MXPA00007142A - Chemokine receptor antagonists and methods of use therefor - Google Patents

Abstract

Disclosed is a method of treating a subject with a disease associated with aberrant leukocyte recruitment and/or activation. The method comprises administering to the subject a therapeutically effective amount of a compound represented by structural formula (I), and physiologically acceptable salts thereof. Z is a cycloalkyl or non-aromatic heterocyclic ring group fused to one or more carbocyclic aromatic rings and/or heteroaromatic rings, wherein each ring in Z is independently substituted or unsubstituted;Y is a covalent bond, -O- or -CO-;n is an integer from one to about five;X is a covalent bond or -CO-;and M is>NR2,>CR1R2;R1 is -H, -OH, an aliphatic group, -O- (aliphatic group), -SH or -S- (aliphatic group);R2 is an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzylic group, a substituted benzylic group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.

Description

ANTAGONISTS OF RECEPTORS OF CHEMOQUINES AND METHODS FOR THEIR USE RELATED APPLICATIONS This application is a continuation, in part, of US Serial No. 09 / 010,321, filed on January 21, 1998, which is a continuation, in part, of Serial No. 08 / 891,518, filed. on July 11, 1997, which claims the priority of United States Provisional Application Serial No. 60 / 021,716, filed July 12, 1996, so that all its teachings are incorporated herein by reference.

BACKGROUND OF THE INVENTION Chemoattractant cytokines and chemokines are a family of proinflammatory mediators that promote the recruitment and activation of multiple leukocyte and lymphocyte lineages. They can be released by several types of tissue cells after 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 the 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, designated as the CXC chemokines (a-chemokines), and the CC chemokines (β-chemokines), in which the first two conserved cysteines are separated for an intervening residue, or adjacent, respectively (Baggiolini, M. and Dahinden, CA, Immunology Today, 15: 127-133 (1994)). The chemokines C-X-C include a number of potent chemoattractants and activators of neutrophils, such as interleukin 8 (IL-8), PF4 and peptide-2 that activates neutrophils (NAP-2). CC chemokines include RANTES (Regulated on Activation, Normal T Expressed and Secreted), the inflammatory proteins of macrophages la and lß (MlP-l and MlP-lβ), 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 which do not appear to be chemoattractants for neutrophils. Chemokines, such as RANTES and MlP-la, have been implicated in a wide variety of acute and chronic human inflammatory diseases that include respiratory diseases, such as asthma and allergic disorders. Chemokine receptors are elements of a superfamily of G-protein coupled receptors (GPCRs) that share structural features that reflect a common mechanism of signal transduction action (Gerard, C. and Gerard, NP, Annu Rev. Immunol., 12 : 775-808 (1994), Gerard, C. and Gerard, NP, Curr Opin. Immunol., 6: 140-145 (1994)). The conserved features include seven hydrophobic domains that cover the plasma membrane, which are connected by extracellular and intracellular hydrophilic circuits. Most of the primary sequence homology occurs in the hydrophobic transmembrane regions, the hydrophilic regions being more diverse. The first receptor for the C-C chemokines that was cloned and expressed binds the MlP-la and RANTES chemokines. Accordingly, this / RANTES receptor was designated CC chemokine receptor 1 (also referred to as CCR-1; Neote, K., et al., Cell, 72: 415-425 (1993); Horuk, R. et al. col., WO 94/11504, May 26, 1994; Gao, J.-I. et al., J. Exp. Med., 177: 1421-1427 (1993)). Three new receptors have been characterized that bind and / or signal response to RANTES: CCR3 mediates the binding and chemokine signaling including eotaxin, RANTES, and MCP-3 (Ponath et al., J. Exp. Med., 183: 2437 (1996)), CCR4 binds chemokines including RANTES, MlP-la, and MCP-1 (Power, et al., J. Biol. Chem., 270: 19495 (1995)), and CCR5 binds chemokines including MlP- la, RANTES, and MlP-lβ (Samson, et al., Biochem. 35: 3362-3367 (1996)). RANTES is a chemotactic chemokine for a variety of cell types, including monocytes, eosinophils and a subset of T cells. The responses of these different cells may not all be mediated by the same receptor, and it is possible that the CCR1, CCR4 and CCR5 receptors show some selectivity in the distribution and function of the receptor among the receptors. types of leukocytes, as has already been shown for CCR3 (Ponath et al.). In particular, the ability of RANTES to induce targeted migration of monocytes and a circulating T-cell memory population (Schall, T. et al., Na ture, 347: 669-71 (1990)) suggests that this chemokine and its receptor (s) can play a critical role 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. Antagonists have not yet been successfully developed for receptors for larger proteins, such as chemokines and C5a. Small molecule antagonists of the interaction between the chemokine CC receptors and their ligands, including RANTES and MlP-la, would provide useful compounds to inhibit damaging inflammatory processes "activated" by the interaction of receptor ligands, as well as valuable tools for the Investigation of receptor-ligand interactions.

SUMMARY OF THE INVENTION It has now been found that a number of small organic molecules are antagonists of chemokine receptor function and can inhibit the activation and / or recruitment of leukocytes. An antagonist of the chemokine receptor function is a molecule that can inhibit the binding of one or more chemokines, including CC chemokines, such as RANTES and / or MlP-la to one or more of the chemokine receptors on leukocytes and / or other cell types. As a consequence, cellular processes and 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 aberrant leukocyte recruitment and / or activation is described. The method comprises administering to the subject a therapeutically effective amount of a compound or small organic molecule, which is an antagonist of the chemokine receptor function. The small organic compounds or molecules that have been identified as antagonists of the chemokine receptor function are described in detail hereinafter, and can be used for the manufacture of a medicament for the treatment or prevention of a disease associated with recruitment. and / or aberrant activation of leukocytes. The invention also relates to the described compounds and to small organic molecules for use in the treatment or prevention of a disease associated with the aberrant recruitment and / or activation of leukocytes. The invention also includes pharmaceutical compositions comprising one or more of the compounds or small organic molecules that have been identified herein as antagonists of the chemokine function and a suitable pharmaceutical carrier. The invention further relates to novel compounds that can be used to treat an individual with a disease associated with leukocyte recruitment and / or activation.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a schematic view showing the preparation of the compounds represented by Structural Formulas (I) and (II). Figure 2 is a schematic view showing the preparation of the compounds represented by Structural Formulas (I) and (II), where Z is represented by the Structural Formulas (IV) and where Ring A in Z is substituted with - (CH2 ) t-C00H, - (CH2) t-COOR 2o - (CH2) tC (0) - NR21R22, Figure 3 is a schematic view 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 is Wa- Figures 4A-4F show the structures of a number of exemplary compounds of the present invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to small molecular compounds that are antagonists of chemokine receptor function. Accordingly, 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 wing migration of leukocytes, integrin activation, transient increases in the concentration of free calcium intracellular [Ca ++], and / or release of granules of proinflammatory mediators. The invention further relates to a method of treatment, including prophylactic and therapeutic treatments of a disease associated with aberrant leukocyte or chemokine-mediated recruitment and / or activation of the chemokine receptor __, including chronic inflammatory disorders characterized by the presence of RANTES, response T cells Mpl-la, MCP-2, MCP-3 and / or MCP-4, monocytes and / or eosinophils; including but not limited to diseases such as arthritis (e.g., 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 allograft rejection, acute allograft rejection ), graft disease with respect to host, as well as allergies and asthma. Other diseases associated with aberrant recruitment and / or activation of leukocytes that can be treated (including prophylactic treatments) with the methods described herein are inflammatory diseases associated with infection of the Human Immunodeficiency Virus (HIV), for example, encephalitis associated with the AIDS, AIDS-related maculopapular skin rash, AIDS-related interstitial pneumonia, AIDS-related enteropathy, periportal hepatic inflammation associated with AIDS, and AIDS-related glomerulus nephritis. The method comprises administering to the subject in need of treatment an effective amount of a compound (i.e., one or more compounds) that inhibits the chemokine receptor function, inhibits the binding of chemokine to leukocytes and / or other cell types and / o that inhibits the migration of leukocytes and / or activation in sites of inflammation. According to the method, chemokine-mediated chemotaxis and / or activation of pro-inflammatory cells carrying receptors for chemokines can be inhibited. As used herein, "pro-inflammatory cells" include, but are not limited to leukocytes; since the chemokine receptors can be expressed on other cell types, such as neurons and epithelial cells. 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 with one or more aromatic rings and / or carbocyclic heteroaromatic rings, and Y is a covalent bond, -0- or -C0- n is an integer of one to about five, n is preferably one, two or three X is a covalent bond or -CO-, M is > NR2 or > CR? R2. Preferably, M is > C (OH) R2, Ri is -H, -OH, an aliphatic group, -0- (aliphatic group), -SH or -S- (aliphatic group). Preferably, Ri is -H or -OH. R2 is 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 non-aromatic-substituted heterocyclic group. Preferably, R2 is an aromatic group or a substituted aromatic group. In a preferred embodiment, -X- and -Y- in the Formula Structure (I) are each a covalent bond and the antagonist of the chemokine receptor function is a compound represented by the Formula Structural (II): (II) wherein: Z, n and M are as described above for the Structural Formula (I). In another preferred embodiment, -X- is a covalent bond, -Y- is -CO- and the antagonist of the chemokine receptor function is a compound represented by Structural Formula (III): (III) Preferably, Z is a tricyclic ring system, comprising two carbocyclic aromatic groups fused to a seven or eight membered cycloalkyl group or a non-aromatic heterocyclic ring. In an example, Z is represented by the Structural Formula (IV): (IV) The phenyl rings in Structural Formula (IV), labeled "A" and "B" are referred to herein as "Ring A" and "Ring B", respectively. The central ring, labeled with a "C" is referred to as "Ring C" and may be, for example, a non-aromatic carbocyclic ring of six, seven or eight members (e.g., a cycloheptane or cyclooctane ring) or a heterocyclic ring not aromatic 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 the Structural Formula (IV), the tricyclic ring system is connected to Y in the General Formula (I) by a single covalent bond between Y and a ring atom in Ring C: Ring A and / or Ring B may be unsubstituted. Alternatively, Ring A and / or Ring B may have one or more substituents. Suitable substituents are as described hereinafter for substituted aromatic groups. In one example, Ring A or Ring B is substituted with (CH2) t-C00H, or - (CH2) t-C (0) NR21R22, t is an integer from zero to about 3. R20, R21 or R22 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, -NHC (0) -O- (group aliphatic) -NHC (O) -0- (aromatic group) or NHC (0) -0- (non-aromatic heterocyclic group). Additionally, R and R, taken together with the nitrogen atom to which they are attached, can form a non-aromatic heterocyclic ring. Ring C optionally contains one or more additional substituents. When Ring C is a non-aromatic carbocyclic ring, suitable substituents are as hereinafter described for substituted aliphatic groups. When Ring C contains one or more heteroatoms, suitable substituents are as described below for the non-aromatic heterocyclic rings. Preferably, Ring C is unsubstituted or substituted with an electron removal group. Suitable electron removal groups include -CN, alkylsulfonyl, carboxamido, carboxylic alkyl esters, -N02 and halogens (e.g., -BR and -Cl). Alternatively, Ring C is substituted with a group selected from -CH? -NR ^ R12, -CH2-OR 11 -CH2-NH-CO-NR11-R12 / CH2-0-CO-NRuR12. R 11 and R are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, -NHC (O) -0- (aliphatic group), or NHC (O) -O- (aromatic group). Additionally, R11 and R12, taken together with the nitrogen atom to which they are attached, can form a non-aromatic heterocyclic ring. Examples of suitable tricyclic ring systems represented by Structural Formula (IV) are provided by the Structural Formulas (V) - (VIII), shown below: (VIII) in which: Xi is a chemical bond, -S-, -CH2- or -CH2S-. Preferably, Xi is -S- in the Structural Formulas (V) and (VII). Preferably, Xi is -CH2S- in the Structural Formulas (VI) and (VIII), W is -H or an electron removal group, as described above for the Structural Formula (IV). A preferred electron removal group is -CN, Wa is a group selected from -CH2-NRn-R12, -CH2-ORn, -CH2-NH-CO-NR11R12, or -CH2-0-CO-NR11R12. R11 and R12 are as defined in Structural Formula (IV). Ring A and Ring B in Structural Formulas (V) - (VIII) are 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 (IX) - (VXII),. { Ila) -, (Xllb) and (XIIc): (X) (XI) (XII) (Xlla) (Xllb) (XIIc) The rings A-C in the Structural Formulas (IX) - (XII), (Xlla), (Xllb) and (XIIc) are as described for the Structural Formula (IV). Rc is an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group. Preferably, R c is a substituted C 1 -C 20 aliphatic group, a C 1 or C 2 aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group. In one example, Rc is - (CH2) s -COOH, - (CH2) s-COOH 30 (CH2) s-C (0) NR31R32. s is an integer from zero to about 3. R30, R31 and R32 are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, -NHC (O) -0- (aliphatic group) , -NHC (0) -0- (aromatic group) or -NHC (0) -0- (non-aromatic heterocyclic group). In addition, R31 and R32, taken together with the nitrogen atom to which they are attached, can form a non-aromatic heterocyclic ring. Preferred examples of tricyclic ring systems represented by the Structural Formulas (IX) - (XII), (Xlla), (Xllb) and (XIIc) are shown below in Structural Formulas (XIII) - (XVI), (XVIa), (XVIb) and (XVIc): V is W or Wa, which are as described above for the Structural Formulas (V) - (VIII).

In another preferred embodiment, Z is a system of tricyclic rings comprising one or more heteroatom groups fused to a cycloalkyl group of seven or eight members or to a non-aromatic heterocyclic ring. The (XVII) (XVIII) examples are represented by the Structural Formulas (XVII) - (XXI), (XXIa), (XXIb) and (XXIc): Ring A in Structural Formulas (XVII) - (XXI), (XXIa), (XXIb) and (XXIc) is a substituted or unsubstituted aromatic group. Ring B in structural formulas (XVII) - (XXI), (XXIa), (XXIb) and (XXIc) is a substituted or unsubstituted heteroaryl group.

Wb is -H, -CN, -CH2-NR) HA 1nRl'12 CH2-0-C0-NR11R12, R11 and R12 are as defined above for Structural Formula (IV). In still another preferred embodiment, the antagonist of the chemokine function is a compound represented by the Structural Formulas (XXII) and (XXIII): (XXII) (xxin; In the Structural Formulas (XXII) and (XXIII), Xi is as defined above for the Structural Formulas (V) and (VI); n is an integer from two to five; W is -H, -CN, alkylsulfonyl, carboxamido or carboxy alkyl. In the Structural Formulas (XXII) and (XXIII), the Ring A is substituted with R8 and Rg, where R8 and R9 are independently -H, a halogen, alkoxy or alkyl, or, taken together with ring A, form a naphthyl group. M is > N (alkanoyl), > (aroyl), > N (aralcoyl), > N (alkyl), > N (aralkyl), > N (cycloalkyl), > C (0H) (aryl) or > CH (heteroaryl). The present invention also includes novel compounds represented by the Structural Formulas (II) and (III). In one embodiment, the novel compounds are represented by Structural Formulas (II) and (III), wherein Z is a group, in which one or more heteroaromatic rings are fused to a cycloalkyl ring or a non-cyclic heterocyclic ring. aromatic. Each Z-ring is independently substituted or unsubstituted. Examples of suitable Z groups are represented by the Structural Formulas (XVII) - (XXII), (XXIa), (XXIb) and (XXIc). Ring A, Ring B, M, Wb, Ri, R2, Rc and n are as described in the Structural Formulas (XVII) to (XXIc). In another embodiment, the novel compounds represented by the structural formulas (II) and (III) have a group Z represented by the Structural Formulas (V) and (VI). At least one of the Rings A and B is substituted. M, W, Ri, R2 and n are as described in the Structural Formulas (V) and (VI). In another embodiment, the novel compounds represented by the Structural Formulas (II) and (III) have a group Z represented by the Structural Formulas (VII) and (VIII). Ring A, Ring B, M, Wa, Ri, R2 and n are as described in the Structural Formulas (VII) and (VIII). In another embodiment, the novel compounds represented by the Structural Formulas (II) and (III) have a Z group represented by the Structural Formulas (XIII) - (XVI), (XVIa), (XVIb) and (XVIc). The Ring A, the Ring B, M, Ri, R2, Rc and n are as described in the Structural Formulas (XIII) to (XVIc). V is -CN, CH2-NR1: LR12, -CHs-OR11, -CH2-NH-CO-NR R12, -CH2-0-CO-NRnR12. R11 and R12 are as defined above for Structural Formula (IV). In another embodiment, the novel compounds represented by the Structural Formulas (II) and (III) have a group Z represented by the Structural Formulas (XVI). Ring A, Ring B, M, Rl r R2 and n are as described in the Structural Formulas (XVI). V is -H and Rc is an aliphatic group of C? O-C2o, a substituted C? Or? C2o aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group. In one example, Rc is - (CH2) s-COOH, - (CH2) s-COOH30 or - (CH2) s-C (0) -NR31R32, where s, R30, R31 are as described above. Preferably, R c is an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group. In still another embodiment, the novel compounds represented by the Structural Formulas (II) and (III) have a group Z represented by the Structural Formulas (XXII) and (XXIII). Ring A, Ring B, M, W, and n are as described in the Structural Formulas (XXII) to (XXIII). Ra and Rg are, independently, a halogen, alkoxy or alkyl, or taken together with ring A, form a naphthyl group. Also included in the present invention are the physiologically acceptable salts of the compounds represented by the Structural Formulas (I) to (XXIII). 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, perchloric acid and the like. Compounds with a quaternary ammonium group also contain a counter-anion, such as chloride, bromide, iodide, acetate, perchlorate and the like. The salts of the compounds containing a carboxylic acid or other functional acid group can be prepared by reaction with a suitable base, for example, a hydroxide base. The salts of functional acid groups contain a counter-cation, such as sodium, potassium, and the like. As used herein, the aliphatic groups include linear, branched or cyclic Ci-Cβ hydrocarbons, which are completely saturated or which contain one or more units of unsaturation. 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 phenyl-alkyl-CO- and "aroyl" refers to arylcarbonyl including benzoyl, naphthoyl and the like. The term "halogen" means fluorine, chlorine, bromine, and iodine. The term "aryl", as opposed to the term "aromatic group" means phenyl. The term "substituted phenyl" means aryl substituted with alkyl, halogen, alkoxy, nitro, amino, acetamido, cyano and trifluoromethyl and naphthyl. "Aralkyl" means - (CH2) x-phenyl, where x is an integer from one to four that includes benzyl. It should be noted that the terms "aromatic group", "aromatic carbocyclic group" and "heterocyclic aromatic group" are defined below and have different meanings of the term "aryl". Aromatic groups include carbocyclic aromatic groups, such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl, and 2-anthracyl, and heterocyclic aromatic groups, such as N-imidazolyl, 2-imidazole, 2-thienyl, - thienyl, 2-furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl , 2-pyrazinyl, 2-thiazole, 4-thiazole, 5-thiazole, 2-oxazolyl, 4-oxazolyl and 5-oxazolyl. The aromatic groups also include fused polycyclic aromatic ring systems, in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more heteroaryl rings. Examples include 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazole, 2-benzooxazole, 2-benzimide zol, 2-quinolinyl , 3-quinolinyl, 1-isoquinlysyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, and acridintyl. Within the scope of the term "aromatic group", as used herein, a decalin ~ phthalimide, benzodiazepines, benzooxacepins, benzo oxacines, phenothiazines, and jßspve ^ groups The non-aromatic heterocyclic rings are non-aromatic carbocyclic rings, which include one or more heteroatoms such as nitrogen, oxygen or sulfur in the ring. The ring can have five, six, seven or other members. Examples include 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothio phenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thio morpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrro lidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl. "Heterocyclic ring", as opposed to "heteroaryl group" and "non-aromatic heterocyclic ring" is defined as imidazole, benzimidazole, pyridine, pyrimidine, thiazole, benzothiazole, thienyl, benzothienyl. It is further to be noted that the terms "heterocyclic aromatic group" and "non-aromatic heterocyclic ring" are defined above and have different meanings from the term "heterocyclic ring". Suitable substituents on an alkyl, heterocyclic aliphatic, aromatic, non-aromatic ring or benzyl group include, for example, -OH, halogen (-Br, -Cl, -I and -F) -O (aliphatic group, substituted aliphatic group, benzyl, substituted benzyl, aromatic group or substituted aromatic group), -CN, -N02, COOH, -NH2, -NH (aliphatic group, substituted aliphatic group, benzyl, substituted benzyl, aromatic group or substituted aromatic group), -N ( aliphatic group, substituted aliphatic group, benzyl, substituted benzyl, aromatic group or substituted aromatic group) 2, -COO (aliphatic group, substituted aliphatic group, benzyl, substituted benzyl, aromatic group or substituted aromatic group), -CONH2, -CONH ( aliphatic group, substituted aliphatic group, benzyl, substituted benzyl, aromatic group or substituted aromatic group)), -SH, -S (aliphatic group, substituted aliphatic group, benzyl, substituted benzyl, or substituted aromatic group) and -NH-C ( = NH) -NH2 . A substituted non-aromatic heterocyclic ring, benzyl group, or aromatic group may also have an aliphatic group or substituted aliphatic group as a substituent. A substituted alkyl or aliphatic group may also have a non-aromatic heterocyclic, benzyl, substituted benzyl ring, aromatic group or substituted aromatic group as a substituent. A substituted non-aromatic heterocyclic ring can also have = 0, = S, = NH or = (aliphatic group, aromatic group or substituted aromatic group) as a substituent. A substituted aliphatic ring, substituted aromatic, substituted non-aromatic heterocyclic or substituted benzyl group may have more than one substituent. In the structural formulas described herein, the individual or double bond by which a chemical group or fraction is connected to the rest of the molecule or compound is indicated by the following symbol: For example, the corresponding symbol in Structural Formula (V) or (VIII) indicates that the tricyclic ring system representing Z in Structural Formula (I) is connected to the alkylene group in Structural Formula (I) by a bond individual covalent between the alkylene group and the carbon ring in Ring C that adheres to W. A "subject" is preferably a mammal, such as a human, but may also be an animal in need of veterinary treatment, eg, animals domestic (for example, dogs, cats, and the like, farm animals (e.g., cows, sheep, pigs, horses and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). A "therapeutically 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 in a subject with a disease associated with aberrant leukocyte recruitment and / or activation. Examples of such processes include leukocyte migration, activation of mtegrin, transient increases in the concentration of intracellular free calcium [Ca2 +] 1 and release of granules of proinflammatory mediators. Alternatively, a "therapeutically 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 prevention or a decrease in symptoms associated with recruitment and / or activation. aberrant leukocytes. The amount of compound administered to the individual 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 the 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 doses depending on these and other factors. Typically, a therapeutically effective amount of the compound can range from about 0.1 mg per day to about 100 mg per day for an adult. Preferably, the dose ranges from 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, suspensions or lozenges or by 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 (eg, by diet), topically, by inhalation (eg, intrabronchial, intranasal, oral inhalation or intranasal drops) or rectally, depending on the disease or condition to be treated. Oral or parenteral administration are preferred modes of administration. The compound can be administered to the individual in combination with an acceptable pharmaceutical or physiological carrier as part of a pharmaceutical composition for the treatment of HIV infection, inflammatory disease, or other diseases described 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 may contain inert ingredients that do not interact with the compound. Standard formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. Suitable carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing approximately 0.9% mg / ml benzyl alcohol), phosphate buffered saline, Hank's solution, Ringer lactate and the like. Methods for encapsulating compositions (such as in a hard gelatin or cyclodextran 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 assessed using suitable assays, such as receptor adhesion assays, and chemotaxis assays. For example, as described in the Embodification Section, the small adhesion molecule antagonists of RANTES and MlP-la have been identified using THP-1 cells that bind RANTES and chemotax in response to RANTES and MlP-la as a model. for chemotaxis of leukocytes. Specifically, a high-throughput receptor binding assay that monitors 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 adhesion of RANTES and MlP-la. The compounds of the present invention can also be identified by virtue of their ability to inhibit activation steps triggered by the binding of a chemokine to its receptor, such as chemotaxis, integrin activation and granule mediator release. They can also be identified by virtue of their ability to block RANTES and MlP-mediated HL-60, T-cell, peripheral blood mononuclear cell and eosinophil chemotactic response. The compounds described herein can therefore be prepared with the schemes shown in Figures 1-3. The schemes are described in more detail below.

Figure 1 is a schematic view showing the preparation of the compounds represented by Structural Formula (I). L1, L2 and L3 in Figure 1 are suitable leaving groups such as halogen; p-toluene sulfonate, mesylate, alkoxy and phenoxy. Other symbols are as defined above. The reduction reaction in 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 ranging from 0 ° C to the reflux temperature and for 5 minutes to 72 h. The compounds represented by formula II in Figure 1 can be prepared by procedures described in JP 61/152673, U.S. Patent 5089496, WO 89/10369, WO 92/20681 and WO 93/02081, all of which teachings are Incorporate here by reference. A chlorination reaction in the step of Figure 1 can be carried out with reagents, such as thionyl chloride. The reaction can be carried out in an inert solvent such as methylene chloride at 0 ° C to reflux temperature for 5 minutes to 72 hours. The hydroxy group can also be converted to other leaving groups by methods familiar to those skilled in the art.

The cyanation reaction in step 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 range from 0 ° C to 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 U.S. Patent 5672611, the teachings of which are incorporated herein by reference. The alkylation reactions in 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 a base, such as potassium carbonate or sodium hydride and a catalyst such as an alkali metal iodide (when necessary). The reaction temperature can range from room temperature to the reflux temperature and for 5 minutes to 72 h. The product of the synthetic scheme shown in Figure 1 can be decianated using a reducing agent such as lithium aluminum hydride (LAH) in an inert solvent such as ether or tetrahydrofuran (THF) at 0 ° C to the reflux temperature for the solvent used for 5 minutes to 72 hours. Figure 2 is a schematic view showing the preparation of the compounds represented by the Formulas Structural (I) and (II), where Z is represented by Structural Formulas (IV) and where Ring A in Z is substituted with (CH2; COOH, - (CH2) t-COOR 2'0u or - (CH2) t C (O) - NR21R22.

In Figure 2, the hydrolysis reaction can be carried out in a mixture of aqueous alkali metal hydroxide solution and a solvent, such as methanol, ethanol, tetrahydrofuran (THF) or dioxane at room temperature to the reflux temperature for the solvent used for 5 minutes to 72 h. The acylation reaction can be carried out using dicyclohexylcarbodiimide (DCC) or (l-ethyl-3- (3-dimethyl aminopropyl) 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 from 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-COOH, - (CH2) s-COOR33, or - (CH2) SC (O) -NR31R32, can be prepared by the appropriate 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 rest of the synthesis is as described in Figures 1 and 2. Figure 3 is a schematic view showing the preparation of the compounds represented by the Structural Formulas (I) and (II), where Z is represented by the Formulas Structural (VIII) and (XIII-XVI) and where V is Wa. The reduction of the cyano group to an amine in Figure 3 can be carried out using metal hydrides or catalytic reduction processes. Suitable reducing agents include lithium aluminum hydride (LAH), diisobutyl aluminum hydride (DIBAL-H), borane-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 corresponding intermediate imine, which can be converted to the amine using similar reduction processes. Although Figures 1-3 show the preparation of the compounds in which Rings A and B are phenyl rings, analogous compounds with heteroaryl groups can be prepared for Rings A and B using the starting materials with heteroaryl groups in the corresponding positions , which can be prepared according to the methods described in JP 61/152673, U.S. Patent 5089496, WO 59/10369, WO 92/20681, and WO 93/02081. The invention is illustrated by the following examples which are not intended to be limited in any way.

EXEMPLIFICATION Example 1- Preparation of 4- (4-chlorophenyl) 1- [3- (5-cyano-5H-dibenzo [a, d] cycloheptene-5-yl) propyl] piperidin-4-ol.

They were added to a solution of 5H-dibenzo [a, d] heptene-5-carbonitrile cyclo (described in J. Med. Chem. 1994, 37, 804-810) (500 mg) in DMF (10 ml) sodium hydride to 60% (110 mg) and l-bromo-3-chloropropane (0.30 ml), and the mixture was stirred at room temperature 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 dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 5- (3-chloropropyl-5H-dibenzo [a, d] cycloheptene-5-carbonitrile.) They were added, without purification, to a chloride obtained in solution 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 ° C for 24 hours. The ethyl acetate was 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.The residue was purified by gel chromatography. silica 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: 479 (M + 1).

Example 2 - Preparation of 4- (4-chlorophenyl) -1- [3- (5-cyano-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-yl) propyl] piperidin-4-ol .

Following the procedure of example 1, but substituting 5,1-dibenzo [a, d] cycloheptene-5-carbonitrile with 10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-carbo nitrile, the title compound was prepared.

? -NRM (CDCI3) 5: 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,), 7, 93-7, 97 (2H, m). MS m / s: 471 (M + 1).

Example 3 - Preparation of 4- (4-chlorophenyl) -1-3- (11-cyano-6,11-dihydrodibenz (b, e) oxepin-11-yl) propyl] piperidin-4-ol.

Following the procedure of Example 1, but substituting 5,1-dihydrodibenz [b, e] oxepin-11-carbonitrile with 5H-dibenzo [a, d] cycloheptene-5-carbonitrile, the title compound was prepared. 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- (11-Cyano-6,11-dihydro dibenz [b, e] oxepin-11-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. 1 H-NMR (CDCl 3) 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-6,11-dihydro-2-fluorodibenz [b, e] oxepin-11-yl) propyl] piperidin-4-ol .

Following the procedure of Example 1, but replacing 5H-dibenzo [a, d] cycloheptene-5-carbonitrile with 6,11-dihydro-2-fluorodibenz [b, e] oxepin-11-carbonitriyl, the compound of Title.

^ -RN (CDCI3) 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-carbonitrile with 2-bromo-6,11-dihydrodibenz [b, e] oxepin-11-carbonitriyl, the compound of Title.

XH-NMR (CDCl 3) 5: 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: Pration of 4- (4-Chlorophenyl) -1- [3- (11-cyano-6,11-dihydro-2-methyldibenz [b, e] oxepin-11-yl) propyl] piperidin-4-ol . Following the procedure of example 1, but substituting 5,1-dihydro-2-methyldibenz [b, e] oxepin-11-carbonitriyl for 5H-dibenzo [a, d] cycloheptene-5-carbonitrile, the Title. 1 H-NMR (CDCl 3) 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 (lH, m). MS m / z: 487 (M + 1).

Example 8 - Pration of 4- (4-chlorophenyl) -1- [3- (11-cyano-3,4-dichloro-6,11-dihydro-dibenz [b, e] oxepin-11-yl) propyl] piperidin -4-ol.

Following the procedure of example 1, but substituting 5, 4-dibenzo [a, d] cycloheptene-5-carbonitrile with 3,4-dichloro-6,1, -dihydrodibenz [b, e] oxepin-11-carbo-nitrile, the composed of the title. 1 H-NMR (CDC13) d: 1.40-1.71 (5H, m), 2.00-2.10 (2H, m), 2.28-2.50 (5H,), 2.65- 2.85 (3H, m), 5.04 (1H, d), 5.46 (1H, d), 6.99-7.03 (lH, m), 7.26-7.44 (7H, m); 7.91-7.95 (2H, m). MS m / z: 541 (M + 1).

Example 9 - Pration of 4- (4-chlorophenyl) -1- [3- (11-cyano-6,11-dihydro-2,3-methylenedioxydibenz [b, e] oxepin-11-yl) propyl] piperidin-4 -o1 Following the procedure of Example 1, but substituting 5,1-dihydro-2,3-methylenedioxydibenz [b, e] oxepin-11-carbonitrile, 5H-dibenzo [a, d] cycloheptene-5-carbonitrile, the compound of Title. 1 H-NMR (CDC13) 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, brd), 6.68 (1H, s), 6 , 97-7.01 (lH, m), 7.26-7.43 (7H, m), 7.83-7.87 (2H, m), MS m / z: 517 (M + l).

Example 10 - Pration of 4- (4-chlorophenyl) -1- [3- (11-cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) propyl] piperidin-4-ol.

Following the procedure of Example 1, but substituting 5,1-dihydrodibenzo [b, e] thiepin-11-carbonitrile for 5H-dibenzo [a, d] cycloheptene-5-carbonitrile, the title compound was pred.

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 - Pration of 1- [3- (11-Cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) propyl] -4-phenylpiperidin-4-ol. Following the procedure of Example 10, but substituting 4- (4-chlorophenyl) -4-hydroxypiperidine with 4-hydroxy-4-phenylpiperidine, the title compound was pred. * H-NMR (CDCl 3) 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 - Pration of 4- (4-Bromophenyl) -1- [3- (11-cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) propyl] piperidin-4-ol.

Following the procedure of Example 10, but replacing 4- [4-chlorophenyl) -4-hydroxypiperidine with 4- (4-bromophenyl) -4-hydroxypiperidine, the title compound was pred.

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 - Pration of 1- [3- (2-Bromo-11-cyano-6,11-dihydrodibenzo [b, e] thiepin-1-yl) propyl] -4- (4-chlorophenyl) piperidin-4-ol .

Following the procedure of example 1, but replacing 5H-dibenzo [a, d] cycloheptene-5-carbonitrile with 2-bromo-6,11-dihydrodibenzo [b, e] thiepin-11-carbonitriyl, the compound of Title. H-NMR (CDCl 3) d: 1.63-1.78 (5H, m), 2.03-2.14 (2H, m), 2.35-2.52 (4H, m), 2.72. -2.80 (3H, m), 3.00-3.10 (1H, m), 4.15 (1H, brd), 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, 15 - Preparation of 4- (4-Chlorophenyl) -1- [3- (11-cyano-6,11-dihydro-5-oxo dibenzo [b, e] thiepin-11-yl) propyl] piperidin-4 -ol. Following the procedure of example 1, but substituting 5,1-dihydro-5-oxo-dibenzo [b, e] thiepin-11-carbonitrile for 5H-dibenzo [a, d] cycloheptene-5-carbonitrile, the title compound was prepared . The diastereomers were separated by silica gel chromatography. Isomer 1 ? -NRM, (CDCl3) 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.

XH-NMR (CDCl 3) 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- - ol.

Following the procedure of Example 1, but substituting 5,1-dihydro-5,5-dioxodibenzo [b, e] thiepin-11-carbo-nitrile for 5H-dibenzo [a, d] cycloheptene-5-carbonitrile, the composed of the title.

XH-NMR (CDCl 3) 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-11-yl) propyl] piperidin-4-ol.

It was added to a solution of 4- (4-chlorophenyl) -1- [3- (11-cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl-propyl] piperidin-4-ol (430 mg ) in THF (10 ml) the 1M lithium aluminum hydride solution in THF (1.5 ml) and the mixture was heated to reflux for 3 hours, the reaction mixture was cooled with ice, water (0.06 ml). ), then 15% aqueous sodium hydroxide (0.06 ml) was added cautiously, then water (0.18 ml) The granular salt was removed by filtration and the filtrate was concentrated by distillation under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate-hexane (1: 1) to obtain the title compound (280 mg).

XH-NMR (CDCl 3) 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, brs), 4.48 (1H, brt), 4.68 (1H, brs), 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] cycloheptene-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] cycloheptene-5-yl) propyl] piperidin-4-ol, prepared the title compound.

XH-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,), 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-y1) propyl] piperidin-4-o1. 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 (-chloro nyl) -1- [3- (11-cyano-6,11-dihydrodibenz [b, e] oxepin-11-yl) propyl] piperidin-4-ol, the title compound was prepared .

XH-NMR (CDCl 3) d: 1.36-1.49 (2H, m), 1.58-1.67 (2H, m), 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 20 - Preparation of 4- (4-Chlorophenyl) -1- [3- (6,11-dihydro-11-iminodibenzo [b, e] thiepin-11-yl) propyl] piperidin-4-ol.

It was added to a solution of 4- (4-chlorophenyl) -1- [3- (11-cyano-6,11-dihydrodibenzo [b, e] thiepin-11-yl) propyl] piperidin-4-ol (1, 92 g) in dichloromethane (30 ml) at -78 ° C a dichloromethane solution of 1 M diisobutyl aluminum hydride (10 ml). The reaction mixture was warmed to room temperature, 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 removed by distillation under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate to obtain the title compound (1.16g).

XH-NMR (CDCl 3) d: 1.65-1.80 (5H, m), 2.02-2.18 (2H, m), 2.45-2.60 (6H,), 2.78- 2.86 (2H, m), 3.82 (1H, d), 4.25 (1H, d), 7.05-7.45 (12H, m), 8.28 (1H, brs). MS m / z: 491 (M + 1).

Example 21 - Preparation of 4- f4-Chlorophenyl) -1- [3- (11-aminomethyl-6,11-dihydrodibenzo [b, e] thiepin-1-yl) propyl] piperidin-4-ol.

Sodium borohydride (220 mg) was added to a solution of 4- (4-chlorophenyl) -1- [3- (6,11-dihydro-ll-iminodibenzo [b, e] thiepin-11-yl) propyl] piperidin -4-ol (600 mg) in methanol (15 ml) and the mixture was stirred at room temperature within 10 hours. The solvent was removed by distillation 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 removed by distillation under reduced pressure to obtain the title compound (600 mg). MS m / z: 493 (M + 1).

Example 22 - Preparation of Phenyl N- [2- [3- [4- (4-chlorophenyl) -4-hydroxypiperidino] propyl] -2- (6,11-dihydro-dibenzo [b, e] tiepin-11-il ) ethyl] carbamate. They were added to a solution of 4- (4-chlorophenyl) -1- [3- (ll-aminomethyl-6,11-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) 0 ° C, and the mixture was stirred in the course of 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, and washed with aqueous sodium chloride, and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography 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, brs), 6.96-7.54 (17H, m). MS m / z: 613 (M + 1).

Example 23 - Preparation of 1- [2- f 3- [4- (4-chlorophenyl) -4-hydroxypiperidino] propyl] -2- (6,11-dihydrodibenzo [b, e] tiepin-11-yl) ethyl] -3- (hydroxypropyl) urea.

They were added to a solution of phenyl N- [2- [3- [4- (4-chlorophenyl) -4-hydroxypiperidino] propyl] -2- (6,11-dihydro-dibenzo [b, e] tiepin-11- il] ethyl] carbamate (300 mg) in DMF (10 ml) 3-amino-1-propanol (70 mg), potassium carbonate (130 mg) and the mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. chromatography on silica gel eluting with ethyl acetate-methanol (9: 1) to obtain the title compound (200 mg). 2H-NMR (CDC13): d: 1.40-1.70 (6H, m), 2.01-2.08 (2H, m), 2.30-2.63 (8H, m), 3, 12 (2H, q), 3.42 (2H, t), 4.00-4.12 (2H, m), 4.22-4.28 (2H, m), 4.82 (1H, brt) , 4.99 (1H, brs), 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] cycloheptene-5-yl) -3-propioyl] piperidin-4-ol.

To a solution of 10, 11-dihydro-5H-dibenzo [a, d] cycloheptene-5-carbonitrile (500 mg) in THF (5 ml) was added a solution of 1.6 M n-butyl lithium hexane (1.8 mM). ml) at 0 ° C. The mixture was warmed to room temperature, and stirred for 20 minutes. To the cooled reaction mixture was added at 0 ° C ethyl 3- (4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl) propionate (310 mg), dropwise, as a solution in THF, and heated The mixture was stirred at 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 magnesium sulfate was dried over. The solvent was removed by distillation 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 (CDCU 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), 7.10-7.31 (12H, m). MS m / z: 460 (M + l) Examples 28-59 can be prepared by the methods indicated in the schemes in Figures 1-3 and the procedures described above.

Example 60 Membrane Preparations for Chemokine Union and Union Assays.

Membranes were prepared from THP-1 cells (ATCC # TIB202). The cells were harvested by centrifugation, washed twice with PBS (phosphate-buffered saline), and the cell pellets were frozen at -70 to -85 ° C. Frozen granule was thawed in cold ice lysis buffer, which consisted of 5 mM HEPES (N-2-hydroxy-ethylpiperazine-N'-2-ethane sulfonic acid), pH 7.5, 2 mM EDTA (ethylenediaminetetraacetic acid) ), 5 μg / ml of each aprotinin, leupeptin, and chemostatin (protease inhibitors), and 100 μg / ml of PMSF (phenyl methane sulfonyl fluoride - also a protease inhibitor), at a concentration of 1 to 5 x 107 cells / ml). This procedure resulted in cell lysis. The suspension was mixed well until re-suspending the entire frozen cell pellet. The remains of nuclei and cells were removed by centrifugation of 400 x g in the course of 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 over the course of 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 of each aprotinin, leupeptin, and chemostatin, and 10 μg / ml of PMSF (approximately 0.1 ml per 108 cells). All lumps were re-dissolved using a mini-homogenizer, and the total protein concentration was determined using a protein assay kit (Bio-Rad, Hercules, CA, cat # 500-0002). An aliquot of the membrane solution was then taken and frozen at -70 to -85 ° C until needed.

The Binding Assays used the membranes described above. The membrane protein (from 2 to 20 μg of total membrane protein) was incubated with RANTES 125I-labeled or MlP-la 0.1 to 0.2 nM, with or without unlabeled competitor (RANTES or MlP-la) or various concentrations of compounds. The binding reactions were performed in 50 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), in the course of 60 minutes 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-impregnated in 0.3% polyethyleneimine. The filters were rinsed with approximately 600 μl of binding buffer containing 0.5 M NaCl, dried and the amount of radioactivity adhered per scintillation counter was determined in a Topcount beta-plate counter. The activities of the test compounds are indicated in the following Table as IC50 values or the concentration of inhibitor required for 50% inhibition of specific binding in receptor binding assays using -AIR NTES or 125MIP-A as ligand and cell membranes. THP-1. The specific binding is defined as the total union minus the non-specific binding; the non-specific binding is the amount of cpm detected still in the presence of Rantes not labeled in excess or 125MPI-la.

Table BIOLOGICAL DATA Example IC50 ((μM) 1 0.088 2 0.052 3 0, 11 4 0.39 5 0.19 6 0.30 7 0.38 10 0.097 11 11 12 0.099 13 0.38 14 0.28 15 0, 61 16 0.079 17 0.070 18 0.055 19 0.059 22 0.69 23 2.2 24 0.16 25 0.13 26 0.61 27 0.48 Those skilled in the art will be able to recognize, or determine, using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is intended that such equivalents be within the scope of the following claims.

Claims (43)

1. CLAIMS 1. A method of treating a disease associated with aberrant leukocyte recruitment and / or activation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by the following structural formula: and their physiologically acceptable salts, wherein: Y is a covalent bond, -O- or -C0-; n is an integer from one to five; X is a covalent bond or -CO-; M is > NR2 or > CR? R2; Ri is -H, -OH, an aliphatic group, -O- (aliphatic group), -SH or -S- (aliphatic group); R2 is 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; Z is represented by the following structural formula: wherein Ring C is a substituted or unsubstituted C6 to C8 non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring and is linked to the remainder of the molecule by a single covalent bond between Y and a carbon atom in Ring C; and Ring A and Ring B are each, independently, substituted or unsubstituted.
2. 2. The method of claim 1, wherein X is a covalent bond and Y is an individual covalent bond between a carbon atom in Ring C and fraction (CH2) n.
3. 3. The method of claim 2, wherein Z is represented by a structural formula selected from: wherein: Xi is -S-, -CH2- or -CH2S-; and W is -H or an electron removal group.
4. 4. The method of claim 3, wherein Z is represented by the following structural formula:
5. 5. The method of claim 4, wherein W is -H or CN.
6. 6. The method of claim 5, wherein Ri is OH.
7. The method of claim 6, wherein M is > C (0H) R2 and n is three.
8. The method of claim 7, wherein R2 is a substituted or unsubstituted aromatic group.
9. 9. The method of claim 1, wherein X is a covalent bond and Y is -CO-.
10. The method of claim 2, wherein Z is represented by a structural formula selected from: wherein: Xi is -S-, -CH.2- or -CH2S-; W is -H, -CN, alkylsulfonyl, carboxamide or carboxyalkyl; Ring A is substituted with Rs and Rg; R8 and Rg are each, independently, -H, a halogen, alkoxy or alkyl, or R8 and Rg, taken together with Ring A, form a naphthyl group; n is an integer of 2-5; M is > N (alkanoyl), > N (aroyl), > N (aralcoyl), > N (alkyl), N > (aralkyl), N > (cycloalkyl), > C (OH) (aryl) or > CH (heteioaryl).
11. 11. The method of claim 1, wherein the compound is represented by a structural formula selected from:
12. 12. The method of claim 2, wherein Z is represented by a structural formula selected from: wherein Rings A, B, C are each, independently, substituted and not substituted.
13. The method of claim 1, wherein Z is: wherein V is -H, an electron removal group, -CH2-NRUR12, -C ^ -OR11, -CH2-NH-CO-NR11R12 or -CH2-0-CO-NRnR12; R11 and R12 are each, independently, -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, -NHC (0) -0- (aliphatic group), -NHC (0) -0 - (aromatic 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.
14. A method of treating a disease associated with aberrant leukocyte recruitment and / or activation, which comprises administering to a subject in need thereof a therapeutically-effective amount of a compound represented by the following structural formula: and its physiologically acceptable salts, wherein: Y is a covalent bond, -0- and -C0- n is an integer from 1 to 5; X is a covalent bond or -C0-; M is > NR2 or > CR? R2; Ri is -H, -OH, an aliphatic group -0- (aliphatic group), SH- or -S- (aliphatic group); R2 is 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; Z is represented by the following structural formula: wherein Ring A is a carbocyclic aromatic ring or a heteroaromatic ring, Ring B is a heteroaromatic ring and each ring in Z is substituted or unsubstituted, independently; Wb is -H, -CN, -CH2-NR11R12 / -CH2-OR, 11, -CH2-NH-CO-NRnR12 or -CH2-0-C0-NRnR12; R 11 and R each, independently, -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, -NHC (0) -O- (aliphatic group), NHC (O) -0 - (aromatic group) or R11 and R12 taken together with the nitrogen atom to which they are attached form an aromatic heterocyclic ring.
15. 15. A compound represented by the following structural formula: and their physiologically acceptable salts, wherein: Y is a covalent bond or -C (0) -; X is a covalent bond; M is > NR2 or > CR? R2; Ri is -H, -OH, an aliphatic group, -O- (aliphatic group), -SH or -S- (aliphatic group); R2 is 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; n is an integer from one to five; Z is represented by the following structural formula: W is -H, -CN, alkylsulfonyl, carboxamido or carboxyalkyl; and Ring A is substituted with R8 and R9, where: R8 and R9 are each, independently, a halogen, alkoxy or alkyl, or R8 and Rg, taken together with Ring A, form a naphthyl group.
16. 16. The compound of claim 15, wherein Y is a covalent bond.
17. 17. The compound of claim 16, wherein M is > N (alkanoyl), > (aroyl), > N (aralcoyl), > (alkyl), > (aralkyl), > (cycloalkyl), > C (OH) (aryl) or > CH (heteroaryl).
18. 18. A compound represented by the following structural formula: and their physiologically acceptable salts, wherein: y is a covalent bond or -C (O) -; n is an integer from one to five; X is a covalent bond; M is > NR2 or > CR? R2; Ri is -H, -OH, an aliphatic group, -O- (aliphatic group), -SH or -S- (aliphatic group); R2 is 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; Z is represented by the following structural formula: wherein Ring A is an aromatic carboxylic ring or a heteroaromatic ring, Ring B is a heteroaromatic ring and each ring in Z is independently substituted or unsubstituted; Wb is -H, -CN, CH2-NRR12, CH2-ORn, -CH2-NH-C0- NRnR12 or -CH2-0-CO-NRX1R12; R11 and R12 are each, independently, -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, -MHC (0) -O- (aliphatic group), -NHC (O) -O - (aromatic group) or R11 and R12 taken together with the nitrogen atom to which they are attached form a non-aromatic heterocyclic ring.
19. 19. The compound of claim 18, wherein Y is a covalent bond.
20. 20. Use of a compound for the manufacture of a medicament for the treatment or prevention of a disease in a subject, said disease being associated with aberrant recruitment and / or activation of leukocytes, and said compound being represented by the following structural formula: and their physiologically acceptable salts, wherein: Y is a covalent bond -O- or -CO-; n is an integer from one to five; X is a covalent bond or -CO-; M is > NR2 or > CR? R2; Ri is -H, -OH, an aliphatic group, -O- (aliphatic group), -SH or -S- (aliphatic group); R2 is 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; Z is represented by the following structural formula: wherein Ring A is a carbocyclic aromatic ring or a heteroaromatic ring, Ring B is a heteroaromatic ring and each ring in Z is substituted or unsubstituted, independently; Wb is -H, -CN, -CH2-NRnR12, -CH ^ OR11, -CHz-NH-CO-NR ^ R12 -CHz-O-CO-NR ^ R12; R > 1i1 and R122 are each, independently, -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, -NHC (0) -0- (aliphatic group), NHC (O) - O- (aromatic group) or R11 and R12 taken together with the nitrogen atom to which they are attached form an aromatic heterocyclic ring.
21. The use of claim 20, wherein X and Y are each a covalent bond
22. 22. A compound represented by the following structural formula and their physiologically acceptable salts, wherein: Y is a covalent bond or -C (0) -; X is a covalent bond; M is > NR2 or > CRXR2; Ri is -H, -OH, an aliphatic group, -O- (aliphatic group), -SH or -S- (aliphatic group); R2 is 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; n is an integer from one to five; Z is wherein V is -H, an electron removal group, CH2-NRnR12, CH2-ORn, -CH2-NH-CO-NR ^ R12 or -CH2-0-CO-NR1: LR12; R11 and R12 are each, independently, -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, -NHC (O) -O- (aliphatic group), -NHC (O) -O - (aromatic group) or Rn 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 substituted or unsubstituted, independently.
23. 23. The compound of claim 22, wherein Y is a covalent bond.
24. 24. The compound of claim 23, wherein W is CN.
25. 25. The compound of claim 24, wherein Ri is OH.
26. 26. The compound of claim 25, wherein M is > C (OH) R2 and n is three.
27. 27. The compound of claim 26, wherein R2 is a substituted or unsubstituted aromatic group.
28. 28. The compound of claim 22, wherein Ring A is substituted with R8 and Rg, wherein: R8 and R9 are, independently, a halogen, alkoxy or alkyl, or, taken together with Ring A, form a naphthyl group.
29. 29. The compound of claim 28, wherein M is > N (alkanoyl), > N (aroyl), > N (aralcoyl), > N (alkyl), > N (aralkyl), > (cycloalkyl), > C (OH) (aryl) or > CH (heteroaryl).
30. 30. Use of a compound for the manufacture of a medicament for the treatment or prevention of a disease in a subject, said disease being associated with aberrant recruitment and / or activation of leukocytes, and said compound being represented by the following structural formula: and their physiologically acceptable salts, wherein: Y is a covalent bond, -O- or -C (O) -; X is a covalent bond or -C (O) -; M is > NR2 or > CR? R2; Ri is -H, -OH, an aliphatic group, -O- (aliphatic group), -SH or -S- (aliphatic group); R2 is 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; n is an integer from one to five; Z is wherein V is -H, an electron removal group, -CH2-NR11R12, -CH2-OR11, -CH2-NH-CO-NRnR12 or -CH2-0-CO-NR1: LR12; R 11 and R are each, independently, -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, -NHC (O) -O- (aliphatic group), NHC (0) -0 - (aromatic 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 substituted or unsubstituted, independently.
31. 31. The use of claim 30, wherein X and Y are each a covalent bond.
32. 32. Use of a compound for the manufacture of a medicament for the treatment or prevention of a disease in a subject, said disease being associated with aberrant recruitment and / or activation of leukocytes, and said compound being represented by the following structural formula: and their physiologically acceptable salts, wherein: Y is a covalent bond, -O- or -CO-; n is an integer from one to five; X is a covalent bond or -CO-; M is > NR2 or > CR? R2; Ri is -H, -OH, an aliphatic group, -O- (aliphatic group), -SH or -S- (aliphatic group); R2 is 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; Z is represented by the following structural formula: wherein Ring C is a substituted or unsubstituted C6 to C8 non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring and is attached to the remainder of the molecule by a single covalent bond between Y and a carbon atom in Ring C; and Ring A and Ring B are each, independently, substituted or unsubstituted.
33. 33. The use of claim 32, wherein X is a covalent bond and Y is an individual covalent bond between a carbon atom in Ring C and fraction (CH2) 2.
34. 34. The use of claim 33, wherein Z is represented by a structural formula selected from: wherein: Xi is -S-, -CH2- or -CH2S-; and W is -H or an electron removal group.
35. 35. The use of claim 32, wherein Z is represented by a structural formula selected from: wherein: Xi is -S-, -CH.2- or -CH2S-; W is -H, -CN, alkylsulfonyl, carboxamido or carboxyalkyl; Ring A is substituted with R8 and Rg; R8 and Rg are each, independently, -H, a halogen, alkoxy or alkyl, or R8 and Rg, taken together with Ring A, form a naphthyl group; n is an integer of 2-5; M is > N (alkanoyl), > N (aroyl), > N (aralcoyl), > N (alkyl), > N (aralkyl), > N (cycloalkyl), > C (OH) (aryl) or > CH (heteroaryl).
36. 36. The use of claim 32, wherein the compound is represented by a structural formula selected from:
37. 37. The use of claim 32, wherein Z is represented by a structural formula selected from: wherein Rings A, B and C are each, independently, substituted or unsubstituted.
38. 38. Use of a compound for the manufacture of a medicament for the treatment or prevention of a disease associated with the aberrant recruitment and / or activation of leukocytes in a subject, this arthritis disease being selected, psoriasis, multiple sclerosis, ulcerative colitis , Crohn's disease, allergies, asthma, AIDS-associated encephalitis, AIDS-related maculopapular skin rash, AIDS-related interstitial pneumonia, AIDS-related enteropathy, AIDS-related periportal hepatic inflammation, and AIDS-related glomerulus nephritis, and said compound being represented by the following structural formula: and their physiologically acceptable salts, wherein: Y is a covalent bond, -O- or -CO-; n is an integer from one to five; X is a covalent bond or -CO-; M is > NR2 or > CR? R2; Ri is -H, -OH, an aliphatic group, -O- (aliphatic group), -SH or -S- (aliphatic group); R2 is 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; Z is represented by the following structural formula: wherein Ring C is a non-aromatic substituted or unsubstituted C8-substituted carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring and is attached to the remainder of the molecule by a single covalent bond between Y and a carbon atom in Ring C; and Ring A and Ring B are each, independently, substituted or unsubstituted.
39. 39. The use of claim 38, wherein X is a covalent bond and Y is a single covalent bond between a carbon atom in Ring C and fraction (CH2) n-
40. 40. The use of claim 39, wherein Z It is represented by a structural formula selected from: wherein: Xi is -S-, -CH2- or -CH2S-; and W is -H or an electron removal group,
41. 41. The use of claim 39, wherein Z is represented by a structural formula selected from: wherein: Xi is -S-, -CH2- or -CH2S-; W is -H, -CN, alkylsulfonyl, carboxamido or carboxyalkyl; ring A is substituted with R8 and Rg; R8 and Rg are each, independently, -H, a halogen, alkoxy or alkyl, or R8 and Rg, taken together with Ring A, form a naphthyl group; n is an integer of 2-5; M is > (alkanoyl), > N (aroyl), > N (aralcoyl), > N (alkyl), > N (aralkyl), > N (cycloalkyl), > C (OH) (aryl) or > CH (heteroaryl).
42. 42. The use of claim 38, wherein the compound is represented by a structural formula selected from:
43. 43. The use of claim 38, wherein Z is represented by a structural formula selected from: wherein the rings A, B and C are each, independently, substituted or unsubstituted. ANTAGONISTS OF CHEMICALS RECEPTORS