EP1204664A1 - 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 (1) or Z-Y-(CH2)n -X-NR50R5 and physiologically acceptable salts thereof.

Description

CHEMOKINE RECEPTOR ANTAGONISTS AND METHODS OF USE THEREFOR

RELATED APPLICATION

This application is a continuation-in-part of U.S. Serial No. 09/363.099, filed July 29, 1999, which is a continuation-in-part of U.S. Serial No. 09/362,836, filed July 28, 1999, which is a continuation-in-part of U.S. Serial No. 09/235,100, filed January 21, 1999, which is a continuation-in-part of U.S. Serial No. 09/146,827, filed September 4, 1998; the entire teachings of each of the above-referenced applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Chemoattractant cyto ines or chemokines are a family of proinflammatory mediators that promote recruitment and activation of multiple lineages of leukocytes and lymphocytes . They can be released by many kinds of tissue cells after activation. Continuous release of chemokines at sites of inflammation mediates the ongoing migration of effector cells in chronic inflammation. The chemokines characterized to date are related in primary structure. They share four conserved cysteines, which form disulfide bonds. Based upon this conserved cysteine motif, the family is divided into two main branches, designated as the C-X-C chemokines

(α-chemokines) , and the C-C chemokines (β-chemokines) , in which the first two conserved cysteines are separated by an intervening residue, or adjacent respectively (Baggiolini, M. and Dahinden, C. A., Immunology Today, 15:127-133 (1994) ) .

The C-X-C chemokines include a number of potent chemoattractants and activators of neutrophils, such as interleukin 8 (IL-8) , PF4 and neutrophil-activating peptide-2 (NAP-2) . The C-C chemokines include RANTES (Regulated on Activation, Normal T Expressed and Secreted) , the macrophage inflammatory proteins l and lβ(MIP-l and MIP-lβ) , 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-lα, have been implicated in a wide range of human acute and chronic inflammatory diseases including respiratory diseases, such as asthma and allergic disorders.

The chemokine receptors are members of a super amily of G protein-coupled receptors (GPCR) which share structural features that reflect a common mechanism of action of signal transduction (Gerard, C. and Gerard, N.P., Annu Rev. Immunol . , 12:775-808 (1994); Gerard, C. and Gerard, N. P., Curr. Opin . Immunol . , 6: 140-145

(1994)) . Conserved features include seven hydrophobic domains spanning the plasma membrane, which are connected by hydrophilic extracellular and intracellular loops. The majority of the primary sequence homology occurs in the hydrophobic transmembrane regions with the hydrophilic regions being more diverse. The first receptor for the C-C chemokines that was cloned and expressed binds the chemokines MlP-lα and RANTES.

Accordingly, this MIP-l /RANTES receptor was designated C-C 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 . , 177:1421-1427 (1993)). Three receptors have been characterized which bind and/or signal in response to RANTES: CCR3 mediates binding and signaling of chemokines including eotaxin, RANTES, and MCP-3 (Ponath et al., J^". Exp . Med . , 183:2437 (1996)), CCR4 binds chemokines including RANTES, MlP-lα, and MCP-1 (Power, et al., J. Biol . Che . , 270:19495 (1995)), and CCR5 binds chemokines including MlP-lα, 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 receptors CCR1 , CCR4 and CCR5 will show some selectivity in receptor distribution and function between leukocyte types, as has already been shown for CCR3 (Ponath et al . ) . In particular, the ability of

RANTES to induce the directed migration of monocytes and a memory population of circulating T-cells (Schall, T. et al., Nature, 347:669-71 (1990)) suggests this chemokine and its receptor (s) may 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. No successful antagonists have yet been developed to the receptors for the larger proteins such as chemokines and C5a. Small molecule antagonists of the interaction between C-C chemokine receptors and their ligands, including RANTES and MlP-lα, would provide compounds useful for inhibiting harmful inflammatory processes "triggered" by receptor ligand interaction, as well as valuable tools for the investigation of receptor-ligand interactions.

SUMMARY OF THE INVENTION

It has now been found that a class of small organic molecules are antagonists of chemokine receptor function and can inhibit leukocyte activation and/or recruitment. An antagonist of chemokine receptor function is a molecule which can inhibit the binding and/or activation of one or more chemokines, including C-C chemokines such as RANTES and/or MlP-lα, 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 with 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 disclosed as well as a method of treating a disease mediated by chemokine receptor function. The method comprises administering to the subject a therapeutically effective amount of a compound or small organic molecule which is an antagonist of chemokine receptor function. Compounds or small organic molecules which have been identified as antagonists of chemokine receptor function are discussed in detail herein below, and can be used for the manufacture of a medicament for treating or for preventing a disease associated with aberrant leukocyte recruitment and/or activation. The invention also relates to the disclosed compounds and small organic molecules for use in treating or preventing a disease associated with aberrant leukocyte recruitment and/or activation. The invention also includes pharmaceutical compositions comprising one or more of the compounds or small organic molecules which have been identified herein as antagonists of chemokine function and a suitable pharmaceutical carrier. The invention further relates to novel compounds which can be used to treat an individual with a disease associated with aberrant leukocyte recruitment and/or activation and methods for their preparation.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a schematic showing the preparation of the compounds represented by Structural Formula (I), ( I I I ) and ( IV) .

Figure 2 is a schematic showing the preparation of representative compounds of Structural Formula (I) , (III) and (IV) wherein Z is represented by Structural Formulas (VIII) and wherein Ring A and/or Ring B in Z can be substituted with - (O) _u- (CH₂) _t-COOR²⁰,

- (0) _u- (CH₂) _t-OC (O) R²⁰- , (0) _u- (CH₂) _t-C (0) -NR²¹R²² or

- (0)_u- (CH₂)_t-NHC(0)0-R²⁰.

Figure 3 is a schematic showing the preparation of the compounds represented by Structural Formula (I) ,

(III) and (IV) , wherein Z is represented by Structural Formula (VIII) .

Figure 4 is a schematic showing the preparation of compounds represented by Structural Formulas (I) , (III) and (IV) , wherein Z is represented by Structural Formula (VIII), wherein W is H.

Figure 5 is a schematic showing the preparation of compounds represented by Structural Formulas (I) , (III) and (IV) , wherein Z is represented by Structural Formula (VIII), wherein W is H.

Figure 6 shows the preparation of compounds represented by Structural Formula (I), where in Z is represented by Structural Formulas (VIII) and wherein Ring A and/or Ring B in Z is substituted with -(0)_u-(CH₂)_t-COOR²⁰, u is one.

Figure 7 shows the preparation of compounds represented by Structural Formula (I), wherein Z is represented by Structural Formulas (VIII) and wherein Ring A or Ring B in Z is substituted with -(0)_u- (CH₂)_t-COOR²⁰, u is zero.

Figure 8A is a schematic showing the preparation of 4- (4-chlorophenyl) -4-fluoropiperidine .

Figure 8B is a schematic showing the preparation of 4-4-azido-4- (4-chlorophenyl) piperidine . Figure 8C is a schematic showing the preparation of 4- (4-chlorophenyl) -4-methylpiperidine .

Figure 9A is a schematic showing the preparation of compounds represented by Structural Formulas (I), (VIII) and (VIII) wherein R¹ is an amine.

Figure 9B is a schematic showing the preparation of compounds represented by Structural Formulas (I), (VIII) and (VIII) wherein R¹ is an alkylamine.

Figure 9C is a schematic showing the preparation of 2- (4-chlorophenyl) -1- ( N-methyl ) ethylamine.

Figure 9D is a schematic showing the preparation of 3- (4-chlorophenyl) -3-chloro-l-hydroxypropane .

Figure 9E is a schematic showing the preparation of 3- (4-chlorophenyl) -1-N-methylaminopropane . Figure 10A is a schematic showing the preparation of 3- (4-chlorophenyl) -3-hydroxyl-3-methyl-l-N- methylaminopropane .

Figure 10B is a schematic showing the preparation of 1- (4-chlorobenzoyl) -1, 3-propylenediamine . Figure IOC is a schematic showing three procedures for the preparation of compounds represented by Structural Formulas (I), (XVII), (XVIII), (XIX) and (XX) wherein Z is represented by Structural Formulas (VIII)- (X) , (Xa) , (Xb) or (Xc) and wherein Ring A or Ring B in Z is substituted with R^40, In Figure IOC, R⁴⁰ is represented by - (0)_u- (CH₂) _t-C(0) -ΝR²¹R²², u is one, t is zero.

Figure 10D is a schematic showing the preparation of 4- (4-chlorophenyl) -4-pyridine.

Figures 11A-11K show the structures of exemplary compounds of the present invention.

Figure 12 is a schematic showing the preparation of compounds of formula (XV-b) .

Figure 13 is a schematic showing the preparation of compounds of formula (XV-c) . Figure 14 is a schematic showing the preparation of compounds of formula (XV-e) .

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to small molecule compounds which are modulators of chemokine receptor function. In a preferred embodiment, the small molecule compounds are antagonists of chemokine receptor function. Accordingly, processes or cellular responses mediated by the binding of a chemokine to a receptor can be inhibited (reduced or prevented, in whole or in part) , including leukocyte migration, integrin activation, transient increases in the concentration of intracellular free calcium [Ca⁺⁺]i, and/or granule release of proinflammatory mediators . The invention further relates to a method of treatment, including prophylactic and therapeutic treatments, of a disease associated with aberrant leukocyte recruitment and/or activation or mediated by chemokines or chemokine receptor function, including chronic inflammatory disorders characterized by the presence of RANTES, MlP-lα, MCP-2, MCP-3 and/or MCP-4 responsive T cells, monocytes and/or eosinophils, including but not limited to diseases such as arthritis (e.g., rheumatoid arthritis), atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfusion injury, diabetes mellitus (e.g., type 1 diabetes mellitus) , psoriasis, multiple sclerosis, inflammatory bowel diseases such as ulcerative colitis and Crohn ' s disease, rejection of transplanted organs and tissues (i.e., acute allograft rejection, chronic allograft rejection) , graft versus host disease, as well as allergies and asthma. Other diseases associated with aberrant leukocyte recruitment and/or activation which can be treated (including prophylactic treatments) with the methods disclosed herein are inflammatory diseases associated with Human Immunodeficiency Virus (HIV) infection, e.g., AIDS associated encephalitis, AIDS related maculopapular skin eruption, AIDS related interstitial pneumonia, AIDS related enteropathy, AIDS related periportal hepatic inflammation and AIDS related glomerulo nephritis. The method comprises administering to the subject in need of treatment an effective amount of a compound (i.e., one or more compounds) which inhibits chemokine receptor function, inhibits the binding of a chemokine to leukocytes and/or other cell types, and/or which inhibits leukocyte migration to, and/or activation at, 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, chemokine-mediated chemotaxis and/or activation of pro-inflammatory cells bearing receptors for chemokines can be inhibited. As used herein, "pro-inflammatory cells" includes but is not limited to leukocytes, since chemokine receptors can be expressed on other cell types, such as neurons and epithelial cells.

While not wishing to be bound by any particular theory or mechanism, it is believed that compounds of the invention are antagonists of the chemokine receptor CCR1 , and that therapeutic benefits derived from the method of the invention are the result of antagonism of CCR1 function. Thus, the method and compounds of the invention can be used to treat a medical condition involving cells which express CCR1 on their surface and which respond to signals transduced through CCR1 , as well as the specific conditions recited above.

In one embodiment, the antagonist of chemokine receptor function is represented by the structural formula (I) : Z L N M

\ /

(I) Z is a cycloalkyl or non-aromatic heterocyclic ring group fused to a pyridine ring and to a carbocyclic aromatic or heteroaromatic ring, wherein each ring in Z is independently substituted or unsubstituted.

L is a C_x-C₁₈ hydrocarbyl group wherein, optionally one or more of the carbon atoms is replaced by a heteroatom such as nitrogen, oxygen or sulfur. M is >NR² or >CR¹R².

R¹ is -H, -OH, -N_3/ a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, -0- (aliphatic group) , -O- (substituted aliphatic group) , -SH, -S- (aliphatic group) , -S- (substituted aliphatic group), -OC (O) - (aliphatic group), -O-C (O) - (substituted aliphatic group), -C (0) O- (aliphatic group), -C (0)0- (substituted aliphatic group), -C00H, -CN, -CO-NR³R⁴, -NR³R⁴; or R¹ can be a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains 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, a substituted non-aromatic heterocyclic group, -0- (substituted or unsubstituted aromatic group) or -0- (substituted or unsubstituted aliphatic 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 non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.

R¹ and R², R³ and R⁴, or R⁵ and R⁶ taken together with the atom to which they are bonded, can alternatively form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.

In a preferred embodiment, L in Structural Formula

(I) is a chemical group represented by Structural Formula

(II) :

Y (CH₂)_n X

(ID Y is a covalent bond, -0-, -CO- or =CH- . n is an integer from one to eighteen, more preferably n is an integer from one to about five, most preferably n is three.

X is a single covalent bond or -CO-, and the antagonist of chemokine receptor function is represented by Structural Formula (III) : (III)

Z and M are as described above for Structural Formula (I) .

Y, n and X are as described above for Structural Formula (II) . In another preferred embodiment, X and Y in

Structural Formula (III) are each a covalent bond and the antagonist of chemokine receptor function is a compound represented by Structural Formula (IV) : / \

(CH₂)_n- ^■N M

\ /

(IV) n is an integer from one to about five. n is preferably three . Z 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 (V) :

(V)

Z, M and n are as described above for Structural Formula (IV) .

In another preferred embodiment, X is a covalent bond, Y is a double bond and the antagonist of chemokine receptor function is a compound represented by Structural formula (VI) :

(VI) Z, M and n are as described above for Structural Formula (IV) . Preferably n is two.

In embodiments where M is >CR¹R² and R¹ is a covalent bond between the carbon atom at M and an adjacent carbon atom in the ring which contains M, the antagonist of chemokine function can be represented by Structural Formulas (IVa) and (Via) .

(IVa) (Via)

Z, n, and R² are as described in Structural Formula (i;

Preferably, Z is a tricyclic ring system comprising a five, six, seven or eight membered cycloalkyl or a non- aromatic heterocyclic ring group fused to a pyridine ring and to a carbocyclic aromatic group or a heteroaryl group. In one example, Z is represented by Structural Formula (VII) :

(VII) The pyridine ring labeled with an "A" , and the phenyl ring labeled with a "B" are herein referred to as "Ring A" and "Ring B" respectively. The central ring labeled with a "C", is herein referred to as "Ring C" and can be, for example, a five, six, seven or eight membered non-aromatic carbocyclic ring (e.g., a cycloheptane or cyclooctane ring) or a non-aromatic heterocyclic ring. When Ring C is a non-aromatic heterocyclic ring, it can contain one or two heteroatoms such as nitrogen, sulfur or oxygen. When Z is represented by Structural Formula (VII) , the tricyclic ring system can be connected to Y in Structural Formula (III) by a single or double covalent bond between Y and a ring atom in Ring C .

Each ring can be unsubstituted or can have one or more substituents . Suitable substituents are as described herein below for substituted aromatic groups. In one example, Ring B is substituted with

- (O) _u- (CH₂) _t-COOR²⁰, - (O) _u- (CH₂) _t-OC (0) R²⁰'

- (0)_u- (CH₂)_t-C(0) -NR²¹R²² or - (0) _u- (CH₂) _t-NHC (O) O-R²⁰. u is zero or one. t is an integer, such as an integer from zero to about three, and the methylene group -(CH₂)_t- can be substituted, as described herein for aliphatic groups, or unsubstituted. R²⁰, R²¹ or R²² 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, R²¹ and R²², taken together with the nitrogen atom to which they are bonded, form a non- aromatic heterocyclic ring. In another example, Ring B is substituted with R⁸ and R⁹, wherein R⁸ and R⁹ are independently -H, a halogen, alkoxy or alkyl, or, taken together with Ring B, form a naphthyl group Ring C optionally contains one or more additional substituents as described herein below. Preferably, Ring C is substituted with an electron withdrawing group or is unsubstituted. Suitable electron withdrawing groups include -CN, -CH=NH, alkylimines, alkylsulfonyl , carboxamido, carboxylic alkyl esters, -N0₂ and halogens (e.g., -Br and -Cl). Alternatively, Ring C is substituted with a group selected from -CH₂-NR¹¹R¹², -CH₂-OR¹¹, -CHs-NH-CO-NR^R¹², -CH₂-0-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 or a non-aromatic heterocyclic group. Alternatively, R¹¹ and R¹², taken together with the nitrogen atom to which they are bonded, form a non- aromatic heterocyclic ring.

Examples of suitable tricyclic ring systems represented by Structural Formula (VII) are provided by Structural Formulas (VIII) - (X) , (Xa) , (Xb) and (Xc) shown below:

Xi is a covalent bond, -S-, -CH 2 ' " CH₂ — CH₂ - , - CH₂ — S - ,

^•S-CH₂-, -0-CH₂-, -CH₂-0-, -NR_C-CH₂-, -CH₂-NR_C -SO-CH 2 '

-CH₂-SO-, -S(0)₂-CH₂-, -CH₂-S(0)₂-, -CH=CH-, -NR_c-CO- or -CO-NR_c-, -0- or a bond. X_x is preferably -CH₂-CH₂-, -CH₂-S- or -CH₂-0-.

R_c is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzylic group or a substituted benzylic group. In one example, R_c is - (CH₂) _s-C00R³⁰, - (CH₂)_s-C(0) -NR³¹R³² or - (CH₂) _S-NHC (0) -O-R³⁰. s is an integer from zero to about 3; and 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. Alternatively, R³¹ and R³², taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring. W is -H, an electron withdrawing group or is selected from -C^-NR^R¹², -CH₂-0R¹¹, -CR^-NH-CO-NR^R¹², -CH₂-0-CO-NR^llR¹² or -CH₂-NHC(0) -0-R¹¹.

R¹¹ and R¹² are as defined above in Structural Formula (VII) . Ring B in Structural Formulas (VIII) - (X) can be unsubstituted or substituted as described in Structural Formula (VII) .

In a preferred embodiment Ring B in Structural Formulas (VIII) - (X) is substituted para to the carbon atom in Ring B which is bonded to X_: in Ring C, and the tricyclic ring system is represented by Structural Formulas (XI) - (XIII) shown below:

(XIII)

X_x and W are as defined above in Structural Formulas (VIII) - (X) .

R⁴⁰ is a substituent as described herein for aromatic groups. In one embodiment, R⁴⁰ is -OH, -COOH, a halogen, -N0₂, an aliphatic group, a substituted aliphatic group, an aromatic group, substituted aromatic group, -NR²R²⁵, -CONR²R²⁵, -C(=NR⁶⁰)NR²¹R²², -Q- (aliphatic group) , -Q- (substituted aliphatic group) , -O- (aliphatic group) , -0- (substituted aliphatic group) , -O- (aromatic group) ,

-0- (substituted aromatic group) , an electron withdrawing group, -(0)_u-(CH₂)_t-C(0)OR²⁰, - (O) _u- (CH₂) _t-0C (0) R²⁰,

- (0 ) _u - ( CH₂ ) _t - C (0) -NR²¹R² or - ( 0 ) _u- ( CH₂ ) _t -NHC (O ) O-R 20

Q ,

R- 20 R' 21 R' 22 R^' 24 ,25 60

R^' u and t are as described herein.

Preferably R⁴⁰ is an aliphatic group, substituted aliphatic group, -O- (aliphatic group) or -O- (substituted aliphatic group) . More preferably R⁴⁰ is an -0-alkyl, such as -0-CH₃, -0-C₂H₅, -0-C₃H₇ or -0-C₄H₉. In this preferred embodiment the antagonist of chemokine receptor function is a compound represented by Structural Formulas (XIV) - (XVI) shown below:

(XVI ;

n is as defined above in Structural Formula (II) . M is as described above in Structural Formula (I) .

X_lf W and R⁴⁰ are as described above in Structural Formulas (XI) - (XIII) . Preferably in Structural Formulas (XIV) -(XVI) X_± is -CH₂-0-, W is -CN, M is >C(OH)R², R⁴⁰ is -0-CH₃ and n is three.

In another embodiment, R⁴⁰ can be represented by - (O) _u- (CH₂) _t-C (O) -NR²¹R²², wherein u is one, t is zero, and R²¹ and R²² are as described herein. In this embodiment, R²¹ and R²² can each independently be -H, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, or R²¹ and R²² taken together with the nitrogen atom to which they are bonded form a substituted or unsubstituted nonaromatic heterocyclic ring (e.g., pyrrolidine, piperidine, morpholine) . In another embodiment, R⁴⁰ can be represented by

- (0)_u- (CH₂) _t-C(0) -NR²¹R²², wherein u is zero, t is one to about three, and R²¹ and R²² are as described herein.

In another embodiment, R⁴⁰ can be represented by

- (0)_u- (CH₂) _t-C(0) -NR²¹R²², wherein both u and t are zero, and R²¹ and R²² are as described herein.

In another embodiment, R⁴⁰ is an aliphatic group (e.g., methyl, ethyl, propyl) that is substituted with -NR²⁴R²⁵ or -CONR²⁴R²⁵, wherein R²⁴ and R²⁵ are as described herein. For example, R⁴⁰ can be represented by

In another embodiment, R⁴⁰ is -O-C (0) -NR²¹R²⁶, wherein R²¹ is as described herein, R²⁶ can be -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -C (0) -0- (substituted or unsubstituted aliphatic group), -C (0) -0- (substituted or unsubstituted aromatic group), -S (0) ₂- (substituted or unsubstituted aliphatic group), -S (0) ₂- (substituted or unsubstituted aromatic group) or R²¹ and R²⁶, taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring. In additional embodiments, R⁴⁰ can be -S (0) ₂- R¹R^ or -N-C (0) -NR²¹R²², wherein R²¹ and R²² are as described herein.

In a preferred embodiment, the chemokine receptor antagonist can be represented by Structural Formula I wherein n is three, M is C(OH)R², R² is a phenyl group or a halophenyl group (e.g., 4-chlorophenyl) and Z is represented by Structural Formula (VI) wherein X_λ is -CH₂-0-. In one example of this embodiment, R⁴⁰ can be -©-(substituted aliphatic group), such as, R⁴⁰ can be

In particularly preferred embodiments, R⁴⁰ is

In another embodiment, the antagonist of chemokine activity can be represented by Structural Formula (XVII)

;xvιr

and physiologically acceptable salts thereof. n, Y and X are as described in Structural Formula (I). M is >NR², >CR¹R², -0-CR^xR²-0- or -CH₂-CR¹R²-0- . R¹ and R² are as described in Structural Formula (I) Z is as described herein, preferably Z is as described in Structural Formulas (XI) - (XIII) . More preferably, Z is as described in Structural Formula (XI) q¹ is an integer, such as an integer from zero to about three, and q² is an integer from zero to about one. The ring containing M can be substituted or unsubstituted. Thus, the antagonist of chemokine function can be represent by, for example, Structural Formulas (XVIla) - (XVIIK) :

(XVIIc) (XVIId)

■ (CHzJrr-N M

(XVIIe

(XVIIf) (xviig)

(XVIIh) (XVIIi)

(XVIIj) (XVIIk) and physiologically acceptable salts thereof, wherein Z, n and M are as described in Structural Formula (XVII) , and the ring which contains M is substituted or unsubstituted. The ring containing M can have one or more suitable substituents which are the same or different. Suitable substituents for the ring which contains M and other nonaromatic heterocyclic rings are as described herein. For example, the ring containing M can be substituted with a methyl, ethyl, propyl, butyl or oxo group .

The nitrogen atom in the ring containing M can be a tertiary nitrogen as depicted in Structural Formula (IV) , or the nitrogen atom can be quaternized with a suitable substituent, such as a C_x to about C₆ or a C_x to about C₃ substituted or unsubstituted aliphatic group. Compounds which comprise a quaternary nitrogen atom can also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like.

The antagonist of chemokine function can be represented by Structural Formula (XVII) wherein the heterocyclic ring containing M is substituted with a suitable bivalent group which is bonded to two atoms that are in the ring, thereby forming a bicyclic moiety. Suitable bivalent groups include, for example, substituted or unsubstituted bivalent aliphatic groups, such as a C^Cg alkylene group.

The antagonist of chemokine receptor function can comprise a variety of bicyclic moieties. In one embodiment, the antagonist of chemokine receptor function can be represented by Structural Formula (XVIII) : (XVIII) and physiologically acceptable salts thereof.

M is >NR², >CR^XR², -0-CR^xR²-0- or -CH₂-CR¹R²-0- . Preferably, M is >NR² or >CR¹R². R¹, R² and n are as described in Structural Formula (I) , and Z are as described herein. Preferably, Z is as described in Structural Formulas (XI) - (XIII) . More preferably, Z is as described in Structural Formula (XI) .

In another embodiment, the antagonist of chemokine receptor function is represented by Structural Formula (XIX) : z-Y- (cii)_n -x- NRF°R⁵

(XIX

and physiologically acceptable salts thereof.

Z is as described herein, preferably as described in Structural Formulas (XI) - (XIII) . More preferably, Z is as described in Structural Formula (XI) . n is an integer, such as an integer from one to about four. Preferably, n is one, two or three. More preferably n is two. In alternative embodiments, other aliphatic or aromatic spacer groups (L) can be employed for (CH₂)„.

R⁵⁰ and R⁵¹ are each independently -H, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, -NR³R⁴, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group or a covalent bond between the nitrogen atom an adjacent carbon atom.

R³ and R⁴ 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.

R³ and R⁴ taken together with the atom to which they are bonded, can alternatively form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.

In a preferred embodiment R⁵⁰ is a substituted aliphatic group, such as a substituted _λ to about C₁₂ alkyl group, and R⁵¹ is -H or a substituted or unsubstituted aliphatic group. More preferably, R⁵⁰ is a substituted linear or. branched C₂ to about C₇ aliphatic group wherein one or more carbon atoms can be replaced by a heteroatom, such as nitrogen, oxygen or sulfur, and R⁵¹ is -H or a linear or branched C_λ to about C₆ or a C to about C₃ aliphatic group wherein one or more carbon atoms can be replaced by a heteroatom. R⁵⁰ and R⁵¹ can be substituted with one or more suitable substituents, as described herein, preferably with an aromatic group (e.g., phenyl , 4-halophenyl) . For example, R⁵⁰ can be selected from the group consisting of: The activity of chemokine receptor antagonists represented by Structural Formula XIX can be affected by the character of the nitrogen atom to which R⁵⁰ and R⁵¹ are bonded. It is believed that compounds in which said nitrogen atom is basic can have potent chemokine receptor antagonist activity. It is known that the basicity of a nitrogen atom can be decreased when the nitrogen atom is bonded to a carbonyl group, sulfonyl group or a sulfinyl group. Therefore, it is preferred that neither R⁵⁰ nor R⁵¹ comprise a carbonyl group, sulfonyl group or sulfinyl group that is directly bonded to the nitrogen atom.

In another aspect, the antagonist of chemokine receptor function is represented by Structural Formula (XX) :

(XX) and physiologically acceptable salts thereof. n, Y and X are as described in Structural Formula (I) . M is >NR² or >CR².

R² is as described in Structural Formula (I) . Z is as described in Structural Formulas (IV) - (VIII) and/or (XI) - (XVII) , (XVIIIa) or (XVIIIb) . Preferably, Z is as described in Structural Formula (XVIIIa) or (XVIIIb) .

A^" is a physiologically acceptable anion. Preferably, A^" is Cl^" or Br^" .

The chemokine receptor antagonist described herein can be prepared and administered as active compounds or as prodrugs . Generally, prodrugs are analogues of pharmaceutical agents which can undergo chemical conversion by metabolic processes to become fully active. For example, A prodrug of the invention can be prepared by selecting appropriate groups for R 40 In one embodiment, a prodrug can be represented by Structural Formula (XXI) :

(XXI) wherein, R⁴⁰ is Q-substituted aliphatic group, and the aliphatic group is substituted with - (O) _u- (CH₂) _t-C (O) OR²⁰, wherein Q is -C(0)0-, u is one, t is zero and R²⁰ is a cyclic aliphatic group. For example, when the substituted aliphatic group is a substituted ethyl group, R⁴⁰ can be represented by:

Such a prodrug can be converted to an active chemokine receptor antagonist represented by Structural Formula (XXI) , wherein R⁴⁰ is -COOH.

Another embodiment of the invention provides novel compounds employed in these methods . Also included in the present invention are physiologically acceptable salts of the compounds represented by Structural Formulas (I) through (XX) . Salts of compounds containing an amine or other basic group can be obtained, for example, by reacting with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acetic acid, citric acid, perchloric acid and the like. Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Salts of compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base, for example, a hydroxide base. Salts of acidic functional groups contain a countercation such as sodium, potassium, ammonium, calcium and the like.

As used herein, aliphatic groups include straight chained, branched or cyclic C₁-C₂₀ hydrocarbons which are completely saturated or which contain one or more units of unsaturation. Preferred aliphatic groups are C_x to about C₁₀ hydrocarbons . More preferred are C_λ to about C₆ or C_λ to about C₃ hydrocarbons . One or more carbon atoms in an aliphatic group can be replaced with a heteroatom, such as nitrogen, oxygen or sulfur. For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic Ci-Cso alkyl, alkenyl or alkynyl groups.

An aminoalkyl group is an alkyl group substituted with -NR²⁴R²⁵, R²⁴ and R²⁵ are as described herein. Preferably the alkyl moiety comprises one to about twelve, more preferably one to about six carbon atoms. The alkyl moiety of an aminoalkyl group can be unsubstituted or substituted as described herein for aliphatic groups. Examples of suitable aminoalkyl groups include aminomethyl, 2-aminoethyl , 3-aminopropyl , 4-aminobutyl, dimethylaminoethyl , diethylaminomethyl , methylaminohexyl, aminoethylenyl and the like.

A hydrocarbyl group includes straight chain hydrocarbons which are completely saturated or which contain one or more units of unsaturation. Optionally, one or more of the carbon atoms in a hydrocarbyl group may be replaced with a heteroatom such as oxygen, nitrogen or sulfur. 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 alkyl substituted carbonyl; "aralkanoyl" refers to phenyl -alkyl -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, wherein x is an integer from one to four including benzyl . Aromatic or aryl groups include carbocyclic aromatic groups such as phenyl, 1 -naphthyl, 2 -naphthyl, 1-anthracyl and 2-anthracyl, and heterocyclic aromatic or heteroaryl 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, 5-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. Where these rings are fused, for example, to Ring C, the stated point of attachment can be either of the two fused bonds.

Aromatic groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings. Examples include tetrahydronapthyl, 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 within the scope of the term "aromatic group", as it is used herein, is a group in which one or more carbocyclic aromatic rings and/or heteroaromatic rings are fused to a cycloalkyl or non-aromatic heterocyclic ring. Examples include decalin, phthalimido, benzodiazepines, benzooxazepines, benzooxazines, phenothiazines, and groups represented by the following structural formulas:

The term "non-aromatic ring" includes non-aromatic carbocyclic rings and non-aromatic heterocyclic rings. 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 be five, six, seven or eight-membered and/or fused to another ring, such as a cycloalkyl or aromatic ring. Examples of non-aromatic rings include, for example, 1, 3-dioxolan-2-yl, 3-lH-benzimidazol-2-one, 3 - 1 -alkyl -benzimidazol-2 -one , 3-l-methyl-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl , 2-tetrahyrothiophenyl , 3-tetrahyrothiophenyl , 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-alkyl- phthalimidyl, tetrahydronapthyl , benzocyclopentane, benzocyclohexane, benzoxane, benzopyrolidine, benzopiperidine, benzoxolane, benzothiolane, benzothiane, tetrahydrofuran-2-one-3-yl, 2, 5-dihydro-5-oxo-4H-l, 2, 4- thiadiazol-3-yl, 2-oxo-3H-l, 2,3, 5-oxathiadiazol-4-yl,

"Heterocyclic ring" includes "heteroaryl group" and "non-aromatic heterocylic ring" . Examples of heterocyclic rings include imidazole, benzimidazole, pyridine, pyrimidine, thiazole, benzothiazole, thienyl, benzothienyl .

Suitable substituents on an alkyl, aliphatic, aromatic, non-aromatic heterocyclic ring or benzyl group include, for example, an electron withdrawing group, an aliphatic group, substituted aliphatic group, azido, -OH, a halogen (-Br, -Cl, -I and -F) , -0- (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) , -CN, -N0₂, -COOH, -NH₂, -NH (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) , -N- (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) , -COO (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) , -CONH₂, - CONH (aliphatic, substituted aliphatic group, benzyl, substituted benzyl, aromatic or substituted aromatic group), -CON (aliphatic, substituted aliphatic group, benzyl, substituted benzyl, aromatic or substituted aromatic group) ₂, -OS0₂NH₂, -OS0₂NH (aliphatic, substituted aliphatic group, benzyl, substituted benzyl, aromatic or substituted aromatic group), -OS0₂N (aliphatic, substituted aliphatic group, benzyl, substituted benzyl, aromatic or substituted aromatic group) _2/ -S0₂NH₂, -S0₂NH (aliphatic, substituted aliphatic group, benzyl, substituted benzyl, aromatic or substituted aromatic group), -S0₂N (aliphatic, substituted aliphatic group, benzyl, substituted benzyl, aromatic or substituted aromatic group) ₂, -SH, -SO_k (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) (k is 0, 1 or 2) , -NH-C (=NH) -NH₂, ureido, oxalo, amidino, -C(=NR⁶⁰)NR²¹R²²,=NR⁶⁰, - (0) _u- (CH₂) _t-COOR²⁰ ,

- (O) _u- (CH₂) _t-OC (0) R²⁰, - (O) _u- (CH₂) _t-C (O) -NR²¹R²²,

- (O) _u- (CH₂) _t-NHC (0) O-R²⁰, - (0) _u- (CH₂) _t-C (O) OR²⁰, -(0)_u- (CH₂)_t-OC(0)R²°, -(0)_u-(CH₂)_t-C(0) -NR²¹R²²,

- (0)_u- (CH₂)_t-NHC(0)0-R²⁰, -Q-H, -Q- (aliphatic group) ,

-Q- (substituted aliphatic group), -Q- (aryl) , -Q- (aromatic group) , -Q- (substituted aromatic group) , -Q- (CH₂) _p- (substituted or unsubstituted aromatic group) (p is an integer from 1-5) , -Q- (non-aromatic heterocyclic group) or -Q- (CH₂) _p- (non-aromatic heterocyclic group) . R²⁰, R²¹ and R²² are independently -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -NHC (O) -0- (aliphatic group), -NHC (0) -0- (aromatic group) or -NHC (0) -O- (non-aromatic heterocyclic group), or R²¹ and R²², taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring.

R⁶⁰ is a -H, -OH, -NH₂, an aromatic group or a substituted aromatic group. t is an integer from zero to about three, and the methylene group, -(CH₂)_t-, can be substituted, as described herein for aliphatic groups, or unsubstituted. u is zero or one. Q is -0-, -S-, -S(0)-, -S(0)₂-, -0S(0)₂-, -C(0)-,

-0C(0)-, -C(0)0-, -C(0)C(0) -0-, -0-C(0)C(0) -, -C(0)NH-, -NHC(O)-, -0C(0)NH-, -NHC(0)0-, -NH-C (0) -NH- , -S(0)₂NH-, -NHS(0)₂-, -N(R²³)-, -C(NR²³)NHNH-, -NHNHC (NR²³) - , -NR²⁴C (O) - or -NR²⁴S(0)₂-. R²³ is -H, an aliphatic group, a benzyl group, an aryl group or non-aromatic heterocyclic group.

R²⁴ and R²⁵ are independently -H, -OH, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, non-aromatic heterocyclic group, or R²⁴ and R²⁵ taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non- aromatic heterocyclic ring.

A substituted non-aromatic heterocyclic ring, benzyl group or aromatic group can also have an aromatic group, an aliphatic or substituted aliphatic group, as a substituent . When a non-aromatic ring (carbocyclic or heterocyclic) or an aromatic ring (carbocyclic aromatic or heteroaryl) is substituted with another ring, the two rings can be fused. A substituted aliphatic group can also have an oxo group, epoxy group, non-aromatic heterocyclic ring, benzyl group, substituted benzyl group, aromatic group or substituted aromatic group as a substituent. 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, substituted non-aromatic heterocyclic ring or substituted benzyl group can have more than one substituent, which can 'be the same or different.

Acyl groups include substituted and unsubstituted aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl and aromatic sulfonyl.

Suitable electron withdrawing groups include, for example, alkylimines, alkylsulfonyl , carboxamido, carboxylic alkyl esters, -CH=NH, -CN, -N0₂ and halogens. The compounds disclosed herein may be obtained as different sterioisomers (e.g., diastereomers and enantiomers) . For example, when the antagonist of chemokine receptor function is represented by Structural Formula (III) and Z is represented by Structural Formula (VII) , the carbon atom in Ring C which is bonded to Y may be in the R or S sterioconfiguration. It is pointed out that the invention includes all isomeric forms and racemic mixtures of the disclosed compounds and a method of treating a subject with both pure isomers and mixtures thereof, including racemic mixtures.

It is understood that one sterioisomer can have greater activity than another, The desired isomer can be determined by screening for activity, employing the methods described herein. In the structural formulas depicted herein, the single or double bond by which a chemical group or moiety is connected to the remainder of the molecule or compound is indicated by the following symbol : For example, the corresponding symbol in Structural Formula (VIII) or (IX) indicates that the tricyclic ring system, which represent Z in Structural Formula (IV) , is connected to the alkylene group in Structural Formula (IV) by a single covalent bond between the alkylene group and the ring carbon in Ring C which is bonded to W.

A "subject" is preferably a bird or a mammal, such as a human, but can also be an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, fowl, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).

An "effective amount" of a compound is an amount which 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, integrin activation, transient increases in the concentration of intracellular free calcium [Ca²⁺] _± and granule release of proinflammatory mediators. Alternatively, an "effective amount" of a compound is a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in the prevention of or a decrease in the symptoms associated with a disease associated with aberrant leukocyte recruitment and/or activation.

The amount of compound administered to the individual will depend on the type and severity of the disease and on 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 skilled artisan will be able to determine appropriate dosages depending on these and other factors. Typically, an 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 dosage 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, e.g. theophylline, β-adrenergic bronchodilators, corticosteroids, antihistamines, antiallergic agents, immunosuppressive agents (e.g., 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 tablets 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 (e.g., dietary), transdermally, topically, by inhalation (e.g., 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 conjunction with an acceptable pharmaceutical or physiological carrier as part of a pharmaceutical composition for treatment of HIV infection, inflammatory disease, or the other diseases discussed above. Formulation of a compound to be administered will vary according to the route of administration selected (e.g., solution, emulsion, capsule) . Suitable carriers may contain inert ingredients which 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 pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate- buffered saline, Hank's solution, Ringer ' s-lactate and the like. Methods for encapsulating compositions (such as in a coating of hard gelatin or cyclodextran) are known in the art (Baker, et al . , "Controlled Release of

Biological Active Agents", John Wiley and Sons, 1986). The activity of compounds of the present invention can be assessed using suitable assays, such as receptor binding assays and chemotaxis assays. For example, as described in the Exemplification Section, small molecule antagonists of RANTES and MlP-lα binding have been identified utilizing THP-1 cells which bind RANTES and chemotax in response to RANTES and MlP-lα as a model for leukocyte chemotaxis. Specifically, a high through-put receptor binding assay, which monitors ¹²⁵I -RANTES and ¹²⁵I-MIP-lα binding to THP-1 cell membranes, was used to identify small molecule antagonists which block binding of RANTES andMIP-lα. Compounds of the present invention can also be identified by virtue of their ability to inhibit the activation steps triggered by 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 andMIP-l mediated HL-60, T-cell, peripheral blood mononuclear cell, and eosinophil chemotactic response.

The compounds disclosed herein can be prepared accordingly to the schemes shown in Figures 1-5. The schemes are described in greater detail below.

Figure 1 is a schematic showing the preparation of compounds represented by Structural Formulas (I) and

(II) , wherein Z is represented by Structural Formula (IV) , wherein W is CN.

L¹, L² and L³ in Figure 1 are suitable leaving groups such as halogen; p-toluene sulfonate, mesylate, alkoxy and phenoxy. The other symbols are as defined above. The reduction reaction in Step 1 of Figure 1 is performed 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 O'C up to the reflux temperature and for 5 minutes to 72 h. Compounds represented by formula II in Figure 1 can be prepared by procedures disclosed in JP 61/152673, U.S. Patent 5089496, WO 89/10369, WO 92/20681 and WO 93/02081, the entire teachings of which are incorporated herein by reference.

A chlorination reaction in step 2 of Figure 1 can be performed with reagents such as thionyl chloride. The reaction can be carried out in an inert solvent such as methylene chloride at O'C up to the reflux temperature for 5 minutes to 72 h. The hydroxy group can be 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. Reaction temperatures range from O'C up to the reflux temperature for 5 minutes to 72 h. Compounds represented by Formula V in Figure 1 can also be prepared by the procedures described in J. Med. Chem. 1994, 37, 804-810 and U.S. Patent 5672611, the entire 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 up to the reflux temperature and for 5 minutes to 72 h. The product of the synthetic scheme shown in Figure 1 can be decyanated using a reducing agent such as lithium aluminum hydride (LAH) in an inert solvent such as ether or tetrahydrofuran (THF) at O'C up to the reflux temperature for the solvent used for 5 minutes to 72 h.

Figure 2 is a schematic showing the preparation of representative compounds of Structural Formula (I) , (III) and (IV) , wherein Z is represented by Structural Formula (VIII) and wherein Ring A and/or Ring B in Z can be substituted with - (0) _u- (CH₂) _t-COOR²⁰, - (O) _u- (CH₂) _t-0C (0) R²⁰, - (0)_u- (CH₂)_t-C(0) -NR²¹R²² or - (O) _u- (CH₂) _t-NHC (0) -O-R²⁰. In Figure 2, the hydrolysis reaction may 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 up 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-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. Compounds represented by Structural Formulas

(I) , (III) and (IV) wherein Z is represented by Structural Formulas (VIII) -(XI), wherein X_λ is -CO-N(R_c)- and R_c is - (CH₂)_s-COOR³⁰, - (CH₂)_s-C(0) -NR³¹R³² or - (CH₂) _S-NHC (O) -O-R³⁰ can be prepared by suitable modification of the scheme shown in Figures 1 and 2. One modification utilizes the starting material shown in Figures 1 and 2, wherein X_λ 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 schematic showing the preparation of the compounds represented by Structural Formula (I) , (III) and (IV) wherein Z is represented by Structural Formula (VIII) . 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) , 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 up to the reflux temperature for 5 minutes to 72 h. It is also possible to isolate the corresponding imine intermediate, which can be converted to the amine using similar reduction processes .

Figure 4 is a schematic showing the preparation of compounds represented by Structural Formulas (I) , (III) and (IV) , wherein Z is represented by Structural Formula (VIII), wherein W is H. The reduction of the double bond in step 1 of Figure 4 can be carried out using the catalytic reduction process. Suitable catalyst include palladium-carbon, platinum oxide or Ranney-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 minuets to 72 h. The alkylation reactions in step 2 of Figure 4 can be carried out using the same as those in step 5 of Figure 1. Figure 5 is a schematic showing the preparation of compounds represented by Structural Formulas (I) , (III) and (IV) , wherein Z is represented by Structural Formula (VIII), wherein W is H. The alkylation reaction in step 1 of Figure 5 can be carried out using the same as those in step 5 of Figure 1. The reduction of the double bond in step 2 of Figure 5 can be carried out using the same as those in step 1 of Figure 4.

Figure 6 shows the preparation of compounds represented by Structural Formula (I) , where in Z is represented by Structural Formulas (VIII) and wherein Ring A and/or Ring B in Z is substituted with

- (0)_u- (CH₂) _t-COOR²⁰, u is one. In Figure 6, 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 up to the reflux temperature for the solvent used for 5 minutes to 72 h. Figure 7 shows the preparation of compounds represented by Structural Formula (I) , wherein Z is represented by Structural Formulas (VIII) and wherein Ring A or Ring B in Z is substituted with

- (0) _u- (CH₂) _t-COOR²⁰, u is zero. L4 is a suitable leaving group such as halogen or trifluoromethylsulfonate. In

Figure 7, a palladium coupling reaction such as Stille coupling, Suzuki coupling, Heck reaction, or carboxylation using carbon monoxide can be carried out using a palladium catalyst such as tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium chloride, and palladium acetate in a solvent such as tetrahydrofuran (THF) , 1,4-dioxane, toluene, dimethylformamide (DMF), or dimethylsufoxide (DMSO) in the presence of additive (when necessary) such as triphenylphosphine,

1,1' -bis (diphenylphosphino) ferrocene, triethylamine, sodium bicarbonate, tetraethylammonium chloride, or lithium chloride at room temperature up to the reflux temperature for the solvent used for 5 minutes to 72 h.

Figure 8A shows the preparation of N-benzyl-4- (4- chlorophenyl) -4-hydroxypiperidine . Step 1

To a stirred solution of commercially available 4- (4-chlorophenyl) -4-hydroxypiperidine (10 g, 47 mmol . , 1) in anhydrous DMF (10 L) was added benzyl bromide (5.6 mL, 47 mmol) and K₂C0₃ (7.4 g, 94 mmol.) and stirred at RT overnight. Excess solvent was removed under reduced pressure, brought up into CH₂C1₂ (100 mL) washed with H₂0 (2 X 50 mL) . Organic layer separated, dried over Na₂S0₄ and charged on a silica gel flash column. Eluting off with 2% Me0H/CH₂Cl₂ 10 g 2 (80% yield) was obtained as a viscous liquid. MS m/z: (M+ 303) Step 2 N-benzyl-4 - (4-chlorophenyl) -4-fluoropiperidine

To a cold (-78°C) solution of 2 (10 g, 33 mmol) in CH₂C1₂ (20 mL) was slowly added DAST (diethylaminosulfur trifluoride, 5.3 mL, 39.8 mmol) under an inert atmosphere. The reaction was stirred at -78 °C for an additional 45 min. The reaction was quenched at -78 °C by the slow addition of enough saturated aqueous sodium bicarbonate solution to afford a pH >8. This reaction resulted a quantitative conversion of the starting material to a 1:1 mixture of fluoropiperidine 3 and 4- (4- chlorophenyl) tetrahydropyridine 4. The mixture of 3 and 4 (3.5 g, mixture, ~35% yield) was purified via silica gel flash chromatography, eluting with 2% Me0H/CH₂Cl₂. This mixture proved to be inseparable by silica gel flash chromatography. In order to separate out the desired product, the mixture of 3 and 4 were subjected to osmium tetroxide oxidation. To a stirred solution of the mixture of 3 and 4 (1.8 g) in acetone/H₂0 (5:1, 10 mL) was added a catalytic amount of Os0₄ in isopropanol (2.5 mol %, 1 mL) and N-methylmorpholine-N-oxide (0.69 g, 6.56 mmol). The reaction was stirred at RT overnight. The reaction was then evaporated to dryness, brought up into CH₂C1₂ and washed with ΝaHS03. This reaction resulted in the dihydroxylation of the undesired 4 to 5 and the clean separation of the desired fluoropiperidine 3 (1.0 g, 55% yield) from the byproduct by silica gel flash chromatography eluting with 2% MeOH/CH₂Cl₂. MS m/z:

(M+306)

Step 3

4- (4-chlorophenyl) -4-fluoropiperidine To a cold (0°C) solution of 3 (1.07 g, 3.5 mmol) in

1, 2-dichloroethane was added 1, 1-chloroethylchloroformate (0.45 mL, 4.2 mmol). The reaction was then heated to reflux for 2 hrs. Excess solvent was removed and the residue was brought up into 5 mL methanol. The mixture was refluxed for 2 hrs and excess methanol was removed under reduced pressure. Precipitation of the hydrochloride salt of 6 by the addition of CH₂Cl₂/hexane (1:1) followed by filtration resulted in the quantitative isolation of the desired crystalline product 6 (80%, 0.70 g) . MS m/z: (M+215)

The product of this scheme can be used to prepare compounds of Structural Formula (I) wherein R¹ is -F. Figure 8B shows the preparation of 4-azido-4- ( 4- chlorophenyl) piperidine . To a cold (0°C) solution of 1 (3.0 g, 14 mmol) in anhydrous dioxane (15 mL) under an inert atmosphere was added NaN₃ (1.0 g, 15.4 mmol) followed by the slow dropwise addition of and BF₃»OEt (4.4 mL, 35 mmol). The reaction was stirred at O^'C for 3 hrs and was quenched at 0°C by the slow careful addition of saturated aqueous NaHC0₃ to basicity. The organic ' layer was separated and dried over Na₂S0₄. The reaction mixture was purified via silica gel flash chromatography eluting a 2 g 1:3 mixture of azidopiperidine 2 and olefin 3 with 2% MeOH/CH₂Cl₂. The mixture can be used directly to prepare compounds represented by Structural Formula (I) wherein R¹ is -N₃. Figure 8C shows the preparation of N-benzyl-4- methylpiperidine . Step 1

To a cold (-78 'C) stirred solution of 1.4 M methyllithium in THF (39 mL, 54 mmol) under an inert atmosphere was added N-benzyl-4 -oxopiperidine (1, 5.1 g, 27 mmol). The reaction was stirred at -78 °C for 2hrs . The reaction was quenched by the slow addition of saturated aqueous ΝH₄C1, the organic layer was separated and dried over Na₂S0₄. Pure methylpiperidine (2) was isolated via silica gel flash chromatography eluting with 5% MeOH/CH₂Cl₂. MS m/z: (M+206) Step 2 N-benzyl-4- (4-chlorophenyl) -4-methylpiperidine :

To a flask containing chlorobenzene (10 mL, excess) and methylpiperidine (0.42 g, 2.06 mmol, 2) was added aluminum trichloride (1.65 mL, 12.4 mmol). The reaction was heated to reflux for 24 hrs. Excess chlorobenzene was removed under reduced pressure and pure 3 was obtained via silica gel flash chromatography eluting with % EtOAc/hexane. MS m/z: (M+ 300) Step 3

4- (4-chlorophenyl) -4-methylpiperidine: Fig. 8c To a cold (0°C) solution of N-benzyl-4- (4- chlorophenyl) -4-methylpiperidine (3) (0.41 g, 1.4 mmol) in CH₂C1₂ was 1.1 equivalent of 1- chloroethylchloroformate. The reaction was then heated to reflux for 2 hrs. Excess solvent was removed and the residue was brought up into methanol. The mixture was refluxed for 2 hrs and excess methanol was removed under reduced pressure. Precipitation of the hydrochloride salt 4 by the addition of CH₂C1₂ followed by filtration resulted in the quantitative isolation of the desired crystalline product 4 (100%, 0.34 g) . MS m/z: (M+ 210) The product of this scheme can be used to prepare compounds of Structural Formula (I) wherein R¹ is -CH₃.

Figures 9A shows the preparation of compounds represent by Structural Formula (I) wherein R¹ is an amine. The azido functionality can be reduced with a variety of reducing agents such as triphenylphosphine, lithium aluminum hydride, sodium borohydride, in a solvent such as tetrahydrofuran or diethyl ether in reaction temperature ranges from 0°C to reflux with a reaction time of between 5 minutes and 72 hours. Figure 9B shows the preparation of compounds represent by Structural Formula (I) wherein R¹ is -CH₂NH₂. To a cold (0°C) stirred solution of cyano containing molecule (0,50 g, 0.14 mmol) in a solvent such as diethyl ether or THF (5 mL) can be added a reducing agent such as lithium aluminum hydride (8 mg, 0.21 mmol). The reaction can then be stirred at 0°C to reflux from 5 minutes to 72 hours. The reaction can then be quenched by the careful addition of H₂0 (o.21 mL) , 15% aqueous KOH (0.21 mL) . The organic payer can then be separated and dried over Na₂S0₄. Pure amino compound can be obtained via silica gel flash chromatography.

Figure 9C shows the preparation of 2- (4- chlorophenyl) -1- (N-methyl ) ethylamine. Step 1 To a solution of A1C1₃ (1.96 g, 14.7 mmol) in anhydrous CH₂C1₂ (50 mL) , Borane- tert-butyl amine complex (2.57 g, 29.6 mmol) was added at 0°C under argon protection, stirred for 10 minutes and clear solution was formed. 4-Chlorophenacyl bromide (1, 1.11 g, 4.91 mmol) in CH₂C1₂ (5 mL) was added to the resulted mixture at 0°C . The reaction was stirred for 1.5 hours and then quenched by the addition of 0.1 N HC1 (25 mL) . The mixture was extracted with EtOAc (80 mL x 3), dried over MgS04 and concentrated in vacuo. Chromatographic purification on silica gel (Hexane/EtOAc = 9:1) provided 0.85 g (84%) of 2- (4-chlorophenyl) -1-bromoethylene (2). MS m/z: (M+ 219) . Step 2 A mixture of 2- (4-chlorophenyl) -1-bromoethylene (2, 1.02 g, 4.62 mmol), EtOH (3 mL) and H₂NMe in H₂0 (6 mL, 40% w/w) was heated at 135 0°C over night. The mixture was cooled down to room temperature. The mixture was extracted with Et₂0 (5mL x 2), dried over MgS0₄ and concentrated in vacuo. Chromatographic purification on silica gel (CH₂Cl₂/MeOH/NH₄OH = 9/1/0.1) provided 0.61 g 2- (4-chlorophenyl) -1- (N-methyl ) ethylamine (3, 79%). MS m/z: (M+ 170) .

Figure 9D shows the preparation of 3- (4- chlorophenyl) -3-hydroxyl-3-methyl-l-N-methylaminopropane Step 1

To 3, 4 ' -Dichloropropylphenone (1, 1.10 g, 5.40 mmol) in anhydrous THF at 0°C under the protection of argon, was added MeMgBr (2.50 mL, 7.35 mmol) dropwise at 0°C. The reaction was stirred at room temperature for an additional hour. The reaction was quenched by adding saturated aqueous ΝH₄C1. The reaction was then extracted with Et₂0 (60 mL x 2), dried over MgS0₄ and concentrated in vacuo. Chromatographic purification on silica gel (Hexane/EtOAc = 10/1) provided 1.0 g (85%) of 3- (4- chlorophenyl) -3-hydroxy-3-methyl-l-bromoropane (2). MS m/z: (M+ 219) . Step 2

A mixture of 3, 3, 3- (4-Chlorophenyl) -hydroxylmethyl- 1-bromoropane (2, 1.04 g, 4.74 mmol), EtOH (5 mL) and H₂NMe in H₂0 (10 mL, 40% w/w) was heated at 135 0°C for 3 hours. The mixture was cooled down to room temperature. The mixture was extracted with Et₂0 (5mL x 2), dried over MgS0₄ and concentrated in vauco. Chromatographic purification on silica gel (CH₂Cl₂/MeOH/NH₂OH = 9/1/0.1) provided 1.01 g 3- (4-chlorophenyl) -3-hydroxyl-3-methyl-l- N-methylaminopropane (3, 99%). MS m/z: (M+ 214). Figure 9E shows the preparation of 3- (4- chlorophenyl) -1-N-methylaminopropane .

A mixture of 3- (4-chlorophenyl) -1-bromoropane (1, 0.70 g, 3.73 mmol), EtOH (3 mL) and H₂ΝMe in H₂0 (6 mL, 40% w/w) was heated at 135 0°C overnight. The mixture was then cooled down to room temperature. The mixture was extracted with Et₂0 (5 L x 2), dried over MgS0₄ and concentrated in vacuo. Chromatographic purification on silica gel (CH₂Cl₂/MeOH/NH₄OH = 9/1/0.1) provided 0.5 g (76%) of 3- (4-chlorophenyl) - 1-N-methylaminopropane (2). MS m/z: (M+ 189) .

Figure 10A shows the preparation of 3- (4- chlorophenyl ) -3-hydroxyl-3-methyl-l-N-methylaminopropane . Step 1

To 3, 4 ' -Dichloropropylphenone (1, 1.10 g, 5.40 mmol) in anhydrous THF at 0°C under the protection of argon, was added MeMgBr (2.50 mL, 7.35 mmol) dropwise at 0°C. The reaction was stirred at room temperature for an additional hour. The reaction was quenched by adding saturated aqueous NH₄C1. The reaction was then extracted with Et₂0 (60 L x 2), dried over MgS0₄ and concentrated in vacuo. Chromatographic purification on silica gel (Hexane/EtOAc = 10/1) provided 1.0 g (85%) of 3- (4- chlorophenyl) -3-hydroxy-3-methyl-l-bromoropane (2). MS m/z: (M+ 219) . Step 2

A mixture of 3, 3, 3- (4-Chlorophenyl) -hydroxylmethyl- 1-bromoropane (2, 1.04 g, 4.74 mmol), EtOH (5 mL) and H₂NMe in H₂0 (10 mL, 40% w/w) was heated at 135 0°C for 3 hours. The mixture was cooled down to room temperature. The mixture was extracted with Et₂0 (5mL x 2), dried over MgS0₄ and concentrated in vauco. Chromatographic purification on silica gel (CH₂Cl₂/MeOH/NH₂OH = 9/1/0.1) provided 1.01 g 3- (4-chlorophenyl) -3-hydroxyl-3-methyl-l- N-methylaminopropane (3, 99%). MS m/z: (M+ 214).

Figure 10b shows the preparation of l-(4- c lorobenzoyl) -1, 2-ethylenediamine Step 1 tert-Butyl N- (2-aminoethyl) carbamate (1, 0.50 g g, 3.12 mmol) was added to the mixture of 4-chlorobenzoic acid chloride (0.547 g, 3.12 mmol) and Et₃Ν (1.74 mL, 12.5 mmol) in CH₂C1₂ (20 mL) under the protection of argon. Stirring at room temperature for 2 hours. The reaction mixture was diluted with H₂0 (25 mL) , extracted with CH₂C1₂ (50 mL x 2), dried over MgS0₄ and concentrated in vacuo. Chromatographic purification on silica gel (CH ₂Cl₂/MeOH = 95/5) to provide 0.86 g (2, 93%) of the desired product tert-Butyl 3- (4-chlorobenzoyl) -1- (2- aminoethyl) carbamate. MS m/z: (M+ 299) . Step 2

Trifluoroacetic acid (7.5 mL) was added to the solution of tert-Butyl 3- (4-chlorobenzoyl) -1- (2- aminoethyl) carbamate (2, 0.86 g, 2.89 mmol) in CH₂C1₂ (35 mL) at 0°C. Stirring at room temperature for 30 minutes. Concentration in vacuo provided 0.88 g (95%) of the desired product 1- (4-chlorobenzoyl) -1, 2-ethylenediamine (3) . MS m/z: (M+ 199) .

Compounds prepared according to the schemes presented in Figures 9C-9E, 10A and 10B can be used to prepare compounds represented by Structural Formula (XIX) . Figure 10C shows three procedures for the preparation of compounds represented by Structural Formulas (I), (VII), (VIII) and (IX), wherein Z is represented by Structural Formula (III) and wherein Ring A or Ring B in Z is substituted with R⁴⁰- In Figure 10C, R⁴⁰ is represented by

- (0)_u- (CH₂)_t-C(0) -NR²¹R²², u is one, t is zero.

In Figure 10C a compound containing a phenol can be reacted with a carbonate equivalent, such as a carbamoyl chloride (method A) , an isocyanate (method B) or an acylimidazole (method C) , in the presence of a base such as sodium hydroxide, potassium carbonate or sodium carbonate in a solvent such as dimethylformamide or tetrahydrofuran, at a temperature from 0°C to reflux temperature for a period of about 5 minutes to about 72 hours.

Figure 12 shows the preparation of compounds represented by Compound (XV-b) . In Step 1 of Figure 12, a Grignard reaction can be carried out in a solvent such as ether, or tetrahydrofuran (THF) at 0°C up to the reflux temperature for the solvent used for 5 minuets to 72 h. Compound XIII is available commercially.

In Step 2 of Figure 1, bromination can be carried out with brominate agents such as hydrobromic acid, bromotrimethylsil^'ane or boron tribromide-methyl sulfide complex in a solvent such as acetic acid, dichloromethane or dichloroethane at room temperature up to the reflux temperature for the solvent used for 5 minutes to 72 h. Figure 13 shows the preparation of compounds of formula (XV-c) . The Friedel-Crafts acylation can be carried out using an acid chloride in the presence of a Lewis acid, such as aluminum trichloride or titanium tetrachloride, in a solvent such as dichloromethane, dichloroethane, nitrobenzene or carbon disulfide. The acylation reaction can be run at a temperature of about room temperature up to the reflux temperature of the chosen solvent, and for a period of about 5 minutes to about 72 hours.

Figure 14 shows the preparation of compounds of formula (XV-e) . In Step 1 of Figure 13, a chlorosulfonylation can be carried out using chlorosulfonic acid in a solvent, such as dichloromethane, or in the absence of a solvent at a temperature of about 0°C to about 60 °C for a period of about 5 minutes to about 72 hours. In Step 2 of Figure 12, a coupling reaction can be carried out using an amine in the presence of a base, such as triethylamine, in a solvent such as dichloromethane, acetone, ethanol, THF or DMF. The reaction can be carried out at a temperature of about room temperature up to the reflux temperature of the selected solvent, and for a period of about 5 minutes to about 72 hours.

Although Figures 1-7 show the preparation of compounds in which B is a phenyl ring and Figures 12-14 show the preparation of compounds in which Rings A and B are both phenyl rings, analogous compounds with heteroaryl groups for Ring A and/or Ring B can be prepared by using the starting materials with heteroaryl groups in the corresponding positions, which can be prepared according to methods disclosed in JP 61/152673, U.S. Patent 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.

EXEMPLIFICATION

Example 1

4- (4 -Chlorophenyl) -1- [3- (5 , ll-dihydro-7- methoxypyrido [2, 3-c] [1] benzoxepin-5-propyl] piperidin-4-ol Step 1

To a solution of 5 , ll-dihydro-7-methoxypyrido [2 , 3- c] [1] benzoxepin-5-one (5.0g) in THF (50ml) was added 1.1M cyclopropylmagnesium bromide THF solution (25ml) at 0°C. The 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 off under reduced pressure. The residue was filtered and washed with ethyl acetate-hexane (1:2) to give 5-cyclopropyl-5 , 11-dihydro- 7-methoxypyrido [2, 3-c] [1] benzoxepin-5-ol (5.0g).

Step 2 To a solution of the product of step 1 (4.3g) in acetic acid (30ml) was added 48% aqueous HBr (25ml) 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 dilute NaOH solution. 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 silica gel chromatography eluting with ethyl acetate-hexane (1:4) to give 5- (3-bromopropylidene) -5, 11- dihydro-7-methoxypyrido [2 , 3-c] [1] benzoxepine (5.6g) .

^-NMR (CDC1₃) δ: 2.74(2H,q), 3.46(2H,t), 3.78(3H,s), 5.25 (2H,brs) , 6.07(lH,t), 6.72-6.82 (3H, m) , 7.21- 7.42(5H,m), 7.56(lH,dd), 8.45(lH,dd).

Step 3

To a solution of the product of step 2 (160mg) in ethanol (3ml) and acetic acid (1ml) were added 10% Pd-C (79mg) was stirred under hydrogen (under a balloon) at room temperature for 24 hour. The mixture was filtered through the celite and distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography eluting with ethyl acetate-hexane (1:2) to give 5- (3-bromopropyl) -5, ll-dihydro-7- methoxypyrido [2 , 3-c] [1] benzoxepine (48mg) .

^:H-NMR (CDC1₃) δ: 1.80-2.45 (4H, m) , 3.33 -3.39 (2H, m) , 3.59(lh,dd), 3.77(3H,s), 4.98(lH,d), 5.44(lH,d), 6.70- 6.79(2H,m), 7.08-7.14 (5H, m) , 7.52(lH,dd), 8.41(lH,dd).

Step 4 To a solution the product of step 3 (45mg) in DMF (lml) were added 4- (4-chlorophenyl) -4-hydroxypiperidine (54mg) and potassium carbonate (19mg) 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 and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-methanol (10:1) to give the titled compound (19mg) .

^XH-NMR (CDC1₃) δ: 1.50 (1H, brs) , 1.67-1.72 (2H, m) , 2.00- 2.47(10H,m), 2.76-2.81 (2H,m) , 3.59(lH,dd), 3.77(3H,s), 4.97(lH,d) , 5.43 (lH,d) , 6.72 -6.78 (2H, m) , 7.06-7.13 (2H, m) , 7.26-7.44 (4H,m) , 7.52 (lH,dd) , 8.37(lH,dd) . MS m/z: 479 (M+l)

Examples 2 - 157 which can be represented by Structural Formulas (XIV) and (XVI) and are presented in Table 1 and Table la, can be prepared by methods set forth in the schemes in Figure 1-5 and the procedures described above.

Table 1 Table 1 (cont.) Table 1 (cont.) Table 1 (cont.) Table 1 (cont.)

Table la

Ex X1 W M R1 R2 R40

106 -CH2-0- -H CR1R2 -OH -OCH2CH20H

107 -CH2-0- -H CR1R2 -OH -OCH2CH20CH3

108 -CH2-0- -H CR1R2 -OH B

109 -CH2-0- -H CR1R2 -OH C

110 -CH2-0- -H CR1R2 -OH D

111 -CH2-0- -H CR1R2 -OH E

112 -CH2-0- -H CR1R2 -OH F

113 -CH2-0- -H CR1R2 -H -OH

114 -CH2-0- -H CR1R2 -H -OCH2CH20H

115 -CH2-0- -H CR1R2 -H -OCH2CH20CH3 /

116 -CH2-0- -H CR1R2 -H / — \ A

117 -CH2-0- -H CR1R2 -H _ _ ^cι C

118 -CH2-0- -H CR1 2 -H D

119 -CH2-0- -H CR1R2 -H F

120 -CH2-0- CN CR1R2 -OH -OCH2CH20H

121 -CH2-0- -CN CR1R2 -OH -OCH2CH20CH3

122 -CH2-0- -CN CR1R2 -OH B / o NH₇

123 -CH2-0- -CN CR1R2 -OH C

124 -CH2-0- -CN CR1R2 -OH D

125 -CH2-0- -CN CR1R2 -OH E

126 -CH2-0- -CN CR1R2 -OH F

127 -CH2-0- -CN CR1R2 -H -OH

128 -CH2-0- -CN CR1R2 -H -OCH2CH20H

129 -CH2-0- -CN CR1R2 -H -0CH2CH20CH3

130 -CH2-0- -CN CR1R2 -H A

131 -CH2-0- -CN CR1R2 -H C

132 -CH2-0- -CN CR1R2 -H D

133 -CH2-0- -CN CR1R2 -H F

145 -CH2-0- -CN CR1R2 C

146 -CH2-0- -CN CR1R2 D

147 -CH2-0- -CN CR1R2 F

148 -CH2-CH2- -H CR1R2 -OH -OCH2CH20H

149 -CH2-CH2- -CN- CR1R2 -OH F /

150 -CH2-CH2- -H CR1R2 -OH -0CH2CH2OH

151 -CH2-CH2- -CN CR1R2 -OH F >C^0H

152 -CH2-S- -H CR1R2 -OH -0CH2CH20H

153 -CH2-S- -CN CR1R2 -OH F

154 -CH2-S- -H CR1R2 -OH -0CH2CH20H

155 -CH2-S- -CN CR1R2 -OH F

156 -CH2-0- -H CR1R2 -OH G

157 -CH2-0- -CN CR1R2 -OH G Example 158

Membrane Preparations for Chemokine Binding and Binding Assays

Membranes are prepared from THP-1 cells (ATCC #TIB202) . Cells are harvested by centrifugation, washed twice with PBS (phosphate-buffered saline) , and the cell pellets are frozen at -70 to -85°C. The frozen pellet is thawed in ice-cold lysis buffer consisting of 5 mM HEPES (N-2- hydroxyethylpiperazine-N' -2-ethane-sulfonic acid) pH 7.5, 2 mM EDTA (ethylenediaminetetraacetic acid) , 5 μg/ml each aprotinin, leupeptin, and chymostatin (protease inhibitors) , and 100 μg/ml PMSF (phenyl methane sulfonyl fluoride - also a protease inhibitor) , at a concentration of 1 to 5 x 10⁷ cells/ml. This procedure results in cell lysis. The suspension is mixed well to resuspend all of the frozen cell pellet. Nuclei and cell debris are removed by centrifugation of 400 x g for 10 minutes at 4°C. The supernatant is transferred to a fresh tube and the membrane fragments are collected by centrifugation at 25,000 x g for 30 minutes at 4°C. The supernatant is aspirated and the pellet is resuspended in freezing buffer consisting of 10 mM HEPES pH 7.5, 300 mM sucrose, lμg/ml each aprotinin, leupeptin, and chymostatin, and 10 μg/ml PMSF (approximately 0.1 ml per each 10⁸ cells). All clumps are resolved using a minihomogenizer, and the total protein concentration is determined using a protein assay kit (Bio-Rad, Hercules, CA, cat #500-0002) . The membrane solution is then aliquoted and frozen at -70 to -85°C until needed.

Binding Assays utilize the membranes described above.

Membrane protein (2 to 20 μg total membrane protein) is incubated with 0.1 to 0.2 nM ¹²⁵I-labeled RANTES or MlP-lα with or without unlabeled competitor (RANTES or MlP-lα) or various concentrations of compounds. The binding reactions are performed in 60 to 100 μl of a binding buffer consisting of 10 mM HEPES pH 7.2 , 1 mM CaCl₂, 5 mM MgCl₂, and 0.5% BSA (bovine serum albumin), for 60 min at room temperature. The binding reactions are terminated by harvesting the membranes by rapid filtration through glass fiber filters (GF/B or GF/C, Packard) which are presoaked in 0.3% polyethyleneimine . The filters are rinsed with approximately 600 μl of binding buffer containing 0.5 M NaCl , dried, and the amount of bound radioactivity is determined by scintillation counting in a Topcount beta-plate counter. The activities of test compounds can be reported as IC₅₀ values or the inhibitor concentration required for 50% inhibition of specific binding in receptor binding assays using ¹²⁵I -RANTES or ¹²⁵MIP-lα as ligand and THP-1 cell membranes. Specific binding can be defined as the total binding minus the non-specific binding; nonspecific binding can be the amount of cpm still detected in the presence of excess unlabeled RANTES or ¹²⁵MIP-lα.

Table 2

BIOLOGICAL DATA

Example ICso (μM⁾

1 <1

265 <1

266 <1

267 <1

269 <1

270 <1

271 <1

Example 264 :

4- (4 -fluorophenyl) -1- [3- (5 , ll-dihydro-7- hydroxy [1] benzoxepino [2 , 3 -b] pyridin-5-ylidene) propyl] piperidine-4-ol To a solution of 5- (3-bromopropylidene) -5 , 11- dihydro-7-methoxy- [1] benzoxepino [2 , 3-b] pyridine (2.59 g) in DMF (10 ml) was added 4- (4 -Fluorophenyl) -4- hydroxypiperidine (1.02 g) and triethylamine (835 μM) . The solution was stirred at room temperature for 23 hours. The reaction was quenched with water, extracted with ethyl acetate, and evaporated in vacuo . The residue was purified by silica gel chromatography (87:10:3 ethyl acetate: methanol: triethylamine) to yield 0.9 g (39%) of the title compound. ^-N R (DMSO) δ: 1.64-1.69 (2H, m) , 1.74-1.85 (2H, m) , 2.27-2.52 (8H, m) , 4.81 (1H, s) , 5.16

(2H, brs) , 6.08 (1H, t) , 6.62-6.71 (3H,. ) , 7.12 (2H, t) , 7.40-7.51 (3H, m) , 7.72 (1H, dd) , 8.48 (1H, dd) , 9.09

(1H, s) . ESI-MS m/z: 447 (M + 1) . Example 265:

4- (4 -fluorophenyl) -1- [3- (5 , ll-dihydro-7- hydroxy [1] benzoxepino [2, 3-b] pyridin) propyl] piperidine-4- ol To a solution of the compound of Example 264 (0.80 g) in ethanol (20 mL) was added palladium hydroxide (0.20 g) and concentrated hydrochloric acid (1 mL) . The solution was shaken under 40 PSI of hydrogen for 48 hours. The reaction was filtered and evaported in vacuo . The residue was purified by silica gel chromatography (87:10:3 ethyl acetate :methanol : triethylamine) to yield 0.5 g (62%) of 4- (4 -fluorophenyl) -1- [3- (5 , ll-dihydro-7- hydroxy [1] benzoxepino [2 , 3 -b] pyridin-5-) propyl] piperidine- 4-ol. XH-NMR (DMSO) 6:1.64-1.69 (2H, m) , 1.74-1.85 (2H, m) , 1.80-1.95 (4H, m) , 2.20-2.70 (5H, m) , 4.82 (1H, d) , 5.31 (1H, d) , 6.59-6.66 (2H, m) , 6.93 (1H, d) , 7.10 (2H, t) , 7.23 (1H, dd) , 7.49 (2H, dd) , 7.70 (1H, d) , 8.37 (1H, d) , 9.23 (1H, s) . ESI-MS m/z: 449 (M + 1) .

Example 266:

4- (4 -fluorophenyl) -1- [3- (5, ll-dihydro-7-N,N- dimethylcarbamoyl [1] benzoxepino [2 , 3 -b] pyridin) propyl] piperidine-4 -ol To a stirred solution of the compound of Example 265 (1.0 mmol) and K₂C0₃ (1.5 mmol) in THF (10 mL) at RT was added N, ΛJ-dimethylcarbamoylchloride (1.2 mmol). The reaction was stirred at reflux for 24 hrs. Excess solvent was removed and pure compound was isolated via silica gel chromatography eluting with 5% MeOH/CH₂Cl₂. MS m/z: (M+ 535)

^XH-ΝMR (CDC1₃) 6:1.64-1.69 (2H, m) , 1.74-1.85 (2H, m) , 1.80-2.40 (8H, m) , 2.65 (2H, m) , 2.91 (3H, s) , 3.00 (3H, s) , 3.53 (1H, t) , 4.93 (1H, d) , 5.37 (1H, d) , 6.87-7.06 (6H, m) , 7.35-7.42 (3H, m) 8.29 (1H, dd) . ESI-MS m/z: 520 (M + 1) .

Example 267:

4- (4 -fluorophenyl) -1- [3- (5, ll-dihydro-7- trifluoromethylmethanesulfonyloxy [1] benzoxepino [2 , 3- b] pyridin) propyl] piperidine-4-ol .

To a solution of the compound of Example 265 (1.0 g) in pyridine (10 ml) was added trifluoromethanesulfonic acid anhydride (0.55 ml) at 0°C, and the mixture was stirred at room temperature for 1 hour. Water and diethyl ether 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 off under reduced pressure, and the residue was purified by silica gel chromatography eluting with ethyl acetate-methanol (10:1) to give the titled compound (1.1 g) .

^XH-NMR (CDC1₃) 6:1.44-1.80 (6H, m) , 2.00-2.50 (8H, m) , 2.68 (2H, m) , 3.66 (1H, t) , 5.01 (1H, d) , 5.49 (1H, d) , 7.00 (2H, m) , 7.11-7.18 (4H, m) , 7.41-7.53 (3H, m) , 8.42 (1H, dd) .

ESI-MS m/z:581 (M + 1) .

Example 268 :

4- (4 -fluorophenyl) -1- [3- (5, ll-dihydro-7- carboxy [1] benzoxepino [2 , 3-b] pyridin) propyl] piperidine-4- ol

A mixture of the compound of Example 267 (500 mg) , potassium acetate (330 mg) , palladium (II ) diacetate (10 mg) , 1, 1 ' -bis (diphenylphosphino) ferrocene (93 mg) , in dimethylsulfoxide (10 ml) was purged with carbon monoxide for 5 minutes and stirred under a carbon monoxide balloon at 60°C for 3 hours. Water was added to the reaction mixture, the precipitation was filtered. The solid were dissolved with ethyl acetate and dilute sodium hydroxide solution. The aqueous layer was separated and neutralized with dilute hydrochloric acid. The precipitation was filtered to give the titled compound (250 mg) . - MR (MeOD) 6:1.56-1.91 (4H, m) , 1.95-2.101 (1H, m) , 2.20-2.41 (3H, m) , 2.85-3.37 (7H, m) , 3.94 (1H, dd) , 4.98 (1H, d) , 5.45 (1H, d) , 6.95-7.08 (2H, m) , 7.11 (1H, d) , 7.24 (1H, dd) , 7.43 (2H, dd) , 7.72-7.94 (3H, m) , 8.37 (1H, d) . MS m/z: 477

Example 269:

4- (4 -fluorophenyl) -1- [3- (5, ll-dihydro-7-methoxycarbonyl [1] benzoxepino [2 , 3-b] pyridin) ropyl] piperidine-4-ol .

The title compound was prepared by following the procedure of Example 268, but replacing the solvent with N-methyl pyrrolidone/methanol .

^-NMR (CDC1₃) 6: 1.30-1.50 (2H, m) , 1.65-1.75 (2H, m) , 1.95-2.15 (4H, m) , 2.20-2.45 (4H, ) , 2.60-2.75 (2H, m) , 3.72 (1H, t), 3.84 (3H, s) , 4.97 (1H, d) , 5.49 (1H, d) , 6.93 (2H, t), 7.07-7.12 (2H, m) , 7.37-7.53 (3H, m) , 7.84- 7.88 (2H, m) , 8.30 (1H, m) . ESI-MS m/z: 491 (M + 1)

Example 270:

4- (4 -fluorophenyl) -1- [3- (5, ll-dihydro-7- (1-hydroxy-l- methyl -ethyl) [1] benzoxepino [2,3- b] pyridin) propyl] piperidine-4-ol .

To a solution of the compound of Example 269 (60mg) in THF (6ml) were added methylmagnesium chloride (3.0M, 0.16ml) dropwise at 0 °C, and the mixture was stirred at room temperature for 2 hour, the reaction mixture was quenched by saturated ammonium aqueous, then ethyl acetate and water was added to the mixture. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-methanol (95:5) to give the titled compound (20mg) . XH-NMR (CDC1₃) δ: 1.30-1.80 (10H, m) , 2.00-2.45 (7H, m) , 2.65-2.75 (2H, m) , 3.66 (1H, t) , 4.97 (1H, d) , 5.47 (1H, d) , 6.93 (2H, t) , 6.95-7.12 (4H, m) , 7.27-7.53 (7H, m) , 8.30 (1H, m) . ESI-MS m/z: 491 (M + 1) .

Example 271:

4- (4 -fluorophenyl) -1- [3- (5, ll-dihydro-7- (1-carboxy-l- methylethyl) -oxy [1] benzoxepino [2,3- b] pyridin) propyl] piperidine-4-ol .

To a solution of the compound of Example 265(200mg) in DMF (5ml) were added sodium hydride (60% in oil,

25mg) , ethyl 2-bromoisobutylate (0.052ml) 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 with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to give the titled compound (170mg) . ^-NMR (CDCI₃) δ: 1.23 (3H, t), 1.37-1.75 (10H, m) , 1.90- 2.39 (9H, m) , 2.65-2.74 (2H, m) , 3.54 (1H, dd) , 4.23 (2H, q) , 4.95 (1H, d) , 5.41 (1H, d) , 6.65-6.78 (2H, m) , 6.95- 7.13 (4H, m) , 7.41-7.55 (3H, m) , 8.38 (1H, dd) . MS m/z: 563

Those skilled in the art will be able to recognize, or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

What is claimed is:

1. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject an effective amount of a compound represented by the following structural formula:

^■

and physiologically acceptable salts thereof, wherein:

Y is a single covalent bond; n is an integer from one to about four; X is a single covalent bond;

M is >NR², >CR^XR², -O-CR^-O- or -CH₂-CR¹R²-0-; The ring containing M is substituted or unsubstituted; q¹ is an integer, such as an integer from zero to about three; q² is an integer from zero to about one; R¹ is -H, -OH, -N₃, a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group,

-0- (aliphatic group), -0- (substituted aliphatic group), -SH, -S- (aliphatic group), -S- (substituted aliphatic group), -OC (0) - (aliphatic group), -O-C(O)- (substituted aliphatic group), -C (0) 0- (aliphatic group), -C (0) 0- (substituted aliphatic group), -C00H, -CN, -CO-NR³R⁴, -NR³R⁴ or R¹ is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;

R² is -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, a substituted non-aromatic heterocyclic group, -0- (substituted or unsubstituted aromatic group) or -0- (substituted or unsubstituted aliphatic 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 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 bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;

Z is represented by:

wherein:

W is -H, an electron withdrawing group, -CH_j-NR^R", -CH₂-OR¹¹, -CH=NH, -CH₂-NH-CO-NR¹¹R¹², -CHs-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 or a non- aromatic heterocyclic group; or R¹¹ and R¹², taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;

Xj is -S-, -S-CH₂-, -CH₂-S-, -CH₂-0-, -0-CH₂-, -CO-NR_c-, -NR_c-CO-, -CH₂-S(0)₂-, -S(0)₂-CH₂-, -CH₂-NR_C-, -NR_C-CH₂-, -CH₂-CH₂-, -CH=CH-, -CH₂-SO-, -SO-CH₂-, -O- or a bond;

R_c is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and

Ring A and Ring B are independently substituted or unsubstituted.

2. The method of Claim 1 wherein

R¹ is -H, -OH, -N₃, -CN, a halogen, a substituted aliphatic group, an aminoalkyl group, -0- (aliphatic group), -0- (substituted aliphatic group) , -NR³R⁴ or R¹ is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M; R² is -NR⁵R⁶, a substituted acyl group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, -0- (substituted or unsubstituted aromatic group) ; or R¹ and R² taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.

3. The method of Claim 1 wherein q¹ and q² are zero, and the compound is represented by the structural formula: ^■(CHzλr-N M

The method of Claim 3 wherein M is >CR 1¹DR2^:

5. The method of Claim 1 wherein q¹ is one and q² is zero, and the compound is represented by the structural formula:

6. The method of Claim 5 wherein M is >CR^XR².

7. The method of Claim 1 wherein q¹ is one and q² is two, and the compound is represented by the structural formula:

8. The method of Claim 7 wherein M is >NR .

9. The method of Claim 1 wherein q¹ is one and q² is two, and the compound is represented by the structural formula:

10. The method of Claim 9 wherein M is -O-CR^-O- or -CH₂-CR¹R²-0-.

11. The method of Claim 9 wherein:

M is >NR² or >CR¹R²; and

R¹ is a substituted aliphatic group or an aminoalkyl group.

12. The method of Claim 9 wherein: M is >NR² or >CR¹R²; and

R² is -0- (substituted or unsubstituted aromatic group) .

13. The method of Claim 1 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X_: in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is -OH, -COOH, -N0₂, halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, -NR²⁴R²⁵, -C0NR²⁴R²⁵, Q- (aliphatic group), Q- (substituted aliphatic group), -0- (aliphatic group), -0- (substituted aliphatic group), -0- (aromatic group), -0- (substituted aromatic group), an electron withdrawing group, - (0) _u- (CH₂) _t-C (0) OR²⁰, -(0)_u-(CH₂)_t-OC(0)R²⁰, -(0)_u-(CH₂)_t-C(0)-NR²¹R²² or -(0)_u-(CH₂)_t-NHC(0)0-R²°; R²⁰, R²¹ and 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 bonded, form a non-aromatic heterocyclic ring;

Q is -NR²C(0)-, -NR²S(0)₂- or -C(0)0-;

R²⁴ and R²⁵ are independently -H, -OH, an aliphatic group or a substituted aliphatic group; u is zero or one; and t is an integer from zero to about 3.

14. The method of Claim 12 wherein R⁴⁰ is represented by -(0)_u-(CH₂)_t-C(0)-NR²¹R²².

15. The method of Claim 13 wherein u is zero and t one to about three.

16. The method of Claim 13 wherein u is one and t is zero.

17. The method of Claim 13 wherein u and t are both zero.

18. The method of Claim 12 wherein R⁴⁰ is a aliphatic group that is substituted with -NR²R²⁵ or -CONR²⁴R²⁵.

19. The method of Claim 12 wherein R⁴⁰ is -0- (aliphatic group) or -©-(substituted aliphatic group).

20. The method of Claim 12 wherein R⁴⁰ is -COOH.

21. The method of Claim 1 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X_: in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is -C (=NR⁶⁰) NR²¹R²², -O-C (0) -NR²¹R²⁶, -S(0)₂-NR²¹R²² or -N-C (0) -NR²¹R²²; wherein

R²¹ and 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 bonded, form a substituted or unsubstituted non-aromatic heterocyclic ring;

R²⁶ is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -C (0) -O- (substituted or unsubstituted aliphatic group), -C (0) -0- (substituted or unsubstituted aromatic group), -S (0) ₂- (substituted or unsubstituted aliphatic group), -S (0) ₂- (substituted or unsubstituted aromatic group) ; or

R²⁶ and R²¹, taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring.

22. The method of Claim 1 wherein X_λ is -CH₂-0-,

3. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

(

and physiologically acceptable salts thereof, wherein: n is an integer from one to about four; M is >NR², >CR^XR², -0-CR¹R²-0- or -CH₂-CR¹R²-0-;

The ring containing M is substituted or unsubstituted;

R¹ is -H, -OH, -N₃, a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl 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), -C (0)0- (aliphatic group), -C (0) 0- (substituted aliphatic group), -C00H, -CN, -CO-NR³R⁴, -NR³R⁴ or R¹ is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;

R² is -H, -OH, an acyl group, a substituted acyl group, -NR⁵R⁵, 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, a substituted non-aromatic heterocyclic group, -0- (substituted or unsubstituted aromatic group) or -0- (substituted or unsubstituted aliphatic 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 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 bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;

Z is represented by:

wherein:

W is -H, an electron withdrawing group, -CH₂-NRⁿR¹², -CH₂-0Rⁿ, -CH=NH, -CH₂-NH-CO-NR R¹², -CH₂-0-CO-NR¹¹R¹² 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 bonded, form a non-aromatic heterocyclic ring;

X_x is -S-, -S-CH₂-, -CH₂-S-, -CH₂-0-, -0-CH₂- , -CO-NR_c-, -NR_c-C0-, -CH₂-S(0)₂-, -S(0)₂-CH₂-, -CH₂-NR_C-, -NR_C-CH₂-, -CH₂-CH₂-, -CH=CH-, -CH₂-SO-, - SO- CH₂ - , -0- or a bond ;

R_c is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and

Ring A and Ring B are independently substituted or unsubstituted.

24. The method of Claim 23 wherein ring B is substituted para to the carbon atom of ring B that is bonded to _x in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is -OH, -COOH, -N0₂, halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, -NR²⁴R²⁵, -CONR²R²⁵, Q- (aliphatic group), Q- (substituted aliphatic group), -0- (aliphatic group), -0- (substituted aliphatic group), -0- (aromatic group), -0- (substituted aromatic group), an electron withdrawing group, - (0) _u- (CH₂) _t-C (0) OR²⁰, -(0)_u-(CH₂)_t-OC(0)R²⁰, -(0)_u-(CH₂)_t-C(0)-NR²¹R²² or -(0)_u-(CH₂)_t-NHC(0)0-R²⁰;

R²⁰, R²¹ and 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 bonded, form a non-aromatic heterocyclic ring;

Q is -NR²⁴C(0)-, -NR²⁴S(0)₂- or -C(0)0-;

R²⁴ and R²⁵ are independently -H, -OH, an aliphatic group or a substituted aliphatic group; u is zero or one; and t is an integer from zero to about 3.

The method of Claim 23 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X_λ in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is -C (=NR⁶⁰) NR²¹R²², -O-C (0) -NR²¹R²⁶, -S(0)₂-NR²¹R²² or -N-C (0) -NR²¹R²²; wherein

R²¹ and 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 bonded, form a substituted or unsubstituted non-aromatic heterocyclic ring;

R²⁶ is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -C (0) -0- (substituted or unsubstituted aliphatic group), -C (0) -0- (substituted or unsubstituted aromatic group), -S (0) ₂- (substituted or unsubstituted aliphatic group), -S (0) ₂- (substituted or unsubstituted aromatic group) ; or

R²⁶ and R²¹, taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring.

26. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

Z-Y-(CH₂)-X-NR⁵⁰R⁵¹

and physiologically acceptable salts thereof, wherein:

Y is a single covalent bond; n is an integer from one to about four; X is a covalent bond; R⁵⁰ and R⁵¹ are each, independently, -H, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, -NR³R⁴, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group or a covalent bond between the nitrogen atom an adjacent carbon atom;

R³ and R⁴ 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

R³ and R⁴ taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;

Z is represented by:

wherein:

W is -H, an electron withdrawing group, -CH₂-NRⁿR¹², -CH₂-0R^u, -CH=NH, -CH₂-NH-CO-NR¹¹R¹², -CH₂-0-CO-NR^uR¹² 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 bonded, form a non-aromatic heterocyclic ring;

X_τ is -S-, -S-CH₂-, -CH₂-S-, -CH₂-0-, -0-CH₂-, -CO-NR_c-, -NR_c-CO-, -CH₂-S(0)₂-, -S(0)₂-CH₂-, -CH₂-NR_C-, -NR_C-CH₂-, -CH₂-CH₂-, -CH=CH-, -CH₂-SO-, -S0-CH₂-, -O- or a bond;

R_c is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and

Ring A and Ring B are independently substituted or unsubstituted.

27. The method of Claim 26 wherein

R⁵⁰ is a substituted aliphatic group; and R⁵¹ is -H, an aliphatic group or a substituted aliphatic group.

21 The method of Claim 27 wherein R⁵⁰ is an aliphatic group that is substituted with an aromatic group.

29, The method of Claim 27 wherein R⁵⁰ is an aliphatic group that is substituted with a 4-chlorophenyl group .

30. The method of Claim 26 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X_x in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is -C (=NR⁶⁰) NR²¹R²², -O-C (0) -NR²¹R²⁶, -S(0)₂-NR²¹R²² or -N-C (0) -NR²¹R²²; wherein

R²¹ and 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 bonded, form a substituted or unsubstituted non-aromatic heterocyclic ring; R²⁶ is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -C (0) -0- (substituted or unsubstituted aliphatic group), -C (0) -0- (substituted or unsubstituted aromatic group), -S (0) ₂- (substituted or unsubstituted aliphatic group), -S (0) ₂- (substituted or unsubstituted aromatic group) ; or

R²⁶ and R²¹, taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring.

31. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

A^"

^■Y- (CH^ ^■X N M

and physiologically acceptable salts thereof, wherein:

Y is a single covalent bond; n is an integer from one to about four; X is a single covalent bond; A^" is a physiologically acceptable anion;

M is >NR² or >CR²;

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, a substituted non-aromatic heterocyclic group, -0- (substituted or unsubstituted aromatic group) or - 0- (substituted or unsubstituted aliphatic 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 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 bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;

Z is represented by:

wherein:

W is -H, an electron withdrawing group, -CH₂-NR^UR¹², -CH₂-0Rⁿ, -CH=NH, -CH₂-NH-CO-NR¹¹R¹², -CH₂-0-CO-NR^uR¹² 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 bonded, form a non-aromatic heterocyclic ring;

X_x is -S-, -S-CH₂-, -CH₂-S-, -CH₂-0-, -O-CH₂-, -CO-NR_c-, -NR_c-CO-, -CH₂-S(0)₂-, -S(0)₂-CH₂-, -CH₂-NR_C-, -NR_C-CH₂-, -CH₂-CH₂-, -CH=CH-, -CH₂-SO-, -SO-CH₂-, -O- or a bond;

R_c is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and

Ring A and Ring B are independently substituted or unsubstituted.

The method of Claim 31 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X_λ in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is -C (=NR⁶⁰) NR²¹R²², -O-C (0) -NR²¹R²⁶, -S (0)₂-NR²¹R²² or -N-C (0) -NR²¹R²²; wherein

R²¹ and 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 bonded, form a substituted or unsubstituted non-aromatic heterocyclic ring;

R²⁶ is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -C (O) -0- (substituted or unsubstituted aliphatic group), -C (0) -0- (substituted or unsubstituted aromatic group), -S (0) ₂- (substituted or unsubstituted aliphatic group), -S (0) ₂- (substituted or unsubstituted aromatic group) ; or

R²⁶ and R²¹, taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring.

33. A compound represented by the following structural formula:

or physiologically acceptable salt thereof, wherein:

Y is a single covalent bond; n is an integer from one to about four; X is a single covalent bond;

M is >NR², >CR^:R², -O-CR^-O- or -CH₂-CR¹R²-0-;

The ring containing M is substituted or unsubstituted; q¹ is an integer, such as an integer from zero to about three; q² is an integer from zero to about one;

R¹ is -H, -OH, -N₃, a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl 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), -C (0) 0- (aliphatic group), -C (0) 0- (substituted aliphatic group) , -C00H, -CN, -CO-NR³R⁴, -NR³R⁴ or R¹ is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;

R² is -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, a substituted non-aromatic heterocyclic group, -O- (substituted or unsubstituted aromatic group) or -0- (substituted or unsubstituted aliphatic 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 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 bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;

Z is represented by:

wherein: W is -H, an electron withdrawing group, -CH₂-NR^llR^u, -CH₂-OR¹¹, -CH=NH, -C^-NH-CO-NR^R¹² , -C^-O-CO-NR^R¹² 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 bonded, form a non-aromatic heterocyclic ring;

X_λ is -S-, -S-CH₂-, -CH₂-S-, -CH₂-0-, -0-CH₂-, -CO-NR_c-, -NR_c-CO-, -CH₂-S(0)₂-, -S(0)₂-CH₂-, -CH₂-NR_C-, -NR_C-CH₂-, -CH₂-CH₂-, -CH=CH-, -CH₂-S0-, -S0-CH₂-, -0- or a bond; R_c is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and

Ring A and Ring B are independently substituted or unsubstituted.

34. The compound of Claim 33 wherein

R¹ is -H, -OH, -N₃, -CN, a halogen, a substituted aliphatic group, an aminoalkyl group, -0- (aliphatic group), -0- (substituted aliphatic group) , -NR³R⁴ or R¹ is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;

R² is -NR⁵R⁶, a substituted acyl group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, -0-

( substituted or unsubstituted aromatic group) ; or

R¹ and R² taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.

35. The compound of Claim 33 wherein q¹ and q² are zero, and the compound is represented by the structural formula:

36. The compound of Claim 35 wherein M is >CR 1^XDR2

37. The compound of Claim 33 wherein q¹ is one and q² is zero, and the compound is represented by the structural formula:

38. The compound of Claim 37 wherein M is >CRl^XnR2

39. The compound of Claim 33 wherein q¹ is one and q² is two, and the compound is represented by the structural formula:

40. The compound of Claim 39 wherein M is >NR².

41. The compound of Claim 33 wherein q¹ is one and q² is two, and the compound is represented by the structural formula:

42. The compound of Claim 41 wherein M is -0-CR¹R²-0- or -CH.-CR^-O-.

43. The compound of Claim 41 wherein: M is >NR² or >CR^XR²; and

R¹ is a substituted aliphatic group or an aminoalkyl group.

44 . The compound of Claim 41 wherein : M is >NR² or >CR¹R² ; and

R² is -©- ( substituted or unsubstituted aromatic group ) .

45. The compound of Claim 33 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X_x in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is -OH, -COOH, -N0₂, halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, -NR²⁴R²⁵, -CONR²⁴R²⁵, Q- (aliphatic group), Q- (substituted aliphatic group), -0- (aliphatic group), -0- (substituted aliphatic group), -0- (aromatic group), -0- (substituted aromatic group), an electron withdrawing group, - (0) _u- (CH₂) _t-C (0) OR²⁰, -(0)_u-(CH₂)_t-0C(0)R²⁰, -(0)_u-(CH₂)_t-C(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; or

R²¹ and R²², taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;

Q is -NR²C(0)-, -NR²⁴S(0)₂- or -C(0)0-;

R²⁴ and R²⁵ are independently -H, -OH, an aliphatic group or a substituted aliphatic group; u is zero or one; and t is an integer from zero to about 3.

46. The compound of Claim 45 wherein R⁴⁰ is represented by -(0)_u-(CH₂)_t-C(0)-NR²¹R²².

47. The compound of Claim 46 wherein u is zero and t one to about three.

48. The compound of Claim 46 wherein u is one and t is zero .

49. The compound of Claim 46 wherein u and t are both zero .

50. The compound of Claim 45 wherein R⁴⁰ is a aliphatic group that is substituted with -NR²⁴R²⁵ or -CONR²⁴R²⁵.

51. The compound of Claim 45 wherein R⁴⁰ is -0- (aliphatic group) or -0- (substituted aliphatic group)

52. The compound of Claim 45 wherein R⁴⁰ is -C00H.

53. The compound of Claim 33 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X_x in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is -C (=NR⁶⁰) NR²¹R²², -O-C (0) -NR²¹R²⁶, -S(0)₂-NR²¹R²² or -N-C (0) -NR²¹R²²; wherein

R²¹ and 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 bonded, form a substituted or unsubstituted non-aromatic heterocyclic ring;

R²⁶ is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -C (0) -0- (substituted or unsubstituted aliphatic group), -C (0) -0- (substituted or unsubstituted aromatic group), -S (0) ₂- (substituted or unsubstituted aliphatic group), -S (O) ₂- (substituted or unsubstituted aromatic group) ; or R²⁶ and R²¹, taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring.

54. The compound of Claim 33 wherein X_x is -CH₂-0- .

55. A compound represented by the following structural formula:

or physiologically acceptable salt thereof, wherein: n is an integer from one to about four; M is >NR², >CR^XR², -0-CR¹R²-0- or -CH₂-CR¹R²-0-; The ring containing M is substituted or unsubstituted; R¹ is -H, -OH, -N₃, a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl 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), -C(0)0- (aliphatic group), -C (0) 0- (substituted aliphatic group), -C00H, -CN, -CO-NR³R⁴, -NR³R⁴ or R¹ is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M; 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, a substituted non-aromatic heterocyclic group, -0- (substituted or unsubstituted aromatic group) or - 0- (substituted or unsubstituted aliphatic 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 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 bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;

Z is represented by:

wherein:

W is -H, an electron withdrawing group, -CH₂-NRⁿR¹², -CH₂-0R^u, -CH=NH, -CH₂-NH-CO-NRⁿR¹², -CH₂-0-CO-NRⁿR¹² 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 bonded, form a non-aromatic heterocyclic ring;

Xi is -S-, -S-CH₂-, -CH₂-S-, -CH₂-0-, -0-CH₂-, -CO-NR_c-, -NR_c-CO-, -CH₂-S(0)₂-, -S(0)₂-CH₂-, -CH₂-NR_C-, -NR_C-CH₂-, -CH₂-CH₂-, -CH=CH-, -CH₂-SO-, -SO-CH₂-, -O- or a bond;

R_c is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and

Ring A and Ring B are independently substituted or unsubstituted.

56. The compound of Claim 55 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X_x in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is -OH, -COOH, -N0₂, halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, -NR²R²⁵,

-CONR²⁴R²⁵, Q- ( aliphatic group) , Q- ( substituted aliphatic group), -0- (aliphatic group),

-0- (substituted aliphatic group), -0- (aromatic group), -0- (substituted aromatic group), an electron withdrawing group,

- (O) _u- (CH₂) _t-C (0) OR²⁰, - (0) _u- (CH₂) _t-0C (0) R²⁰,

-(0)_u-(CH₂)_t-C(0)-NR²¹R²² or - (0) _u- (CH₂) _t-NHC (0) O-R²⁰; R²⁰, R²¹ and 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 bonded, form a non-aromatic heterocyclic ring;

Q is -NR²⁴C(0)-, -NR²⁴S(0)₂- or -C(0)0-;

R²⁴ and R²⁵ are independently -H, -OH, an aliphatic group or a substituted aliphatic group; u is zero or one; and t is an integer from zero to about 3.

57. The compound of Claim 55 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X_λ in ring C, and Z is represented by the structural formula:

wherein R^4ϋ is -C (=NR⁶⁰) NR²ⁱR² , -O-C (0) -NR¹R^2b, -S (0)₂-NR²¹R²² or -N-C (0) -NR²¹R²²; wherein

R²¹ and 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 bonded, form a substituted or unsubstituted non-aromatic heterocyclic ring; R²⁶ is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -C (0) -0- (substituted or unsubstituted aliphatic group), -C (0) -0- (substituted or unsubstituted aromatic group), -S (0) ₂- (substituted or unsubstituted aliphatic group), -S (0) ₂- (substituted or unsubstituted aromatic group) ; or

R²⁶ and R²¹, taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring.

58. A compound represented by the following structural formula :

Z-Y- (CH₂)-X-NR⁵⁰R⁵¹

and physiologically acceptable salts thereof, wherein:

Y is a single covalent bond; n is an integer from one to about four; X is a covalent bond;

R⁵⁰ and R⁵¹ are each, independently, -H, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, -NR³R⁴, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group or a covalent bond between the nitrogen atom an adjacent carbon atom;

R³ and R⁴ 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

R³ and R⁴ taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;

Z is represented by:

wherein:

W is -H, an electron withdrawing group, -CH₂-NRⁿR¹², -CH₂-0Rⁿ, -CH=NH, -CH₂-NH-CO-NR^uR¹², -CH₂-0-CO-NRⁿR¹² 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 bonded, form a non-aromatic heterocyclic ring;

X_x is -S-, -S-CH₂-, -CH₂-S-, -CH₂-0-, -0-CH₂-, -CO-NR_c-, -NR_c-CO-, -CH₂-S(0)₂-, -S(0)₂-CH₂-, -CH₂-NR_C-, -NR_C-CH₂-, -CH₂-CH₂-, -CH=CH-, -CH₂-SO-, -SO-CH₂-, -0- or a bond;

R_c is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.

59. The compound of Claim 58 wherein

R⁵⁰ is a substituted aliphatic group; and R⁵¹ is -H, an aliphatic group or a substituted aliphatic group.

60. The compound of Claim 59 wherein R⁵⁰ is an aliphatic group that is substituted with an aromatic group.

61. The compound of Claim 59 wherein R⁵⁰ is an aliphatic group that is substituted with a 4-chlorophenyl group .

62. The method of Claim 58 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X_x in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is -C (=NR⁶⁰) NR²¹R²², -O-C (0) -NR²¹R²⁶, -S(0)₂-NR²¹R²² or -N-C (0) -NR²¹R²²; wherein

R²¹ and 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 bonded, form a substituted or unsubstituted non-aromatic heterocyclic ring; R²⁶ is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -C (0) -0- (substituted or unsubstituted aliphatic group), -C (0) -0- (substituted or unsubstituted aromatic group), -S (0) ₂- (substituted or unsubstituted aliphatic group), -S (0) ₂- (substituted or unsubstituted aromatic group) ; or

R²⁶ and R²¹, taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring.

63. A compound reprsented by the following structural formula : A^"

+

Z Y (CH₂) - X N, ,M

and physiologically acceptable salts thereof, wherein:

Y is a single covalent bond; n is an integer from one to about four;

X is a single covalent bond;

A^" is a physiologically acceptable anion;

M is >NR² or >CR²;

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, a substituted non-aromatic heterocyclic group, -0- (substituted or unsubstituted aromatic group) or -0- (substituted or unsubstituted aliphatic 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 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 bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;

Z is represented by:

wherein:

W is -H, an electron withdrawing group, -CH₂-NRⁿR¹², -CH₂-0Rⁿ, -CH=NH, -CH₂-NH-CO-NRⁿR¹², -CH₂-0-CO-NR^uR¹² 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 bonded, form a non-aromatic heterocyclic ring;

Xi is -S-, -S-CH₂-, -CH₂-S-, -CH₂-0-, -0-CH₂-, -CO-NR_c-, -NR_c-CO-, -CH₂-S(0)₂-, -S(0)₂-CH₂-, -CH₂-NR_C-, -NR_C-CH₂-, -CH₂-CH₂-, -CH=CH-, -CH₂-SO-, -SO-CH₂-, -O- or a bond;

R_c is hydrogen, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and

Ring A and Ring B are independently substituted or unsubstituted.

64. The compound of Claim 63 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X_x in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is -C (=NR⁶⁰) NR²¹R²², -0-C (0) -NR²¹R²⁶, -S(0)₂-NR²¹R²² or -N-C (0) -NR²¹R²²; wherein

R²¹ and 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 bonded, form a substituted or unsubstituted non-aromatic heterocyclic ring;

R²⁶ is -H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a non-aromatic heterocyclic group, -C (0) -0- (substituted or unsubstituted aliphatic group), -C (0) -0- (substituted or unsubstituted aromatic group), -S (0) ₂- (substituted or unsubstituted aliphatic group), -S (0) ₂- (substituted or unsubstituted aromatic group) ; or

R²⁶ and R²¹, taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring.