WO2000069435A1 - Il-8 receptor antagonists - Google Patents

Abstract

This invention relates to novel compounds of Formula (I), and compositions thereof, useful in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).

Description

IL-8 RECEPTOR ANTAGONISTS FIELD OF THE INVENTION This invention relates to novel benzoisothiazole substituted compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating LL-8, GRO , GROβ, GROγ, ENA-78 and NAP-2 mediated diseases. BACKGROUND OF THE INVENTION Many different names have been applied to Interleukin-8 (IL-8), such as neutrophil attractant/activation protein- 1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NA ), and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-lα, IL-lβ or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al, J. Gin. Invest. 84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144, 2223 (1990) ; Strieter, et al, Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al, J. Immunol. 148. 3216 (1992). GROα, GROβ, GROγ and NAP-2 also belong to the chemokine α family.

Like IL-8 these chemokines have also been referred to by different names. For instance GROα, β, γhave been referred to as MGSAα, β and γ respectively (Melanoma Growth Stimulating Activity), see Richmond et al, J. Cell Physiology 129, 375 (1986) and Chang et al, J. Immunol 148, 451 (1992). All of the chemokines of the α-family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor.

LL-8, GROα, GROβ, GROγ, NAP-2 and ENA-78 stimulate a number of functions in vitro. They have all been shown to have chemoattractant properties for neutrophils, while IL-8 and GROα have demonstrated T-lymphocytes, and basophiles chemotactic activity. In addition IL-8 can induce histamine release from basophils from both normal and atopic individuals. GRO-α and IL-8 can in addition, induce lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac- 1 (CD1 lb/CD 18) on neutrophils without de novo protein synthesis. This may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many known diseases are characterized by massive neutrophil infiltration. As LL-8, Groα, GROβ, GROγ and NAP-2 promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis, Baggiolini et al, FEBS Lett. 307, 97 (1992); Miller et al, Crit. Rev. Immunol. 12. 17 (1992); Oppenheim et al, Annu. Rev. Immunol. 9. 617 (1991); Seitz et al., J. Clin. Invest. 87. 463 (1991); Miller et al., Am. Rev. Respir. Pis. 146. 427 (1992); Donnely et al., Lancet 341. 643 (1993). In addition the ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis. Strieter et al, Science 258, 1798 (1992). In vitro, IL-8, GROα, GROβ, GROγ and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane, G-protein-linked family, in particular by binding to LL-8 receptors, most notably the B-receptor. Thomas et al., J. Biol. Chem. 266. 14839 (1991); and Holmes et al., Science 253. 1278 (1991). The development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in: Progress in Drug Research. Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993. Hence, the LL-8 receptor represents a promising target for the development of novel anti-inflammatory agents. Two high affinity human IL-8 receptors (77% homology) have been characterized: LL-8Rα, which binds only IL-8 with high affinity, and LL-8Rβ, which has high affinity for LL-8 as well as for GRO-α, GROβ, GROγ and NAP-2. See Holmes et al., supra; Murphy et al., Science 253. 1280 (1991); Lee et al., J. Biol. Chem. 267, 16283 (1992); LaRosa et al., J. Biol. Chem. 267. 25402 (1992); and Gayle et al., J. Biol. Chem. 268. 7283 (1993). There remains a need for treatment, in this field, for compounds which are capable of binding to the LL-8 α or β receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds which are inhibitors of LL-8 receptor binding.

SUMMARY OF THE INVENTION This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 α or β receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular the chemokine is LL-8.

This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I). The present invention also provides for the novel compounds of Formula (I), and pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutical carrier or diluent.

Compounds of Formula (I) useful in the present invention are represented by the structure:

wherein

R is -NH -C(X)-NH- (CRι ₃Ri4)_v - Z;

Z is W, optionally substituted heteroaryl, optionally substituted C5_g cycloalkyl, optionally substituted C I _ I Q alkyl, optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl;

X is =O, or =S; A is CR2θR2i;

Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted

Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; C1 -10 alkoxy; halosubstituted Ci-io alkoxy; azide; (CRgRg)q S(O)_tR4, hydroxy; hydroxy Ci -4alkyl; aryl; aryl Cl-4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic; heterocyclicCι_4alkyl; heteroarylCi-4 alkyloxy; arylC2-10 alkenyl; heteroarylC2-10 alkenyl; heterocyclicC2-10 alkenyl; (CR₈R₈)qNR4R5; C₂-10alkenylC(O)NR4R5; (CR₈R₈)qC(O)NR4R5; (CR₈R₈)qC(O)NR4Rlθ; S(O)₃H; S(O)₃R8; (CR₈R₈)q C(O)Rn; C -10 alkenylC(O)Rn; C2-10alkenylC(O)ORι 1; C(O)Rι 1 ; (CR₈R₈)qC(O)ORi2;

(CR₈R₈)qOC(O)Ri 1; (CR₈R₈)qNR4C(O)Rι 1; (CR₈R₈)q NHS(O)₂Rl₇; (CR₈R₈)q S(O)_t; or two Rl moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring, and wherein the aryl, heteroaryl, and heterocyclic containing rings may be optionally substituted; n is an integer having a value of 1 to 3; m is an integer having a value of 1 or 3; q is 0, or an integer having a value of 1 to 10; t is 0, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3; v is 0, or an integer having a value of 1 to 4;

R4 and R5 are independently hydrogen, optionally substituted Cl-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, heterocyclic Ci-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;

Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CR₈R₈)q S(O)tR4; hydroxy; hydroxyCι_4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; arylC -4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Cl-4 alkyloxy; heterocyclic, heterocyclicC ι_4alkyl; aryl C2-10 alkenyl; heteroarylC2-10 alkenyl; heterocyclicC2-10 lkenyl; (CR R₈)qNR4R5; C2-10alkenylC(O)NR4R₅; (CR₈R₈)qC(O)NR4R5; (CR₈R₈)qC(O)NR₄Rlθ;

S(O)₃H; S(O)₃Rs; (CR₈R₈)qC(O)Rι 1 ; C₂-10 alkenylC(O)Rι 1; C₂-10alkenylC(O)ORι ι ; (CR₈R₈)qC(O)ORι₂; (CR₈R₈)q OC(O) Rπ; (CR₈R₈)qNR4C(O)Rn; (CR₈R₈)qNHS(O)_tRι₈; (CR₈R₈)qS(O)_tNR₄R₅; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring, and wherein the aryl, heteroaryl, and heterocyclic containing rings may be optionally substituted; R6 and R7 are independently hydrogen or a C1-.4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;

R₈ is independently hydrogen or Cl-4 alkyl;

RlO is Ci-io alkyl C(O)2R8;

Rl 1 is hydrogen, C1.4 alkyl, optionally substituted aryl, optionally substituted aryl

Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 -4alkyl; Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl; Rl3 and R 14 are independently hydrogen, optionally substituted Cl-4 alkyl, or one of R13 and R14 may be an optionally substituted aryl;

Rl7 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicC i-4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted; R ₈ is NRgR7, alkyl, arylCι.4 alkyl, arylC2-4alkenyl, heteroaryl, hetroaryl-

Cι_4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclicC .4 alkyl, wherein the aryl, heteoaryl and heterocyclic rings may all be optionally substituted; R20 and R21 are independently hydrogen, halogen, cyano, halosubstituted C 1.1 oalkyl, C 1.1 oalkyl, aryl, aryl C 1.4 alkyl, heteroaryl; heteroarylalkyl, heterocyclic, heterocyclic Ci-4alkyl, (CR₈R₈)qOR4, (CR₈R₈)qC(O)Rπ, (CR₈R₈)qC(O)ORi2, (CR₈R₈)qOC(O) Rl 1, (CR₈R₈)qNR4R5, (CR₈R₈)qNR4C(O)Rn, (CR₈R₈)q C(O)NR4Rιo; and wherein the aryl, heteroaryl, and heterocyclic containing rings may be optionally substituted, provided that both R20 and R21 are not hydrogen; the dotted line indicates optional unsaturation;

the E containing ring is optionally selected from

ⁿ ' ; the asterix * denoting point of attachment of the ring; or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

The compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of IL-8 or other chemokines which bind to the LL-8 α and β receptors. Chemokine mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.

In compounds of Formula (I), suitably Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl, such as CF3; Ci-io alkyl, such as methyl, ethyl, isopropyl, or n-propyl; C2-10 alkenyl; Ci-io alkoxy, such as methoxy, or ethoxy; halosubstituted Ci-io alkoxy, such as trifluoromefhoxy; azide; (CR₈R₈)q S(O)tR4, wherein t is 0, 1 or 2; hydroxy; hydroxy Ci-4alkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl; aryl Cl-4 alkyl, such as benzyl; aryloxy, such as phenoxy; aryl Cl-4 alkyloxy, such as benzyloxy; heteroaryl; heteroarylalkyl; heteroaryl Cl-4 alkyloxy; aryl C2-10 alkenyl ; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR₈R )qNR4R5; C2-10 alkenyl C(O)NR4R₅; (CR₈R₈)q C(O)NR4R5; (CRgR₈)q C(O)NR4Rl0; S(O) H; S(O)₃Rs; (CR₈Rg)q C(O)Rn; C₂-10 alkenyl C(O)Rn; C -10 alkenyl C(O)ORn; C(O)Rn; (CR₈R₈)q C(O)ORι₂; (CR₈R₈)q OC(O) Rn; (CR₈R₈)q NR4C(O)Ri 1, (CR₈R₈)q NHS(O)₂Rπ, (CR₈R₈)q S(O)₂NR4R5; ^{or two R}l moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring. All of the aryl, heteroaryl, and heterocyclic containing moieties above may be optionally substituted as defined herein below. Suitably, s is an integer having a value of 1 to 3. Suitably, q is 0, or an integer having a value of 1 to 10.

It is recognized that the R moiety may be substituted on the benzene ring or the A containing ring, if possible.

When Ri forms a dioxybridge, s is preferably 1. When Rl forms an additional saturated or unsaturated ring, it is preferably 6 membered unsaturated ring resulting in a naphthylene ring system. These rings may be optionally substituted independently, 1 to 3 times, by other Ri moieties as defined above.

Suitably, R4 and R5 are independently hydrogen, optionally substituted Cl-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, heterocyclicC 1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S.

Suitably, Rβ and R7 are independently hydrogen or a Cl-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur.

Suitably, R is independently hydrogen or Cl-4 alkyl.

Suitably, Rio is - 10 alkyl C(O)2R8, such as CH2C(O)2H or CH₂C(O)2CH₃.

Suitably, Rl l is hydrogen, Ci-4 alkyl, aryl, aryl Cl-4 alkyl, heteroaryl, heteroaryl Cι_4alkyl, heterocyclic, or heterocyclic Cι_4alkyl.

Suitably, R12 is hydrogen, Cl-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl. Suitably, R13 and R14 are independently hydrogen, an optionally substituted

Ci-4 alkyl which may be straight or branched as defined herein, or one of R13 and Rl4 are an optionally substituted aryl; v is 0, or an integer having a value of 1 to 4.

When R13 or R14 are an optionally substituted alkyl, the alkyl moiety may be substituted one to three times independently by halogen; halosubstituted Ci-4 alkyl such as trifluromethyl; hydroxy; hydroxy C _4alkyl, Cι_4 alkoxy; such as methoxy, or ethoxy, halosubstituted Ci-io alkoxy, S(O)tR4; aryl; NR4R5; NHC(O)R4; C(O)NR4R5; C(O)OR₈ or (SO) NR₄R₅. Suitably, R17 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi_4alkyl, heterocyclic, or heterocyclicC ι_4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted.

Suitably, Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted -io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted -io alkoxy; azide; (CR₈R₈)q S(O)_tR4; hydroxy; hydroxyCι_4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Ci-4 alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR₈R₈)q NR4R5; C2-10 alkenyl C(O)NR4R5; (CR₈R₈)q C(O)NR4R5; (CR₈R₈)q

C(O)NR4Rlθ; S(O)₃H; S(O)₃R₈; (CR₈R₈)q C(O)Rπ ; C -10 alkenyl C(O)Rn; C2-10 alkenyl C(O)ORn ; (CR₈R₈)q C(O)ORi ; (CR₈R₈)q OC(O) Rn ; (CR₈R₈)q NR4C(O)Rι 1 , (CR₈R₈)q NHS(O)₂Rι₈, (CR₈R₈)q S(O)₂NR₄R₅or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring. The aryl, heteroaryl and heterocyclic moieties noted above may all be optionally substituted as defined herein.

When Y forms a dioxybridge, s is preferably 1. When Y forms an additional saturated or unsaturated ring, it is preferably 6 membered unsaturated ring resulting in a naphthylene ring system. These rings may be optionally substituted 1 to 3 times by other Y moieties as defined above.

Suitably, Rj₈ is NR6R7, alkyl, aryl C .4 alklyl, arylC 2-4 alkenyl, heteroaryl, hetroaryl-C ^alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclicC -4 alkyl, wherein the aryl, heteoaryl and heterocyclic rings may all be optionally substituted. Y is preferably a halogen, Ci-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylene dioxy, NR4R5, thio Ci-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted Ci-4 alkyl, or hydroxy alkyl. Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or di-substituted in the 2'- position or 2'-, 3 '-position.

While Y may be substituted in any of the 5 ring positions, Y is preferably mono-substituted in the 2 -position or 3'- position, with the 4 - preferably being unsubstituted. If the ring is disubstituted, the substituents are preferably in the 2' or 3' position of a monocyclic ring. While both Ri and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are substituted. Suitably X is =O, or =S.

A is suitably C R2θR21- ^ *^{s note}d that the A containing ring may be saturated or unsaturated.

Suitably R20 and R21 are independently hydrogen, halogen, cyano, halosubstituted Ci-io alkyl; Ci-io alkyl; ; aryl; aryl Cl-4 alkyl; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic Ci-4alkyl; (CR₈R )q OR4, (CR R₈)q C(O)Rn; (CR₈R₈)q C(O)ORi₂; (CR₈R₈)q OC(O) Rπ; (CR₈R₈)q NR4R5; (CR₈R₈)q NR4C(O)Rι 1; (CR₈R )q C(O)NR4Rio, and wherein the aryl, heteroaryl, and heterocyclic containing rings may be optionally substituted, provided that both R20 and R2 are not hydrogen In compounds of Formula (I), suitably Z is W, optionally substituted heteroaryl, optionally substituted C5_₈ cycloalkyl, optionally substituted C\_\Q alkyl, optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl.

Suitably, Wi is

Suitably, the E' containing ring is optionally selected from

The E' containing ring, denoted by its point of attachment through the asterix

(*), may optionally be present. If not present the ring is a phenyl moiety which is substituted by the Y terms as shown. The E ring may be substituted by a (Y)_n moiety in any ring, saturated or unsaturated, and is shown for purposes herein substituted only in the unsaturated ring(s). When Z is an optionally substituted C5_₈ cycloalkyl ring, the ring may be substituted by (Y)_n as defined above.

When Z is an optionally substituted Cι_ιo alkyl, an optionally substituted

C2-10 alkenyl, or an optionally substituted C2-10 alkynyl, these moieties may be optionally substituted one or more times independently by halogen; nitro; cyano; halosubstituted Ci-io alkyl, such as trifluoromethyl; Ci-io alkoxy; halosubstituted

Ci-io alkoxy; S(O)tR4; hydroxy; hydroxy Ci-4alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryloxy; heteroaryl Ci-4 alkyloxy; heterocyclic, heterocyclic Cι_4alkyl; heterocyclic-oxy; heterocyclic C\_\ alkyloxy; NR4R5; C(O)NR4R5; C(O)NR4Rιo;

S(O)3H; S(O)3R₈; C(O)Rπ; C(O)ORi2; OC(O) Rn; NR4C(O)Rn- When Z is an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl these moieties may also, in addition to those moieties noted above, may also be optionally substituted with aryl, aryl Ci-4 alkyl, heteroaryl, and heteroarylalkyl. In compounds of Formula (I), when Z is a heteroaryl (HET) ring, it is suitably a heteroaryl ring or ring system. If the HET moiety is a multi ring system, the ring containing the heteroatom does not need to be directly attached to the urea moiety. All the rings in this ring system may be optionally substituted as defined herein. Preferably the HET moiety is a pyridyl, which may be 2-, 3- or 4-pyridyl. If the ring is a multi system ring it is preferably benzimidazole, dibenzothiophene, or an indole ring. Other heterocyclic rings of interest include, but are not limited to thiophene, furan, pyrimidine, pyrrole, pyrazole, quinoline, isoquinoline, quinazolinyl, pyridine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.

In compounds of Formula (I), the HET ring may be optionally substituted independently one to three times by Y(_n) as defined above.

Suitably, Rj is NR6R7, alkyl, arylCl-4alkyl, arylC 2-4 alkenyl, heteroaryl, hetroaryl-Cι_4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclicC 1.4 alkyl, wherein the alkyl, aryl, heteroaryl, and heterocyclic, containing moieties may be optionally substituted as defined herein.

As used herein, "optionally substituted" unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted Ci-ioalkyl; Ci-io alkoxy, such as methoxy or ethoxy; S(O)_m' Ci-io alkyl, wherein m' is 0, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl; amino, mono & di-substituted amino, such as in the NR4R5 group; NHC(O)R4; C(O)NR4Rs; C(O)OH; S(O)2NR4R5; NHS(O)2Rl9_, Ci-io alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted Ci-io alkyl, such CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, optionally substituted heterocylic, optionally substituted heterocylicalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, wherein these aryl, heteroaryl, or heterocyclic moieties may be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; C -io alkoxy; S(O) 'Ci-io alkyl; amino, mono & di-substituted amino, such as in the NR4R5 group; Ci-io alkyl, or halosubstituted Ci-io alkyl, such as CF3_? nitro, cyano and S(O)₂NR4R5_

Rl9 is suitably Ci-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicC i-4alkyl. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety or sulfoxyamide, or phenolic moiety. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.

The following terms, as used herein, refer to:

• "halo" - all halogens, that is chloro, fluoro, bromo and iodo.

• "C _ιoalkyl" or "alkyl" - both straight and branched chain radicals of 1 to

10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, wo-butyl, tert- butyl, n-pentyl and the like.

• The term "cycloalkyl" is used herein to mean cyclic rings, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like. • The term "alkenyl" is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l- propenyl, 1 -butenyl, 2-butenyl and the like.

• "aryl" - phenyl and naphthyl; • "heteroaryl" (on its own or in any combination, such as "heteroaryloxy", or "heteroaryl alkyl") - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.

• "heterocyclic" (on its own or in any combination, such as "heterocyclicalkyl") - a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.

• The term "arylalkyl" or "heteroarylalkyl" or "heterocyclicalkyl" is used herein to mean Ci-io alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated. • "sulfinyl" - the oxide S (O) of the corresponding sulfide, the term "thio" refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S(O)2 moiety.

• The term "wherein two Rl moieties (or two Y moieties) may together form a 5 or 6 membered saturated or unsaturated ring" is used herein to mean the formation of a ring system, such as a napthylene ring system or a phenyl moiety having attached a 6 membered partially unsaturated ring attached, such as a C cycloalkenyl, i.e hexene, or a C5 cyloalkenyl moiety, cyclopentene. Exemplified compounds of Formula (I) include: N-(3-chloro- 1 ,2-benzisothiazole-2-oxide)-N'-(2-bromophenyl) urea METHODS OF PREPARATION Methods of Preparation

The compounds of Formula (I) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below. The synthesis provided for in these Schemes is applicable for the producing of Formula (I) having a variety of different Z, Rj, and E groups which are reacted, employing optional substituents which are suitably protected to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. Once the urea nucleus has been established, further compounds of these formulas may be prepared by applying standard techniques for functional group interconversion, well known in the art. While the schemes are shown with various compounds of Formula (I) this is merely for illustration purposes only and not a limitation on the extent of synthesis available using these methods.

Another aspect of the invention is the novel process for making compounds of Formula (I), which process comprises a) reacting a compound of the formula

with a compound of the formula: C(X)-N- (CR₁₃Ri₄)_v - Z;

to yield a compound of Formula (I).

Another aspect of the present invention is the novel process of producing novel compounds of the formula:

Compounds of formula (A) may be prepared starting with the dichloride L; Scheme- 1 as outlined in Scheme 1. The dichloride 1 -Scheme- 1 may be converted to the nitro compound 2-Scheme-l using standard nitration conditions such as nitric and sulfuric acid in a suitable organic solvent such as methylene chloride. The bromide 2-Scheme-l may be converted to the sulfide 3-Scheme-l using 2- trimethylsilylethanethiol and a base such as sodium hydride in a suitable organic solvent such as THF or DMF.

Scheme 1

a) HN0₃, H₂S0₄, CH₂C_I2, b) NaH, HSCH₂CH₂TMS, THF

The desired cyclic sulfoxamine can be prepared as outlined in Scheme 2. The nitro compound l-Scheme-2 can be converted to the aniline 2-Scheme-2 using standard conditions such as ammonia in refluxing xylenes. The sulfide 2-Scheme-2 can be converted to the sulfoxide 3-Scheme-2 using standard conditions such as mCPBA in a suitable organic solvent such as methylene chloride. The sulfoxide 3^ Scheme-2 can be converted to the cyclic sulfoxamine 4-Scheme-2 by first conversion of the sulfoxide 3-Scheme-2 to the thionyl chloride using standard conditions such as thionyl chloride in a suitable organic solvent such as methylene chloride, followed by in situ cyclization promoted by a suitable base such as triethylamine or potassium carbonate. The aniline 5-Scheme-2 can be obtained from the nitro compound 4-Scheme-2 using standard reduction conditions such as tin (II) chloride in a suitable organic solvent such as ethanol. Scheme 2

a) NH₃, xylenes b) mCPBA, ChL.Cg c) SO-,^, then TEA d) SnC_β, ethanol

Alternatively, the desired sulfoxamine 5-Scheme-3 can be obtained from the dichloride 1 -Scheme-3 as outlined in Scheme 3. The dichloride 1 -Scheme-3 can be converted to the dinitro compound 2-Scheme-3 using standard conditions such as sodium nitrate in a suitable organic solvent such as THF. The dinitro compound 2^ Scheme-3 can be converted to the sulfoxide 3-Scheme-3 using standard conditions such as mCPBA in a suitable organic solvent such as methylene chloride. The sulfoxide can be converted to the sulfinyl chloride 4-Scheme-3 under standard conditions such as sulfuryl chloride in a suitable organic solvent such as methylene chloride. The sulfinyl chloride 4-Scheme-3 can be converted to the cyclic sulfoxamine 5-Scheme-3 by first reduction to the diamine using standard conditions such as tin (II) chloride in ethanol followed by in situ cyclization in the presence of an amine base such as triethylamine. Scheme 3

a) NaN0₂, THF b) mCPBA, CH₂C,₂ c) S0₂C_β d) SnC_E, ethanol, then TEA

Alternatively, the cyclic sulfoxamine 4-Scheme-4 can be prepared from the sulfoxide l-Scheme-4 as outlined in scheme 4. The sulfoxyl chloride 2-Scheme-4 can be obtained from the sulfoxide l-Scheme-4 using standard conditions such as sulfuryl chloride in a suitable organic solvent such as methylene chloride. The sulfoxyl chloride 2-Scheme-4 can be converted to the sulfoxamide 3-Scheme-4 using standard conditions such as ammonia hydroxide in a suitable organic solvent such as methylene chloride. The cyclic sulfoxamine 4-Scheme-4 can be obtained from the sufloxamide 3-Scheme-4 using standard methodolgy such as potassium carbonate in a suitable organic solvent such as methanol. The nitro compound ; Scheme-4 can be converted to the aniline using conditions described earlier. Scheme 4

a) S0₂CI₂; b) H₄NOH; c) K₂C0₃

If the desired alpha substituted cyclic sulfoxamines 4-Scheme-5 can not be prepared starting from commercially available substituted benzylhalides, they can be prepared as outlined in Scheme 5. The cyclic sufoxamine l-Scheme-5 can be converted to the BOC protected compound 2-Scheme-5 using standard conditions such as BOC anhydride in a suitable organic solvent such as THF. The substituted cyclic sulfoxamine 3-Scheme-5 can be prepared from the sulfoxamine 2-Scheme-5 by first deprotonation using a suitable base such as sodium hydride in a suitable organic solvent such as THF followed by addition of the desried alkyl halide. The cyclic sulfoxamine 4-Scheme-5 can be obtained from the sulfoxamine 3-Scheme-5 by first removal of the BOC group using standard methods such as TFA in a suitable organic solvent such as methylene chloride followed by reduction of the nitro group to the aniline using standard conditions such as tin (II) chloride in a suitable organic solvent such as ethanol. Scheme 5

c, d

a) (BOC)₂Q; b) NaH, R₁₈Br; c) TFA; d) SnCI₂

The final compounds of Formula (I), may be obtained from compounds of Formula (A) by condensation with an appropriate isocyanate or isothio cyanate derivative, such as the 2-bromophenyl shown in Scheme 5 below, in a suitable organic solvent, preferably DMF or ethanol.

Scheme 5

a) 2-bromophenyl isocyanate, DMF

SYNTHETIC EXAMPLES

The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. All temperatures are given in degrees centigrade, all solvents are highest available purity and all reactions run under anhydrous conditions in an argon atmosphere unless otherwise indicated.

In the Examples, all temperatures are in degrees Centigrade (°C). Mass spectra were performed upon a Fisons platform 8139 mass spectrometer using electron ionization unless otherwise indicated. ^H-NMR (hereinafter "NMR") spectra were recorded at 400 MHz using a Bruker Am 400 spectrometer. Multiplicities indicated are: s=singlet, d=doublet, dd=doublet of doublets, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat. indicates a saturated solution, eq indicates the proportion of a molar equivalent of reagent relative to the principal reactant. General Method: Synthesis of N, N'- phenyl urea To a solution of phenyl isocyanate ( 1.0 equiv.) in dimethyl formamide (1ml) the corresponding aniline (1.0 equiv.) was added. The reaction mixture was stirred at 80°C until complete (3-16 hrs.), then removed solvent under vacuum. The purification, yields and spectral characteristics for each individual compound are listed below. Additional synthetic methods are provided for in WO 96/25157 whose disclosure is incorporated herein by reference.

Example 1 Preparation of N-(3-chloro-l,2-benzisothiazole-2-oxide)-N'-(2-bromophenyl) urea. a) Preparation of 2,6-dichloro-α-bromo-3-nitrotoluene.

To a solution of 2,6-dichloro-α-bromotoluene (5 g) in sulfuric acid (12.5 mL) and CH2CI2 (15 mL) is added a solution of nitric acid (1.65 mL) in sulfuric acid (4.5 mL) at 0°C and the reaction is allowed to warm to rt. Upon completion, the reaction mixture is poured into ice water (125 mL) and extracted with methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 5.18 g (87%) of 2,6- dichloro-α-bromo-3-nitrotoluene as a yellow solid which requires no further purification. b) Preparation of 2,6-dichloro-alpha-(2-trimethylsilylethylthio)-3-nitrotoluene.

To a suspension of sodium hydride (1 mmol) in THF (5 mL) at 0°C is added 2-trimethylsilylethyl thiol (1 mmol). After 10 min, 2,6-dichloro-α-bromo-3- nitrotoluene (1 mmol) is added in THF (1.0 mL) and the reaction is allowed to warm to rt. Upon completion reaction is quenched with water (10 mL) and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2,6- dichloro-alpha-(2-trimethylsilylethylthio)-3-nitrotoluene which can be purified by either column chromatography or recrystalization. c) Preparation of 2-amino-6-chloro-alpha-(2-trimethylsilylethylsulfoxide)-3- nitrotoluene.

To a solution of 2,6-dichloro-alpha-(2-trimethylsilylethylthio)-3-nitrotoluene (1 mmol) in methylene chloride (1 mL) was bubbled ammonia gas at rt. Upon completion of the reaction, the reaction mixture was diluted with methylene chloride and washed with water. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated under educed pressure to give 2-amino-6-chloro-alpha-(2-trimethylsilylethylsulfoxide)-3-nitrotoluene which can be purified by either column chromatography or recrystalization. d) Preparation of l-chloro-4-nitro-2,3-benzisothiazole-2-oxide.

To a solution of 2-amino-6-chloro-alpha-(2-trimethylsilylethylsulfoxyl)-3- nitrotoluene) (1 mmol) in methylene chloride (5 mL) at -78°C is added triethylamine (4 mmol) and sulfuryl chloride (2 mmol). Upon completion, the reaction is quenched with water and extracted with ethylacetate. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give l-chloro-4-nitro-2,3-benzisothiazole-2-oxide which can be purified by either column chromatography or recrystalization. e) Standard procedure for the oxidation of a sulfoxide to the sulfonyl chloride. Preparation of l-chloro-4-nitro-2,3-benzisothiazole-2-oxide.

To a solution of 2-amino-6-chloro-alpha-(2-trimethylsilylethylsulfoxyl)-3- nitrotoluene) (1 mmol) in methylene chloride (5 mL) at -78°C is added triethylamine (4 mmol) and sulfuryl chloride (2 mmol). Upon completion, the reaction is quenched with water and extracted with ethylacetate. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give l-chloro-4-nitro-2,3-benzisothiazole-2-oxide which can be purified by either column chromatography or recrystalization. f) Standard procedure for the reduction of a nitro group. Preparation of 4- amino- 1- chloro-2,3-benzisothiazole-2-oxide.

To a solution of l-chloro-4-nitro-2,3-benzisothiazole-2-oxide (1 mmol) in ethanol (5 mL) is added tin (II) chloride (3 mmol). Upon completion the reaction mixture is diluted with ethyl acetate (100 mL) and sat. sodium bicarbonate (100 mL) is added upon which point the tin salts precipitate and are removed by filtration. The organic layers are dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-amino-lchloro-2,3-benzisothaizole-2-oxide which can be purified by either column chromatography or recrystalization. g) Preparation of 6-chloro-alpha-(2-trimethylsilylethylsulfoxy)-2,3-dinitrotoluene. The standard procedure is followed as outlined in experimental (c) above. h) Preparation of 6-chloro-alpha-(2-trimethylsilylethylsulfoxy)-2,3-dinitrotoluene. The standard procedure is followed as outlined in experimental (d) above to give 6-chloro-alpha-(2-trimethylsilylethylsulfoxy)-2,3-dinitrotoluene which can be purified by either column chromatography or recrystalization. i) Preparation of 4-amino-l-chloro-2,3-benzisothiazole-2-oxide from 6-chloro-alpha- chlorosulfinyl-2,3-dinitrotoluene.

The standard procedure outlined above was followed to give 4-amino-l- chloro-2,3-benzisothiazole-2-oxide which can be purified by either column chromatography or recrystalization. j) Preparation of 2,6-dichloro-3-nitro-alpha-(chlorosulfoxyl) toluene.

The standard procedure outlined above was followed to give 2,6-dichloro-3- nitro-alpha-(chlorosulfoxyl) toluene which can be purified by either column chromatography or recrystalization. k) Preparation of 2,6-dichloro-3-nitro-alpha-(aminosulfoxyl) toluene. To a solution of 2,6-dichloro-3-nitro-alpha-(chlorosulfoxyl) toluene (1 mmol) in methylene chloride ( 1 mL) was bubbled ammonia gas at rt. Upon completion of the reaction, the reaction mixture is filtered to remove the ammonia chloride salts and the crude reaction mixture is concentrated under reduced pressure to give 2,6-dichloro-3-nitro-alpha-(aminosulfoxyl) toluene which can be purified by either column chromatography or recrystalization.

1) Preparation of l-chloro-4-nitro-2,3-benzisothiazole-2-oxide.

To a solution of 2,6-dichloro-3-nitro-alpha-(aminosulfoxyl) toluene (1 mmol) in methanol (1 mL) was added potassium carbonate (2 mmol) at rt. Upon completion of the reaction, the reaction mixture is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give l-chloro-4-nitro-2,3-benzisothiazole-2-oxide which can be purified by either column chromatography or recrystalization. m) Preparation of l-chloro-4-nitro-2,3-[(N-tert-butylcarboxy)benzisothiazole-2- oxide]. To a solution of l-chloro-4-nitro-2,3-benzisothiazole-2-oxide (1 mmol) in THF (1 mL) was added BOC anhydride (1.1 mmol) at rt. Upon completion of the reaction, the reaction mixture is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give l-chloro-4- nitro-2,3-[(N-tert-butylcarboxy)benzisothiazole-2-oxide] which can be purified by either column chromatography or recrystalization. n) Preparation of l-chloro-4-nitro-2,3-[(N-tert-butylcarboxy)-2',2'-dimethyl- benzisothiazole-2-oxide] . To a solution of give l-chloro-4-nitro-2,3-[(N-tert- butylcarboxy)benzisothiazole-2-oxide] (1 mmol) in THF (1 mL) is added sodium hydride (2.2 mmol) at 0°C. After 15 min, iodomethane (2.2 mmol) is added and the reaction mixture is warmed to rt. Upon completion of the reaction, the reaction mixture is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to l-chloro-4-nitro-2,3-[(N-tert-butylcarboxy)- 2 ',2 -dimethyl -benzisothiazole-2-oxide] which can be purified by either column chromatography or recrystalization. o) Preparation of l-chloro-4-nitro-2,3-(2',2'-dimethyl-benzisothiazole-2-oxide). To a solution of l-chloro-4-nitro-2,3-[(N-tert-butylcarboxy)-2',2'-dimethyl- benzisothiazole-2-oxide] (1 mmol) in methylene chloride (1 mL) was added TFA (2 mmol) at 0°C and the reaction mixture is allowed to warm to rt. Upon completion of the reaction, the reaction mixture is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to l-chloro-4-nitro-2,3- (2',2'-dimethyl-benzisothiazole-2-oxide) which can be purified by either column chromatography or recrystalization. p) Preparation of l-chloro-4-amino-2,3-(2',2'-dimethyl-benzisothiazole-2-oxide). The standard procedure was followed using l-chloro-4-nitro-2,3-(2',2 - dimethyl-benzisothiazole-2-oxide) to give l-chloro-4-amino-2,3-(2',2 -dimethyl- benzisothiazole-2-oxide) which can be purified by either column chromatography or recrystalization.

METHOD OF TREATMENT The compounds of Formula (I), or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated IL-8 cytokine production by such mammal's cell, such as but not limited to monocytes and or macrophages, or other chemokines which bind to the IL-8 α or β receptor, also referred to as the type I or type II receptor.

Accordingly, the present invention provides a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an LL-8 α or β receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular, the chemokines are IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78.

The compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine function, in particular LL-8, GROα, GROβ, GROγ, NAP-2 or ENA- 78, such that they are biologically regulated down to normal levels of physiological function, or in some case to subnormal levels, so as to ameliorate the disease state. Abnormal levels of LL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 for instance in the context of the present invention, constitute: (i) levels of free IL-8 greater than or equal to 1 picogram per mL; (ii) any cell associated IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 above normal physiological levels; or (iii) the presence IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 above basal levels in cells or tissues in which LL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 respectively, or upregulation of the interleukin-8 receptors is produced.

There are many disease states in which excessive or unregulated LL-8 production is implicated in exacerbating and/or causing the disease. Chemokine mediated diseases include psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft vs. host reaction, alzheimers disease, allograft rejections, malaria, restinosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis or undesired hematopoietic stem cells release.

These diseases are primarily characterized by massive neutrophil infiltration, T-cell infiltration, or neovascular growth, and are associated with IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 production which is responsible for the chemotaxis of neutrophils into the inflammatory site or the directional growth of endothelial cells. In contrast to other inflammatory cytokines (IL-8, GROα, GROβ, GROγ, or NAP-2) has the unique property of promoting neutrophil chemotaxis, enzyme release including but not limited to elastase release as well as superoxide production and activation. The α-chemokines but particularly, GROα, GROβ, GROγ, or NAP-2, working through the IL-8 type I or II receptor can promote the neovascularization of tumors by promoting the directional growth of endothelial cells. Therefore, the inhibition of IL-8 induced chemotaxis or activation would lead to a direct reduction in the neutrophil infiltration.

Recent evidence also implicates the role of chemokines in the treatment of HIV infections, Littleman et al., Nature 381, pp661 (1996) and Koup et al., Nature 381, pp 667 (1996).

The present invention also provides for a means of treating, in an acute setting, as well as preventing, in those individuals deemed susceptible to, CNS injuries by the chemokine receptor antagonist compounds of Formula (I).

CNS injuries as defined herein include both open or penetrating head trauma, such as by surgery, or a closed head trauma injury, such as by an injury to the head region. Also included within this definition is ischemic stroke, particularly to the brain area.

Ischemic stroke may be defined as a focal neurologic disorder that results from insufficient blood supply to a particular brain area, usually as a consequence of an embolus, thrombi, or local atheromatous closure of the blood vessel. The role of inflammatory cytokines in this are has been emerging and the present invention provides a mean for the potential treatment of these injuries. Relatively little treatment, for an acute injury such as these has been available.

TNF-α is a cytokine with proinflammatory actions, including endothelial leukocyte adhesion molecule expression. Leukocytes infiltrate into ischemic brain lesions and hence compounds which inhibit or decrease levels of TNF would be useful for treatment of ischemic brain injury. See Liu et al., Stoke, Vol. 25., No. 7, pp 1481-88 (1994) whose disclosure is incorporated herein by reference.

Models of closed head injuries and treatment with mixed 5-LO/CO agents is discussed in Shohami et al., J. of Vaisc & Clinical Physiology and Pharmacology, Vol. 3, No. 2, pp. 99-107 (1992) whose disclosure is incorporated herein by reference. Treatment which reduced edema formation was found to improve functional outcome in those animals treated.

The compounds of Formula (I) are administered in an amount sufficient to inhibit IL-8, binding to the IL-8 alpha or beta receptors, from binding to these receptors, such as evidenced by a reduction in neutrophil chemotaxis and activation. The discovery that the compounds of Formula (I) are inhibitors of IL-8 binding is based upon the effects of the compounds of Formulas (I) in the in vitro receptor binding assays which are described herein. The compounds of Formula (I) have been shown to be inhibitors of type II LL-8 receptors.

As used herein, the term "IL-8 mediated disease or disease state" refers to any and all disease states in which IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 plays a role, either by production of IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 themselves, or by IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 causing another monokine to be released, such as but not limited to IL-1, IL-6 or TNF. A disease state in which, for instance, fL-1 is a major component, and whose production or action, is exacerbated or secreted in response to IL-8, would therefore be considered a disease stated mediated by LL-8.

As used herein, the term "chemokine mediated disease or disease state" refers to any and all disease states in which a chemokine which binds to an IL-8 α or β receptor plays a role, such as but not limited IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78. This would include a disease state in which, IL-8 plays a role, either by production of IL-8 itself, or by IL-8 causing another monokine to be released, such as but not limited to IL-1, IL-6 or TNF. A disease state in which, for instance, LL-1 is a major component, and whose production or action, is exacerbated or secreted in response to IL-8, would therefore be considered a disease stated mediated by IL-8. As used herein, the term "cytokine" refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response. A cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them. For instance, a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte. Many other cells however also produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes and B-lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cytokines include, but are not limited to, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (LL-8), Tumor Necrosis Factor-alpha (TNF-α) and Tumor Necrosis Factor beta (TNF-β).

As used herein, the term "chemokine" refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response, similar to the term "cytokine" above. A chemokine is primarily secreted through cell transmembranes and causes chemotaxis and activation of specific white blood cells and leukocytes, neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth muscle cells. Examples of chemokines include, but are not limited to, IL-8, GRO-α, GRO-β, GRO-γ, NAP-2, ENA-78, IP- 10, MlP-lα, MlP-β, PF4, and MCP 1, 2, and 3.

In order to use a compound of Formula (I) or a pharmaceutically acceptable salt thereof in therapy, it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. This invention, therefore, also relates to a pharmaceutical composition comprising an effective, non- toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.

Compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation. The compounds of Formula (I) may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures. The compounds of Formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax. A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25mg. to about lg. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.

Compounds of Formula (I) may be administered topically, that is by non- systemic administration. This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the Formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the Formulation.

Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.

Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.

Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100 C. for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.

Compounds of formula (I) may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques. Compounds of Formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.

For all methods of use disclosed herein for the compounds of Formula (I), the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight. The daily parenteral dosage regimen about 0.001 to about 80 mg/kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, administered one to four, preferably two or three times daily. The daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day. It will also be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of

Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

The invention will now be described by reference to the following biological examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. BIOLOGICAL EXAMPLES

The IL-8, and Gro-α chemokine inhibitiory effects of compounds of the present invention are determined by the following in vitro assay: Receptor Binding Assays:

[125i] IL-8 (human recombinant) is obtained from Amersham Corp., Arlington Heights, LL, with specific activity 2000 Ci/mmol. Gro-α is obtained from NEN- New England Nuclear. All other chemicals are of analytical grade. High levels of recombinant human IL-8 type α and β receptors were individually expressed in Chinese hamster ovary cells as described previously (Holmes, et al., Science, 1991, 253, 1278). The Chinese hamster ovary membranes were homogenized according to a previously described protocol (Haour, et al., J Biol Chem., 249 pp 2195-2205 (1974)). Except that the homogenization buffer is changed to lOmM Tris-HCL, ImM MgS04, 0.5mM EDTA (ethylene-diaminetetra- acetic acid), ImMPMSF (α-toluenesulphonyl fluoride), 0.5 mg/L Leupeptin, pH 7.5. Membrane protein concentration is determined using Pierce Co. micro-assay kit using bovine serum albumin as a standard. All assays are performed in a 96-well micro plate format. Each reaction mixture contains 125j JL_ (0.25 nM) or 125j Gro-α and 0.5 μg/mL of LL-8Rα or 1.0 μg/mL of IL-8Rβ membranes in 20 mM Bis- Trispropane and 0.4 mM Tris HCl buffers, pH 8.0, containing 1.2 mM MgSO4, 0.1 mM EDTA, 25 mM NaCl and 0.03% CHAPS. In addition, drug or compound of interest is added which has been pre-dissolved in DMSO so as to reach a final concentration of between O.OlnM and 100 uM. The assay is initiated by addition of 125J_IL_ After 1 hour at room temperature the plate is harvested using a Tomtec 96-well harvester onto a glass fiber filtermat blocked with 1% polyethylenimine/0.5% BSA and washed 3 times with 25 mM NaCl, 10 mM TrisHCl, 1 mM MgSO4, 0.5 mM EDTA, 0.03 % CHAPS, pH 7.4. The filter is then dried and counted on the Betaplate liquid scintillation counter. The recombinant IL- 8 Rα, or Type I, receptor is also referred to herein as the non-permissive receptor and the recombinant IL-8 Rβ, or Type II, receptor is referred to as the permissive receptor.

Respresentative compounds of Formula (I), Examples 1 to 4, have been found to have positive inhibitory activity of < 30 μmg in this assay. Chemotaxis Assay: The in vitro inhibitory properties of these compounds are determined in the neutrophil chemotaxis assay as described in Current Protocols in Immunology, vol I, Suppl 1, Unit 6.12.3., whose disclosure is incorporated herein by reference in its entirety. Neutrophils where isolated from human blood as described in Current Protocols in Immunology Vol I, Suppl 1 Unit 7.23.1, whose disclosure is incorporated herein by reference in its entirety. The chemoattractants LL-8, GRO-α, GRO-β, GRO-γ and NAP-2 are placed in the bottom chamber of a 48 multiwell chamber (Neuro Probe, Cabin John, MD) at a concentration between 0.1 and 100 nM. The two chambers are separated by a 5um polycarbonate filter. When compounds of this invention are tested, they are mixed with the cells (0.001 - 1000 nM) just prior to the addition of the cells to the upper chamber. Incubation is allowed to proceed for between about 45 and 90 min at about 37°C in a humidified incubator with 5% CO2. At the end of the incubation period, the polycarbonate membrane is removed and the top side washed, the membrane then stained using the Diff Quick staining protocol (Baxter Products, McGaw Park, LL, USA). Cells which have chemotaxed to the chemokine are visually counted using a microscope.

Generally, four fields are counted for each sample, these numbers are averaged to give the average number of cells which had migrated. Each sample is tested in triplicate and each compound repeated at least four times. To certain cells (positive control cells) no compound is added, these cells represent the maximum chemotactic response of the cells. In the case where a negative control (unstimulated) is desired, no chemokine is added to the bottom chamber. The difference between the positive control and the negative control represents the chemotactic activity of the cells. Elastase Release Assay:

The compounds of this invention are tested for their ability to prevent Elastase release from human neutrophils. Neutrophils are isolated from human blood as described in Current Protocols in Immunology Vol I, Suppl 1 Unit 7.23.1.

PMNs 0.88 x 10⁶ cells suspended in Ringer's Solution (NaCl 118, KC1 4.56, NaHCO3 25, KH2PO4 1.03, Glucose 11.1, HEPES 5 mM, pH 7.4) are placed in each well of a 96 well plate in a volume of 50 ul. To this plate is added the test compound (0.001 - 1000 nM) in a volume of 50 ul, Cytochalasin B in a volume of 50 ul (20ug/ml) and Ringers buffer in a volume of 50 ul. These cells are allowed to warm (37 °C, 5% CO2, 95% RH) for 5 min before LL-8, GROα, GROβ, GROγ or NAP-2 at a final concentration of 0.01 - 1000 nM was added. The reaction is allowed to proceed for 45 min before the 96 well plate is centrifuged (800 xg 5 min) and 100 ul of the supernatant removed. This suppernatant is added to a second 96 well plate followed by an artificial elastase substrate (MeOSuc- Ala- Ala-Pro- Val- AMC, Nova Biochem, La Jolla, CA) to a final concentration of 6 ug/ml dissolved in phosphate buffered saline. Immediately, the plate is placed in a fluorescent 96 well plate reader (Cytofluor 2350, Millipore, Bedford, MA) and data collected at 3 min intervals according to the method of Nakajima et al J. Biol Chem 254 4027 (1979). The amount of Elastase released from the PMNs is calculated by measuring the rate of MeOSuc- Ala- Ala-Pro- Val-AMC degradation. TNF-α in Traumatic Brain Injury Assay

The present assay provides for examination of the expression of tumor necrosis factor mRNA in specfic brain regions which follow experimentally induced lateral fluid-percussion traumatic brain injury (TBI) in rats. Adult Sprague-Dawley rats (n=42) were anesthetized with sodium pentobarbital (60 mg/kg, i.p.) and subjected to lateral fluid-percussion brain injury of moderate severity (2.4 atm.) centered over the left temporaparietal cortex (n=18), or "sham" treatment (anesthesia and surgery without injury, n=18). Animals are sacrificed by decapitation at 1, 6 and 24 hr. post injury, brains removed, and tissue samples of left (injured) parietal cortex (LC), corresponding area in the contralateral right cortex (RC), cortex adjacent to injured parietal cortex (LA), corresponding adjacent area in the right cortex (RA), left hippocampus (LH) and right hippocampus (RH) are prepared. Total RNA was isolated and Northern blot hybridization is performed and quantitated relative to an TNF-α positive control RNA (macrophage = 100%). A marked increase of TNF- α mRNA expression is observed in LH (104±17% of positive control, p < 0.05 compared with sham), LC (105±21%, p< 0.05) and LA (69±8%, p < 0.01) in the traumatized hemisphere 1 hr. following injury. An increased TNF- α mRNA expression is also observed in LH (46±8%, p < 0.05), LC (30±3%, p < 0.01) and LA (32±3%, p < 0.01) at 6 hr. which resolves by 24 hr. following injury. In the contralateral hemisphere, expression of TNF- α mRNA is increased in RH (46±2%, p < 0.01), RC (4±3%) and RA (22±8%) at 1 hr. and in RH (28±11%), RC (7±5%) and RA (26±6%, p < 0.05) at 6 hr. but not at 24 hr. following injury. In sham (surgery without injury) or naive animals, no consistent changes in expression of TNF- α mRNA are observed in any of the 6 brain areas in either hemisphere at any times. These results indicate that following parasagittal fluid- percussion brain injury, the temporal expression of TNF-α mRNA is altered in specific brain regions, including those of the non-traumatized hemisphere. Since TNF- α is able to induce nerve growth factor (NGF) and stimulate the release of other cytokines from activated astrocytes, this post-traumatic alteration in gene expression of TNF-α plays an important role in both the acute and regenerative response to CNS trauma. CNS Injury model for IL-β mRNA: This assay characterizes the regional expression of interleukin-lβ (IL-lβ) mRNA in specific brain regions following experimental lateral fluid-percussion traumatic brain injury (TBI) in rats. Adult Sprague-Dawley rats (n=42) are anesthetized with sodium pentobarbital (60 mg/kg, i.p.) and subjected to lateral fluid-percussion brain injury of moderate severity (2.4 atm.) centered over the left temporaparietal cortex (n=18), or "sham" treatment (anesthesia and surgery without injury). Animals are sacrificed at 1, 6 and 24 hr. post injury, brains removed, and tissue samples of left (injured) parietal cortex (LC), corresponding area in the contralateral right cortex (RC), cortex adjacent to injured parietal cortex (LA), corresponding adjacent area in the right cortex (RA), left hippocampus (LH) and right hippocampus (RH) are prepared. Total RNA is isolated and Northern blot hybridization was performed and the quantity of brain tissue IL-lβ mRNA is presented as percent relative radioactivity of IL-lβ positive macrophage RNA which was loaded on same gel. At 1 hr. following brain injury, a marked and significant increase in expression of LL-lβ mRNA is observed in LC (20.0±0.7% of positive control, n=6, p < 0.05 compared with sham animal), LH (24.5±0.9%, p < 0.05) and LA (21.5±3.1%, p < 0.05) in the injured hemisphere, which remained elevated up to 6 hr. post injury in the LC (4.0±0.4%, n=6, p < 0.05) and LH (5.0±1.3%, p < 0.05). In sham or naive animals, no expression of IL-lβ mRNA is observed in any of the respective brain areas. These results indicate that following TBI, the temporal expression of IL-IB mRNA is regionally stimulated in specific brain regions. These regional changes in cytokines, such as EL- IB play a role in the post- traumatic.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the are can, using the preceding description, utilize the present invention to its fullest extent. Therefore the

Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

What is claimed is:

1. A compound of the formula:

wherein

R is -NH -C(X)-NH- (CRι₃Rι₄)_v - Z;

Z is W, optionally substituted heteroaryl, optionally substituted C5_₈ cycloalkyl, optionally substituted CI_IQ alkyl, optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl; X is =O, or =S; A is CR₂()R2i;

Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CR R₈)q S(O)_tR4, hydroxy; hydroxy Ci-4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic; heterocyclicC i-4alkyl; heteroarylCi-4 alkyloxy; arylC2-10 alkenyl; heteroarylC2-10 alkenyl; heterocyclicC2-10 alkenyl; (CR₈R₈)qNR4R5; C₂-10alkenylC(O)NR4R5; (CR₈R₈)qC(O)NR4R5; (CR₈R₈)qC(O)NR4Rlθ; S(O)₃H; S(O)₃Rs; (CR₈R₈)q C(O)Rn; C₂-10 alkenylC(O)Rn; C2-10alkenylC(O)ORι 1; C(O)Rι 1; (CR₈R₈)qC(O)ORi2;

(CR₈R₈)qOC(O)Rn; (CR₈R₈)qNR4C(O)Rn; (CR₈R₈)q NHS(O)₂Ri₇; (CR R )q S(O)2NR4R5; or two Ri moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring, and wherein the aryl, heteroaryl, and heterocyclic containing rings may be optionally substituted; n is an integer having a value of 1 to 3; m is an integer having a value of 1 or 3; q is 0, or an integer having a value of 1 to 10; t is 0, or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3; v is 0, or an integer having a value of 1 to 4; R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, heterocyclic Ci-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;

Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CR₈R₈)q S(O)_tR4; hydroxy; hydroxyCi-4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Ci-4 alkyloxy; heterocyclic, heterocyclicC ι_4alkyl; aryl C2-10 alkenyl; heteroarylC2-10 alkenyl; heterocyclicC2-10^alkenyl; (CR R₈)qNR4R5; C₂-10alkenylC(O)NR4R5; (CR₈R₈)qC(O)NR4R5; (CR₈R₈)qC(O)NR4Rlθ; S(O)₃H; S(O)₃R8; (CR₈R₈)qC(O)Rn; C₂-10 alkenylC(O)Rn; C₂-10alkenylC(O)ORι ι; (CR₈R₈)qC(O)ORι₂; (CR₈R₈)q OC(O) Rn; (CR₈R₈)qNR4C(O)Rn; (CR₈R₈)qNHS(O)₂Ri₈; (CR₈R₈)qS(O)₂NR₄R5; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring, and wherein the aryl, heteroaryl, and heterocyclic containing rings may be optionally substituted;

R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;

R₈ is independently hydrogen or C1-.4 alkyl;

RlO is Ci-10 alkyl C(O)2R8; Rl l is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _4alkyl; R 2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl;

R 3 and R 14 are independently hydrogen, optionally substituted Ci-4 alkyl, or one of R13 and R14 may be an optionally substituted aryl;

Rl7 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC _4alkyl, heterocyclic, or heterocyclicC i-4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;

R ₈ is NRgR7, alkyl, arylCι.4 alkyl, arylC2-4alkenyl, heteroaryl, hetroaryl-

C _4alkyl, heteroarylC2_4 alkenyl, heterocyclic, heterocyclicC 1.4 alkyl, wherein the aryl, heteoaryl and heterocyclic rings may all be optionally substituted; R20 and R21 are independently hydrogen, halogen, cyano, halosubstituted

Ci-ioalkyl, Ci-ioalkyl, aryl, aryl Cl-4 alkyl, heteroaryl; heteroarylalkyl, heterocyclic, heterocyclic Ci-4alkyl, (CR₈R₈)qOR4, (CR₈R₈)qC(O)Rn, (CR₈R₈)qC(O)ORi2, (CR₈R₈)qOC(O) Rn, (CR₈R₈)qNR4R5, (CR₈R₈)qNR4C(O)Rn, (CR₈R₈)q C(O)NR4Rlθ; and wherein the aryl, heteroaryl, and heterocyclic containing rings may be optionally substituted, provided that both R20 and R21 are not hydrogen; the dotted line indicates optional unsaturation;

the E containing ring is optionally selected from

; the asterix * denoting point of attachment of the ring; or a pharmaceutically acceptable salt thereof.

2. The compound according to Claim 12 wherein Ri is halogen, cyano, nitro, CF3, C(O)NR4R5, alkenyl C(O)NR4R5, C(O)NR4Rιo, alkenyl C(O)ORι l, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or (CR R₈)qS(O)2NR4R5.

3. The compound according to Claim 1 wherein at least one of R20 ^and R-21 ^1S alkyl or halogen.

4. The compound according to Claim 1 wherein Z is W.

5. The compound according to Claim 4 wherein Y is halogen, Ci-4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR4R5, thioCι_4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted Ci-4alkyl, or hydroxy substituted alkyl.

6. The compound according to Claim 4 wherein Z is an optionally substituted heteroaryl.

7. The compound according to Claim 1 which is: N-(3-chloro-l,2-benzisothiazole-2-oxide)-N'-(2-bromophenyl) urea or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising an effective amount of a compound according to any of Claims 1 to 7, and a pharmaceutically acceptable carrier or diluent.

9. A method of treating a chemokine mediated disease state, wherein the chemokine binds to an IL-8 α or β receptor in a mammal, which comprises administering to said mammal an effective amount of a compound according to Claim 1.

10. The method according to Claim 9 wherein the mammal is afflicted with a chemokine mediated disease selected from psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulo-nephritis, thrombosis, alzheimers disease, graft vs. host reaction, or allograft rejections, atherosclerosis, gingivitis, or osteoporosis.