MXPA00007141A - Chemokine receptor antagonists and methods of use therefor - Google Patents

Abstract

Disclosed are novel compounds and a method of treating a disease associated with aberrant leukocyte recruitment and/or activation. The method comprises administering to a subject in need an effective amount of a compound represented by structural formula (I) and physiologically acceptable salts thereof.

Description

ANTAGONISTS OF THE RECEPTORS OF QUIMIOKINAS AND METHODS OF UTILIZATION FOR THEMSELVES RELATED REQUESTS This application is a continuation in part of the USA. Serial No. 09 / 148,515, filed September 4, 1998, which is a continuation in part of the US. Serial No. 09 / 009.-577, filed on January 21, 1998 and currently abandoned, the teachings of which are hereby incorporated in their entirety as a reference.

BACKGROUND OF THE INVENTION Chemoattractant cytokines or chemokines are a family of proinflammatory mediators that promote the recruitment and activation of multiple leukocyte and lymphocyte lineages. They can be released by many types of tissue cells after their activation. The continuous release of chemokines in sites of medium inflammation in the continuous migration of effector cells in chronic inflammation. The chemokines characterized to date are related in their primary structure. They share four conserved cysteines, which form disulfide bonds. Based on this conserved cysteine motif, the family is divided into two main branches, called CXC chemokines (a-chemokines) and CC chemokines (ß-chemokines), where the first two conserved cysteines are separated by an intermediate residue or are adjacent, respectively (Baggioli-ni, M. and Dahinden, CA, Immunology Today, 15: 127-133 (1994)). C-X-C chemokines include a series of potent chemoattractants and activators of neutrophils, such as interleukin 8 (IL-8), PF4 and neutrophil activating peptide-2 ("NAP-2"). C-C chemokines include ARANTES "(Regulated when activated, expressed and secreted by T normal), inflammatory proteins of macrophages la and lß ("MlP-la" and "MlP-lß"), eotaxin and human monocyte chemotactic proteins 1-3 ("MCP-1", "MCP-2", " MCP-3"), which have been characterized as chemoattractants and activators of monocytes or lymphocytes, but do not appear to be chemoattractants for neutrophils. Chemokines, such as RANTES and MlP-la, have been implicated in a wide range of acute and chronic human inflammatory diseases, including respiratory diseases, such as asthma and allergic disorders. The chemokine receptors are members of a superfamily of G-protein coupled receptors ("GPCRs"), which share structural characteristics that reflect a common mechanism of action of signal transduction (Gerard, C. and Gerard, NP, Annu. Immunol., 12: 775-808 (1994), Gerard, C. and Gerard, NP, Curr. Opi. Immunol., 6: 140-145 (1994)). The conserved features include seven hydrophobic domains that expand across the plasma membrane, which are connected by extracellular and intracellular hydrophilic loops. Most of the primary sequence homology occurs in the hydrophobic transmembrane regions, the hydrophilic regions being more diverse. The first receptor for C-C chemokines that was cloned and expressed is bound to the MlP-la and RANTES chemokines. Accordingly, this MIP-la / RANTES receptor was termed CC chemokine receptor 1 (also referred to as CCR-1; Neote, K. et al., Cell, 72: 415-425 (1993); Horuk, R. et al., WO 94/11504, May 26, 1994; Gao, J.-I. et al., J. Exp. Med., 77: 1421-1427 (1993)). Three receptors that bind and / or signal in response to RANTES have been characterized: CCR3 mediates the binding and signaling of chemokines including eotaxin, RANTES and MCP-3 (Ponath et al., J. Exp. Med., 183 : 2437 (1996)); CCR4 binds to chemokines including RANTES, MlP-la and MCP-1 (Power et al., J. Biol. Chem., 270: 19495 (1995)), and CCR5 binds to chemokines including MlP-la, RANTES and MlP-lβ (Samson et al., Biochem 35: 3362-3367 (1996)). RANTES is a chemokine chemokine for a variety of cell types, including monocytes, eosinophils and a subset of T cells. The responses of these different cells may not be mediated by the same receptor and it is possible that the CCR1 receptors, CCR4 and CCR5 show some selectivity in the distribution and function of receptors between leukocyte types, as has already been shown for CCR3 (Ponath et al.). Specifically, the ability of RANTES to induce targeted migration of monocytes and a memory population of circulating T cells (Schall, T. et al., Na ture, -347: 669-71 (1990)) suggests that this chemokine and its (s) receptor (s) may have a critical function in chronic inflammatory diseases, since these diseases are characterized by destructive infiltrates of T cells and monocytes. Many existing drugs have been developed as antagonists of the receptors for biogenic amines, for example as antagonists of the dopamine and histamine receptors. No receptor antagonist has yet been successfully developed for larger proteins, such as chemokines and C5a. Small-molecule antagonists of the interaction between CC chemokine receptors and their ligands, including RANTES and MlP-la, would provide useful compounds to inhibit the damaging inflammatory processes "triggered" by receptor-ligand interaction, as well as valuable tools for Investigation of receptor-ligand interactions.

SUMMARY OF THE INVENTION It has now been found that a class of small organic molecules are antagonists of the function of chemokine receptors and can inhibit the activation and / or recruitment of of leukocytes. An antagonist of chemokine receptor function is a molecule that can inhibit the binding and / or activation of one or more chemokines, including CC chemokines such as RANTES, MlP-la, MCP-2, MCP-3 and / or MCP-4 to one or more chemokine receptors on leukocytes and / or other cell types. As a consequence, processes and cellular responses mediated by chemokine receptors can be inhibited by these small organic molecules. Based on this discovery, a method of treating a subject with a disease associated with an aberrant leukocyte recruitment and / or activation, as well as a method of treating a disease mediated by the function of chemokine receptors is described. The method consists of administering to a subject in need of treatment an effective amount of a compound or of a small organic molecule that is an antagonist of the function of the chemokine receptors. Compounds or small organic molecules that have been identified as antagonists of chemokine receptor function are discussed in detail hereinafter and can be used for the manufacture of a medicament for treating or preventing a disease associated with recruitment and / or aberrant activation of leukocytes. The invention also relates to the compounds and small organic molecules described for use in the treatment or prevention of a disease associated with an aberrant recruitment and / or activation of leukocytes. The invention also includes pharmaceutical compositions consisting of one or more compounds or small organic molecules that have been identified herein as antagonists of chemokine function and a suitable pharmaceutical carrier. The invention also relates to new compounds that can be used to treat an individual with a disease associated with an aberrant recruitment and / or activation of the leukocytes and with methods for their preparation.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a diagram showing the preparation of the compounds represented by the Structural Formulas (I) and (ID - Figure 2 is a diagram showing the preparation of representative compounds of the Structural Formulas (I) and (II), where Z is represented by the Structural Formulas (IV) and where the A Ring and / or Ring B in Z may be substituted with - (O) u- (CH2) t-COOR20, - (O) u- (CH2) t-OC (0) R20, - (0) u- (CH2) tC (0) -NR21R22 or - (O) u- (CH2) t-NHC (O) -O-R20 Figure 3 is a diagram showing the preparation of the compounds represented by the Structural Formulas (I) and (II) ), where Z is represented by the Structural Formulas (VIII) and (XIII) - (XVIc) and where V is Wa. Figure 4 is a diagram showing the preparation of the compounds represented by the Structural Formulas (I) and ( II), where Z is represented by the Structural Formula (IV), where W is H. Figure 5 is a diagram showing the preparation of the compounds represented by the Structural Formulas (I) and (II), where Z is represented for the Formula Est ructural (IV), where W is H. Figure 6A-6AD shows the structures of a series of exemplary compounds of the present invention. Figure 7 shows the preparation of compounds represented by Structural Formula (I), where Z is represented by the Structural Formulas (VI) and where the Ring a and / or Ring B in Z are substituted with - (O) u- ( CH2) t-COOR20, where u is one. Figure 8 shows the preparation of compounds represented by Structural Formula (I), where Z is represented by the Structural Formulas (VI) and where Ring A or Ring B in Z are substituted with - (O) u- (CH2 ) t COOR2o where u is zero.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to small molecule compounds that are modulators of the function of chemokine receptors. In a preferred embodiment, the small molecule compounds are antagonists of the function of the chemokine receptors. Consequently, cellular processes or responses mediated by the binding of a chemokine to a receptor can be inhibited (reduced or prevented, in whole or in part), including the migration of leukocytes, the activation of integrins, the transient increases in concentration of free calcium [Ca ++] intracellular and / or the release of the granules of proinflammatory mediators. The invention also relates to a method of treatment, including prophylactic and therapeutic treatments, of a disease associated with an aberrant or chemokine-mediated recruitment and / or activation of chemokines or by the function of chemokine receptors, including disorders chronic inflammatories characterized by the presence of T cells, monocytes and / or eosinophils that respond to RANTES, MlP-la, MCP-2, MCP-3 and / or MCP-4, including, but not limited to, diseases such as arthritis (eg, example, rheumatoid arthritis), atherosclerosis, arteriosclerosis, ischemia / reperfusion injury, diabetes mellitus (for example, diabetes mellitus type 1), psoriasis, multiple sclerosis, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease , rejection of transplanted organs and tissues (ie, acute rejection of allografts, chronic rejection of allografts), graft disease against the host ed, as well as allergies and asthma. Other diseases associated with an aberrant recruitment and / or activation of leukocytes that can be treated (including prophylactic treatments) with the methods described here are inflammatory diseases associated with infection by the Human Immunodeficiency Virus ("HIV"), for example AIDS-associated encephalitis, maculopapular skin rash related to AIDS, interstitial pneumonia related to AIDS, AIDS-related enteropathy, periportal hepatic inflammation related to AIDS and AIDS-related glomerulonephritis. The method consists in administering to the subject in need of treatment an effective amount of a compound (ie, of one or more compounds) that inhibits the function of the chemokine receptors, which inhibits the binding of a chemokine to leukocytes and / or other cell types and / or that inhibits leukocyte migration to, and / or leukocyte activation in, sites of inflammation. The invention further relates to methods of antagonizing a chemokine receptor, such as CCR1, in a mammal, comprising administering to the mammal a compound as described herein. According to the method, chemotaxis and / or chemokine-mediated activation of proinflammatory cells carrying chemokine receptors can be inhibited. As used herein, the term "proinflammatory cells" includes, but is not limited to, leukocytes, since qui-myokin receptors can be expressed in other cell types, such as neurons and epithelial cells. Not wishing to be bound by any particular theory or mechanism, we think that the compounds of the invention are antagonists of the chemokine receptor CCR1 and that the therapeutic benefits derived from the method of the invention are the result of the antagonism of the CCR1 function. Therefore, the method and compounds of the invention can be used to treat a medical condition involving cells expressing CCRl on its surface and responding to signals transduced through CCRl, as well as the specific conditions cited above. In one embodiment of the present invention, the antagonist of chemokine receptor function is represented by Structural Formula (I): (I) wherein: Z is a cycloalkyl or a non-aromatic heterocyclic ring fused to one or more carbocyclic aromatic rings and / or heteroaromatic rings; And it is a covalent bond, -0-, -CO- or = CH-; n is an integer, such as an integer from one to about five; n is preferably one, two or three. In alternative embodiments, other aliphatic or aromatic spacers (L) for (CH2) n; X is a covalent bond or -C0-; M is > NR2 or > CRXR2; preferably, M is > C (0H) R2; R1 is -H, -OH, -N3, halogen, an aliphatic group, -0- (aliphatic group), -0- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (group aliphatic substituted), -OC (O) - (aliphatic group), -0-C (0) - (substituted aliphatic group), -C (0) 0- (aliphatic group), -C (0) 0- (group substituted aliphatic), -COOH, -CN, -CO-NR3R4 or -NR3R4; or R1 may be a covalent bond between the ring atom in M and an adjacent carbon atom in the ring containing M; R1 is preferably -H or -OH; R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; R2 is preferably an aromatic group or a substituted aromatic group; R3, R4, R5 and R6 are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a group non-aromatic heterocyclic or substituted non-aromatic heterocyclic group; R1 and R2, R3 and R4 or R5 and R6, taken together with the atom to which they are attached, can alternatively form a substituted or unsubstituted carbocyclic or heterocyclic non-aromatic ring. In embodiments where M is > CR1R2 and R1 is a covalent bond between the carbon atom in M and an adjacent carbon atom in the ring containing M, the antagonist of the chemokine function can be represented by the Structural Formula (la): (the) where Z, n and R2 are as described in Structural Formula (I). In a preferred embodiment, -X- and -Y- in the Formula Structural (I) are each a covalent bond and the antagonist of chemokine receptor function is a compound represented by Structural Formula (II): (II) where Z, n and M are as described above for Structural Formula (I). In another preferred embodiment, -X- is a covalent bond, -Y- is -CO- and the antagonist of chemokine receptor function is a compound represented by Structural Formula (III): (neither: Preferably, Z is a tricyclic ring system consisting of two carbocyclic aromatic groups fused to a cycloalkyl group of six, seven or eight members or to a non-aromatic heterocyclic ring. In one example, Z is represented by the Structural Formula (IV): (IV) Reference is here made to the phenyl rings in Structural Formula (IV), marked with an "A" and a "B", such as "Ring A" and "Ring B", respectively. Reference is made to the central ring, marked with a "C", as "Ring C" and may be, for example, a non-aromatic carbocyclic ring of six, seven or eight members (for example, a ring of cycloheptane or cyclooctane) or a non-aromatic heterocyclic ring. When Ring C is a non-aromatic heterocyclic ring, it may contain one or two heteroatoms such as nitrogen, sulfur or oxygen. When Z is represented by Structural Formula (IV), the tricyclic ring system can be connected to Y in Structural Formula (I) by a simple covalent bond between Y and a ring atom in Ring C. Ring A and / or Ring B may not be replaced. Alternatively, Ring A and / or Ring B may have one or more substituents. Suitable substituents are those described below. In one example, Ring A or Ring B are substituted by - (O) u- (CH 2) tC (O) OR 20, - (O) u- (CH 2) t-OC (O) R 20, - (O) u- (CH2) t "C (O) -NR21R22 or - (0) u- (CH2) t-NHC (0) -0-R20; u is zero or one; t is an integer, such as a number whole from zero to about three, and the methylene group, - (CH) t-, may be substituted or unsubstituted; R2o R21 or R are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group. Alternatively, R21 and R22, taken together with the nitrogen atom to which they are attached, can form a non-aromatic heterocyclic ring; Ring C eventually contains one or more substituents as described herein below. Preferably, Ring C is unsubstituted or substituted with an electron withdrawing group. Suitable electron withdrawing groups include -CN, -CH2 = NH, alkylimines, alkylsulfonyl, carboxamido, carboxylic alkyl esters, -N02 and halogens (for example, -Br and -Cl). Alternatively, Ring C is substituted with a group selected from -CH2-NR12, -CH2-ORu, -CH2-NH-CO-NR1-tR-12 CH2-0-C0-NR1J-R1 or -CH2-NHC (0) -OR 111 R11 and R12 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group. Alternatively, R11 and R12, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring. Examples of suitable tricyclic ring systems represented by Structural Formula (IV) are given by the Structural Formulas (V) - (VIII), shown below: (VIII) X? it is a covalent bond, -S-, -CH2- or -CH2-S-. Preferably, Xi is -S- in the Structural Formulas (V) and (VII). Preferably, Xi is -CH2-S- in the Structural Formulas (VI) and (VIII). W is -H or an electron withdrawing group, as described above for Structural Formula (IV). A preferred electron withdrawing group is -CN. Wa is a group selected from -CH2-NR11R12, -CH2-0R1: L, -CH2-NH-C0-NRUR12, -CH2-0-CO-NR R12 or -CH2-NHC (O) -O-R11. R11 and R12 are as defined in Structural Formula (IV). Ring A and Ring B in Structural Formulas (V) - (VIII) may be as described above in Structural Formula (IV). Other examples of suitable tricyclic ring systems represented by Structural Formula (IV) are shown below in Structural Formulas (XI), (XII), (Xlla), (Xllb) and (XIIc): (XI) (XII) A c B A B (Xlla) (Xllb) (XIIc) The Rings A-C in the Structural Formulas (XI) - (XII), (Xlla), (Xllb) and (XIIc) are as described for the Structural Formula (IV). Rc is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group. Preferably, Rc is a substituted C?-C2o aliphatic group, a C1-C20 aliphatic group. an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group. In one example, R c is - (CH 2) s-COOR 30, - (CH 2) s-OC (O) R 30, - (CH 2) SC (O) -NR 31 R 32 or - (CH 2) s-NHC (0) -O- R30. s is an integer from one to about three. R30, R31 and R32 are independently -H, an aliphatic group a substituted aliphatic group, an aromatic group, a substituted aromatic group or a substituted or unsubstituted non-aromatic heterocyclic group. Alternatively, R31 and R32, taken together with the nitrogen atom to which they are attached, can form a non-aromatic heterocyclic ring. The following are preferred examples of tricyclic ring systems represented by the Structural Formulas (XI) - (XII), (Xlla), (Xllb) and (XIIc) in the Structural Formulas (XIII) - (XVI), (XVIa) ), (XVIb) and (XVIc): (XIII) (XIV) (xv) (XVI) (XVIa) (XVIb) (XVIc) V may be W or Wa, which are as described above for the Structural Formulas (V) - (VIII). In another preferred embodiment, Z is a tricyclic ring system consisting of one or more aromatic groups (is cir, heteroaryl or aromatic carbocyclic) fused to a cycloalkyl group of six, seven or eight members or to a non-aromatic heterocyclic ring. The examples are represented by the Structural Formula (XVII): (XVII) where X2 is -S-CH2- -CH2-S-, -CH2-0- -0-CH2- -CO-NRr -NRc-CO-, -CH2-S (0) 2-, -S (0) 2 -CH2-, -CH2-NRC-, -NRC-CH2-, -CH2-CH2-, -CH = CH-, -CH2-SO-, -SO-CH2-. Ring A and Ring B in Structural Formulas (XVII) are independently substituted or unsubstituted aromatic groups. In one example, Ring A is a substituted or unsubstituted heteroaryl group and Ring B is a substituted or unsubstituted aromatic carbocyclic group. In another example, Ring A and Ring B are independently substituted or unsubstituted heteroaryl groups. In yet another example, Ring A is a substituted or unsubstituted heteroaryl group, preferably a pyridyl group, and Ring B is a substituted or unsubstituted phenyl group. Ring A and / or Ring B may be substituted with R40, which is a substituent as described herein. Preferably, R40 is an aliphatic group, a substituted aliphatic group, -O- (aliphatic group) or -O- (substituted aliphatic group). More preferred R40 is -O-alkyl, such as -0-CH3, -0-C2H5, -0-C3H7 or -O-C4H9. In a preferred embodiment, Ring a is a pyridyl group, Ring B is a phenyl group and Ring B is substituted in position para to the carbon atom in Ring B which is also attached to X2 in Ring C. Wb is -H, -CH = NH, -CN, -CH2-NRnR12, -CH2-0RU, -CH2-NH-C0- NRnR12, -CH2-0-CO-NRnR12 O -CH2-NHC (0) -0-R 11 R11 and R12 are as defined above for the structural formula (IV). In yet another embodiment, the chemokine antagonist is a compound represented by the Structural Formulas (XXII) and (XXIII): (XXII) (XXIII) In the Structural Formulas (XXII) and (XXIII), Xx can be as defined above for the Structural Formulas (V) and (VI); n is an integer from two to five; W can be -H, -CN, -CH = NH, an electron withdrawing group, -CH2- NRnR12, -CH2-OR 11 -CH2-NH-CO-NR R12, -CHz-O-CO-NR ^ R12 or -CH2- In the Structural Formulas (XII) and (XXIII), Ring A may be substituted with R8 and R9, where R8 and R9 are independently -H, a halogen, alkoxy or alkyl or, taken together with Ring A, they form a naphthyl group. M is > N (alkanoyl), > N (aroyl), > N (aralcoyl), > N (alkyl), > N (aralkyl), > (cycloalkyl), > C (OH) (aryl) or > CH (heteroaryl). In another embodiment, the antagonist of the chemokine activity can be represented by the Structural Formula (XXIV): (XXIV) and their physiologically acceptable salts. n, Y, X and M are as described in the Structural Formula (i). Z is as described in the Structural Formulas (IV) - (VIII) and / or (XI) - (XVII). q is an integer, such as an integer from zero to about three, and the ring containing M may be substituted or unsubstituted. Therefore, the antagonist of the chemokine function can be represented, for example, by the Structure Formulas (XXIVa) - (XXIVd): (XXIVc) (XXIVd) and their physiologically acceptable salts, wherein Z, n and M are as described in Structural Formula (XXIV) and the ring containing M is substituted or unsubstituted. Another embodiment of the invention provides new compounds used in these methods. Also included in the present invention are physiologically acceptable salts of the compounds represented by the Structural Formulas (I) to (XXIVd). The salts of compounds containing an amine or other basic group can be obtained, for example, by reaction with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acetic acid, citric acid, perchloric acid and Similar. Compounds with a quaternary ammonium group also contain a counter-anion such as chloride, bromide, iodide, acetate, perchlorate and the like. The salts of compounds containing a carboxylic acid or other acid functional group can be prepared by reaction with a suitable base, for example a hydroxide base. The salts of acid functional groups contain an anti-cation such as sodium, potassium, ammonium, calcium and the like. As used here, aliphatic groups include Ci-Cg straight-chain, branched or cyclic hydrocarbons which are completely saturated or which contain one or more units of unsaturation. For example, suitable aliphatic groups include linear, branched or cyclic, substituted or unsubstituted C, -C20 alkyl, alkenyl or alkynyl groups. An "alkyl group" is a saturated aliphatic group, as defined above. The term "alkoxy" refers to an alkyl ether chain with an alkyl group. "Alkanoyl" refers to carbonyl substituted with alkyl; "aralkanoyl" refers to phenylalkyl-CO- and "aroyl" refers to arylcarbonyl, including benzoyl, naphthoyl, and the like. The term "halogen" means fluoro, chloro, bromo and iodo. The term "substituted phenyl" means phenyl substituted by alkyl, halogen, alkoxy, nitro, amino, acetamido, cyano and trifluoromethyl and naphthyl. "Aralkyl" means - (CH2) x-aryl, where x is an integer from one to four, including benzyl. Aromatic groups include carbocyclic aromatic groups, such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl, and heterocyclic or heteroaryl aromatic groups, such as N-imidazolyl, 2-imidazolyl, 4-imidazolyl , 5-imidazolyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl and 5-oxazolyl. When these rings are fused, for example, to Ring C, the established point of attachment can be either of the two fused bonds. Aromatic groups also include polycyclic aromatic ring systems in which a carbocyclic aromatic ring or a heteroaryl ring is fused to one or more different rings. Examples include tetrahydro-naphthyl, 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl, 2-benzooxazolyl, 2- benzimidazolyl, 2-quinolinyl, 3-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 1-isoindolyl, 3-isoindolyl and acridinyl. Also included in the scope of the term "aromatic group", as used herein, is a group in which one or more carbocyclic aromatic rings and / or heteroaryl rings are fused to a non-aromatic cycloalkyl or heterocyclic ring. Examples include benzocyclopentane, benzocyclohexane, decalin, phthalimido, benzodiazepines, benzooxazepines, benzooxazines, phenothiazines and groups represented by the following structural formulas: The non-aromatic heterocyclic rings are non-aromatic carbocyclic rings that include one or more heteroatoms, such as nitrogen, oxygen or sulfur, in the ring. The ring may have five, six, seven or eight members and / or be fused to another ring, such as a cycloalkyl or aromatic ring. Examples include 3-lH-benzimidazol-2-one, 3-l-alkylbenzimidazol-2-one, 3-l-methylbenzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrofuran, Drothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidyl, 1-3-alkylphthalimidyl, benzoxane, benzopyrolidine, benzopiperidine, benzoxolane, benzothiolane, benzothiane, and "Heterocyclic ring" includes "heteroaryl group" and "non-aromatic heterocyclic ring" and is defined as imidazole, benzimidazole, pyridine, pyrimidine, thiazole, benzothiazole, thienyl, benzothienyl. Suitable substituents on a heterocyclic alkyl, aliphatic, aromatic or non-aromatic ring or a benzyl group include, for example, an electron withdrawing group, an aliphatic group, a substituted aliphatic group, azido, -OH, a halogen (-Br, -Cl, -I and -F), -O- (aliphatic, aliphatic group) substituted, benzyl, substituted benzyl, aromatic or substituted aromatic), -CN, -N02, -COOH, -NH2, -NH (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group), -N- (group aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic) 2 r -COO (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group), -CONH2, -CONH (aliphatic group, substituted aliphatic, benzyl , substituted benzyl, aromatic or substituted aromatic), -CON (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic) 2, -SH, -SOk- (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or aromatic substitute gone) (k is 0, 1 or 2), -NH-C (= NH) -NH2, - (0) u- (CH2) t-C00R, - (0) u- (CH2) t-0C (0 ) R .20 (0) u- (CH2) tC (0) -NR21R22 or - (0) u- (CH2) t-NHC (0) 0-R20; R20, R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group, and wherein R21 and R22, taken together with the nitrogen atom to which they are together, they can form a non-aromatic heterocyclic ring. u is an integer such as zero or one. t is an integer, such as an integer from zero to about three, and the methylene group, - (CH2) t ~. it can be replaced or not replaced. A non-aromatic heterocyclic ring, a benzyl group or a substituted aromatic group may also have a group aliphatic or aliphatic substituted as a substituent. A substituted aliphatic or aliphatic group may also have a non-aromatic heterocyclic ring, a benzyl, substituted benzyl, aromatic or aromatic group substituted as a substitutent. A substituted non-aromatic heterocyclic ring can also have = 0, = S, = NH or = N (aliphatic, aromatic or substituted aromatic group) as a substituent. A substituted aliphatic, substituted aromatic or substituted nonaromatic heterocyclic ring or a substituted benzyl group may have more than one substituent. Suitable electron withdrawing groups include, for example, alkylimines, alkylsulfonyl, carboxamido, carboxylic alkyl esters, -CH = NH, -CN, -N02 and halogens. Suitable acyl groups include substituted and unsubstituted aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl, and aromatic sulfonyl. The compounds described herein can be obtained as different stereoisomers (for example, diastereomers and enantiomers). For example, when the antagonist of chemokine receptor function is represented by Structural Formula (I) and Z is represented by Structural Formula (IV), the carbon atom of Ring C that is attached to Y may be in the stereoconfiguration R or S. It is noted that the invention includes all isomeric forms and racemic mixtures of the described compounds and a method of treating a subject with pure isomers and mixtures thereof, including racemic mixtures. It is understood that one stereoisomer may be more active than another. The de-seed isomer can be determined by making a selective study in terms of activity, using the methods described herein.

In the structural formulas represented here, the single or double bond by which a group or chemical moiety is connected to the rest of the molecule or compound is in- given by the following symbol: \ For example, the corresponding symbol in Structural Formula (V) or (VIII) indicates that the tricyclic ring system, which represents Z in Structural Formula (I), is connected to the alkylene group in Structural Formula (I) by a single covalent bond between the alkylene group and the ring carbon of Ring C which is attached to. A "subject" is preferably a bird or a mammal, such as a human, but may also be an animal in need of veterinary treatment, for example domestic animals (eg, dogs, cats and the like), farm animals (e.g. cows, sheep, poultry, pigs, horses and the like) and laboratory animals (for example, rats, mice, guinea pigs and the like). An "effective amount" of a compound is an amount that results in the inhibition of one or more processes mediated by the binding of a chemokine to a receptor on a subject with a disease associated with an aberrant recruitment and / or activation of the leukocytes. Examples of such methods include leukocyte migration, integrin activation, transient increases in intracellular free calcium [Ca2 +] concentration and release of proinflammatory mediator granules. Alternatively, an "effective amount" of a compound is an amount sufficient to achieve a desired therapeutic and / or prophylactic effect, such as an amount that results in the prevention or reduction of symptoms associated with a disease associated with a recruitment. and / or aberrant activation of leukocytes. The amount of compound administered to the individual It will depend on the type and severity of the disease and the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of disease. The person skilled in the art will be able to determine the appropriate dosages depending on these and other factors. Typically, an effective amount of the compounds may vary in the range of about 0, 1 mg per day to approximately 100 mg per day for an adult. Preferably, the dosage varies in the range of about 1 mg per day to about 100 mg per day. An antagonist of chemokine receptor function can also be administered in combination with one or more additional therapeutic agents, for example theophylline, β-adrenergic bronchodilators, corticosteroids, antihistamines, anti-allergic agents, immunosuppressive agents (eg cyclosporin A, FK). -506, prednisone, methylprednisolone) and the like. The compound can be administered by any suitable route, including, for example, orally in capsules, pensions or tablets, or parenteral administration. Parenteral administration can include, for example, systemic administration, such as by intramuscular, intravenous, subcutaneous or intraperitoneal injection. The compound can also be administered orally (for example, through the diet), topically, transdermally, inhalatively (for example, intrabronchial, intranasal, oral inhalation or intrana-salt drops) or rectally, depending on the disease or condition that is to be treated. Oral or parenteral administration is the preferred mode of administration. The compound can be administered to the individual together with an acceptable pharmaceutical or physiological carrier as part of a pharmaceutical composition for treatment of HIV infection, of an inflammatory disease or of the other diseases discussed above. The formulation of a compound to be administered will vary according to the selected route of administration (e.g., solution, emulsion, capsule). Suitable carriers can contain inert components that do not interact with the compound. Standard techniques of pharmaceutical formulation can be employed, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. Pharmaceutical carriers suitable for parenteral administration include, for example, sterile water, physiological saline solution, bacteriostatic saline solution (saline containing approximately 0.9% mg / ml benzyl alcohol), phosphate buffered saline solution, Hank, Ringer-lactate and the like. Methods for encapsulating compositions (such as in a hard gelatin or cyclodextrin coating) are known in the art (Baker et al., "Controlled Relase of Biological Active Agents," John Wiley and Sons, 1986). The activity of the compounds of the present invention can be determined using suitable assays, such as receptor binding assays and chemotaxis assays. For example, as described in the Examples Section, small molecule antagonists of the binding of RANTES and MlP-la have been identified using THP-1 cells that bind RANTES and that undergo chemotaxis in response to RANTES and MIP-la as model for leukocyte chemotaxis. Specifically, a high-throughput receptor binding assay that controls the binding of 125I-RANTES and 125I-MIP-la to the membranes of THP-1 cells was used to identify small molecule antagonists that block the binding of RANTES and MlP- the. The compounds of the present invention can also be identified by virtue of their ability to inhibit the activation steps triggered by the binding of a chemokine to its receptor, such as chemotaxis, activation of integrins and the release of mediators from the graphs. null They can also be identified by virtue of their ability to block the chemotactic response of HL-60, T cells, peripheral blood mononuclear cells and eosinophils mediated by RANTES and MlP-la. The compounds described herein can be prepared according to the schemes shown in Figures 1-5 and 7-8. The schemes are described in more detail below. Figure 1 is a diagram showing the preparation of the compounds represented by the Structural Formulas (I) and (II), where Z is represented by the Structural Formula (IV), where W is CN. L1, L2 and L3 in Figure 1 are suitable leaving groups, such as halogen, p-toluenesulfonate, mesylate, alkoxy and phenoxy. The other symbols are as defined above. The reduction reaction of Step 1 of Figure 1 is carried out with a reducing agent such as sodium borohydride or lithium aluminum hydride ("LAH") in an inert solvent, such as methanol or tetrahydrofuran (THF). The reaction is carried out at temperatures in the range of 0 ° C to reflux temperature and for 5 minutes to 72 h. The compounds represented by Formula II of Figure 1 can be prepared by procedures described in JP 61/152673, US Pat. 5089496, WO 89/10369, WO 92/20681 and WO 93/02081, the teachings of which are hereby incorporated in their entirety by way of reference. A chlorination reaction can be carried out in step 2 of Figure 1 with reagents such as thionyl chloride. The reaction can be conducted in an inert solvent, such as methylene chloride, at 0 ° C to the reflux temperature, for 5 minutes to 72 h. The hydroxy group can also be converted to other leaving groups by methods familiar to those skilled in the art. The cyanation reaction of stage 3 of Figure 1 can be carried out using reagents such as copper cyanide, silver cyanide or sodium cyanide in an inert solvent, such as benzene or toluene. The reaction temperatures vary between 0 ° C and the reflux temperature, for 5 minutes to 72 h. The compounds represented by Formula V in Figure 1 can also be prepared by the methods described in J. Med. Chem. 1994, 37, 804-810 and in US Pat. 5672611, whose teachings are here incorporated in their entirety as a reference. The alkylation reactions of steps 4 and 5 of Figure 1 can be carried out in a solvent such as acetone, methyl ethyl ketone, ethyl acetate, toluene, tetrahydrofuran (THF) or dimethylformamide (DMF), in the presence of such a base as potassium carbonate or sodium hydride and a catalyst such as an alkali metal iodide (when necessary). The temperature of the reaction can vary between room temperature and reflux temperature and for 5 minutes to 72 hours. The product of the synthetic scheme shown in Figure 1 can be distilled using a reducing agent such as lithium aluminum hydride (LAH) in an inert solvent, such as ether or tetrahydrofuran (THF), at 0 ° C to reflux temperature for the solvent used, for 5 minutes to 72 hours. Figure 2 is a diagram showing the preparation of representative compounds of Structural Formulas (I) and (II), where Z is represented by Structural Formula (IV) and where Ring A and / or Ring B in Z can be substituted with - (O) u- (CH2) t-COOR 20 - (0) u- (CH2) t-OC (?) R 20 (0) u- (CH2) tC (0) -NR21R22 or - ( O) u- (CH2) t-NHC (O) -O-R20. In Figure 2, the hydrolysis reaction can be carried out in a mixture of an aqueous solution of alkali metal hydroxide and a solvent such as methanol, ethanol, trahydrofuran (THF) or dioxane, at room temperature up to the reflux temperature for the solvent used, for 5 minutes to 72 h. The acylation reaction can be conducted using dicyclohexylcarbodiimide (DCC) or (l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (DEC) in a solvent such as tetrahydrofuran (THF), dimethylformamide (DMF) or methylene chloride, in the presence of a base such as pyridine or triethylamine (when necessary) at temperatures of 0 to 100 ° C, for 5 minutes to 72 h.The compounds represented by the Structural Formulas (I) and (II), where Z is represented by the Structural Formula (XVI), X is -CO-N (Rc) - and Rc is - (CH2) s-COOR30, - (CH2) sC (0) -NR31R32 or - (CH2) S-NHC (O) -O-R30, can be prepared by suitable modification of the scheme shown in Figure 1. A modification uses the starting material shown in Figure 1, where X is -CO-NH- The amide is then alkylated with L3 - (CH2) s-COOR30 using the alkylation procedures described above L3 is a suitable leaving group The remainder of the synthesis is as described in Figures 1 and 2. Figure 3 is a diagram showing the preparation of the compounds represented by the Structural Formulas (I) and (II), where Z is represented by the Structural Formulas (VIII) and (XIII) - (XVI) and where V It's Wa. The reduction of the cyano group to an amine in Figure 3 can be carried out using metal hydrides or by catalytic reduction processes. Suitable reducing agents include lithium aluminum hydride (LAH), diisobutyl aluminum hydride ("DIBAL-H"), bora-non-methyl sulfide complex or sodium borohydride. The reduction can be carried out in an inert solvent, such as ether, tetrahydrofuran (THF), methylene chloride or methanol, at -78 ° C to reflux temperature, for 5 minutes to 72 h. It is also possible to isolate the intermediate imine co- corresponding, which can be converted to the amine using similar reduction procedures. Figure 4 is a diagram showing the preparation of compounds represented by the Structural Formulas (I) and (II), where Z is represented by the Structural Formula (IV), where W is H. The reduction of the double bond in the step 1 of Figure 4 can be carried out using the catalytic reduction process. Suitable catalysts include palladium-carbon, platinum oxide or Raney nickel. The reduction can be carried out in an inert solvent, such as methanol, ethanol or acetic acid, at temperatures of 0 to 70 ° C, under a hydrogen pressure of 1 to 100 atm., For 5 minutes to 72 h. The alkylation reactions in step 2 of Figure 4 can be carried out using the same reagents and conditions as those of step 5 of Figure 1. Figure 5 is a schematic showing the preparation of compounds represented by the formulas Structural (I) and (II), where Z is represented by the Structural Formula (IV), where W is H. The alkylation reaction in Step 1 of Figure 5 can be carried out using the same reagents and conditions as those of step 5 of Figure 1. The reduction of the double bond in step 2 of Figure 5 can be carried out using the same reagents and conditions as those of stage 1 of Figure 4. Figure 7 shows the preparation of compounds represented by Structural Formula (I), where Z is represented by Structural Formula (VI) and where Ring A and / or Ring B in Z are substituted with - (O) u- (CH2) t- COOR20, where u is one. In Figure 7, the alkylation reaction can be carried out in a solvent such as acetone, methyl ethyl ketone, ethyl acetate, toluene, tetrahydrofuran (THF) or dimethylformamide (DMF), in the presence of a base, such as potassium carbonate. or sodium hydride, and a catalyst, such as an alkali metal iodide, at room temperature to the reflux temperature for the solvent used, for 5 minutes to 72 h. Figure 8 shows the preparation of compounds represented by Structural Formula (I), where Z is represented by Structural Formula (VI) and where Ring A or Ring B in Z are substituted with - (0) u- (CH2 ) t-COOR 2o where u is zero. L is a suitable leaving group, such as halogen or trifluoromethylsulfonate. In Figure 8, a palladium coupling reaction, such as Stille coupling, Suzuki coupling, Heok reaction or carboxylation using carbon monoxide, can be carried out using a palladium catalyst, such as tetrakis ( triphenylphosphate) -palladium, bis (triphenylphosphine) palladium chloride and palladium acetate, in a solvent such as tetrahydrofuran (THF), 1,4-dioxane, toluene, dimethylformamide (DMF) or dimethyl sulfoxide ("DMSO"), in presence of an additive (when necessary), such as triphenylphosphine, 1, 1"* -bis (diphenylphosphino) ferrocene, triethylamine, sodium bicarbonate, tetraethylammonium chloride or lithium chloride, at room temperature to the reflux temperature for the solvent used, for 5 minutes to 72 hours Although Figures 1-5 and 6-7 show the preparation of compounds in which Rings A and B are phenol rings, analogous compounds with heteroaryl groups can be prepared for Rings A and B use The starting materials with heteroaryl groups in the corresponding positions, which can be prepared according to the methods described in JP 61/152673, US Pat. 5089496, WO 89/10369, WO 92/20681 and WO 93/02081. The invention is illustrated by the following examples, which are not intended to be limiting in any way. EXAMPLES Example 1 - Preparation of 4- (4-chlorophenyl) -1- [3- (5-cyano-no- 5H-dibenzo [a, d] diclohepten-5-yl) propyl] piperidin-4-ol To a solution of 5H-dibenzo [a, d] cyclohepte-non-5-carbonitrile (described in J. Med. Chem. 1994 , 37, 804-810) (500 mg) in DMF (10 ml) were added 60% sodium hydride (110 mg) and l-bromo-3-chloropropane (0.30 ml) and the mixture was stirred at room temperature. environment for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride and sessed over magnesium sulfate. The solvent was distilled under reduced pressure to obtain 5- (3-chloropropyl-5H-dibenzo [a, d] cycloheptene-5-carbonitrile.) Without purification, it was added to a solution obtained of chloride in DMF (10 ml) 4- ( 4-chlorophenyl) -4-hydroxypiperidine (650 mg), potassium carbonate (950 mg) and potassium iodide (50 mg) and the mixture was stirred at 70 [deg.] C. for 24 hours, water and ethyl acetate were added to the The reaction mixture was separated, the organic layer was separated and washed with saturated aqueous sodium chloride and dried over magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was purified by chromatography on silica gel eluting with ethyl acetate. hexane (1: 1) to obtain the title compound (700 mg) XH-NMR (CDC13) d: 1.22-1.34 (2H, m), 1.60-1.80 (3H, m) , 1.93-1.99 (2H, m), 2.16-2.28 (6H, m), 2.56-2.60 (2H, m), 6.98 (2H, s), 7 25-7.47 (10H, m), 8.00-8.03 (2H, m) MS m / z: 469 (M + 1) Example 2 - Preparation of 4- (4-chlorophenyl) - 1- [3- (5-cia-no-10, 11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) propyl] -piperidin-4-ol Following the procedure of example 1, but replacing 5H-dibenzo [a, d] cycloheptene-5-carbohydrate nitrile with 10, 11-dihydro-5H-dibenzo [a, d] cycloheptene-5-carbonitrile, the title compound was prepared. XH-NMR (CDC13) d: 1.43-1.49 (2H, m), 1.61-1.66 (2H, m), 1.93-2.02 (3H, m), 2.24-2.32 (4H, m), 2.48-2 , 62 (4H, m), 2.96-3.06 (2H, m), 3.35-3.45 (2H, m), 7.11-7.41 (10H, m), 7.93-7.97 (2H, m). MS m / z: 471 (M + 1).

Example 3 - Preparation of 4- (4-chlorophenyl) -1- [3- (11-cyano-no-6,11-dihydrodibenz [b, e] oxepin-11-yl) propyl] piperidin-4-ol Following the The procedure of Example 1, but substituting the 5H-dibenzo [a, d] cycloheptene-5-carbo-nitrile with 6,11-dihydrosdibenz [b, e] oxepin-11-carbonitriyl, prepared the title compound. XH-NMR (CDC13) d: 1.37-1.68 (5H, m), 1.99-2.09 (2H, m), 2.24-2.50 (5H, m), 2.65 -2.69 (2H, m), 2.78-2.85 (1H, m), 5.03 (1H, d), 5.45 (1H, d), 7.02-7.43 (10H , m), 7.82-7.86 (1H, m), 7.95-8.00 (1H, m). MS m / z: 473 (M + 1).

Example 4 - Preparation of 1- [3- (ll-cyano-6,11-dihydrodi-benz [b, e] oxepin-1-yl) propyl] -4- (4-fluorophenyl) piperidin-4-ol Following the procedure of Example 3, but substituting 4- (4-chlorophenyl) -4-hydroxypiperidine with 4- (4-fluorophenyl) -4-hydroxypiperidine, the title compound was prepared. H-NMR (CDC13) d: 1.40-1.68 (4H, m), 1.88-2.08 (3H, m), 2.29-2.50 (5H, m), 2.63 -2.67 (2H, m), 2.77-2.84 (1H, m), 5.03 (1H, d), 5.44 (1H, d), 6.95-7.46 (10H , m), 7.81-7.85 (1H, m), 7.94-7.99 (1H, m). MS m / z: 457 (M + 1). Example 5 - Preparation of 4- (4-chlorophenyl) -1- [3- (11-cyano-no-6,11-dihydro-2-fluorodibenz [b, e] oxepin-11-yl) propyl] -piperidine- 4-ol Following the procedure of example 1, but replacing 5H-dibenzo [a, d] cycloheptene-5-carbo-nitrile with 6,11-dihydro-2-fluorodibenz [b, e] oxepin-11-carbonitrile, prepared the title compound. XH-NMR (CDC13) d: 1.37-1.69 (5H, m), 1.98-2.09 (2H, m), 2.25-2.48 (5H, m), 2.65-2.70 (2H, m), 2.78-2 , 87 (1H, m), 5.01 (1H, d), 5.42 ~ (1H, d), 6.99-7.11 (3H, m), 7.25-7.43 (6H, m), 7.54-7.59 (1H, m), 7.92-7.95 (1H, m). MS m / z: 491 (M + 1). Example 6 - Preparation of 1- [3- (2-bromo-11-cyano-6,11-dihydrodibenz [b, e] oxepin-11-yl) propyl] -4- (4-chlorophenyl) -piperidin-4- ol Following the procedure of example 1, but replacing 5H-dibenzo [a, d] cycloheptene-5-carbo-nitrile with 2-bromo-6,11-dihydrodibenz [b, e] oxepin-11-car-bonitrile , the title compound was prepared. XH-NMR (CDC13) d: 1.37-1.69 (5H, m), 1.97-2.09 (2H, m), 2.24-2.48 (5H, m), 2.66 -2.85 (3H, m), 5.00 (1H, d), 5.43 (1H, d), 6.97-7.02 (2H, m), 7.24-7.46 (7H , m), 7.91-7.95 (2H, m). MS m / z: 551, 553 (M + 1).

Example 7 - Preparation of 4- (4-chlorophenyl) -1- [3- (11-cyano-no-6,11-dihydro-2-methyldibenz [b, e] oxepin-11-yl) propyl] pi-peridin -4-ol Following the procedure of Example 1, but substituting 5H-dibenzo [a, d] cycloheptene-5-carbo-nitrile with 6, 11-dihydro-2-methyldibenz [b, e] oxepin-11-car-bonitrile, the title compound was prepared. XH-NMR (CDC13) d: 1.40-1.70 (5H, m), 1.98-2.09 (2H, m), 2.25-2.52 (8H, m), 2.68-2.73 (2H, m), 2.81-2 , 90 (1H, m), 5.00 (1H, d), 5.44 (1H, d), 6.98-7.43 (9H, m), 7.63 (1H, d), 7, 94-7.98 (1H, m). MS m / z: 487 (M + 1).

Example 8 - Preparation of 4- (4-chlorophenyl) -1- [3- (11-cyano-no-3,4-dichloro-6,11-dihydrodibenz [b, e] oxepin-11-yl) propyl] piperidine -4-ol Following the procedure of Example 1, but substituting 5H-dibenzo [a, d] cycloheptene-5-carbo-nitrile with 3,4-dichloro-6,11-dihydrodibenz [b, e] oxepin- 11-Carbonitrile, the title compound was prepared. 1 H-NMR (CDC13) d: 1.40-1.71 (5H, m), 2.00-2.10 (2H,), 2.28-2.50 (5H, m), 2.65-2.85 (3H, m), 5.04 I V? , d), 5.46 (1H, d), 6.99-7.03, 1H, m), 7.26-7.44 (7H, m), 7.91-7.95 (2H, m ). MS m / z: 541 (M + 1). Example 9 - Preparation of 4- (4-chlorophenyl) -1- [3- (11-cyano-no-6,11-dihydro-2,3-methylenedioxydibenz [b, e] -oxepin-11-yl) propyl] piperidin-4-ol Following the procedure of example 1, but substituting 5H-dibenzo [a, d] cycloheptene-5-carbo-nitrile with 6,11-dihydro-2,3-methylenedioxydibenz [b, e] oxe -pin-11-carbonitrile, the title compound was prepared. 1 H-NMR (CDCl 3) d: 1.60-1.90 (5H, m), 2.30-2.50 (2H, m), 2.80-3.30 (8H, m), 5.05 (1H, d), 5.45 (1H, d), 6.02 (2H, broad d), 6.68 (1H, s), 6.97-7.01 (1H, m), 7.26 -7.43 (7H, m), 7.83-7.87 (2H, m). MS m / z: 517 (M + 1).

Example 10 - Preparation of 4- (4-chlorophenyl) -1- [3- (11-cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) propyl] piperi-din-4-ol Following the The procedure of Example 1, but substituting the 5H-dibenzo [a, d] cycloheptene-5-carbo-nitrile with 6,1-dihydrodibenzo [b, e] thiepin-11-carbonitriyl, was prepared the title compound. XH-NMR (CDC13) d: 1.63-1.76 (5H, m), 2.03-2.16 (2H, m), 2.37-2.52 (4H, m), 2.72. -2.85 (3H, m), 3.03-3.10 (1H, m), 4.10 (1H, d), 4.54 (1H, d), 7.13-7.44 (10H , m), 7.81-7.87 (2H, m). MS m / z: 489 (M + 1). Example 11 - Preparation of 1- [3- (11-eiano-6,11-dihydro-dibenzo [b, e] thiepin-1-yl) propyl] -4-phenylpiperidin-4-ol Following the procedure of example 10, but replacing 4- (4-chlorophenyl) -4-hydroxypiperidine with 4-hydroxy-4-f-nylpiperidine, the title compound was prepared. XH-NMR (CDC13) d: 1.63-1.77 (5H, m), 2.02-2.16 (2H, m), 2.37-2.52 (4H, m), 2.72. -2.85 (3H, m), 3.03-3.10 (1H, m), 4.10 (1H, d), 4.55 (1H, d), 7.13-7.52 (10H , m), 7.81-7.88 (2H, m). MS m / z: 455 (M + 1). Example 12 - Preparation of 4- (4-bromophenyl) -1- [3- (11-cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) propyl] piperi-din-4-ol Following the procedure of Example 10, but substituting 4- (4-chlorophenyl) -4-hydroxypiperidine for 4- (4-bromophenyl) -4-hydroxypiperidine, the title compound was prepared. XH-NMR (CDCI3) d: 1.64-1.82 (5H, m), 2.02-2.12 (2H, m), 2.32-2.48 (4H, m), 2.69. -2.85 (3H, m), 2.99-3.09 (1H, m), 4.07 (1H, d), 4.50 (1H, d), 7.11-7.46 (10H , m), 7.79-7.86 (2H, m). MS m / z: 533, 535 (M + 1). Example 13 - Preparation of 1- [3- (2-bromo-11-cyano-6,11-dihydrodibenzo [b, e] tiepin-11-yl) propyl] -4- (-clo ofenyl) -piperidin-4- Following the procedure of example 1, but replacing 5H-dibenzo [a, d] cycloheptene-5-carbo-nitrile with 2-bromo-6,11-dihydrodibenzo [b, e] thiepin-11-carbonitrile, the composed of the title. XH-NMR (CDC13) d: 1.63-1.78 (5H, m), 2.03-2.14 (2H, m), 2.25-2.52 (4H, m), 2.72-2.80 (3H, m), 3.00-3.10 ( 1H, m), 4.15 (1H, broad d), 4.50 (1H, d), 7.07-7.45 (10H, m), 7.73-7.81 (1H, m), 7.95 (1H, d). MS m / z: 567, 569 (M + 1). Examples 14 and 15 - Preparation of 4- (4-chlorophenyl) -1- [3- (11-cyano-6,11-dihydro-5-oxodibenzo [b, e] tiepin-11-yl) propyl] piperidin-4-ol Following the procedure of example 1, but replacing 5H-dibenzo [a, d] cycloheptene-5-carbo-nitrile with 6,11-dihydro-5- Oxodibenzo [b, e] thiepin-11-carbonitrile, the title compound was prepared. The diastereomers were separated by chromatography on silica gel. Isomer 1: 1 H-NMR (CDC13) d: 1.20-1.35 (1H, m), 1.63-1.69 (4H, m), 2.04-2.84 (10H, m), 4.21 (1H, d), 4.31 (1H, d), 7.18-7.65 (9H, m), 8.03-8.13 (3H, m). MS m / z: 505 (M + 1). Isomer 2: ^ -RMN (CDCI3) d: 1.25-1.38 (1H, m), 1.65-2.15 (6H, m), 2.28-2.82 (8H, m), 4.65 (1H, d), 4.82 (1H, d), 7.27-7.56 (9H, m), 7.92-8.00 (3H, m). MS m / z: 505 (M + 1). Example 16 - Preparation of 4- (4-chlorophenyl) -1- [3- (11-cyano-6,11-dihydro-5,5-dioxodibenzo [b, e] thiepin-11-yl) propyl] piperidin-4 -o1 Following the procedure of example 1, but replacing 5H-dibenzo [a, d] cycloheptene-5-carbo-nitrile with 6,11-dihydro-5, 5-dioxodibenzo [b, e] tiepin-11-carbonitrile, the title compound was prepared. XH-NMR (CDC13) d: 1.40-2.72 (14H, m), 3.08-3.22 (1H, m), 4.58 (1H, d), 5.58 (1H, d) ), 7.29-7.58 (9H, m), 7.99-8.13 (3H, m). MS m / z: 521 (M + 1). Example 17 - Preparation of 4- (4-chlorophenyl) -1- [3- (6,11-dihydrodibenzo [b, e] thiepin-ll-yl) propyl] piperidin-4-ol To a solution of 4- (4 -chlorophenyl) -1- [3- (ll-cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) propyl] piperi-din-4-ol (430 mg) in THF (10 ml), a THF solution of 1 M lithium aluminum hydride (1.5 ml) was added and the mixture was heated at reflux for 3 hours. The reaction mixture was cooled with ice and water (0.06 ml) was added, then 15% aqueous sodium hydroxide (0.06 ml) and then water (0.18 ml) carefully. The granular salt was filtered and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1: 1) to obtain the title compound (280 mg). ^ -RMN (CDC13) d: 1.55-1.80 (4H, m 2.03-2.16 (2H, m 2.25-2.52 (6H, m) 2.72-2.80 (2H, m), 3.90 (1H, broad s), 4.48 (1H, broad t), 4.68 (1H, broad s), 6.96-7.45 (12H, m). MS m / z: 464 (M + 1). Example 18 - Preparation of 4- (4-chlorophenyl) -1- [3- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) propyl] piperidin-4-ol Following the procedure of Example 17, but substituting 4- (4-chlorophenyl) -1- [3- (ll-cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) propyl] piperidin-4-ol with 4- (4-chlorophenyl) -1- [3- (5-cyano-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) propyl] piperidin-4-ol, the title compound was prepared . ^ -NMR (CDC13) d: 1.40-1.58 (2H, m), 1.62-1.71 (2H, m), 1.98-2.20 (4H, m), 2.30 -2.42 (4H, m), 2.67-2.78 (2H, m), 2.95-3.08 (2H, m), 3.30-3.44 (2H, m), 4 , 01 (1H, t), 7.10-7.46 (12H, m). MS m / z: 446 (M + 1). Example 19 - Preparation of 4- (4-chlorophenyl) -1- [3- (6,11-dihydrodibenz [b, e] oxepin-11-yl) propyl] piperidin-4-ol Following the procedure of example 17, but substituting 4- (4-chlorophenyl) -1- [3- (ll-cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) propyl] piperidin-4-ol with 4- (4-chlorophenyl) ) -1- [3- (ll-cyano-6,11-dihydrodi-benz [b, e] oxepin-11-yl) propyl] piperidin-4-ol, the title compound was prepared. XH-NMR (CDC13) d: 1.36-1.49 (2H, m), 1.58-1.67 (2H,), 1.95-2.33 (8H, m), 2.63- 2.68 (2H, m), 3.74 (1H, t), 4.95 (1H, d), 5.48 (1H, d), 6.95-7.39 (12H, m). MS m / z: 448 (M + 1). Example 2Q - Preparation of 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-11-iminomethyldibenzo [b, e] thiepin-11-yl) propyl] pi-peridin-4-ol A solution of 4- (4-chlorophenyl) -1- [3- (ll-cyano-6, 11- dihydrodibenzo [b, e] thiepin-11-yl) propyl] piperi-din-4-ol (1.92 g) in dichloromethane (30 ml) at -78 ° C, a 1M solution in dichloromethane of sodium hydride was added. diisobutyl and aluminum (10 ml). The reaction mixture was warmed to room temperature and stirred for 30 minutes. Water and dichloromethane were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was distilled under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate to obtain the title compound (1.16 g). XH-NMR (CDC13) d: 1.65-1.80 (5H, m), 2.02-2.18 (2H, m), 2.45-2.60 (6H, m), 2.78. -2.86 (2H, m), 3.82 (1H, d), 4.25 (1H, d), 7.05-7.45 (12H, m), 8.28 (1H, broad s) . MS m / z: 491 (M + 1). Example 21 - Preparation of 1- [3- (11-aminomethyl-6,11-dihydrodibenzo [b, e] thiepin-11-yl) ropil] -4- (4-chlorophenyl) i-peridin-4-ol To a solution of 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-11-iminodibenzo [b, e] thiepin-11-yl) propyl] pi-pe idin-4-ol (600 mg) in methanol (15 ml) was added sodium borohydride (220 mg) and the mixture was stirred at room temperature for 10 hours. The solvent was distilled under reduced pressure. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (600 mg). MS m / z: 493 (M + 1). Example 22 - Preparation of N- [11- [3- (4- (4-chlorophenyl) -4-hydroxypiperidino) propyl] -6,11-dihydrodibenzo [b, e] thiepin-11-yl) phenyl methylcarbamate A Solution of 4- (4-chlorophenyl) -1- [3- (11-aminomethyl-6,1- dihydrodibenzo [b, e] thiepin-11-yl) propyl] -piperidin-4-ol (610 mg) in THF (20 ml), triethylamine (0.2 ml) and phenyl chlorocarbonate (0.16 ml) were added at 0 ° C and the mixture was stirred for 1 hour. Water and ethyl acetate were added to the reaction mixtureThe organic layer was separated and washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was distilled under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate to obtain the title compound (400 mg). XH-NMR (CDC13) d: 1.40-2.90 (15H, m), 4.05-4.12 (2H, m), 4.38 (1H, d), 4.50-4.60 (1H, m), 5.98 (1H, broad s), 6.96-7.54 (17H, m). MS m / z: 613 (M + 1). Example 23 - Preparation of 1- [11- [3- (4- (4-chlorophenyl) -4-hydroxypiperidino) propyl] -6,11-dihydrodibenzo [b, e] thiepin-11-yl] methyl-8- ( 3-hydroxypropyl) urea To a solution of N- [2- [3- [4- (4-chlorophenyl) -4-hydroxypiperidino] propyl] -2- (6,11-dihydrodibenzo [b, e] -thiepin-11] phenyl-ethyl) carbamate (300 mg) in DMF (10 ml), 3-amino-1-propanol (70 mg) and potassium carbonate (130 mg) were added and the mixture was stirred at room temperature for 16 hours. hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was distilled under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-methanol (9: 1) to obtain the title compound (200 mg). ^ -RMN (CDCI3) d: 1.40-1.70 (6H, m), 2.01-2.08 (2H, m), 2.30-2.63 (8H, m), 3.12 (2H, c), 3.42 (2H, t), 4.00-4.12 (2H, m), 4.22-4.28 (2H, m), 4.82 (1H, broad t) , 4.99 (1H, broad s), 6.98-7.45 (12H, m). MS m / z: 594 (M + 1). Example 24 - Preparation of 4- (4-chlorophenyl) -1- [3- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -3-propioil] pipe-ridin-4- ol To a solution of 10, 11-dihydro-5H-dibenzo- [a, d] cycloheptene-5-carbonitrile (500 mg) in THF (5 ml), a 1.6 M solution in n-butyl hexane was added. -lithium (1.8 ml) at 0 ° C. The mixture was warmed to room temperature and stirred for 20 minutes. To the reaction mixture cooled to 0 ° C ethyl 3- (4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl) propionate (310 mg) was added dropwise as a solution in THF (2 ml) and The mixture was heated to room temperature and stirred for 30 minutes. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was distilled under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate-hexane (1: 1) to obtain the title compound (380 mg). XH-NMR (CDC13) d: 1.57-1.62 (2H, m 1.91-2.01 (3H, m 2.27-2.84 (10H, m 3.30-3.44 (2H, m), 4.65 (1H, s), 7.10-7.38 (12H, m). MS m / z: 460 (M + 1). Examples 28-59 can be prepared by the methods set forth in the schemes of Figures 1-5 and the procedures described above. Example 60 - Membrane preparations for chemokine binding and binding assays Membranes of THP-1 cells (ATCC # TIB202) were prepared. The cells were harvested by centrifugation, washed twice with PBS (phosphate buffered saline) and the cell pellets were frozen at a temperature of -70 to -85 ° C. The frozen pellets were thawed in ice-cold lysis buffer consisting of 5 mM HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid), pH 7.5, 2 mM EDTA (ethylenediaminetetraacetic acid), 5 μg / ml of each of aprotinin, leupeptin and chemostatin (protease inhibitors) and 100 μg / ml of "PMSF" (phenylmethanesulfonyl fluoride - which is also a protease inhibitor), at a concentration of 1 to 5 x 107 cells / ml. This procedure results in cell lysis. The suspension was mixed well to resuspend all the frozen cell pellet. Nuclei and cell debris were removed by centrifugation at 400 x g for 10 minutes at 4 ° C. The supernatant was transferred to a new tube and the membrane fragments were collected by centrifugation at 25,000 x g for 30 minutes at 4 ° C. The supernatant was aspirated and the pellet was resuspended in freezing buffer, consisting of 10 mM HEPES, pH 7.5, 300 mM sucrose, 1 μg / ml aprotinin, leupeptin and chemostatin and 10 μg / ml PMSF (approx. 0.1 ml per 108 cells). All lumps were dissolved again using a mini-homogenizer and the total pro tein concentration was determined using a protein assay kit (Bio-Rad, Hercules, CA, cat # 500-0002). The membrane solution was then aliquoted and frozen at -70 to -85 ° C until needed. The binding assays used the membranes described above. Membrane protein (2 to 20 μg of total membrane protein) was incubated with 0.1 to 0.2 nM of RANTES or MIP-la labeled with 125 I, with or without unlabeled competitor (RANTES O MlP-la) or several concentrations of compounds. The binding reactions were carried out in 60 to 100 μl of a binding buffer consisting of 10 mM HEPES, pH 7.2, 1 mM CaCl 2, 5 mM MgCl 2 and 0.5% "BSA" (bovine serum albumin), for 60 min at room temperature. The binding reactions were terminated by collecting the membranes by rapid filtration through glass fiber filters (GF / B or GF / C, Packard), which were pre-packed in 0.3% polyethyleneimine. The filters were washed with approximately 600 μl of binding buffer containing 0.5 M NaCl, dried and the amount of bound radioactivity determined by scintillation counting in a Topcount beta-plate counter. The activities of the test compounds are given in the following Table as IC 50 values or inhibitor concentration necessary for 50% inhibition of specific binding in receptor binding assays that employ 125 I-RANTES or 125 I-MIP-1 as Ligand and THP-cell membranes 1. The specific binding is defined as the total binding minus the unspecified binding; the non-specific binding is the amount of cpm still detected in the presence of an excess of unlabeled RANTES or of 125 I-MIP-la.

BIOLOGICAL DATA Table Example 61 can be prepared by methods set forth in the schemes of Figures 1-5 and by the procedures described above. Example 62-4- (4-Chlorophenyl) -1- [3- (5,11-dihydro-7-methoxypyrido [2, 3-c] [l] benzoxepin-5-propyl] piperidin-4-ol Step 1 To a solution of 5, 11-dihydro-7-methoxypyrido [2, 3-c] [1] benzoxepin-5-one (5/0 g) in THF (50 ml), a 1.1 solution was added. M in THF of cyclopropylmagnesium bromide (25 ml) at 0 ° C. This reaction mixture was warmed to room temperature and stirred for 30 minutes. Aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride and dried with magnesium sulfate. The solvent was distilled under reduced pressure. The residue was filtered and washed with ethyl acetate-hexane (1: 2) to obtain 5-cyclopropyl-5,11-dihydro-7-methoxypyrido [2, 3-c] [1] benzoxepin-5-ol (5.0 g). Step 2 To a solution of the product of step 1 (4.3 g) in acetic acid (30 ml), 48% aqueous HBr (25 ml) was added at 10 ° C. The reaction mixture was warmed to room temperature and stirred for 12 hours. Water and ethyl acetate were added to the reaction mixture and neutralized with a dilute solution of NaOH. The organic layer was separated and washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was distilled under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate-hexane (1: 4) to obtain 5- (3-bromopropylidene) -5,1-dihydro-7-methoxypyrido [2, 3-c] [l ] benzoxepin (5.6 g). XH-NMR (CDC13) d: 2.74 (2H, c), 3.46 (2H, t), 3.78 (3H, s), 5.25 (2H, broad s), 6.07 (1H , t), 6.72-6.82 (3H, m), 7.21-7.42 (5H, m), 7.56 (1H, dd), 8.45 (1H, dd). Step 3 To a solution of the product from step 2 (160 mg) in ethanol (3 ml) and acetic acid (1 ml), 10% Pd-C (79 mg) was added and stirred under hydrogen (under a balloon). at room temperature for 24 hours. The mixture was filtered through celite and distilled under reduced pressure. The residence was purified duo by preparatory thin layer chromatography, eluting with ethyl acetate-hexane (1: 2), to obtain 5- (3-bromopropyl) -5,11-dihydro-7-methoxypyrido [2, 3-c] [1] benzoxepin (48 mg). XH-NMR (CDC13) d: 1.80-2.45 (4H, m), 3.33-3.39 (2H, m), 3.59 (1H, dd), 3.77 (3H, s) ), 4.98 (1H, d), 5.44 (1H, d), 6.70-6.79 (2H, m), 7.08-7.14 (5H, m), 7.52 (1H, dd), 8.41 (1H, dd). Step 4 To a solution of the product from step 3 (45 mg) in DMF (1 ml), 4- (4-chlorophenyl) -4-hydroxypiperidine (54 mg) and potassium carbonate (19 mg) were added and the mixture was stirred at 50 ° C for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with saturated aqueous sodium chloride and dried with magnesium sulfate. The solvent was distilled under reduced pressure. The residue was purified by chromatography on silica gel, eluting with ethyl acetate-methanol (10: 1), to obtain the title compound (19 mg). ^ -NMR (CDC13) d: 1.50 (1H, broad s), 1.67-1.72 (2H, m), 2.00-2.47 (10H, m), 2.76-2, 81 (2H, m), 3.59 (1H, dd), 3.77 (3H, 4.97 (1H, d), 5.43 (1H, d) 6.72-6.78 (2H, m), 7.06-7.13 (2H, m), 7.26-7.44 (4H, m), 7.52 (1H, dd), 8, 37 (1H, dd). MS m / z: 479 (M + 1). Examples 63-312 can be prepared by the methods set forth in the schemes of Figures 1-5 and 6-7 and the methods described above. Those skilled in the art will be able to recognize, or be able to determine, using only routine experimentation, many equivalents of the specific embodiments of the invention described herein. Said equivalents are intended to be protected by the appended claims.

Claims (90)

1. CLAIMS 1. A method of treating a disease associated with an aberrant recruitment and / or activity of leukocytes, comprising administering to a subject an effective amount of a compound represented by the following structural formula: -Y- - (c? Yn- -X- -N M and their physiologically acceptable salts, wherein: Y is a covalent bond, n is an integer from one to four, X is a covalent bond and M is > NR2 or > CRXR2; R1 is -H, -OH, an aliphatic group, -O- (aliphatic group), -O- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group), - OC (O) - (aliphatic group), -0-C (O) - (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 O -NR3R4; R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, an non-aromatic heterocyclic group or substituted non-aromatic heterocyclic group, wherein: R3, R4, R5 and R6 are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a group substituted aromatic, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group, or R1 and R2, R3 and R4 or R5 and R6, taken together with the which are joined together, form a substituted or unsubstituted carbocyclic or heteroaromatic non-aromatic ring; Z is represented by the following structural formula: where: Ring A and Ring B are independently substituted or unsubstituted; Wa is 1l1rR.12 -CH = NH, -CH2-OR 11 -CH2-NH-CO-NR1 CH2-0-CO-NR11R12 or -CH2-NHC- (0) -O-R11 and R11 and R12 are independently -H, an aliphatic group , a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group, or R11 and R12, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
2. 2. The method of Claim 1, wherein Ring A or Ring B are substituted with - (O) u- (CH2) t-COOR20, - (0) u- (CH2) tC (0) -NR21R22 or - (0) u- (CH2) t-NHC (0) -0-R20; u is zero or one; t is an integer from zero to 3, and R20, R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
3. 3. The method of Claim 1, wherein R1 is -OH.
4. 4. The method of Claim 3, wherein M is > C (OH) R2 and n is three.
5. 5. The method of Claim 4, wherein R2 is a substituted or unsubstituted aromatic group.
6. 6. A method of treating a disease associated with an aberrant recruitment and / or activation of leukocytes, comprising administering to a subject in need thereof an effective amount of a compound of the following structural formula: -Y- • (ci-ys- -x- -N M and its physiologically acceptable salts, where: Y is a covalent bond; n is an integer from one to four; X is a covalent bond, and M is > NR2 or > CR1R2; R1 is -H, -OH, an aliphatic group, -0- (aliphatic group), -0- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group), - OC (0) - (aliphatic group), -0-C (0) - (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a heterocyclic group non-aromatic or a substituted non-aromatic heterocyclic group, wherein: R3, R4, R5 and R6 are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group , a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R1 and R2, R3 and R4 or R5 and R6, taken together with the atom to which they are attached, form a substituted or unsubstituted carbocyclic or heterocyclic non-aromatic ring; Z is represented by a structural formula selected from: where W is -H or an electron withdrawing group and Ring A and Ring B are independently substituted or unsubstituted.
7. 7. The method of Claim 6, wherein Ring A or Ring B are substituted with - (O) u- (CH2) t-COOR20, - (0) u- (CH2) tC (O) -NR21R22 or - (0) u- (CH2) t-NHC (0) -0-R2 °, where: u is zero or one, t is an integer from zero to 3 and R 2o R 21 or R are independently -H, a aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
8. 8. The method of Claim 6, wherein W is -H or -CN.
9. 9. The method of Claim 8, wherein R1 is -OH.
10. 10. The method of Claim 9, wherein M is > C (OH) R2 and n is three.
11. 11. The method of Claim 10, wherein R2 is a substituted or unsubstituted aromatic group.
12. 12. A method of treating a disease associated with an aberrant recruitment and / or activation of leukocytes, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula: -Y- "(CHz) and their physiologically acceptable salts, wherein: Y is a covalent bond, n is an integer from one to five, X is a covalent bond and M is > NR2 or > CRXR2; R1 is -H, -OH, an aliphatic group, -0- (aliphatic group), -O- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group), - OC (O) - (aliphatic group), -OC (0) - (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a heterocyclic group non-aromatic or a substituted non-aromatic heterocyclic group, wherein: R3, R4, R5 and R6 are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group , a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R1 and R2, R3 and R4 or R5 and R6, taken together with the atom to which they are attached, form a substituted or unsubstituted carbocyclic or heterocyclic non-aromatic ring; Z is represented by a structural formula selected from: where: Ring A and Ring B are independently substituted or unsubstituted; Wa is -CH2-NRnR12, -CH = NH, -CH2-0Rn, -CH2-NH-CO-NR R12, -CHz-O-CO-NR ^ R12 or -CH2-NHC (O) -O-R11; R11 and R12 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group; or R11 and R12, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
13. The method of Claim 12, wherein Ring A or Ring B are substituted with - (O) u- (CH 2) t-COOR 2o (0) u- (CH 2) t C (0) -NR 21 R 22 or - ( 0) u- (CH2) t-NHC (0) -0-R20, where: u is zero or one, t is an integer from zero to 3 and R20, R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
14. 14. The method of Claim 12, wherein R1 is -OH.
15. 15. The method of Claim 14, wherein M is > C (OH) R2 and n is three.
16. 16. The method of Claim 15, wherein R2 is a substituted or unsubstituted aromatic group.
17. 17. A method of treating a disease associated with an aberrant recruitment and / or activation of leukocytes, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula: -Y- - (ciy- -N and their physiologically acceptable salts, wherein: Y is a covalent bond, n is an integer from one to five, X is a covalent bond and M is > NR2 or > CR1R2; R1 is -H, -OH, an aliphatic group, -O- (aliphatic group), -O- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group), - OC (O) - (aliphatic group), -0-C (O) - (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a heterocyclic group non-aromatic or a substituted non-aromatic heterocyclic group, wherein: R3, R4, R5 and R6 are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group , a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R1 and R2, R3 and R4 or R5 and R6, taken together with the atom to which they are attached, form a substituted or unsubstituted carbocyclic or heterocyclic non-aromatic ring; Z is represented by a structural formula selected from: Rc / A B wherein: rings A, B and C are independently substituted or unsubstituted, and Rc is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group.
18. 18. The method of Claim 17, wherein Z is represented by a structural formula selected from: where W is -H or an electron withdrawing group.
19. 19. The method of Claim 18, wherein the Ring A Ring B are substituted with - (O) u- (CH2) t-COOR20 (0) u- (CH2) tC (0) -NR, 2"1nR2" 2 or - (0) u- (CH2) t-NHC (0) -0-R, 2¿0u, where: u is zero or one, t is an integer from zero to 3 and R 2o R '21 or R are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R, 21 r and r R 22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
20. 20. The method of Claim 1 wherein Rc is (CH2) S-COOR, 3O0U, - (CH2) sC (0) -NR31R32 or - (CH2) S-NHC (O) -O-R30, where: s is an integer from one to three, R30, R31 or R32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R31 and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
21. 21. The method of Claim 18, wherein W is -H or -CN.
22. 22. The method of Claim 21, wherein R1 is -OH.
23. 23. The method of Claim 22, wherein M is > C (OH) R2 and n is three.
24. 24. The method of Claim 23, wherein R2 is a substituted or unsubstituted aromatic group.
25. 25. The method of Claim 17, wherein Z is represented by a structural formula selected from: where Wa is -CH2-NR R12, -CH2-ORn, -CH = NH, -CH2-NH-CO-NR1: LR12, -CH2-0-CO-NRnR12 or -CH2-NHC (O) -O-R11 , where: R11 and R12 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group, or R11 and R12, taken together with the nitrogen atom to which they are united, they form a non-aromatic heterocyclic ring.
26. 26. The method of Claim 25, wherein Ring A or Ring B are substituted with:?) U- (CH2) t-COOR (0) u- (CH2) t-C (0) -NR21R22 or - (0) u- (CH2) -NHC (0) -0-R20; u is zero or one; t is an integer from zero to 3, and R20, R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R 21 and R, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
27. 27. The method of Claim 25, wherein Rc is - (CH2) s-COOR 30 - (CH2) SC (O) -NR, 3J11DR3- "2 or - (CH2) S-NHC (O) -OR 30 where : s is an integer from one to three, R30, R31 or R32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R31 and R32, taken together with the nitrogen atom to which they are attached, they form a non-aromatic heterocyclic ring
28. 28. The method of Claim 25, wherein R1 is -OH
29. 29. The method of Claim 28, wherein M is > C ( OH) R2 and n is three
30. 30. The method of Claim 29, wherein R2 is a substituted or unsubstituted aromatic group
31. 31. A method of treating a disease associated with an aberrant recruitment and / or activation of leukocytes, consisting of in administering to a subject in need thereof an effective amount of a compound represented by the following formula the structural: -Y- - (H?); R -x- -N M and their physiologically acceptable salts, wherein: Y is a covalent bond, n is an integer from one to five, X is a covalent bond and M is > NR2 or > CRXR2; R1 is -H, -OH, an aliphatic group, -O- (aliphatic group), -O- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group), - OC (O) - (aliphatic group), -OC (O) - (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a group non-aromatic heterocyclic or substituted non-aromatic heterocyclic group, wherein: R3, R4, R5 and Rd are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, an aromatic group substituted, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R1 and R2, R3 and R4 or R5 and R6, taken together with the atom to which they are attached, form a substituted or unsubstituted carbocyclic or heterocyclic non-aromatic ring; Z is represented by a structural formula selected from: where: Ring A is a substituted or unsubstituted heteroaryl group; Ring B is a substituted or unsubstituted heterocyclic or heteroaryl aromatic group; X2 is -S-CH2-, -CH2-S-, -CH2-0-, -0-CH2-, -C0-NRc-, -NRC-CO-, -CH2-S (0) 2-, -S (0) 2-CH2-, -CH2-NRC-, -NRC-CH2-, -CH2-CH2-, -CH = CH-, -CH2-SO-, -SO-CH2-; Wb is -H, -CH = NH, -CN, -CH2-NRnR12, -CH2-OR11, -CH2-NH-CO-NRUR12, -CH2-0-CO-NR1: LR12 O -CH2-NHC (0) -0-R1: L; R > n1 and R .12 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R 11 and R, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring, and Rc is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group.
32. 32. The method of Claim 31, wherein Ring A or Ring B are substituted with - (O) u- (CH 2) t-COOR 20, - (0) u- (CH 2) t C (0) -NR 21 R 22 or - (0) u- (CH2) t-NHC (0) -0-R20; u is zero or one; t is an integer from zero to 3, and R, R or R are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
33. 33. The method of Claim 31, wherein Rc is - (CH2) s-COOR30, - (CH2) sC (0) -NR31R32 or - (CH2) S-NHC (0) -O-R30, where: s is an integer from one to three, R, R or R are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R31 and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
34. 34. The method of Claim 31, wherein R1 is -OH.
35. 35. The method of Claim 34, wherein M is > C (OH) R2 and n is three.
36. 36. The method of Claim 35, wherein R 2 is a substituted or unsubstituted aromatic group 3 377 ..
37. The minimum residue of the RReeiivviinnddiiccaacciióó: n 35, where R 2 is a halogen-substituted aromatic group
38. 38. The method of Claim 37, where R2 is a 4-chlorophenyl group.
39. 39. The method of Claim 31, wherein Ring B is a substituted or unsubstituted heteroaryl group.
40. 40. The method of Claim 39, wherein Ring A is a substituted or unsubstituted pyridyl group.
41. 41. The method of Claim 31, wherein Ring A is a substituted or unsubstituted pyridyl group and Ring B is a substituted or unsubstituted aromatic carbocyclic group.
42. 42. The method of Claim 31, wherein Ring A is a pyridyl group and Ring B is a substituted or unsubstituted phenyl group.
43. 43. The method of Claim 42, wherein M is > C (OH) R2 and n is three.
44. 44. The method of Claim 43, wherein R2 is a aromatic group substituted with halogen.
45. 45. The method of Claim 44, wherein R2 is a 4-chlorophenyl group.
46. 46. The method of Claim 40, wherein: Ring B is a pyridyl group, n is three, M is > C (OH) R2 and R2 is a chlorophenyl group.
47. 47. A compound represented by the following structural formula: and their physiologically acceptable salts, wherein: n is an integer from one to five; M is > NR2 or > CRXR2; R1 is -H, -OH, an aliphatic group, -O- (aliphatic group), -O- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group), - OC (O) - (aliphatic group), -OC (O) - (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a hetero group -non-aromatic cyclic or substituted non-aromatic heterocyclic group, wherein: R3, R4, R5 and R6 are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a group substituted aromatic, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R1 and R2, R3 and R4 or R5 and R6, taken together with the atom to which they are attached, form a substituted or unsubstituted carbocyclic or heterocyclic non-aromatic ring; Z is represented by a structural formula selected from: where: Ring A is a substituted or unsubstituted heteroaryl group; Ring B is a substituted or unsubstituted carbocyclic or heteroaryl aromatic group; X2 is -S-CH2-, -CH2-S-, -CH2-0-, -0-CH2-, -CO-NRc-, -NRC-CO-, -CH2-S (0) 2-, -S (0) 2-CH2-, -CH2-NRC-, -NRC-CH2-, -CH2-CH2-, -CH = CH-, -CH2-SO-, -SO-CH2-; Wb is -H, -CH = NH, -CN, -CH2-NR1: LR12, -CH2-ORxl, -CH2-NH-CO-NR1XR12, -CH2-0-CO-NR11R12 or -CH2-NHC (O) -O-R11; R11 and R12 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R 11 and R, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring, and Rc is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group.
48. 48. The compound of Claim 47, wherein the Ani- either A or Ring B are substituted with - (O) u- (CH2) t-COOR20, - (O) u- (CH2) tC (O) -NR2XR- (0) u- (CH2) t-NHC ( O) -O-R20; u is zero or one; t is a number. whole from zero to 3, and R 20 R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
49. 49. The compound of Claim 47, wherein Rc is - (CH2) s-COOR 30 - (CH2) sC (0) -NR31R32 or (CH2) s-NHC (0) -OR 30 where: s is a whole number from one to three, R 30 R 31 or R 32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R31 and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
50. 50. The compound of Claim 47, wherein R1 is -OH.
51. 51. The compound of Claim 50, wherein M is > C (OH) R2 and n is three.
52. 52. The compound of Claim 51, wherein R2 is a substituted or unsubstituted aromatic group.
53. 53. The compound of Claim 51, wherein R2 is an aromatic group substituted with halogen.
54. 54. The compound of Claim 53, wherein R2 is a 4-chlorophenyl group.
55. 55. The compound of Claim 47, wherein Ring B is a substituted or unsubstituted heteroaryl group.
56. 56. The compound of Claim 55, wherein Ring A is a substituted or unsubstituted pyridyl group.
57. 57. The compound of Claim 47, wherein Ring A is a substituted or unsubstituted pyridyl group and Ring B is a substituted or unsubstituted aromatic carbocyclic group.
58. 58. The compound of Claim 47, wherein Ring A is a pyridyl group and Ring B is a substituted or unsubstituted phenyl group.
59. 59. The compound of Claim 58, wherein M is > C (OH) R2 and n is three.
60. 60. The compound of Claim 59, wherein R2 is a substituted or unsubstituted aromatic group.
61. 61. The compound of Claim 59, wherein R2 is an aromatic group substituted with halogen.
62. 62. The compound of Claim 61, wherein R2 is a 4-chlorophenyl group.
63. 63. The method of Claim 56, wherein: Ring B is a pyridyl group, n is three, M is > C (OH) R2 and R2 is a 4-chlorophenyl group.
64. 64. A compound represented by the following structural formula: and their physiologically acceptable salts, wherein: n is an integer from one to five; M is > NR2 or > CR1R2; R1 is -H, -OH, an aliphatic group, -0- (aliphatic group), -0- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group), -OC (O) - (aliphatic group), -O-C (O) - (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a heterocyclic group non-aromatic or a substituted non-aromatic heterocyclic group, wherein: R3, R4, R5 and R6 are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group , a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R1 and R2, R3 and R4 or R5 and R6, taken together with the atom to which they are attached, form a substituted or unsubstituted carbocyclic or heterocyclic non-aromatic ring; Z is represented by the following structural formula: where: Wa is -CH2-NR1: LR12, -CH2-OR 11 -CH = NH, -CHz-NH-CO-NR ^ R12, CH2-0-C0-NRxlR12 or -CH2-NHC (0) -O-R11; R11 and R12 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group, or R11 and R12, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring, and Ring A and Ring B are independently substituted or unsubstituted.
65. 65. The compound of Claim 64, wherein R1 is -OH.
66. 66. The compound of Claim 64, wherein M is > C (0H) R2 and n is three.
67. 67. The compound of Claim 66, wherein R2 is a substituted or unsubstituted aromatic group.
68. 68. A compound represented by the following structural formula: and their physiologically acceptable salts, wherein: n is an integer from one to five; M is > NR2 or > CRXR2; R1 is -H, -OH, an aliphatic group, -O- (aliphatic group), -O- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group), - OC (O) - (aliphatic group), -0-C (O) - (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a hetero group -non-aromatic cyclic or substituted non-aromatic heterocyclic group, wherein: R3, R4, R5 and R6 are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a group substituted aromatic, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R1 and R2, R3 and R4 or R5 and R6, taken together with the atom to which they are attached, form a substituted or unsubstituted carbocyclic or heterocyclic non-aromatic ring; Z is represented by a structural formula selected from: where: Q is -CH2-0-, -CH2-NRC-, -CH2-SO-, -CH2-S02- -CH2-CH2-, -CH = CH- or -CO-NRc-; Wb is -CH = NH, -CN, -CH2-NR R12, -CH2-OR1, L, -CH2-NH-CO-NRuR12, -CH2-0-C0-NR R12 or -CH2-NHC (O) - O-R11, R11 and R are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R 11 and R, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; Ring A and Ring B are independently substituted or unsubstituted; Rc is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group.
69. 69. The compound of Claim 68, wherein Ring A or Ring B are substituted with - (0) u- (CH2) t-COOR20, - (0) u- (CH2) tC (0) -NR21R22 or ( 0) u- (CH2) t-NHC (O) -O-R20, where u is zero or one; t is an integer from zero to 3, and R 20 R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R 21 and R, 22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
70. 70. The compound of Claim 68, wherein Rc is -: CH2; -COOR 30 (CH2) sC (0) -NR31R32 or - (CH2) s-NHC (0) -O-R30, where: s is an integer from one to three, R 30 R 31 or R are independently -H , an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R 31 and R > 32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
71. 71. The compound of Claim 68, wherein R1 is -OH.
72. 72. The compound of Claim 68, wherein M is > C (OH) R2 and n is three.
73. 73. The compound of Claim 72, wherein R2 is a substituted or unsubstituted aromatic group.
74. 74. A compound represented by the following structural formula: and their physiologically acceptable salts, wherein: n is an integer from one to five; M is > NR2 or > CR1R2; R1 is -H, -OH, an aliphatic group, -O- (aliphatic group), -O- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group), - OC (O) - (aliphatic group), -OC (O) -. { substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a heterocyclic group non-aromatic or a substituted non-aromatic heterocyclic group, wherein: R3, R4, R5 and R6 are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group , a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R1 and R2, R3 and R4 or R5 and R6, taken together with the atom to which they are attached, form a carbocyclic or heterocyclic ring. non-aromatic substituted or unsubstituted clico; Z is represented by the following structural formula: where: Rc is an aliphatic group C? -C2o, a substituted C? -C20 aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group, Ring A and Ring B are independently substituted or not replaced.
75. 75. The compound of Claim 74, wherein Ring A or Ring B are substituted with - (0) u- (CH2) t-COOR20, - (0) u- (CH2) tC (0) -NR21R22 or ( 0) u- (CH2; NHC (0) -O-R20, where u is zero or one, t is an integer from zero to 3, and R 20 R21 or R22 are independently -H, an aliphatic group, a group substituted aliphatic, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group, or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring
76. 76. The compound of Claim 74 , where Rc is ; CH2) ss - CCOOOORR3300 ,, - ((CCHH22)) ss - CC ((00)) --NNRR3311RR3322 oo - ((CCHH22)) SS-NHC (O) -O-R30, where: s is an integer from one to three, R 30 R31 or R32 are independently -H, an aliphatic group a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R31 and R32, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
77. 77. The compound of Claim 74, wherein Rc is an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group.
78. 78. The compound of Claim 77, wherein R1 is -OH.
79. 79. The compound of Claim 78, wherein M is > C (OH) R2 and n is three.
80. 80. The compound of Claim 79, wherein R2 is a substituted or unsubstituted aromatic group.
81. 81. A method of treating a disease associated with an aberrant recruitment and / or activation of leukocytes, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula: -Y- - (i-yír -x- -N M / and their physiologically acceptable salts, wherein: Y is a covalent bond, n is an integer from one to five, X is a covalent bond and M is > NR2 or > CR1R2; R1 is -H, -OH, an aliphatic group, -O- (aliphatic group), -0- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group), - OC (O) - (aliphatic group), -OC (0) - (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; R is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a heterocyclic group non-aromatic or a substituted non-aromatic heterocyclic group, wherein: R3, R4, R5 and R6 are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group , a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R1 and R2, R3 and R4 or R5 and R6, taken together with the atom to which they are attached, form a substituted or unsubstituted carbocyclic or heterocyclic non-aromatic ring; Z is represented by the following structural formula: where: Xi is a covalent bond, -S-, -CH2- or -CH-S-; W is -H or an electron withdrawing group; Ring A and Ring B are independently substituted or unsubstituted, with the proviso that one of Ring A or Ring B is substituted with - (O) u- (CH2) t-COOR20, - (0) u- ( CH2) tC (0) -NR21R22 or - (O) u- (CH2) t-NHC (0) -O-R20, where: u is zero or one, t is an integer from zero to 3 and R20, R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
82. 82. A compound represented by the following structural formula: (CHp -N M and their physiologically acceptable salts, where: M is > NR2 or > CRXR2; R1 is -H, -OH, an aliphatic group, -0- (aliphatic group), -O- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group), - OC (0) - (aliphatic group), -0-C (0) - (substituted aliphatic group), -CN, -COOH, -C0-NR3R4 or -NR3R4; R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a heterocyclic group non-aromatic or a substituted non-aromatic heterocyclic group, wherein: R3, R4, R5 and R6 are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group , a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R1 and R2, R3 and R4 or R5 and R6, taken together with the atom at which are joined, form a substituted or unsubstituted carbocyclic or heterocyclic ring; n is an integer from one to five; Z is represented by the following structural formula: where: W is an electron withdrawing group and at least one of Ring A and Ring B is independently substituted or unsubstituted and one of Ring A or Ring B is substituted with - (O) u- (CH2) t-COOR : 20 - (0) u- (CH2) tC (O) -NR21R22 or - (0) u- (CH2) t-NHC (O) -O-R20, where: u is zero or one, t is a number whole from zero to 3 and R 20 R 21 or R, 22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
83. 83. A compound represented by the following structural formula: and their physiologically acceptable salts, where: n is an integer from one to five; M is > NR2 or > CRXR2; R1 is -H, -OH, an aliphatic group, -O- (aliphatic group), -0- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group), - OC (O) - (aliphatic group), -OC (0) - (substituted aliphatic group), -CN, -COOH, -CO-NR3R4 or -NR3R4; R2 is -H, -OH, an acyl group, a substituted acyl group, -NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a heterocyclic group non-aromatic or a substituted non-aromatic heterocyclic group, wherein: R3, R4, R5 and R6 are independently -H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group , a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R1 and R2, R3 and R4 or R5 and R6, taken together with the atom to which they are attached, form a substituted or unsubstituted carbocyclic or heterocyclic non-aromatic ring; Z is represented by a structural formula selected from: where: X2 is -CH2-0-, -CH2-NRC-, -CH2-SO- -CH2-S02- -CH2-CH2-, CH = CH- or -CO-NRc-; Wb is -H, -CH = NH, -CN, -CH2-NRnR12; -CH2-OR 11 -CH2-NH-C0- NRnR12, -CH2-0-CO-NR1: LR12 or -CH2-NHC (0) -0-R11; R, 1x1 ± and R, 12 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R11 and R12, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; Ring A and Ring B are independently substituted or unsubstituted, and Rc is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group.
84. 84. The compound of Claim 83, wherein Ring A or Ring B are substituted with - (0) u- (CH 2) t-COOR 20, - (0) u- (CH 2) t C (0) -NR 21 R 22 or - (O) u- (CH2) t-NHC (O) -O-R20, where: u is zero or one, t is an integer from zero to 3 and R20, R21 or R22 are independently -H, an alifá group -tico, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or taken together with the nitrogen atom to which they are attached, they form a non-aromatic heterocyclic ring.
85. 85. The compound of Claim 83, wherein Rc is - (CH2) s-COOR30, - (CH2) sC (0) -NR31R32 or - (CH2) S-NHC (O) -O-R30, where: s is a number whole from zero to three, R30, R31 or R32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R 31 and R, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring.
86. 86. The compound of Claim 83, wherein R1 is -OH. 7.
87. The compound of Claim 83, wherein M is > C (OH) R¿ and n is three.
88. 88. The compound of Claim 87, wherein R2 is a substituted or unsubstituted aromatic group.
89. 89. The compound of Claim 83, wherein Ring B of Z is substituted with R40 in position para to the carbon atom of Ring B which is also attached to X2 of Ring C and Z is represented by the following structural formula: where: R40 is -OH, halogen, an aliphatic group, a substituted aliphatic group, -O- (aliphatic group), -O- (substituted aliphatic group), -O- (aromatic group), -O- (group substituted aromatic), an electron withdrawing group, - (0) u- (CH2) t-COOR20, - (0) u- (CH2) t-OC (0) R2 °, - (0) u- (CH2) t-C (0) -NR21R22 or - (0) u- (CH2) t-NHC (0) 0-R2 °; R20, R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are attached, form a non-aromatic heterocyclic ring; u is zero or one, and t is an integer from zero to 3.
90. 90. A method of antagonizing a chemokine receptor in a mammal in need thereof, comprising administering an effective amount of a compound of Claim 47 to the mammal.