MXPA01000822A - Il-8 receptor antagonists - Google Patents

Abstract

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

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-8 (IL-8), as neutrophil-activating / activating protein-1 (NAP-1), monocyte-derived neutrophil chemotactic factor (MDNCF), neutrophil activation (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. AND WHAT 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, 5 643 (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 bursts Respiratory, binding to and activating receptors of the seven-transmembrane family, chained to G protein, in particular binding to IL-8 receptors, most notably the B receptor. Thomas et al., J. Biol. Chem. 266, 14839 (1991 ); and Holmes et al., Science 253. 1278 (1991). The development of non-peptide small molecule antagonists for members of this family receiver has precedents. For a summary consult R. Freidinger in: Proqress ¡n 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 with 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 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) or (II). The present invention also provides novel compounds of formula (I), and (II) and pharmaceutical compositions comprising a compound of formula (I) and (II) 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 (X2) -NH- (CR? 3Ri4) v -Z; Z is W, HET, optionally substituted CMO alkyl, optionally substituted C2-10 alkenyl, or optionally substituted C2-10 alkynyl; X is C (X?) 2, O, N-Ri?, C = 0, or S (0) m-; XI is independently hydrogen, halogen, C1-10 alkyl, NR4R5, C (O) NR4R5, optionally substituted CMO alkyl, d-10 alkoxy, C1-10 alkoxy halosubstituted, hydroxy, aryl, arylalkyl of C? -4 , aryloxy, aryl-C 1-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, C 1-4 heterocyclic alkyl, or C 1-4 heteroarylaxykyloxy; with the proviso that both X1 are not hydrogen; X2 is = O, or = S; A is CH2, C (O), or C (S); R1 is independently selected from hydrogen; halogen; nitro; cyano; CMO alkyl substituted; C1-10 alkyl; C2-10 alkenyl; C-MO alkoxy; C.sub.10 -halosubstituted alkoxy; azide; (CR8R8) qS (O) tR, hydroxy; hydroxyalkyl of C- O ", aryl; arylalkyl of C-; aryloxy; arylalkyloxy of C-; heteroaryl; heteroarylalkyl; heterocyclic; heterocyclic alkyl of C-; heteroarylalkyloxy of C? -; arylalkenyl of C2-? or; heteroarylalkenyl of C -2-10; 5 C2- or C6 heterocyclic alkenyl; (CR8R8) qNR4R5; C2-10 alkenyl C (O) NR4R5; (CR8R8) qC (O) NR4R5; (CR8R8) qC (O) NR4R10; S (O) 3H; S (O) 3R8; (CR8R8) qC (O) R; alkenyl alkenyl of C2-? OC (O) ORn; C (0) Rn; (CR8R8) qC (O) OR12; (CR8R8) qOC (O) R1? (CR8R8) qNR4C (0) R11; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) R ??; (CR8R8) qNHS (0) 2Ri7; (CR8R8) qS (O) 2NR4R5, or two R1 portions together can form -O- (CH2) sO- or a 5-6 membered saturated or unsaturated ring, n is an integer having a value of 1 to 3; m is an integer that has a value of 1 to 3, m 'is an integer that has a value of 1 or 2, 15 p is an integer that has a value of 1 to 3, q is 0, or an integer that has a value of 1 to 10; s is an integer that has a value of 1 to 3, t is 0, or an integer that has a value of 1 or 2; v is 0, or an integer that has a value of 1 to 4; HET is an optionally substituted heteroaryl; R 4 and R 5 are independently hydrogen, optionally substituted C 1 - alkyl, optionally substituted aryl, C 1 - optionally substituted arylalkyl, optionally substituted heteroaryl, Í ^^^ ^ ^^ ^ ^ MJ ^ ^^ *. ... 1illÉÉíllííWÍ! >; T¡ri¡? Ít '7? The heteroarylalkyl of optionally substituted C 1-4, heterocyclic, or C 1-4 heterocyclic alkyl, or R 4 and R 5 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; And it is independently selected from hydrogen; halogen; nitro; cyano; CH 0 alkyl substituted; CMO alkyl; C2-10 alkenyl; C-O alkoxy; Halo-substituted C-MO alkoxy, azide; (CR8R8) qS (0) tR4; hydroxy; hydroxy C-MO alkyl; aril; arylaxy aryloxy; C? -4 arylalkyloxy; heteroaryl; heteroarylalkyl; Heterocyclic heterocyclyloxy; C 4 heterocyclic alkyl; C2-arylalkenyl; C2-10 heteroarylalkenyl; C2-10 heterocyclic alkenyl; (CR8R8) qNR4R5; C2-10 alkenyl C (O) NR4R5; (CR8R8) qC (O) NR4R5; (CR8R8) qC (O) NR4R10; S (O) 3R8; (CR8R8) q C (O) Rn; alkenyl of C2-? o-C (O) Rn; C2-10 alkenyl C (O) ORn; (CR8R8) qC (O) OR12; (CR8R8) qOC (O) Rn; (CRßRßJqNF CÍOJRn; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) R ??; (CR8R8) qNHS (O) 2Ra; (CR8R8) qS (O) 2NR R5; or two portions AND together can form -O- (CH2) s-O or a 5-6 membered saturated or unsaturated ring; R6 and R7 are independently hydrogen or an alkyl group of C1-4, 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 selected from oxygen, nitrogen or sulfur; Rs is independently hydrogen or C? - alkyl; R10 is C? -? Or C (O) 2R8 alkyl; - ^ _ í ____ & _ ^ _ m_ ^ i R ?? is hydrogen, C- alkyl, optionally substituted aryl, optionally substituted C 1-4 arylalkyl, optionally substituted heteroaryl, optionally substituted C 1 -C 4 heteroarylalkyl, optionally substituted heterocyclic, or C 1 -alkyl. optionally substituted heterocyclic; R-? 2 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 R14 may be an optionally substituted aryl; R15 and R16 are independently hydrogen, or an optionally substituted C-? -4 alkyl; R-I7 is C? -4alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl of C1.4, heterocyclic, or C4-4alkyl heterocyclic, in which the rings containing aryl, heteroaryl and heterocyclic may all optionally be replaced; Ris is hydrogen, C? -4 alquiloalkyl, aryl, arylC1-4alkyl, heteroaryl, heteroalkylalkyl, heterocyclic, or C1alkyl. heterocyclic, all of which may all be optionally substituted; Ra is NR6R7, alkyl, arylalkyl of C? -, arylalkenyl of C2-4, heteroaryl, heteroarylalkyl of C1-4, heteroarylalkenyl of C2-4, heterocyclic, or C? -alkyl heterocyclic, in which rings containing aryl , heteroaryl and heterocyclic may all be optionally substituted; - * ----- * > • "« - »•» - - --- - -Ji. ^ »^^^ 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.

The compounds of formula (II) useful in the present invention are represented by the structure: (R in which ^^^^ g ^ s ^^^^^^^ R is -NH -C (X2) -NH- (CR? 3R? 4) v -Z; Z is W, HET, optionally substituted C? -? Alkyl, optionally substituted C2-10 alkenyl, or optionally substituted C2-10 alkynyl; X is C (X?) Or N; X1 is hydrogen, halogen, C1-10 alkyl, NR4R5, C (O) NR4Rs, optionally substituted C1-10 alkyl, CMO alkoxy, C1-10 alkoxy halosubstituted, hydroxy, aryl, arylC1-4 alkyl, aryloxy , C 1-4 arylalkyloxy, heteroaryl, C 1-4 heteroarylalkyl, heterocyclic, C 1-4 heterocyclic alkyl, or C 1-4 heteroarylalkyloxy; X2 is = 0, or = S; A is CR? 8; R1 is independently selected from hydrogen; halogen; nitro; cyano; C1-10 alkyl substituted; C-O alkyl; C2-10 alkenyl; CMO alkoxy; CMO alkoxy is substituted; azide; (CRsR8) qS (0) tR4, hydroxy; C1-10 hydroxyalkyl; aril; C1-4 arylalkyl; aryloxy; C1-4 arylalkyloxy; heteroaryl; C 1-4 heteroarylalkyl; heterocyclic; C1.4 heterocyclic alkyl; C 1-4 heteroarylalkyloxy; C2-10 arylalkenyl; C2-10 'heteroarylalkenyl, C2-10 heterocyclic alkenyl; (CR8R8) qNR4R5; C2-10 alkenyl C (O) NR4R5; (CRsR8) qC (O) NR4R5; (CR8R8) qC (O) NR4R10; S (O) 3H; S (0) 3Rβ; (CRßRß) qC (0) R ??; alkenyl of C2-? o-C (O) Rn; alkenyl of C2-? o-C (0) ORn; C (O) Rn; (CR8R8) qC (O) OR12; (CR8R8) qOC (0) Rn; (CR8R8) qNR4C (0) R11; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) R ??; (CR8R8) qNHS (O) 2R17; or (CR8R8) qS (0) 2NR4R5; or two R-i portions together can form -O- (CH2) sO- or a 5-6 membered saturated or unsaturated ring; m is an integer that has a value of 1 to 3; n is an integer that has a value of 1 to 3; p is an integer that has a value of 1 to 3; q is 0, or an integer that has a value of 1 to 10; s is an integer that has a value of 1 to 3; t is 0, or an integer that has a value of 1 or 2; v is 0, or an integer that has a value of 1 to 4; HET is an optionally substituted heteroaryl; R4 and Rs are independently hydrogen, optionally substituted C -? Alquilo alquiloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted C? -4 hetero heteroaryl, heterocyclic, or heterocyclic C alquilo alquilo 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-MO alkyl; C2-10 alkenyl; C-MO alkoxy; C.sub.10 -halosubstituted alkoxy, azide; (CR8R8) qS (O) tR4; hydroxy; hydroxy C-MO alkyl; aril; C1- arylalkyl; aryloxy; C1-4 arylalkyloxy; heteroaryl; heteroarylalkyl of C -? - 4; heteroarylalkyloxy of C? -; heterocyclic; C 1-4 heterocyclic alkyl; arylalkenyl of C2-? 0; C2-? o heteroarylalkenyl; heterocyclic alkenyl of C2-? 0; (CR8R8) qNR R5; C2-10 alkenyl C (O) NR4R5; (CR8R8) qC (O) NR4R5; (CR8R8) qC (O) NR4R10; S (O) 3R8; (CR8R8) q C (0) Rn; alkenyl of C2.?o-C(0) Rn; alkenyl of C2.10-C (O) ORn; (CR8R8) qC (O) OR12; (CR8R8) qOC (0) R11; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) R ??; (CR8R8) qNHS (O) 2Ra, or (CRsR8) qS (O) 2NR R5; or two portions AND together can form -O- (CH2) s-O or a 5-6 membered saturated or unsaturated ring; Re and R7 are independently hydrogen or an alkyl group of C1-4, or Re and R7 together with the nitrogen to which they adhere 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; R-io is C- |.? O-C (O) 2 R8 alkyl; R 11 is hydrogen, C 1 - alkyl, optionally substituted aryl, optionally substituted C arylalkyl, optionally substituted heteroaryl, optionally substituted C - heteroarylalkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C 1-4 alkyl; R 12 is hydrogen, optionally substituted C 1 -10 alkyl aryl or optionally substituted arylalkyl; R 3 and R are independently hydrogen, C 4 alkyl optionally substituted, or one of R 3 and R 14 may be an optionally substituted aryl; R15 and R16 are independently hydrogen, or an optionally substituted C1-4 alkyl; R1 is C? - alkyl, aryl, arylalkyl, heteroaryl, C? -4 hetero heteroaryl, heterocyclic, or C?-Heterocyclic alkyl, wherein the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted; Lanes are hydrogen, C 1-4 alkyl, aryl, C? -4 arylalkyl, heteroaryl, C? -4 heteroarylalkyl, heterocyclic, or C 1-4 heterocyclic alkyl, all of which may all be optionally substituted; Ra is NReR7, alkyl, arylalkyl of C 1-4, arylalkenyl of C 2-4, heteroaryl, heteroarylalkyl of C 4, heteroarylalkenyl of C 2-4, heterocyclic, or C 4 heterocyclic alkyl, in which the rings which they contain aryl, heteroaryl and heterocyclic can all 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) and (II) 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 IL-8 receptors. H.H. Chemokine-mediated diseases for treatment, therapeutically or prophylactically, in animals, include disease states such as those noted herein in the Methods of Treatment section. As you can easily see, the difference between the compounds of formula (I) and (II) lie in the unsaturation of the ring containing A, and hence the substitutions on the portions X and A. The remaining terms, which are defined below, are the same for both compounds of formula (I) and (II) unless otherwise indicated. i ^ j ^ fl j || | ^ | gfi ^ Conveniently, Ri is independently selected from hydrogen; halogen; nitro; cyano; C1-10 alkyl substituted, such as CF3; CMO alkyl, such as methyl, ethyl, isopropyl, or n-propyl; C2-10 alkenyl; CMO alkoxy, such as methoxy, or ethoxy; C.sub.mo haloosubstituted, like trifluoromethoxy; azide; (CR8R8) qS (O) tR4, where t is 0, 1 or 2; hydroxy; C1-10 hydroxyalkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl; C1-4 arylalkyl, as benzyl; aryloxy, such as phenoxy; C1.4 arylalkyloxy, such as benzyloxy; heteroaryl; heteroarylalkyl of C 1-4 heteroarylalkyloxy; C2-10 arylalkenyl; C2-10 heteroarylalkenyl; heterocyclic alkenyl of 10 C2-10; (CR8R8) qNR4R5; alkenyl of C2-? 0-C (O) NR4R5; (CR8R8) qC (O) NR4R5; (CR8R8) qC (O) NR4R? O; S (O) 3H; S (O) 3Rs; (CRßRß) qC (0) Rn; C2-? o-C (0) R alkenyl; alkenyl of C2.?o-C(0)ORn; C (0) Rn; (CR8R8) qC (O) OR? 2; (CR8Rβ) qOC (0) Rn; (CRßR8) qNR4C (0) Rn; (CR8R8) qC (NR4) NR4R5; (CRßR8) qNR4C (NR5) R ??; (CR8R8) qNHS (0) 2Ri7; or (CR8R8) qS (O) 2NR4R5; or two 15 R1 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. Preferably, R1 is different from azido for the methods of use herein. It is recognized that the R1 portion can be substituted on the benzene ring or the ring containing A, if possible. Conveniently, s is an integer that has a value of 1 to 3, and m is an integer that has a value of 1 to 3.

^^^^^^^^^^^^^^? ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^^^^^^^^^^^^^^^^ When Ri forms a dioxi bridge, s is preferably 1. When Ri forms an additional saturated ring or unsaturated, it is preferably a 6-membered ring, which preferably results in a naphthalene ring system. Those additional rings can be substituted independently, 1 to 3 times, by the other portions R < ? as defined above. Preferably Ri is hydrogen, halogen, cyano, nitro, CF3, (CR8R8) qC (O) NR4R5, C2-? Alkenyl or C (0) NR4R5, (CR8R8) qC (O) R4R? Or, C2- alkenyl 10 C (O) OR? 2, heteroaryl, C 1-4 heteroarylalkyl, C 2 -? O heteroarylalkyl, or S (0) 2 NR 4 Rs - Conveniently, R and R 5 are independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted arylalkyl of C 1-4, optionally substituted heteroaryl, optionally substituted heteroaryl C 1-4 alkyl, heterocyclic, C 1-4 heterocyclic alkyl, or R 4 and R 5 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. Conveniently R6 and R7 are independently hydrogen or an alkyl group of C1.4, 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 of oxygen, nitrogen or sulfur.

Conveniently, Rs is independently hydrogen or C1-4 alkyl. Conveniently, q is 0 or an integer having a value of 1 to 10.

Conveniently, R10 is C? -? Or C (0) 2R8 alkyl, such as CH2C (O) 2H or CH2C (O) 2CH3. Conveniently, Rn is hydrogen, C? -4 alkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or C1-4 heterocyclic alkyl. Conveniently, R 2 is hydrogen, CMO alkyl, optionally substituted aryl or optionally substituted C 1-4 arylalkyl. Conveniently, R 3 and R 14 are independently hydrogen, optionally substituted C 1-4 alkyl which may be straight or branched as defined herein, or one of R 3 and R 14 are an optionally substituted aryl; v is 0, or an integer having a value of 1 to 4. When R 3 or R 14 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? -4, C1-4 alkoxy; as methoxy, or ethoxy, halosubstituted C1-10 alkoxy, S (O) tR4; aril; NR4R5; NHC (O) R4; C (O) NR4Pv5; or C (O) OR8. Conveniently, R17 is C? -4 alkyl, aryl, arylalkyl, heteroaryl, C? -4 hetero heteroarylalkyl, heterocyclic, or heterocyclic alkyl ^^ áá ^^?, *,. r, ^. ..... ** A * ¿? * *? M * ~.,. .. ^^. A. ^ ... ..,. - ,, ... ^? ^. , - «,? Lt 1 C? -4, in which the rings containing aryl, heteroaryl and heterocyclic can all be optionally substituted. Conveniently, Y is independently selected from hydrogen; halogen; nitro; cyano; CMO alkyl substituted; Ci- 10 alkyl; C2-10 alkenyl; CMO alkoxy; halosubstituted alkoxy of C? -? o, azide; (CR8Rd) qS (0) tR4; hydroxy; hydroxyalkyl of CMO; aril; C1-4 arylalkyl; aryloxy; C1-4 arylalkyloxy; heteroaryl; C 1-4 heteroarylalkyl; C 1-4 heteroarylalkyloxy; heterocyclic; C? -4 heterocyclic alkyl; C2-10 arylalkenyl; C2-? o heteroarylalkenyl; C2-10 heterocyclic alkenyl; (CR8R8) qNR R5; C2-? o-C (O) NR4R5 alkenyl; (CR8R8) qC (O) NR R5; (CR8R8) qC (0) NR4R? O; S (O) 3Rs; (CR8R8) qC (0) Rn; alkenyl of C2-? o-C (0) Rn; alkenyl of C2.10-C (O) ORn; (CR8Rs) qC (0) OR? 2; (CRßRß) qOC (0) Rn; (CR8R8) qNR4C (0) R ??; (CR8R8) qC (NR4) NR4R5; (CR8Rβ) qNR4C (NRs) R ??; (CR8R8) qNHS (O) 2Ra, or (CRßR8) qS (O) 2NR4R5; or two portions AND together they can form -O- (CH2) sO- or a 5-6 membered saturated or unsaturated ring. Preferably, Y is other than azido for the methods of use herein. Conveniently, n is an integer that has a value of 1 to 3. When Y forms a dioxy bridge, s is preferably 1. The aryl, heteroaryl and heterocyclic containing portions noted above for Y may all be optionally substituted as defined herein. When Y forms an additional ring saturated or not saturated, is preferably a 6-membered ring, which more preferably results in a naphthylene ring system. Those additional rings may be optionally substituted 1 to 3 times by other Y portions as defined above. Conveniently, Ra is NRßR7, alkyl, arylalkyl of C4-4, arylalkenyl of C2-, heteroaryl, heteroarylalkyl of C1.4, heteroarylalkenyl of C2-4, heterocyclic, heterocyclic alkyl of C4-4, in which rings containing aryl, heteroaryl and heterocyclic may all be optionally substituted. And is preferably a halogen, C? -4 alkoxy, optionally substituted aryl, optionally substituted C? -4 ar aryloxy or arylalkoxy, methylenedioxy, NR4R5, C1-4 thioalkyl, thioaryl, halo-substituted CMO alkoxy, C1-6alkyl 10 or hydroxyalkyl of C? -? O. More preferably Y is mono substituted halogen, disubstituted halogen, monosubstituted alkoxy, alkoxy Disubstituted, methylenedioxy, aryl, or alkyl. More preferably those groups are mono or di-substituted at the 2-position or the 2'-, 3'- position when Z is W and W is a phenyl ring (such as when no E group is present). Although Y may be substituted at any of the 5 ring positions when W is a phenyl portion, Y is preferably mono-substituted in the 2'- position, or 3'- position, with the 4'- preferably being unsubstituted. If the phenyl ring is disubstituted, the substituents are preferably in the 2 'or 3' position of a monocyclic ring. Although R1 and Y can both be hydrogen, it is preferred that at least one of the rings be replaced, preferably both rings are substituted. In compounds of formula (I), A is conveniently CH2, C (S) or C (S). It is noted that in the formula (I) the ring containing A is saturated. In compounds of formula (II), A is conveniently CRiß-5 It is also noted that in formula (II) the ring containing A contains unsaturation. Conveniently, R 18 is hydrogen, C 1-4 alkyl, aryl, C 1-4 arylalkyl, heteroaryl, C 1-4 heteroarylalkyl, heterocyclic, or C? -4 heterocyclic alkyl, all of which may be optionally substituted. of C? - or optionally substituted, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl. Conveniently p is an integer having a value of 1 to 3. 15 Conveniently, W is Conveniently, the ring containing E is optionally selected from the asterisk * denotes the point of adhesion of the ring.

Preferably, Z is The ring E, denoted by its point of attachment through the asterisk (*), may optionally be present. If it is not present, the ring is a phenyl portion that is substituted by the terms Y as shown above. Ring E can be substituted for a Y portion in any ring, saturated or unsaturated, and is shown for purposes of the present substituted only in the unsaturated ring (s). Conveniently, X2 is = 0, or = S. In compounds of formula (I), X is conveniently C (X?) 2l N-R18, O, C = O, or S (O) m-, and m 'is an integer having a value of 1 or 2 .

Preferably X is O, N-R? 8, C = O, or S (O) m-. More preferably X is S (0) m-. More preferably X is S (O) m- and m 'is 2, when A is CH2. When X is C (X?) 2, both X1 can not be hydrogen. Preferably in compounds of formula (I), when X is C (X -?) 2, then one of X1 is an electron acceptor group such as an unsubstituted alkyl, such as CF3 or C (O) NR4Rs- In compounds of formula (II), X is conveniently C (Xt) or N, preferably C (X?). Conveniently, Xi is independently hydrogen, halogen, NR4R5, C (O) NR4Rs, optionally substituted CMO alkyl, CMO alkoxy, haloalubstituted C-MO alkoxy, aryl, C1-4 arylalkyl, aryloxy, C? -4 arylalkyloxy, heteroaryl, heteroarylalkyl of C? -, heterocyclic, C? - heterocyclic alkyl, or heteroarylalkyloxy of C -? -. The alkyl group can be optionally substituted one or more times by hydroxy, NR R5, or halogen, preferably, for compounds of formula (I), when X is C (X -?) 2, at least one of X-i is hydrogen. For compounds of formula (II), X1 is preferably hydrogen or an electron acceptor group, such as halo-substituted alkyl, such as CF3 or C (O) NR4R5. HET is an optionally substituted heteroaryl portion, as defined below for optional substituents and for particular heteroaryl moieties. Conveniently R15 and R-iß are independently hydrogen, or a C? .4 alkyl, optionally substituted as defined above for R13 and R? . As used herein, "optionally substituted" unless specifically defined, shall mean groups such as , _ ". .. ",, and ¡¡Jg¡ | } Halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted CMO alkyl; CMO alkoxy, such as methoxy or ethoxy; alkyl of CMo-S (0) m "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 R5; 5 C (O) OH; S (O) 2 NR4R5; NHS (O) 2 R19, C 1 -10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; Halo-substituted C 0 alkyl, such as CF 3; an optionally substituted aryl, such as phenyl, or an arylalkyl optionally substituted as benzyl or phenethyl, optionally substituted heterocyclic, optionally substituted alkylheterocyclic, heteroaryl optionally Substituted, optionally substituted heteroarylalkyl, and wherein those aryl, heteroaryl, or heterocyclic containing portions may be substituted once or twice by halogen; hydroxy; alkyl substituted by hydroxy; CMO alkoxy; C 0 S (O) m alkyl; amino, amino mono and disubstituted, as in the group NR R5; CMO alkyl, or CMO alkyl has been replaced as CF3. R19 is conveniently C alquilo -4 alquilo alkyl, aryl, C? - arylalkyl, heteroaryl, C? -4 hetero heteroarylalkyl, heterocyclic, or heterocyclic C-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, acid lactic acid oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of formula (I) 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. • "Alkyl of C O" ° "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, tert-b iWo, n-pentyl and the like . • "Cilcoalkyl" is used herein to mean cyclic radicals, preferably from 3 to 8 carbons, including but not 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, 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 5"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, or benzimidazole. • "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; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine. "Arylalkyl" or "heteroarylalkyl" or "alkylheterocyclic" is used herein to mean CMO alkyl, as defined above, adhered to an aryl, heteroaryl or heterocyclic moiety, as defined herein, unless otherwise indicated otherwise. 20 • "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. i7 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^ '-' '- ^ ftMa Üfc -' ^.

• 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 bicyclic ring system, or a phenyl portion having a saturated or unsaturated 5 or 6 membered ring as a Ce cycloalkenyl, ie hexene, or a cycloalkenyl portion of C5, cyclopentene, or a fully unsaturated 5 or 6 membered ring such as benzene, i.e. , resulting in a naphthylene ring. Exemplified compounds of formula (I) include: N ^ -Bromopheni-N I .S-dihydro ^ -dixo-x-benzisothiazole ^ -yl) urea; N - [(1,3-D yhydro-2,2-dioxo-4-fluoro-2,1-benzisothiazo) -7-yl] -N '- (2-bromophenyl) urea; N - [(1,3-Dihydro-2,2-dioxo-4-chloro-2,1-benzisothiazo) -7-yl] -N '- (2,3-dichlorophenyl) urea; N - [(1,3-Dihydro-2,2-dioxo-4-chloro-2,1-benzisothiazo) -7-yl] -N '- (2-chlorophenyl) urea; N - [(1,3-Dihydro-2,2-dioxo-4-chloro-2,1-benzisotiazo) -7-yl] -N '- (2-methoxyphenyl) urea; N - [(1,3-Dihydro-2,2-dioxo-4-chloro-2,1-benzisotiazo) -7-yl] -N'-isopropylurea; N - [(1,3-Dihydro-2,2-dioxo-4-chloro-2,1-benzothiazo) -7-yl] -N '- (2-bromophenyl) urea; ¿¿¿¿¿¿¿¿¿¡¡^ ^ ^^ l ^ g ^^ kí ^ ^^^^ jí ^ gui | ^ u ^ N - [(1, 3-D¡hidro-2, 2-dioxo-4-cyano-2,1-benzisothiazo) -7-yl] -N '- (2-bromophenyl) urea; N - [(1,3-Dihydro-2,2-dioxo-4-bromo-2,1-benzisothiazo) -7-yl] -N '- (2-bromophenyl) urea; The compounds of formula (I) exemplified further include: N- (4-Bromophenyl) -N '- (1,3-dihydro-2,2-dioxo-2,1-benzisothiazol-7-yl) urea; Methods of preparation The compounds of formula (I) and (II) 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) and (II) having a variety of different Z, Ri, and E 'groups which are reacted, using optional substituents which are suitably protected to achieve compatibility with the reactions described herein. Subsequent deprotection, in those cases, then provides 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) and (II) this is simply for objects of illustration only and not a limitation of the degree of synthesis available using those methods.

SCHEME 1 a) SnCl2, EtOAc b) Et3N, CH2CI2 If the desired cyclic sulfonamide 2-scheme 1 is not commercially available, the corresponding heterocyclic sulfamide can be prepared from the available compound 1-scheme 1 commercially with reduction of the nitro group using suitable reducing conditions such as SnCl 2, hydrogen and Pd / C or zinc metal in a suitable organic solvent such as ethyl acetate and cyclization using triethylamine in methylene chloride. The alternating reaction conditions for the cyclic sulfonamide of 2-scheme 1 can be achieved by cyclization of 2-chlorobenzylsulfonamide with potassium carbonate and copper-bronze powder under pressure using a polar solvent or using a high boiling solvent such as 2,3-dimethylaniline at 100-180 ° C, preferably about 180 ° C, or reacting the sodium salt of acid 2- . ^ ..... ^^^^,. » The aminobenzylsulfonic acid with phosphorus oxychloride at 130-170 ° C, preferably about 170 ° C, for between 1-24 hours, preferably about 3 hours.

SCHEME 2 a) Ph3P oxide, Et3N, TFAA, 1,2-dichloroethane If the desired heterocyclic compound 2-scheme 2 is not commercially available, then it can be prepared from the commercially available compound 1 -schema 2 with triphenyl phosphine oxide, triethylamine, trifluoroacetic anhydride in an aprotic solvent such as 1,2-dichloroethane.

SCHEME 3 a) Zn, NH4C I, THF / H20 If the desired heterocyclic compound 2-scheme 3 is not commercially available, then it can be prepared from the compound 1 -schema 3 commercially available with zinc and ammonium chloride in THF / H 2 O.

SCHEME 4 a) Aluminum amalgam, Et20 If the desired heterocyclic compound 2-scheme 4 is not commercially available, then it can be prepared from * ^ | jÉ thus ^ g ^^^^ j? g ^ j ^^^ aj | ^^^ g ^ compound 1 - Scheme 4 commercially available with aluminum amalgam in diethyl ether or THF.

SCHEME 5 a) HONO b) Na2N03 c) H2S04 If the desired heterocyclic compound 3-scheme 5 is not commercially available, then it can be prepared from the compound 1 -schema 5 commercially available with nitrous acid to the diazonium salt, followed by treatment with sodium sulfite to the hydrazine 2-scheme 5. Cyclization can be achieved with sulfuric acid to give 3; scheme 5. An alternative method to obtain 3-scheme 5 would be reduction of ndazolinone with lithium aluminum hydride. ,. ., ..to . & »ÉMa.riáai = É¡aí¡ ^^ SCHEME 6 a) NaNO3, 3M H2SO4, CH2CI2, 23 ° C b) Pd / C, MeOH If the desired aniline 3-scheme 6 is not commercially available the corresponding nitro compound can be prepared from 1 -scheme 6, under standard nitration conditions (using HN03 or NaNO3) at 0-100 ° C, preferably about 23 ° C , under acidic conditions such as acetic acid, acetic anhydride, or under a biphasic condition such as aqueous sulfuric acid and chlorinated solvent such as methylene chloride. The nitro compound is then reduced to the corresponding aniline using suitable reducing agents, such as H / Pd in an organic solvent, such as MeOH, DMF or ethyl acetate (alternatively SnCl2 in EtOH, or LiAIH4 or zinc metal in acetic acid) at 0 -100 ° C. Other commercially available heterocyclic compounds such as Indoline, type, Oxindole, Isatin, Indazole and Indazolinone can be converted to the desired anilines through this process.

ESQUEHA 7 a) PhNCO, DMF, 80 ° C The ortho-substituted phenylureas in 2-scheme 7 can be prepared by standard conditions involving the condensation of the commercially available optionally substituted aryl isocyanate (Aldrich Chemical Co., Milwake, Wi.) With the corresponding aniline 1_; Scheme 7 in an aprotic solvent such as DMSO, DMF, toluene or methylene chloride at room temperature or elevated temperature from 1 h to 24 h. Alternatively the desired isocyanates can be made by condensing the amine 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). The aromatic rings of the compounds can be further functionalized by conditions well known in the art, such as bromination or other electrophilic substitution reactions. These substituents can be further manipulated using standard nucleophilic substitutions as a reaction with an anion (as • - "*.» »» «-» «ft ~ ^ - ^ -., -. .. ..., .-. .. - ^ a--. J« aB aA ... "^ > - ^ 53 ^^ «sodium methoxide), or in palladium-catalyzed coupling reaction chemistry. Another aspect of the invention is the novel process for producing a compound of formula (I), in particular when A is CH 2 and X is 5 S (O) m whose process comprises a process for producing a compound of formula (I), is defined above, wherein A is CH2 and X is S (O) m, which process comprises: a) reacting the compound of the formula: with a compound of the formula: C (X2) -N- (CR? 3R? 4) v-Z; To yield a compound of formula (I).

Another aspect of the present invention are the novel compounds of formula (A) and the novel processes for manufacturing the compounds of formula (A) whose process comprises reacting the corresponding nitro compound, Formula (B) under conventional reducing conditions to yield the corresponding aniline derivative. Another aspect of the present invention is the new process for producing the new compounds of the formula: Whose procedure comprises reacting a compound of formula: H (C) Under standard nitration conditions to yield a compound of formula (B). Yet another aspect of the present invention is a process for producing a compound of formula (C), which process comprises reacting a compound of the formula (D) under conditions of reduction and cyclization of the corresponding reduced amine to yield a compound of formula (D).

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 otherwise indicated. 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 indicates 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.

General Method: Synthesis of N.N'-phenylurea. To a solution of Phenyl isocyanate (1.0 eq.) In dimethylformamide (1 ml) was added the corresponding aniline (1.0 eq.). The reaction mixture was stirred at 80 ° C until complete (3-16 hours), then the solvent was removed under vacuum. The purification, yields and spectrum characteristics of each compound individual are listed right away. Additional synthetic methods are provided in PCT U.S.A. 96/02260 filed on February 16, 1996, the disclosure of which is hereby incorporated by reference in its entirety.

EXAMPLE 1 Preparation of N- (2-bromophenyl) -N, - (1,3-Dihydro-2,2-dioxo-2,1-benzisothiazo) -7-ylurea a) Preparation of 1,3-dihydro-1,2-benzisothiazole-2,2-dioxide To a solution of 2-nitro-alpha-toluenesulfonyl chloride (5.0 g, 21.3 mmol), in 250 ml of ethyl acetate. ethyl tin chloride II (19.2 g, 85 mmol) was added. The reaction was stirred at 70 ° C overnight and then poured into ice and neutralized with sodium bicarbonate. The solution was then extracted with ethyl acetate and the solvents were evaporated. The crude reaction mixture was then diluted with methylene chloride and excess trethylamine was added. The solution was stirred at 25 ° C overnight and the solvent was evaporated and the product was obtained by chromatography of the resulting solid on silica gel (EtOAc / hexane (1 equiv./1 equiv.)). (500 mg, 14%). 1 H NMR (CDCl 3): d 7.25 (d, 1 H), 7.24 (t, 1 H), 7.07 (t, 1 H), 6.91 (d, 1 H), 6.62 (s, 1 H), 4.40 (s, 2H). b) Preparation of 4-nitro-1,3-dihydro-1,2-benzisothiazole-2,2-dioxide 1,3-dihydro-1,2-benzisothiazole-2,2-dioxide (400 mg, 2.40 mmol) dissolved in methylene chloride (40 ml) followed by the addition of sodium nitrate (0.22 g, 2.60 mmol). The addition of sulfuric acid (5.0 ml / 3M) was then made, followed by the addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture is diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH / CH 2 Cl 2) gave the desired product (150 mg, 29%). 1 H NMR (CDCl 3): d 8.11 (d, 1 H), 7.57 (d, 1 H), 7.09 (t, 1 H), 4.50 (s, 2 H). c) Preparation of 4-amino-1,3-dihydro-1,2-benzisothiazole-2,2-dioxide To a solution of 4-nitro-1,3-dihydro-1,2-benzisothiazole-2,2 - dioxide (100 mg, 5.0 mmol) in methanol (50 ml) and 10% Pd / C (50 mg) was added. The mixture was rinsed with argon, then hydrogen was bubbled through the solution for 10 minutes and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol.

The solvent was evaporated and chromatography of the resulting solid on silica gel (10% MeOH / CH 2 Cl 2) gave the desired product (64 mg, 74%). 1 H NMR (270 MHz, CD 3 OD) d 6.86 (t, 1 H), 6.62 (d, 1 H), 6.55 (d, 1 H), 4.35 (s, 2 H). d) Preparation of N- [1,3-Dihydro-1,2-benzisothiazole-3,3-dioxide] -N '- [12-bromophenyl] urea N- [1,3-Dihydro-1, 2-benzisothiazole-3,3-dioxide] -N '- [2-bromophenyljurea of 4-amino-1,3-Dihydro-1,2-benzothiazole-2,2-dioxoid (64 mg, 0. 35 mmole) in accordance with the procedure of General Method B. The product was purified by chromatography of the resulting solid on silica gel.

(EtOAc / hexane (1 equiv./1 equiv.)). (45 mg, 34%). 1 H NMR (270 MHz, CD 3 SO 2 CD 3) d 9.70 (s, 1 H), 9.04 (s, 1 H), 8.51 (s, 1 H), 8.08 (d, 1 H), 7.67 (t, 1 H), 7.60 (d, 1 H), 7.34 (t, 1 H), 7.04 (d, 2H), 6.96 (t, 1 H), 4.58 (s, 2H). Using analogous methods to those described above or in the schemes, the following compounds can be synthesized: Example 2: N- (1,3-Dihydro-4-bromo-1,2-benzisothiazole-3,3-dioxide) -N'- phenylurea Example 3: N - [(1,3-Dihydro-2,2-dioxo-4-fluoro-2,1-benzisothiazo) -7-yl] -N '- (2-bromophenyl) urea; (M ": 398.1, 400.1) Example 4: N - [(1,3-Dihydro-2,2-dioxo-4-chloro-2,1-benzisothiazo) -7-yl] -N '- (2,3 -dichlorophenyl) urea; (M-: 403.9, 406.2, 408.0) ^^ gj ^^^^^^^^^^^^^^ Example 5: N - [(1,3-D-Hydro-2,2-d -oxo-4-chloro-2,1-benzisot) azo) -7-yl] -N '- (2-chlorophenyl) urea; (M ": 370.1, 372.1) Example 6: N - [(1,3-Dihydro-2,2-dioxo-4-chloro-2,1-benzisothiazo) -7-yl] -N '- (2-methoxyphenyl) ) urea; (M ": 366.2, 358.1) Example 7: N - [(1,3-Dihydro-2,2-dioxo-4-chloro-2,1-benzisothiazo) -7-] - N ' -isopropylurea; (M ": 304.1, 306.2) Example 8: N - [(1,3-Dihydro-2,2-dioxo-4-chloro-2,1-benzisothiazo) -7-yl] -N '- (2-bromophenyl) ) urea; (M ": 414, 416) Example 9: N - [(1,3-Dihydro-2,2-dioxo-4-cyano-2,1-benzisothiazo) -7- 10 yl] -N'- (2-bromophenyl) urea; (M ': 404.9, 407.1) Example 10: N - [(1,3-Dihydro-2,2-dioxo-4-bromo-2,1-benzothiazo) ~ 7-iij-N' - ( 2-bromophenyl) urea; (M ": 457.9, 459.9, 461.9) Example 11: N (2-indazole) -N '- (2-bromophenyl) urea; MS (M + H = 331.1; M-H = 329.2) 15 Method of treatment The compounds of the formulas (I) and (II) or their pharmaceutically acceptable salts can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any pathological condition in a human, or other mammal, exacerbated or caused by excessive production or unregulated of IL-8 cytokines by said mammalian cell, such as but not limited to monocytes and / or macrophages, or - ^ ^ fea5 ^^^^ - ^^^^, ^^ jj ^ g¡jggg ^ gg other chemokines that bind to the receptor of IL-8 a or β, also referred to as the type I or type II receptor.

For the purposes of the present, the term formula (I) also refers to compounds of formula (II) unless indicated otherwise. Accordingly, the present invention provides a method for treating a chemokine-mediated disease, 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 some cases at subnormal levels, in order to improve the pathological state. Abnormal levels of IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78 for example in the context of the present invention are: (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 levels . ^ ^. ^ .A ^. - .... -. What are the basal baselines in cells or tissues in which respectively IL-8, GROa, GROß, GRO ?, NAP are produced? -2 or ENA-78. There are many pathological states in which excessive or unregulated production of IL-8 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 vs. 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. Infected Dis. (1998), 26 (4), 840-846; Sanders, et al., J. Virol. (1998), 72 (2), 934-942; Sethu, et al., Clin. Exp. Immunol. (1997), 110 (3), 362-369; Zhu, et al., Am. J. Physiol. (1997), 273 (4, pt.1), L814-L-824; 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 Síreckfus el al., J. Geronlol., Ser. A (1997), 52a (6), M343- M351; Hermann, T. WO 95/31722; 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 elaslase 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 chemokine in the eradication of HIV infections, Littieman et al., Nalure 381, p. 661 (1996) and Koup el al., Naíure 381, pp. 667 (1996).

The present invention also provides a means to accurately treat, as well as to prevent, in susceptible individuals, CNS lesions with the chemokine receptor antagonism compounds of the formula (I). CNS lesions as defined herein include both open or penetrating cephalic traumas, as well as those resulting from surgery, as well as closed vascularized injuries, such as those resulting from a lesion in the cephalic region. Ischemic infarction, particularly in the brain area, is also included within this definition. Ischemic infarction can be defined as a focal neurological disorder that results from inadequate blood supply to a particular area of the brain, usually as a consequence of an embolus, iabos or local areymaloma closure of the blood spleens. The role of the inflammatory cilocines in this area has been emerging and the present invention provides a means for the positive irradiation of these lesions. Relatively very little, for an accurate injury such as this has been available. FNT-a is a cytokine with proinflammatory actions, including the expression of adhesion molecules of endoleal leukocytes. The leukocytes will infiltrate the ischemic lesions of the brain and therefore the compounds that inhibit or reduce the levels of TNF are useful for the eradication of the ischemic brain injury. See Liu ei al., Síoke, Vol. 25., No. ^^^^^ iM ^^ - ^^^^^. ^. ^ .-? ^. -a -, ...- .. ..- m ^^ h ^ u? m ^ t ^^^^^ ^^^^^^^^^^^^^^^^^^^^^ 1481-88 (1994) whose description is included in the present reference manner. Some models of closed cephalic lesions and irradiation with mixed 5-LO / CO agents are discussed in Shohami et al., J. of Vaisc & 5 Clinical Physiology and Pharmacology, Vol. 3, No. 2, pp. 99-107 (1992) whose description is included in the present reference manner. It was found that irradiation that reduces the formation of edema improves the functional result in the animals brought. The present evidence also indicates the use of inhibitors of IL-10 8 in the irradiation of aerosol. The first reference Boisvert et al., J Clin Invesl, 1998, 101: 353-363 shows, by means of the bone marrow transplantation, that the absence of IL-8 receptors in germ cells (and, likewise, in monocytes / macrophages) leads to a reduction in the development of aminosclerotic plaques in mice with LDL receptor deficiency.

You will hear references of support are: Aposlolopoulos, et 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, 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. The compounds of formula (I) are administered in a sufficient amount to prevent IL-8, which binds to IL-8 alpha receptors or beía, be fixed to these receptors, as evidenced by a reduction in the chemioxis and acíivación of neuóófilos. 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 in vitro receptor binding assays described in the present. The compounds of formula (I) have proven to be inhibitors of IL-8 receptors of lipo II. As used, the term "IL-8-mediated palliative illness or disease" refers to any paiological process in which IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78 play a role, either by production of the same IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78, or because IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78 causes the release of hear monocyte, as for example, but not limiting to IL-1, IL-6 or TNF. A paiological pathway in which, for example, IL-1 is a major component, and whose production or action is exacerbated or secreted in response to IL-8, would thus be considered a paiological pathway mediated by IL-8. As used in the present, the term "chemokine-mediated disease or paíologic pathway" refers to any paiological pathway in which a chemokine that binds a receptacle IL-8 a or β plays a role, such as, for example, but not limited to IL-8, GROa, GROß, GRO ?, NAP-2 or ENA-78. This would include a pathological condition in which IL-8 plays a role, either by production of IL-8, or by IL-8 causing the release of another monocyte, as well as for example, but not limited to IL-1, IL-6 or TNF. A paíológico esíado in which, for example, IL-1 is a main component, and whose If the production or action is exacerbated or secret in response to IL-8, a pathological condition mediated by IL-8 would be considered as such. As used herein, the term "cyclocline" refers to any secreted polypeptide that affects the functions of the cells and is a molecule that modulates the interactions between the cells in the inflammatory or haematopoielic immune response. A cycloocin 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 monocytes, such as natural killer cells, fibroblasts, basophils, neutrophils, endophelial cells, cerebral asyroids, bone marrow stryromic cells, epidermal kerainocytes, and B-lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cyclohexane include, but are not limited to, nferleucine-1 (IL-1), nlerleucine-6 (IL-6), inerieucin-8 (IL-8), lumoral necrosis factor-alpha (TNF-a) and facíor of necrosis sheet befa (FNT-ß). As used in the present, 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 hematopoietic response, similar to the term "cytokine" above. A chemokine is secreted mainly through cell transmembranes and causes the chemocytosis and acyivation of blood cells specific white and leukocytes, neulrófilos, monociíos, macrophages, T cells, B cells, endoíeliales cells and soft muscle cells. Examples of chemokines include, but were 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. 5 In order to use a compound of the formula (I) or a pharmaceuically acceptable salt thereof in the therapy, this will normally be formulated in a pharmaceutical composition according to the pharmaceutical standard practice. This invention, for its part, also refers to a pharmaceutical composition comprising an effective, non-toxic quality of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent. The compounds of the formula (I), their pharmaceutically acceptable salts and pharmaceutical compositions incorporating them should be administered conveniently by any of the routes conventionally used for the administration of drugs, for example, oral, topical, parenterally or by inhalation. The compounds of the formula (I) can be administered in the conventional dosage forms prepared by combining a compound of the formula (I) with standard pharmaceutical carriers in accordance with the procedures conventional. The compounds of the formula (I) can also be administered in conventional doses in combination with a second known lerapeutically active compound. These procedures may include mixing, granulating and compressing or dissolving the ingredients of ^ A * .. »^^^, > , ^ .. ^. ¿^ - ".. A- .. ^^ a ^ -i ^. , .-- ^^ ._ Z, J ^^ t? ^ & m ^^^? ^^^. ^ ^^? the right way for the desired preparation. It may be noted that the pharmaceutically acceptable form or character of the pharmaceutically acceptable cation or diluent is determined by the amount of the acive ingredient with which it is to be combined, the administration route, and you will hear well-known variables. The carrier (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. The usable pharmaceutical carrier must be, for example, a solid or liquid. Some examples of solid carriers are lactose, earth, sucrose, urea, gelaine, agar, pecillin, acacia, magnesium silica, esieraic acid, and the like. Some examples of liquid carriers are whey, peanut oil, olive oil, water and the like. In a similar manner, the carrier or diluent may include a reagent material known in the art, such as glyceryl monostearation or glyceryl disallation 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 done in lableries, placed in a hard gelatin capsule in the form of powder or granules or in the form of an icicles or an iable. The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 g. When a liquid carrier is used, the preparation will be in the form of a serum, emulsion, soft gelatin capsule, injectable sterile liquid such as an ampule or liquid non-aqueous suspension. dtiiii. * j * t »M * t ?? * iimi * < J & Jllm The compounds of the formula (I) can be administered topically, ie by non-sysiemic administration. This includes the application of a compound of formula (I) exlernamente to the epidermis or the oral cavity and the installation of said compound in the ear, eye and nose, so that the compound does not enter considerably into the blood stream. By the syllabus, the sysiemic 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 point of inflammation as liniments, lotions, creams, ointments and grasses and goies suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w / w, for example from 1% to 2% by weight of the formulation. However, it can comprise as much as 10% in w / w but preferably will comprise less than 5% w / w, most preferably from 0.1% to 1% w / w of the formulation. Lotions in accordance with the present invention include those suitable for application to the skin or eye. An ophthalmic lotion may comprise a sterile aqueous solution optionally containing a bactericide and can be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to accelerate the drying and to cool the skin, such as alcohol or acetone, and / or a softener such as glycerol or an oil such as castor oil or arachis oil. The creams, ointments or pastures according to the present invention are semi-solid formulations of the active ingredient for extense application. They can be made by mixing finely divided or powdered ingredients, 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, melonic soap; a mucilage; an oil of nalural origin such as almond, corn, arachis, beaver or olive oil; wool grease or its derivatives or a fatty acid such as eseric acid or oleic June with an alcohol such as propylene glycol or macrogel. The formulation may include any surface active agent such as an anionic, cationic or nonionic surfactant, such as an sorbitan or a polyoxyelylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as siliceous silicas, and other ingredients such as lanolin, may also be included. Goies in accordance with the present invention may comprise sterile aqueous or oleaginous solutions or suspensions and can be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and / or fungicidal agent and / or any suitable preservative oil, 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 in an auo-socket or at 98-100 ° C for half an hour. Allemafivamenle, the solution can be spherilized by filiration and transferred to the holder by means of an aseptic technique. Some examples of suitable bactericidal and fungicidal agents for inclusion in the golas are niírato or acetate fen i I mercuric (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Some suitable solvents for the preparation of an oil solution include glycerol, dilute alcohol and propylene glycol. The compounds of the formula (I) can be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, iniravaginal or iniravalial inirareal administration. Subcutaneous and muscular forms of parenteral administration are generally preferred. The appropriate dosage forms for said administration may prepare by means of conventional techniques. The compounds of the formula (I) can also be administered by inhalation, that is, by oral and in-oral inhalation administration. Suitable dosage forms for such administration, such as an aerosol formulation or metered dose inhaler, can be prepared by conventional techniques. For all the methods of use disclosed herein for the compounds of the formula (I), the daily oral dose regimen will preferably be from about 0.01 to about 80 mg / kg of the body weight of the body. The approximately daily parenteral dose regimen 0. 001 to approximately 80 mg / kg of the body weight of the body. The daily topical dose regimen will preferably be from 0.1 mg to 150 mg, administered from 1 to 4, preferably 2 or 3 times daily. The daily inhalation dose regimen will preferably be from about 0.01 mg / kg to about 5 mg / kg per day. Those skilled in the art will also recognize that the optimum amount and spacing of the individual doses of a compound of formula (I) or its pharmaceutically acceptable salt will be determined by the nature and extent of the condition to be irritated, in the form, via and place of administration, and the particular patient to be removed, and said optimum grades can be determined by conventional techniques. An expert in the technique may also note that the optimum course of the year, that is, the number of doses of a compound of formula (I) or its pharmaceutically acceptable salt administered per day for a defined number of days, may be determined by those skilled in the art using the course Conventional of the tests of determination of fraíamienío. The invention will now be described with reference to the following biological examples which are merely illusory and which do not precede being a limitation of the field of the present invention.

BIOLOGICAL EXAMPLES The inhibitory effects of the chemokine of IL-8, GRO-a of the compounds of the present invention are determined with the following in vitro assay: Receptor binding assays: [125 I] IL-8 (human recombinanie) is forced from Amersham Corp., Arlinglon Heighis, IL, with specific activity of 2000 Ci / mmol. The Gro-a is obtained from NEN- New England Nuclear. The chemicals are of an analytical nature. The high levels of recombinant human IL-8 receptors and ß recombinants were expressed indi- vidually in Chinese hamster ovary cells as described earlier (Holmes, et al., Science, 1991, 253, 1278). The Chinese hamster ovary membranes are They were homogenized in accordance with the previously described proocool (Haour, et al., J Biol Chem., 249 pp 2195-2205 (1974)). Except that the homogenization pH regulator was changed to 10 mM Tris-HCL, 1 mM MgSO4, 0.5 mM EDTA (ethylenediamine-acetic acid), 1 m MPMSF (a-toluenesulfonyl fluoride), 0.5 mg / L Leupeptin, pH 7.5. The The proininic membrane concentration was determined using the Pierce Co. microassay equipment using bovine serum albumin as a standard. All tests were carried out in a 96-well microplate format. Each reaction mixture contains 125 I-IL-8 (0.25 Nm) 0/1251 Gro-a and 0.5 μg / ml of IL-8Ra or 1.0 μg / ml membranes of 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 EDTA, 25 mm NaCl, and 0.03% CHAPS. In addition, the drug or compound of interest is added, which has been pre-determined 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 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 flashing counter Belaplaie. Reference is also made to the receptor of IL-8 Ra, recombinant, or type I, herein as the non-permissive receptor and reference is made to the receptor IL-8Rβ, recombinant, or type II, as the permissive receptor. It has been observed that the representative compounds of the formula (I), example 1, 3 to 10, and a representative compound of the formula (II), example 11, possess positive inhibitory activity of < 30 μmg in this assay.

Chemocyte assay: 20 The in vitro inhibitory properties of these compounds were determined in the pneumophilic chemocyte assay as described in Currení Proíocols ¡Immunology, vol. I, Suppl 1, Unif 6.12.3., Whose explanation is included in the present by way of reference in their identity. They were isolated The neutrophils of human blood as described in Currenf Protocols in Immunology Vol. I, Suppl 1 Unil 7.23.1, whose explanation is included in the present reference manner in its identity. The chemoatoryins 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 the compounds of this invention are tested, they are mixed with the cells (0.001-1000 nM) just before the addition of the cells in the upper chamber. The incubation may come from enire around 45 and 90 min at about 37 ° C in a humidified incubator with 5% CO2 At the end of the incubation period, the polycarbonate membrane is removed and the upper area is washed, the membrane is then stained using the protocol Diff Quick (Baxíer Producís, McGaw Park, IL, USA). The cells that chemokine chemokine were subjected to had visualized using a microscope. 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 duplicate and each compose is repeated at least 4 times. For certain cells (posiive confrol cells), no compound was added, said cells represented the maximum chemocyclic response of the cells. In the case where a negative (not spiked) conlrol is desired, chemokine is not added to the lower chamber. The difference between positive and negative control represented the chemocyclic activity of the cells Elasiase release assay: The compounds of this invention were tested for their ability to prevent the release of elassae from human pneumophiles. The neulrophiles were isolated from human blood as described in Curreni Proíocols in Immunology Vol. I, Suppl 1 Unií 7.23.1. PMNs 0.88 x 106 cells suspended in Ringer's solution (NaCI 118, KCl 4.56, NaHC03 25, KH2PO4 1.03, glucose 11.1, HEPES 5 mm, pH 7.4) were placed in each well of a 96-well plate in a volume of 50 ul. To this plate was 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. These cells were allowed to enfibriate (37 ° C, 5% CO2, 95% RH) for 5 minutes before IL-8, GROa, GROß, GRO? or NAP-2 at a final concentration of 0.01 to 1000 nM. The reaction was allowed to proceed for 45 minutes after centrifugation of the 96-well plate (800 xg 5 min.) And 100 ul of the removed supernatant. This supernatant was added to a second 96-well plate followed by an artificial elastase pool (MeOSuc-Ala-Ala-Pro-Val-AMC, Nova Biochem, La Jolla, CA) at a final concentration of 6 ug / ml dissolved in Saline regulated phosphate solution. Immediately afterwards, the plate was placed in a fluorescent 96-well plate reader (Cylofluor 2350, Millipore, Bedford, MA) and data were collected at 3-minute intervals according to the Nakajima period and to the J. Biol Chem 254 4027 (1979).

The amount of elasiasa released from PMNs was calculated by measuring the degradation rate of MeOSuc-Ala-Ala-Pro-Val-AMC.

TNF-a assay in radicular brain injury 5 This test provides for the examination of the expression of tumor necrosis factor mRNA in specific brain regions following an experimentally induced lateral fluid percussion brain injury (TBI) in rats since the FNT-a is able to induce nerve growth factor (NGF) and it is the release of more cytokines from acolytes, said Posiumauic allyration in the expression of the TNF-a gene plays an important role in the acute and regenerative response for CNS trauma. A suitable assay can be found in WO 97/35856 or WO 97/49286 whose explanations are included in the present by way of reference. 15 Model of CNS injury by IL-ß mRNA This assay characterizes the regional expression of interleukin 1 ß (IL-1 ß) mRNA in specific brain regions following traumatic brain injury from experimental lateral fluid percussion (TBI) in rats . 20 The results of these tests indicate that following the TBI, the temporal expression of IL-1β mRNA is stimulated regionally in specific brain regions. Such regional changes in cytokines, such as IL-1β, play a role in pathological or regenerative sequelae of post-rabies. brain injury. A suitable assay can be found in WO 97/35856 or WO 97/49286 whose explanations are included in the present by way of reference.

In vivo aerosol test: In vivo models for measuring aerosol in mice are based on the Paigen et al test with some modifications as described below. See Paigen B, Morrow A, Holmes PA, Miíchell D, Williams RA. Quanlifaíive assessmení of aíheroscleroíic lesions in mice. 10 Atherosclerosis 68: 231-240 (1987) and Grooí PHE, van Vlijmen BJM, Benson GM, Hofker MH, Schiffelers R, Vidgeon-Hart M, Havekes LM. Quantilaíive assessmenl of aortic aherosclerosis in APOE * 3 Leiden ransgenic mice and iís relaíionship to serum exposure. Artereioscler Thromb Vasc Biol. 16: 926-933 (1996). 15 Sectioning and removal of the aortic sinus Cross 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 ligated for analysis. After equilibrating the tissue in the OCT compound overnight, 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 surrounded 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 idenified by the appearance of multiple valve leaflets, 10mm alimentary sections are taken and mounted on gelatinized slides. The sections are air-dried for 1 hour and subse- quently flushed briefly in 60% isopropyl alcohol. Sections are stained with oil red O, congermed with Mayer's hematoxylin, covered using glycerol gelaine and sealed with nail varnish.

Quantification of aerosol in the aortic root Ten alveolar sections of the aortic root are observed using an Olympus BH-2 microscope equipped with a 4x objective and a video camera (Hiíachi, HV-C10). 24 color images are acquired and analyzed using a PC (Daiacell Penlium P5-133, Dalacell Berks, UK) coupled with a frame recording labyrinth (Snapper, Active Imaging Ltd, 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 areas of lesosclerofic lesion is carried out by means of the hand drawing around the lesion using the Optimas software. The colors are outlined to quantify areas that are red in the lesions. Absolute values for cross-sectional areas of injuries and areas * ^^^^^ j ^^^^^^^ * j ^^^^^^ J. ^ ¡^^^^^^ - ^^^^ ¿¿^^^^ dyed with red are obliged by calibrating the software using an image of the grid on a hemocytometer slide. All publications, including but not limited to patents and patent applications, cited in this specification are incorporated in the present by reference as each individual publication was specifically and individually indicated to be incorporated by reference in the present as it is written in its entirety. . The foregoing description describes folall the invention including the preferred embodiments thereof. Modifications and improvements of the modalities specifically described in the present will be within the scope of the following claims. Without further elaboration, it is believed that an expert in the art can, using the foregoing description, utilize the present invention in all its exigency. Therefore, the examples in the present are considered merely illusive and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims (18)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula: Wherein R is -NH-C (X2) -NH- (CR? 3R? 4) v-Z; Z is W, optionally substituted, C2- or optionally substituted C2-10 alkynyl or C2-10 alkynyl optionally susliluido; X 15 is N; X1 is hydrogen, halogen, Cpo alkyl, NR4R5, C (O) NR R5, optionally substituted C1-10 alkyl, C1-10 alkoxy, halo-substituted C7 alkoxy, hydroxy, aryl, arylC1-4 alkyl, aryloxy, C 1-4 arylalkyloxy, heleroaryl, C 1-4 heteroarylalkyl, helerocyclic, C 1-4 heyerocycloalkyl or d-4 heleroarylalkyloxy; X2 is = 0, or = S; A is CRiß; R1 is selected 20 independently from hydrogen; halogen; nilro; cyano; CMO alkyl has disappeared; CMO alkyl; C2-10 alkenyl; CMO alkoxy; CMO alkoxy halosusliuuide; azide; (CR8R8) qS (O) tR4, hydroxy; hydroxy alkyl of CMOÍ aryl; arylalkyl of C? -4; aryloxy; arylalkyloxy of C? -; heeroeroil; heteroarylalkyl of C -? - 4; helerocyclic; alkyl-cyclic alkyl of C1.4; C 1 - heteroarylalkyloxy; C2-arylalkyl or C; C2-10 heteroarylalkenyl; heterocyclic alkenyl of C2.10; (CR8R8) qNR4R5; C2-10-C (O) NR4R5 alkenyl; (CR8R8) qC (O) NR4R5; (CR8R8) qC (0) NR4R? O; S (O) 3R8; (CR8R8) qC (0) Rn; C2-10-C (O) Rn alkenyl; alkenyl of C2.10-C (O) ORn; C (O) ORn; (CR8R8) qC (O) OR? 2; (CR8R8) qOC (O) Rn; (CR8R8) qNR4C (0) Rn; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) R ??; (CR8R8) qNHS (O) 2R17 or (CR8R8) qS (O) 2NR4R5; or two R1 portions together can form -O- (CH2) sO- or a 5-6-membered ring unsaturated or unsaturated, and in which the aryl, heeroaryl, and heierocyclic-containing rings can optionally be suslides; m is an enlero and has a value of 1 to 3; n is an enlero that has a value of 1 to 3; p is an integer that has a value of 1 to 3; q is 0 or an integer that has a value of 1 to 10; s is an integer that has a value of 1 to 3; t is 0 or an integer having a value of 1 or 2; v is 0 or an integer having a value of 1 to 4; HET is an optionally substituted heteroaryl; R4 and R5 are independently hydrogen, optionally substituted C1-4alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted, heteroarylalkyl, cyclic, heterocyclic alkyl, C? _ Alkyl, or R4 and R5 together with the nihologen to which they are attached form a 5- to 7-membered ring which may optionally be an additional heleroatome selected from O / N / S; And it is independently selected from hydrogen; halogen; child cyano; CMO alkyl is halous; CMO alkyl; C2-? o alkenyl; CMO alkoxy; alkoxy of CMO halosusliíuido, azida; (CR8R8) qS (O) tR4; hydroxy; hydroxy alkyl of CM; aril; arylalkyl of C? -4; aryloxy; C? -4 arylalkyloxy; heeroeroil; heeroarylalkyl of C -? 4, heteroarylalkyloxy of C-; heterocyclic; C4-helerocyclic alkyl; C2-arylalkenyl; C2-? ooaryloarylkenyl; C2-10 heterocyclic alkenyl; (CR8R8) qNR4R5; alkenyl of C2-? 0-C (O) NR4R5; (CR8R8) qC (O) NR4R5 (CR8R8) qC (O) NR4R? 0; S (O) 3R8; (CR8R8) q C (0) Rn; alkenyl of C2-? 0-C (O) Rn alkenyl of C2.?o-C(0)ORn; (CR8R8) qC (O) OR? 2; (CR8R8) qOC (0) Rn (CR8R8) qNR4C (O) Rn; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) R ?? (CR8R8) qNHS (O) 2Ra; or (CR8R8) qS (O) 2NR4R5 or two Y portions together can form -O- (CH2) sO or a 5-6 membered saturated or unsaturated ring, and in which the rings containing aryl, heteroaryl, and heterocyclics they may optionally be susífied; R6 and R are independently hydrogen or an alkyl group of C? -, or R6 and R7 together with the niologen to which they are attached form a 5- to 7-membered ring whose ring may optionally contain an additional hetero-atom whose heteroatom is selected from oxygen, niigogen or sulfur; Rs is independently hydrogen or C? -4 alkyl; R10 is C1-10-C (O) 2R8 alkyl; Rn is hydrogen, C? -4 alquiloalkyl, optionally substituted aryl, optionally substituted C ar-4 aralkylalkyl, optionally heteroaryl optionally substituted, optionally substituted C? --optionally optionally cyclic heteroaryl, or optionally substituted heterocyclic C -? 4-alkyl-4alkyl; R-? 2 is hydrogen, CMO alkyl, optionally substituted aryl or optionally substituted arylalkyl; R13 and R-? are independently hydrogen, optionally substituted C 1 - alkyl, or one of R 13 and R 14 may be an optionally substituted aryl; R15 and R1 are independently hydrogen, or an optionally substituted C3-4 alkyl; R17 is C4-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclic C1-4alkyl, in which the aryl, heteroaryl and heterocyclic rings may all be optionally substituted; Ris is hydrogen, C? -4 alkyl, aryl, C? -4 ar arylalkyl; heteroaryl, heteroarylalkyl of C? -4, heterocyclic or heterocyclic alkyl of C? -4) which may all be optionally substituted; Ra is NR6R7, alkyl, arylalkyl of C4-4, arylalkenyl of C2-4, heteroaryl, heteroarylalkyl of C1-4, heteroarylalkenyl of C2-4, heterocyclic or heterocyclic alkyl of C4-4; and wherein the rings containing aryl, heteroaryl and heterocyclic may optionally be substituted; W is the ring that contains E is optionally selected from the asterisk denoting the point of attachment of the ring; or its pharmaceutically acceptable salt. ^^^^^^ ^^^^ ^^^^ £ ^ l ^ g ^^^ 4 ^ ^^^^^^ 3te ^ £ ^ 3! Gg ^^

2. - The compound according to claim 1, characterized in that X2 is oxygen.

3. The compound according to claim 1, further characterized in that v is 0. 5

4. The compound according to claim 1, further characterized because Ri is halogen, cyano, Ni, CF3, C (O) NR4R5 , C2-C alkynyl, 0 C (O) NR4R5, C (O) R4R? 0, C2-C10 alkynyl, C (O) 2OR? 2, heeroaryl, Caryl-heyeroarylalkyl, C2. , or S (O) 2NR4R5.

5. The compound according to claim 1, further characterized in that R? 8 is hydrogen.

6. The compound according to any of claims 1 to 5, further characterized in that Z is W.

7. The compound according to claim 6, further characterized in that Y is halogen, CMO alkoxy, optionally substituted aryl optionally substituted C 1 -4 alkoxyaryl, CMO alkyl, or C 0 hydroxyalkyl.

The compound according to claim 1 which is N- (2-indozole) -N '- (2-bromophenyl) urea; or its pharmaceutically acceptable salt.

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

10. The use of a compound according to claim 1, for the manufacture of a medicament for bringing a chemokine-mediated disease, characterized in that the chemokine binds an α-ß or β-receptor in a mammal.

11. The use of a method according to claim 10, further characterized in that the chemokine-mediated disease is selected from psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, respiratory distress syndrome in adults, initial disease. inflammatory, Crohn's disease, ulcerative colitis, 10 infarction, septic shock, endo-toxic shock, gram-negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glumerulonephritis, thrombosis, angiogenesis or unwanted release of hemalopoieic stem cells, rhinovirus infections, and various indications of bone resorption , Alzheimer's, graft vs. host reaction or rejections of 15 alloinjerío.

12. A process for producing a compound of the formula Wherein R is -NH -C (X2) -NH- (CR? 3R14) v-Z; Z is W, HET; optionally substituted Ci-10 alkyl, C2-? or optionally substituted C2-10 alkynyl optionally substituted C2-10 alkynyl; X is S (O) m-; X2 is = 0, or = S; A is CH2; R1 is independently selected from hydrogen; halogen; nitro; cyano; CMO alkyl is durable; CMO alkyl; C2-10 alkenyl; CMO alkoxy; CMO alkoxy has been substituted; azide; (CRsRs) qS (O) tR4, hydroxy; hydroxy CMC alkyl; aril; arylalkyl of C? -4; aryloxy; C1-4 arylalkyloxy; heteroaryl; heleroarylalkyl 10 of C1-4; heyerocyclic; C1-4 heterocyclic alkyl; C1-4-hexyaryloxykyloxy; C2-10 arylalkenyl; C2-10 heleroarylalkenyl; C2.o.o;, heyerocyclic alkenyl; (CR8R8) qNR4R5; C2_? o-C (O) NR4R5 alkenyl; (CR8R8) qC (O) NR4R5; (CR8R8) qC (O) NR4R? O; S (O) 3R8; (CR8R8) qC (O) Rn; alkenyl of C2-? 0-C (O) Rn alkenyl of C2-? o-C (O) ORn; C (0) ORn; (CRsR8) qC (O) OR? 2 15 (CRßRβ) qOC (0) Rn; (CR8R8) qNR4C (O) R1 ?; (CR8R8) qNR4C (NR5) R ??; (CRdR8) qNHS (0) 2R17 or (CR8R8) qS (O) 2NR4R5; or two portions R- \ together can form -O- (CH2) sO- or a ring of 5 to 6 members unsaturated or unsaturated, and in which the rings containing aryl, heteroaryl, and heterocyclic can optionally be substituted; n is an engineer that 20 has a value of 1 to 3; m is a value that has a value of 1 to 3; m 'is an integer that has a value of 2; q is 0 or an integer that has a value of 1 to 10; s is an integer that has a value of 1 to 3; t is 0 or an integer having a value of 1 or 2; v is 0 or an integer having a value of 1 to 4; p is an integer that it has a value of 1 to 3; HET is an optionally substituted heteroaryl; R 4 and R 5 are independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted arylalkyl, optionally substituted C 4 arylalkyl, optionally substituted heteroaryl, optionally C 5 optionally substituted alkyl, cyclic heteroaryl, cyclic heteroaryl alkyl, or R 4 and Rs juni with the nihilogen to which they are adhered form a 5- to 7-membered ring which may optionally be an additional hetero-atom selected from O / N / S; And it is independently selected from hydrogen; halogen; child cyano; CM0 alkyl is halous; C? alkyl? 10 w, C2-? 0 alkenyl; C 0 alkoxy; C-haloalkoxy substituted, azide; (CR8R8) qS (O) tR4; hydroxy; hydroxy C alquilo - alkyl; aril; arylalkyl of C? -4; aryloxy; Arylalkyloxy of C; heteroaryl; C6-4 heteroarylalkyl; C4-4 heteroarylalkyloxy; heterocyclic; C 4 heterocyclic alkyl; C2-arylalkyl or C; C2-? o heteroarylalkenyl; heterocyclic alkenyl of C2-? o; (CR8R8) qNR4R5; Alkenyl of C2-? 0-C (O) NR4R5; (CR8R8) qC (O) NR4R5; (CR8R8) qC (O) NR4R? 0; S (O) 3R8; (CR8R8) q C (0) Rn; C2.10-C (O) Rn alkenyl; C2-10 alkenyl C (0) ORn; (CR8R8) qC (O) OR12; (CR8R8) qOC (0) Rn; (CR8R8) qNR4C (0) Rn; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) R ??; (CR8R8) qNHS (O) 2Ra; or (CR8R8) qS (O) 2NR4R5 or two portions Y together can form -O- (CH2) s-O or A saturated or unsaturated 5 to 6 membered ring, and in which the aryl, heteroaryl, and heterocyclic containing rings may optionally be substituted; Re and R7 are independently hydrogen or a C1-4 alkyl group, or Re and R7 together with the nihologen to which they are attached form a ring from 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; R 10 is C 0 -C 0 (2) R 8 alkyl; R n is hydrogen, C 1 - alkyl, optionally substituted aryl, C arylalkyl; optionally substituted, heteroaryl optionally substituted, heteroarylalkyl of C ?. optionally susliluido, optionally cyclic heteroaryl, or optionally alkyl heterocyclic C optionally susíiuuido; R-? 2 is hydrogen, CMO alkyl, optionally aryl optionally substituted or arylalkyl optionally susliluido; R 13 and R 14 are independently hydrogen, optionally substituted C alkyl, or one of R 13 and R 4 can be an optionally substituted aryl; R15 and R16 are independently hydrogen, or an optionally substituted C? -4 alkyl; R17 is C? - alkyl, aryl, arylalkyl, heteroaryl, C-hephenoarylalkyl, cyclic heteroaryl, or cyclic-cyclic alkyl, in which aryl, heteroaryl, and helerocyclic rings can optionally be substituted; Ra is NR6R7, alkyl, arylalkyl of C? -4? C2-4 arylalkenyl, heteroaryl, C-heteroarylalkyl, C2-4 heteroarylalkenyl, heterocyclic or C-heterocyclic alkyl; and wherein the rings containing aryl, heteroaryl and heterocyclic may be optionally substituted; W is ^^^^^^^^^^^^^^^ K ^^^^ g ^^^^^^^^^^^^^^^^^^^^^^^ ggj ^^ g ^ ^^^^^ g ^^^^ g ^^^^^^^^^ A ^^^^^^ ß ^^^^^^^^^ the ring containing E is optionally selected from the asterisk denoting the point of attachment of the ring; or its pharmaceutically acceptable salt; whose method comprises a) reacting a compound of the formula with a compound of the formula: C (X2) -N- (CR? 3Ri4) v-Z; wherein R ^ m, X 2, R 3, R, v and Z are as defined in formula (I) to produce a compound of formula (I).

13. The method according to claim 12 further characterized in that the compound of the formula (A) is produced a) by reacting a compound of the formula (B): in which Ri, and m are as defined in accordance with formula (I); under conventional reducing conditions to produce a compound of the formula (A).

14. The process according to claim 13 for producing a compound of the formula (B): in which Ri, and m are as defined in accordance with formula (I); said process comprises reacting a compound of the formula (C) in which Ri and m are as defined in accordance with formula (I); under standard nitration conditions to produce a compound of the formula (B). s .. ^ ", J,"., _. . ... ^. Ü,. .. ", ..tohta Adato, ^^^^^^^^ - ^. A ... c * - *. * -. **, ^^» *. * ..

15. - The method according to claim 14 further characterized in that the compound of the formula (C) is produced, as defined above, which process comprises reacting a compound of the formula (D) under reducing conditions to produce the corresponding reduced portion, and then under cyclization conditions to produce a compound of the formula (C).

16.- A compound of the formula in which Ri is independently selected from hydrogen; halogen; child cyano; CMO alkyl has been discontinued; CMO alkyl; C2-I0 alkenyl; CMO alkoxy; Halo alkoxy halosusliuuide; azide; (CRβR8) qS (O) tR 4, hydroxy; hydroxy CMC alkyl; aril; arylalkyl of C? -4; aryloxy; C? -4 arylalkyloxy; heleroaryl; C6-4 heteroarylalkyl; heterocyclic; heterocyclic alkyl C1-; C4-4 heteroarylalkyloxy; C2-10 arylalkenyl; C2-10 heteroarylalkenyl; C2-10 heterocyclic alkenyl; (CR8R8) qR4Rs; C2-10 alkenyl C (O) NR4R5; (CR8R8) qC (O) NR4R5; (CR8R8) qC (O) NR4R10; S (O) 3R8; (CR8Rβ) qC (0) Rn; alkenyl of C2-? 0-C (O) Rn; alkenyl of C2.?o-C(0)ORn; 5 C (0) ORn; (CR8R8) qC (O) OR12; (CR8R8) qOC (0) Rn; (CR8R8) qNR4C (0) Rn; (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) Rn; (CR8R8) qNHS (O) 2R17 or (CR8R8) qS (O) 2NR4R5; or two R1 portions 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 substituted 10 optionally; n is an integer that has a value of 1 to 3; m is an integer that have a value of 1 to 3; q is 0, or an integer that have a value of 1 to 10; s is an integer that have a value of 1 to 3; t is 0 or an integer having a value of 1 to 2; R 4 and R 5 are independently hydrogen, optionally substituted C alkyl, optionally substituted aryl, C arylalkyl. Optionally substituted, optionally substituted heteroaryl, optionally substituted heteroaryl, heterocyclic, heterocyclic C-4-alkyl, optionally substituted C 2-4 alkyl, R 4 and R 5 together with the nihologen to which they are attached form a 5-7 membered ring which may optionally be additional iron ore selected from O / N / S; Rs is independent 20 hydrogen or C? -4 alkyl; R10 is C? -? 0-C (O) 2R8 alkyl; R n is hydrogen, C 1 - alkyl, optionally substituted aryl, C optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted C 4 heteroarylalkyl, optionally substituted heterocyclic, or C 4 optionally substituted heterocyclic; R 2 is hydrogen, CMO alkyl, optionally substituted aryl or optionally substituted arylalkyl; R? is C 1-4 alkyl, aryl, arylalkyl, heteroaryl, d-4 heteroarylalkyl, heterocyclic, or heterocyclic C 1-4 alkyl, in which the aryl, heteroaryl and heterocyclic rings may all be optionally substituted.

17.- A compound of the formula wherein R1 is independently selected from hydrogen; halogen; nilro; cyano; CMO alkyl substituted; CMO alkyl; C2-? o alkenyl; C 0 alkoxy; CMO alkoxy halosuslifuido; azide; (CR8R8) qS (O) tR4, 15 hydroxy; hydroxy CMC alkyl; aril; arylalkyl of C? -4; aryloxy; C? -4 arylalkyloxy; Heferoaryl; Heleroarylalkyl of C? -4; helerocyclic; C1-4 helerocyclic alkyl; Heleroarylalkyloxy of C? -4; C2-10 arylalkenyl or C2-10 heteroarylalkenyl; heterocyclic alkenyl of C2-? 0; (CR8R8) qNR R5; C2-? o-C (O) NR4R5 alkenyl; (CR8R8) qC (O) NR4R5; (CR8R8) qC (O) NR4R? O; S (O) 3Rs 20 (CRsR8) qC (O) Rn; alkenyl of C2-? o-C (O) Rn; alkenyl of C2-? o-C (0) ORn C (O) ORn; (CR8Rs) qC (O) OR12; (CR8R8) qOC (O) Rn; (CR8R8) qNR4C (O) R ?? (CR8R8) qC (NR4) NR4R5; (CR8R8) qNR4C (NR5) R ??; (CR8R8) qNHS (O) 2R17 or (CR8Rd) qS (O) 2NR4R5; or two R1 portions together can form -O- (CH2) sO- or G ^ jj ^ a ring of 5 to 6 members saturated or unsaturated, and in which the rings containing aryl, heteroaryl, and heterocyclic can be optionally substituted; n is an integer that has a value of 1 to 3; m is an integer that have a value of 1 to 3; q is 0, or an integer that have a value of 1 to 10; s is an integer that have a value of 1 to 3; í is 0 or a value that has a value of 1 to 2; R4 and R5 are independently hydrogen, optionally substituted C alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, heterocyclic, C? -4 heterocyclic alkyl, or R4 and R5 together with the nitrogen to which they adhere form a ring of 5 to 7 members which may optionally be obtained from an additional nitrogen selected from O / N / S; R8 is independently hydrogen or C? - alkyl; Rio is CMO-CÍO ^ RS alkyl; RH is hydrogen, C-alkyl. optionally substituted aryl, optionally substituted C.sub.4-4 arylalkyl, optionally substituted heleroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclic, or optionally heterocyclic C? -4 alkyl optionally substituted; R 2 is hydrogen, CMO alkyl, optionally substituted aryl or optionally substituted arylalkyl; Ru is C, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, or heterocyclic CH alkyl, in which the aryl, heteroaryl and heterocyclic rings may all be optionally substituted.

18. - A method for making a compound according to claim 1, further characterized in that said method comprises reacting a compound of the formula: (A) in which A, X, R1 and m are as defined in formula (I) and R is NH2, with a compound of the formula: C (X2) -N- (CR? 3R? 4) v-Z; wherein X 2, R 3, R 4, v and Z are as defined in formula (I), to produce a compound of formula (I).