MXPA98006690A - Antagonists of the cc receiver - Google Patents

Abstract

The present invention relates to certain cyclic amine derivatives of formula (I), which are antagonists of the CCR-3 receptor, to pharmaceutical compositions containing them, to methods for the preparation of said compounds.

Description

ANTAGONISTS OF THE RECEIVER CCR-3 FIELD OF THE INVENTION The present invention relates to certain cyclic amine derivatives which are CCR-3 receptor antagonists, to pharmaceutical compositions containing them, to methods for their use and to methods for the preparation of said compounds.

BACKGROUND OF THE INVENTION Tissue eosinophilia is a characteristic of various pathological states such as asthma, rhinitis, eczema, inflammatory bowel diseases and parasitic infections (see Bousquet, J. et al., N. Eng. J. Med., 323: 1033-1039 (1990). ) and Kay, AB, and Corrigan, CJ, Br. Med. Bull. 48: 51-64 (1992)). In asthma, the accumulation and activation of eosinophils is associated with lesions in the bronchial epithelium and with hyperresponsiveness to mediators of constriction. It has been established that chemokines such as RANTES, eotaxin, MCP-2, MCP-3 and MCP-4 activate eosinophils (see Baggiolini, M. and Dahinden, CA, Immunol Today., 15: 127-133 (1994), Rot, AM et al., J. Exp. Med., 176, 1489-1495 (1992) and Ponath, PD et al., J. Clin. Invest., Vol. 97 # 3, 604-612 (1996)) . No embargo.a unlike RANTES and MCP-3 which also induce the migration of other leukocyte cell types, eotaxin is selectively chemotactic the eosinophil (see Griffith-Johnson, OA et al., Biochem. Biophys. Res. Commun 197: 1167 (1993) and José, PJ et al., Biochem. Biophys., Res. Commun. 207, 788 (1994)). A etal, REF::.. A specific eosinophil accumulation at the site of administration of eotaxin well after intradermal or intraperitoneal injection or aerosol inhalation after (see Griffith-Johnson, D was observed.. 28125 Biochem Biophys Res. Commun., 197: 1167 (1993); José, PJ et al., J. Exp. Med., 179: 881-887 (1994); Rothenberg, ME et al., J. Exp. Med., 181, 1211 (1995) and Ponath, PD, Clin. Invest., Vol. 97, # 3, 604-612 (1996)).

The CCR-3 receptor has been identified as an important chemokine receptor that is used by eosinophils for their response to eotaxin, RANTES and MCP-3. It is expressed predominantly on the surface of eosinophils and is highly selective for eotaxin. When transfected into a murine pre-β lymphoma line, the CCR-3 receptor binds eotaxin, RANTES and MCP-3 and confers chemotactic responses in these cells to these chemokines (see Ponath P.D. et al., J. Exp.

Med., 183, 2437-2448 (1996)).

Recently, some studies have shown that pretreatment of eosinophils with an anti CCR3 mAb completely inhibits eosinophil chemotaxis to eotaxin, RANTES and MCP-3 (see Heath H. et al., J. Clin. Invest., Vol. 99, # 2, 178-184 (1997), which indicates that the CCR-3 antagonists are useful for the treatment of inflammatory diseases mediated by eosinophils.

Glucocorticoids such as dexamethasone, methprednisolone and hydrocortisone have been used for treating many eosinophil-related transtomos, including bronchial asthma (R.P.Schleimer et al., Am. Rev. Respir Dis., 141, 559 (1990)). It is believed that glucocorticoids inhibit the survival of eosinophils mediated by I L-5 and I L-3 in these diseases. However, prolonged use of glucocorticoids can lead to side effects such as glaucoma, osteoporosis and growth retardation in patients (see Hanania NA et al., J. Allergy and Clin. Immunol., Vol. 96, 571-579 ( 1995) and Saha MT et al., Pediatric Acta, Vol. 86, # 2, 138-142 (1997)). It is therefore desirable to possess an alternative means to treat eosinophil-related diseases without these undesired side effects occurring.

DESCRIPTION OF THE INVENTION The present invention provides a means of combating diseases induced by eosinophils, such as asthma.

In a first aspect, the invention provides compounds selected from the group of compounds represented by the formula (I): Ar. (FHE) -CR3R4- (CHR- m - - < (I) wherein: T and U are both nitrogen; or one of T and U is nitrogen and the other is carbon; R1 and R2 are, independently of one another, hydrogen or alkyl; n is an integer from 0 to 2, provided that if n is 0, then either T or U are carbon; m is an integer from 0 to 3; Ar and Ar1 are, independently of one another, aryl or heteroaryl; F is alkylene, alkenylene or a bond, provided that if T and U are nitrogen and F is alkylene, then R4 is not aryl.

Each R is independently hydrogen or alkyl, or R together with either R3 or R4 and the atoms to which they are attached form a carbocycle or a heterocycle; R3 and R4, independently of one another, are selected from: (i) hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heteroalkyl, cyano or - (alkylene) -C (O) -Z where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy or heteroaralkyloxy, with the proviso that R3 and R4 are not both hydrogen; or (ii) R3 and R4 together with the carbon atom to which they are attached form a carbocycle or a heterocycle; E is -C (O) N (R5) -, -SO2N (R5) -, -N (R6) C (O) N (R5) -, -N ^ SO ^ R5) -, -N (R6) C (S) N (R5) -, -N (R6) C (O) -, -N (Rβ) C (O) O -, - OC (0) N (R6) - or -N (R6) SOr, wherein: R5 is: (i) hydrogen, alkyl, acyl, haloaicyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, heteroalkyl, or - (alkylene) -C (O) -Z, wherein Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy or heteroaralkyloxy; or (ii) R5 together with either R3 or R4 and the atoms to which they are attached form a heterocycloamino group; and Rβ is hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, heteroalkyl, or - (alkylene) -C (O) -Z, wherein Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy or heteroaralkyloxy, with the condition that when T is nitrogen, and E is -C (O) N (R5) -, -SO2N (R5) -, -N (Rβ) C (O) N (R5) -, N (R6) SO2N ( R5) -, or -N (R6) C (S) N (R5) -, then m > 0; Q is-R7-W-Rβ-, where: R7 is an alkylene chain of between 1 and 6 carbon atoms inclusive; R8 is a bond or an alkylene chain of between 0 and 4 carbon atoms inclusive; W is a bond or a group selected from -0 (0) -, -NR9-, -O-, -S (O) or, -C (O) N (R9) -, -N (R9) C (O ) -, -N (R9) S02-, -SO2N (R9) -, -N ^ CíO ^ R9) -, -N (R9) SO2N (R9) - or -N (R9) C (S) N (R9) -, wherein: R9 is hydrogen, alkyl, acyl, haioalkyl, cycloalkyl, cycloalkylalkyl, aryl aralkyl, araiquenyl, heteroaryl , heteroaralkyl, heterocycloalkyl, heteroalkyl, or - (alkylene) -C (O) -Z, where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl , heteroaryloxy or eteroaralkyloxy, as long as T is nitrogen and U is carbon, then W is not -C (O) N (R9) - as well as prodrugs, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.

In a second aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.

In a third aspect, this invention provides a method of treating a disease in a treatable mammal by administering a CCR-3 receptor antagonist, comprising administering a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt. Disease states include respiratory diseases such as asthma.

Unless otherwise indicated, the following terms used in the specification and in the claims have the meanings indicated below: "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, for example methyl, ethyl, propyl, 2-propyl, pentyl and the like.

"Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms containing at least one double bond, for example ethenyl, propenyl, and the like.

"Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example methylene, ethylene, propylene, 2-methylpropylene, pentylene and the like.

"Alkenylene" means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, for example ethenylene, 2,4-pentadienylene, and the like . "Acyl" means a radical -C (0) R wherein R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haioalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, for example acetyl, benzoyl, tenoyl and the like.

"Acyloxy" means a radical -OC (O) R wherein R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl, or optionally substituted phenyl, for example acetoxy, benzoyloxy, and the like.

"Acylamino" means a radical -NRC (0) R 'wherein R is hydrogen or alkyl and R' is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl, or optionally substituted phenyl, for example acetylamino, trifluoroacetylamino, benzoylamino, methylacetylamino, and the like.

"Halo" means fluoro, chloro, bromo or iodo, preferably fluoro and chloro.

"Haloalkyl" means an alkyl substituted with one or more same or different halo atoms, for example -CH2Cl, -CF3, -CH2CF3, -CH2CCI3, and the like.

"Cycloalkyl" means a monovalent cyclic hydrocarbon radical saturated with a three to six carbon ring, for example cyclopropyl, cyclohexyl and the like. "Carbocycle" means a cyclic group saturated with a ring of 3 to 6 atoms in which all the ring atoms are carbon, for example cyclopentyl, cyclohexyl and the like.

"Monosubstituted amino" means a radical -NHR in which R is alkyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl, for example methylamino, (1-methylethyl) amino, phenylamino and the like.

"Disubstituted amino" means a radical -NRR 'wherein R and R' are independently alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di (1-methylethyl) amino, methylbenzylamino and the like.

"Aryl" means a monovalent monocyclic or monocyclic aromatic hydrocarbon radical with ring of 6 to 10 carbon atoms, and optionally independently substituted with one or more substituents, preferably one or two substituents selected from alkyl, haloalkyl, heteroalkyl.cycloaikyl, cycloalkylalkyl, halo, cyano, nitro, acyloxy, optionally substituted phenyl, heteroaryl, heteroaralkyl, amino, monosubstituted amino, disubstituted amino, acylamino, hydroxylamino, amidino, guanidino, cyanoguanidinyl, hydrazino, hydrazido, -OR (where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl), -S (0) nR (where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, phenyl optionally substituted , heteroaryl, heteroaralkyl, amino, amino, mono or disubstituted amino), -C (0) R (where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl), -COOR (where R is hydrogen, alkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl), - (alkylene) COOR (where R is hydrogen, alkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl), methylenedioxy, 1,2-ethylenedioxy, -CONR'R "or - (alkylene) CONR 'R' (wherein R 'and R "are independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryl, and heteroaralkyl.) More specifically the term" aryl "includes, but is not limited to, phenyl, -naphthyl, 2-naphthyl and derivatives thereof.

"Optionally substituted phenyl" means a phenyl group which is optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, halo, nitro, cyano, -OR (where R is hydrogen or alkyl), -NRR '(where R and R 'are independently of each other hydrogen or alkyl), -COOR (where R is hydrogen or alkyl) or -CONR'R "(where R' and R" are independently selected from hydrogen or alkyl). "Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical with a ring of 5 to 10 atoms containing one, two or three heteroatoms in the ring selected from N, O or S, with the remaining ring atoms being C. The aromatic radical is optionally substituted independently with one or more substituents, preferably one or two substituents selected from alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, halo, cyano, nitro, acyloxy, optionally substituted phenyl, amino, monosubstituted amino, disubstituted amino, acylamino, hydroxyamino , amidino, guanidino, cyanoguanidinyl, hydrazino, hydrazido, -OR (where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl), -S (O) pR (where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, amino or aminomono or disubs substituted), -C (O) R (where R is hydrogen, alkyl, alkenyl, cycloalkium, heteroalkyl, haloalkyl or optionally substituted phenyl), -COOR (where R is hydrogen, alkyl or optionally substituted phenyl), - (alkylene-COR (where R is hydrogen, alkyl or optionally substituted phenyl), -methylenedioxy, 1,2-ethylenedioxy, -CONR'R "or - (alkylene) CONR'R" (where R 'and R "are selected independently of hydrogen, alkyl, cycloalkyl, haloalkyl, cycloalkylalkyl or optionally substituted phenyl.) More specifically, the term "heteroaryl" includes, but is not limited to, pyridyl, pyrrolyl, thiophene, pyrazolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, indolyl, carbazolyl, azaindolyl, benzofuranyl, benzotriazolyl, benzisoxazolyl, purinyl, quinolinyl, benzopyranyl and derivatives thereof "ether-cycloamino" means a saturated or unsaturated monovalent cyclic group with a ring of 5 to 8 atoms, wherein at least one ring atom is N and optionally contains a second heteroatom in the ring selected from the group consisting of N, O or S (O) n (where n is an integer from 0 to 2), the remaining atoms being ring C. The ring h Eterocycloamino may be fused to a heteroaryl ring, or may optionally be independently substituted with one or more substituents, preferably one or two substituents selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino , monosubstituted amino, disubstituted amino, -COOR (where R is hydrogen or alkyl), -XR (where X is 0 or S (0) n, n is an integer from 0 to 2, and R is hydrogen, alkyl, haloaikyl, cycloalkio, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl), or -CONR'R "(where R 'and R" are independently selected from hydrogen or alkyl). Representative examples include, but are not limited to, pyrrolidino, piperidino, 4-benzoylpiperidino, morpholino, piperazino, 4- (4-benzyloxyphenyl) piperazino, indolino, and the like.

"Heterocycle" or "heterocyclyl" means a saturated or unsaturated cyclic radical with a ring of 3 to 8 atoms in which one or two ring atoms are heteroatoms selected from N, O or S (O) n (where n is an integer of 0 to 2) The heterocycle ring can be optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, acylamino, amino, amino monosubstituted, disubstituted amino, -COOR (where R is hydrogen or alkyl), -XR (where X is O or S (O) n, where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, cycloalkyl, aralkyl, aryl, heteroaryl or heteroaralkyl), or -CONR'R "(wherein R 'and R" are independently selected from hydrogen or alkyl.) Representative examples include but are not limited to tetrahydropyranyl, piperidino, 1- (4-chlorophenyl) piperidino, and the like. "Heteroalkyl" means an alkyl, cycloalkyl or cycloalkylalkyl radical as defined above, carrying a substituent containing a heteroatom selected from N, O, S (O) n, (where n is an integer from 0 to 2. Representative substituents include -Ni ^ R ", -OR", or -S (O) nRc, where n is an integer from 0 to 2, Ra is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, or -COR (where R is alkyl), Rb is hydrogen, alkyl, -S02R (where R is alkyl or hydroxyalkyl), -S02NRR '(where R and R' are independently of each other hydrogen or alkyl), -CONR'R " (where R 'and R "are independently selected from hydrogen or alkyl) and R ° is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, amino, monosubstituted amino, or disubstituted amino Representative examples include, but are not limited to, 2-methoxyethyl, benzyloxymethyl, thiophen-2-ylthiomethyl and if milar.

"Hydroxyalkyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, with the proviso that if two hydroxy groups are present, both are not in the same carbon atom. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2- (methylpropyl), 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3 -dihydroxypropyl, 1- (hydroxymethi) l-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1- ( hydroxymethyl) -2-hydroxyethyl.

"Cycloalkylalkyl" means a radical -RaR in which R "is an alkylene group and Rb is a cycloalkyl group as defined above, for example cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, and the like." Aralkyl "means a radical -RaRb in which R" is an alkylene group and R "is an aryl group as defined above, for example benzyl, phenylethyl, 3- (3-chlorophenyl) -2-methylpentyl, and the like .

"Heteroaralkyl" means a radical -RaRb in which Ra is an alkylene group and Rb is a heteroaryl group as defined above, for example pyridin-3-ylmethyl, 3- (benzofuran-2-yl) propyl, and Similar.

"Heterocyclylalkyl" means a radical -RaRb in ei that Ra is an alkylene group and R ° is a heterocyclyl group such as defined above, for example tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-ylethyl and the like.

"Alkoxy", "haloalkoxy", "aryloxy", "heteroaryloxy", "aralkyloxy" or "heteroaralkyloxy" mean a radical -OR in which R is alkyl, haloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl respectively as defined above , for example methoxy, phenoxy, pyridin-2-yloxy, benzyloxy and the like.

"Optional" or "optionally" means that the event or circumstance described below may occur, but it need not occur, and that the description includes examples in which the event or circumstance occurs and examples in which it does not. For example, "heterocycle group optionally mono or disubstituted with an alkyl group" means that the alkyl may be present, but need not be present, and the description includes situations in which the heterocycle group is mono or disubstituted with an alkyl group and situations in which the heterocycle group is not substituted with an alkyl group.

"Amino protecting group" refers to those organic groups which are intended to protect nitrogen atoms against undesired reactions during synthetic processes, for example benzyl, benzyloxycarbonyl (CBZ), t-butoxycarbonyl (BOC), trifluoroacetyl, and the like.

Compounds that have the same molecular formula but that differ in the nature or sequence of union of their atoms or in the arrangement of their atoms in space are called "isomers". The isomers that differ in the arrangement of their atoms in space are called "stereisomers." Stereisomers that are not mirror images of one another are called "diastereomers", and those that are mirror images not overimposibies of one another are called "enantiomers". When a compound has a center of asymmetry, for example when it is linked to four different groups, the existence of a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its center of asymmetry, and is described by the sequence rules R- and S- of Cahn and Prelog, or it can be characterized by the way in which the molecule rotates the plane of polarized light , and that is called dextrorotatory or levorotatory (that is, like the isomers (+) or (-), respectively). A chiral compound can exist either as a single enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".

The compounds of this invention may possess one or more centers of asymmetry; such compounds can therefore be produced as individual (R) or (S) - stereoisomers, or as mixtures thereof. For example, if the substituents R3 and R4 in a compound of formula (I) are different, then the carbon to which they are attached is a center of asymmetry and the compound of formula (I) can exist as a stereoisomer (R) - or (S) -. Unless otherwise indicated, the description or nomenclature of a particular compound in the specifications and claims is intended to include both the individual enantiomers and the racemic or other mixtures thereof. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry", 4"edition, J. March, John Wiley and Sons, New York , 1992).

A "pharmaceutically acceptable excipient" means an excipient that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic and non-undesirable from a biological point of view or from another point of view, and includes an excipient that is acceptable for veterinary use as well as for human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one of these excipients.

A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the starting compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, acid benzoic, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesutphonic acid, 2-naphthalenesulfonic acid, 4-Toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-en-1) -carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; O well (2) salts formed when an acidic proton present in the starting compound is replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or it is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

A "leaving group" has the meaning conventionally associated therewith in synthetic organic chemistry, ie, an atom or group capable of being displaced by a nucleophile, and includes halogen, alkanesulfonyloxy, arenesulfonyloxy, ester or amino such as chlorine, bromine , iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy, N, O-dimethylhydroxylamino and the like.

A "prodrug" means any compound that releases an active starting drug according to Formula (I) in vivo when said prodrug is administered to a mammal. Prodrugs of a compound of Formula (I) are prepared by modifying the functional groups present in the compound of Formula (I) in such a way that the modifications can be cleaved in vivo to liberate the starting compound. Prodrugs include compounds of Formula (I) in which a hydroxy, sulfhydryl or amino group in the compound (I) is attached to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino or sulhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate and benzoate derivatives), carbamates (e.g.

N, N-dimethylaminocarbonyl) or hydroxy functional groups in compounds of Formula (I) and the like.

"Treating" or "treating" a disease includes: (1) preventing the disease, that is, preventing the clinical symptoms of the disease from developing in a mammal that may be exposed or predisposed to the disease, but still does not experience or present symptoms of the disease, (2) inhibit the disease, that is, stop or reduce the development of the disease or its clinical symptoms, or (3) alleviate the disease, that is, cause 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 achieve said treatment of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and age, weight, etc. of the mammal to be treated.

The nomenclature used in this application is generally based on the recommendations of the IUPAC, for example: A compound of Formula (I) wherein T and U are nitrogen, n and m are 1, R, R1. R2 and R3 are hydrogen, R4 is 1-methylethyl, E is -C (O) NH-, F is a bond, Q is -CHr, Ar is phenyl, Ar1 is 3,4-chlorophenyl and the stereochemically at carbon that R3 and R4 are joined is RS is called N-. { 1 (RS) - [4- (3,4-Dichlorobnsyl) piperazin-1-ylmethyl] -2-methylpropyl} benzamide.

A compound of Formula (I) wherein T and U are nitrogen, n and m are 1, R, R1, R2 and R3 are hydrogen, R4 is 1.1-dimethylethyl, E is -NHC (O) NH-, F is a bond, Q is -CHr, Ar is phenyl, Ar1 is 3,4-chlorophenyl and the stereochemistry in the carbon to which R3 and R4 are joined is RS is called 1-. { 1 (RS) - [4- (3,4-Dichlorobenzyl) piperazin-1-yl-methyl] -2,2-dimethylpropyl} -3-phenylurea.

A compound of Formula (I) in which T and U are nitrogen, n and m are 1, R, R 2 and R 3 are hydrogen, E is -C (O) NR 5 -, R 4 and R 5 together form a 3-pyrrolin indigo , F is a bond, Q is -CHr, Ar is 4-methylphenyl; Ar1 is 3,4-chlorofenyl and the stereochemistry at the carbon to which R3 and R4 are attached is RS is called. { 2- (RS) - (4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -1- (4-methylbenzoyl) -3-pyrroline A compound of formula (I) in which T is nitrogen, U is carbon, n and m are 1, R, R1, R2 and R3 are hydrogen, R4 is 1-methylethyl, E is -C (O) NH-, F is a bond, Q is -CH2-, Ar is 4-methylphenyl, Ar1 is 3,4-chlorophenyl and the stereochemistry at the carbon to which R3 and R4 are attached is S is called N-. {1 (SH4- (3,4-dichlorobenzyl) piperidin-1-ylmethyl] -2-methylpropylH -roet -.- De-i-zamide. l-? or Representative compounds of this invention are as described below: I. Representative compounds of Formula (I) wherein T and U = nitrogen; m and n = 1; R = R1 = R "'= R1 = hydrogen, Q = -CH ..-; E = -C (0) NH- and other groups are as defined below: or M or > or ) OR and they are named as: 2. N- dihydrochloride salt. { 1- (S) - [4- (3, -dichlorobenzyl) piperazin-1-ylmethyl] -2, 2-dimethyl-propyl} -4-me ilbenzamide. 3. N- dihydrochloride salt. { 1- (S) - [4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl} -4-methoxybenzamide. 4. N- | 1- (RS) -14- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl} 3, 4-methylenedioxy-benzamide. 1 . N- (1- (RS) - [4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl) -picolin ida dihydrochloride. 8. N- dihydrochloride salt. { 1- (S) - [4- (3, -dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl) -4-methylbenzamide. 19. N- | l- (S) - [4- (3, -dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl} -2-naf alenamide. 25. N-. { 1- (RS) - [4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl) -2- (thiophen-2-yl) acetamide. 35. N-. { 1- (R) -cyclohexyl-2- [4- (3,4-dichlorobenzyl) piperazin-1-yl] ethyl} -4-chloro-benzamide. 37. N-. { 1- (RS) - [4- (3, 4-dichlorobenzyl) piperazin-1-ylmethyl] -3-methylbutyl} -4-phenylbenzamide.

OR 44. N-. { 1- (RS) -14- (3,4-d-chlorobenzyl) piperaz i 1-? Lmet? L] -2-methylpropyl} -3- (4-methylfeml) -acn lamida II. Representative compounds of Formula (I) are those in which T = nitrogen; U = carbon; m and n = 1; R = R1 = R "= R = hydrogen; F = link; E = -C (0) NH- and other groups are as defined below: or N) t to? - > or t and are named as: 57. N- hydrochloride salt. { 1- (S) - [4- (3, 4-d? Chlorobenz? 1) p? Per? D? N-1-? Lmet? L] -2-met? Lprop? L} -4-methylbenzamide. 59. N-. { 1- (RS) - [4- (4-Ammo-5-chloro-2-methox? phenylcarbonylaminomethyl) p? pe? dm-1-? lmethyl] -2-methylpropyl 1} -4-met? Lben m? Da. III. Representative compounds of Formula (I) are those in which T and U = nitrogen; m and n = 1; R = R1 = R '- RJ = hydrogen; Q = -CH, - and F = link; E = -C (0) NR-; Rb together with R4 are the atoms to which they are bonded = heterocycloammo group and other groups are as defined below with the following: to tO O and are named as: 77. Sal dihydrochloride. { 1- (4-methylbenzoyl) -2 (RS) - [4- (3,4-dichlorobenzyl) piperazin-1-yl ethyl] Ipiperidine. IV. Representative compounds of Formula (I) are those in which T and U = nitrogen; m and n = 1; R = R1 = R "= R (= hydrogen; Q = -CH, -; E = -NHC (0) NH-; and other groups are as defined below the following: or OR to tO O and are named as: 82. l-. { 1- (R) - [4- (3,4-Dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl} -3- (3-methoxyphenyl) urea, 84. l-. { 2- (RS) - [4- (3,4-Dichlorobenzyl) piperazin-1-yl] cyclohexyl) -3- (3-methoxyphenyl) urea. 92.! -. { ! - (RS) - [4- (3,4-Dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl) -3-benzylurea. to l-n t V. Representative compounds of Formula (I) in which T = nitrogen; U = carbon; and n = 1; R = R1 = R '= R * = hydrogen; F = link; E = -NHC (0) NH- and other groups are as defined below the following: and are named as: 98. l- (1- (S) - [4- (3,4-Dichlorobenzyl) piperidin-1-ylmethyl] -2-methylpropyl) -3- (3-methoxy phenyl) urea, to tO l-? OR SAW. Representative compounds of Formula (I) are those in which T and U = nitrogen; m and n = 1; R = R1 = R¿ = R! = hydrogen; Q = -CH, -; E = -NHC (S) NH- and other groups are as defined below: J to t I? and they are named as: 107. l-. { 1- (RS) - [4- (4-Chlorobenzyl) piperazin-1-yl] -2-methylpropyl} -3- (3-methylphenyl) -2-thiourea. 111. 1- (1- (RS) - [4- (3, -dichlorobenzyl) piperazin-1-yl] -3-methylbutyl) -3- (2,4-difluorophenyl) -2-thiourea. VII. Representative compounds of Formula (I) are those in which T and U = nitrogen; m and n = 1; R = R1 = R2 = R '= hydrogen; F = link; Q = -CH, -; E = -S0? NH- and other groups are as defined below: t o sv and are named as: 117. N-. { 1- (R) - [4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl} -4-fluorobenzene-sulphonamide. 120. N-. { 1- (RS) - [4- (3, -dichlorobenz 1) pi perazin-l-ylmethyl] -3-methylbuti1} -2, 4-dichlorobenzene sulfonamide. VIII. Representative compounds of Formula (I) are those in which T and U = nitrogen; m and n = 1; R = R1 = R '= RJ = hydrogen; F = link; Q = -CH, -; E = -NHC (O) -; and other groups are as defined below: and are named as: to O 128. 2- (RS) -I 4- (3,4-Dichlorobenzyl) piperazin-1-ylmet: il] -N- (4-ethyl phenyl) -propionamide dihydrochloride salt. 130. 2- (R) - [4- (3,4-Dichlorobenzyl) piperazin-1-ylmethyl] -N- (4-methylphenyl) cyclopentane-1- (R) -carboxamide dihydrochloride IX are representative compounds of Formula (1) in which T = carbon, U = nitrogen, n = 1; R = R1 = R2 = RJ = hydrogen; F = link; Q • = -CH2-; E = -C (0) NH-; and other groups are as defined below: and are named as: 133. N- i 1- [1 (RS) - [! - (3,4-Dichlorobenzyl) piperidin-4-ylmethyl] -2-methylpropyl} -4-methylbenzamide, Certain compounds of Formula (I) are preferred: (i) A preferred group of compounds is that in which: n is l; m is O or 1; F is a link; Q is an alkylene chain of from 1 to 16 carbon atoms inclusive, more preferably methylene; and E is -C (O) N (R5) -, -SO2N (R5) -, -N (Rβ) C (O) N (R5) - or -N (R6) C (0) -. Among the previously preferred group, a more preferred group of compounds is that in which; R, R1, R2 and R3 are hydrogen; and E is -C (O) N (R5) -, preferably -C (O) NH-. Another more preferred group of compounds is that in which: R, R1, R2 and R3 are hydrogen, and E is -N (R6) C (O) N (R5) -, preferably -NHC (O) NH-. Among these groups of preferred and more preferred compounds, a particularly preferred group of compounds is that in which T and U are nitrogen, another particularly preferred group of compounds is that in which T is nitrogen and U is carbon, yet another group in particular Preferred compound is that in which T is carbon and U is nitrogen, s among the preferred, most preferred and particularly preferred groups in which T and U are both nitrogen or among which T is nitrogen and U is carbon, the groups more preferred are those in which: R4 is alkyl or heteroalkyl, preferably 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl, more preferably 1-methylethyl or 1, 1-dimethylethyl, Ar is a heteroaryl or aryl ring, preferably a pyridin-2-yl, pyridin-3-yl, quinolin-3-yl or 5-methyl-thiophen-2-yl ring or a phenyl ring optionally substituted with one , two or three sub agents selected from alkyl, heteroalkyl, alkoxy, acyl, -SO2R (where R is alkyl, amino or mono- or disubstituted amino), methylenedioxy, hydroxy, halo, amino, mono- or disubstituted amino, -CONR'R "(where R 'YR' are hydrogen or alkyl) or -COOH, more preferably a phenyl ring optionally substituted with one or two substituents selected from methyl, methoxy, fluoro, chloro, dimethylamino, acetyl, hydroxy, amino, methylenedioxy, -S02Me, 2- acetylaminoethyl, 2 - [(R) -amino-3-methylbutyrylamino] ethyl, 2-amino-ethyl, aminomethyl, hydroxymethyl aminocarbonyl, 20 -COOH, more preferably phenyl, 4-chlorophenyl, 3,4-dif-luorophenyl, 4-methylphenyl , 3-methoxyphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-methylenedioxyphenyl, 4-methylsulfonylphenium, 4- [(2-acetyi-amino) ethyl] phenyl, 4-. { 2 - [(R) -amino-3-methylbutyrylamino] ethyl} -phenyl, 4- (2-aminoethyl) phenyl, 4- (aminomethyl) phenyl, 4- (hydroxymethyl) phenyl, 3-aminocarboniiphenyl, 3-carboxyphenyl, 2,5-di-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl or 4-aminophenyl, and Ar 1 is a heteroaryl or aryl ring, preferably 1-acetylindo-3-yl, 3-methylbenzo-thiophen-2-yl or 5-nitrothiophen-3-yl, or a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro, or mono mono or disubstituted amino, more preferably a phenyl ring substituted with one or two substituents selected from methyl, methoxy, chloro, fluoro, trifluoromethyl or nitro, more preferably 4-nitrofenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-nitrophenyl, 3-chloro-4-p-chlorophenyl or 3,4 -dichlorophenyl.

Among the groups where T is carbon and U is previously preferred, more preferred and particularly preferred nitrogen, the most preferred compounds are those in which: R 4 is alkyl or heteroalkyl, preferably methyl, 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl.

Ar is a heteroaryl or aryl ring, preferably a pyridin-2-yl, pyridy-3-yl, quinolin-3-yl or 5-methylthiophen-2-yl ring or a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, acyl -S02R (where R is alkyl, amino or amino mono or disubstrtuye), methylenedioxy, hydroxy, halo, amino, amino mono or disubstituted, -CONR'R "(where R 'and R" are hydrogen or alkyl) or -COOH, more preferably a phenyl ring optionally substituted with one or two substituents selected from methyl, methoxy, fluoro, chloro, dimethylamino, acetyl, hydroxy, amino, methylenedioxy, -SO2Me, 2-acetylaminoethyl, - [(R) amino-3-methylbutyrylamino] ethyl, 2-amino-ethyl, aminomethyl, hydroxymethyl, aminocarbonyl or -COOH, more preferably phenyl, 4-chlorophenyl, 3,4-difluorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-methylenedioxyphenyl, 4-methylsulfonylphenyl, 4 - [(2-acetylamino) -eti l] phenyl, 4-. { 2 - [(R) -amino-3-methylbutyrylamino] ethyl} phenyl, 4- (2-aminoethyl) phenyl, 4- (aminomethyl) phenyl, 4- (hydroxymethyl) phenyl, 3-aminocarbonyl-phenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl or 4-aminophenyl; and Ar 1 is a heteroaryl or aryl ring, preferably 1-acetylindo-3-yl, 3-methylbenzo-thiophen-2-yl, 5-nitrothiophen-3-yl or a phenyl ring optionally substituted with one, two or three substituents selected from between alkyl, heteroalkion, alkoxy, halo, trifluoromethyl, nitro, or mono or disubstrtuid amino, more preferably a phenyl ring substituted with one or two substituents selected from methyl, methoxy, chloro, fluoro, trifluoromethyl or nitro, more preferably 4-nitrophenyl , 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-fluorophenyl or 3,4-dichlorophenyl.

Among the preferred groups above, the particularly preferred compounds are those of formula I in which n and m are 1; F is a link; Q is an alkylene chain of 1 to 6 carbon atoms inclusive; and E is -C (0) N (R5) -, - SO2N (R5) -, -N (R6) C (O) N (R5) - or -N (R6) C (O) -; particularly in which R, R \ R2, and R3 are hydrogen; and E is -CIOJRR5"), particularly where T and U are both nitrogen, particularly where R4 is alkyl or heteroalkyl and R5 is hydrogen, particularly where Ar and Ar1 are aryl, particularly where R4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl, particularly where Ar is a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroacyl , alkoxy, acyl, -S02R (where R is alkyl, amino or mono- or disubstituted amino), methylenedioxy, hydroxy, halo, amino, mono- or disubstituted amino, -CONR'R "(where R 'and R" are hydrogen or alkyl) ) or -COOH; and Ar1 is a phenyl ring optionally substudy with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro or amino mono or disubstrtuid, particularly where Ar is phenyl, -chlorophenyl, 3,4-difluorophenyl, 4-methylphenyl, 3-met oxyphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-methylenedioxyphenyl, 4-methylsulfonylphenyl, 4 - [(2-acetylamino) ethyl] phenyl, 4- (2 - [(R) -amino-3-methylbutyryl -amino] ethyl) phenyl, 4- (2-aminoethyl) phenyl, 4- (aminomethyl) -phenyl, 4- (hydroxymethyl) phenyl, 3-aminocarbonylphenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl, 3,5- dimethoxyphenyl, 3,4-dimethoxyphenyl or 4-aminophenyl; and Ar 1 is 4-n-phenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-fluoro-phenyl or 3,4-dichlorophenyl; particularly wherein R 4 is 1-methylethyl; Ar is 4-methylphenyl; Ar 1 is 3,4-dichlorophenyl; and Q is methylene; for example; N- diclohydrate salt. { 1- (S) - [4- (3,4-dichlorobenzyl) piperazip-1-ylmethyl] -2-methylpropyl) -4-methylbenzamide; or wherein R 4 is 1,1-dimethylethyl; Ar is 4-methylphenyl; Ar 1 is 3,4-dichlorophenyl; and Q is methylene; for example, N- dihydrochloride salt. { 1- (SH4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2,2-dimethylpropyl.} -4-methylbenzamide.

Among those preferred compounds of formula I in which n and m are 1; F is a link; Q is an alkylene chain of 1 to 6 carbon atoms inclusive; R, R \ R2, and R3 are hydrogen; E is -C (O) N (R5) -; T and U are both nitrogen; R4 is alkyl or heteroalkyl and R5 is hydrogen, those in which Ar is an aryl ring are preferred; and Ar 1 a heteroaryl ring; particularly in which R 4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl; particularly in which Ar is a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, acyl, -SO2R (where R is alkyl, amino or amino mono or disubstrtuido), methylenedioxy, hydroxy, halo , amino, amino mono or disubstrtuido, -CONR'R "(where R 'and R" are hydrogen or alkyl) or -COOH; and Ar 1 is 1-acetylindo-3-ylo, 3-methylbenzothiophen-2-yl or 5-nitrothiophen-3-yl.

They are also preferred among those preferred compounds of Formula I wherein n and m are 1; F is a link; Q is an alkylene chain of 1 to 6 carbon atoms inclusive; R, R \ R2 and R3 are hydrogen; and E is C (O) N (R5) -; T and U are both nitrogen; R 4 is alkyl or heteroalkyl and R 5 is hydrogen, those in which Ar is an heteroaryl ring; and Ar1 is an aryl ring; particularly in which R4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl; particularly where Ar is pyridin-2-yl, pyridin-3-yl, quinolin-3-yl or 5-ethylthiophen-2-yl. Pyridin-3-yl, quinolin-3-yl or 5-methylthiophen-2-yl; and Ar1 is a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro or mono mono or disubstituted amino; particularly in which Ar1 is 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-fluorophenyl or 3,4- dichlorophenyl.

Among those preferred compounds of formula I, wherein n and m are 1; F is a link; Q is an alkylene chain of 1 to 6 carbon atoms inclusive; R, R1, R2 and R3 are hydrogen and E is -C (O) N (R5) -, those in which T is nitrogen and U is carbon; particularly wherein R4 is alkyl or heteroalkyl and R5 is hydrogen; particularly where Ar and Ar1 are aryl; particularly wherein R 4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl; particularly in which Ar is a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, acyl, -S02R (where R is alkyl, amino or amino mono or disubstrtuido), methylenedioxy, hydroxy, halo , amino, mono or disubstituted amino, -CONR'R "(where R 'and R" are hydrogen or alkyl) or -COOH; and Ar1 is a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro or amino mono or disubstrtuido; particularly in which Ar is phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-methylenedioxyphenyl, 4-methylsulfonylphenyl, 4 - [(2) -acetylamino) ethyl] phenyl, 4-. { 2- [(R) -amino-3-methylbutyrylamino] ethyl} phenyl, 4- (2-aminoethyl) phenyl, 4- (aminomethyl) -phenyl, 4- (hydroxymethyl) phenyl, 3-aminocarbonylphenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4- dimethoxyphenyl or 4-aminophenyl; and Ar 1 is 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-n-phenyl, 3-chloro-4-fluorophenyl or 3,4-dichlorophenyl; particularly wherein R 4 is 1-methylethyl; Ar is 4-methylphenyl; Ar 1 is 3,4-dichlorophenyl; and Q is methylene; and N- 1- (S) - dihydrochloride salt is named. { 4- (3,4-dichlorobenzyl piperidin-1-ylmethyl] -methylpropyl H-methylbenzamide, or wherein R 4 is 1-methylethyl, Ar is 4- (2-aminoethyl) phenyl, Ar 1 is 3,4-dichlorophenyl, and Q is methylene, and is referred to as N- 1- (R) - [4- (3,4-dichlorobenzyl) piperidin-1-ylmethyl] -2-methyl-propyl} -4- (2- aminoethyl) benzamide.

Among those preferred compounds of formula I in which n and m are 1; F is a link; Q is an alkylene chain of 1 to 6 carbon atoms inclusive; R, R \ R2 and R3 are hydrogen; and E is -C (O) N (R5) -; T is nitrogen and U is carbon; R4 is alkyl or heteroalkyl and R5 is hydrogen, those in which Ar is a heteroaryl ring are preferred; and Ar1 is an aryl; particularly in which R 4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl; particularly wherein Ar is pyridin-2-yl, pyridin-3-yl, quinolin-3-yl or 5-methylthiophen-2-yl; and Ar1 is an optionally substi tuted phenyl ring with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, halo trifluoromethyl, nitro or amino mono or disubstrtuido; particularly in which Ar1 is 4-n-phenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-fluorophenyl or 3,4- dichlorophenyl; particularly wherein R 4 is 1-methylethyl; Ar is 5-methylthiophen-2-yl; Ar 1 is 3,4-dichlorophenyl; and Q is methylene; and it is named as, N- hydrochloride salt. { 1- (R) - [4- (3,4-dichlorobenzyl) piperidin-1-ylmethyl] -2-methyl-propyl} -5-methylthiophen-2-carboxamide.

Among those preferred compounds of formula I, wherein n and m are 1; F is a link; Q is an alkylene chain of 1 to 6 carbon atoms inclusive; R, R \ R2 and R3 are hydrogen; and E is -C (O) N (R5) -, those in which T is carbon and U is nitrogen; particularly wherein R4 is alkyl or heteroalkyl; and R5 is hydrogen; particularly in which Ar is an aryl or heteroaryl ring; and Ar1 is an aryl ring; particularly wherein R 4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl; particularly in which Ar is a pyridin-2-yl, pyridin-3-yl, quinolin-3-yl or 5-methythiophen-2-yl ring, or a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, acyl, -S02R (where R is alkyl, amino or amino mono or disubstrtuido), methylenedioxy, hydroxy, halo, amino, amino mono or disubstituted, -CONR'R "(where R 'and R" are hydrogen or alkyl) or -COOH; and Ar1 is an optionally substi tuted phenyl ring with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro or mono mono or disubstituted amino.

Among those preferred compounds of formula I in which n and m are 1; F is a link; Q is an aikylene chain of 1 to 6 carbon atoms inclusive; and E is -C (O) N (R5) -, SO2N (R5) -, -N (R?) C (O) NR5) - or -N (R6) C (O) -, those in the that R, R \ R2 and R3 are hydrogen; and E is -N (Rβ) C (O) N (R 5) -; particularly where T and U are both nitrogen; particularly wherein R4 is alkyl or heteroalkyl; and Rs and R6 are hydrogen; particularly where Ar and Ar1 are aryl; particularly wherein R4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl, particularly where Ar is a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyo, alkoxy, acyl, -SO2R (where R is alkyl, amino or amino mono or disubstrtuido), -CONR'R "(where R 'and R "are hydrogen or alkyl) or COOH, and Ar1 is a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, halo trifluoromethyl, nitro or amino mono or disubstrtuid; that Ar is phenyl, 4-chlorophenyl, 3,4-difluorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-methylenedioxyphenyl, 4-methylsulfonylphenyl, 4- [(2-acetylamino) ethyl ] phenyl, 4- {2 - [(R) -amino-3-methylbutyryl-amino] ethyl} phenyl, 4- (2-aminoethyl) phenyl, 4-aminomethyl) -phenyl, 4- (hydroxymethyl) phenyl, 3-aminocarbonylphenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl or 4-aminophenyl, and Ar 1 is 4-nitrophenyl, 4-trifluoromethyiphenyl, 4-chlorophenyl, 3,4 -difluoro-phenyl, 2,3-dichlorophenyl, 3-, methyl-4-nitrophenyl, 3-chloro-4-fluoro-phenyl or 3,4-dichlorophenyl, particularly where R 4 is 1-methylethyl; methoxyphenyl, Ar1 is 3,4-dichlorophenyl, and Q is methylene; Example, 1-. { 1 (R) - [4- (3,4-Dichlorobenzyl) piperazin-1-ylmethyl-2-methyl-propyl} -3- (3-methoxyphenyl) urea.

Among those preferred compounds of formula I in which n and m are 1; F is a link; Q is an alkylene chain of 1 to 6 carbon atoms inclusive; R, R \ R2 and R3 are hydrogen; and E is -N (R6) C (0) NR5) -, those in which T is nitrogen and U is carbon; particularly wherein R4 is alkyl or heteroalkyl; and R5 and R6 are hydrogen; particularly in those where Ar and Ar 1 are aryl; particularly wherein R 4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl; particularly where Ar is a phenyl ring optionally substrtuid with one, two or three substrtuents selected from alkyl, heteroalkyl, alkoxy, acyl, -S02R (where R is alkyl, amino or amino mono or disubstrtuye), methylenedioxy, hydroxy, halo , amino, mono or disubstituted amino), methylenedioxy, hydroxy, halo, amino, mono mono or disubstituted amino, -CONR'R "(where R 'and R" are hydrogen or alkyl) or -COOH; and Ar1 is a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro or mono mono or disubstituted amino; particularly in which Ar is phenyl, 4-chlorophenium, 3,4-difluorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-methylenedioxyphenyl, 4-methyl-sulfonylphenyl, 4 - [( 2-Acetylamino) ethyl] phenyl, 4- 2 - [(R) -amino-3-methylbutyrylamino] ethyl} -phenyl, 4- (2-aminoethyl) phenyl, 4- (amino-methyl) phenyl, 4- (hydroxymethyl) phenyl, 3-aminocarbonylphenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl, 3,05-dimethoxyphenyl, 3, 4-dimethoxyphenyl or 4-aminophenium; and Ar 1 is 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-fluoro-phenyl or 3,4-dichlorophenyl; particularly wherein R 4 is 1-methylethyl; Ar is 3-methoxyphenyl; Ar 1 is 3,4-dichlorophenyl; and Q is methylene; for example, 1-. { 1- (RH 4 - (3,4-dichlorobenzyl) piperidin-1-ylmethyl] -2-methylpropyl.} - 3 - (3-methoxyphenyl) urea.

Among those preferred compounds of formula I in which n and m are 1; F is a link; Q is an alkylene chain of 1 to 6 carbon atoms inclusive; R, R \ R2 and R3 are hydrogen; and E is -N (Rβ) C (O) NC (R5) -, those in which T is carbon and U is nitrogen; particularly wherein R4 is alkyl or heteroalkyl; and R5 and Rβ are hydrogen; particularly where Ar and Ar1 are aryl; particularly wherein R 4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl; particularly in which Ar is a phenyl ring optionally substituted with one, two or three substrtuents selected from alkyl, heteroalkyl, alkoxy, acyl, -S02R (where R is alkyl, amino or amino mono or disbustrtuid), methylenedioxy, hydroxy, halo , amino, mono or disubstituted amino, -CONR'R "(where R 'and R" are hydrogen or alkyl) or -COOH; and Ar1 is a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro or mono- or disubstituted amino.

Finally, preferred compounds of formula I are those in which T is carbon and U is nitrogen; n is 1; m is 0; F is a link; Q is an alkylene chain; and E is -C (O) N (R5) -, -SO2N (R5) -, -N (R6) C (O) N (R5) - or -N (Rβ) C (O) -; particularly in which R, R1, R2 and R3 are hydrogen; and E is -C (O) N (R5) -; particularly wherein R4 is alkyl or heteroalkyl; and R5 is hydrogen; particularly in which Ar is an aryl or heteroaryl ring; and Ar1 is an aryl ring; particularly wherein R 4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl; particularly wherein Ar is pyridin-2-yl, pyridin-3-yl, quinolin-3-yl or 5-methylthiophen-2-yl, or a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, acyl, -S02R (where R is alkyl, amino or amino mono or disubstrtuye), methylenedioxy, hydroxy, halo, amino, mono mono or disubstituted amino, -CONR'R "(where R 'and R" are hydrogen or alkyl) or -COOH; and Ar1 is an optionally substrtuided phenyl ring with one, two or three substrtuents selected from alkyl, heteroalkion, alkoxy, halo trifluoromethyl, nrtro or amino mono or disubstituted amino.

Also, among those preferred compounds of formula I in which T is carbon and U is nrtrogen; n is 1; m is 0; F is a link; Q is an alkylene chain; and E is -COMR5) -, -SO2N (R5) -, - (NRβ) C (O) N (R5) - or N (R6) C (O) -, those in which R, R1, R2 are preferred and R3 are hydrogen; and E is - < NRβ) C (O) N (R 5) -; particularly wherein R4 is alkyl or heteroalkyl; and R5 and R6 are hydrogen; particularly in which Ar is an aryl or heteroaryl ring; and Ar1 is an aryl ring; particularly wherein R 4 is 1- ethylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl; particularly wherein Ar is pyridin-2-yl, pyridin-3-yl, quinolin-3-yl or 5-methylthiophen-2-yl, or a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, acyxi, acyl, S02R (where R is alkyl, amino or mono- or disubstituted amino), methyndiioxy, hydroxy, halo, amino, mono- or disubstituted amino, -CONR'R "(where R 'and R" are hydrogen or alkyl) ) or -COOH; and Ar1 is a phenyl ring optionally substituted with one, two or three substrtuents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro or amino mono or disubstituted amino.

Particularly preferred exemplary compounds of the invention at this time are the following: N- dihydrochloride salt. { 1- (S) - [4- (3,4-dic.orobendl) -piperazin-1-ylnr.ethyl] -2-methylpropyl H-methylbenzamide. N- dihydrochloride salt. { 1- (SH4- (3,4-Dichlorobenzyl) -pipßrazin-1-ylmethyl] -2,2-dimethylpropyl-H-methylbenzamide, 1-. {1- (R) - [4- (3,4-dichlorobenzyl) piperazine -1-ylmethyl] -2-methylpropyl.} - 3 - (3-methoxyphenii) urea N-. {1- (RSH 4 - (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl} -3,4-Methylenedioxybenzamide N- ({1- (SH4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2,2-dimethylpropyl H-methylsulphonylbenzamide dihydrochloride N- dihydrochloride salt. {1- (S) - [4- (3,4-Dichlorobenzyl) piperazin-1-ylmethyl] -2,2-dimethylpropyl} -4-acetylbenzamide N- (1- (S-) dihydrochloride ) - [4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2,2-dimethylpropyl.} - 4-cimethylaminobenzamide N- (1-) (4-) dihydrochloride salt 3,4-dichlorobnsyl) piperazin-1-ylmethyl] -2,2-dimethylpropyl.} - 5-methylthiophen-2-carboxamide N- 1- (RSH 4 - (3,4-dichlorobenzyl) piperazin-1-ylmethi] -2,2-dimethylpropyl.) -4-methoxybenzamide, N-. {1 - (RS) - [4- (3,4-dichlorobenzyl) piperazin-1-methylmethyl] -2,2-dimethylpropyl. -3-cyanobenzamide, N-. {1- (RSH4- (3,4-d) iclorobenzyl) pipßrazin-1-ylmethyl] -2-methylpropyl) -3,4-difluorobenzamide.

N- dihydrochloride salt. { 1- (RSH 3 -methyl-4- (3,4-dichlorobendl) piperazin-1-ylmethyl-2-methylpropyl} -4-methylbenzamide, N-4- dihydrochloride salt (RH 4 - (3,4-dichlorobendl) piperidin-1-ylmethyl] -2-methylpropyl.} -1- [4- (2-acetylaminoethyl)] benzamide, 4- [2- (2- (R) -amino-3-methylbutyrylamino) ethyl dihydrochloride] -N- { 1- [4- (3,4-dichlorobendl) piperidin-1-ylmethyl] -2-methylpropyl.} -benzamide N- (4-) - (4) -hydrochloride salt - (3,4-Diorobendl) piperidin-1-ylmethyl] -2,2-dimethylpropyl.} -1- [4- (2-aminoethyl)] benzamide N-. {4- (RH4-) hydrochloride salt (3,4-dichlorobnsyl) piperidin-1-ylmethyl] -2,2-dimethylpropyl.] -1- (4-aminomethyl) benzamide. 1-. {1- (RSH4- (3,4-didorobendl) piperazin -1-ylmethyl] -2-methylpropyl] -3- (3-aminocarbonylphenyl) urea N- ({4- (R) - [4- (3,4-dichlorobendl) piperidin-1-hydrochloride salt ilmethyl] -2,2-dimethylpropyl.) -1-quinoline-3-carboxamide, 1- ({1- (SH4- (3,4-dichlorobenzyl) piperidin-1-ylmethyl] -2,2-dimethylpropyl > 3- (3-carboxyphenyl) urea 1- { 1- (S) - [4- (3,4-dichlorobendl) piperidin-1-ylm ethyl] -2,2-dimethylpropyl} -3- (3-aminocarbonylphenyl) urea. 1- Hydrochloride salt. { 1- (SH4- (3,4-dichlorobenzyl) piperidin-1-ylmethyl] -2-methylpropyl) -3- (3,5-dimethoxyphenyl) urea. 1-. { 1- (RS) - [4- (3,4-didorobendl) piperidin-1-ylmethyl} -2-methylpropyl} -3- (3,4-dimethoxyphenyl) urea. N-. { 1- (RSH4- (4-chlorobendl) piperazin-1-ylmethyl] -2-methylpropyl.} -4-methylbenzamide.

N-. { 1- (RS) - [4- (4-Nitrobenzyl) piperazin-1-ylmethyl] -2-methylpropyl} -4-methyl-β-pzamide.

N-. { 1- (RSH4- (3,4-difluorobendl) piperazin-1-ylmethyl] -2-methylpropyl.} -4-methylbenzamide, N-. {1- (RSH4- (3,4-didorob? Ndl) pip? -1-ilmethyl] -2, 2-dimethylpropyl} -4-methylbenzamide. N-. { 1 - (RS) - [4- (2,3-didorobendl) piperazin-1-methylmethyl] -2-methylpropyl} -4-methylbenzamide. N-. { 1 - (RSH 4 - (3-methyl-4-nitrobendl) pipßrazin-1-methylmethyl] -2-methylpropyl.) -4-methylbenzamide N-. {1- (RSH 4 - (3-chloro-4-fluorobenzyl) ) pipßrazin-1-ylmethyl] -2-methylpropyl.} -4-methylbenzamide, N-. {1- (R) - [4- (3-chloro-4-fluorob-yl) piperazin-1-ylmethyl] -2 , 2-dimethylpropyl, 4-methylbenzamide, N-. {1- (RH4- (3-methylbenzthiophen-2-ylmethyl) piperazin-1-ylmethyl] -2,2-dimethylpropyl} -4-methylbenzamide N-. {1- (R) - [4- (1-Acetylindol-3-ylmethyl) piperazin-1-ylmethyl] -2,2-dimethylpropyl} -4-methylbenzamide N- {1} - (RH 4 - (5-Nitropiofßn-3-ylmethyl) piperazin-1-ylmethyl] -2,2-dimethylpropyl.} -4-methylbenzamide N- 1- (RH 4 - (4-nrtrobendl) piperazin-1-ylmethyl) ] -2-methylpropyl.} -4-methylbenzamide N- ({4- (R) - [4- (4-nrtrobenzyl) piperidin-1-ylmethyl] -2,2-dimethylpropyl} hydrochloride salt. - 1-pyridine-2-carboxamide, N- 4- (R) - [4- (4-nrtrobendl) piperidin-1-ylmethyl] -2,2-dimethylpropyl.] -1-pyridine-2-carboxamide. - { 4- (R) - [4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2,2-dimethylpropir) -1-quinoline- 3-carboxamide. 1 - . 1 - . 1 -. { 1 - (R) - [4- (3,4-Dichlorobendl) piperidin-1-methylmethyl] -2-methylpropyl} -3-. { 3-methoxyphenyl) urea. Salt N -hydrochloride. { 4- (R) - [4- (3,4-didorobendl) piperidin-1-ylmethyl-2-methylpropi} -1- (3-methyl) thiophene-2-carboxamide. N -hydrohydrate salt. { 4- (R) - [4- (3,4-diordobendl) piperidin-1-ylmethyl] -2-methylpropyl} - 1 -. { 4- (2-aminoethyl)] benzamide. N- 4- (RSH4- (3,4-doorobendl) piperidin-1-ylmethyl] -2-methylpropyl} -1- (4-methyl) benzamide N- {4 - (R) hydrochloride salt - [4- (3,4-dichlorobendl) piperidin-1-ylmethyl] -2,2-dimethylpropyl] -1- (4-methyl) bßnzamide N-. {4- (R) - [4- (3,4-dichlorobendl) piperidin-1-ylmethyl] -2,2-dimethylpropyl.} -1- (4-methylsulfonyl) benzamide N- ({4- (R) - [4- ( 3,4-dichlorobendl) piperidin-1-ylmethyl] -2l2-dimethylpropyl.} -1- (5-methylthiophen) -2-carboxamide N-. {4- (R) - [4- (3,4 -dichlorobenzyl) piperidin-1-ylmethyl] -2,2-dimethylpropyl.} -1- (4-hydroxymethyl) benzamide Salt trifluoroacetate of 1- {1- (RH4- (3,4-dichlorobendl) piperidin-1-ylmethyl] -2,2-dimethylpropyl.} - 3 - (3-methoxyphenyl) urea 1-. {1- (RH4- (3,4-dichlorobendl) piperidin-1-ylmethyl] 2- methylpropyl.} - 3 - (3,4,5-trimethoxyphenyl) urea 1-. {1- (RH 4 - (3,4-dichlorobendl) piperidin-1-ylmethyl] -2,2-dimethylpropyl. -3- (3,4,5-trimethoxyphenyl) urea.1 -. {- 1 - (R) - [4- (3,4-dichlorobenzyl) piperidin-1-methylmethyl] -2-methylpropyl} -3 - (3-methylsulfonylaminopheni i) urea 1 -. { 1 - (R) - [4- (3,4-dichlorobnster) piperidin-1-ylmethyl] -2-methylpropyl} -3- (3-acetylaminophenyl) urea. 1 -. { 1 - (R) - [4- (3,4-dichlorobnster) piperidin-1-ylmethyl] -2-methylpropyl} -3- (3-N-methylsulfoni-N-methylaminophenyl) urea. 1-. { 1- (R) - [4- (3,4-dichlorobendl) piperidin-1-ylmethyl] -2-methylpropyl} -3- (3-dimethylaminosulfonylaminophenyl) urea.

The compounds of the present invention can be prepared in a variety of different ways known to those skilled in the art. Preferred methods include, but are not limited to, the general synthetic procedures described below.

The starting materials and reagents used in the preparation of these compounds are available either commercially from suppliers such as Aldrich Chemical Co., (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie, or Sigma (St. Louis, Missouri, USA), or are prepared by methods conoddos by those experts in the field, following the procedures established in references such as Fieser and Fieser's Reagents for Organic Synthesis, volumes 1-17 (John Wiley and Sons, 1991); Rodd 's Chemistry of Carbon Compounds, volumes 1-5 and supplements (Elsevier Sdence Publishers, 1989), Organic Reactions, volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 1992), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are purely illustrative of some methods by which the compounds of this invention can be synthesized, being able to carry out various modifications of these schemes, which will be suggested to an expert in the field in reference to this discovery. The starting materials and intermediates of the reaction can be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. These materials can be characterized by conventional methods, including physical constants and spectral data.

Synthesis of the compounds of the formula (I) In general, the compounds of the formula (I) in which n, m, R, R? R2, R3, R4, R5, Q and Ar1 are as defined above are prepared from aminoalkyl derivatives of formulas II (a-c), and carboxyalkyl derivatives of formulas II (d-f), as shown in Figure 1 below. pd (T &U = N) He (T = N; U = C) ^ S- 1 pf (T = C; U = N) The synthesis of the compounds of formulas II (af) and their conversion to compounds of Formula (I) is described in detail in schemes AE and FJ, respectively.

Synthesis of the compounds of formula ll (af) Preparation of the compounds of formula Ha A compound of formula Ha wherein n is 1 or 2, m is at least 1, and R, R? R2, R3, R4, R5, Q and Ar1 are as defined above is prepared as shown in scheme A below.

Esauema A Ar, - PG-N (R5) CR3R4 (In general, the compounds of formula Ha are prepared in two steps by first converting a compound of formula 1 or 2 into an N-protected aminoalkyl derivative of formula 3 through the methods (a) or (b) respectively, followed by elimination of the amino protecting group at 3 as described in detail below.

Preparation of compounds of formula 3 Method (a) In method (a), an N-protected aminoalkyl derivative of formula in which PG is an amino protecting group (eg, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), benzyl and the like) is prepared by reacting a compound of formula 1 with a compound of formula 4 PG-N (R5) CR3R4 (CHR) m.?X 4 wherein X is an aldehyde (-CHO), ketone (-C (O) R where R is alkyl), carboxy (-COOH) or a reactive carboxy derivative, for example, acid halide. The reaction conditions used depend on the nature of the group X. If X is an aldehyde or ketone group, the reaction is carried out in reducing aminadon conditions, for example in the presence of a suitable reducing agent (for example sodium danoborohydride, sodium triacetoxyborohydride, and the like), and an organic acid (e.g. glacial acetic acid, trifluoroacetic acid and the like), at room temperature to yield 3 directly. Suitable solvents for the reaction are halogenated hydrocarbons (for example 1, 2-dooroethane, doroform and the like). If X is a carboxy group, the reaction is carried out in the presence of a suitable coupling agent (for example NN-dicidohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, and the like) in a suitable organic solvent (e.g. methylene duroxide, tetrahydrofuran and the like) to yield an amide intermediate. Reduction of the amide intermediate with a suitable reducing agent (for example, diborane, lithium aluminum hydride and the like) in an etheric organic solvent such as ether or tetrahydrofuran yields a compound of formula 3. If X is an acid derivative such as hydrochloric acid, the reaction is carried out in the presence of a suitable base such as triethylamine, pyridine in an organic solvent (for example methylene duroxide, dichloroethane, N, N-dimethylformamide, and the like) to yield an amide intermediate which is a in turn reduced to the corresponding compound of formula 3 as described above.

In general, the compounds of formula 4 are either commercially available or can be prepared by well-known methods in the field of organic chemistry. Some examples of such procedures are illustrated and described in detail below.

, C0R (m-l = 1 or 2) (iv) PG-N (R5) CR3R * (CHR) m., COCI 4 (ml »1 or 2) (i) an aldehyde of formula 4 (X is a -CHO) in which m-1 = 0 is prepared in a suitable from the corresponding "natural or non-natural amino acid" of formula 4 wherein m-1 = 0 and X is a carboxy group by reducing the carboxy group to an aldehyde group with a suitable reducing agent such as DIBAL-H®. An aldehyde of formula 4 in which m-1 = 1 or 2 can be prepared, if desired, from an aldehyde or ketone (X = - COR where R is alkyl) of formula 4 in which m-1 = 0 in condidones of Wittig's reaction. For example, an aldehyde 4 in which m-1 = 1 and R is hydrogen or alkyl is prepared by condensing the corresponding aldehyde or ketone of formula 4 wherein m-1 = 0 with a Wittig reagent derived from doromethyl methyl ether, followed by the acid hydrolysis of the resulting enol ether intermediate. An aldehyde 4 in which m-1 = 2 and R is hydrogen or alkyl can be prepared by condensing the corresponding aldehyde or ketone 4 wherein m-1 = 0 with a Wittig reagent derived from bromoacetate or from 2-bromopropionate respectively, followed of the sequential reduction of the double bond and the ester group in the resulting unsaturated cfc./J ester intermediate: The double bond is reduced under hydrogenated reaction conditions and the ester group is reduced to the aldehyde group with a reductive agent such as DIBAL- H®. The acetone of formula 4 wherein m-1 = 0 can be prepared from the cc-amino acids of formula 4 by converting the < r-amino acids 4 to a Weinreb amide, followed by treatment with an organometallic reagent, such as a Grignard reagent or an organolithium reagent of formula RMgBr or RU (where R is an alkyl group) respectively.

In general, both natural and non-natural amino acids are commercially available from suppliers such as Aldrich and Bachem. Examples of non-natural amino acids include homoserin, homodsteine, N-a-methylarginine, norieudine, N-methylisoleudin, phenylglycine, hydroxyproline, pyroglutamine, ornithine, 2-aminoisobutyric acid, chi-cyclohexylalanine, 3- (1-naphthyl) alanine, 3 - (2-naphthyl) alanine, citruyine, pipecolinic acid, piperazic acid, 4-chlorophenylalanine, 4-fluorophenylalanine and sarcosine. The synthesis of α-aminodads 4 in which R 3 and R 5 together form a morpholino ring and a thiomorpholino ring and R 4 is hydrogen, are described in Kogami Y., Okawa K .., Bull. Chem. Soc. Jpn., 60, 2963, (1987). (ii) compounds of formula 4 wherein X is a carboxy group and n-1 0 can be prepared from the corresponding aldehydes of formula 4 (X is -CHO), prepared as described in (i) above, by oxidizing the aldehyde group as a suitable oxidant people (e.g., potassium permanganate and the like). Alternatively, they can be prepared from the J3-unsaturated esters formed in the Wittig reaction, see (i) above by reducing the double bond followed by hydrolysis of the ester group by well-known methods in the art. (iii) Compounds of formula 4 wherein X is -C (O) R (where R is alkyl) and m-1 = 0, 1 or 2 can be prepared by alkylating the corresponding aldehyde of formula 4 (X is -CHO) with a Grignard reagent followed by the oxidization of the resulting alcohol with a suitable oxidizing agent such as pyridinium dichromate and the like. Alternatively, they can be prepared from the corresponding acid of formula 4 as described in (i) above. (iv) Compounds of formula 4 in which X is an acid derivative, for example an acid chloride, can be prepared from the corresponding compounds of formula 4 (X is -COOH), prepared as described in (iii) above, browning the carboxy group with a suitable chlorinating agent (e.g., oxalyl chloride, thionyl chloride and the like) in a suitable organic solvent such as doruro of methylene and the like.

Alternatively, a compound of formula 3 can be prepared by reacting a compound of formula 1 with an alkylating agent of formula PG-N (R5) CR3R4 (CHR) mY 5 Wherein Y is a leaving group in alkylated condions such as halo (for example, doro, bromo, or iodo) or a sulfonyloxy group (for example methylsutfonyloxy or 4-methylphenylsulfonyloxy or trifluoromethylsulfonyloxy). The reaction is carried out in the presence of a base such as sodium carbonate, sodium hydride, triethylamine and the like. Suitable solvents are aprotic organic solvents such as tetrahydrofuran, N, N-dimethylformamide and the like.

In general, compounds of formula 5 wherein Y is a halo or sulfonyloxy group can be prepared from compounds of formula 4 by reducing the aldehyde, ketone or carboxy group to an alcohol, followed by treatment with a suitable halogenating agent (by example thionyl doride, thionyl bromide, carbon tetrabromide in presence of triphenylphosphine and the like) or a supthanelladon agent (for example methylsulfonyl chloride, paratoluenesulfonyl chloride and triflic anhydride) respec tively. Suitable aldehyde, ketone or carboxy reducing agents include lithium aluminum hydride, borane and the like.

In some cases, a compound of the formula H can be prepared by reacting a compound of formula 1 with a nitro-olefin conjugate in Michael adidon reaction conditions, followed by reduction of the nitro group in standard hydrogenated conditions. Conjugated nitro-defines are commercially available or can be prepared by methods described in the literature, for example see Corßy, E. J. et al. J. Am. Chem. Soc, 100 (19), 8924-5 (1978). A detailed description of the synthesis of an N-alkylaminopiperazine of formula Ha by this method is presented in example 2.

Method (b) In method (b), an N-protected aminoalkyl derivative of formula 3 is prepared by reacting a compound of formula 2 with a compound of formula 6 Ar1-Q-J 6 (wherein J is a group X or Y as defined above) using the reaction conditions described in method (a) above. Method (b) is particularly suitable for preparing compounds of formula Ha wherein Q contains an amido or carbonyl group.

In general, the compounds of formula 6 are commercially available or can be prepared by well-known methods in the field. For example, the aralkyl halides and the aralkyl ades, such as benzene bromide, bromide 3,4-dinobenzene, phenylacetic acids and 2-phenylpropionic acids are available commerically. Others can be prepared from suitable starting materials such as phenylacetic acid, phenylpropanol, 2-pyridineethanol, nicotinic acid, etc., following the procedures described for the synthesis of compounds of formulas 4 and 5 in method (a) above. Compounds of formula 6 in which Q is an alkylene chain interrupted by an amido group and J is a halo or sulphonyloxy group can be prepared following the procedures described in the State Patent No. 4,880,808.

Conversion of the compounds of formula 3 to compounds of formula Ha.

In step 2, N 3 -protected aminoalkyl derivatives, formed in Step 1 by method (a) or (b), are converted to a compound of formula Ha by eliminating the amino-protecting group. The conditions used depend on the nature of the proton group. For example, if the proton group is the tert-butoxycarbonyl group, it is removed under acid hydrolysis reaction conditions, whereas if it is the benzoyl group, it is removed under catalytic hydrogenation reaction conditions.

A compound of formula Ha in which R5 is other than hydrogen can be prepared, if desired, by alkylating the corresponding compound of formula Ha in which R5 is hydrogen with an alkylating agent R '? where Y is a leaving group under alkylate conditions, using the reaction conditions described in method (a) of scheme A.

The compounds of formulas 1 and 2 are prepared as described below by reacting a piperazine or a homopiperazine of formula 7 with a compound of formula 6, or 4 or 5 respec- tively, followed by elimination of the amino-protecting group, using the condidones. of reacton described in method (a) above.

The piperazines and homopiperazines of formula 7 such as piperazine, 2- or 3-methylpiperazines, homopiperazine, are available commercially. The piperazines 7 can also be prepared by the methods described in European Patent Publication No. 0685844 and US Patent No. 3,267,104. Detailed descriptions of the synthesis of a compound of formula 1 are presented in which n = 1 by this method in examples 1, 5 and 7.

Preparation of the compounds of formula lb. A compound of formula ilb in which m is at least 1 and n, R, R 2, R 3, R 4, R 5, Q and Ar 1 are as defined in the Summary of the invention can be prepared from a compound of formula 8 wherein n is 0, 1 or 2, respec- tively, as illustrated in Scheme B below.

Scheme B In general, an aminoalkyl derivative of formula 11b is prepared by reacting a compound of formula 8 with a compound of formula 4 or 5 (see Scheme A) to yield an N-protected aminoalkyl derivative of formula 9, followed by removal of the proton group of amino. The conversion of a compound of formula 8 to a compound of formula IIb is carried out in the reaction conditions described in method (a) of Scheme A above.

Compounds of formula 8 in which n is 0, 1 or 2 can be prepared from suitable pyrrolidinones, piperidinones or 4-keto-odahydroazepines protected in N, Respectively, by procedures conoddos. Some examples of said processes are described below: (i) compounds of formula 8 are prepared in which n is 0 or 1 and Q is an alkylene chain by reacting a N-protected 3-pyrrolidinone or a N-protected 4-piperidinone. suitable, respec- tively, with a readitive of Wittig Br "(Ph) 3P + -alkylene-Ar.sub.1 to yield an alkene intermediate.The reduction of the olefinic bond, followed by the elimination of the amino-protecting group then gives compounds of formula 8.

The 4-hydroxypiperidines, 3-pyrrolidinoles, 3-pyrrolidinones and 4-piperidinones are commercially available. 4-keto-odahydroazepine can be prepared from 2,4-diketo-N-benzylhexahydroazepine (see Hong Hu G. and Erik Jagdmann Jr., Tet.

Lett., 36 (21), 3659-62 (1995) by conoddo procedures.

Detailed descriptions of the synthesis of compounds of formula IIb are presented in Examples 3 and 4 by this method.

Preparadón of the compounds of formula He A compound of formula He in which m is 0 or 1, R 3 is hydrogen and n, R, R 2, R 4, R 5, Q and Ar 1 are as defined in the Summary of the invention can be prepared from a compound of formula 14 or 10, respec- tively, as illustrated in Scheme C below.

Scheme C 12 »(m - 1) i2-2 (m = 0) 1. reduction 2. N? 0 CRO5 ' IIc (m = 0 or 1) A compound of formula He in which m is 1 can be prepared, as shown in method (a), by reacting a compound of formula 10 with a phosphonate ylide of formula 11 in Wittig reaction conditions, is dedr, in the presence of a strong non-nucleophilic base (e.g., sodium hydride, sodium amide, and the like) and in a suitable aprotic organic solvent (e.g., tetrahydrofuran and the like) to yield an α, β-unsaturated ester of formula 12. The ester d ß-unsaturated 12 becomes the corresponding alcohol derivative 13a (m = 1) by first converting 12 to an aldehyde, followed by treatment with an organometallic readivo such as a Grignard readivo or an organolithium readivo of formula R MgBr or R Li, respectively. The double bond is reduced in hydrogenation reaction conditions and the ester group is reduced to the aldehyde group with a suitable reductive agent such as DIBAL-H®. The alcohol 13a is then converted to a compound of the formula He by oxidization of the alcohol group to the ketone group, followed by treatment with an amine of the formula NH (R5) in reductive aminadon reaction conditions. The oxidon reaction is carried out with suitable oxidizing reagents, such as pyridinium dichromate in an aprotic solvent, such as dimethylformamide and the like.

A compound of formula He in which m is 0 can be prepared, as shown in method (b) from a compound of formula 14 by converting 14 into the corresponding alcohol derivative 13b (m = 0) by reducing the group ester to aldehyde followed by treatment with an appropriate organometallic readivo. The compound 13b is then converted to the compound He in which m is 0 by carrying out the oxidation and reducing aminadon steps, using the reaction conditions described above. Compounds of formula He can also be prepared in which m is 0 by the methods described in the PCT publication application No. WO 92/12128.

Compounds of formula in which n is 0, 1 or 2 are prepared by N-alkylating a 3-pyrrolidone, a 4-piperidone or a 4-keto-odahydroazepine, respec- tively with a compound of formula Ar1-QY wherein Y is a leaving group in alkylation conditions, as described in method (a) (2) of Scheme A.

Compounds of formula 14 (n = 1) are prepared by N-alkylating an ethyl isonipecotate with a compound of formula Ar1-QY wherein Y is a leaving group under alkylated conditions as described in method (a) from Scheme A.

Detailed descriptions of the synthesis of a compound of the formula lie are provided in which m is 0 or 1 in examples 9 and 10, respec tively.

Preparation of compounds of formula lid and He A carboxyalkyl derivative of formula lid (U = N) and He (U = C) in which m, n, R1, R2, R3, R4, Q and Ar1 are as defined in the Summary of the invention from a compound of formula 1 or 8, respec- tively, as illustrated in Scheme D below.

Scheme D 1 123 (U = N) íacu.

A carboxy derivative of formula lid or He is prepared, as shown above, a compound of formula 1 or 8 having to react with an alkylating agent of formula in which Y is a halo or sulfonyl group, followed by hydrolysis of the ester group. The alkylation reaction is carried out according to the reaction conditions previously described (see Scheme A, method (a)). The hydrolysis of the ester group is carried out in the presence of an aqueous base (for example sodium hydroxide, lithium hydroxide and the like) in an alcoholic organic solvent such as methanol, ethanol and the like. The reaction proceeds well at room temperature or under heating. Alternatively, a carboxyethyl derivative of the formula lid or He in which R3 is hydrogen is prepared by reacting a compound of formula 1 or 8 with a β-unsaturated ester of formula 16 in Michael adidon reaction condidons, that is, in Presented from a suitable base such as a methoxide and in a protic organic solvent (for example methanol, ethanol and the like), to yield a 3-propionate derivative of formula 17a or 17b, respectively. The hydrolysis of the ester group in 17a or 17b gives the corresponding carboxyethyl derivative of formula lid or He, respectively, in which R3 is hydrogen.

The compounds of formula 1 or 8 are prepared as previously described in Schemes A and B, respectively. The compounds of formula 15 and 16 are available either commerially or can be prepared according to conventional methods in the field. For example, cc, β-unsaturated acids and esters derived from halo such as, for example, methyl 2-bromo-2-methylpropionate, methyl 2-bromopropionate, methyl 3-bromo-2-methylpropionate, methyl-c-bromophenylacetate, methyl methacrylate, are commercially available. A detailed description of the synthesis of a carboxyethylpiperazine of formula lid by this method is presented in Example 6.

Preparation of compounds of formula llf A carboxyalkyl derivative of formula Ilf wherein n, m, R? R2, R3, R4, Q and Ar1 are as defined in the Summary of the invention can be prepared from a compound of formula 17 or respec tively, such and as illustrated in scheme E below Scheme E A carboxyalkyl derivative of formula Ilf can be prepared by reacting a compound of formula 10 or 18 with a Wittig readivo of formula Br- (PH3P) (CHR) mCR3R CO2Et, followed by reduction of the double bond and hydrolysis of the ester group to the acid in the resulting unsaturated ester 19, as previously described. Alternatively, compounds of formula Ilf can be prepared from 18 (in which R is hydrogen or alkyl) by following the reaction procedures described for the synthesis of compound 4 wherein X is carboxy in scheme A, method (a).

Compounds of formula 18 can be prepared from compounds of formula 14 by methods well known in the art. The compounds of formula ll (d-f) are used for the synthesis of compounds of Formula (I) in which E is an inverse amide, is dedr, -N (R6) CO-.

Synthesis of compounds of Formula (I) from compounds of formula II (a-f).

Compounds of formula (I) are prepared from compounds of formulas 11 (a-f) as described in schemes F-J below. The compounds of formula (I) wherein E is -C (0) N (R5) - are prepared as described in Scheme F below: Scheme F A compound of formula (I) in which E is an amide group can be prepared either: (i) by reacting a compound of formula ll (ac) with an additive agent Ar-FC (O) L wherein L is a group projection on adladon condids, such as a halo (particularly Cl or Br) or imidazolide. Suitable solvents for the reaction include polar aprotic solvents (for example, dichloromethane, THF, dioxane, and the like). When an adducted halide is used as the adsorbing agent, the reaction is carried out in the presence of a non-nudeophilic organic base (for example triethylamine or pyridine, preferably pyridine); or: (ii) heating a compound of formula II (a-c) with an acid anhydride. Suitable solvents for the reaction are tetrahydrofuran, dioxane and the like. Examples of detailed embodiments of the conversion of a compound of formula Ha and llb to compounds of formula (I) in which n is 1 and E is -C (O) NH- are presented in Examples 1, 3, 4, 5 and 10. . The compounds of formula (I) wherein E is -N (Rβ) C (O) N (R5) - or -N (R6) C (S) N (R5) - are prepared as described in Scheme G a continuaadón: Scheme G l. CDl / TCDl (i) IlCa-c) + 2. N? (Rd) - (F) -Ar A compound of formula (I) in which E is a urea / thiourea group can be prepared either: (i) by reacting a compound of formula II (ac) with an adivant agent such as a carbonyl diimidazole / thiocarbonyl diimidazole, followed by displacement nucleophilic group of the imidazole group with a primary or secondary amine. The reaction takes place at room temperature. Suitable solvents include polar organic solvents (for example tetrahydrofuran, dioxane and the like); (ii) by reacting a compound of formula II (a-c) with a carbamoyl / thiocarbamoyl halide. The reaction is carried out in the presence of a non-nudeophilic organic base. Suitable solvents for the reaction are dichloromethane, 1,2-dichloroethane, tetrahydrofuran or pyridine; or (iii) a compound of formula II (a-c) having to react with an isodanate / isothiocyanate in an aprotic organic solvent (for example benzene, tetrahydrofuran, dimethylformamide and the like).

Detailed descriptions of the conversion of a compound of formula Ha to a compound of formula (I) in which n is 1 and E is -NHC (O) NH- or -N (R6) C (S) NRS) - are presented. in Examples 2 and 8. A detailed description of the conversion of a compound of formula He in which m is 0 in a compound of formula (I) in which E is -NHC (O) NH- is presented in example 9.

The compounds of formula (I) wherein E is -S02N (R5) - are prepared as described in Scheme H below: Scheme H A compound of formula (I) wherein E is a sulfonamido group can be prepared by reacting a compound of formula ll (a-c) with a sulfonyl halide, using the reaction conditions described in method (i) of Scheme F.

The sulfonyl halides are available commerically or can be prepared by methods such as those described in (1) Langer, R. F .; Dog. J. Chem. 61, 1583-1592, (1983); (2) Aveta, R. et al .; Gazetta Chimica Italiana, 116, 649-652, (1986); (3) King, J.F. and Hillhouse, J. H .; Dog. J. Chem., 54, 498, (1976); and (4) Szymonifka, M.J. and Heck, J. V .; Tet. Lett., 30, 2869-2872 (1989).

A detailed description of the conversion of a compound of formula Ha into a compound of formula (I) wherein n is 1 and E is -N (R6) SOr is presented in Example 7.

The compounds of formula (I) wherein E is -N (R6) S02N (R5) - are prepared as described in Scheme I below: Scheme I A? -F-N (R6) S02L I? (A-c) Ar- (F) -N (R?) S02N (Rs) -CR R4- (CHR) m-T U-Q-Ar1 (D A compound of formula (I) in which E is a suffamide group can be prepared by reacting a compound of formula II (ac) with a sulfamoyl halide, using the reaction conditions described in method (i) of Scheme E. Sulfamoyl halides are commercially available or can be prepared by methods such as those described in Graf, R .; Germán Patent, 931225 (1952) and Catt, J.D. and Matler, W.L .; J. Org. Chem., 39, 566-568, (1974).

The compounds of formula (I) wherein E is -N (Rβ) C (O) - are prepared as described in Scheme J below: Scheme J H (d-f) + Ar-F-NH (R6) A compound of formula (I) in which E is an inverse amide can be prepared by reacting a compound of formula II (df) with an amine in the presence of a suitable coupling agent (for example N, N-dicidohexylcarbodiimide, 1- (3) -dimethylaminopropyl) -3-ethylcarbodiimide and the like), in a suitable organic solvent such as methylene chloride, tetrahydrofuran, dimethylformamide and the like. A detailed description of the conversion of a compound of formula lid to a compound of formula (I) in which n is 1 and E is -NHC (O) - is presented in Example 6.

The compounds of the invention are CCR-3 receptor antagonists and inhibit the uptake of eosinophils by the CCR-3 chemokines such as RANTES, eotaxin, MCP-2, MCP-3 and MCP-4. The compounds of this invention and the compositions containing them are useful in the treatment of diseases induced by eosinophils such as allergic or inflammatory diseases and by inducing allergic respiratory diseases such as asthma, allergic rhinitis, pulmonary hypersensitivity diseases, hypersensitivity pneumonitis, eosinophilic pneumonias ( for example chronic eosinophilic pneumonia); inflammatory bowel diseases (for example Crohn's disease and ulcerative colitis); as well as inflammatory psoriasis and dermatoses such as dermatitis and eczema.

The CCR-3 antagonistic adivity of the compounds of this invention was measured in in vitro tests such as ligand binding assays and chemotaxis assays as described in more detail in Examples 15, 16 and 17. Adivity was tested I live in the model of Balb / c mice with asthma induced by ovalbumin as described in greater detail in Example 18.

In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted methods of administration for agents with similar utilities. The actual amount of compound of this invention, that is, of the active ingredient, will depend on numerous factors such as 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 form of administradón, as well as other fadores.

The therapeutically effective amounts of compounds of formula (I) may be in the range of about 0.05 to 20 mg per kilogram of body weight of the receptor per day; preferably about 0.1 to 10 mg / kg / day. Thus, for the administration to a 70 kg person, the dosage interval will be more preferably between 7 mg and OJg per day.

In general, the compounds of this invention will be administered as pharmaceutical compositions by any of the following routes: oral administration, inhalation (for example, oral or intranasal inhalation) or parenteral (for example intramuscular, intravenous or subcutaneous). A preferred mode of administration is oral using a suitable daily dosage that can be adjusted according to the degree of the disease. The compositions can be presented in the form of tablets, dragees, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs or any other suitable composition. Another preferred mode of administration of compounds of this invention is by inhalation. This is an effective means of administering a therapeutic agent directly to the respiratory tract for the treatment of diseases such as asthma and other similar or related airway diseases (see U.S. Patent 5,607,915).

The choice of formulation depends on various factors such as the mode of administration of the drug and the bioavailability of the drug substance. For administration by inhalation, the compound can be formulated in the form of liquid solutions or suspensions, propellants in aerosol or in dry powder form, and packaged in a suitable dispenser for administration. There are three types of pharmaceutical inhalation devices - nebulizer inhalers, fixed dose inhalers (MDI) and dry powder inhalers (DPI). The nebulization devices produce a jet of air at great speed that fadlita that the therapeutic agents (which have been formulated in liquid form) are nebulized in the form of fog that is transported to the respiratory tract of the payer. The MDIs typically present the formulated packaged with a compressed gas. After the adduct, the device discharges a measured amount of therapeutic agent through the compressed gas, thus offering a reliable method for administering a fixed amount of agent. DPIs administer therapeutic agents in the form of a fluid powder that can be dispersed in the inspiratory flow of the pantee while breathing through the device. In order to obtain a fluid powder, the therapeutic agent is formulated with an excipient, such as, for example, a side. A measured amount of the therapeutic agent is deposited in a receptacle in the form of a capsule and dispensed to the payer in each application.

Recently, pharmaceutical formulations have been developed specifically for drugs that have an insufficient bioavailability based on the premise that the bioavailability can be increased by increasing the superfidal area, that is, decreasing the particle size. For example, in U.S. Patent No. 4,107,288 a pharmaceutical formulation is described which has particles in the size range of 10 to 1000 nm in which the adipose material is supported by a crosslinked matrix of macromolecules. US Pat. No. 5,145,684 discloses the production of a pharmaceutical formulation in which the drug substance is sprayed to nanoparticles (with an average particle size of 400 nm) in the presence of a surface modifier, and to its it is dispersed in a liquid medium to yield a pharmaceutical formulation having a considerably increased bioavailability.

The compositions are, in general, composed of a compound of formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable ex pients are non-toxic, collaborate in the administration and do not adversely affect the therapeutic benefit of the compound of formula (I). Such excipient can be any solid, liquid, semi-solid exdient or, in the case of a gaseous aerosol composition, which is generally within the skill of one skilled in the art.

The solid pharmaceutical excipients include starch, cellulose, talc, glucose, steroid, sucrose, gelatin, malt, rice, flour, gypsum, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, skimmed milk powder and the like. . Liquid and semi-solid exdpients can be selected from glycerol, propylene glycol, water, etand and various oils, including those originating from petroleum, animal, vegetable or synthetic, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid transporters, in particular for injection soludates, are water, saline solution, aqueous glucose and glycols.

Compressed gases can be used to disperse a compound of this invention in the form of an aerosol. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

Other pharmaceutically suitable excipients and their formulations are described in Remington's Pharmaceutical Sdences, edited by E.W. Martin (Mack Publishing Company, 18 *, Ed. 1990).

The concentration of the compound in a formula can vary over the entire range employed by those skilled in the art. Typically, the formula will contain, in percent by weight (% weight) of about 0.01 to 99.99% of a compound of formula (I) based on the total formulation, the remainder constituting one or more pharmaceutically acceptable excipients. . Preferably, the compound is present at a concentrate of about 1 to 80% by weight. Representative representative pharmaceutical formulations are described in Example 14.

Examples Synthetic Examples Example 1 Synthesis of N- dihydrochloride salt. { 1- (S) - [4- (3,4-didorobendl) piperazin-1-ylmethyl] -2-methylpropyl} -4-methylbenzamide.

Stage 1 3,4-Dichlorobendyl bromide (35.20 g, 150 mmol) was added to a solution of N- (tert-butoxycarbonyl) piperazine (24.84 g, 130 mmol) and triethylamine (20.91 ml, 150 mmol) in doroform (100 ml) for 30 min. After 1 h, the reaction mixture was diluted with ethyl acetate and the product was precipitated as the hydrochloride salt by adding a 1N solution of aqueous hydrogen chloride. The solid product was filtered, washed with water and resuspended with ethyl acetate. Two equivalents of 1 N aqueous sodium hydroxide solution were added and the free amine was extracted into ethyl acetate. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated to give 1- (tert-butoxycarbonyl) -4- (3,4-dichlorobenzyl) piperazine (45g).

Stage 2 Trifluoroacetic acid (75 ml, 974 mmol) was added to a solution of 1- (tert-butoxycarbonyl) -4- (3,4-dichlorobenzyl) piperazine (45 g, 130 mmol) in doroform (75 ml). The reaction mixture was stirred for 1 h at room temperature and then basified with a sodium hydroxide solution. The product was extracted into ethyl acetate and the organic phase was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo to yield 1- (3,4-dichlorobendl) piperazine (35.8 g) in form of a solid.

Stage 3 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (5.08 g, 26.5 mmol) is added to a solution of 1- (3,4-dichlorobendl) piperazine (5 g, 20.4 mmol) and L- BOC-valina (5J6g, 26.5 mmol) in methylene chloride. After 2 h, the product was extracted into ethyl acetate. The organic phase was washed with sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography with hexanes / ethyl acetate (1: 1) as eluent yielded 1- (SH4- (3,4-dichlorobendl) piperazin-1-ylcarbonyl] -N- (tert-butoxycarbonyl) -2-methylpropylamine (5). , 46g) in the form of a foam.

Stage 4 1 N ethereal hydrogen chloride solution (80 ml, 80 mmol) was added to a solution of 1- (S) - [4- (3,4-dichlorobendl) piperazin-1-ylcarbonyl] -N- (t? Rc) -butoxycarbonyl) -2-methylpropylamine (4.28 g, 9.64 mmol) in methanol (50 ml) and the reaction mixture was heated to 70 ° C. After 2.5 hours, the reaction mixture was concentrated and the solid was suspended in ether and filtered to yield the bis-hydrochloride salt of 1- (S) - [4- (3, 4-dichlorobenzyl) piperazin-1-ylcarbonyl] -2-methylpropylamine. The product was dissolved in water, treated with triethylamine (4.0 ml, 28.9 mmoi) and the free amine was extracted into ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated to yield 1- (S) - [4- (3,4-dichlorobenzyl) piperazin-1-ylcarbonyl] -2-methylpropylamine (3.2g. ) in the form of the free amine.

Stage 5 A solution of 1.0 M diborane in tetrahydrofuran (65.2 ml, 65.2 mmol) was added to a solution of 1- (SH4- (3,4-dichlorobenzyl) piperazin-1-ylcarbonyl] -2-methylpropylamine (3 , 2 g, 9.3 mmol) in tetrahydrofuran (15 ml) The mixture was refluxed under a nitrogen atmosphere for 2 h and then concentrated in vacuo.The residue was dissolved in methanol, added with 6 N hydrogen durion solution. (50ml) and then reheated to 70 ° C. After heating for 1 h, the reaction mixture was cooled and basified with sodium hydroxide solution and the product was extracted into ethyl acetate. it was washed with sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated to give 1- (SH4- (3,4-didorobendl) piperazin-1-ylmethyl] -2-methylpropylamine (3.53 g) in shape of an oil.

Stage 6 P-toluoyl duride (0.48 ml, 3.63 mmol) was added to a solution of 1- (S) - [4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropylamine (1 g, 3.0 mmol) and triethylamine (0.633 ml, 4.54 mmol) in methylene chloride under nitrogen atmosphere. After 1 h, the product was extracted into ethyl acetate and the organic phase was washed with sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Column chromatography with hexanes ethyl acetate (1: 2) yielded N-. { 1- (S) - [4- (3,4-Dichlorob-β-pi) piperazin-1-ylmethyl] -2-methylpropyl} -4-methyl-benzamide (1.2 g) as an oil. The free amine was dissolved in ether and 3.5 equivalents of 1N ethereal HCl solution (10Jml) was added. Filtration of the resulting solid gave the bis hydrochloride salt N-. { 1 - (S) - [4- (3,4-Dichlorobendl) piperazin-1-ylmethyl] -2-methylpropyl} -4-methyl-benzamide (1.2 g), mp. 227.8 - 228.9 ° C. 1. Proceeding as described in Example 1, Steps 1-4, above, but replacing the L-BOC-valine in Step 3 with DL-BOC-valine, 1- (RS) - [4- (3, 4-dichlorobendl) piperazin-1-ylcarbonyl] -2-methylpropylamine, which after reduction (Step 5) and reaction with 3,4-methylenedioxybenzoyl doride (Step 6) yielded N-. { 1- (RS) - [4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl} -3,4-methylenedioxybenzamide. 2. Proceeding as described in Example 1, steps 1-4 above, but substrtuting the L-BOC-valine in Step 3 with L-BOC-tert-leudna (commercially available from Fluka), 1- ( S) - [4- (3,4-doorobendl) piperazin-1-ylcarbonyl] -2,2-dimethylpropylamine, which was reduced to 1- (SH4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] - 2,2-dimethylpropylamine (Step 5), and then reacted with: 4-methylsulfonylbenzoyl chloride, 4-acetoxybenzoyl chloride, 4-N, N-dimethylaminobenzoyl chloride, 5-methyl-2-tenoyl chloride; 4-methylbenzoyl chloride, to yield N- ({1- (S) - [4- (3,4-dichlorobendl) piperazin-1-ylmethyl] -2,2-dimethylpropylH-methylsulfonylbenzamide, dihydrochloride, mp 190 - 191 ° C; N- ({1- (S) - [4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2,2-dimethylpropyl} -4-acetoxybenzamide dichloride salt, mp. 241-242 ° C; N- ({1- (S) - [4- (3,4-dichlorobendl) piperazin-1-ylmethyl-2,2-dimethylpropyl} -4-N, dihydrochloride. N-dimethylaminobenzamide, mp 101 , 5-105 ° C; N- dihydrochloride salt. { 1- (S) - [4- (3,4-Dichlorobendl) piperazin-1-ylmethyl] -2,2-dimethylpropyl} -5-methyl-2-thiophenecarboxamide, mp. 249-253 ° C; and N-1 - (SH4- (3,4-dichlorobendl) piperazin-1-ylmethyl] -2,2-dimethylpropyl} -4-methylbenzamide dihydrochloride, following the procedure described in Steps 5 and 6 above. 3. Proceeding as described in Example 1, Steps 1-4 above, but substrtuting the L-BOC-valine in Step 3 by DL-BOC-tert-leudin, 1- (RS) - [4- (3 , 4-dichlorobenzyl) piperazin-1-ylcarbonyl] -2,2-dimethylpropylamine, which was reduced to 1- (RSH 4 - (3,4-dichlorobendl) piperazin-1-ylmethyl] -2,2-dimethylpropylamine (Step 5 ), and then was reacted with: 3-? anobenzoyl chloride, and 3,4-difluorobenzoyl chloride, to yield N- 1- (RS) - [4- (3,4-dichlorobendl) piperazin-1-ylmethyl) ] -2,2-dimethylpropyl.} - 3-cyanobenzamide and N-. {1- (RS) - [4- (3,4-dichlorobendl) piperazin-1-ylmethyl] -2,2- dimethylpropyl.} - 3,4-difluorobenzamide, respec tively. 4. Proceeding as described in Example 1, but substituting N- (tert-butoxycarbonyl) piperazine in Step 1 with 3-methyl-N- (tert-butoxycarbonyl) piperazine and L-BOC-valine in Step 3 with DL -BOC-valine was obtained the N- dihydrochloride salt. { 1- (RS) - [3-Methyl-4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl} -4- "ißtiibenzamida.

Example 2 Synthesis of 1 -. { 2- [4- (3,4-Dídorobendl) piperazin-1-yl] cidohexyl} -3- (3-methoxyphenyl) urea Step 1 A mixture of 1-nitroddohexene (311 mg, 2.45 mmol), dichlorobenzylpiperazine (prepared as described in Example 1) (600 mg, 2.45 mmol) and triethylamine (512 μl, 3.68 mmol) was stirred. in methylene chloride (10ml) at room temperature under nitrogen atmosphere for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed with hexanes / ethyl acetate (2: 1) as eluent to give 1- (3,4-dichlorobendl) -4- (2-nitrocydohexyl) piperazine (461 mg) as an oil.

Stage 2 Platinum (IV) oxide (15 mg, 0.07 mmol) was added to a solution of 1- (3,4-dichlorobenzyl) -4- (2-nitro-cyclohexyl) piperazine (187 mg, 0.50 mmol) in acetic acid. gladal (5ml) The reaction mixture was stirred under nitrogen atmosphere at room temperature for 6 hours. The reaction mixture was then filtered through a celite filter. The filtrate was basified with 15% sodium hydroxide solution and the product was extracted into ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to yield 1- (3,4-dichlorobendl) -4- (2-aminocidohexyl) piperazine (119mg) as an oil.

A soludon of 1- (3,4-didorobendl) -4- (2-aminoddohßxil) piperazine (100 mg, 0.29 mmol) and 3-methoxyphenylisocyanate (38 μl, 0.29 mmol) in methylene dichloride (5 ml) was stirred at room temperature. After 17 h, the product was extracted into ethyl acetate, washed with bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. Column chromatography with methylene chloride / methanol (97: 3) as eluent yielded 1-. { 2- [4- (3,4-d.chlorobendl) piperazin-1-yl] cyclohexyl} -3- (3-methoxyphenyl) urea (64 mg) as an oil consisting of the trans diastereomer.

Example 3 Synthesis of N-. { 1- (S) - [4- (3,4-dichlorobenzyl) piperidin-l-ylmethyl] -2-methylpropyl} -4-methylbenzamide Step 1: n-Butyllithium / 43.2 ml, 2M in pentane, 108 mmol) was slowly added to an ice-cold suspension of 3,4-dimeric triphenyl phosphonium bromide (54 g, 108 mmol) (prepared by stirring equimolar amounts of bromide of 3, 4-doorobendlo and triphenylphosphine in THF at 65 ° C overnight) in dry THF (500 ml) under an argon atmosphere. After 15 min, the reaction mixture was allowed to warm to room temperature, and stirred for 2 hours adidonally. 1-tert-Butoxycarbonyl-4-piperidone (21.42 g, 108 mmol) was added and the stirring was continued overnight. Hexane (2 1) was added and the reaction was stirred and then filtered. The filtrate was concentrated in vacuo to yield 41.8 g of an orange gum. Column chromatography on 0.5 kg flash grade silica, eluting with a gradient of 70% methylene chloride / hexane to 100% methylene chloride, followed by a gradient of 1% methanol / methylene chloride to 5% methanol / methylene chloride yielded 1- (tert-butoxycarbonyl) -4- (3,4-dichlorobenzylidene) piperidine (29 g) as a brown oil.

Step 2 Platinum oxide (0.3) was added to a solution of 1- (tert-butoxycarbonyl) -4- (3,4-dichlorobenzylidene) piperidipa (29 g, 84.7 mmol) in ethyl acetate (500 ml. ) and the mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through celite and the filtrate was concentrated to yield 1- (tert-butoxycarbonyl) -4- (3,4-dichlorobendl) piperidine (30 g) as a brown oil.

Step 3 Trifluoroacetic acid (50 ml) was added to a solution of 1- (tert-butoxycarbonyl) -4- (3, 4-dichlorobendl) piperidine (24 g, 69 J mmol) in methylene duride (150 ml) and the reaction mixture was stirred for 1 hour. The solvent was removed under reduced pressure, followed by the addition of ethyl acetate (200 ml) and the resulting mixture was basified with 1 N aqueous sodium hydroxide. The organic phase was separated, dried over magnesium sulfate and the solvent was removed under reduced pressure to yield 4- (3,4-diciorobendl) piperidine (17.1 g) as a light brown solid.

Step 4 L-BOC-valine (1.3 g, 5.98 mmol) and 1- (3-dimethylaminopropyl) -3-etiicarbodiimide (1.15 g, 5.98 mmol) were added to a 4 ( 3,4-dichlorobenzyl) piperidine (1.12 g, 4.57 mmol) in methylene duride (15 ml) and the reaction mixture was stirred at room temperature under an argon atmosphere. After 3 h, the solvents were removed under vacuum and water (10 ml) and ethyl acetate (25 ml) were added. The organic phase was separated, dried over magnesium sulfate and concentrated, under reduced pressure. Column chromatography with ethyl acetate / hexane 15-20% as eluent yielded 1- (S) - [4- (3,4-dichlorobenzyl) piperidin-1-ylcarbonyl] -N- (tert-butoxycarbonyl) -2- methylpropylamine (1.89 g) in the form of a rubbery foam.

Step 5 To a solution of 1- (S) - [4- (3,4-dichlorobendl) piperidin-1-ylcarbonyl] -N- (tert-butoxycarbonyl) -2-methylpropylamine (5.9 g, 13.2 mmol ) in trifluoroacetic acid (30 ml) was added at room temperature in methylene chloride (100 ml). After 4 h, the reaction mixture was concentrated and the residue was taken up with ethyl acetate (200 ml) and water (100 ml) while adjusting the pH to 8 with aqueous solution of 15% sodium hydroxide. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic portions were dried over magnesium sulfate, filtered and concentrated in vacuo to give 1- (S) - [4- (3,4-dichlorobenzyl) piperidin-1-ylcarbonyl] -2-methylpropylamine / 4.53 g. ) in the form of a colorless gum.

Step 6 To a solution of 1- (S) - [4- (3,4-dichlorobendl) piperidin-1-ylcarbonyl] -2-methylpropylamine (4.53 g, 13.3 mmol) in dry tetrahydrofuran (100 ml) diborane (92.4 ml, 92.4 mmol, 1M in THF) was added, and the reaction mixture was stirred under argon atmosphere at 65 ° C. After 3 h, the reaction mixture was cooled in an ice bath and aqueous hydrochloric acid (60 ml, 6N) was added slowly under stirring. The reaction mixture was concentrated in a rotary evaporator and the aqueous solution was stirred at 100 ° C. After 1 h, the reaction mixture was cooled to 0 ° C and potassium hydroxide beads were added slowly until a pH of 8. The solution was extracted twice with ethyl acetate (100 ml), dried over sodium sulfate, anhydrous magnesium and concentrated in vacuo. The colorless liquid (3.84 g) was flash chromatographed eluting with MeOH / CH2CI2 2.5-10% containing 1% NH4OH. The free amine was dissolved in anhydrous ether and ethereal HCl was added to yield 1- (S) - [4- (3,4-dichlorobendlpiperidin-1-ylmethyl] -2-methylpropylamine in the form of the sai HCl.

Step 7: p-Toluoyl chloride (0.14 mL, 1 mmol) was added to a solution of 1- (S) - [4- (3,4-dichlorobenzyl) piperidin-1-ylmethyl] -2-methylpropylamine (0). , 33 g, 1 mmol) in dry pyridine (7 ml) at 0 ° C under argon atmosphere. The solution was stirred for 30 min at 0 ° C and then allowed to warm to room temperature. After 3 h, the reaction mixture was concentrated under reduced pressure and water (10 ml) was added. The product was extracted with ethyl acetate and the organic phase was dried with magnesium sulfate and then concentrated in vacuo. The crude product (0.5 g) is chromatographed eluting with a gradient of 1% to 4% methanol / methylene duride to yield N-. { 1- (SH4- (3,4-dichlorobendl) piperidin-1-ylmethyl] -2-methylpropyl.} -4-methyl-benzamide (0.25 g) in a partially solidified gum fopna Example 4 N-. 1 - (RS) - [4- (4-Amino-5-doro-2-methoxyphenylcarbonylaminomethyl) piperidin-1-methylmethyl-2] -methylpropyl.} -4-methylbenzamide Stage 1 Diisopropylethylamine (17.4 ml, 134 mmol) was added to a solution of (DL) -valinol (9.85 g, 95 mmol) in methylene chloride (100 ml). The reaction mixture was cooled to 0 ° C, treated with a solution of ptoluoyl chloride (12.8 ml, 91 mmol) in methylene chloride (50 mil) and then allowed to warm to room temperature. After stirring for 3 hours, an excess of aqueous sodium hydroxide solution was added and the reaction was transferred to a decantadon funnel. The organic phase was separated and the aqueous phase was washed with a methylene chloride cap. The combined organic phases were washed with water and saline, dried over magnesium sulfate and concentrated in vacuo. Chromatography eluting with 25% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes afforded N-p-toluoyl valinol (18.04 g).

Stage 2 Dimethylsulfoxide (2.2 ml, 31 mmol) was slowly added via syringe to a stirred solvent at -78 ° C oxalyl chloride (15 ml, 171 mmol) in methylene chloride (35 ml) under an inert atmosphere. After 10 min, a solution of N-p-toluoyl valinol (6.0 g, 29 mmol) in methylene dichloride (50 ml) was added and the stirring was maintained for 15 minutes adidonal. Triethylamine (6 ml, 389 mmol) was added and the reaction was allowed to warm to room temperature. After 1.5 hours, the reaction was diluted with 50% ethyl acetate in exes and washed with saline and water. Filtration through a silica gel filter and subsequent elimination of the solvent produced a solid residue. Chromatography eluting with 20% ethyl acetate in hexanes, followed by 33% ethyl acetate in hexanes afforded N-p-toluoyl valinaldheido (3.6 g) as a solid, which was used in Step 6.

Step 3 Tert-butoxycarbonyl anhydride (6.69 g, 30.6 mmol) was added to a solution of 4- (aminomethyl) piperidine (7 g, 61.3 mmol) in chloroform (40 ml) at 0 ° C. The reaction mixture was allowed to warm to room temperature for 3 h and then 15 h adidnal was stirred. The reaction mixture was washed with water, the organic phase was separated and dried over magnesium sulfate, filtered and concentrated to give N-tert-butoxycarbonyl-4- (aminomethyl) piperidine (6.55 g) as a a pale yellow oil.

Step 4: 1,1'-Carbonyldiimidazole (1.61 g, 9.91 mmol) was added to an acid solution. 4-amino-5-chloro-2-methoxybenzoic acid (2.0 g, 9.91 mmol) in dimethylformamide (5 ml). After stirring for 5 min. At room temperature, a solution of N-tert-butyloxycarbonyl-4- (aminomethyl) piperidine (1 J7 g, 8.26 mmd) in dimethylformamide (5 ml) was added and the reaction mixture was heated to room temperature. 55 ° C. After 23 h, the product was extracted into ethyl acetate and the organic phase was washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. Flash chromatography of the crude product with ethyl acetate / hexanes 2: 1 as eluent yielded N-tert-butyloxycarbonyl-4- (4-amino-5-chloro-2-methoxy-phenylcarbonylaminomethyl) piperidine (2.63 g) in shape of a foam.

Stage 5 To a solution of N-tert-butyloxycarbonyl-4- (4-amino-5-doro-2-methoxyphenylcarbonylaminomethyl) piperidine (500 mg, 1.26 mmol) in methane! (30 ml) was added a solution of ethereal 1N hydrogen duride (12.6 ml, 12.6 mmol). The solution was heated to 50 ° C. The reaction mixture became heterogeneous in 5 min. After 1.5 h, the reaction mixture was concentrated to yield a white solid which was suspended in diethyl ether and filtered to give 4- (4-amino-5-chloro-2-methoxy-phenylcarbonylaminomethyl) piperidine as the bis hydrochloride salt (433 mg).

Step 6: To a heterogeneous mixture of 4- (4-amino-5-chloro-2-methoxyphenylcarbonylaminomethyl) piperidine (304 mg, 0.82 mmol) and triethylamine (309 μl, 2.21 mmol) in methylene chloride (20 ml ) was added Nd-toluoyl valinaldheido aldheido (150 mg, 0.68 mmol) and sodium triacetoxyborohydride (216 mg, 1.02 mmol) at room temperature. After 1 h the reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution. The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography of the crude product with methylene chloride / methanol 97: 3 as eluent yielded N-. { 1- (RS) - [4- (4-amino-5-doro-2-methoxyphenylcarbonylaminomethyl) piperidin-1-ylmethyl] -2-methyl-propyl} -4-methylbenzamide (139 mg) in the form of a foam.

Example 5 Sal dihydrochloride. { 1- (4-methylbenzoyl) -2 (R) - [4- (3,4-dichlorobenzyl) pipßrazin-1-ylmethyl]} pyrrolidine Step 1 1-Ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydroxide (1.03 g, 7 mmol) was added to a solution of N-BOC-D-proline (1.51 g, 7 mmol) in chloride of methylene (12 ml), and the reaction mixture was stirred at room temperature. After 0.5 h, 3,4-dichlorobenedipiperazine (1.32 g, 5.4 mmol) [prepared as described in Example 1] and the agitation continued for 16 h. The reaction mixture was quenched with water, basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate phase was separated and washed with saline solution, dried over magnesium sulfate and concentrated. Flash chromatography with 30% acetone in dichloromethane as eluent yielded 2 (R) - [4- (3,4-dichlorobenzyl) piperazin-1-ylcarbonyl]} -N- (tert-butoxycarbonyl) pyrrolidine (1.2 g) in the form of an oil.

Step 2 Borane (15.8 mL, 1.0 M solution in THF) was added dropwise to a solution of 2 (RH4- (3,4-dichlorobenzyl) -piperazin-1-ylcarbonyl].} -N- (tert-butoxycarbonyl) pyrrolidine (1.0 g, 2.26 mmol) in tetrahydrofuran (5 ml) under nitrogen atmosphere and the reaction mixture was heated to reflux. After 2 h, the reaction mixture was cooled to room temperature and quenched with 6N hydrochloric acid. The reaction mixture was refluxed for a further 2 hours, cooled to room temperature and then basified with 10% aqueous sodium hydroxide solution. The product was extracted with ethyl acetate and the organic phase was separated and washed with saline solution, dried over magnesium sulfate and concentrated. Purification by column chromatography with methylene chloride containing 10% ammonium hydroxide in methanol as eluent yielded 2 (RH4- (3,4-dichlorobenzyl) p1perazin-1-ylmethyl] pyrrolidine (0.62 g) in shape of an oil.

Stage 3 Triethylamine (0.19 ml, 1.5 mmol) and p-toluoyl duride (0.11 ml, 0.84 mmol) were added to a solution of 2 (R) - [4- (3,4-dichlorobendl) -peperazin-1-methylmethyl pyrrolidine (0.25 g, 0J6 mmol) in methylene chloride (5 ml). After 1 h, the reaction mixture was quenched with water and the product was extracted with ethyl acetate. The ethyl acetate phase was washed with saline solution, dried over magnesium sulfate and concentrated. A preparative TLC with 5% methanol in methylene chloride yielded. { (1- (4-methylbenzoyl) -2 (R) -. {4- (3,4-dioriorobenzyl) -piperazin-1-ylmethyl].}. Pyrrolidine in the form of 0.245 g of an oil which was converted to its salt dihydrochloride and recrystallized from a mixture of methanol-ethyl acetate to give di (1- (4-methylbenzoyl) -2 (R) -4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl dihydrochloride. Pyrrolidine (0.18 g) as a white solid, mp 249.6-250, 1 ° C.

Example 6 Synthesis of 2- (RS) - [4- (3,4-dichlorobendl) piperazin-1-ylmethyl] -N- (4-methylphenyl) propionamide.

Stage 1 A mixture of 3,4-dichloro-benzylpiperazine (2.47 g, 10.1 mmol), methyl methacrylate (2.2 mL, 21 mmol) and sodium method (49 mg, 0.91 mmol) was heated to reflux. in methanol (20 ml). After 72 h, the reaction mixture was concentrated under reduced pressure to yield a pale yellow oil (3.02 g). Column chromatography on silica gel with ethyl acetate as eluent yielded methyl 2- (RS) -4- (3,4-dichlorobendl) piperazin-1-ylmethyl] propionate (1.52 g) as an oil pale yellow.

Step 2 2- (RS) - was dissolved. { Methyl 4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] propionate (470 mg, 1.36 mmol) and lithium hydroxide monohydrate (185 mg, 4.41 mmol) in water (5 mL) and methanol ( 15 ml) and stirred at room temperature. After 21 h, the solvents were removed under reduced pressure. The resulting residue was taken up in a mixture of methylene chloride and water, and the aqueous phase was acidified (to pH about 4) with 1 M HCl. The phases were separated and the aqueous phase was extracted with several per ones of methylene chloride. . The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to yield 2- (RS) - [4- (3,4-dichlorobendl) piperazin-1-ylmethyl] propionic acid (444 mg) as a yellow foam. pale.

Stage 3 1-Ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride (a388 mg, 2.02 mmol) was added to a solution of 2- (RS) - [4- (3,4-dichlorobendl) piperazine-1 acid. - ilmethyl] propionic (609 mg, 1.84 mmol), p-toluidine (219 mg, 2.04 mmol) and dimethylaminopyridine (22 mg0.18 mmol) in methylene doride (20 ml). After 4 h, the mixture was diluted with methylene chloride and washed with water. The organic phase was separated, dried over sodium sulfate and the solvent was removed under reduced pressure to yield an orange foam (839 mg). Column chromatography on silica gel with ethyl acetate as eluent yielded 2- [4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -N- (4-methylphenyl) propionamide (636 g, 82%) in white foam shape. A solution of M-hydrochloric acid in ether (4.2 ml) was added to a solution of this product (593 mg, 1.41 mmol) in methanol, and the solvent was removed under reduced pressure. The resulting viscous oil was triturated with ether / hexanes to yield 2- (RS) - [4- (3,4-dihydrobenzyl) piperazin-1-ylmethyl] -N- (4-methylphenyl) propionamide (245 mg) in of the hydrochloride salt, mp 256.2-256J ° C.

Example 7 N -hydrohydrate salt. { 1- (RH4- (3,4-dichlorobendl) piperazin-1-ylmethyl} -2-methypropyl] -4-fluorobenzenesulfonamide Tri-latylamine (21 ml, 0.15 mmol) and 4-fluorobenzenesu-fonyl chloride (29 mg, 0.15 mmol) were added to a solution of l (R) - [4- (3,4-dichlorobenzyl) piperazine- 1-ylmethyl] -2-methylpropylamine (50 mg, 0.15 mmol) [prepared as described in Example 1 above] in methylene doride (1.5 ml). The reaction mixture was stirred for 2 h, and then concentrated. Purification by flash chromatography with methylene: methanol 20: 1 as eluent yielded N- (1- (R) - [4- (3,4, -dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl. 4-Fluorobenzenesulfonamide (49 mg) in Fopna of a solid.

Example 8 1 - . 1 -. { 1 - (RS) - [4- (3,4-Dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl} -3-methoxybenzyl-2-tiorurea 3-Methoxibendl isothiocyanate (22 mg, 0.12 mmol) was added to a solution of 1- (RS) - [4- (3,4-Dichlorobendl) piperazin-1-ylmethyl] -2-methylpropylamine (40 mg, 0.12 mmol) [prepared as described in Example 1 substituting L-N-BOC-valine with DL-N-BOC-valine] in methylene chloride (1.5 mil). The reaction mixture was stirred for 2 h and then concentrated. Purification by flash chromatography with methylene doride: methanol. 20: 1 as eluent yielded 1-. { 1- (RS) - [4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl} -3-methoxyibendl-2-thiourea (18 mg) as a solid.

Example 9 1-. { - (RSH1- (3,4-dichlorobenzyl) piperidin-4-yl] -2-methylpropyl.} - 3 - (3-methoxyphenyl) urea Step 1 3,4-Dichlorobenzyl bromide (1.83 g, 7.63 mmol) was added to an isonipecotate solution of ethyl (1 g, 6.36 mmol) and triethylamine (1.33 mL, 9.54 mmol). in methylene chloride solution (10 ml) at room temperature. After 17 h, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution (10 ml).

The organic phase was dried over magnesium sulfate, filtered and concentrated. Flash chromatography with hexanes / ethyl acetate 9: 1 followed by hexanes / ethyl acetate 6: 1 yielded ethyl (1J8 g) as a pale yellow oil.

Step 2 A 1.5 M solution of DIBAL-H® in toluene (1.27 ml.1, 90 mmol) was added dropwise over 10 min to a solution of ethyl 1- (3,4-didorobendl) isonipecotate ) (500 mg, 1.58 mmol) in toluene (5 ml) at -78 ° C. After 40 min, aqueous sodium bicarbonate solution was added and the reaction mixture was warmed to room temperature. The product was extracted into diethyl ether. The organic phase was dried over magnesium sulfate, filtered and concentrated to give 1- (3,4-dichlorobenzyl) -4-formylpyridine (430 mg) as an oil.

Step 3: Isopropylmagnecio doruro in tetrahydrofuran (3.7 ml, 7.35 mmol, 2.0 M) was added to a solution of 1- (3,4-dichlorobenzyl) -4-formylpyridine (1 g, 3.67 mmol). in tetrahydrofuran (10 ml) at 0 ° C. After 30 min, the reaction mixture was warmed to room temperature and stirred an additional 30 min. The reaction mixture was then diluted with diethyl ether and washed with sodium bicarbonate solution (10 ml). The organic phase was separated and dried over magnesium sulfate, filtered and concentrated. The residue was subjected to flash chromatography (hexanes / ethyl acetate 1: 1) to yield alcohol 1 (RSH (3,4-dic-orotenzyl) pyridine). -4-yl 2-methylpropanol (617 mg) in the form of an oil.

Step 4 Pyridnium dichromate (6 g, 15.9 mmol) was added to a solution of 1 (RS) -. { (3,4-dichlorobenzyl) pyridip-4-yl] -2-methylpropanol (617 mg, 1.95 mmol) in N, N-dimethylformamide (35 ml) at 0 ° C: After 4.5 h, the mixture of The reaction was diluted with ethyl acetate and washed with a sodium bicarbonate solution, filtered and concentrated. The residue was subjected to flash chromatography (ethyl acetate / hexanes 1.5: 1) to yield 1 - [3,4-dichlorobendl) pyridin-4-yl] -2-methylpropanone (432 mg) as an oil.

Step 5 Ammonium acetate (1.43 g, 18.33 mmol) followed by sodium cyanoborohydride (130 mg, 1.86 mmol) was added to a 1 - [(3, 4-dichlorobenzyl) pyridin-4-yl] -2-methylpropanone (583 mg, 1.86 mmol) in methanol (10 mL) at room temperature. After 50h, adidonal amounts of ammonium acetate (1.43 g, 18.33 mmol) and sodium cyanoborohydride (130 mg, 1.86 mmol) were added. After 17 h, the reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution (10 ml). The organic phase was separated and dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in ethyl acetate and the product was extracted into 1N HC1 solution. The acidic aqueous phase was basified with sodium hydroxide solution and the product was extracted into ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was subjected to flash chromatography (methylene chloride / methanol 90:10, followed by 80:20) to yield 1- (RS) - [(3,4, -dichlorobenzyl) pyridin-4-yl] -2-methylpropylamine (390 mg) in the form of an oil.

Step 6 3-Methoxyphenyl isocyanate (37 μL, 0.28 mmol) was added to a solution of the 1- (RS) - [(3,4-Dichlorobendl) pyridin-4-yl] -2-methylpropylamine above (88 mg, 0.28 mmol) in methylene chloride solution (2 ml) at room temperature. After 1 h, the reaction mixture was diluted with ethyl acetate and washed with sodium bicarbonate solution (5 ml). The organic phase was separated and dried over magnesium sulfate, filtered and concentrated to obtain 1-y1- (RSH1- (3,4-dichlorobendl) piperidin-4-yl.} - 2-methylpro? Il.} -3- (3-M-methoxyphenyl) urea (104 mg) as a white solid, mp 161, 4-161, 8 ° C.

Proceeding as described in Example 9, Step 6 above, but substrtuting 1- (RSH (3,4-dichlorobendl) pyridin-4-yl] -2-methylpropylamine with l- (R) - [4- (3,4-dichlorobendl) piperazin-1-ylmethyl] -2-methylpropylamine (prepared as described in Example 1), 1- was obtained. {1- (R) - [1- (3,4 -dichlorobenzyl) piperazin-1-yl] -2-methylpropyl) -3-methoxyphenyl) urea.

Example 10 N-Hydrohydrate salt. { 1 - [(RSH1- (3,4-didorobendl) piperidin-4-ylmethyl] -2-methylpropi-H-methylbenzamide.

Step 1 To a 4-piperidone dorhydrate suspension (3.52 g, 22.99 mmol) in ethanol (40 ml) was added triethylamine (10.8 ml, 91.6 mmol), followed by the addition of 3-bromide. , 4-doorobenzyl (5.0 g, 20.8 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and ethyl acetate. The ethyl acetate phase was separated, washed with saline solution, dried over magnesium sulfate and concentrated in vacuo. Column chromatography with 25% ethyl acetate and 25% dichloromethane in hexanes yielded 1- (3,4-dichlorobenzyl) -4-piperidone (4.4 g) as a colorless oil.

Step 2 To a suspension of sodium hydride (0.33 g, 13.2 mmol) in dry toluene (15 ml) were added triethyl phosphonoacetate (2.6 ml, 13.2 mmol) at a rate such that the internal temperature reaction temperature remained below 25 ° C. After stirring at room temperature for 0.5 h, the reaction mixture was again cooled to below 25 ° C and a solution of 1- (3,4-didorobendl) -4-piperidone was added dropwise. (3.10 g, 12 mmol) in toluene (6 ml). Once the reaction was completed, a gummy precipitate formed. The mixture was heated at 60-65 ° C for 10 min, and then cooled to room temperature. The starting liquid was decanted and the residue was washed with more toluene. The combined toluene phases were filtered through a celite filter and concentrated in vacuo to yield ethyl [1- (3,4-dichlorobendl) piperidin-4-ylidene] acetate (3.9 g) as a oil that was used in the next stage without any additional purification.

Step 3 [1- (3,4-Diorobendl) piperidin-4-ylidene] -acetic acid ethyl ester (3.9 g, 11.9 mmol) was dissolved in tetrahydrofuran (25 mL) and ethanol (25 mL) and subjected to a hydrogenated over platinum hydroxide (0.1 g) at room temperature and atmospheric pressure. The reaction mixture was filtered through a celite filter and concentrated in vacuo to give ethyl [1- (3,4-dichlorobendl) pipridin-4-yl] acetate (31.91 g) as a semi-solid. .

Step 4 DIBAL-H ® (6.0 mL, 10.35 mmol, 1.5 M in toluene) was added to a solution of ethyl [1- (3,4-dichlorobendl) -piperidin-4-yl] acetate (1.9 g, 5.8 mmol) in dry toluene (60 ml) at -60 ° C under nitrogen atmosphere. The reaction mixture was stirred in a dry ice bath for 0.5 h, quenched with saturated sodium bisulphite solution and allowed to warm to room temperature. The aqueous phase was separated and basified with 2N sodium hydroxide to pH between 8 and 9, and the product was extracted with diethyl ether. The combined ether phases were washed with saline solution and dried sodium sodium sulfate. After concentration, the residue was dissolved in dry tetrahydrofuran (30 ml) and cooled to 0 ° C.

Isopropyl magnesium chloride (2.0 M, 5.8 ml) was added dropwise and the resulting reaction mixture was allowed to warm to room temperature. After 0.5 h, the reaction mixture was quenched with water and extracted with diethyl ether. The ether phase was washed with saline solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified on a column of silica gel with 25% acetone, 25% dichloromethane in hexanes to give 1 (RSH 1 - (3,4-dichlorobendl) piperidin-4-ylmethyl] -2-methylpropanol (0J5 g) in the form of an oil.

Step 5 Pyridinium dichromate (4.0 g, 10.63 mmol) was added to a solution of 1 (RS) - [1- (3,4-dichlorobendl) piperidin-4-ylmethyl] -2-methylpropanol (0, 5 g, 1.5 mmol) in dimethylformamide (25 ml) at 0 ° C. The resulting solution was stirred at 0 ° C until the starting material was consumed and quenched with water, basified with 2N sodium hydroxide and extracted with ethyl acetate. The organic phase was washed with water, saline solution, and then dried over sodium sulfate. The residue was purified on silica gel with 25% acetone, 25% dichloromethane in hexanes to give 1- [1- (3,4-dichlorobendl) piperidin-4-yl] -3-methyl-2-butanone (0.32 g) in the form of an oil.

Step 6: To a solution of 1- [1- (3,4-didorobendl) piperidin-4-yl] -3-methyl-2-butathione (0.16 g, 0.49 mmol) in methanol (1.5 ml Ammonium acetate (0.38 g, 4.93 mmol) was added followed by sodium cyanoborohydride (31 mg, 0.5 mmoi), stirring the resulting sodon at room temperature. After 48 h, dorhydric acid (conc.) Was added until pH 2 was reached, and the volatiles were removed in vacuo. The residue was dissolved in water and washed with ethyl acetate. The aqueous phase was then basified until pH > 10 and extracted with ethyl acetate. The ethyl acetate phase was washed with saline solution, dried over sodium sulfate and concentrated to yield 1- (RS) - [1- (3,4-dichlorobendl) -piperidin-4-ylmethyl] -2-methylpropi! amine (0.16 g) in the form of an oil which was used in the next step without further purification.

Step 7: p-Toluoyl chloride (0.077 ml, 0.58 mmol) was added to a solution of 1- (RS) - [1- (3,4-dichlorobendl) piperidin-4-ylmethyl] -2-methylpropylamine (0). , 16 g, 0.49 mmol) in dichloromethane (2 ml) and triethylamine (0.12 ml, 1.63 mmol). The reaction mixture was stirred at room temperature for 1.5 h and quenched with water. The product was then extracted with dichloromethane and the organic phase was washed with saline and dried over sodium sulfate. The crude product was purified by preparative TLC with 25% acetone, 25% dichloromethane in hexanes to give 0.21 g of N- 1- [1- (RS) - [4 (S ^ -dichlorobend piperidin ^ -ylmethyl- S-methylpropyl H-methylbenzamide in the form of an oil, which was converted to the hydrochloride salt (0.15 g), mp 233.9-235.5 ° C.

EXAMPLE 11 N- Hydrochloride salt. { 1- (R) - [4- (dichlorobendl) piperidin-1-ylmethyl] -2-methylpropyl} -5-methylthiophen-2-carboxamide To a solution of 1- (R) - [4- (3,4-dichlorobenzyl) piperidin-1-ylmethyl] -2-methylpropylamine (0.52 g, 1.58 mmol) [prepared as described in Example 3 , Step 5) in methylene chloride (15 ml) was added 5-methyl-2-thiophenecarboxylic acid (0.29 g, 2.05 mmol), followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0, 39 g, 2.05 mmol), and the solution was stirred under argon atmosphere overnight at room temperature. After concentrating the reaction mixture, water (10 ml) and ethyl acetate (25 ml) were added, and the reaction mixture was stirred while adjusting the pH to 8 with dilute aqueous potassium carbonate solution. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (25 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material (0.86 g) was chromatofrafied in flash on silica gel, eluting with 2% methanol / methylene chloride (containing 1% ammonium hydroxide) to yield 0.64 g of produced as a gum . Anhydrous HCl / ether (5 ml) was added to an ethereal solution of the product, resulting in a gummy precipitate which was subsequently dissolved in methanol (10 ml) and recovered to obtain N- -hydrochloride salt. { 1- (R) - [4- (dichlorobbendl) piperidin-1-ylmethyl] -2-methylpropyl} -5-methiothiophen-2-carboxamide (0.72 g as a pale yellow foam.

EXAMPLE 12 N- 1- (RH 4 - (dichlorobissent) piperidin-1-ylmethyl] -2-methylpropyl > -4- (2-aminoethyl) benzamide dichloride salt Step 1 A solution of 4-bromophenethylamine (10 g, 50 mmoi), di-tert-butyldicarbonate (21, 82 g, 100 mmol), triethylamine (13.9 ml, 100 mmol) and anhydrous methanol (350 g) were refluxed. ml) for 2 h. The reaction mixture was concentrated in vacuo and the residue was stirred with water, filtered, washed with water and dried under vacuum to yield N- (tert-butoxycarbonyl) -4-bromophenethylamine (15 g).

Stage 2 To a 0 ° C solution of N- (tert-butoxycarbonyl) -4-bromophenethylamine (12.82 g, 42.6 mmol) in anhydrous ether (200 ml) under an argon atmosphere was added dropwise n-butyllithium ( 34 ml, 85.2 mmol, 2.5 M in hexane). The slightly yellow solution turned milky white and was stirred for 15 min at 0 ° C, followed by 1 h at room temperature. The resulting mixture was cooled to -78 ° C in an acetone-dry ice bath. Dry carbon dioxide was bubbled through the stirring reaction mixture for 30 min, and then the reaction mixture was allowed to slowly return to room temperature for 30 min. Water (100 ml) was added, and the pH was adjusted to 8 with dilute aqueous potassium carbonate solution, and the aqueous phase was separated and extracted with ethyl acetate. The aqueous phase was cooled, then to 0 ° C and acidified to pH 3 with 3N aqueous hydrochloric acid. The resulting white precipitate was filtered, washed with water and dried to provide 4- [2- (N-tert-butoxycarbonylamino) ethyl] benzoic acid (7.8 g).

Step 3 To a room temperature solution of 1- (R) - [4- (3,4-dichlorobenzyl) -piperidin-1-ylmethyl] -2-methylpropylamine (1 g, 3.04 mmol) [prepared as described in he Example 3, Step 5] in methylene chloride (30 mL) was added 4- [2- (N-tert-butoxycarbonylamino) ethyl] benzoic acid (1 g, 3.8 mmol), followed by 1- (3-dimethyl) aminopropyl) -3-ethylcarbodiimide (0J3 g, 3.8 mmol), stirring the solution under argon atmosphere overnight at room temperature. After concentrating the reaction mixture, water (25 ml) and ethyl acetate (60 ml) were added. And the reaction mixture was stirred while adjusting the pH to 8 with dilute aqueous potassium carbonate solution. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organic phases were dried over magnesium sulfate and concentrated. The resulting crude product was flash chromatographed on silica gel, eluting with 2% -4% methanol / methylene chloride containing 1% ammonium hydroxide to yield N- 1- [1 (R) - [1- (3,4-dichlorobenzyl) pipßridin-4-ylmethyl] -2-methylpropyl} -4- [2- (N-tert-butoxy-carbonylamino) ethyl] benzamide in the form of a white foam.

Stage 4 To a solution at room temperature of the N-. { 1- [1 (R) - [1- (3,4-dichlorobenzyl) piperidin-4-ylmethyl] -2-methylpropyl} -4- [2- (N-t-trc-butoxycarbonylamino) ethyl] -benzamide above (1.34 g, 2.32 mmol) in methylene chloride (30 ml) was added trifluoroacetic acid (30 ml). After 3 h, the reaction mixture was concentrated in vacuo and the residue was stirred with ethyl acetate (100 ml) and water (50 ml), while adjusting the pH to 8 with 15% aqueous sodium hydroxide solution. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic parches were dried with magnesium sulfate and concentrated. The crude product was flash chromatographed on silica gel, eluting with 3% methanol / methylene chloride (containing 1% ammonium hydroxide). The product in its free base form was dissolved in anhydrous ether and 1 N anhydrous HCl in ether was added to yield the N-1- (R) - [4- (dichlorobendl) piperidin-1-ylmethyl) dihydrohydrate salt] -2- methylpropyl} -4- (2-aminoethyl) benzamide, m.p. 190.5-261, 6 ° C.

Example 13 1-. { 1- (R) - [4- (3,4-dichlorobendl) piperidin-1-yl] -2-methylpropyl} -3- (3-methoxyphenyl) urea To a solution at room temperature of 1- (R) - [4- (3,4-dichlorobendl) piperidin-1-ylmethyl] -2-methylpropylamine (0.349 g, 1.06 mmol) [prepared as described in Example 3, steps 4 and 5, but using D-BOC-valine instead of L-BOC-valine] in methylene chloride (50 ml) was added 3-methoxyphenylisocyanate (0.17 ml, 1.27 mmol), and the The reaction mixture was stirred at room temperature under an argon atmosphere for 2 h. The reaction mixture was concentrated in vacuo and the crude product was chromatographed in flash on silica, eluting with methanol / methylene chloride 1% -3% (containing 1% ammonium hydroxide). The product was dissolved in anhydrous ether and anhydrous 1 N HCl in ether was added to precipitate 1-. { 1- (R) - [4- (3,4-dichlorobendl) piperidin-1-yl] -2-methylpropi} 3- (3-methoxyphenyl) urea in the form of the hydrochloride salt (0.29 g), m.p. 107 - 112 ° C.

Proceeding as seen in Example 13 above, but substrtuting 3-methoxyphenyl-isocyanate with 3,4,5-trimethoxyphenyl isodannate gave 1-. { 1- (R) - [4- (3,4-dichlorobenzyl) piperidin-1-ylmethyl] -2-methyl propyl} -3- (3,4,5-trimethoxyphenyl) urea.

Proceeding as described in Example 13 above, but substituting 3-methoxyphenyl-isodanate with 3,4,5-trimethoxyphenyl isodannate and 1- (R) - [4- (3,4-dichlorobendl) piperidin-1-methylmethyl] - 2-Methylpropylamine with 1- (R) - [4- (3,4-dinophenyl benzyl) piperidin-1-ylmethyl] -2,2-dimethylpropylamine gave 1-. { 1- (R) - [4- (3,4-dichlorobendl) piperidin-1-ylmethyl] -2,2-dimethyl propyl} -3- (3,4,5-trimethoxyphenyl) urea.

Proceeding as described in Example 13 above, but substrtuting 3-methoxyphenyl-isodanate with 3-n-phenyl-phenylisodate gave 1-. { 1- (RH4- (3,4-didorobendl) piperidin-1-ylmethyl] -2-methylpropii.} - 3 - (3-nitrophenyl) urea which was converted into the corresponding 1-. (1- (R ) - [4- (3,4-dichlorobenzyl) p -peridin-1-ylmethyl] -2-methylpropir) -3- (3-aminophenyl) urea under conditions of catalytic hydrogenating using a Pt02 catalyst followed by the reaction with doruro of methyl sulfonyl to give 1-. { 1- (R) - [4- (3,4-didorobendl) piperidin-1-ylmethyl] -2-methylpropyl} -3- (3-methylsulphonylaminophenyl) urea.

Example 14 Formulation examples Representative pharmaceutical formulations containing a compound of Formula (I) are presented below.

Tablet formulation The following ingredients are thoroughly mixed and compressed into tablets with a single groove. Ingredient Amount per tablet, mg Compound of this invention 400 Corn starch 50 Croscarmellose sodium 25 Sodium 120 Magnesium stearate 5 Formula in capsule The following ingredients are thoroughly mixed and filled into hard gelatin capsules. Ingredient Quantity per capsule, mg Compound of this invendón 20O Ladosa, dried in spray 148 Magnesium stearate 2 Suspension formula The following ingredients are mixed to obtain a suspension for oral administration. Ingredient Amount per tablet, mg Compound of this invention 1.0 g fumaric acid 0.5 g Sodium chloride 2.0 g methylparaben 0.15 g propylparaben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co .) 1.0 g flavoring 0.035 ml dye 0.5 mg distilled water csp 100 ml Injectable formulation The following ingredients are mixed to obtain an injectable formula. Ingredient Amount Compound of this invention 0.2 g Acetate buffer 2.0 ml Sodium, 0.4 M HCl (1 N) or NaOH (1 N) c.s. p. Suitable pH Water (distilled, sterile) q.s.p. 20 ml Example 15 In vitro test for binding to the CCR-3 receptor The CCR-3 antagonistic adiety of the compounds of this invention was determined by its ability to inhibit the binding of 12Sl-eotaxin to transferant cells L1.2 CCR-3 (see Ponath , PD et al., J. Exp. Med., Vol. 183, 2437-2448, 1996). The test was carried out on Costar plates of 96 polypropylene concave bottom podles. The compounds to be tested were dissolved in DMSO and then diluted with binding buffer (50 mM HEPES, 1 mM CaCl 2, 5 mM MgCl 2, 0.5% bovine serum albumin (BSA), 0.02% sodium acid, pH 7, 24), so that the final concentration of DMSO was 2%. 25 μl of the test solution or only buffer with DMSO (control plates) were added to each podllo, followed by the addition of 25 μl of 125l-eotaxin (100 pmol) (NEX314, New England Nudear, Boston, MA), and 1.5 x 10 cells transfected L1.2 CCR-3 in 25 μl binding buffer. The final reaction volume was 75 μl.

After incubating the reaction mixture at room temperature for 1 h, the reaction was stopped by filtering the reaction mixture through a filter on a plate treated with polyethyleneimine Packard Unifilter GF / C (Packard, Chicago, II.). The filters were washed four times with ice-cold wash buffer containing 10 mM HEPES and 0.5 M sodium chloride (pH 7.2), and dried at 65 ° C for about 10 min. 25 μl per well of Microscint-20 ™ scintillation fluid (Packard) was added and the radiated retention in the filters was determined using the Packard Top Count ™.

The compounds of this invention were adivas in this assay.

The IC 50 value (concentration of test compound required to reduce the binding of 1 5l-eotaxin to transfected L1.2 CCR-3 cells by 50%) for some of the invendone compounds was: EXAMPLE 16 Inhibition of eotaxin-mediated chemotaxis of transfectant cells L1.2 CCR-3 in an in vitro assay The CCR-3 antagonistic adiety of the compounds of this invention was determined by measuring the inhibition of eotaxin-mediated chemotaxis of the cells L1.2 CCR-3 transfectors using a slight modification of the method described by Ponath, PD et al., J. Clin. Invest., 97: 604-612 (1996). The assay was performed on a 24-pod chemotaxis plate (Costar Corp., Cambridge, MA). Transferant cells L1.2 CCR-3 were grown in culture medium containing RPM1 1640, 10% Hyclone ™ fetal calf serum, 55 mM 2-mercaptoethanol and 418 genetidine (0.8 mg / ml). From 18 to 24 h before the assay, the transfected cells were treated with n-butyric acid at a final concentration of 5mM / 1 x 10ß cells / ml, isolated and resuspended at 1 x 10 7 cells / ml in assay medium containing equal parts of RPMI 1640 and Medium 199 (M 199) with 0.5% bovine serum albumin.

Human eotaxin suspended in phosphate-buffered saline solution at 1 mg / ml in the lower chamber was added to a final concentration of 100 nm. Culture inserts penetrating the pod with a pore size of 3 microns were inserted into each well (Costar Corp., Cambridge, MA) and L1.2 cells (1 x 106) were added in the upper chamber to a final volume of 100 μl. The test compounds were added in DMSO in both the upper and lower chambers, so that the final volume of DMSO was 0.5%. The test was performed respecting two groups of controls. The positive control contained cells without compound to be tested in the upper chamber, and only eotaxin in the lower chamber. The negative control contained cells without compound to be tested in the upper chamber and neither eotaxin nor compound to be tested in the lower chamber. The plate was incubated at 37 ° C. After 4 h, the inserts were removed from the chambers and the cells that had migrated to the lower chamber were counted by pipetting 500 μl of the cell suspension of the lower chamber into 1.2 ml Cluster tubes (Costar) and counting them in a FACS for 30 sec.

The compounds of this invention were adivas in this assay.

The Clso value (concentration of test compound required to reduce the binding of 1 5l-eotaxin to transfected cells L1.2 CCR-3 by 50%) for some of the invendone compounds was: EXAMPLE 17 Inhibition of eotaxin-mediated chemotaxis of human eosinophils -in vitro test The ability of the compounds of the invention to inhibit eotaxin-mediated chemotaxis of human eosinophils was evaluated by employing a slight modification of the procedure described in Carr, MW Y cois ., Proc. Natl. Acad. Sd.

USA, 91: 3652-3656 (1994). The experiments were performed using 24-well chemotaxis plates (Costar Corp., Cambridge, MA). Eosinophils were isolated from blood using the procedure described in the PCT application, Pub. No. WO 96/22371. The endothelial cells used were the ECV 304 endothelial line obtained from the European Collection of Animal Cell Cultures (Portón Down, Salisbury, United Kingdom). The endothelial cells were cultured in 6.5 mm diameter tissue culture inserts Biocoat® Transwell (Costar Corp., Cambridge, MA) with a pore size of 3.0 μM. Culture medium for ECV 304 cells consisted of M199 with fetal bovine serum ai 10%, L-glutamine and antibiotics. The test medium consisted of equal parts of RPMI 1640 and M199, with 0.5% BSA. 2 x 10 s ECV 304 cells were plated 24 h before assay on each insert of the chemotaxis píaca of 24 pods, and incubated at 37 ° C. 2 nM of eotaxin diluted in assay medium was added to the lower chamber. The final volume in the lower chamber was 600 μl. Tissue culture inserts coated with endothelial cells were inserted into each podllo. To the upper chamber 106 eosinophils suspended in 100 μl of assay buffer were added. Compounds to be tested dissolved in DMSO were added to both the upper and lower chamber, so that the final volume of DMSO in each well was 0.5%. The test was measured according to two groups of controls. The positive control contained cells in the upper chamber and eotaxin in the lower chamber. The negative control contained cells in the upper chamber and only assay buffer in the lower chamber. Plates were incubated at 37 ° C in 5% CO2 / 95% air for 1 - 1, 5h.

The cells that had migrated to the lower chamber were counted using flow cytometry. 500 μl of the cell suspension of the lower chamber was placed in a tube, and the relative cell counts were obtained by obtaining points for a fixed period of 30 seconds.

The compounds of this invention were added in this trial.

Example 18 Inhibition by eosinophil flux CCR-3 antagonists in the lungs of balb / c mice sensitized with ovalbumin - in vivo assay The ability of invertebrate compounds to inhibit leukocyte infiitradon in the lungs was determined by measuring the inhibition of eosinophil accumulation in the bronchoalveolar lavage fluid (BAL) of balb / c mice sensitized with ovalbumin (OA) after challenge. with aerosolized antigen. Briefly, balb / c mice weighing 20 to 25 g were sensitized with OA (10 μg in 0.2 ml of aluminum hydroxide solution) intraperitoneally on days 1 and 14. After one week, the mice were divided. in ten groups. Compounds to be tested were administered either only vehicle (control group) or antieotaxin antibody (positive control group). After 1 h, the mice were placed in a Plexiglas box and exposed to an OA aerosol generated by a PARISTAR ™ nebulizer (PARÍ, Richmond, VA) for 20 min. Mice that had not been sensitized or challenged were included as a negative control. After 24 or 72 h, the mice were anesthetized (urethane, approximately 1 g / kg i.p.), a tracheal cannula was inserted (PE 60 tube) and the lungs were washed four times with 0.3 ml of PBS. The LBA liquid was transferred to plastic tubes and stored on ice. The total leukocytes were determined in a 20 μl aliquot of the BAL fluid by the Coulter Counter ™ (Coulter, Miami, FL). Differential counts of leukocytes were made in Cytospin ™ preparations that had been stained with a Wright's Modified Tindon (Diff-Quick ™) by light microscopy using standard morphological criteria.

The compounds of this invention were added in this trial.

The previous invention has been described in greater detail to the illustrations and examples, with the aim of providing greater understanding and daring. It will be obvious to an expert in the field that changes and modifications may be implemented within the scope of the appended claims. Accordingly, it will be understood that the foregoing description is intended to be illustrative and not restrictive. The scope of the invention will be determined, therefore, not by reference to the above description, but will be determined in reference to the following appended claims, together with the full scope of equivalents covered by such claims.

All patents, patent applications and publications cited in this solidity are hereby incorporated by reference in their entirety for all purposes and to the same extent as if each patent, patent application or individual publication had been individually denoted.

It is noted that with respect to this date, the best method conoddo by the applicant to carry out the aforementioned invention, is the one that results from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (73)

1. A compound selected from the compounds of formula (I): (I) caraderized because T and U are both nitrogen; or one of T and U is nitrogen and the other is carbon; R1 and R2 are, independently of one another, hydrogen or alkyl; n is an integer from 0 to 2, provided that if n is 0, then either T or U are carbon; is an integer from 0 to 3; Ar and Ar1 are, independently of one another, aryl or heteroaryl ', F is alkylene, alkenylene or a bond, provided that if T and U are nitrogen and F is alkylene, then R4 is not aryl, each R is independently hydrogen or alkyl, or R together with either R3 or R4 and the those that are united form a carbocycle or a heteroddo; R3 and R4, independently of one another, are selected from: (i) hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cidoalkylalkyl, heteroaryl, heteroaralkyl, heteroddyl, heterocyclylalkyl, heteroalkyl, damage or - (alkylene) -C (O) - Z wherein Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy or heteroaralkyloxy, with the proviso that R3 and R4 are not both hydrogen; or (ii) R3 and R4 together with the carbon atom to which they are attached form a carbocycle or a heterocycle; E is -C (O) N (R5) -, -SO2N (R5) -, -N (Rβ) C (O) NR5) -, -N- (R6) SO2N (R5) -, -N- (R6) ) C (S) N (R5) -, -N (Rβ) C (O) -, -N (Rβ) -C (O) O-, -OC (O) N (Rβ) - or -N (Rβ) ) SOr, where: R5 is: (i) hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, araiquenyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, heteroalkyl, or - (alkylene-C (O) -Z, where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy or heteroaralkyloxy; or (ii) R5 together with either R3 or R4 and the atoms to which they are attached form a heterozydoamino group; Y Rd is hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, dcloalkylalkyl, aryl, aralkyl, araiquenyl, heteroaryl, heteroaralkyl, heterodclialkyl, heteroalkyl, or - (alkylene) -C (O) -Z, where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy or heteroaralkyloxy, with the proviso that when T is nitrogen and E is -C (O) NR5) -, -SO2N (R5) -, -N (Rs) C (O) N (R5) -, -N (Rs) -SO2N (R5) -, or -N (Rß) C (S) N (R 5) -, then m > 0; Q is -R7-W-Rβ-, where: R7 is an alkylene chain of between 1 to 6 carbon atoms inclusive; Rs is a bond or an alkylene chain of between 0 and 4 indusive carbon atoms; W is a bond or a group selected from -C (O) -, -NR9-, -O-, -S (O) or -r > -COMR9), -NíR ^ CÍO) -, -N (R9) SOr. -SOzNfR9) -, -N (R9) C (O) N (R9) -, -NíR ^ SOzNíR9) - or -NÍR ^ -QSMR9) -, wherein: R9 is hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroddoalkyl, heteroalkyl, or - (alkylene) -C (O) -Z, where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy or heteroaralkyloxy, with the proviso that when T is nitrogen and U is carbon, then W is not -C (O) N (R9) -; as well as prodrugs, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.

2. The compound of claim 1, characterized in that: n and m are 1; F is a link; Q is an alkylene chain of 1 to 6 carbon atoms indusive; Y E is -C (O) N (R5) -, -SO2N (R5) -, -N (Rβ) C (O) N (R5) - or -N (Rβ) C (O) -.

3. The compound of claim 2, characterized in that: R, R1, R2 and R3 are hydrogen; and E is -C (O) N (R5) -.

4. The compound of claim 3, characterized in that T and U are both nitrogen.

5. The compound of claim 4, characterized in that R 4 is alkyl or heteroalkyl and R 5 is hydrogen.

6. The compound of claim 5, characterized in that Ar and Ar1 are aryl.

7. The compound of claim 6, characterized in that R 4 is 1-methyethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl.

The compound of claim 7, wherein Ar is a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, acyl, -S02R (where R is alkyl, amino or mono or disubstituted amino) ), methylenedioxy, hydroxy, halo, amino, mono mono or disubstituted amino, -CONR'R "(where R 'and R" are hydrogen or alkyl) or -COOH; and Ar1 is a phenyl ring optionally substituted with one, two or three of its constituents selected from alkyl, heteroalkyl, alkoxy, halo trifluoromethyl, nitro or mono mono or disubstituted amino.

9. The compound of claim 8, characterized in that Ar is phenyl, 4-chlorophenyl, 3,4-difluorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-methyl-phenyloxyphenyl, 4-methylsulfonylphenyl, - [(2-acetylamino) ethyl] phenyl, 4- (2 - [(R) -amino-3-methylbutyrylamino] ethyl) phenyl, 4- (2-aminoethyl) phenyl, 4- (aminomethyl) -phenyl, 4- (hydroxymethyl) phenyl, 3-aminocarbonylphenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl or 4-aminophenyl; and Ar 1 is 4-nitrophenyl, 4-trifluoromethyl-phenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-n-phenyl, 3-chloro-4-fluoro-phenyl or 3,4-dichlorophenyl.

10. The compound of claim 9, characterized in that R is 1-methylethyl; Ar is 4-methylphenyl; Ar1 is 3,4-doorophenyl; and Q is methylene; that is, N- dihydrochloride salt. { 1- (S) - [4- (3,4-dichlorobendl) piperazin-1-ylmethyl] -2-methylpropyl} -4-methylbenzamide.

11. The compound of claim 9, characterized in that R 4 is 1,1-dimethylethyl; Ar is 4-methylphenyl; Ar1 is 3,4-doophenyl; and Q is methylene; that is, N- dihydrochloride salt. { 1- (S) - [4- (3,4-Dichlorobenzyl) piperazin-1-ylmethyl] -2,2-dimethylpropyl} -4-methylbenzamide.

12. The compound of claim 5, characterized in that Ar is an aryl ring; and Ar 1 a heteroaryl ring.

13. The compound of claim 12, wherein R 4 is 1-methylethyl, 1,1-dimethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl.

14. The compound of claim 13, wherein Ar is a phenyl ring optionally substituted with one, two or three selected substituents of alkyl, heteroalkyl, alkoxy, acyl, -SO2R (where R is alkyl, amino or mono or disubstituted amino), methylenedioxy, hydroxy, halo, amino, mono mono or disubstituted amino, -CONR'R "(where R 'and R" are hydrogen or alkyl) or -COOH; and Ar 1 is 1-acetylindol-3-yl, 3-methylbenzothiophen-2-yl or 5-nrtrstiofen-3-yl.

15. The compound of claim 5, wherein Ar is a heteroaryl ring; and Ar1 is an aryl ring.

16. The compound of claim 15, wherein R 4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl.

17. The compound of claim 16, wherein Ar is pyridin-2-yl, pyridin-3-yl, quinolin-3-yl or 5-methylthiophen-2-yl; and Ar1 is a phenyl ring optionally substituted with one, two or three substrtuents selected from alkyl, heteroalkyl, alkoxy, halo trifluoromethyl, nitro or mono mono or disubstituted amino.

18. The compound of claim 17, characterized in that Ar1 is 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-fluorophenyl or 3,4-dichlorophenyl.

19. The compound of claim 3, characterized in that T is nitrogen and U is carbon.

20. The compound of claim 19, wherein R4 is alkyl or heteroalkyl and Rs is hydrogen.

21. The compound of claim 20, characterized in that Ar and Ar1 are aryl.

22. The compound of claim 21, wherein R 4 is 1-methylethyl, 1,1-dimethylethyl or 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl.

23. The compound of claim 22, wherein Ar is a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, acyl, -S02R (where R is alkyl, amino or amino mono or disubstituted), methylenedioxy, hydroxy, halo, amino, mono mono or disubstituted amino, -CONR'R "(where R 'and R" are hydrogen or alkyl) or -COOH; and Ar1 is a phenyl ring optionally substituted with one, two or three substrtuents selected from alkyl, heteroalkyl, alkoxy, halo trifiuoromethyl, nitro or mono mono or disubstituted amino.

24. The compound of claim 23, characterized in that Ar is phenyl, 4-chlorophenyl, 3,4-difluorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-methylenedioxyphenyl, 4-methylsulfonylphenyl, - [(2-acetylamino) ethyl] phenyl, 4-. { 2 - [(R) -amino-3-methylbutyrylamino] ethyl} phenyl, 4- (2-aminoethyl) phenyl, 4- (aminoethyl) phenyl, 4- (hydroxymethyl) phenyl, 3-aminocrbonylphenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl or 4-aminophenyl; and Ar 1 is 4-n-phenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-fluoro-phenyl or 3,4-dichlorophenite. .

25. The compound of claim 24, characterized in that R 4 is 1-methylethyl; Ar is 4-methylphenyl; Ar1 is 3,4-doorophenyl; and Q is methylene; and it is named N- dihydrochloride salt. { 1- (SH4- (3,4-didorobendl) piperidin-1-ylmethyl] -2-methylpropyl-methylbenzamide.

26. The compound of claim 24, characterized in that R 4 is 1-methylethyl; Ar is 4- (2-aminoethyl) phenyl; Ar 1 is 3,4-dichlorophenyl; and Q is methylene; and it is named N- dihydrochloride salt. { 1- (R) - [4- (3,4-dichlorobenzyl) piperidin-1-ylmethyl] -2-methy1propyl} -4- (2-aminoethyl) benzamide.

27. The compound of claim 20, characterized in that Ar is a heteroaryl ring; and Ar1 is an aryl.

28. The compound of claim 27, characterized in that R 4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl.

29. The compound of claim 28, characterized in that Ar is pyridin-2-yl, pyridin-3-yl, quinolin-3-yl or 5-methylthiophen-2-yl; and Ar1 is an optionally substrtuided phenyl ring with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro or mono- or disubstituted amino.

30. The compound of claim 29, characterized in that Ar1 is 4-n-phenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-fluorophenyl or 3,4-dichlorophenyl.

31. The compound of claim 31, characterized in that R 4 is 1-methylethyl; Ar is 5-methyryophen-2-yl; Ar1 is 3,4-diodophenyl, and Q is methylene; and it is named N- hydrochloride salt. { 1- (R) -4- (3,4-didorobendl) piperidin-1-ylmethyl] -2-methylpropyl} -5-methylthiophen-2-carboxamide.

32. The compound of claim 3, characterized in that T is carbon and U is nitrogen.

33. The compound of claim 32, characterized in that R 4 is alkyl or heteroalkyl; and R5 is hydrogen.

34. The compound of claim 33, wherein Ar is an aryl or heteroaryl ring, and Ar 1 is an aryl ring.

35. The compound of claim 34, characterized in that R 4 is 1-methylethyl, 1,1-dimethyl-beta, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl.

36. The compound of claim 35, characterized in that Ar is a pyridin-2-yl, pyridin-3-yl, quinolin-3-yl or 5-methylthiophen-2-yl ring, or a phenyl ring optionally substudy with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, acyl, -S02R (where R is alkyl, amino or mono- or disubstituted amino), methylenedioxy, hydroxy, halo, amino, amino mono or disubstituted, -CONR'R "(where R and R 'are hydrogen or alkyl) or -COOH, and Ar1 is a phenyl ring optionally substute with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro or amino mono or disubstituted amino.

37. The compound of claim 2, characterized in that R, R1, R2 and R3 are hydrogen; and E is -N (R6) C (O) N (R5) -.

38. The compound of claim 37, characterized in that T and U are both nitrogen.

39. The compound of claim 38, characterized in that R 4 is alkyl or heteroalkyl; and R5 and Rβ are hydrogen.

40. The compound of claim 39, characterized in that Ar and Ar1 are aryl.

41. The compound of claim 40, caraderized because R4 is 1-methylethyl, 1,1-dimethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl.

42. The compound of claim 41, wherein Ar is an opsonally substrtute phenyl ring with one, two or three substituents selected from alkyl, heteroalkyl, akoxy, acyl, -S02R (where R is alkyl, amino or amino mono or disubstituted), methylenedioxy, hydroxy, halo, amino, mono mono or disubstituted amino, -CONR'R "(where R 'and R" are hydrogen or alkyl) or -COOH; and Ar1 is a phenyl ring optionally substituted with one, two or three substrtuents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro or amino mono or disubstituted amino.

43. The compound of claim 42, characterized in that Ar is phenyl, 4-chlorophenyl, 3,4-difluorophenyl, 4-methylphenyl, 3-methoxyphosphino-4, 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-methylenedioxyphenito, 4-methylsulfonylphenyl. , 4 - [(2-acetylamino) ethyl] phenyl, 4-. { 2 - [(R) -amino-3-methylbutyrylamino] ethyl} phenyl, 4- (2-aminoethyl) phenyl, 4- (aminomethyl) phenyl, 4-hydroxymethyl) phenyl, 3-aminocarbonylphenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl or 4-aminophenyl; and Ar 1 is 4-n-phenyl, 4-trifluoromethyl-phenyl, 4-chlorophenyl, 3,4-difluoro-enyl, 2,3-dichlorophenyl, 3-methyl-4-n-phenyl, 3-chloro-4-fluoro-phenyl or 3,4-dichlorophenyl .

44. The compound of claim 43, characterized in that R4 is 1-methylethyl; Ar is 3-methoxyphenyl; Ar 1 is 3,4-dichlorophenyl; and Q is methylene; that is, 1- 1- (R) - [4- (3,4-dichlorobenzyl) piperazin-1-ylmethyl] -2-methylpropyl} -3- (3-methoxyphenyl) urea.

45. The compound of claim 37, characterized in that T is nitrogen and U is carbon.

46. The compound of claim 45, characterized in that R 4 is alkyl or heteroalkyl; and R5 and Rβ are hydrogen.

47. The compound of claim 46, characterized in that Ar and Ar1 are aryl.

48. The compound of claim 47, characterized in that R 4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl.

49. The compound of claim 48, wherein Ar is an opsonally substrtute phenyl ring with one, two or three substrtuents selected from alkyl, heteroalkyl, alkoxy, acyl, -S02R (where R is alkyl, amino or mono mono or disubstituted amino), methylenedioxy, hydroxy, halo, amino, mono or disubstituted amino, -CONR'R "(where R 'and R" are hydrogen or alkyl) or -COOH; and Ar1 is an opsonally substrtuided phenyl ring with one, two or three substrtuents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro or mono mono or disubstituted amino.

50. The compound of claim 49, characterized in that Ar is phenyl, 4-chlorophenyl, 3,4-difluorophenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-methylenedioxyphenyl, 4-methylsulfonylphenyl, - [(2-acetylamino) ethyl] phenyl, 4-. { 2 - [(R) -amino-3-methylbutyrylamino] ethyl} phenyl, 4- (2-aminoethyl) phenyl, 4- (aminomethyl) phenyl, 4- (hydroxymethyl) phenyl, 3-aminocarbonylphenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl, 3,5-dimethoxyphenium, 3,4-dimethoxyphenyl or 4-aminophenyl; and Ar 1 is 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-fluoro-phenyl or 3,4-dichlorophenyl .

51. The compound of claim 50, characterized in that R 4 is 1-methylethyl; Ar is 3-methoxyphenite; Ar1 is 3,4-doorophenyl; and Q is methylene; that is, 1 -. { 1 - (R) - [4- (3,4-didorobendl) piperidin-1-yl-methyl] -2-methyl-propyl} -3- (3-methoxyphenyl) urea.

52. The compound of claim 37, characterized in that T is carbon and U is nitrogen.

53. The compound of claim 52, wherein R 4 is alkyl or heteroalkyl; and R5 and R6 are hydrogen.

54. The compound of claim 53, characterized in that Ar and Ar1 are aryl.

55. The compound of claim 54, characterized in that R 4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl.

56. The compound of claim 55, wherein Ar is a phenyl ring optionally substituted with one, two or three substrtuents selected from alkyl, heteroalkyl, alkoxy, acyl, -SO2R (where R is alkyl, amino or amino mono or disubstituted), methylenedioxy, hydroxy, halo, amino, mono mono or disubstituted amino, -CONR'R "(where R 'and R" are hydrogen or alkyl) or -COOH; and Ar1 is a phenyl ring optionally substrtuided with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nrtro or amino mono or disubstrtuye.

57. The compound of claim 1, wherein T is carbon and U is nitrogen; n is 1; m is O; F is a link; Q is an alkylene chain; and E is -C (O) N (R5) -, -SO2N (R5) -, -N (Rβ) C (O) N (R5) - or -N (Rβ) C (O) -.

58. The compound of claim 57, characterized in that R, R1, R2 and R3 are hydrogen; and E is -C (O) N (R5) -.

59. The compound of claim 58, characterized in that R 4 is alkyl or heteroalkyl; and R5 is hydrogen.

60. The compound of claim 59, wherein Ar is an aryl or heteroaryl ring; and Ar1 is an aryl ring.

61. The compound of claim 60, characterized in that R4 is 1-methylethyl, 1,1-dimethyl-ethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl.

62. The compound of claim 61, characterized in that Ar is pyridin-2-yl, pyridin-3-yl, quinolin-3-yl or 5-methylo-phenyl-2-yl, or a phenyl ring opdonally substituted with one, two or three substrtuents selected from alkyl, heteroalkyl, alkoxy, acyl, -SO2R (where R is alkylated, amino or mono or disubstituted amino), methylenedioxy, hydroxy, halo, amino, amino mono or disubstituted, -CONR'R "(where R 'and R "are hydrogen or alkyl) or -COOH; and Ar1 is a phenyl ring optionally substituted with one, two or three substrtuents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro or amino mono or disubstrtuye.

63. The compound of claim 57, characterized in that R, R \ R2 and R3 are hydrogen; and E is - (NRβ) C (O) N (R 5) -.

64. The compound of claim 63 wherein the R4 is alkyl or heteroalkyl; and R5 and R6 are hydrogen.

65. The compound of claim 64, characterized in that Ar is an aryl or heteroaryl ring; and Ar1 is an aryl ring.

66. The compound of claim 65, wherein R 4 is 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl.

67. The compound of claim 66, characterized in that Ar is pyridin-2-yl, pyridin-3-yl, quinolin-3-yl or 5-methylthioen-2-yl, or a phenyl ring optionally substituted with one, two or three substrtuents selected from alkyl, heteroalkyl, alkoxy, acyl, -S02R (where R is alkyl, amino or mono- or disubstituted amino, methylenedioxy, hydroxy, halo, amino, mono-disubstituted amino, -CONR'R "(where R 'and R" they are hydrogen or alkyl) or -COOH, and Ar1 is a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro or amino mono or disubstituted amino.

68. A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound of any one of claims 1 to 67 and a pharmaceutically acceptable excipient.

69. Compounds of general formula: caraderized because n, m, R, R1-R4, T, U, Q and Ar1 are as in claim 1 and X is a group Hi ^ R5), HN (Rβ) - or carboxy, and R5 and Rβ are as defined in claim 1.

70. A process for the manufacture of the compounds according to any of claims 1 to 67, characterized in that it comprises: transforming the X group of a compound with the general formula Eg where n, m, R, R1-R4, T, U, Q and Ar1 are as in claim 1 and X is a group HN (R5), HN (Rβ) - or carboxy, and R5 and Rβ are as defined in claim 1, in a group Ar- (F) - (E) -, wherein Ar, F and E are as in claim 1, or (b) for the manufacture of a pharmaceutically acceptable salt of a compound of formula (I) bearing a basic or basic substituent, converting said compound of formula (I) into said sai.

71. The compounds according to any of claims 1 to 67 provided they are manufactured in accordance with the process claimed in claim 70 or with a chemically obvious equivalent thereof.

72. The compounds according to any of claims 1 to 67, for use as therapeutically additive substances, against respiratory diseases such as asthma.

73. The use of the compounds according to any of claims 1 to 67 in the control or prevention of diseases, particularly asthma, or for the manufacture of pharmaceutical preparations having said adivity.