MXPA00002286A - 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). Compounds of Formula (I) are represented, interalia, by structure (I) wherein interalia, R is -NH-C(X)-NH- (CR13R14)v-Z;Z is optionally substituted phenyl or napthyl, 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 a mono- or di-substituted carbon as defined herein;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 : ¿.- .-: St. Iík. involved 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); and 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 Druq 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. yes sj? & 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- (CR13Ru) v -Z; Z is W, optionally substituted heteroaryl, optionally substituted C5-8 cycloalkyl, C? -α or optionally substituted alkyl, C2-? Or optionally substituted alkenyl, or a C2-? Alkynyl or optionally substituted; X is = 0, or = S; A is CR20R2 ?; Ri is independently selected from hydrogen; halogen; nitro; cyano; C1-10 alkyl substituted; C-MO alkyl; C2-? o alkenyl; C-MO alkoxy; halo-substituted C-MO alkoxy; azide; (CR8R8) qS (0) tR4, hydroxy; hydroxyalkyl of C1-; aril; A- arylalkyl; aryloxy; C? -4 arylalkyloxy; heteroaryl; heteroarylalkyl; heterocyclic; C? -4 heterocyclic alkyl; C 1 - heteroarylalkyloxy; C2-arylalkenyl; C2-? o heteroarylalkenyl; heterocyclic alkenyl of C2-? 0; (CR8R8) qNR R5; C2-10-C (0) NR4R5 alkenyl; (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 (O) ORn; (CR8R8) qC (0) OR12; (CR8R8) qOC (0) R1?; (CR8R8) qNR4C (O) Rn; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) R1?; (CR8R8) qNHS (O) 2R17; (CR8R8) qS (O) 2NR4R5; or two RT moieties together can form -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 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; R4 and R5 are independently hydrogen, optionally substituted C?-Alkyl, optionally substituted aryl, optionally substituted C?-Arylalkyl, optionally substituted heteroaryl, optionally substituted C -? 4-heteroarylalkyl, heterocyclic, heterocyclic C? -4-alkyl , or R 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; And it is independently selected from hydrogen; halogen; nitro; cyano; Halo-substituted C-O alkyl; C-MO alkyl; C2-10 alkenyl; C-MO alkoxy; Halo substituted alkoxy, azide; (CR8R8) qS (O) tR; hydroxy; hydroxyalkyl of C? -; aril; arylalkyl of C? -; aryloxy; A-arylalkyloxy of C-i. 4; heteroaryl; heteroarylalkyl; C- heteroarylalkyloxy; heterocyclic; C 1-4 heterocyclic alkyl; C2-arylalkenyl; C2-10 heteroarylalkenyl; heterocyclic alkenyl of C2-? 0; (CR8R8) qNR4R5; C2-10-C (0) NR4R5 alkenyl; (CR8R8) qC (0) NR4R5; (CR8R8) qC (O) NR4R10; S (0) 3H; S (0) 3R8 (CR8R8) q C (0) Rn; C2-10-C (O) Rn alkenyl; C2-10-C (O) alkenyl ORn (CR8R8) qC (O) ORn; (CR8R8) qC (O) OR12; (CRßRß? CÍOJRn (CR8R8) qNR4C (O) Rn; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) R11 (CR8R8) qNHS (O) 2R? 8; (CR8R8) qS (0) 2NR4R5; or two portions Y together can form -0- (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 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 C? - alkyl; R-io is C?.? 0-C (O) 2R8 alkyl; R n is hydrogen, C 1-4 alkyl, optionally substituted aryl, optionally substituted C 1-6 arylalkyl, optionally substituted heteroaryl, optionally substituted C 1-4 heteroarylalkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C 1-4 alkyl; R 12 is hydrogen, C-MO alkyl, optionally substituted aryl or optionally substituted arylalkyl; R13 and R are independently hydrogen, optionally substituted C? -4 alkyl, or one of R13 and R may be an optionally substituted aryl; R15 and R16 are independently hydrogen, or an optionally substituted C1-4 alkyl; R-? is C- [alpha] 4 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl of C- [alpha] -4, heterocyclic, or heterocyclic alkyl of C [beta], in which the aryl, heteroaryl and heterocyclic rings may all be optionally substituted; R18 is NR6R7, alkyl, arylC1-4alkyl, arylalkenylC2-, heteroaryl, heteroarylalkylC1-, heteroarylalkenylC2-, heterocyclic, C?-Heterocyclic alkyl, in which the aryl, heteroaryl and heterocyclic rings may all be optionally replaced; R20 and R21 are independently hydrogen, halogen, cyano, halo-substituted C-MO alkyl, C-MO alkyl, aryl, C? - arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, C-? - heterocyclic alkyl, (CR8R8) qOR4, (CR8R8) qC (0) Rn, (CR8R8) qC (O) ORn, (CR8R8) qC (0) OR? 2, (CRßRßJqOCÍOJRn, (CR8R8) qNR4R5, (CRßRßJqNFUCÍOJRn, (CR8R8) qC (0) NR4R5; (CR8R8) qC (O) NR4R? 0, or together R20 and R21 can form = R22, and where the rings containing aryl , heteroaryl, and heterocyclic may be optionally substituted, with the additional proviso that R2o and R2? are not hydrogen, R22 is a C? - alkyl, aryl, arylalkyl of C-? - heteroaryl, heteroarylalkyl, heterocyclic, or alkyl Ci ^ heterocyclic, and where all those portions can 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.

- -" 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), R-i is conveniently independently selected from hydrogen; halogen; nitro; cyano; Halo substituted alkyl, such as CF3; C-O alkyl, such as methyl, ethyl, isopropyl, or n-propyl; C2-? o alkenyl; CMO 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; C1-4 hydroxyalkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl; C 1 - arylalkyl, such as benzyl; aryloxy, such as phenoxy; C 1 - arylalkyloxy, such as benzyloxy; heteroaryl; heteroarylalkyl; C 1 - heteroarylalkyloxy; arylalkenyl of C2-? 0; C2-? o heteroarylalkenyl; C2-10 heterocyclic alkenyl; (CR8R8) qNR R5; C2-? o-C (O) NR4R5 alkenyl; (CR8R8) qC (O) NR4R5; (CR8R8) qC (O) NR4R10; S (0) 3H; S (O) 3R8; (CR8R8) qC (0) R ??; C2-10-C (O) Rn alkenyl; C2-10 alkenyl C (O) ORn; (CR8R8) qC (0) ORn; (CR8R8) qC (0) OR? 2; (CR8R8) qOC (O) Rn; (CR8R8) qNR4C (O) Rn; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) Rn; (CR8R8) qNHS (O) 2R17; (CR8R8) qS (0) 2NR4R5; or two Ri portions together can form -0- (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, preferably on the benzene ring. When R-i 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 R5 are independently hydrogen, optionally substituted C?-Alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, heterocyclic, C-alkyl, ? - heterocyclic, or R4 and R5 together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally consist of an additional heteroatom selected from O / N / S. Conveniently Re and R7 are independently hydrogen or an alkyl group of C? -4, or R6 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 select oxygen, nitrogen or sulfur. Conveniently, Rs is independently hydrogen or C? -4 alkyl. Conveniently, R10 is C? -? Or C (O) 2R8 alkyl, as CH2C (O) 2H or CH2C (O) 2CH3. Conveniently, Rn is hydrogen, C? -4 alquiloalkyl, aryl, arylalkyl of C -? --4, heteroaryl, heteroarylalkyl of C? -, heterocyclic, or C heter-4 heter heter heter heter heter heter alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo alquilo C1 Conveniently, R-? 2 is hydrogen, CMO alkyl, optionally substituted aryl or optionally substituted arylalkyl. Conveniently, R 13 and Ru are independently hydrogen, an optionally substituted C 1 -C 4 alkyl which may be straight or branched as defined herein, or one of R 13 and Ru are optionally substituted aryl; v is 0, or an integer having a value of 1 to 4. When R 13 or Ru is an optionally substituted alkyl, the alkyl portion can be substituted one to three times independently by halogen; C 1 -halosubstituted alkyl as trifluoromethyl; hydroxy; hydroxyalkyl of C? -4, alkoxy of C?? - 4; as methoxy, or ethoxy, halosubstituted C1-10 alkoxy, S (O) tR4; aril; NR4R5; NHC (0) R4; C (0) NR4R5; or C (0) OR8. Conveniently, R-? 7 is C? - alkyl, aryl, arylalkyl, heteroaryl, C- heteroarylalkyl, heterocyclic, or C? -4 heterocyclic alkyl, in which the aryl, heteroaryl and heterocyclic rings can all be optionally substituted. Conveniently, Y is independently selected from hydrogen; halogen; nitro; cyano; Halo-substituted C-MO alkyl; C? -? 0 alkyl; C2-? o alkenyl; C -? - 10 alkoxy; halo-substituted alkoxy of C-t. ? o, azida; (CRsR8) qS (0) R; hydroxy; hydroxyalkyl of C? -4; aril; arylalkyl C? -4; aryloxy; C? -4 arylalkyloxy; heteroaryl; heteroarylalkyl; C4-4 heteroarylalkyloxy; heterocyclic; C? -4 heterocyclic alkyl; C2-arylalkyl or C; C2-? o heteroarylalkenyl; heterocyclic alkenyl of C2-? o; (CR8R8) qNR4R5; C2-10-C (O) NR4R5 alkenyl; (CR8R8) qC (O) NR4R5; (CR8R8) qC (O) NR4R10; S (O) 3H; S (O) 3R8; (CR8R8) qC (O) Ru; alkenyl of C2-? 0-C (O) Rn; alkenyl of C2-? O-C (O) OR ??; (CR8R8) qC (O) ORu; (CR8R8) qC (O) OR12; (CR8R8) qOC (O) Rn; (CR8R8) qNR4C (0) Ru; (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) 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 NR6R, alkyl, arylalkyl of C? -4, arylalkenyl of C2-4, heteroaryl, heteroarylalkyl of C? -4, heteroarylalkenyl of C2-4, heterocyclic, heterocyclic alkyl of C? -4, wherein the aryl, heteroaryl and heterocyclic rings can all be optionally substituted. And it is preferably a halogen, C? -4 alco alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylenedioxy, NR 4 R 5, C? -4-thioalkyl, thioaryl, halo-substituted alkoxy, optionally substituted C?-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 disubstituted 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 monosubstituted 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. 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 R2? they are independently hydrogen, halogen, cyano, C1-10 halo substituted, C1-10 alkyl, aryl; arylalkyl of C? -4; heteroaryl; heteroarylalkyl 1-4; heterocyclic, C1-4 heterocyclic alkyl; (CR8R8) qOR4, (CR8R8) qC (0) Ru; (CR8R8) qC (0) OR ??; (CR8R8) qC (0) OR? 2; (CR8R8) qOC (0) Ru; (CR8R8) qNR4R5; (CR8R8) qNR4C (0) Ru; (CR8R8) qC (0) NR4R? O; or (CR8R8) qC (0) NR4R5; and wherein the rings containing aryl, heteroaryl, and heterocyclic may be optionally substituted, with the proviso that R2o and R21 are not hydrogen; or R20 and R21 together form a double bond connected to a group R22, as in = R22- Conveniently, R22 is a C4-4 alkyl, aryl, arylC1-4 alkyl, heteroaryl; heteroarylalkyl, heterocyclic, or heterocyclic C 4 -alkyl, and wherein all those portions may be optionally substituted. Preferably, R20 and R21 form a methylene group. Conveniently, R15 and R6 are independently hydrogen, or an optionally substituted C4-4 alkyl as defined above for R13 and Ru. In the compounds of formula (I), conveniently Z is W, optionally substituted heteroaryl, optionally substituted C5-8 cycloalkyl, optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, or a C2- alkynyl. 10 optionally substituted. Conveniently, W is ^^^^^^^^ 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 is shown for objects here substituted only in the unsaturated ring (s). When Z is an optionally substituted C5-8 cycloalkyl ring, the ring may be optionally substituted by the term (Y) n as defined above. When Z is an optionally substituted Ci.io alkyl, a C2-? Or optionally substituted alkenyl, or a C2-? Alkynyl or optionally substituted portion, those portions may be optionally substituted one or more times independently by halogen; nitro; cyano; Halo substituted alkyl of CMO, such as trifluoromethyl; CMO alkoxy; halosubstituted alkoxy of C?.? 0; S (0) tR4; hydroxy; hydroxyalkyl of C? -4; aryloxy; arylalkyloxy of C? -; heteroaryloxy; Heterocyclic heterocyclyloxy; C? -4 heterocyclic alkyl; oxyhetocyclic; C4-4 heterocyclic alkyloxy; 5 NR4R5; C (0) NR4R5; C (O) NR4R10; S (O) 3H; S (0) 3R8; C (0) Rn; C (O) OR? 2; OC (0) Ru; or NR4C (0) R ?? When Z is an optionally substituted C2-? 0 alkenyl, or an optionally substituted C2-? Alkynyl, those portions may also, in addition to those substituent groups noted above, be optionally substituted with aryl, arylalkyl of C? -4, heteroaryl, and heteroarylalkyl groups of C? -4 (whose aryl and heteroaryl containing moieties may also be optionally substituted). In the compounds of formula (I), when Z is a heteroaryl ring (HET), it is conveniently a ring or ring system heteroaryl. 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 ring The multiple system 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. js? m? & uS »». J > .

In the compounds of formula (I), the HET ring can be optionally substituted independently by the term (Y) n as defined above. As used herein, "optionally substituted" unless specifically defined, shall mean groups such as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted CMO alkyl; C1-10 alkoxy, such as methoxy or ethoxy; Ci.io-SiOJm '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 NR4Rs; NHC (0) R4; C (0) NR4R5; C (O) OH; S (0) 2NR4R5; NHS (O) 2 R19, C10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; HMO alkyl substituted, 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; CMO alkoxy; C1-10 alkyl -S (0) m '; amino, amino mono and di-substituted, as in the group NR4R5; CMO alkyl, or C-10 alkyl halosubstituted as CF3. R 9 is conveniently C 1 - alkyl, aryl, arylalkyl C1-4, heteroaryl, heteroarylalkyl of C? -4, heterocyclic, or C? -4 heterocyclic alkyl. '^ asft? i a-aiB = fc' .., 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 The 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, are refer to: • "Halo" - all halogens, ie chlorine, fluorine, bromine and iodine. • "CMO alkyl" or "alkyl" - both 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, ferf-butyl, n-pentyl and the like. • "Cilcoalkyl" is used in the present to mean radicals cyclic, preferably from 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, as, but not limited to, pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiazole, 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 "^^^ ^ ^ ^ ^ ^ ^ ^ ^ gSB BSB ^^^^^^^^^^ S ^^^^^^^^^^^^^^^^^^ formerly, adhered to an aril portion, heteroaryl or heterocyclic, as defined herein, unless otherwise indicated: • "sulfinyl" - the S (O) oxide of the corresponding sulfide, the term "uncle" refers to the sulfide, and the term "sulfonyl" "refers to the fully oxidized S (0) 2 portion." The term "wherein two Ri portions (or two Y portions) may together form a saturated or unsaturated 5 or 6 membered ring" is used herein to meaning the formation of a ring system, such as a naphthalene ring system or a phenyl portion having a 6-membered partially unsaturated ring adhered, such as a C6 cycloalkenyl, ie hexene, or a cycloalkenyl portion of C5, cyclopentene Illustrative compounds of formula (I) include: N - [(1,3) -Dydro-2,2-dioxo-3-methyl-4-chloro-2,1-benzisothiazo) -7-yl] - N '- [2-bromophenyl] urea N - [(1, 3) -Dihid ro-2,2-dioxo-3-propyl-4-chloro-2,1-benzisothiazo) -7-yl] - N '- [2-bromophenyl] urea N - [(1-hydro-2,2-dioxo -3,3-dimethyl-4-chloro-2,1-benzisothiazo) -7-yl] -N '- [2-bromophenyl] urea N - [(1,3) -Dihydro-2,2-dioxo-3 -fluoro-4-chloro-2,1-benzisothiazo) -7-yl] -N '- [2-bromophenyl] urea N - [(1,3) -Dihydro-2,2-dioxo-3-methylamide-4 -chloro-2,1-benzisothiazo) -7-yl] -N '- [2-bromophenyl] urea N - [(1,3) -Dihydro-2,2-dioxo-3-methyl-3-methylamide-4 -chloro-2,1-benzisothiazo) -7-yl] -N '- [2-bromophenyl] urea N - [(1,3) -Dihydro-2,2-dioxo-3-methylene-4-chloro-2 , 1-benzisothiazo) -7-yl] -N '- [2-bromophenyl] urea N - [(1,3) -Dihydro-2,2-dioxo-3- (benzothiazol-2-yl) -4-chloro -2,1-benzisothiazo) -7-yl] -N '- [2-bromophenyl] urea It is recognized that the compounds of the present invention can exist as stereoisomers, regioisomers, or diastereomers.

They may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of those compounds are included within the scope of the present invention.

Methods of preparation The compounds of formula (I) can be obtained by applying synthetic procedures, some of which are illustrated in the diagrams right away. The synthesis provided by these schemes is applicable for the production of formula (I) having a variety of different groups Z, Ri, 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 said 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 ^^ mátjj ^^^^^^ gStx ^^ AcOH / H20 or sulfuryl chloride and acetic anhydride to form the sulfonyl chloride 3-equema 1. The sulfonyl chloride can be converted to the corresponding sulfonamide 4-scheme 1 using NH4OH followed by acidification or using ammonia gas in an organic solvent such as methylene chloride. The cyclic sulfonamide 5-scheme 1 can be cyclized under basic condition as potassium carbonate, and copper metal, as a catalyst followed by acidification.

SCHEME 2 10 R20 = H, H R2? = Me, propyl 20 a) NaH, allyl bromide b) Na [(CH3) 3Si] 2N, Mel or CH3 (CH2) 2I c) NaBH4, Pd (Ph3) 4 d) NaN03, H2SO4 / H20 or NH4N03, TFAA The cyclic sulfonamide 4-scheme 2 can be prepared by protection of the nitrogen compound 1 - Scheme 2 - »*» • * ..-. * »- & -., * -... É-fiti-¡-taii - MH preferably as the allyl compound using allyl bromide and a base such as sodium hydride. Alkylation of 2-scheme 2 with the desired alkyl halide in the presence of a suitable base such as sodium hexamethyldisilazane gives the compound 3-scheme 2. Compound 4; Scheme 2 can be obtained by removal of the allyl group under suitable conditions, preferably using a palladium catalyst in the presence of a reducing agent such as sodium borohydride, tributyl tin hydride or an organic acid such as 2-ethylhexanoic acid. 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. The unsaturated cyclic sulfonamide 3-scheme 3 can be prepared from the sulfonamide 2-scheme 3 by alkylation with the The desired 2-substituted alkyl halide and a base such as hexamethyldisilazane in the appropriate organic solvent as THF followed by removal of contaminant. The nitro compound 4-scheme 3 can be prepared from the sulfonamide 3-scheme 3 first by removing the allyl group by standard conditions such as palladium catalyst in the presence of an agent reducing agent such as sodium borohydride, tributyltin hydride or an organic acid such as 2-ethylhexanoic acid, and second incorporation of nitro functionality by standard nitration conditions such as nitrate sodium in sulfuric acid and water, ammonium nitrate and trifluoroacetic acid, or nitric acid in acetic anhydride.

SCHEME 3 R20 = Me, H R2i = Me, F a) NaH03 > H2S04 / H20 b) NaH, allyl bromide c) NaH, Mel or Li [(CH3) 3Si] N, (PhS02) 2NF d) NaBH4, Pd (Ph3) 4 An alternative method to form the nitro compound 5-scheme 2 is shown in Scheme 3. The nitro compound 2-scheme 3 can be prepared from 1-echema 3, under standard nitration conditions such as sodium nitrate in sulfuric acid and water, ammonium nitrate and trifluoroacetic acid, or nitric acid in acetic anhydride. The compound, 5-scheme 3 can be obtained using the same series of reactions, and conditions described above for the compound 5-scheme 2. ÍÍH-riM-W-Í-Í - É- «j ^ jjSj ^ g ^ SCHEME 4 a) SnCl2, EtOH b) 2-BrPhNCO, DMF Compound 3-scheme 4 can be obtained from the compound nitro 1- scheme 4 using standard reduction conditions preferably SnCl2 in EtOH to give the aniline 2-scheme 4. The heterocyclic phenylureas ortho-substituted 3-scheme 4 can be prepared under standard conditions, such as by condensation of the desired aryl isocyanate (commercially available) with the aniline 2; corresponding scheme 4 in an aprotic solvent such as DMF at room temperature or heating. Another aspect of the present invention is an analogous process for producing the compounds of formula (I) which process comprises reacting a compound of the formula: wherein 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 for formula (I) to produce a compound of formula (I) and then, if necessary, deprotect or convert a precursor of Ri, A, or Z to a group Ri, A or Z. In this process the desired isocyanate, a compound of formula (IV) is manufactured by condensation of the amine of 2- scheme 4 with triphosgene in the presence of base (such as potassium carbonate) or by reaction of the carboxylic acid with diphenyl phosphoazide in the presence of a base (such as triethylamine). An alternate process for making the compounds of formula (I) is a process comprising: a) reacting a compound of the formula: wherein A, Ri and m are as defined in formula (I); with a compound of the formula: C (X) -N- (CR? 3Ru) v-Z; wherein A, Ri, m, X, R13, R14 > v and Z are as defined in formula (I) to yield a compound of formula (I), and then if necessary, deprotect or convert a precursor of R ?, A, or Z to a group Ri, A or Z.

Another aspect of the present invention is a process for making a compound of the formula: wherein R1 (m and A are as defined for formula (I): reducing a compound of the formula: in which Ri, m and A are as defined for formula (I); under conditions suitable to yield a compound of formula (II). Another aspect of the present invention are the novel compounds of formula (III) as represented by the structure: in which Ri, m and A are as defined for formula (I); Another aspect of the present invention are the novel compounds of formula (II) as represented by the structure: in which Ri, m and A are as defined for formula (I); 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-rf1.3 -) - Dihydro-2,2-dioxo-3-methyl-4-chloro-2.1-benzisothiazo) -7-H-N'-r2-bromopheniHurea 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). 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 acidification with concentrated hydrochloric acid After cooling, 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 mmoles), copper powder (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 divided between acetate Ethyl 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-d-oxo-4-chloro-2,1-20-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 mixture of The reaction 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 (456 mg, 1.87 mmol) in THF (10 ml) at -78 ° C, sodium bis (trimethylsilyl) amide (1.0 M in THF, 1.87 ml, 1.87 mmol) was added. . The reaction mixture was stirred at room temperature for about 30 minutes. After cooling to -78 ° C again, methyl iodide (0.14 ml, 2.25 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 (330 g, 68%). EI-MS m / z 258.5 (M +). q) Preparation of 1,3-dihydro-2,2-dioxo-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 (330 mg, 1.27 mmol) in THF (10 ml), sodium borohydride (104.6 mg, 2.54 mmol) and tetrakis (triphenylphosphona) palladium (0) were added ( 59 mg, 0.05 mmol). 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 5 was dried and concentrated. Chromatography of the residue on silica gel (50% ethyl acetate / hexane) gave the desired product (200 g, 72%). EI-MS m / z 218.5 (M +). h) Preparation of 1, 3-dihydro-2,2-dioxo-4-chloro-7-nitro-3-methyl-10 2.1-benzisothiazole 1,3-dihydro-2,2-dioxo-4-chloro 3-methyl-2,1-benzisothiazole (200 mg, 0.92 mmol) was dissolved in methylene chloride (30 ml) followed by the addition of sodium nitrate (86 mg, 1.01 mmol). Then the addition of sulfuric acid (0.18 ml / 3M) was made, followed by the addition of an amount catalytic sodium nitrite. The mixture could be stirred. After about 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 on silica gel (50% ethyl acetate / hexane) gave the desired product (50 mg, 21%). EI-MS m / z 263.5 (M +). ÉllÉteÉI ^ M-tf-flM --- t-ÍÍ - ^^ i) Preparation of 1, 3-dihydro-2,2-dioxo-4-chloro-3-methyl-7-amino-2,1-bencisotiazol. To the solution of 1, 3-dihydro-2,2-dioxo-4-chloro-3-methyl-7-nitro-2,1-benzisothiazole (50 mg, 0.19 mmol) in ethanol (5 ml), 5-tin chloride (II) was added ) (214 mg, 0.95 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 (32 mg, 72%). EI-MS m / z 233.5 (M +). i) Preparation of N - [(1,3) -Dihydro-2,2-dioxo-3-methyl-4-chloro-2,1-benzothiazole) -7-ill-N'-2-bromophen Nurea To a solution of 2-bromo phenyl socianate (26 mg, 0.13 15 mmol) in DMF (1.0 ml), 1,3-dihydro-2,2-dioxo-4-chloro-7-amino- 2,1-benzisothiazole (32 mg, 0.13 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 (30 mg, 50%). EI-MS m / z 430 (M +).

^^^^ Mt ^ .- ^. ^ ^ ?? e ^? ^.,. < • < «*, ... «^ - > «*" - H í &J¿asW EXAMPLE 2 Preparation of N-α (1,3) -dihydro-2,2-dioxo-3-propyl-4-chloro-2,1-benzisothiazo) -7 -iH-N'-r2-bromophenipurea a) Preparation of 1-allyl-3-hydro-2,2-dioxo-3-propyl-4-chloro-2,1-benzisothiazole After the procedure of example (1f) except for the substitution of iodide of methyl with propyl iodide, the title compound was prepared in 43% yield. EI-MS m / z 286.5 (M +). B) Preparation of 3-dihydro-2,2-dioxo-4-chloro-3-propyl-2,1-benzisothiazole After the procedure of example (1g), the title compound was prepared in 76% yield . EI-MS m / z 244.1 (M +). 15 c) Preparation of 1,3-dihydro-2,2-dioxo-4-chloro-3-propyl-7-nitro-2,1-benzisothiazole 1,3-dihydro-2,2 -dioxo-4-chloro-3-propyl-2,1-benzisothiazole (131 mg, 0.54 mmole) was dissolved in chloroform (30 ml) followed by the addition of ammonium nitrate (44 mg, 0.54 mmole) and trifluoroacetic anhydride (397 mg, 214.4 mmol). The mixture could be stirred. After 24 hours, the reaction mixture was diluted with chloroform and extracted with water. The organic layer was dried with MgSO and filtered. The solvent was evaporated and the chromatography of the t «.---,. ^. Ai-t? - tt- ». .. ^? á ^^. ^ ~. The resulting solid on silica gel (50% ethyl acetate / hexane) yielded the desired product (28 mg, 20%). ). EI-MS m / z 289.1 (M +). d) Preparation of 1,3-dihydro-2,2-dioxo-4-chloro-3-propyl-7-amino-2,1-benzisothiazole After the procedure of example (1 i), the compound of title in 92% yield. EI-MS m / z 261.1 (M +). e) Preparation of N-fd ^ -Dihydro ^^ - dioxo-S-propyl ^ -chloro ^ .l-benzisotiazo) -7-l-N'-r2-bromophenyl-lurea After the procedure of example (1j), the title compound was prepared in 49% yield. EI-MS m / z 456.1, 458.2 (M +).

EXAMPLE 3 Preparation of N-r (1-hydro-2,2-dioxo-3,3-dimethyl-4-chloro-2,1-benzisothiazo) -7-in-N'-f2-bromophenylpyurea a) Preparation 1, 3-d-Hydro-2,2-d-oxo-4-chloro-7-nitro-2,1-benzisothiazole 1,3-dihydro-2,2-dioxo-4-chloro-2 , 1-benzisothiazole (1.5 mg, 0.92 mmol) was dissolved in methylene chloride (30 ml) after the addition of sodium nitrate (86 mg, 1.01 mmol). Then the addition of sulfuric acid (0.18 ml / 3m) was made, followed by the addition of a catalytic amount of f ^^^ gBg ^^^^^^^^^^^^^^^ te ^^^^ - ^^^^^^^^^^^^ sodium nitrite. The mixture could be stirred. After about 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 on silica gel (50% ethyl acetate / hexane) gave the desired product (50 mg, 21%). EI-MS m / z 263.5 (M +). b) Preparation of 1-allyl-2,2-dioxo-3,3-dihydro-4-chloro-7-nitro-2,1-benzisothiazole To a solution of 1,3-dihydro-2,2-dioxo-4 -chloro-2,1-benzisothiazole (1.1 g, 4.43 mmol) in DMF (20 ml), sodium hydride (60%, 178 mg, 4.43 mmol) and allyl bromide (0.42 ml, 4.87 mmol) were added. The reaction mixture was stirred at 60 ° C for about 3 hours and then cooled to room temperature for about 16 hours. The reaction mixture was partitioned between ethyl acetate and 10% HCl. The combined organic phase was dried and concentrated. Chromatrog raphy of the residue on silica gel (20% ethyl acetate / hexane) gave the desired product (800 mg, 65%). EI-MS m / z 289.1 (M +). c) Preparation of 1-allyl-2,2-d-oxo-3,3-dimethyl-4-chloro-7-nitro-2,1-benzisothiazole To a solution of 1-allyl-2,2-dioxo 3,3,3-dihydro-4-chloro-7-nitro-2,1-benzisothiazole (100 mg, 0.35 mmol) in DMF (5 ml), sodium hydride (60%, 28 mg, 0.7 mmol) was added. After stirring at room temperature for about 30 minutes, iodomethane (99.4 mg, OJ mmoles) was added. Then the reaction mixture was stirred at 70 ° C for 2 hours. The reaction mixture was partitioned between ethyl acetate and 10% HCl. The combined organic phase was dried and concentrated. Chromatography the residue on silica gel (10% ethyl acetate / hexane) gave the desired product (87 mg, 80%). EI-MS m / z 317.2 (M +). d) Preparation of 1-hydroxy-2,2-dioxo-3,3-dimethyl-4-chloro-7-nitro-2,1-benzisothiazole After the procedure of the example (1g), prepared the title compound in 45% yield. EI-MS m / z 277.2 (M +). e) Preparation of 1-hydro-2,2-d-oxo-3,3-dimethyl-4-chloro-7-amino-2,1-benzisothiazole After the procedure of example (1 i), it was prepared the title compound in 98% yield. EI-MS m / z 247.1 (M +). f) Preparation of N - [(1-hydro-2,2-dioxo-3,3-dimethyl-4-chloro-2,1-benzothoxa) -7-III-N '- [ 2-bromophenylillurea 20 After the procedure of example (1j), the title compound was prepared in 52% yield. EI-MS m / z 443.1, 445.2 (M +).

EXAMPLE 4 Preparation of N-F (1,3) -dihydro-2,2-dioxo-3-fluoro-4-chloro-2.1-benzisothiazo) -7-ill-N'-r2-bromopheniriurea a) Preparation of 1-allyl-3,3-dihydro-2,2-dioxo-4-chloro-7-nitro-2,1-benzisothiazole To a solution of 1-allyl-2,2-dioxo-3 , 3-dihydro-4-chloro-7-nitro-2,1-benzisothiazole (358 mg, 1.24 mmol) in THF (15 ml) at -78 ° C, was added lithium bis (trimethylsilyl) amide (1.0M in THF, 1.49 ml, 1.49 mmol). The reaction mixture was stirred at -78 ° C for about 1 hour, then N-fluorobenzenesulfonimide (547 mg, 2.25 mmol) was added. The reaction mixture was stirred at room temperature for about 1 hour. It was then 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 (200 mg, 53%), EI-MS m / z 307.1 (M +). b) After the procedure of the example (1 g) except for the substitution of 1,3-dihydro-2,2-dioxo-3-methyl-4-chloro-2,1-benzisothiazole for 1-hydro-2,2- dioxo-3-hydro-3-fluoro-4-chloro-7-nitro-2,1-benzisothiazole, the title compound was prepared in 62% yield. EI-MS m / z 267.1 (M +).

HMMMH- c) Preparation of 1,3-d? Hydro-2,2-dioxo-3-fluoro-4-chloro-3-methyl-7- amino-2,1-benzisothiazole To the solution of 1,3-dihydro-2 , 2-dioxo-4-chloro-3-fluoro-7-nitro-2,1-benzisothiazole (100 mg, 0.4 mmol) in ethanol (10 ml), tin (II) chloride (443 mg, 2.0 mmol) was added ). The reaction mixture was stirred at room temperature for about 16 hours. Subsequently all the solvent was evaporated. Chromatography of the residue on silica gel (50% ethyl acetate / hexane) gave the desired product (43 mg, 47%). EI-MS m / z 237.2 (M +). 10 d) Preparation of N - [(1,3) -dihydro-2,2-dioxo-3-fluoro-4-chloro-2,1-benzisothiazole) -7-n-N '- [2-bromophenylurea A a solution of 2-bromophenyl isocyanate (25 mg, 0.13 mmol) in DMF (1.0 ml) was added 1,3-dihydro-2,2-dioxo-3-fluoro-4-chloro-7- 15 amino-2 , 1-benzisothiazole (30 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for about 16 hours. The product was purified by precipitation of methylene chloride and hexane and filtered (17 mg, 31%). EI-MS m / z 434.1, 436.1 (M +). By using the methods analogous to those indicated above, the following compounds were prepared: EXAMPLE 5 Nr (1, 3) -dihydro-2,2-dioxo-3-methylamine-4-chloro-2,1-benzisothiazo) -7-n-N'-r2-bromophenipyurea EM (EI) m / e 473.2 (mH) EXAMPLE 6 Nr (1,3) -dihydro-2,2-dioxo-3-methyl-3-methylamine-4-chloro-2,1-benzisothiazo) -7-ill-N'-r2-bromophenyl urea EM (EI) m / e 473.2 (mH) EXAMPLE 7 10 Nr (1,3) -dihydro-2,2-dioxo-3-methylene-4-chloro-2,1-benzothiazo-7-n-N'-r 2 -bromophenyl urea EM (EI) m / e 472.2 (mH) EXAMPLE 8 Nf (1,3) -dihydro-2,2-dioxo-3- (benzothiazol-2-yl) -4-chloro-2,1-benzisothiazo) -7- 15 in-N'-r 2 -bromophenin urea pf 145-152 ° C 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 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 .. ^? * ^. **** ^ ^ tjr | ^ m ftj other chemokines that bind to the receptor of IL-8 a or β, also referred to as the type I or type II receptor. Accordingly, the present invention provides a method of treating a disease mediated by chemokine, wherein 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 invention. 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 biologically regulated at normal levels of physiological function, or in certain cases 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 a 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 above 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. The chemokine-mediated diseases * bmlm < ^,. * ». ^, ^^^ ,, m tsmm - - ^ o - ** - *** »*** - include psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, respiratory distress syndrome in adults, intestinal disease inflammatory, Crohn's disease, ulcerative colitis, infarction, septic shock, endotoxic shock, negative gram sepsis, 5 toxic shock syndrome, cardiac and renal reperfusion injury, glumerulonephritis, thrombosis, graft reaction against host, Alzheimer's disease, rejections of allograft, malaria, restinosis, angiogenesis or unwanted release of hematopoietic stem cells, rhinovirus infections, and various 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. Infected 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 Johnston, 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 ai al., J. Geronlol., Ser. A (1997), 52A (6), M343-M351; Hermann, T. W095 / 31722; and Chaudhary, et al., Endocrinology (Balíimore) (1992), 130 (5), 2528-34. These diseases are characterized mainly by massive neutrophil infiltration, T cell infiltration, or growth ^^ te ^ gi ^^^^ g ^ gagteaM ^^^^^ T ^? ^ g ^^ neovascular, and are associated with the production of IL-8, GROa, GROß, GRO ?, NAP-2 or ENA- 78 which is responsible for the chemocytosis of neutrophils in the inflammatory site or the directional growth of the endoihelial cells. In contrast to inflammatory diseases (IL-8, GROa, GROß, GRO? Or NAP-5 2), it has the unique property of promoting neutrophil chemocytosis, including the release of but not limited to the release of elasiasa as well as the production and activation of superoxide. The a-chemokines, but paricularly, GROa, GROß, GRO? or NAP-2, which work in the lipo I or II receptor IL-8 can promote neovascularization of tumors by promoting the directional growth of the endoíeliales cells. Therefore, the inhibition of the induced chemolaxis of IL-8 or activation can lead to a direct reduction in neutrophil infiltration. Recent evidence also implicates the role of chemokines in the trafficking of HIV infections, Liííleman et al., Nalure 381, pp, 661 (1996) and Koup el al., Nalure 381, pp, 667 (1996). The present invention also provides a means of treatment, in an acute fixation, as well as prevention, in those individuals susceptible to CNS damage by the anhydrocyanin receptor compounds of chemokine of the formula (I). CNS injuries, as defined in the present, include open-head or rash injuries, such as surgery, or closed head injury, as a damage to the head region.

Also included in this definition is ischemic infarction, particularly in the brain area. Ischemic infarction can be defined as a focal neurological inflammation resulting from inadequate blood supply to a particular area of the brain, usually as a consequence of an embolus, anus, or local arelomaiosa closure of the blood spleens. The role of inflammatory cilocines in that area has arisen and the present invention provides a means for the potential treatment of said damages. Relatively low traffic, for acute damage as well as allergies, has been available. The TNF-a is a cilocin with proinflamal actions, including the expression of adhesion molecules of endoíeliales leukocytes. 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 15th year of cerebral ischemic damage. See Liu el al., Síoke, Vol. 25., No. 7, pp. 1481-88 (1994), the description of which is incorporated herein by reference. Models of closed head injury and trauma with mixed 5-LO / CO agents are described in Shohami et al., J. of Vaisic & 20 Clinical Physiology and Pharmacology, Vol. 3, No. 2, pp. 99-107 (1992), whose description is incorporated in the présenle by reference. It was found that the treatment that reduces the formation of edema improves the functional result in said treated animals.

The current evidence also indicates the use of IL-8 inhibitors in the irradiation of alellosclerosis. The first reference, Boisvert et al., J. Clin. Invest, 1998, 101: 353-363 shows, from the bone marrow transplantation, that the absence of IL-8 receptors in stem cells (and, therefore, 5 in monocytes / macrophages) leads to a reduction in the development of atherosclerotic plaques in mice deficient in LDL receptor. Additional support references are: Apostolopoulos, al., Arterioscler Thromb Vasc Biol. 1996. 16: 1007-1012; Liu, et al., Arterioscler Thromb Vasc Biol, 1997, 17: 317-323; Rus, al., Alherosclerosis. 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 e al., Arterioscler Thromb, 1994, 14: 47-53. The compounds of the formula (I) will be administered in a quantity sufficient to inhibit IL-8, bind IL-8 alpha or beta receptors, from which they bind to these receptors, as evidenced by a reduction in chemolaxis and neulrophilic acclivation. The discovery that the compounds of the formula (I) are inhibitors of the IL-8 bond is based on the effects of the compounds of the formulas (I) in the binding assays in vitro receptor described in the présenle. 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 that 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 the release of monocyte, but not limitation to IL-1, IL-6 or FNT. A case of disease 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 a disease condition mediated by IL-1. 8 As used herein, the term "disease or condition of chemokine-mediated disease" 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 IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78. This includes a disease cycle in which IL-8 has a function, either in the production of IL-8 itself, or IL-8 that causes it to be released, to listen to monocyte, such as but not being limited to IL- 1, IL-6 or FNT. 15 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 context mediated by IL-1. 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 inleractions between cells in the inflammatory or hematopoiemic immune response. A cilokine includes, but is not limited to, monocytes and lymphokines, despite the cells that produce them. For example, it is generally referred to that a monocline is produced and ^ &mM ^ ^ ... * m ~ "^ to * a * h * a ^ <. ^^^. ,, - ^ A ^^^ secret by a mononuclear cell, such as a macrophage and / or Several cells, however, also produce monocytes, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, cerebral astrocytes, bone marrow stryromatic cells, epidermal keralinocytes, and B-lymphocytes. lymphokines to be produced by lymphocyte cells Examples of cytokines include, but are not limited to, interleukin-1 (IL-1), inerieucin-6 (IL-6), inerieucin-8 (IL-8), factor lumoral-alpha necrosis (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 the cells in the immune, inflammatory or haematopoietic response, similar to the term no "cyanococline." A chemokine is secreted mainly from the cell membranes and causes the chemocytosis and acyivation of specific white blood cells and leukocytes, neulrophils, monocytes, macrophages, T cells, B cells, endoihelial 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 the formula (I) or a pharmaceutically acceptable salt thereof in the therapy, it will normally be formulated in a pharmaceutical composition according to the standard pharmaceutical practice. This invention, by itself, also refers to a The pharmaceutical composition comprising an effective, non-toxic composition 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 my techniques 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, lepraeulically-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 shape and character of the character or pharmaceutically acceptable dilute 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 container thereof. j M ^^^ sa ******* The pharmaceutic carrier used can be, for example, a solid or a liquid. Examples of solid carriers are lactose, Ierra alba, sucrose, icarus, gelaine, agar, pecillin, acacia, magnesium stearic acid, 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-saving 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.

In this way, if a solid carrier is used, the preparation can be converted into iables, placed in a hard gelatin capsule in the form of a powder or pellet or in the form of an icicles or lacquer. The solid carrier amount 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, ie by non-systemic administration. The foregoing includes the application of a compound of formula (I) externally to the epidermis or the oral cavity and the inslalation of said compound in the ear, eyes and nose, so that the compound does not significantly enlighten the bloodstream. In comparison, the sysiemic administration refers to oral, intravenous, intraperitoneal and muscular administration.

Formulations suitable for topical administration include liquid or semiliquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and suitable for administration to the 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. That may, 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. 10 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 golas. Lotions or liniments for application to the skin They may also include an agent to accelerate the drying and cooling of the skin, such as an alcohol or acetone, and / or a moisturizer such as glycerol or a lal oil such as castor oil or arachis oil. Creams, ointments or passages according to the present invention are semi-solid formulations of the active ingredient for the exoteric application. Esías can be done by mixing a finely ground or powdered acive ingredient, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the help of suitable machinery, with a greasy or non-greasy base. The base can comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a mellalic soap; a mucilage; an nalural oil such as almond, corn, araquis, castor oil or olive; wool grease or its derivatives or an ial fatty acid such as eseric acid or oleic acid with an alcohol such as propylene glycol or macrogel. The formulation may incorporate any suitable surface-active agent such as an anionic, cationic or non-ionic surfactant agent such as a sorbitan ester or a polyoxyelylene derivative thereof. Exemplary ionic agents such as nalural gums, cellulose derivatives or inorganic materials such as silaceae silicas, and other ingredients such as lanolin, may also be included. The beads 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 suitable preservative solvent, and preferably including a surface active agent. The resulting solution can then be clarified by filtering, transferring to a suitable container which is then sealed and sterilized by autoclaving or maintained at 98-100 ° C for half an hour. Ultimately, the solution can be sterilized by filtering and transferring to the container by means of an aseptic technique. Examples of suitable bactericidal or fungal agents for inclusion in the golas are nilrate or phenolimmercuric acetate (0.002%), benzalkonium chloride (0.01%) and & x ^ ¡^ ^ ¿¿Chlorhexidine acetylide (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, i.e. by intravenous, inhramuscular, subcutaneous, intralesional, inlaral, iniravaginal or intraperitoneal administration. Subcutaneous and intraluminal forms of parental 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, i.e., by intravenous 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 the 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 the body weight. The daily parenteral dose regimen will be around 0.001 to about 80 mg / kg of lolal body weight. The daily topical dose regimen will preferably be from 0.1 mg to 150 mg, administered from one to the next, 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 salt . - + *** * MC * H ^ Pharmaceutically acceptable ethic of the same will be determined by the nature and extent of the condition being irradiated., the form, route, and administration, and the particular patient who is being treated, and that said optimal degrees can be determined by conventional techniques. It will also be appreciated by a person skilled in the art that the optimum course of irradiation, ie, 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, is can be discerned by said experts in the art using the conventional course of fralarienle delermination tests. The invention will now be described with reference to the following biological examples which are merely illusive and are not considered 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: [125 I] IL-8 (human recombinance) is obtained from Amersham Corp., Arlingin Heighis, IL, with specific activity of 2000 Ci / mmoles. The Gro-a is made by NEN-New England Nuclear. All other chemicals are J ^^ jg of analytical degree. 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-luenesulfonyl fluoride), 0.5 mg / L of leupepinine, 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 125I-IL-8 (0.25Nm) 0/1251 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, plus the drug or compound of interest, which has been predisposed in DMSO to reach a final concentration of 0.01 nM and 100 uM. The assay was initiated by the addition of 125 I-IL-8. After 1 hour at ambient temperature, the plate was cultured using a Tamtec 96-well harvester in a fiberglass 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 then It was dried and counted in the liquid scintillation column of beia plate. The IL-8 receptor Ra, recombinase, or lipo I, is also referred to herein as the non-permissive receptor and reference is made to the IL-8Rβ receptor, recombinanle, or lipo 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 Currenl Protocole in Immunology, vol. I, Suppl 1, Unit 6.12.3, the description of which is incorporated herein by reference in its tolality. The neutróphils were isolated from human blood as described in Currenl Prolocols in Immunology Vol. I, Sup / 1. 1 Unit 6: 12.3, whose description is incorporated herein by reference in its illegality. The chemoattractants IL-8, GRO-a, GRO-β, GRO-? and NAP-2 are placed in the lower chamber of a chamber of 48 multiple cavities (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 may proceed from around 45 and 90 min at about 37 ° C in a humidified incubator with 5% C02. At the end of the incubation period, the polycarbonate membrane is removed and the upper area is washed, the membrane then Use the Diff Quick protocol (Baxter Producís, McGaw Park, IL, USA). Cells that chemokine chemoklaxis were visualized using a telescope. Generally, 4 fields were 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 (posiivoid cells), no compound was added, said cells represented the maximum chemolytic response of the cells. In the case where a negative conirol is desired (not reduced), chemokine is not added to the lower chamber. The difference between the posilive growth and the negative balance represent the chemotactic activity of the cells.

Elastase Release Assay The compounds of this invention were tested for their ability to prevent the release of elasasis from human nephrophiles. Neulrophiles are isolated from human blood as described in Curreni Prolocols in Immunology Vol. I. Suppl 1 Unit 7.23.1. The PMNs 0.88 x 106 cells Suspended in Ringer's solution (NaCl 118, KCl 4.56, NaHC03 25, KH2P04 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 cyclocalasin B in a volume of 50 ul (20ug / ml) and the Ringer's pH regulator in a volume of 50ul. Said cells could be calendered (37 ° C, 5% C02.95% 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 10 regulated phosphate saline solution. Immediately, the plate was placed in a fluorescent 96-well plate reader (Cyofofor 2350, Millipore, Bedford, MA) and the data were collected at 3 min intervals. according to the method of Nakajima et al J. Biol Chem 254 4027 (1979). The amount of elasilase released from the PMNs is calculated by measuring the rate of degradation of MeOSuc-Ala-Ala-Pro-Val-AMC.

TNF-α Assay in Brain Irrazoic Damage This trial provides for the examination of the expression of lumoral necrosis factor mRNA in specific brain regions that follow the experimental cerebral fluid percussion injury induced in rats (TNF) in rats since FNT -a is able to induce the nerve growth factor (NGF) and stimulates the release of other cilokines from the activated astrocytes, said post-traumatic alteration in the expression of the gene , ^ g ^^^^ T ^ te < ^^^^ ßte ^ M < - ^^ r ^^ dHKgB ^^^^^ l | ^ r ^; ^^^ r ^^^^^^ FNT-a plays an important role in the acute and regenerative response to the CNS rash. 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 nelirucin-1β mRNA (IL-1β) in specific brain regions following cerebral radiculoembolic percussion injury of experimental fluid (TBI) in rats. The results of these tests indicate that following the TBI, the temporal expression of IL-1β mRNA is regionally reduced in specific brain regions. Such regional changes in cytokines, ethers such as IL-1β, play a role in pathological or regenerative sequelae after the 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.

In vivo aerosol test: 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 aíherosclerolic lesions in mice. Atherosclerosis 68: 231-240 (1987) and Grool PHE, van Vlijmen BJM, Benson GM, Hofker MH, Schiffelers R, Vidgeon-Hart M, Havekes LM. Quaníiíafive assessmení of aortic aherosclerosis in APOE * 3 Leiden íransgenic mice and iís relaíionship to serum choleslerol exposure. Artereioscler Thromb Vasc Biol. 16: 926-933 (1996). 5 Sectioning and staining of the aortic sinus Cross sections of the aortic root are described 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 10 are ligated 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 ice freezes around the mandrel with dry ice. The hearts are then sectioned perpendicular to the axis of the aorta, starting at the heart and proceeding in the direction of the aorta. Once the aortic root has been idenified by the appearance of fresh valve leaflets, alternating 10mm sections are ligated and mounted on gelatinized slides. The sections are air-dried for 1 hour and subsequently briefly rinsed in 60% isopropyl alcohol. Sections are stained with oil red O, coated with Mayer hemaxililin, covered using glycerol gelatin and sealed with nail varnish. nH ¿g ^ i. . . ^^ - ^ Av? É? *.

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 (Daiacell Pentium P5-133, Daiacell Berks, UK) coupled with a frame recording labyrinth (Snapper, Acive Imaging Lid, Berks, UK) and the software is run Optimums (version 5.1, Optimums Corp., WA, USA). The images were captured under identical conditions of the microscopes, camera and PC. The quantification of the lesion-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 red-stained areas are obtained by software calibration using an image of the grid on a hemocytometry slide. All publications, including but not limited to patents and patent applications, contained 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 foregoing description describes the invention as the preferred embodiments thereof. Modifications and improvements to the modalities specifically described in this ^ .. atoamZu? ato ** - are within the scope of the following claims. Without further elaboration, it is believed that an expert in the art can, using the foregoing description, use the present invention to its fullest extent. Therefore, the examples in the present are considered 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 below.

Claims (16)

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, C5-8 cycloalkyl optionally susíiuuido, optionally CMO alkyl susíiuuido, C2-? 0 alkenyl optionally susíiuuido, or a C2-? 0 alkynyl optionally susíiuuido; X is = 0, or = S; A is CR2oR2i; Ri is independently selected from hydrogen; halogen; nilro; cyano; CMO alkyl is halous; C -? 0 alkyl; C2-? 0 alkenyl; Ci- 10 alkoxy; CMO alkoxy halosusliluido; azide; (CR8R8) qS (0) tR4, hydroxy; hydroxyalkyl of C? -4; aril; arylalkyl of C? -4; aryloxy; C1-4 arylalkyloxy; heeroeroil; heeroarylalkyl; heyerocyclic; C4-helerocyclic alkyl; C4-4 heteroarylalkyloxy; arylalkenyl of C2-? 0; C2-? 0 -hearyoarylalkenyl; alkenyl 20 heyerocyclic of C2-10; (CR8R8) qNR4R5; C2-10-C (O) NR4R5 alkenyl; (CR8R8) qC (0) NR4R5; (CR8R8) qC (O) NR4R? 0; S (0) 3H; S (0) 3R8; (CR8R8) q C (0) R ??; C2-10-C (O) Ru alkenyl; alkenyl of C2-? 0-C (O) ORn; (CR8R8) qC (0) ORu; (CR8R8) qC (0) OR? 2; (CR8R8) qOC (0) Rn; (CR8R8) qNR4C (0) Ru; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) Rn; (CR8R8) qNHS (0) 2R? 7; (CR8R8) qS (0) 2NR4R5; or two portions Ri junies can form -0- (CH2) sO- or a ring of 5 to 6 members unsaturated or salted, and in which rings containing aryl, heleroaryl, and heterocyclics can optionally be 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 from 1 to 10; í 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; R4 and R5 are independently hydrogen, optionally substituted C alquilo alkyl, Optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroalkyl, heterocyclic, C?-Heterocyclic alkyl, or R 4 and Rs together with the nitrogen to which they are attached form a ring from 5 to 7 members that you can optionally request from an additional heleroalome selected from 15 O / N / S; And it is independently selected from hydrogen; nilro halogen; cyano; alkyl or haloalicylic acid; C? -? o alkyl; C2-? alkenyl or CMO alkoxy; CMO alkoxy halosusliluido, azide; (CR8R8) qS (0) tR4; hydroxy hydroxyalkyl of C? -4; aril; Ci ^ arylalkyl; aryloxy; C.sub.4 -heleroaryl arylalkyloxy; heleroarylalkyl; C4-4 heteroarylalkyloxy; heterocyclic; I rent 20 of C? -4 heterocyclic; arylalkenyl of C2-? 0; C2-? 0 -hearyoarylalkenyl; C2-? 0 oleyl cyclic alkenyl; (CR8R8) qNR4R5; C2-? 0- C (0) NR4R5 alkenyl; (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; Oia S-H-BB-S títa ^ j? TaMr ^ ß (CR8R8) qC (0) ORn; (CR8R8) qC (0) OR? 2; (CR8R8) qOC (0) Ru; (CR8R8) qNR4C (0) Ru; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) Ru; (CR8R8) qNHS (0) 2R18; (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; R6 and R7 are independently hydrogen or an alkyl group of C? -4, or R6 and R7 together with the nihologen 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 C? -4 alkyl; Rio is C? -? O-C (0) 2R8 alkyl; Ru is hydrogen, C? -4 alquiloalkyl, optionally susiloyl aryl, optionally suslyyl arylalkyl, optionally substituted heleroaryl, optionally substituted C? -4 hetero heteroarylalkyl, optionally substituted heterocyclic, or optionally substituted C?-Heterocyclic alkyl; R 2 is hydrogen, C?-Α? Alkyl, optionally substituted aryl or optionally substituted arylalkyl; R 3 and R 14 are independently hydrogen, C 1 - optionally substituted alkyl, or one of R 13 and Ru can be an optionally substituted aryl; R15 and R16 are independently hydrogen, or a C? - optionally substituted alkyl; R? 7 is C? - alkyl, aryl, arylalkyl, heleroaryl, C? - heteroaryl, heterocyclic, or C? - heterocyclic alkyl, in which the aryl, heteroaryl and heterocyclic rings may all be optionally substituted; R? 8 is NR6R, alkyl, arylalkyl of C-, arylalkenyl of C2-, heteroaryl, C2-4 heteroarylalkyl, C2- heteroarylalkenyl, helerocyclic, C-helerocyclic alkyl, in which the aryl, heleroaryl and heterocyclic rings can all be optionally substituted; R20 and R2? they are independently hydrogen, halogen, cyano, halo substituted alkyl, CMO alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroarylalkyl, helerocyclic, C4-4 helerocyclic alkyl, (CR8R8) qOR4, (CR8Rβ) qC (0) R11 t (CR8R8) qC (0) ORn, (CR8R8) qC (0) OR ?2, (CRβR8) qOC (0) R ??, (CR8R8) qNR4R5, (CR8R8) qNR4C (0) Rn, (CR8R8) qC (0) NR4R5; (CR8R8) q C (O) NR4R? 0, or together R20 and R2? they can form = R22; and wherein the rings containing aryl, heteroaryl, and heterocyclic may optionally be substituted; with the additional condition that R2o and R2? they are not hydrogen; R22 is a C? - alkyl, aryl, C? - arylalkyl; heeroeroil; heteroarylalkyl, heterocyclic, or heterocyclic C 1-4 alkyl, and wherein all those portions may optionally be substituted; W is the ring containing E is optionally selected from: | ^^ | ^^ ^^ the asterisk * denoted the point of adhesion of the ring; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, further characterized in that at least one of R20 and R2? it's an alkyl Optionally susliuid, halogen, (CR8Rs) qC (0) NR4R5, optionally substituted heleroaryl or an optionally substituted heterocyclic, or R20 and R2? they are together a methylene.

3. The compound according to claim 1, further characterized in that X is oxygen.

4. The compound according to claim 1 or 3, further characterized in that Ri is halogen, cyano, nitro, CF3, C (0) NR4R5, C (O) NR4R-? 0, alkenyl C (0) ORu, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or (CR8R8) qS (0) NR4R5.

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 Y is halogen, C1-4 alkoxy, aryl optionally substituted, arylalkoxy optionally substituted, methylenedioxy, NR R5, thioalkyl of C? -4, thioaryl, halo alkyloxy, alkyl of C? Optionally susliuido, or substituted hydroxyalkyl.

7. The compound according to claim 4, further characterized in that Z is an optionally substituted heteroaryl. ^ átoüST -'tíí .-.;, | ta ^ &

8. The compound according to claim 1 further characterized because it is: N - [(1,3) -Dihydro-2,2-dioxo-3-meityl-4-chloro-2,1-benzisoyiazo) -7-yl] -N '- [2-bromophenyl] urea, N - [(1,3) -Dihydro-2,2-dioxo-3-propyl-4-chloro-2,1-benzisolzozo) -7-yl] -N' - [2-Bromophenyl] urea, N - [(1-hydro-2,2-dioxo-3,3-dimethyl-4-chloro-2,1-benzisolzozo) -7-yl] -N '- [2- bromophenyl] urea, N - [(1,3) -Dihydro-2,2-dioxo-3-fluoro-4-chloro-2,1-benzisolzozo) -7-yl] -N '- [2-bromophenyl] ] urea, N - [(1,3) -Dihydro-2,2-dioxo-3-melilamide-4-chloro-2,1-benzisolzozo) -7-yl] -N '- [2-bromophenyl] urea, N - [(1,3) -Dihydro-2,2-dioxo-3-meityl-3-meitylamide-4-chloro-2,1-benzisothiazo) -7-yl] -N '- [2-bromophenyl] urea , N - [(1,3) -Dihydro-2,2-dioxo-3-melylene-4-chloro-2,1-benzisoyiazo) -7-yl] -N '- [2-bromophenyl] urea, N- [(1, 3) -Dihydro-2,2-dioxo-3- (benzoliazol-2-yl) -4-chloro-2,1-benzisoyiazo) -7-yl] -N '- [2-bromophenyl] urea , or pharmaceutically acceptable salts thereof.

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

10. The use of an effective amount of a compound according to any of claims 1 to 8 for the manufacture of a medicament for treating a chemokine-mediated disease in a mammal, wherein the chemokine is linked to an IL-receptor. 8 V or "ß".

11. The use according to claim 10, 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's disease, ulcerative colitis, septic shock, endoioxic shock, gram-negative sepsis, septic shock syndrome, infarction, cardiac and renal reperfusion damage, glumerulonephritis, Irombosis, eosclerosis, bone resorption diseases, Alzheimer's disease, graft reaction with host host or allograft rejections.

12. A process for producing a compound of the formula (I) according to claim 1, whose method comprises: a) reacting a compound of the formula: with a compound of the formula: C (X) -N- (CR? 3Ru) v-Z; where A, R (m, X, R13, Ru, v and Z are as defined in formula (I) to yield a compound of formula (I), and subsequently, if necessary, disprolegate, or convert a precursor to Ri, A, or Z to a group R ^ A or Z. 13.- A procedure to make 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: ate¿afc- where A, Ri and m are as defined in formula (I), under appropriate conditions of reduction to yield a compound of formula (II). 14. A compound of the formula: where A, Ri and m are as defined in formula (I). 15.- A compound of the formula where A, Ri and m are as defined in formula (I). 16. A process for producing a compound of formula (I) according to claim 1, whose method comprises reacting a compound of the formula: u ^ ¡| ^ wherein A, Ri and m are as defined in formula (I), with a compound of formula NH2-C (X) -N- (CR13Ru) 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.