MXPA00002283A - Il-8 receptor antagonists - Google Patents

Abstract

This invention relates to novel spiro containing compounds of Formula (I), and compositions thereof, useful in the treatment of diesease states mediated by the chemokine, Interleukin-8 (IL-8). Compounds of Formula (I) are represented, interalia, by structure (I) wherein, R is -NH -C(X)-NH- (CR13R14)v-Z;Z is optionally substituted phenyl or naphtyl, optionally substituted heteroaryl, optionally substituted C5-8 cycloalkyl, optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl;X is=O, or=S;A is carbon which is contained within a 3-7 membered spiro ring, which ring may optionally contain a heteroatom selected from O/N/S;v is 0, or an integer having a value of 1 to 4;or a pharmaceutically acceptable salt thereof.

Description

RECEPTOR ANTAGONISTS IL-8 FIELD OF THE INVENTION This invention relates to novel substituted benzoisothiazole compounds, pharmaceutical compositions, methods for their preparation, and use thereof for treating diseases mediated by IL-8, GROa, GROß, GRO ?, ENA-78 and NAP-2.

BACKGROUND OF THE INVENTION Many different names have been applied to interleukin (IL-8), as neutrophil activating / activating protein -1 (NAP-1), monocyte-derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), 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 that include macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF. , IL-1a, IL-1β or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al., J. Clin. 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). GROa, GROß, GRO? and NAP-2 also belong to the family chemokine. Similar to IL-8, these chemokines have been referred to by different names. For example GROa, ß,? have been referred to as MGSAa, ß and? respectively (Growth Stimulating Activity of Melanoma or Growth Stimulating Activity Melanoma), see Richmond et al., J. Cell Physiology 129, 375 (1986) and Chang et al., J. Immunol 148, 451 (1992). All chemokines in the family that possess the ELR motif directly preceding the CXC motif bind to the IL-8B receptor. IL-8, GROa, GROß, GRO ?, NAP-2 and ENA-78 stimulate a number of functions in vitro. All of them have been shown to have chemoattractant properties for neutrophils, whereas IL-8 and GROa have demonstrated chemotactic activity of basophils and T-lymphocytes. In addition IL-8 can induce histamine release from basophils of both normal and atopic individuals. GRO-a and IL-8 may also induce lysozomal enzyme release and neutrophil respiratory bursts. IL-8 has also been shown to increase surface expression of Mac-1 (CD11 b / CD18) on neutrophils without de novo protein synthesis. This may contribute to increased adhesion of neutrophils to vascular endothelial cells. Many known diseases are characterized by massive infiltration of neutrophils. Like IL-8, Groa, GROß, GRO? 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. Dis 146, 427 (1992); Donnely et al., Lancet 341, 643 (1993). In addition, ELR chemokines (those that contain the ELR motif of amino acids just before the CXC motif) have also been implicated in angiostasis. Strieter et al., Science 258, 1798 (1992). In vitro, IL-8, GROa, GROß, GRO? and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory bursts, binding to and activating receptors of the seven-transmembrane family, chained to G protein, particularly binding to IL-8 receptors, most notably the receptor B. Thomas et al., J. Biol. Chem. 266, 14839 (1991); v Holmes et al., Science 253, 1278 (1991). The development of non-peptide small molecule antagonists for members of this recipient family is unprecedented. For a summary consult R. Freidinger in: Proqress in Drug Research, Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993. Hence, the IL-8 receptor represents a promising target for the development of new anti-inflammatory agents. Two IL-8 receptors of high human affinity (77% homology) have been characterized: IL-8Ra, which binds only to IL-8 with high affinity, and IL-8Rβ, which has high affinity for IL-8 as well as for GRO-a, GROß, GRO? 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 that are capable of binding the IL-8 a or β receptor. Therefore, conditions associated with an increase in the production of IL-8 (which is responsible for chemotaxis of neutrophils and subsets of T cells in the inflammatory site) would benefit by compounds that are inhibitors of IL-8 receptor binding.

BRIEF DESCRIPTION OF THE INVENTION This invention provides a method for treating a chemokine-mediated disease, characterized in that the chemokine is one that binds to an IL-8 a or β receptor and which method comprises administering an effective amount of a compound of formula (I) or an acceptable salt pharmaceutically thereof. In particular, the chemokine is IL-8. This invention also relates to a method for inhibiting the binding of IL-8 to its receptors in a mammal in need thereof comprising administering to said mammal an effective amount of a compound of formula (I). The present invention also provides novel compounds of formula (I), and pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutical carrier or diluent.

The compounds of formula (I) useful in the present invention are represented by the structure: wherein R is -NH -C (X) -NH- (CR13R? 4) v -Z; Z is W, optionally substituted heteroaryl, optionally substituted C5-8 cycloalkyl, optionally substituted C-MO alkyl, optionally substituted C2-10 alkenyl, or an optionally substituted C2-? Alkynyl; X is = O, or = S; R1 is independently selected from hydrogen; halogen; nitro; cyano; Halo-substituted C-MO alkyl; C-MO alkyl; C2-10 alkenyl; CMO alkoxy; halo-substituted C-MO alkoxy; azide; (CR8R8) qS (O) tR4, hydroxy; hydroxy C de -4 alkyl; aril; C1-4 arylalkyl; aryloxy; arylalkyloxy of C -? - 4; heteroaryl; C6-4 heteroarylalkyl; heterocyclic; C1-4 heterocyclic alkyl; C 1-4 heteroarylalkyloxy; C2-10 arylalkenyl; C2-10 heteroarylalkenyl; heterocyclic alkenyl of C2-? o; (CR8R8) qNR4R5; C2 -? 0-C (O) NR4R5 alkenyl; (CR8R8) qC (O) NR4R5; (CR8R8) qC (O) NR4R? 0; S (O) 3H; S (O) 3R8; (CR8R8) qC (O) Rn; alkenyl of C2-? 0-C (O) Rn; alkenyl of C2-? 0-C (O) ORn; .. * - á »," (CR8Rß) qC (0) OR ??; (CR8R8) qC (O) OR12; (CR8R8) qOC (O) Rn; (CRßRßJqNF CÍOJRn; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) R ..; (CR8R8) qNHS (O) 2R? 7; (CR8R8) qS (O) 2NR4R5; or two Ri portions together can forming -O- (CH2) sO- or a 5-6 membered saturated or unsaturated ring, and in which the aryl, heteroaryl, and heterocyclic containing rings can be optionally substituted; n is an integer having a value of 1 to 3, m is an integer that has a value of 1 or 3, q is 0, or an integer that has a value of 1 to 10, t is 0, or an integer that has a value of 1 or 2; 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 C1-4 alkyl, optionally substituted aryl, arylalkyl ? -4 optionally substituted, optionally substituted heteroaryl, optionally substituted C? -4 heteroarylalkyl, heterocyclic, C?? 4 heterocyclic alkyl, or R4 and R5 together with the nitrogen to which they are attached form a ring of 5 to 7 members which may optionally consist of an additional heteroatom selected from O / N / S; And it is independently selected from hydrogen; halogen; nitro; cyano; Halo-substituted C-MO alkyl; C-O alkyl; C2-? o alkenyl; C-MO alkoxy; Halo substituted alkoxy, azide; (CR8R8) qS (O) tR4; hydroxy; hydroxy C de -4 alkyl; aril; C1-4 arylalkyl; aryloxy; C1-4 arylalkyloxy; heteroaryl; heteroarylalkyl; C- heteroarylalkyloxy; heterocyclic; C 1-4 heterocyclic alkyl; C2-arylalkyl or C; C2-? o heteroarylalkenyl; C2-10 heterocyclic alkenyl. (CR8R8) qNR4R5; C2-? o-C (O) NR4R5 alkenyl; (CR8R8) qC (O) NR4R5; (CR8R8) qC (O) NR4R10; S (O) 3H; S (O) 3R8 (CR8R8) qC (O) Rn; alkenyl of C2-? 0-C (O) Rn; C2-10-C (O) alkenyl ORn (CR8Rβ) qC (0) ORn; (CR8R8) qC (O) OR12; (CR8R8) qOC (O) Rn (CR8R8) qNR4C (O) Rn; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) Rn (CR8R8) qNHS (O) 2R? 8; (CR8R8) qS (O) 2NR4R5; or two portions AND together can form -O- (CH2) s-O or a 5-6 membered saturated or unsaturated ring, and in which the aryl, heteroaryl, and heterocyclic containing rings can be optionally substituted; R6 and R7 are independently hydrogen or an alkyl group of C -? - 4, or Re and R7 together with the nitrogen to which they are attached form a ring of 5 to 7 members whose ring may optionally contain an additional heteroatom whose heteroatom is selected from oxygen, nitrogen or sulfur; R8 is independently hydrogen or C1-4 alkyl; R-io is C? -? O-C (O) 2R8 alkyl; R 11 is hydrogen, C 4 alkyl, optionally substituted aryl, optionally substituted C 1-4 arylalkyl, optionally substituted heteroaryl, optionally substituted C 1-4 heteroarylalkyl, optionally substituted heterocyclic, or optionally substituted C 5,6-substituted heterocyclic alkyl; R-? 2 is hydrogen, C-MO alkyl, optionally substituted aryl or optionally substituted arylalkyl; R 3 and Ru are independently hydrogen, optionally substituted C 4 alkyl, or one of R 3 and Ru can be an optionally substituted aryl; R-I5 and Rie are independently hydrogen, or an optionally substituted C-? -4 alkyl; R-? 7 is C? -4 alkyl, aryl, arylalkyl, heteroaryl, C? -4 heteroarylalkyl, heterocyclic, or heterocyclic C? -4alkyl, in which the aryl, heteroaryl and heterocyclic rings may all optionally be replaced; R-is is NR6R7, alkyl, arylalkyl of C 1-4, arylalkenyl of C 2-4, heteroaryl, heteroarylalkyl of C 1-4, heteroarylalkenyl of C 2-4, heterocyclic, alkyl of C-? 4- heterocyclic, in which the rings aryl, heteroaryl and heterocyclic may all be optionally substituted; R2o and R21 together with the carbon to which they are adhered form a 3 to 7 membered ring whose ring may optionally contain an additional heteroatom selected from oxygen, nitrogen or sulfur; and whose ring may be optionally substituted; The dotted line indicates optional unsaturation; W is --- a > i-i ----- > - - i ----- Sja &- the ring containing E is optionally selected from: the asterisk * denotes the point of adhesion of the ring; or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula (I) can also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of IL-8 or other chemokines that bind to the IL-8 a 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 the compounds of formula (I), Ri is conveniently independently selected from hydrogen; halogen; nitro; cyano; Halo-substituted C-MO alkyl, such as CF3; C-MO alkyl, such as methyl, ethyl, isopropyl, or n-propyl; C2-? o alkenyl; C-MO alkoxy, such as methoxy, or ethoxy; Halo-substituted C-MO alkoxy, such as trifluoromethoxy; azide; (CR8R8) qS (O) tR4, where t is 0, 1 or 2; hydroxy; hydroxyalkyl of C -? - 4, such as methanol or ethanol; aryl, such as phenyl or naphthyl; C 1 - arylalkyl, such as benzyl; aryloxy, such as phenoxy; C? -4 arylalkyloxy, such as benzyloxy; heteroaryl; Heteroarylalkyl of Ci- 4; C4-4 heteroarylalkyloxy; arylalkenyl of C2-? 0; C2-? o heteroarylalkenyl; heterocyclic alkenyl of C2-? 0; (CR8R8) qNR R5; C2-? o-C (O) NR4R5 alkenyl; (CR8R8) qC (O) NR4R5; (CR8R8) qC (O) NR4R10; S (O) 3H; S (O) 3R8; (CR8R8) qC (O) Rn; alkenyl of C2-? o-C (O) Rn; C2-10 alkenyl C (O) ORn; (CR8R8) qC (O) ORn; (CR8R8) qC (O) OR12; (CR8R8) qOC (O) Rn; (CR8R8) qNR4C (O) Rn; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) Rn; (CR8R8) qNHS (O) 2Ri7; (CR8R8) qS (O) 2NR4R5; or two Ri portions together can form -O- (CH2) sO- or a 5-6 membered saturated or unsaturated ring. All of the above aryl, heteroaryl, and heterocyclic containing portions may be optionally substituted as defined herein below. Conveniently, s is an integer that has a value of 1 to 3. Conveniently q is 0, or an integer having a value of 1 to 10. It is recognized that the Ri portion can be substituted on the benzene ring or the ring containing A, if possible. When Ri forms a dioxy bridge, s is preferably 1. When Ri forms an additional saturated or unsaturated ring, it is preferably an unsaturated 6-membered ring resulting in a naphthalene ring system. These rings can be optionally substituted independently, 1 to 3 times, by other portions Ri as defined above.

Conveniently, R and R 5 are independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted C 1-4 arylalkyl, optionally substituted heteroaryl, optionally substituted C 1-4 heteroarylalkyl, heterocyclic, C heterocyclic alkyl -, or R4 and R5 together with the nitrogen to which they are adhered form a ring of 5 to 7 members which may optionally consist of an additional heteroatom selected from O / N / S. Conveniently RQ and R are independently hydrogen or a C1-4 alkyl group, or R1 and R7 together with the nitrogen to which they are attached form a 5- to 7-membered ring whose ring may optionally contain an additional heteroatom whose heteroatom is selected of oxygen, nitrogen or sulfur. Conveniently, R8 is independently hydrogen or C1-4 alkyl. Conveniently, R10 is C? -? 0-C (O) 2R8 alkyl, as CH2C (O) 2H or CH2C (O) 2CH3. Conveniently, R n is hydrogen, C 1-4 alkyl, aryl, C 1-4 arylalkyl, heteroaryl, C 1-4 heteroarylalkyl, heterocyclic, or C 1-4 heterocyclic alkyl. Conveniently, R 12 is hydrogen, C-MO alkyl, optionally substituted aryl, or optionally substituted arylalkyl. Conveniently, R 3 and Ru are independently hydrogen, optionally substituted C 1-4 alkyl which may be direct or branched as defined herein, or one of R 3 and R are an optionally substituted aryl.; v is 0, or an integer having a value of 1 to 4. When R-? 3 or R are an optionally substituted alkyl, the alkyl portion can be substituted one to three times independently by halogen; C.sub.4-4 alkyl substituted as trifluoromethyl; hydroxy; hydroxyalkyl of C? -, C? -4 alkoxy; as methoxy, or ethoxy, halosubstituted alkoxy of C-MO, S (O) tR 4; aril; NR4R5; NHC (O) R4; C (O) NR4R5; or C (O) OR8. Conveniently, R-? 7 is C? -4 alkyl, aryl, arylalkyl, heteroaryl, C- heteroarylalkyl, heterocyclic, or C? -4 heterocyclic alkyl, in which the aryl, heteroaryl and heterocyclic rings can all be optionally replaced. Conveniently, Y is independently selected from hydrogen; halogen; nitro; cyano; Halo-substituted C-MO alkyl; C-MO alkyl; C2 -? 0 alkenyl; C? -10 alkoxy; halo-substituted alkoxy of C-i. ? o, azida; (CR8R8) qS (O) tR4; hydroxy; hydroxyalkyl of C? -; aril; arylalkyl C1-4; aryloxy; C1-4 arylalkyloxy; heteroaryl; heteroarylalkyl; C 1-4 heteroarylalkyloxy; heterocyclic; C heterocyclic alkyl; C2-10 arylalkenyl. C2-? o heteroarylalkenyl; heterocyclic alkenyl of C2-? o; (CR8R8) qNR4R5; C2-? o-C (O) NR4R5 alkenyl; (CR8R8) qC (O) NR4R5; (CR8R8) qC (O) NR4R? O; S (O) 3H; S (O) 3R8; (CRßRß) qC (0) R ??; alkenyl of C2-? o-C (0) Rn; alkenyl of C2-? O-C (O) ORn; (CR8R8) qC (O) ORu; (CR8R8) qC (O) OR12; (CR8R8) qOC (O) Rn; (CR8R8) qNR4C (O) Rn; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) Rn; (CR8R8) qNHS (O) 2R18; (CR8R8) qS (O) 2NR4R5; or two portions AND together they can form -O- (CH2) sO- or a 5-6 membered saturated or unsaturated ring. The aryl, heteroaryl and heterocyclic portions noted above may all be optionally substituted as defined herein. When Y forms a dioxy bridge, s is preferably 1. When Y forms an additional saturated or unsaturated ring, it is preferably an unsaturated 6-membered ring resulting in a naphthalene ring system. Those rings can be optionally substituted independently, 1 to 3 times, by other Y portions as defined above. Conveniently, R? 8 is NR6R7, alkyl, arylalkyl of C? -4, arylalkenyl of C2-4, heteroaryl, heteroarylalkyl of C? -, heteroarylalkenyl of C2-4, heterocyclic, heterocyclic alkyl of C1-4, in the which aryl, heteroaryl and heterocyclic rings can all be optionally substituted. And it is preferably a halogen, C? -4 alkoxy, optionally substituted aryl, aryloxy or optionally substituted arylalkoxy, methylenedioxy, NR R 5) C 1-4 thioalkyl, thioaryl, halo-substituted alkoxy, optionally substituted C 1-4 alkyl, or hydroxyalkyl. More preferably Y is mono substituted halogen, disubstituted halogen, monosubstituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably those groups are mono- or di-substituted at the 2'-position or the 2'-, 3'- position. While Y may be substituted in any of the 5 positions of the ring, Y is preferably mono-substituted at 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. Although Ri and Y can both be hydrogen, it is preferred that at least one of the rings be substituted, preferably both rings are substituted. Conveniently X is = O, or = S. A is conveniently CR2oR2i. Conveniently R20 and R21 together with the carbon to which they adhere form a 3-7 membered carbon ring, which ring may be optionally substituted, as defined herein; or R20 and R21 together with the carbon to which they are attached can form a 3- to 7-membered ring containing hetero, which hetero is selected from oxygen, nitrogen or sulfur (also referred to as O / N / S); this ring containing hetero can also be optionally substituted. Preferably the spiro ring is a 5 to 7 member ring, more preferably a 5 member ring. Conveniently, R15 and Rie are independently hydrogen, or a C1-4 alkyl optionally substituted as defined above for R3 and Ru- In compounds of formula (I), conveniently Z is W, optionally substituted heteroaryl, optionally substituted C5-8 cycloalkyl, optionally substituted Ci.ioalkyl, C2-? or optionally substituted alkenyl, or an optionally substituted C2-10 alkynyl. Conveniently, W is .-to- .

Conveniently, the ring containing E is optionally selected from The ring containing E, denoted by this junction point through the asterisk (*), may optionally be present. If it is not present, the ring is a phenyl portion which is substituted by the terms Y as shown. The ring E can be replaced by a portion (Y) n in any ring, saturated or unsaturated, and shown for objects herein substituted only in the unsaturated ring (s). When Z is an optionally substituted C5-8 cycloalkyl ring, the ring may be optionally substituted by (Y) n as defined above. When Z is an optionally substituted Ci.io alkyl, an optionally substituted C2-10 alkenyl, or a C2-? Alkynyl portion or optionally substituted, those portions may be optionally substituted one or more times independently by halogen; nitro; ..-.----- b-. cyano; Halo substituted alkyl of Ci.io, such as trifluoromethyl; C-MO alkoxy; halo-substituted alkoxy of C-MO; S (O) tR4; hydroxy; hydroxyalkyl of C? -; aryloxy; C1 arylalkyloxy; heteroaryloxy; C4-4 heteroarylalkyloxy; heterocyclic; C1-4 heterocyclic alkyl; oxyhetocyclic; C1-4 heterocyclic alkyloxy; NR4R5; C (O) NR4R5; C (O) NR4R? 0; S (O) 3H; S (O) 3R8; C (0) Rn; C (0) ORn; C (O) OR? 2; OC (O) Rn; or NR4C (O) Rn. When Z is a C2-? Or optionally substituted alkenyl, or an optionally substituted C2-? 0 alkynyl, those portions may also, in addition to those portions noted above, also be optionally substituted with aryl, C? - arylalkyl, heteroaryl, and heteroarylalkyl of C? -4. In compounds of formula (I), when Z is a heteroaryl ring (HET), it is conveniently a heteroaryl ring or heteroaryl ring system. If the HET portion is a multiple ring system, the ring containing the heteroatom does not need to be directly adhered to the urea portion. All rings in this ring system may be optionally substituted as defined herein. Preferably the HET portion is a pyridyl, which can be 2-, 3- or 4-pyridyl. If the ring is a multiple system ring it is preferably a benzimidazole ring, dibenzothiophene, or an indole. 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 can be optionally substituted independently by the term (Y) n as defined above. Conveniently, Rd is NR6R, alkyl, arylC1-4 alkyl, C2-4 arylalkenyl, heteroaryl, C6 heteroarylalkyl, C2- heteroarylalkenyl, heterocyclic, C ?- heterocyclic alkyl, in which the portions containing alkyl, aryl, heteroaryl, and heterocyclic may be optionally substituted as defined herein. As used herein, "optionally substituted" unless specifically defined, shall mean groups such as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; C1-10 hydroxy substituted alkyl; C 1 - alkoxy, such as methoxy or ethoxy; C? -? o-S (O) m 'alkyl in which m' is 0, 1 or 2, such as methylthio, methylsulfinyl or methylsulfonyl; amino, amino mono and di-substituted, as in the group NR4R5; NHC (O) R4; C (O) NR Rs; C (O) OH; S (O) 2 NR4R5; NHS (O) 2R19) d-10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; Halo-substituted C? _? alkyl, such as CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl such as benzyl or phenethyl, optionally substituted heterocyclic, optionally substituted heterocillykyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, wherein those aryl, heteroaryl, or heterocyclic portions may be substituted one or two times by halogen; hydroxy; alkyl substituted by hydroxy; C? -? 0 alkoxy; alkyl of C? -10 -S (O) rt; amino, amino mono and di-substituted, as in the group NR4R5; C.sub.1 -C.sub.3 alkyl, or C.sub.1-10 alkyl substituted as CF.sub.3.

R 19 is conveniently C 4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 -alkyl, heterocyclic, or heterocyclic-C 1-4 -alkyl. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of organic and inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic 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 the compounds of formula (I) can also be formed with a pharmaceutically acceptable cation, for example, if a substituent group consists of a carboxy moiety. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali, alkaline earth, ammonium and quaternary ammonium cations. The following terms, as used herein, refer to: • "Halo" - all halogens, ie chlorine, fluorine, bromine and iodine. • "C-MO alkyl" or "alkyl" - either straight or 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, / 'so-propyl, n-butyl, sec-butyl, /' so-butyl, te / f-butyl, n-pentyl and the like. • "Cilcoalkyl" is used herein to mean cyclic radicals, preferably 3 to 8 carbons, including but limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like. • "Alkenyl" is used herein at all times to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited therein, including, but not limited to ethenyl, 1 -propenyl, 2-propenyl, 2-methyl-1 -propenyl, 1 -butenyl, 2-butenyl and the like. • "Aryl" -phenyl and naphthyl. • "Heteroaryl" (alone or in any combination, such as "heteroaryloxy", or "Heteroarylalkyl") - 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, benzimidazole, or benzthiazole. • "Heterocyclic" (alone or in any combination, such as "heterocyclic alkyl") - a 4-10 membered saturated or partially unsaturated ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N , O or S; as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.

"Arylalkyl" or "heteroarylalkyl" or "heterocyclic alkyl" is used herein to mean C1-10 alkyl, as defined above, adhered to an aryl, heteroaryl or heterocyclic moiety, as defined herein, unless Indicate otherwise. • "sulfinyl" - the S (O) oxide of the corresponding sulfide, the term "thio" refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S (O) 2 portion. • The term "wherein two portions Ri (or two portions Y) may together form a saturated or unsaturated ring of 5 or 6 members" is used herein to mean the formation of a ring system, such as a ring system naphthalene or a phenyl portion having a 6-membered partially unsaturated ring adhered, such as a cycloalkenyl of Ce, ie hexene, or a cycloalkenyl portion of C5, cyclopentene.

Methods of preparation The compounds of formula (I) can be obtained by applying synthetic procedures, some of which are illustrated in the drawings below. The synthesis provided by these schemes is applicable for the production of formula (I) having a variety of different groups Z, R1, and E 'which are reacted, using optional substituents which are suitably protected to achieve compatibility with the reactions described in the present. Subsequent deprotection, in those cases, then allows compounds of the nature generally described. Once the urea core has been established, additional compounds of these formulas can be prepared by applying standard techniques for functional group interconversion, well known in the art. Although the schemes are shown with several compounds of formula (I) this is simply for purposes of illustration only and not a limitation of the degree of synthesis available using those methods.

SCHEME 1 . a) KSC (= O) CH3 b) CI2, AcOH / H2O c) NH4OH d) K2CO3, Cu If the desired heterocyclic compound 5-scheme 1 is not commercially available, the commercially available 2,6-dichlorobenzyl bromide can be treated with potassium thioacetate to form the thioacetate 2-ekema 1, followed by oxidation using chlorine gas in AcOH / H2O or sulfuryl chloride and acetic anhydride to form the sulfonyl chloride 3-echema 1. The sulfonyl chloride can be converted to the corresponding sulfonamide 4-scheme 1 using NH 4 OH followed by acidification or using ammonia gas in a suitable organic solvent, preferably methylene chloride. The cyclic sulfonamide 5-scheme 1 can be cyclized under basic conditions using potassium carbonate and a catalytic amount of copper metal followed by acidification.

SCHEME 2 a) NaH, allyl bromide b) Na [(CH3) 3Si] 2N, Br (CH2) 4Br c) NaBH4, Pd (Ph3) 4 d) NH4NO3, TFAA The cyclic sulfonamide 4-scheme 2 can be prepared first by protection of the nitrogen of compound 1-Scheme 2 as an allyl using allyl bromide and a base suitable as sodium hydride to give the compound 2-scheme 2. The 2-scheme 2 compound is alkylated with the desired dihalide using an excess amount of a strong base such as hexamethyldisilazane to give the compound 3-scheme 2. The allyl group is removed under suitable conditions, preferably using a palladium catalyst in the presence of a reducing agent such as sodium borohydride, tributyltin hydride or an organic acid such as 2-ethylhexanoic acid to give compound 4 scheme2. The nitro compound 5 ^ scheme 2 can be prepared from 4-scheme 2, using standard nitration conditions such as sodium nitrate in sulfuric acid and water, ammonium nitrate and trifluoroacetic acid, or nitric acid in acetic anhydride.

SCHEME 3 1 2 3 a) SnCl 2, EtOH b) 2-BrPhNCO, DMF Compound 2-scheme 3 can be obtained from the nitro compound 1-echema 3, using standard reduction conditions preferably SnCl 2 in EtOH. The orthosubstituted heterocyclic phenyl ureas 3-scheme 3 can be prepared by condensation of the desired aryl isocyanate with the corresponding aniline 2-scheme 3 in an aprotic solvent such as DMF at room temperature or heating. Alternatively the desired isocyanates can be made by condensing the amine 2-scheme 3 with triphosgene in the presence of base (such as potassium carbonate) or by reacting the carboxylic acid with diphenyl phosphoazide in the presence of a base (such as triethylamine). Another aspect of the invention is a process for producing a compound of formula (I) which process comprises a) reacting the compound of formula: (II) in which A, Ri, and m are as defined for formula (I); with a compound of the formula: C (X) -N- (CR? 3Ru) v-Z; Wherein X, R13, Ru, v and Z are as defined in formula (I); To yield a compound of formula (I); and then if necessary, check out, or convert a precursor of Ri, A, or Z to a group Ri, A, or Z.

An alternate method for producing the compounds of formula (I) is a process which comprises reacting a compound of the formula: (W) In which A, Ri, and m are as defined for formula (I); With a compound of the formula: NH2-C (X) -N- (CR? 3Ru) v-Z; Wherein X, R 3, Ru, v and Z are as defined in formula (I); To render a compound of formula (I), and then if necessary, deprotect or convert a precursor of R1 f A or Z to a group Ri, A or Z. Another aspect of the present invention is a process for producing a compound of Formula (II): (II) In which A, Ri and m are as defined in formula (I); Whose process comprises reducing a compound of formula (III): wherein A, Ri and m are as defined in formula (I), under suitable reducing conditions to yield a compound of formula (II). Another aspect of the present invention are the novel compounds of the formula: In which A, Ri and m are as defined in formula (I), another aspect of the present invention are the new compounds of the formula: wherein A, Ri, and m are as defined in the formula (I) Suitable methods of manufacturing the compounds of the formula C (X) -N- (CR13Ru) vZ or NH2-C (X) -N- ( CR? 3Ru) vZ can be found in various publications, such as, but not limited to WO98 / 32438, the descriptions of which are incorporated herein by reference.

SYNTHETIC EXAMPLES The invention will now be described by reference to the following examples which are merely illustrative and should not be construed as limiting the scope of the present invention. All temperatures are given in degrees centigrade, all solvents have the highest purity available and all reactions run under anhydrous conditions in an argon atmosphere unless otherwise indicated. In the examples, all temperatures are in degrees centigrade (° C). The mass spectra were carried out under a VG Zab mass spectrometer using the rapid bombardment of atoms, unless indicated otherwise. The 1H-NMR spectra (hereinafter "NMR") were recorded at 250 MHz using a Bruker AM 250 or Am 400 spectrometer. The multiplicities indicated are: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet and br indicate a broad signal. Sat. indicates a saturated solution, eq indicates the proportion of an equivalent molar ratio of a reagent relative to the main reagent.

EXAMPLE 1 Preparation of N-r (1.3 -) - Dihydro-2,2-dioxo-3-methyl-4-chloro-2,1-benzisotriazole) -7-ill-N'-r 2 -bromophenyl-urea a) Preparation of 2,6-dichlorobenzylthio acetate. To a solution of 2,6-dichlorobenzyl bromide (30 grams (hereinafter "g")), 125.5 millimoles (hereinafter "mmoles")) in DMF (30 milliliters (hereinafter "ml") were added. ), potassium thioacetate (15.65 g, 138 mmol). The reaction mixture was stirred at room temperature for about one hour. Then it was divided between ethyl acetate and water. The combined organic phase was dried and concentrated to give the desired product (29.3 g, 99%). EI-MS m / z 241 (M +). b) Preparation of 2,6-dichlorobenzylsulfonyl chloride The 2,6-dichlorobenzylthio acetate (29 g, 121 mmol) and the sodium acetate (68 g) were dissolved in a mixture of glacial acetic acid (646 ml) and water (141 ml). ml). The chloride gas was passed to the solution for about 10 minutes. The mixture was evaporated and the residue was extracted with ethyl acetate. The combined organic phase was dried and concentrated to give the desired product (27 g, 86%). EI-MS m / z 260.5 (M +). c) Preparation of 2,6-dichlorobenzylsulfonamide chloride The 2,6-dichlorobenzylsulfonyl chloride (27 g, 103.6 mmol) in ammonium hydroxide (270 ml) was stirred at room temperature for about 3 hours. In the acidification with cooled concentrated hydrochloric acid a precipitate was separated and filtered to give the desired product (16 g, 64%) EI-MS m / z 239 (M +). d) Preparation of 1,3-dihydro-2,2-dioxo-4-chloro-2.1-benzylsothiazole chloride The 2,6-dichlorobenzylsulfonamide (8 g, 33.47 mmol) was added to the potassium carbonate (4.62 g, 33.47 mmol), copper (560 milligrams (hereinafter "mg")) and N, N-dimethylaniline (10 ml) in a round-bottomed flask. The reaction mixture was stirred at 170 ° C for about 4 hours; then it was cooled to room temperature and partitioned between ethyl acetate and 10% aqueous HCl. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (30% ethyl acetate / hexane) gave the desired product (4 g, 59%). EI-MS m / z 204.5 (M +). e) Preparation of 1-allyl-3-hydro-2,2-dioxo-4-chloro-2,1-benzisothiazole chloride To a solution of 1,3-dihydro-2,2-dioxo-4-chloro-2,1-benzisothiazole (3.18 g, 15.63 mmol) in DMF (15 ml), sodium hydride (60%, 625 mg, 15.63 mmol) and allyl bromide (1.6 ml, 17.2 mmol) were added. The reaction mixture was stirred at room temperature for about 16 hours. It was then partitioned between ethyl acetate and 10% aqueous HCl. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (20% ethyl acetate / hexane) gave the desired product (3 g, 79%). EI-MS m / z 244.5 (M +). f) Preparation of 1-allyl-3-hydro-2,2-dioxo-3-methyl-4-chloro-2,1-benzisothiazole To a solution of 1-allyl-3-hydro-2,2-dioxo-4-chloro-2 , 1-benzisothiazole (500 mg, 2.05 mmol) in THF (10 ml) at -78 ° C, bis (trimethylsilyl) amide sodium (1.0 M in THF, 6.16 ml, 6.16 mmol) was added. The reaction mixture was stirred at room temperature for about 30 minutes. After cooling to -78 ° C again, methyl iodide (0.49 ml, 4.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Then it was partitioned between ethyl acetate and 10% HCl. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (10% ethyl acetate / hexane) gave the desired product (130 g, 68%). EI-MS m / z 258.5 (M +). q) Preparation of 1,3-dihydro-2,2-d-oxo-4-chloro-3-methyl-2,1-benzisothiazole To a solution of 1-allyl-3-hydro-2,2-dioxo-4-chloro-3 -methyl-2,1-benzisothiazole (166 mg, 0.56 mmole) in THF (10 ml), sodium borohydride (43 mg, 1.12 mmol) and tetrakis (triphenylphosphona) palladium (0) (22.3 mg, 0.02 mmol) were added. . The reaction mixture was stirred at room temperature for about 16 hours. Then it was partitioned between ethyl acetate and 10% aqueous HCl. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (50% ethyl acetate / hexane) gave the desired product (115 g, 80%). EI-MS m / z 258.1 (M +). h) Preparation of 1,3-dihydro-2,2-dioxo-4-chloro-7-nitro-3-methyl-2,1-benzisothiazole 1,3-dihydro-2,2-dioxo-4-chloro- 3-methyl-2,1-benzisothiazole (115 mg, 0.45 mmol) was dissolved in methylene chloride (30 ml) followed by the addition of sodium nitrate (39.6 mg, 0.5 mmol) and trifluoroacetic anhydride (331 mg, 1.575 mmol). The mixture was allowed to stir.After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water.The organic layer was dried with MgSO 4 and filtered.The solvent was evaporated and chromatography of the resulting solid silica gel (50% ethyl acetate / hexane) gave the desired product (33 mg, 24%). EI-MS m / z 303.1 (M +). i) Preparation of I.S-dihydro ^^-dioxo ^ -chloro-S-methyl ^ -amino-2.1-benzisothiazole. To the solution of 1,3-dihydro-2,2-dioxo-4-chloro-3-methyl-7-nitro-2,1-benzisothiazole (33 mg, 0.11 mmol) in ethanol (5 ml), chloride was added tin (II) (123 mg, 0.55 mmol). The reaction mixture was stirred at reflux for about 4 hours. It was then cooled to room temperature. NaHCO3 (aqueous) was added to the reaction mixture until pH = 7. Then the solution was extracted with ethyl acetate (3x). The combined organic layer was dried with MgSO 4, filtered and concentrated under reduced pressure to give the desired product (26 mg, 88%). EI-MS m / z 273.1 (M +). i) Preparation of Nr (1.3) -D-Hydro-2,2-d-oxo-3-methyl-4-chloro-2, 1-benzothioazole) -7-p-N '-. 2-bromophenyl-urea To a solution of 2-bromophenyl isocyanate (19 mg, 0.1 mmol) in DMF (1.0 ml), 1,3-dihydro-2,2-dioxo-4-chloro-7-amino-2,1-benzisothiazole was added. (26 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for about 16 hours. Chromatography of the resulting liquid on silica gel (50% ethyl acetate / hexane) gave the desired product (24 mg, 56%). EI-MS m / z 471.2 (M +).

Method of treatment The compounds of the 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 it is exacerbated or caused by an excessive or unregulated production of cytosine IL-8 by said mammalian cell, such as but not limited to monocytes and / or macrophages, or other chemokines that bind to the IL-8 a or β receptor, as well referred to as the type I or type II receiver. Accordingly, the present invention provides a method of treating a disease mediated by chemokine, wherein the chemokine is that which binds to an IL-8 a or β receptor and which method comprises the administration of an effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof. In particular, the chemokines are IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78. The compounds of the formula (I) are administered in an amount sufficient to inhibit the function of the cytosine, in particular IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78, so that they are regulated biologically to normal levels of physiological function, or in certain case at normal levels, to improve the state of the disease. The abnormal levels of IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78 for example in the context of the present invention, constitute: i) levels of free IL-8 greater than or equal to one picogram per ml; ii) any associated cell IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78 of the above normal physiological levels; or iii) the presence of IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78 of the previous basal levels in cells or tissues in which respectively IL-8, GROa, GROß, GRO? NAP-2 or ENA-78. There are several disease states in which the production of excessive or unregulated IL8 is involved in the exacerbation and / or provocation of the disease. Chemokine-mediated diseases include psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, respiratory distress syndrome in adults, inflammatory bowel disease, Crohn's disease, ulcerative colitis, infarction, septic shock, endotoxic shock, gram-negative sepsis , toxic shock syndrome, cardiac and renal reperfusion injury, glumerulonephritis, thrombosis, graft-versus-host reaction, Alzheimer's disease, allograft rejections, malaria, restinosis, angiogenesis or unwanted release of hematopoietic stem cells, rhinovirus infections, and several indications of bone resorption, such as osteoporisis or osteoarthritis. The association of interleukin-8 and rhinovirus can be found in articles such as: Turner, et al., Clin. Infect. Dis. (1988), 26 (4), 840-846; Sanders, et al., J. Vitral. (1998), 72 (2), 934-942; Sethi, et al., Clin. Exp. Immunol, (1997), 110 (3), 362-369, Zhu et al., Am. J. Physiol. (1997), 273 (4, Pt. 1), L814-L824; Terajima, et al., Am. J. Physiol. (1997), 273 (4, Pt. 1), L749-L759; Grunberg, et al., Clin. Exp. Allergy (1997), 27 (1), 36-45; and Johnson, et al., J. Infecí. Dis. (1997), 175 (2), 323-329. The association of interleukin -8 and osteoporosis can be found in articles such as: Streckfus at al., J. Gerontol., Ser. A (1997), 52A (6), M343-M351; Hermann, T. WO95 / 31722; and Chaudhary, et al., Endocrinology (Baltimore) (1992), 130 (5), 2528-34. These diseases are characterized mainly by massive neutrophil infiltration, T cell infiltration, or neovascular growth, and are associated with the production of IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78 which is responsible for the chemotaxis of neutrophils in the inflammatory site or the directional growth of endothelial cells. In contrast to other inflammatory cytokines (IL-8, GROa, GROß, GRO? Or NAP-2), it has the unique property of promoting chemotaxis of neutrophils, releasing from above including but not limited to the release of elastase as well as to the production and activation of superoxide. The a-chemokines, but particularly, GROa, GROß, GRO? or NAP-2, which work in the IL-8 type I or II receptor can promote neovascularization of tumors by promoting the directional growth of endothelial cells. Therefore, inhibition of the induced chemotaxis of IL-8 or activation can lead to a direct reduction in neutrophil infiltration. Recent evidence also implicates the role of chemokines in the treatment of HIV infections, Littieman et al., Nature 381, pp, 661 (1996) and Koup et al., Nature 381, pp, 667 (1996). The present invention also provides a means of treatment, in acute fixation, as well as prevention, in those individuals susceptible to CNS damage by the chemokine receptor antagonist compounds of the formula (I). CNS damage, as defined herein, includes open-head or penetrative trauma, such as surgery, or a damage from closed-head trauma, such as damage to the head region.

- ----------- Also included in this definition is ischemic infarction, particularly the brain area. Ischemic infarction can be defined as a focal neurological disorder that results from insufficient blood supply to a particular area of the brain, usually as a result of an embolus, thrombus, or local anesthetic closure of the blood spleens. The role of inflammatory cytokines in that area has arisen and the present invention provides a means for the potential treatment of such damages. Relatively low treatment, for acute damage such as the above, have been available. Current evidence also indicates the use of IL-8 inhibitors in the treatment of atherosclerosis. The first reference, Boisvert et al., J. Clin. Invest., 1998, 101: 353-363 shows, through bone marrow transplantation, that the absence of IL-8 receptors in stem cells (and, therefore, in monocytes / macrophages) leads to a reduction in the development of atherosclerotic plaques in mice deficient in LDL receptor. Additional support references are: Apostolopoulos, et al., Arterioscler Thromb Vasc Biol. 1996. 16: 1007-1012; Liu, et al., Arterioscler Thromb Vasc Biol, 1997, 17: 317-323; Rus, et al., Atherosclerosis. 1996, 127: 263-271 .: Wang et al., J Biol Chem. 1996. 271: 8837-8842; Yue, et al., Eur J Pharmacol. 1993, 240: 81-84; Koch, et al., Am J Pathol, 1993, 142: 1423-1431; Lee, et al., Immunol Lett, 1996, 53, 109-113; and Terkeltaub et al., Arterioscler Thromb, 1994, 14: 47-53.

FNT-a is a cytokine with proinflammatory actions, including the expression of endothelial leukocyte adhesion molecules. The leukocytes infiltrate the ischemic lesions of the brain and therefore the compounds that inhibit or reduce the levels of TNF are useful for the treatment of cerebral ischemic damage. See Liu et al., Stoke, Vol. 25., No. 7, pp. 1481-88 (1994), the description of which is incorporated herein by reference. Models of closed head injuries and treatment with mixed 5-LO / CO agents are described in Shohami et al., J. of Vaisic & Clinical Physiology and Pharmacology, Vol. 3, No. 2, pp. 99-107 (1992), the disclosure of which is incorporated herein by reference. It was found that the treatment that reduces the formation of edema improves the functional result in said treated animals. The compounds of formula (I) are administered in an amount sufficient to inhibit IL-8, bind to IL-8 alpha or beta receptors, from which they bind to said receptors, as evidenced by a reduction in the chemotaxis and activation of neutrophils. The discovery that the compounds of the formula (I) are inhibitors of the IL-8 binding is based on the effects of the compounds of the formulas (I) on the in vitro receptor binding assays described herein. The compounds of the formula (I) have been shown to be inhibitors of IL-8 type II receptors. As used herein, the term "disease or disease state mediated by IL-8" refers to any disease state in which IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78 has a role, either through the production of IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78 themselves, or by IL-8, GROa, GROß, GRO ?, NAP-2 or ENA 78 that cause that another monocyte be released, such as but not limited to IL-1, IL-6 or FNT. A disease state in which, for example, IL-1 is a major component, and whose production or action is exacerbated or secreted in response to IL-8, is therefore considered to be a disease state mediated by IL-8 . As used herein, the term "disease or disease state mediated by chemokine" refers to any disease state in which a chemokine that binds to an IL-8 a or β receptor has a role, such but not limited to to IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78. The above includes a disease state in which IL-8 has a function, either in the production of IL-8 itself, or IL-8 which causes the release of another monocycline, such as but not limited to IL-1, IL-6 or FNT. A disease state in which, for example, IL-1 is a major component, and whose production or action is exacerbated or secreted in response to IL-8, will therefore be considered a disease state 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 that modulates the interactions between cells in the inflammatory or hematopoietic immune response. A cytokine includes, but is not limited to, monocytes and lymphokines, despite the cells that produce them. For example, reference is generally made to the fact that a monocline is produced and secreted by a mononuclear cell, such as a macrophage and / or monocyte. Several other cells, however, also produce monocins, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal 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 (IL-8), tumor necrosis factor-alpha (TNF-a) 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 that modulates the interactions between cells in the immune, inflammatory or hematopoietic response, similar to the term "cytokine" "previous. A chemokine is secreted primarily 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-a, GRO-β, GRO- ?, NAP-2, ENA-78, IP-10, MIP-1a, 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. The compounds of the formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating said compounds can be conveniently administered by any of the routes conventionally used for the administration of drugs, for example, orally, topically, parenterally or by inhalation . The compounds of formula (I) can be administered in the form of conventional doses prepared by the combination of a compound of formula (I) with standard pharmaceutical carriers according to conventional procedures. The compounds of formula (I) can also be administered in conventional doses in combination with a second known therapeutically active compound. Such procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate for 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 combined, the route of administration and other well-known variables. The carriers must be "acceptable" in the sense that they must be compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

The pharmaceutical carrier used can be, for example, a solid or a liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples 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 in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax. A wide variety of pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation can be converted into tablets, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or tablet. The amount of solid carrier will vary widely, but will preferably be from about 25 mg to about 1 g. 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 a suspension of ampoule or non-aqueous liquid. The compounds of formula (I) can be administered topically, i.e. by non-systemic administration. The above includes the application of a compound of formula (I) externally to the epidermis or the oral cavity and the installation of said compound in the ear, eyes and nose, so that the compound does not significantly enter the bloodstream. 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 eyes, ears or nose The active ingredient may comprise, for topical administration, from 0.001% to 10% w / w, for example from 1% to 2% by weight of the formulation. It can, however, comprise up to 10% w / w, but preferably it 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 eyes. 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 for accelerating the drying and cooling of the skin, such as an alcohol or acetone, and / or a humectant such as glycerol or an oil such as castor oil. or arachis oil. Creams, ointments or pastes according to the present invention are semisolid formulations of the active ingredient for external application. These can be made by mixing an active ingredient in finely ground 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; a natural oil such as almond, corn, araquis, castor oil or olive; wool grease or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or macrogel. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or nonionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silaceae silicas, and other ingredients such as lanolin, may also be included. The drops according to the present invention can comprise sterile aqueous or oily solutions or suspensions and can be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and / or fungal agent and / or any other suitable preservative., and preferably including a surface active agent. The resulting solution can then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintained at 98-100 ° C for half an hour. Alternatively, the solution can be sterilized by filtration and transfer to the container by aseptic technique. Examples of suitable bactericidal or fungal agents for inclusion in the drops are nitrate or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, dilute alcohol and propylene glycol. The compounds of formula (I) can be administered parenterally, ie by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. Subcutaneous and intramuscular forms of parenteral administration are generally preferred. Suitable dosage forms for such administration can be prepared by conventional techniques. The compounds of formula (I) can also be administered by inhalation, that is, by intranasal administration and oral inhalation. Suitable dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, can be prepared by conventional techniques. For all methods of use described herein for the compounds of formula (I), the daily oral dose regimen will preferably be about 0.01 about 80 mg / kg of total body weight. The daily parenteral dose regimen will be from about 0.001 to about 80 mg / kg of total body weight. The daily topical dose regimen will preferably be from 0.1 mg to 150 mg, administered from one to four, preferably two or three times daily. The daily inhalation dose regimen will preferably be about 0.01 mg / kg about 1 mg / kg per day. It will also be recognized by one skilled in the art that the optimum amount and separation of the individual doses of a compound of formula (I) or pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the way , route and administration site, and the particular patient being treated, and that said optimum grades can be determined by conventional techniques. It will also be appreciated by one skilled in the art that the optimum 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, may be discerned by said experts in the art using the conventional course of treatment determination tests. The invention will now be described with reference to the following biological examples which are merely illustrative and are not construed as limiting the scope of the present invention.

BIOLOGICAL EXAMPLES The chemokine inhibitory effects of IL-8, and GRO-a of the 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, IL, with specific activity of 2000 Ci / mmoles. The Gro-a is obtained from NEN-New England Nuclear. All other chemicals are analytical grade. High levels of recombinant human IL-8 type receptors a and β were individually expressed in Chinese hamster ovary cells as previously described (Holmes, et al., Science, 1991, 253, 1278). The Chinese hamster ovary membranes were homogenized according to the protocol described above (Haour, et al., J Biol Chem., 249 pp. 2195-2205 (1974)) Except that the homogenization pH regulator was changed to 10mm. of tris-HCL, 1 mm of MgSO4, 0.5 mm of EDTA (ethylenediaminetetraacetic acid), 1 mm of PMSF (a-toluenesulfonyl fluoride), 0.5 mg / L of leupeptin, pH 7.5 The concentration of membrane proteins is determined using The Pierce Co. microassay kit using bovine serum albumin as a standard All assays were carried out in a 96-well microplate format Each reaction mixture contains 125 I-IL-8 (0.25 Nm) O / 125 I Gro-a and 0.5 μg / ml of IL-8Ra or 1.0 μg / ml of membranes and IL-8Rβ in 20 mm of Bis-Trispropane and 0.4 mm of pH regulators of Tris HCl, Ph 8.0, containing 1.2mm of MgSO4, 0.1 mm of EDTA, 25 mm of NaCl, and 0.03% of CHAPS In addition, the drug or compound of interest is added, which has been pre-dissolved in DMSO to reach a final concentration between 0.01 nM and 100 uM. The assay was initiated by the addition of 125 I-IL-8. After 1 hour at room temperature, the plate was cultured using a Tamtec 96-well harvester on a glass fiber filter blocked with 1% polyethyleneimine-0.5% BSA and washed 3 times with 25 mm NaCl, 10 mm TrisHCI, 1 mm MgSO4, 0.5 mm EDTA, 0.03% CHAPS, pH 7.4. The filter was then dried and counted in the liquid scintillation counter of beta plate. The IL-8 receptor Ra, recombinant, or type I, is also referred to herein as the non-permissive receptor and reference is made to the IL-8Rβ receptor, recombinant, or type II, as the permissive receptor. It has been found that representative compounds of formula (I), examples 1 to 8, have positive inhibitory activity of < 30 μmg in this assay.

Chemotaxis Assay The in vitro inhibitory properties of said compounds are determined in the neutrophil chemotaxis assay as described in Current Protocols in Immunology, vol. I, Suppl 1, Unit 6.12.3, the description of which is incorporated herein by reference in its entirety. Neutrophils were isolated from human blood as described in Current Protocols in Immunology Vol. I, Sup / 1. 1 Unit 6: 12.3, the description of which is incorporated herein by reference in its entirety. The chemoattractants IL-8, GRO-a, GRO-β, GRO-? and NAP-2 are placed in the lower chamber of a 48-cavity multi-chamber (Neuro Probé, Cabin John, MD) at a concentration between 0.1 and 100 nM. The two chambers are separated by a polycarbonate filter of 5 um. When testing the compounds of this invention, they are mixed with the cells (0.001-1000 nM) just before the addition of the cells in the upper chamber. The incubation can proceed from between about 45 and 90 min at about 37 ° C in a humidified incubator --- ^ '. - .. ra --- -fc. , with 5% CO2. At the end of the incubation period, the polycarbonate membrane is removed and the upper area is washed, the membrane is then stained using the Diff Quick staining protocol (Baxter Products, McGaw Park, IL, E.U.A). The cells that underwent chemotaxis to chemokine are counted visually using a telescope. Generally, 4 fields are counted for each sample, these numbers are averaged to give the average number of cells that have migrated. Each sample is tested in triplicate and each compound is repeated at least 4 times. For certain cells (positive control cells), no compound was added, said cells represent the maximum chemotactic response of the cells. In the case where a negative (unstimulated) control is desired, chemokine is not added to the lower 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 were tested for their ability to prevent the release of elastase 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 (NaCI 118, KCl 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, the cytochalasin B in a volume of 50 ul (20ug / ml) and the Ringer's pH regulator in a volume of 50ul. Said cells could be heated (37 ° C, 5% CO2.95% RH) for 5 min. before it was added IL-8 GROa, GROß.GRO? or NAP-2) at a final concentration of 0.01-1000 mM. The reaction could proceed for 45 min. before a 96-well plate (800 xg 5 min.) and 100 ul of the removed supernatant were centrifuged. Said supernatant was added to a second 96-well plate followed by an artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val-AMC, Nova Biochem, La Jolla, CA) at a final concentration of 6 mg / ml dissolved in Saline regulated phosphate solution. Immediately, the plate was placed in fluorescent 96-well plate reader (Cytofluor 2350, Millipore, Bedford, MA) and data were 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 degradation rate of MeOSuc-Ala-Ala-Pro-Val-AMC.

FNT-a assay in traumatic brain injury This trial provides the examination of the expression of tumor necrosis factor mRNA in specific brain regions that follow traumatic brain injury from experimentally induced lateral fluid percussion (TBI) in rats since FNT- a is able to induce nerve growth factor (NGF) and stimulates the release of other cytokines from activated astrocytes, said post-traumatic alteration in the expression of the FNT-a gene plays an important role in the acute and regenerative response for the CNS trauma. A suitable assay can be found in WO 97/35856 or WO 97/49286, the descriptions of which are incorporated herein by reference.

CNS damage model for IL-ß mRNA. This assay characterizes the regional expression of interlucin-1β mRNA (IL-1β) in specific brain regions following traumatic brain injury from experimental lateral fluid percussion (TBI) in rats. The results of these tests indicate that following the TBI, the temporal expression of IL-1β mRNA is regionally stimulated in specific brain regions. Such regional changes in cytokines, ethers such as IL-1β play a role in post-traumatic pathological or regenerative sequelae of brain damage. A suitable assay can be found in WO 97/35856 or WO 97/49286, the descriptions of which are incorporated herein by reference.

Atherosclerosis in vivo assay: The in vivo models for measuring atherosclerosis are based on the Paigen et al test with minor modifications as described below. See Paigen B, Morrow A, Holmes PA, Mitchell D, Williams RA.

Quantitative assessment of atherosclerotic lesions n mice. Atherosclerosis 68: 231-240 (1987) and Groot PHE, van Vlijmen BJM, Benson GM, Hofker MH, Schiffelers R, Vidgeon-Hart M, Havekes LM. Quantitative assessment of aortic atherosclerosis in APOE * 3 Leiden transgenic mice and ¡ts relationship to serum exposure. Artereioscler Thromb Vasc Biol. 16: 926-933 (1996).

Sectioning and staining of the aortic sinus The transverse sections of the aortic root are taken as previously described (1, 2). Briefly, the hearts are bisected just below the level of the atria and the base of the heart plus the aortic root are taken for analysis. After balancing the tissue in the OCT compound during the night, the hearts are immersed in the OCT compound in a cryostat mandrel (Bright Instrument Company Ltd., R.U) with the aorta facing the mandrel. The tissue freezes when surrounding the mandrel with dry ice. The hearts are then sectioned perpendicular to the axis of the aorta, starting at the heart and working in the direction of the aorta. Once the aortic root has been identified by the appearance of three valve leaflets, alternate 10mm sections are taken and mounted on gelatinized slides. The sections are air-dried for 1 hour and subsequently briefly rinsed in 60% sopropyl alcohol. The sections are stained with oil red O, counterstained with Mayer's hematoxylin, covered using glycerol gelatin and sealed with nail varnish.

Quantification of atherosclerosis in the aortic root. Ten alternate sections of the aortic root are observed using an Olympus BH-2 microscope equipped with a 4x objective and a video camera (Hitachi, HV-C10). 24-bit color images are acquired and analyzed using a PC (Datacell Pentium P5-133, Datacell Berks, R.U) coupled with a frame recording board (Snapper.Active Imaging Ltd, Berks, R.U) and runs the software Optimus (version 5.1, Optimums Corp., WA, E.U.A). The images were captured under identical conditions of the microscopes, camera and PC. The quantification of the atherosclerotic lesion areas is carried out by hand drawing around the lesion using the Optimas software. The three colors are set to quantify the areas that are stained red in the lesions. The absolute values for the cross-sectional areas of the lesions and the areas stained red are obtained by software calibration using a grid image on a hemocytometer slide. All publications, including but not limited to patents and patent applications, cited in this specification are incorporated herein by reference as each individual publication was specifically and individually indicated to be incorporated by reference herein as set forth in its entirety. . The above description fully describes the invention including the preferred embodiments thereof. Modifications and improvements of the modalities specifically described herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore, the examples herein are considered merely illustrative and not a limitation of the scope of the present invention in any form. The embodiments of the invention in which an exclusive property or privilege is claimed are defined below.

Claims (17)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula: wherein R is -NH-C (X) -NH- (CR? 3Ru) v-Z; Z is W, optionally substituted heteroaryl, optionally substituted C5-8 cycloalkyl, optionally substituted C-MO alkyl, optionally substituted C2-10 alkenyl, or an optionally substituted C2-? Alkynyl; X is = 0, or = S; A is CR20R2i; R1 is independently selected from hydrogen; halogen; nitro; cyano; Halo-substituted C? -? 0 alkyl; C1-10 alkyl; C2-? o alkenyl; C 10 alkoxy; halo-substituted C-MO alkoxy; azide; (CR8R8) qS (0) tR4, hydroxy; C1-4 hydroxyalkyl; aril; arylalkyl of C? -; aryloxy; C? -4 arylalkyloxy; heteroaryl; heteroarylalkyl; heterocyclic; C 1-4 heterocyclic alkyl; C4-4 heteroarylalkyloxy; C2-arylalkyl or C; C2-? o heteroarylalkenyl; C2-10 heterocyclic alkenyl. (CR8R8) qNR4R5; alkenyl of C2-? o-C (0) NR4R5; (CR8R8) qC (0) NR4R5; (CR8R8) qC (O) NR4R? 0; S (0) 3H; S (0) 3R8; (CR8R8) q C (0) Rn; alkenyl of C2-? 0-C (O) Rn; alkenyl of C2-? 0-C (O) ORn; (CR8R8) qC (0) ORn; (CR8R8) qC (0) OR? 2; (CR8R8) qOC (0) Rn; (CR8R8) qNR4C (0) Ru; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) Ru; (CR8R8) qNHS (0) 2R? 7; (CR8R8) qS (0) 2NR4R5; or two Ri portions together can form -0- (CH2) sO- or a 5-6 membered saturated or unsaturated ring, and in which the aryl, heteroaryl, and heterocyclic containing rings can be optionally substituted; n is an integer that has a value of 1 to 3; m is an integer that has a value of 1 or 3; q is 0, or an integer that has a value of 1 to 10; t is 0, or an integer that has a value of 1 or 2; s is an integer that has a value of 1 to 3; v is 0, or an integer that has a value of 1 to 4; R and R 5 are independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted C 1-4 arylalkyl, optionally substituted heteroaryl, optionally substituted C 1 - heteroaryl, heterocyclic, heterocyclic C 1-4 alkyl, or R and R5 together with the nitrogen to which they are attached form a ring of 5 to 7 members which may optionally consist of an additional heteroatom selected from O / N / S; And it is independently selected from hydrogen; nitro halogen; cyano; C halosubstituted alkyl; C? -10 alkyl; alkenyl of C2-? 0 C1-10 alkoxy; Halo substituted alkoxy, azide; (CR8R8) qS (0) tR4; C1-4 hydroxy hydroxyalkyl; aril; C-M arylalkyl; aryloxy; C 1-4 arylalkyloxy heteroaryl; heteroarylalkyl; d-4 heteroarylalkyloxy; heterocyclic; C 4 heterocyclic alkyl; C2-arylalkyl or C; C2-? 0 heteroarylalkenyl; heterocyclic alkenyl of C2-? 0; (CR8R8) qNR4R5; alkenyl of C2-? 0-C (0) NR4R5; (CR8R8) qC (0) NR4R5; (CR8R8) qC (O) NR4R? 0; S (0) 3H; S (0) 3R8; (CR8R8) q C (0) Rn; C2-10-C (O) Rn alkenyl; C2-10 alkenyl C (O) ORn; (CR8R8) qC (0) ORu; (CR8R8) qC (0) OR12; (CRßRß) qOC (0) R ??; (CR8R8) qNR4C (0) Rn; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) R ??; (CR8R8) qNHS (0) 2R? 8; (CR8R8) qS (0) 2NR4R5; or two portions AND together can form -0- (CH2) s-0 or a 5-6 membered saturated or unsaturated ring, and in which the aryl, heteroaryl, and heterocyclic containing rings can be optionally substituted; Re and R7 are independently hydrogen or a C1-4 alkyl group, or R and R7 together with the nitrogen to which they are attached form a 5- to 7-membered ring whose ring may optionally contain an additional heteroatom whose heteroatom is selected from oxygen, nitrogen or sulfur; R8 is independently hydrogen or C1-4 alkyl; R10 is C? -? Or C (0) 2R8 alkyl; Rn is hydrogen, C? -4 alquiloalkyl, optionally substituted aryl, optionally substituted arylC1-4alkyl, optionally substituted heteroaryl, optionally substituted C1-4 heteroarylalkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC? _4alkyl; R 2 is hydrogen, CMO alkyl, optionally substituted aryl or optionally substituted arylalkyl; R 3 and Ru are independently hydrogen, optionally substituted C 1-4 alkyl, or one of R 3 and Ru can be an optionally substituted aryl; R 15 and R 6 are independently hydrogen, or an optionally substituted C 4 4 alkyl; R? is C1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclic C1-4alkyl, in which the aryl, heteroaryl and heterocyclic rings may all be optionally substituted; R 8 is NR 6 R 7, alkyl, C 1-4 arylalkyl, C 2-4 arylalkenyl, heteroaryl, C 1-4 heteroarylalkyl, C 2-4 heteroarylalkenyl, heterocyclic, C 1 -heterocyclic alkyl, in which aryl rings, heteroaryl and heterocyclic may all be optionally substituted; R2o and R21 are independently hydrogen, halogen, cyano, halo-substituted C-MO alkyl, C-MO alkyl, aryl, C? -4 arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic C1-4 alkyl, (CR8R8) qOR4 , (CR8R8) qC (0) Rn, (CR8R8) qC (0) ORn, (CR8R8) qC (0) OR? 2, (CR8R8) qOC (0) Rn, (CR8R8) qNR4R5, (CR8R8) qNR4C (0 ) Rn, (CR8R8) qC (0) NR4R5; (CR8R8) q C (0) NR4R? Or, or together R20 and R21 can form and wherein the aryl, heteroaryl, and heterocyclic containing rings can be optionally substituted; with the additional proviso that R20 and R21 are not hydrogen; R 22 is a C 1-4 alkyl, aryl, arylalkyl of C? .4; heteroaryl; heteroarylalkyl, heterocyclic, or heterocyclic C 4 -alkyl, and wherein all those portions may be optionally substituted; W is the ring containing E is optionally selected from: the asterisk * denotes the point of adhesion of the ring; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein X is oxygen.

3. The compound according to claim 2, further characterized in that Ri is halogen, year, nitro, CF3, C (0) NR R5, alkenyl C (0) NR4R5. C (0) NR4R? Or, C (0) alkenyl ORn of C2-? O, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or (CR8Rs) qS (0) NR R5.

4. The compound according to claim 1, further characterized in that R20 and R2? they form a 5-member ring.

5. The compound according to claim 1, further characterized in that Z is W.

6. The compound according to claim 5, further characterized in that W is phenyl.

7. The compound according to claim 6, further characterized in that Y is halogen, CMO alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylenedioxy, NR4R5, C? - thioalkyl, thioaryl, halosubstituted alkoxy, C? - optionally substituted, or substituted hydroxyalkyl.

8. The compound according to claim 2, further characterized in that Z is an optionally substituted heteroaryl. -W-faith --- a-. -----------

9. The compound according to claim 1 further characterized because it is: N - [(1-hydro-2,2-dioxo-3,3-cyclopentane-4-chloro) -2,1-benzisothiazo) -7-yl] -N '- [2-bromophenyl] urea.

10. A pharmaceutical composition comprising an effective amount of a compound according to any of claims 1 to 9, and a pharmaceutically acceptable carrier or diluent.

11. The use of an effective amount of a compound according to claim 1 for the manufacture of a medicament for treating a chemokine-mediated disease, wherein the chemokine binds to an IL-8 receptor "a" or "β" "in a mammal.

12. The use according to claim 11, wherein the chemokine-mediated disease is selected from psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, respiratory distress syndrome in adults, arthritis, inflammatory bowel disease, Crohn, ulcerative colitis, septic shock, endotoxic shock, gram-negative sepsis, septic shock syndrome, infarction, cardiac and renal reperfusion injury, glumerulonephritis, thrombosis, atherosclerosis, bone resorption diseases, Alzheimer's disease, graft reaction against host or allograft rejections.

13. A process for producing a compound of the formula (I) according to claim 1, which method comprises: a) reacting a compound of the formula: wherein A, Ri and m are as defined in formula (I), with a compound of the formula NH2-C (X) -N- (CR? 3Ru) v-Z; wherein X, R? 3, Ru, v and Z are as defined in formula (I), to yield a compound of formula (I), and subsequently, if necessary, deprotect, or convert a precursor of Ri, A, or Z to a group Ri, A or Z. 14.- A procedure for making a compound of the formula: wherein A, Ri and m are as defined in formula (I), which process comprises the reduction of a compound of the formula: wherein A, Ri and m are as defined in formula (I), under suitable reduction conditions to yield a compound of formula (II). 15. A compound of the formula: where A, Ri and m are as defined in formula (I). 16.- A compound of the formula where A, Ri and m are as defined in formula (I). 17. A process for producing a compound of formula (I) according to claim 1, which process comprises reacting a compound of the formula: wherein A, Ri and m are as defined in formula (I), with a compound of the formula NH2-C (X) -N- (CR? 3Ru) v-Z; wherein X, R? 3, Ru, v and Z are as defined in formula (I), to yield a compound of formula (I), and subsequently, if necessary, deprotect, or convert a precursor of R1 f A, or Z to a group Ri, A or Z.