. amine (0.211 grams, 51%), M * H 397 (free bae). 7G In a manner similar, substituting N- [2- (4-methoxy-phenyl) -l-methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine for other compounds of formula la, optionally substituting the ieopropyl eulphonyl chloride with other sulfonyl chlorides and Following the procedures described above in Example 7F, the following compounds of formula If were prepared: N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, m.p. 85-86 ° C; (S) -N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride, [α] D 25 + 11.8 ° (c 1, CH.OH); (R) -N- [2- (4-methoxy-f-enyl) -l-methylethyl] -N-ethyl- (l-m-tatansulfonyl-pip-8 -ridin-4-ylmethyl) -amine hydrochloride, [α] 025-12.0 ° (c 1) , CH30H); N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (l-methanesulfonylpi? Eridin-4-ylmethyl) amine dibenzoyl-L-tartrate, p.f. 119-120 ° C; N- [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- (1-trifluoromethylsulfonylpiperidin-4-ylmethyl) amine dibenzoyl-L-tartrate, M * H 423; Dibenzoyl-L-tartrate of N- [2- (3-trifluoromethyl-phenyl) -1-methylethyl] -N-ethyl- (1-y-eopropyl-1-eyl-phenyl-idin-4-ylmethyl) amine, W H 435; N- [2- (2, 3-Dihydrobenzo [1,4] i-oxin-6-yl) -l-methylethyl] -N-ethyl- (1-isopropyle-sulfonyl-piperidin-4-ylmethyl) dibenzoyl-L-tartrate ) amine, M * H 425; N- trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (4-methylphenyl-sulfonyl) piperidin-4-ylmethyl) amine, M * H 604; N- trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (isopropylsulfonyl) piperidin-4-ylmethyl] amine, M * H 556; and N- Trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (methanesulfonyl) piperidin-4-ylmethyl] amine, M * H 528. 7H. N- f2- (4-methanesulfoniiphenyl) -l-methylethyl-N-ethyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride A solution of N- [2- (4-methylthiophenyl) -1-methylethyl] -N-ethyl- (l-methanesulfonyl-piperidin-4-ylmethyl) amine hydrochloride (0.25 grams, 0.6 mmol). in 30% aqueous methanol (7 ml) was added to a solution of Oxona® (0.73 grams, 1.2 rubles) in water (10 ml) at 0 ° C. After 2 hours at 0 ° C, the volume was reduced to 10 ml and the solution was made strongly basic with 3 N sodium hydroxide. The mixture was extracted with ethyl ether (50 ml). The organic phase was dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The product was isolated as a hydrochloride salt with ethyl ether to obtain N- [2- (4-methanesulfonylphenyl) -l-methylethyl] -N-ethyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine hydrochloride (0.25 gram). , 92%), pf 92 - 93 ° C. EXAMPLE 8 Preparation of a compound of formula Ig as described in scheme J 8A. (S) -N- f2- (2,3-dihydrobenzofuran-5-yl) -l-methylethyl -N- ethyl- fl- (morpholin-4-sulphonyl) pyoeridin-4-ylmethylamine To a solution of (* S) -N- [2- (2,3-dihydrobenzofuran-5-yl) -l-methylethyl] -N- ethyl- (pi? eridin-4-ylmethyl) amine (0.2 grams, 0. 66 mmoles) and triethylamine (0.15 grams, 1.48 mmoles) in dichloromethane (4 ml) at 0 ° C, a solution of chlorosuiphonic acid (0.08 grams, 0.66 mmoles) in dichloromethane (0.5 ml) was added dropwise. The mixture was stirred at room temperature for 16 hours, and the solvent was removed under reduced pressure. To the residue was added benzene (4 ml) and phosphorus pentachloride (0.14 grams, 0.67 mmole). The mixture was refluxed for 2 h. The solvent was removed at reduced pressure and the residue was partitioned between ethyl acetate and iodomodium hydroxide. The organic layer was washed with brine, dried with sodium sulfate and concentrated to obtain (S) -N- [2- (2,3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- (1 -chlorosulfonylpiperidin-4-ylmethyl) amine, in the form of a viscous oil (0.18 grams, 70%), M * H 401. A mixture of (S) -N- [2- (2, 3-dihydrobenzofuran-5-yl) ) -1- ethylethyl] -N-ethyl- (1-chlorosulfonylpiperidin-4-ylmethyl) amine (0.18 grams, 0.45 mmol), morpholine (0.04 grams, 0.45 mmol), and diisopropylethylamine (0.12 grams, 0.93 mmol) in Tetrahydrofuran (10 ml) was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was dried with potassium carbonate and evaporated to obtain leaving a residue which was purified by flash chromatography on silica gel eluting with 40% ethyl acetate in hexane. The appropriate fractions were combined and evaporated obtaining (S) -N- [2- (2,3-dihydrobenzofuran-5-yl) -1-methyl-ethyl] -N-ethyl- [1- (morpholine-4- sulfonyl) -piperidin-4-ylmethyl] amine, in the form of an oil, (0.17 g, 85%), M * H 452.

Analysis in% of the hydrochloride salt: found: C, 54.06; H, 7.62; N, 8.24. Theory: C, 54.01; H, 8.00; N, 8.22. 8B. Similarly, substituting (S) -N- [2- (2,3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine on the other hand comprises the formula , optionally substituting the morpholine for other amines, and following the procedures described above in Example 8A, the following compounds of formula IQ were prepared: N- [2- (3-trifluoromethylphenyl) -1-methylethyl Dibenzoyl-L-tartrate. ] -N-ethyl- [1- (dimethylaminosulfonyl) -piperidin-4-yl ethyl] amine, M * H 436; N- [2- (2,3-Dihydrobenzo [1,4] dio-xin-6-yl) -1-methylethyl] -N-ethyl- [1- (dimethylaminosulfonyl) piperi-din-dibenzoyl-L-tartrate 4-ylmethyl] amine, M * H 426; N- [2- (4-trifluoromethylphenyl) -1-methylethyl] -N-ethyl- [1- (dimethylaminosulfonyl) -piperidin-4-ylmethyl] amine dibenzoyl-L-tartrate, M * H 436; (S) -N- [2- (2, 3-dihydrobenzofuran-5-yl) -1-methylethyl] -N-ethyl- [1- (pyrrolidin-1-sulfonyl) iperidin-4-hydrochloride ilmethyl] amine. Analysis in%: found: C, 57.01; H, 7.93; N, 8.53. Theory: C, 56.99; H, 8.19; N, 8.67; M * H 436; (S) -N- [2- (2, 3-dihydrobenzofuran-5-yl) -1-methylethyl] -N-ethyl- [1- (1, l-dioxo-thiomorfoiin-4-eulphonyl) piperidinyl hydrochloride 4-ylmethyl] amine, M "H 500; (S) -N- [2- (2,3-dihydrobenzofuran-5-yl) -1-methylethyl] -N-ethyl- [1- (thiomorpholin-4) hydrochloride -sulfonyl) iperidin-4-ylmethyl] amine Analisys in%: found: C, 53.47; H, 7.56; N, 8.08, Theoretical: C, 53.46; H, 7.69; N, 8.13; M * H 468; N- trifluoroacetate. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (dimethylamino-sulfonylD iperidin-4-ylmethyl] amine; M * H 557. 8C.Acid 3- f4- (.sup.2- (2,3-dihydrobenzofuran-5-yl) -l- methylethyl ethylamino.} methyl) iperidin-1-sulfonylamino-1-pro-ionic A mixture of β-alanine (0.05 grams, 0.56 mmol) and tri-methylethylycyanide (0.11 grams, 1.15 mmol) in acetonitrile was heated to reflux for one hour. A solution of (S) -N- [2- (2, 3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- (l-chlorosulfonylpiperidin-4-ylmethyl) amine (0.2 grams, 0.50) was added. mmoles) in acetonitrile, and the mixture was refluxed for a further 5 hours. The reaction mixture was quenched with methanol and evaporated to a residue which was purified by RP HPLC, with a Vydac C4 column using a gradient of 5-65% water / acetonitrile containing 0.1% trifluoroacetic acid. The appropriate fractions were collected and evaporated to give (S) -3- [4- ( { [2- (2,3-Dihydro-benzofuran-5-yl) -l-methylethyl] ethylamino} methyl) piperidin-1-sulfonylamino] -propionic salt form of trifluoroacetic acid (0.14 grams, 51%), M * H 454. Analysis in%: found: C, 48.22; H, 5.88; N, 7.00. Theory: C, 48.08; H, 5.89; N, 6.73. EXAMPLE 9 Preparation of a compound of formula J_h as described in scheme K 9A. (S) -N-. { 2-f4- ( { F2- (2,3-dihydrobenzof uran-5-yl) -1-methylethyl ethylaminojmethyl) -oiperidin-1-sulfonyl-yl-methanesulfonamide To a cold solution of 2-chloroethylsulfonyl chloride (0.32 grams, 1.99 mmole) in dichloromethane (5 ml), a solution of (S) -N- [1- (2,3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- ( piperidin-4-ylmethyl) amine, (0.60 gram, 1.99 mmol) in dichloromethane (2 ml). The reaction mixture was stirred at room temperature for 16 hours, washed with water, dried with potassium carbonate and the solvent was evaporated to a residue. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 25-50% hexane in ethyl acetate. The appropriate fractions were combined and evaporated to yield (S) -N- [2- (2, 3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- (1-ethene-sulfonyl-piperidin-4-ylmethyl) -amine. , in the form of an oil (0.36 gram, 46%).

To a solution of methanesulfonamide (0.18 grams, 1.84 mmol) in dimethylformamide (2 ml) was added 60% eiodine hydride (0.048 gram, 1.2 mmol) in mineral oil. The reaction mixture was heated to 120 ° for 30 minutes, and cooled to 100 ° C. A solution of (S) -N- [2- (2,3-dihydro-benzsfuran-5-yl) -l-methylethyl] -N-ethyl- (1-ethersulfonylpiperidin-4-ylmethyl) amine (0.36 grams) was added. , 0.92 mmole) in dimethylformamide, all at once. The reaction mixture was heated at 100 ° C for 40 minutes. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was treated with potassium carbonate and the residue was evaporated leaving a residue which was purified by flash chromatography eluting with ethyl acetate. The appropriate fractions were combined and evaporated to yield (S) -N- (2- [4- ( { [2- (2,3-dihydrobenzofuran-5-yl) -l-methylethyl] ethylamino} methyl. ) piperidin-1-sulfonyl] -ethyl.} - methanesulfonamide, in the form of an oil (0.32 grams, 71%). M * H 488. Analysis in% of the hydrochloride salt: found: C, 8.26; H, 7.09; N, 8.10, Theoretical: C, 48.59; H, 7.42; N, 7.73, 9B. Similarly, substituting 2-chloroethylsulfonyl chloride for 3-chloro-3-chloride -chloropropylsulfonyl, and following the procedures described above in Example 9A, prepared the (S) -N-. {2- 2- [4- ( { [2- (2,3-dihydroben-zofuran-5- il) -1-methylethyl] ethylamino.) methyl) piperidin-1-sulfonyl] propyl.} - methanesulfonamide, M * H 502.

EXAMPLE 10 Preparation of a compound of formula Xj. as described in the scheme L Route (a) 10A. N-Í2- [3- (furan-2-carbonylamino) phenyl-1-methylethyl-N-propyl- (1-methanesulfonyl-Piperidin-4-ylmethyl) amine N- [2- (3-nitrophenyl) - 1-methylethyl) -N-propyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine (500 mg) and 10% on carbon palladium (59 mg), with ethanol (25 ml), and hydrogenated at 40 p.s.i. for 18 hours. The resulting solution was filtered and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (10 ml) and a solution of potassium carbonate (500 mg) in water (5 ml) was added. The mixture was cooled in an ice bath. 2-furoyl chloride (0.07 ml) was added and the whole mixture was stirred for 3 hours. The layers were separated and the organic layer was dried with magnesium sulfate, filtered and the solvent was removed. The resulting oil was dissolved in isopropanol and lM hydrochloric acid (1.5 ml) in ether was added. The resulting product was filtered and dried in a desiccator to obtain N- hydrochloride. { 2- [3- (furan-2-carbonylamino) phenyl] -l-methylethyl} -N-propyl- (l-methanesulfonyl-piperidin-4-ylmethyl) amine, M * H 462. 10B. Similarly, substituting N- [2- (3-nitro-phenyl) -l-methylethyl) -N-propyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine for other amines, and optionally substituting 2-furoyl chloride with other carbonyl chlorides, and following the procedures described above in Example 10A, the following compounds of formula Ij were prepared. N- hydrochloride. { 2- [3- (cyclohexancarbomlammo) phenyl] - 1-met? Let? L} -N-propyl- [1- (morph olm-4-carbon? L) p? Pepdm-4-ylmethyl] amine, M * H 513, N- hydrochloride. { 2- [3- (2, 5-d? Oxo-p? Rrol? Dm-l-carbonylamino) phenyl] -1-met ilet ll} -N-propyl- [1- (morph olir-4-carbon? L) p? Pepd? N-4-? Lmet? L] amine, M * H 485, N- hydrochloride. { 2- [4- (cyclohexanedcarbonylamino) f-enyl] -1-methyl-1-yl-N-prop l- [1- (morpholm-4-carbonyl) p-pen-4-ylmethyl] amine, M * H 513, N- Hydrochloride. { 2- [4- (ethylcarboplamino) f-enyl] -1-methylethyl-J-N-propyl- [1- (morpholine-4-caroon? L) p? Per? D? N-4-ylmethyl] amine M * h 459, N- (2- [- (morphine-4-carbon? lammo) f-nyl] -1-met? let? l J-N-propyl- [1- (morpholm -4-carbon? L) p? Per? D? N- 4-? Lmet? L] amine, M * H 516, N- { 2- [- (3-methox? Phen? Lcarbon? Lammo) f enyl] - 1-met? let? lJ-N-propyl- [1- (morpholine-4-carbon? l) p? per? dm-4-? lmethyl] amine, M * H 537, N - { 2- [3- (4-methox? Femlcarbon? Lam? No) phen? L] - 1-met let. L.} - N-propyl- [1- (morpholine-4-carbon l) p? per? d? n-4-? lmet? ll amine, M * H 537, N-. { 2- [3- (2-methoxyphenylcarbonylamino) phenyl] -l-methylethyl} - N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * k H 537; N-. { 2- [3- (furan-2-carbonylamino) phenyl] -l-methylethyl} -N- 5-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M "H 497; N-. { 2- [3- (naphthalene-2-carbonylamino) phenyl] -l-methylethyl} -N- propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M 'H 557; l 10 N-. { 2- [3- (thiophene-2-carbonylamino) phenyl] -l-methylethyl} -N- propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M 'H 513; N-. { 2- [3- (naphthalene-1-carbonylamino) phenyl] -l-methylethyl} -N- propyl- [1- (morpholin-4-carbonyl) pi? Eridin-4-ylmethyl] amine, M 'H ,557; N- trifluoroacetate. { 2 - [3 - (4-Nitrophenylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidn-4-ylmethyl] amine, M * H 551; N- trifluoroacetate. { 2 - [3 - (phenylcarbonylaryrin) phenyl] -20 l -methylethyl} -N-propyl - [1 - (morphine-4-carbonyl) iperidin-4-ylmethyl] amine, M-H 507; N-. { 2 - [3 - (4-chlorofenylcarbonylamino) phenyl] -l-r.-ethylethyl} -N- propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 541; 25 N-. { 2- [3- (-bromophenylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 585; N-. { 2- [3- (4-methylphenylcarbonylamino) phenyl] -1-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M "H 521; N-. {2- [3- (isopropylcarbonylamino) phenyl] -l-methylethyl hydrochloride} -N-propyl- (l-methanesulfonyl-piperidin-4-ylmethyl) amine, M * H 438; 'N- [2 - [3- (phenylethylcarbonylamino) phenyl] -l-methylethyl.} - N-propyl - (1-methanesulfonylpiperidin-4-ylmethyl) mine, M * H 500; N-. { 2- [3- (Butylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- (l-methanesulfonyl-piperidin-4-ylmethyl) amine, M * H 452; N-. { 2- [3- (furan-2-carbonylamino) phenyl] -l-methylethyl} -N-propyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine, M * H 462; N-. { 2- [3- (4-fluorophenylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine, M * H 490; N- hydrochloride. { 2- [3- (Nonylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- (l-methanesulfonyl-piperidin-4-ylmethyl) amine, * H 522; N- hydrochloride. { 2- [3- (cyclohexanedcarbonylamino) phenyl] -1-methylethyl} -N-ethyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine, M "H 464; N- { 2- [4- (cyclohexanecarbonylamino) phenyl] -l-methylethyl}. N-propyl- (l -metanesulfonylpiperidin-4-ylmethyl) amine, M * H 478; N- hydrochloride. { 2- [4- (furan-2-carbonylamino) phenyl] -1-methylethyl} -N-propyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine, M * H 462; and N- Hydrochloride. { 2- [3- (furan-2-carbonylamino) phenyl] -1-methylethyl} -N-ethyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine, M * H 448. Route (b) 10C. N- (2- Í3- (4-sulfamoylphenylcarbonylamino) phenyl-1-methyl-ethyl) -N-propyl- fl- (morpholin-4-carbonylPJperidin-4-methylmetine amine N- [2- (3-aminophenyl) ) -l-methylethyl] -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, (78 mg) in N, -dimethylformamide (2.5 ml) and 4-sulfamidobenzoic acid (40 mg) was added. To this solution was added in the following order 4-methylmorpholine (0.03 ml), 1-hydroxybenzotriazole (27 mg), and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (40 mg). The resulting mixture was stirred at room temperature under nitrogen for 18 hours, and then partitioned between water and ethyl acetate. The organic layer was separated and dried with sodium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to obtain N-. { 2- [3- (4-sulfamoylphenylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl) mine (70 mg), M + H 586. 10D. Similarly, substituting N- [2- (3-amino-phenyl) -l-methylethyl] -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, for other amines of Formula 4, and 4-eulphidoidobenzoic acid being substituted by another benzoic acid derivative and following the procedures described above in Example 10C, the following compounds of formula Ij were prepared: N- hydrochloride. { 2- [3- (4-eulphamoylphenylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 586; N- hydrochloride. { 2- [3- (2, 3-dihydrobenzofuran-5-carbo-ni-lamino) phenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] mine, M * H 541; N- hydrochloride. { 2- [3- (lH-pyrazol-4-carbonylamino) f-nyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 497; N- hydrochloride. { 2- [3- (l-Oxido-pyridine-4-carbonylamino-phenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbo-nyl) piperidin-4-ylmethyl] amine, M * H 524; N- hydrochloride. { 2- [3- (2,3-dihydrobenzo [1,4] dioxin-6-carbonylamino) phenyl] -l-methylethyl} -N-propyl- [1- (morphine-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 565; N- hydrochloride. { 2- [3- (1H-1, 2,4-triazole-3-carbonylamino-phenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbo-nyl) piperidin-4-ylmethyl] amine, M * H 498; Hydrochloride of (R) -N-. { 2- [3- (4-sulfamoylphenylcarbonyl-amino) phenyl] -1-methylethyl} -N-propyl- [1- (isopropylaminocarbonyl) piperidin-4-ylmethyl] amine, M * H 558; and Chlorohydrate e (R) -N-. { 2- [3- (imidazole-4-carbonylamino) phenyl] -l-methylethyl} -N-propyl- [1- (i-propyl aminocarbonyl) piperidin-4-ylmethyl] amine, M * H 469. Route (c) 10E. (R) -N- (2- f3- (4-methoxyphenylcarbonylamino) phenyl) -1-methylethyl-N-propyl- fl- (morpholin-4-carbonyl) or iperidin-4-. ,,. Imetill amine The hydrochloride of (R, R) -N- [2- (4-nitrophenyl] -l-methylethyl] -N-propyl- (1- (phenylethyl) amine, in ethanol (100 ml) and water was dissolved (16 ml) To this solution was added iron powder (2.44 g) and ammonium formate (2.25 g) .The mixture was refluxed for 3 hours, cooled to room temperature and filtered through a filter. The filtrate was evaporated in vacuo, and the residue was partitioned between ethyl acetate and dilute sodium hydroxide solution.The organic layer was dried with sodium sulfate, filtered and the solvent was removed under vacuum to obtain the ( R, R) -N- [2- (4-aminophenyl) -1-methylethyl] -N-propyl- (1-phenylethyl) amine, in the form of a yellow syrup (2.9 g). (R, R ) -N- [2- (4-aminophenyl) -l-methylethyl] -N-propyl- (1-phenylethyl) amine (0.95 g) was dissolved in ethyl acetate (50 ml) and potassium carbonate acid solution ( 50 ml).

The mixture was cooled in an ice bath and 4-methoxybenzoyl chloride (0.55 g) was added. The mixture was stirred for 18 hours and the layers separated. The organic layer was dried with sodium sulfate, filtered and the solvent removed in vacuo. The residue was dissolved in isopropanol and 1M hydrochloric acid (1 equiv.) Was added. The slow addition of ether induced crystallization. The crystals were filtered and dried in a desiccator for 18 hours, yielding the hydrochloride of (R.R) -N-. { 2- [3- (4-methoxyphenylcarbonylamino) phenyl] -l-methylethyl} - N-propyl- (1-phenylethyl) amine (0.98 g), M * H 431. The (R, R) -N-. { 2- [3- (4-methoxyphenylcarbonylamino) phenyl] -1-methylethyl} -N-propyl- (1-phenylethyl) amine (0.98 s) was dissolved in ethanol (100 ml) and added 10% palladium on charcoal (0.1 g).

To this mixture, ammonium formate (1.2 g) was added, and the mixture was heated to reflux for 2 hours, cooled to room temperature, and filtered. The filtrate was evaporated in vacuo, and the residue was partitioned between ethyl acetate and dilute sodium hydroxide. The organic layer was dried with sodium sulfate, filtered and the solvent was removed in vacuo to obtain (R) -N-. { 2- [3- (4-methoxyphenylcarbonylamino) phenyl] -l-methylethyl} propylamine. (R) -N-. { 2- [3- (4-methoxy phenyl carboni lamino) phenyl] -l-methylethyl} propylamine (0.32 g), dichloroethane (20 ml) and 1- (mor-folin-4-carbonyl) piperidine-4-carboxaldehyde (0.32 g), were stirred under nitrogen for 30 minutes. It was added Sodium triacetoxyborohydride (0.5 g), and the mixture was stirred at room temperature for about 72 hours. The mixture was diluted with ethyl ether (50 ml) and 10% sodium hydroxide solution (0 ml). The organic layer was dried with sodium sulfate, filtered and the solvent was evaporated in vacuo. The residue was chromatographed, eluting with methanol / dichloromethane obtaining (R) -N-. { 2- [3- (4-methoxyphenylcarbonylamino) phenyl] -1-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, (0.42 g),]] B2S-42 ° (c 1.0 CH.OH); M * H 537. 10F. Similarly, replacing the (R) -N-. { 2- [3- (4-methoxyphenylcarbonylamino) phenyl] -l-methylethyl} propylamine by other compounds of formula. and optionally substituting 1- (morpholin-4-carborityl) piperidine-4-carboxaldehyde, for other compounds of formula 12, and following the procedures described above in example 10E, the following compounds of formula Ii were prepared: Hydrochloride of (S) -N-. { 2- [3- (Cyclohexanecarbonylamino) phenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, [α] -25 + 16.2 ° (c 1.0 CHC13), M * H 513; Hydrochloride of (R) -N-. { 2- [3- (cyclohexanedcarbonylamino) phenyl] -1-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, [a] -25-30 ° (c 1.0 CHC1, M * H 513; hydrochloride of (S) -N - { 2- [3- (furan-2-carbonylamino) phenyl] -l-methylethyl.} - N -propyl- (1-methansulphylpiperidin-4-ylmethyl) amine, M * H 462; (S) -N-. { 2- [3- (4-f luorofenylcarbonylamino) phenyl] -1-methylethylj-N-propyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine, M * H 490; Hydrochloride of (S) -N-. { 2- [3- (tetrahydrofuran-2-carbonylamino) phenyl] -l-methylethyl} -N-propyl- (l-methanesulfonylpiperidin-4-yl ethyl) amine, M * H 466; Hydrochloride of (S) -N-. { 2- [3- (tetrahydrofuran-2-carbonylamino) phenyl] -1-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 501; (S) -N-. { 2- [3- (4-f luorofenylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 525; Hydrochloride of (S) -N-. { 2- [3- (Cyclohexanecarbonylamino) phenyl] -l-methylethyl} -N-propyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine, M * H 478; Hydrochloride of (S) -N-. { 2- [3- (4-f luorofenylcarbonylamino) -4-methoxyphenyl] -l-methylethyl} -N-propyl- (1-methanesulfonyl-piper? Din-4-ylmethyl) amine, M * H 502; Hydrochloride of (S) -N-. { 2- [3-fluorofenylcarbonylamino) -4-methoxyphenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 537; N- hydrochloride. { 2- [3- (morpholin-4-carbonylamino) phenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 516; N-. { 2- [3- (3,4,5-tpmetox? Phen? Lcarbon? Lam? No) phenyl] -1-methylethyl} -N-propyl- [1- (morphine-4-carbonyl)? Per? D? N-4-ylmethyl] amine, M * H 597, N- Hydrochloride. { 2- [3- (3,5-dichlorophenylcarbonylanu.no) phenyl] -l-met? Let? L} -N-prop? L- [1- (morpholine-4-carbon? L) p? Per? Dm-? -imethyl] amine, M * H 575, N- hydrochloride. { 2- [3 - (benzo [1,3] d? Oxol-5-carbon? Lam? -no) phenyl] -1-met? Let? L} -N-propyl- [1- (morph ol? -4-carbon? L) p? Pepdm-4-? Lmet? L] amine, M * H 551, N- hydrochloride. { 2- [3- (4-tr? F luoromethylphenylcarbonyl-ammo) phenyl] -l-me? Let? L} -N-prop? L- [1- (morpholine-4-car-boml) p? Per? Dm-4-? Lmet? L] amine, M * H 575, N- hydrochloride. { 2- [3- (4-tert-butyl-l-enylcarbonylamine) phenyl] -l-met? Let? L} -N-prop? L- [1- (morpholine-4-carbon? L) p? Per? Dm-4-? Lmet? L] amine, M * H 563, N- hydrochloride. { 2- [3- (-metaneulf omlf enylcarbonyl-boni lamino) phenyl] -1-met? Let? L} -N-propyl- [1- (morpholm-4-carboml) p? Per? D? N-4-? Lmet? L] amine, M * H 585, N- Hydrochloride. { 2- [3- (cyclohexancarbonilanyl.no) phenyl] -l-met? Let? L} -N ethyl- [1- (morph olm-4-carbonyl) p? Per? Dm-4-ylmethyl] amine, M * H 499, N- hydrochloride. { 2- [3- (4-met? Lf enylcarboni lamino) f-nil] -l-met? Let? L} -N-et? L- [1- (morpholm-4-carbon? L) p? Per? D? N-4-ylmethyl sheet, M * H 507, N- hydrochloride. { 2- [3- (4-methoxyphenylcarbonylamino) phenyl] -l-methylethyl} -N-ethyl- [1- (morpholin-4-carbonyl) piperidin-4-yl-ylmethyl] amine, M * H 523; N- hydrochloride. { 2- [3- (furan-2-carbonylamino) f-enyl] -1,5-methylethyl} -N-ethyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl sheet, M * H 483; Hydrochloride of (R) -N-. { 2- [3- (4-methanesulfonyl) enylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- (1-methanesulfonyl-piperidin-4-ylmethyl) amine, M * H 550; ) 10 N- Dichloride. { 2- [3- (pyridin-3-carbonylamino) f-enyl] -1-methylethyl} -N-propyl- [1- (morpholin-4 -carbonyl) piper idin-4-ylmethyl] amine, M * H 508; N- hydrochloride. { 2- [3- (4-trifluoromethoxyphenylcarboml-amino) phenyl] -l-methylethyl) -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 591; N- hydrochloride. { 2- [3- (4-ethyl-f-ethylcarbonylamino) f-nyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl-sheet, M * H 535; N- hydrochloride. { 2- [3- (Biphenylcarbonylamino) f-ethyl] -1-20-methylethyl} -N-propyl- [1- (morpholin-4 -carbonyl) piperidin-4-ylmethyl] amine, M * H 583; Hydrochloride of (R) -N-. { 2- [3- (4-tert-Butylphenylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine, M * H 528; 25 Hydrochloride of (R) -N-. { 2- [3- (4-trifluoromethylphenylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- (1-methanesulfonyl-piperidin-4-ylmethyl) amine, M * H 540; N- hydrochloride. { 2- [3- (4-cyanophenylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 532; N- hydrochloride. { 2- [3- (4-propylphenylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 549; N- hydrochloride. { 2- [3- (-butylphenylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 563; Hydrochloride of (R) -N-. { 2- [3- (4-cyanophenylcarbonylamino) phenyl] -l-methylethyl} -N-propyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine, M * H 497; N- hydrochloride. { 2- [3- (4-tert-Butylphenylcarbonylamino) phenyl] -l-methylethyl} -N-butyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 577; N- (2- [3- (4-methoxyphenylcarbonylamino) phenyl-1-methylethyl} -N-butyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 551; N-. {2- [3- (cyclohexanecarbonylamino) phenyl] -l-methylethyl} -N-butyl- [i- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine hydrochloride, M * H 527; N-. {2- [3- (furan- -carbonylamino) phenyl] -1- hydrochloride methylethyl} -N-butyl- [1- (morphine-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 5i ?; N- hydrochloride. { 2- [3- (benzo [1,3] dioxol-5-carbonylamino-phenyl] -1-methylethyl} -N-butyl- [1- (morpholin-4-carbo-nyl) piperidin-4-ylmethyl] amine, M * H 565; N- hydrochloride. { 2- [3- (4-methoxyphenylcarbonylamino) phenyl] -l-methylethyl} -N-pentyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 565; N- dichloride. { 2- [3- (pyridin-4-carbonylamino) f-ethyl] -1-methylethyl} -N-propyl- [1- (morphine-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 508; N- hydrochloride. { 2- [3- (benzo [1,3] dioxol -5-carbonylamino) phenyl] -l-methylethyl} -N-allyl- [1- (morph ol in- 4-carbonyl) piperidin-4-ylmethyl] amine, M * H 549; N- hydrochloride. { 2- [3- (4-trifluoromethyl) enylcarbonyl-amino) phenyl] -l-methylethyl} -N-propyl- [1- (isopropyl aminocarbonyl) piperidin-4-ylmethyl] amine, M * H 547; N-. { 2- [3- (4-me oxycarbonyl] -carbonylamino) phenyl] -1-methylethyl} -N-propyl- [1- (morpholin-4 -carbonyl) piperidin-4-ylmethyl] amine, M * H 537; N-. { 2- [3- (4-hydroxycarbonylphenylcarbonylamino) phenyl] -1-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl) amine, M * H 565; N- hydrochloride. { 2- [3- (2,3-benzo [1,3] dioxol-5-carbo-nylamino) phenyl] -l-methylethyl} -N- (ethylpropyl) - [1- (morpholin-4- carbonyl) piperidin-4-ylmethyl] amine, M * H 579; N- hydrochloride. { 2- [3- (6-oxo-l, 4, 5, 6-tetrahydropyridazin-3-carbonylamino) phenyl] -l-methylethyl} -N-propyl- [1- (diethylaminocarbonyl) piperidin-4-ylmethyl] amine, M * H 513; N- hydrochloride. { 2- [3- (4-fluorophenylcarbonylamino) -4-methoxyphenyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carboniDpiperidin-4-ylmethyl] amine, m.p. 96-102 ° C, M * H 555; Hydrochloride of (R) -N-. { 2- [3- (4-fluorophenylcarbonylamino) -4-methoxy-enyl] -l-methylethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, m.p. 86-92 ° C, M * H 555; N- hydrochloride. { 2- [3- (4-methanesulfonylphenylcarbonyl-amino) phenyl] -1-methylphenyl} -N-isopropyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 585; N- Isopropionate. { 2- [3- (2,3-benzo [1,3] dioxol-5 -carbo-n-lamino) phenyl] -l-methylethyl} -N- (2, 2, 2-trifluoroethyl) - [1- (dimethylaminocarbonyl) piperidin-4-ylmethyl] amine, M * H 535; Y N- hydrochloride. { 2- [3- (2,3-benzo [1,3] dioxol-5-carbo-nylamino) phenyl] -l-methylethyl} -N-propyl- [1- (me-il-aminocarbonyl) piperidin-4-ylmethyl] amine, M * H 495. EXAMPLE 11 Preparation of compounds of formula Ik as described in scheme M Route (a) HA. N- (2-f4- (morpholine-4-carbonylamino) phenyl-1-methylethyl) -N-propyl- (1-methanesulfonyl-1-piperidin-4-ylmethyl) -amine N- [2- (4-aminophenyl) -l-methylethyl] -N-propyl- (l-methanesulfonyl-iperidin-4-ylmethyl) amine (60 mg) was dissolved in ethyl acetate (ml) and saturated potassium carbonate (1 ml). The sample was cooled in an ice bath at 0 ° C and morpholine-4-carbonyl chloride (0.03 ml) was added. After stirring for 30 minutes, the layers were eeparated. The organic layer was dried with magnesium sulfate, filtered, and the solvent was removed to obtain N-. { 2- [4- (morpholin -carbonylamino) phenyl] -l-methylethyl} -N-propyl- (l-methanesulfonyl-piperidin-4-ylmethyl) amine (90 mg) in the form of a foam, M * H 481. Route (b) -HB. N-f2- {3-isopropylureidophenyl) -l-methyl-ethyl-N-ethyl- (l-methanesulphonyloiperidin-4-ylmethyl) amine hydrochloride To a solution of N- [2- (3-aminophenyl) -l-methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine (0.2 g, 0.567 mmol) in dichloromethane (12 ml), isocyanate was added. isopropyl (0.765 mmol). The reaction mixture was stirred at 22 ° C for 15 h. The solvent was removed under reduced pressure. The product was isolated as the hydrochloride salt, or with ethyl ether, obtaining N- [2- (3-isopropylureidophenyl) -1-methyl-ethyl] -N-ethyl- (1-methanesulfonylpiperidin-4-hydrochloride. ilmethyl) amine (0.205 g, 76%), M * H 439.

Route (c) 11C. N-> 2- (3-carbamoylaminophenyl) -l-methylethyl-N-prooyl- (1-methane-sulphonyl-pyridin-1-methyl) -amine A solution of potassium cyanate (9 mg) in water (0.5 ml) was added to a solution of N. - [2- (3-aminophenyl) -1-methylethyl] -N-propyl- (1-m-8-bis-sulfonyl-piperidin-4-ylmethyl) -amine (40 mg) in water (2 ml) and acetic acid (1 ml). The mixture was stirred at room temperature for about 72 hours and then alkalized to pH 9 with 10% sodium hydroxide. The solution was extracted with dichloromethane and the organic phase was dried with sodium sulfate, filtered, evaporated in vacuo to obtain N- [2- (3-carbamoylaminophenyl) -l-methyl-ethyl] -N-propyl- (1). -metanesulfonylpiperidin-4-ylmethyl) amine (35 mg), M * H 411 2 11D. In a similar manner, substituting N- [2- (3-ammophenyl) -l-methylethyl] -N-ethyl- (piperidin-4-ylmethyl) amine for other amines, and replacing the isopropyl isocyanate with other isocyanates and following the As described above in Example 11B, the following compounds of formula Ik: N- Hydrochloride were prepared. { 2- [3- (3-phenylureido) phenyl] -1-methyl-ethyl} -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 559; Y N- hydrochloride. { 2- [3- (3-phenylureido) phenyl] -l-methylethyl} -N-propyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine, M * H 487. EXAMPLE 12 Preparation of compounds of formula 11 as described in scheme N The following compounds of formula II were prepared in the same manner as the compounds of formula Ij, but substituting the 2-furyl chloride for an eulphonyl chloride, and following the procedures described above in example 10A: N- [2- (3-methanesulfonylaminophenyl) -1-methylethyl hydrochloride ] -N-propyl- [1- (morpholin-4 -carbonyl) piperidin-4-ylmethyl amine, M * H 481; M- [2- (3-methanesulfonylaminophenyl) -1-methylethyl] -N-propyl- (l-methanesulfonyl-piperidin-4-ylmethyl) amine hydrochloride, M * H 445; N-. { 2- [3- (4-Methylphenylsulfonylamino) phenyl] -l-methylethyl} -N- propyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine, M * H 522; N- [2- (4-methanesulfonylaminophenyl) -l-methylethyl] -N-propyl- [i- (morpholin-4-carbonyl) piperidin-4-ylmetillamine hydrochloride, M * H 481; N- hydrochloride. { 2- [4- (methanesulfonylamino) phenyl] -l-methylethyl} -N-propyl- (l-methanesulfonyl-pipendin-4-ylmethyl) amine, M * H 446; Y Hydrochloride de-j_jJ-. { 2- [3- (Benzene-sulfonylamino) phenyl] -1-methylethyl} -N-propyl-p * - (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, M * H 543. EXAMPLE 13 Preparation of compound of formula lm as described in the scheme 0 N-Í2- f3- (4-dimethylaminosulfonylamino) phenyl-1-methylethyl JN-propyl-1- (methanesulfonylpiperidin-4-ylmethyl) amine was dissolved N- [2- (4-aminophenyl) -l-methylethyl] -N-propyl- (1) -metanesulfonylpiperidin-4-ylmethyl) amine (50 mg) in dichloromethane (2 ml) and pyridine (0.01 ml). The mixture was cooled on ice and dimethylsulphamoyl chloride (0.015 ml) was added. The mixture was kept at 5 ° C for about 72 hours, and washed with saturated sodium bicarbonate. The organic layer was dried (Na.SO, filtered and the solvent was removed in vacuo to give N-. {2- [3- (4-dimethylaminosulfonylamino) phenyl) -1-methylethyl} -N-propyl- (l-methanesulfonylpiperidin-4-ylmethyl) amine, in the form of an oil (19 mg), M 'H 475. EXAMPLE 14 Preparation of compounds of formula ln as described in scheme P Dihydrochloride and N- f2- (4-dimethylaminaminophenyl) -l-methylethyl-N-propyl- fl- (morpholin-4-carbonyl) -oiperidin-4-ylmethyl amine A solution of N- [2- (4-aminophenyl) - l-methylethyl] -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine (0.256 mmol) in formic acid (1.0 ml) and 37% formaldehyde (10 ml), was heated at 100 ° C for 6 hours. The reaction mixture was brought to pH 10 with 3N sodium hydroxide solution and extracted with ethyl acetate (25 ml). The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The product was isolated in the form of eal of hydrochloride with ethyl ether to obtain N- [2- (4-dimethyl-amino-aminophenyl) -1-methylethyl] -N-propyl- [1- (morpholine-4-carbonyl) piperidine dihydrochloride. -4-ylmethyl] amine (0.09 g, 77%), M * H 431. EXAMPLE 15 The following formulations are repreeentative pharmaceutical formulations containing a compound of formula I. Formulation of tablets The following ingredients are intimately mixed and compressed into tablets. sing with a doll.

Quantity per Compressed Ingredient, mg Compound of this invention 400 Corn starch 50 Croscarmelloe sodium 25 Lactose 120 Magnesium stearate 5 Capsule Formulation The following ingredients are intimately mixed and the mixture is filled into a hard gelatin capsule.

Quantity per Ingredient capsule, mg Compound of this invention 200 Lactoea, spray dried 148 Magnesium Stearate 2 Formulation of sueoeneionee The following ingredients are mixed to form a suspension for oral administration.

Formulation for injectables The following ingredients were mixed to form a formulation for injectables. Ingredient Amount Compound of this invention 0.2 g 0.4 M solution of buffer 2.0 ml of sodium acetate HCl (IN) OR NaOH (IN) c. s. for proper pH Water (distilled, sterile) q.s. for 20 ml Topical formulation A topical formulation is prepared with the following ingredients: Ingredient Amount, g Compété d'et intent 10? Bread 60 2 TWEEN®60 2 Mineral oil 5 Vaseline 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylated hydroxyanisole) 0 , 01 Water c s. for 100 All the above ingredients except water, are mixed and heated to 60-70 ° C with agitation. Then add a sufficient amount of water at 60 ° C with vigorous stirring to emulsify the ingredients, and then add water q.s. for 100 g. Formulation for suppositories A suppository with a total weight of 2.5 g is prepared by mixing the compound of the invention with Witepsol® H-15 (triglycerides of saturated vegetable acid, Riches-Nelson, Inc., New York) and has the following composition: Compound of this invention 500 witepsol® H-15 reeto Formulation for nasal spray ' A variety of aqueous suspensions containing 0.025 to 0.5 percent active compound are prepared as formulations for nasal sprinklers. The formulations optionally contain inactive ingredients such as microcrystalline cellulose, sodium carboxymethyl cellulose, dextrose, and the like. Hydrochloric acid can be added to adjust the pH. The nasal spray formulations can be supplied by a nasal spray pump that normally delivers 50-100 microliters of formulation per each drive. A typical dosing schedule is 2 to 4 sprays every 4-12 hours. EXAMPLE 16 Radioligand binding study The inhibitory activity of the compounds of this invention was determined in vitro, using a modification of the method described in Hegde, S.S. et al., Br. J. Pharmacol., 1997, 120, 1409-1418.

Cell membranes of Chinese hamster ovary cells expressing the recombinant human muscarinic receptors (m_-ms) were used. The assays were carried out with the radio-ligand [3 H] -methyl eecopolamine (0.4 nM, specific activity 5 84 Ci-mmol "1) in a final volume of 0.25 ml of Trie-Krebe buffer.Specific binding was defined with atropine lμM The tests were carried out using proximity scintillation assay technology.The comparative displacement curves were generated using 10 concentrations of test compounds and analyzed by the iterative curve that is attached to a four parameter logistic equation. ' The values of pICS0 (-log of IC50) were converted into pKi values using the Cheng-Prusoff equation.The compounds of this invention were shown to have activity in this assay.Example 17 Anti-muscarinic activity in anesthetized rats Activity inhibitor of the muscarinic receptor of the compounds of this invention in vivo determined in rats using a modification of the method described in Hegde, SS et al., Proceedings of the 26th Annual Meeting of the International Continence Society ("Proceedings of the Annual Meeting of the Society Continent International ") (August 27 to 30) 1966, Summary 126. Female Sprague-Dawley rats are anesthetized with urethane and they were instrumented for the intravenous administration of drugs and, in some cases, for the measurement of blood pressure, heart rate and internal pressure of the urinary bladder. The effect of the test compounds on the bladder contraction of the bladder induced by the volume and secretion of saliva induced by oxotremorine, was determined in separate groups of animals. The reflex contractions of the bladder induced by volume were induced by filling the bladder with saline solution. The test compounds were intravenously administered cumulatively at a 10 minute interval. Atropine (0.3 mg / kg, iv) was administered at the end of the study as a positive control. In a separate group of animals, the salivary segregation response to oxotremorine (0.1 mg '/ lcg, iv) was determined for a period of 10 minutes, after the animals were dosed intravenously with a single dose of the compound of eneayo The amount of ealiva was determined by placing previously weighed cotton pads, in the mouth of the animals, and re-weighing these pads at 10 minutes after the oxotremorine. The compounds of this invention demonstrated active activity in this assay.

EXAMPLE 18 Antiruscarinic activity in anesthetized dogs The inhibitory activity of the muscarinic receptor of the compounds of this invention in vivo was determined in dogs using a modification of the method described in Newgreen, D.T. et al., J. Urol., 1996, 155 (Suppl 5), 1156. Female dogs were anesthetized with pentobarbital and were intruded for the measurement of arterial pressure, heart rate, contraction of the urinary bladder induced by the pelvic nerve. , and the secretion of saliva induced by the lingual chorda nerve. The pelvic and chorda lingual nerves were stimulated for 20 seconds and 2 minutes, respectively, with a minimum of 10 minutes interval between each group of stimuli. After obtaining two conscientious control responses, the compound was dosed cumulatively, 3 minutes before each stimulation of the pelvic and chorda ling nerves. Atropine (1.0 mg / kg, iv) was given as a poetic control at the end of the study. The compounds of the present invention were active in this assay. ' Although the present invention has been described with reference to specific versions thereof, it should be understood by those skilled in the art that various changes can be made and substantive equivalents can be substituted without departing from the true spirit and scope of the invention. In addition, many modifications can be made to adapt a particular situation, material, composition of a material, process, step or steps of a process, to the spirit and scope objective of the present invention. All these modifications are intended to be included within the scope of the appended claims hereto. It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as priority

Claims (33)

1. ^ CLAIMS l. A compound of formula I characterized in that: R: is each, independently, hydrogen, alkyl, alkyloxy, halogen, haloalkyl, or amino; R2 is each, independently: (1) alkyl, (2) alkyloxy, (3) halogen, (4) haloalkyl, (5) nitro, (6) heterocyclyl, optionally substituted with oxo, (7) -0 (CH2) pX, wherein p is 0-6 and X is independently selected from haloalkyl or aryl, (8) -NRRS, (9) -NR'COR ', (10) -NR6C0NR7R3, (11) -NR'CSR', (12) -NR'CSNR7R5, (13) -NR6S02R9, (14) -NR6S02NR7R ', (15) -SR9, (16) -SOR', (17) -SO.R9, (18) -S02NR7Rβ; OR R1 and R2 taken together with the ring to which they are attached to form a saturated or unsaturated 5 or 6 membered monocyclic ring, optionally containing 0, 1 or 2 heteroatoms selected, independently from each other, between nitrogen, oxygen or sulfur. R3 and R4 are each, independently of each other, lower alkyl, alkenyl or cycloalkyl; Rs is each independently: (1) hydrogen, (2) -COR9, (3) -COOR ', (4) -CONR'R8, (5) -C0 (CH2) nC0R9, (6) -CO (CH2) ) "S02R9, (7) -C0 (CH2) pC0NR7R \ (8) -C0 (CH2) nS02NR? R \ (9) -C0 (CH2)" NRsC0R9, (10) -CO (CH2) nNR6S0.Rs, ( 11) -C0 (CH2) nNR6C0NR7R \ (12) -C0 (CH2) nNR'SO2NR7R \ (13) -CSR9, "* (14) -CSNR7R8, (15) -S? 2R ', (16) -S02NR7Ra, (17) -SO, (CH2) nNRsS02R9, or (18) -S02NRS (CH2) "COOR7; wherein n is 1-6, - Re and R7 are each, independently of each other, hydrogen or lower alkyl, R" is each, independently, hydrogen, alkyl lower, cycloalkyl, aryl or heteroaryl; R9 is each, independently: (1) alkyl, (2) cycloalkyl, (3) arylalkyl, (7) aryl, unsubstituted or mono-, di- or trisubstituted aryl, the substituents being independently selected from lower alkyl, alkyloxy, halogen, haloalkyl, cyano, nitro, -C0NR7R ', -COR7, -COOR7, -NR7R ", -NCOR', -S02R9, -S02NR7R 'or -0 (CH2) _X, where p ee 0-6 and X is haloalkyl or aryl, (8) heterocyclyl, optionally substituted with one or two substituents, selected from lower alkyl, hydroxyl, hydroxyalkyl, oxo, -COR7, or -COOR7, or (9) heteroaryl, ^ optionally substituted with one or two substituents, selected from lower alkyl, alkyloxy, halogen, haloalkyl, cyano, nitro, -CONR7R8, COR7, -COOR7 , -NR7Rβ, -NCOR9, -SOzR9, -S02NR7R8 O -0 (CH2) pX, wherein p is 0-6 and X is halo] -? -. Lo or aryl; and an individual isomer or a racemic or non-racemic mixture of isomers, or a pharmaceutically acceptable salt thereof.
2. 2. The compound according to claim 1, characterized in that R3 and R4 are each, independently of each other, lower alkyl or cycloalkyl.
3. 3. The compound according to claim 2, characterized in that R3 and R4 are each, independently of each other, methyl, ethyl, propyl, isopropyl or cyclopropylmethyl.
4. 4. The compound according to claim 3, characterized in that R3 is methyl and R4 is each independently ethyl, propyl, isopropyl or cyclopropylmethyl.
5. 5. The compound according to claim 4, characterized in that R5 is -S02R9, -COR9, -CONR7R8 or -CO (CH2) "NR6S02R9.
6. 6. The chromatid according to claim 5, characterized in that R5 is -S02R9.
7. 7. The compound according to claim 6, characterized in that R9 is alkyl.
8. 8. The compound according to claim 7, characterized in that R9 is methyl, ethyl or propyl.
9. 9. The compound according to claim 5, characterized in that R5 is -COR9.
10. 10. The compound according to claim 9, characterized in that R9 is heterocyclic or heteroaryl.
11. 11. The compound according to claim 10, characterized in that R9 is morpholino, piperidinyl or 1,2,3,4-tetrahydro [1, 5] naphthyridinyl.
12. 12. The compue. according to claim 5, characterized in that R is -CONR R.
13. 13. The compound according to claim 12, characterized in that R7 and R8 are each, independently of each other, lower alkyl.
14. 14. The compound according to claim 13, characterized in that R7 and R8 are each, independently of each other, methyl, ethyl or propyl.
15. 15. The compound according to claim 5, characterized in that -CO (CH2) nNR6S02R9
16. 16. The compound according to claim 15, characterized in that n is 1-4, R6 is hydrogen, and R9 is alkyl.
17. 17. The compound according to claim 16, characterized in that R9 is methyl, ethyl or propyl.
18. 18. The compound according to claim 8, characterized in that R1 and R2 taken together with the ring to which they are attached form a 5 or 6 element monocyclic ring, saturated or unsaturated, optionally containing 0, 1 or 2 heteroatoms, independently selected between nitrogen, oxygen or sulfur, and in which, the ring is optionally mono or disubstituted with lower alkyl or oxo.
19. 19. The compound according to claim 18, characterized in that R1 and R2 taken together with the ring to which they are attached form a saturated 5 or 6-membered monocyclic ring, optionally containing 0, 1 or 2 oxygen heteroatoms, and in the which ring is optionally mono or disubstituted with lower alkyl or oxo.
20. 20. The compound according to claim 19, characterized in that R1 and R2 taken together with the ring to which they are attached, form indanyl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydro-benzofuran-6-yl, , 3-dimethyl-2, 3-dihydrofuran-5-yl, 3,3-dimethyl-2,3-dihydrofuran-6-yl, or 2,3-dihydrobenzo [1,4] di-oxin-6-yl.
21. 21. The compound according to claim 20, characterized in that R1 and R2 taken together with the ring to which they are attached, form 2,3-dihydrobenzofuranyl, R3 is methyl; R4 is ethyl, and R9 is methyl.
22. 22. The compound according to claim 5, characterized in that R1 is hydrogen, and R2 is alkyloxy, halogen or haloalkyl.
23. 23. The compound according to claim 22, characterized in that R2 is methoxy, ethoxy, propoxy, chlorine, bromine or trifluoromethyl.
24. 24. The compound according to claim 5, characterized in that R1 is hydrogen and R2 is -NR7C0R9.
25. 25. The compound according to claim 24, characterized in that R7 is hydrogen and R9 is aryl, optionally substituted with 1-3 substituents, selected from lower alkyl, alkyloxy, halogen or haloalkyl.
26. 26. The compound according to claim 25, characterized in that R9 is phenyl, optionally substituted with 1-3 substituents, selected from methyl, ethyl, methoxy, ethoxy, chloro or trifluoromethyl.
27. 27. A compound according to formula I, characterized in that it is selected from: N- [2- (2,3-dihydrobenzofuran-5-yl) -1-methylethyl] -N-ethyl- (1 -me taneul fonyl-piper idin-4-ylmethyl) amine, - N- [2- ( 2,3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-propyl - (1 -me taneul fonyl -piperidin-4-ylmethyl) amine, - N- [2- (2,3-dihydrobenzofuran-6 -yl) -l-methylethyl] -N-propyl- [1- (morpholin-4-carbonyl) -pi? eridin-4-ylmethyl] amine; N- [2 - (2,3-Dihydrobenzofur-6-yl) -l-methylethyl] -N-cyclopropylmethyl- [i- (morpholin-4-carbonyl) piperidin-4-ylmethyl) amine; N "-2_ '2' -dihydrobenzofuran-5-yl) -l-methylethyl] -N-ethyl- [1- (morpholin-4-carbonyl) -piperidin-4-ylmethyl] amine; N- [2- (2 , 3-dihydrobenzofuran-5-yl) -l-methylethyl] -N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] amine, - N- [2- (2,3-dihydrobenzo [ 1,4 Idioxin-6-yl) -1-methylethyl] -N-ethyl- [1- (morpholin -carbonyl) piperidin- -ylmethyl] amine, - (S) -N-. { 3- [4- ( { [2- (2,3-dihydrobenzofuran-5-yl) -1-methylethyl] ethylamino} methyl) -piperidin-1-yl] -3-oxo-propyl) methansulfonamide, - N- [2-indan-5-yl) -l-methylethyl] -N-ethyl- (1-methanesulfonyl-piperidin-4-ylmethyl) -amine; N- [2- (indan-5-yl) -l-methylethyl] -N-propyl- (1-methan-eul-fonyl-piperidin-methyl) -amine; N- [2- (3,3-dimethyl-2, 3-dihydrobenzofuran-6-yl) -l-methylethyl] -N-ethyl- [1- (morphine-4-carbonyl) -piperidin-4-ylmethyl ] amine, - N- [2- (3, 3-dimethyl-2, 3-dihydrobenzofuran-6-yl) -l-methylethyl] -N-ethyl- (1-methanesulfonylpiperidin-4-ylmethyl) amine, - N - [2- (4-methoxyphenyl) -l-methylethyl] -N-ethyl- [1- (dimethyl-aminecarbonyl) -piperidin-4-ylmethyl] amine; N- [2- (3-trifluoromethylphenyl) -l-methylethyl] -N-ethyl- [1- (dimethylaminocarbonyl) -piperidin-4-ylmethyl] amine, -N- [2- (3-trif luoromethylphenyl) -l- methylethyl] -N-ethyl- [1- (piperidin-1-carbonyl) -piperidin-4-ylmethyl] amine; N- [2- (4-trifluoromethyl-phenyl) -l-methylethyl] -N-ethyl- [1- (piperidin-1-carbonyl) -piperidin-4-ylmethyl] -amine, - N- [2- (4-trifluoromethyl-phenyl) -l-methylethyl] -N-ethyl- [1- (dimethylamino-carbonyl) -piperidin-4-ylmethyl] amine; N- [2- (3-trifluoromethylphenyl) -l-methylethyl] -N-ethyl- [1- (morphine-4-carbonyl) -piperidin-4-ylmethyl] -amine; N- [2- (3-trifluoromethylphenyl) -1-methylethyl] -N-ethyl- [1- (1,2,3,4-tetrahydro [1,5] naphyridin-1-carbonyl) piperidin-4-ylmethyl ] amine, -. N- [2 - (3-chlorophenyl) -l-methylethyl] -N-ethyl- [1- (piperidin-1-carbonyl) -piperidin-4-ylmethyl] -amine, -N- [2 - (3-trifluoromethyl) enyl) -l-methylethyl] -N-propyl- [1 - (morpholin-4-carbonyl) -piperidin-4-ylme] amine, -N-. { 2- [3- (4-methoxyphenylcarbonylamino) phenyl] -l-methylethyl} - N-propyl - [1-immorpholin-4-carbonyl) piperidin-4-ylmethyl] amine; and N-. { 2- [3- (4-methylphenylcarbonylamino) phenyl] -1-methylethyl} - N-propyl- [1- (morpholin-4-carbonyl) piperidin-4-ylmethyl] mine.
28. 28. A compound according to claim 1 or 27, characterized in that the pharmaceutically acceptable salt is a salt formed from hydrochloric acid, phosphoric acid, trifluoroacetic acid or dibenzoyl-L-tartaric acid.
29. 29. A medicament, characterized in that it contains one or more compounds as claimed in any of claims 1-28, and pharmaceutically acceptable excipients.
30. 30. A medicament according to claim 29, characterized in that it is used for the treatment of diseases related to the muscarinic receptor.
31. 31. A process for the preparation of a compound of the formula I as defined in claim 1, said method is characterized in that it comprises: a) reduction of a compound of formula: with a reducing agent to obtain a compound of formula: b) deprotection of a compound of formula: 20 to give a compound of formula: or c) reaction of a compound of formula: yr NHR-R3 with a compound of formula: O 23 to obtain a compound of formula: Ib or d) reaction of a compound of formula: with a compound of the formula: 0 (S) L- »R. to obtain a compound of formula: Or e) Substitution of the H atom at position 1 of the piperidine ring of the formula: a with the groups described for R5 f) modification of one or more substituents R1-Rs within the definitions given above, and, if desired, conversion of the compound obtained, into a pharmaceutically acceptable acid addition salt.
32. 32. A compound according to any of claims 1-28, characterized in that it is prepared by means of a process as claimed in claim 31, or an equivalent method.
33. 33. The use of a compound according to any of claims 1-28 for the treatment of diseases related to the muscarinic receptor or for the preparation of a medicine useful for the treatment of diseases.