HUP9903949A2 - Il-8 receptor antagonists - Google Patents

Abstract

N-(aryl)guanidines of formula (I) and their salts are new. Z = CN, OR11, CONR15R16, R18, COR11, COOR11, or SO2R17; R = a moiety having an ionisable hydrogen and a pKa of 10 or less; W = a group of formula (a)-(c); W1 = a group of formula (d) or (e); ring E' = optionally a group of formula (f) (optionally substituted by (R1)m), or 1,2-phenylene (j) or a group of formula (g)-(i) (all substituted by R1); ring E = optionally a group of formula (f)-(j) (all optionally substituted by (Y)n); q = 0-10; t = 0-2; s, m, n = 1-3; R1, Y = H, halo, NO2, CN, OH, N3, 1-10C alkyl, 1-10C alkoxy, 1-10C haloalkyl, 1-10C haloalkoxy, 2-10C alkenyl (optionally substituted by CONR4R5, COR11, COOR11, aryl, heteroaryl or heterocyclyl), (CR8R8)qS(O)tR4, 1-4C hydroxyalkyl, aryl, aryloxy, 1-4C alkyl (optionally substituted by aryl, heteroaryl or heterocyclyl), 1-4C alkoxy, (optionally substituted by aryl, heteroaryl or heterocyclyl), heteroaryl, heterocyclyl, (CR8R8)qCONR4R5, (CR8R8)qNR4R5, (CR8R8)qCONR4R10, SO3H, SO3R8, (CR8R8)qCOOR12, (CR8R8)qOCOR11, (CR8R8)qN(R4)COR11, (CR8R8)qNHSO2R19 or (CR8R8)qSO2NR4R5; or R1+R1, Y+Y = O(CH2)sO, or a 5 or 6 membered saturated or unsaturated ring; v = 0-4; R4, R5 = H, or 1-4C alkyl (optionally substituted by aryl, heteroaryl or heterocyclyl), aryl, heteroaryl or heterocyclyl (all optionally substituted); or NR4R5 = V; V = 5-7 membered ring, optionally containing another heteroatom (O, N, S); R6-R8, R13, R14 = H or 1-4C alkyl; or NR6R7 = V; R8 = H or 1-4C alkyl; R10 = (1-10C alkyl)COOR8; R11 = aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl (all optionally substituted), H or 1-4C alkyl; R12 = H, 1-10C alkyl, aryl or aryl(1-4C)alkyl (both optionally substituted); R15, R16 = H, or 1-4C alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl or heterocyclyl(1-4C)alkyl (all optionally substituted); or NR15R16 = V; R = aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl, heterocyclyl(1-4C)alkyl (all optionally substituted), 1-4C alkyl, NR15R16 or OR11; R18 = 1-4C alkyl, aryl, aryl(1-4C)alkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl, or heterocyclyl(1-4C)alkyl (all optionally substituted); R19 (in R18) = 1-4C alkyl, aryl, aralkyl, heteroaryl, heteroaryl(1-4C)alkyl, heterocyclyl, or heterocyclyl(1-4C)alkyl (all optionally substituted); and R19 (in Y) = NR6R7, 1-4C alkyl (optionally substituted), aryl(1-4C)alkyl, aryl(2-4C)alkenyl, heteroaryl, heteroaryl(1-4C)alkyl, heteroaryl(2-4C)alkenyl, heterocyclyl, heterocyclyl(1-4C)alkyl, or heterocyclyl(2-4C)alkenyl; aryl, heteroaryl and heterocyclyl in R1 and Y are optionally substituted.

Description

W

67.366/DE

S.B.G. & K.

International ·

Patent [rod*

PUBLICATION

COPY

IL-Θ RECEPTOR ANTAGONISTS

The invention relates to novel guanidine-containing compounds and processes for their preparation, to the use of the compounds in the treatment of diseases mediated by IL-8, GROa, GROP, GROy, ΕΝΆ-78 and NAP-2, and to pharmaceutical compositions for use in such therapy.

Interleukin-8 (IL-8) is referred to by several names, including neutrophil attractant/activating protein-1 (NAP-1), monocyte-derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils, basophils, and some T cells. IL-8 is produced by most nucleated cells exposed to TNF, IL-1α, IL-Ιβ, and LPS, and IL-8 is produced by macrophages, fibroblasts, endothelial and epithelial cells exposed to these agents, as well as by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP [M. Baggioloni et al., J. Clin. Invest., 84, 1045 (1989); J. Schroder et al., J. Immunol., 139, 3474 (1987); J. Schroder et al., J. Immunol., 144, 2223 (1990); Strieter et al., Science, 243, 1467 (1989); Strieter et al., J. Biol. Chem., 264, 10621 (1989); and Cassatella et al., J. Immunol., 148, 3216 (1992)].

The α-family of chemokines includes GROa, GROP, GROy, and NAP-2. Like IL-8, these chemokines are also referred to by various names. For example, GROa is also known as MGSAa (MGSA: Melanoma Growth Stimulating Activity), GROP is also known as MGSAP, and GROy is also known as MGSAy [see, for example, Richmond et al., J. Cell Physiology, 129, 375 (1986); and Chang et al., J. Immunol., 148, 451 (1992)]. All of the α-family chemokines have an ELR repeat immediately preceding the CXC repeat that binds to the IL-8 B receptor.

IL-8, GROa, GROP, GROy and NAP-2 stimulate a variety of functions in vitro. All of these have previously been shown to have chemoattractant properties on neutrophils, while IL-8 and GROa have chemotactic effects on T-lymphocytes and basophils. In addition, IL-8 induces histamine release from basophils from normal and atopic individuals, and lysosomal enzyme release and respiratory burst from neutrophils. It has also been shown that IL-8 increases surface Mac-1 (CD11b/CD18) expression on neutrophils without de novo protein synthesis, which may contribute to increased neutrophil adhesion to vascular endothelial cells. Massive neutrophil infiltration is a hallmark of many diseases. Since IL-8, GROa, GROP, GROy and NAP-2 promote the accumulation and activation of neutrophils, these cytokines play a role in a wide variety of acute and chronic inflammatory disorders, including psoriasis and rheumatoid arthritis [Baggiolini et al., FEBS Letters, 307, 97 (1992); Miller et al., Crit. Rev. Immunol., 12, 17 (1992); Oppenheim et al., Annu. Rev. Immunol., 9, 617 (1991); Seitz et al., J. Clin. Invest ., 87, 463 (1991); Miller et al., Am. Rev. Respir. Dis., 146,

427 (1992); Donnely et al., Lancet, 341, 643 (1993)]. In addition, ELR cytokines (which contain amino acids corresponding to the ELR repeat immediately before the CXC repeat) are also involved in angiostasis [Strieter et al., Science, 258, 1798 (1992)].

In vitro, IL-8, GROa, GROP, GROy and ΝΆΡ-2 bind to and activate the seven-transmembrane, G-protein coupled family, particularly IL-8 receptors, most notably the B receptor, to induce neutrophil shape change, chemotaxis, granule release and respiratory burst [Thomas et al., J. Biol. Chem., 266, 14839 (1991); and Holmes et al., Science, 253, 1278 (1991)]. There is a history of developing non-peptide, small molecule antagonists for members of this receptor family [see, for example, R. Freidinger, Progress in Drug Research (Birkhauser Verlag, Basel), 40, 33-98 (1993)]. Thus, the IL-8 receptor is a promising target for the development of new anti-inflammatory agents.

Two high-affinity human IL-8 receptors (77% homology) have been described previously: IL-8Rα, which binds IL-8 exclusively with high affinity, and IL-8RPα, which has high affinity for IL-8 as well as GROα, GROP, GROγ, and NAP-2 [Holmes et al., Science, 253, 1278 (1991); 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 significant need for compounds that can bind to the IL-8a or IL-δβ receptor. IL-8 is responsible for neutrophil and T-cell subset chemotaxis to the site of inflammation, and thus compounds that function as inhibitors of IL-8 receptor binding would be beneficial in conditions associated with increased IL-8 production.

One aspect of the invention is a method for treating chemokine-mediated diseases, wherein the chemokine is a chemokine that binds to an IL-8a or IL-δβ receptor, which method comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In particular, the chemokine is IL-8.

The invention also provides a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of formula (I).

In the solution according to the invention, compounds of general formula (I) are used.

W—NH N—(CR ₁₃ R ₁₄ )v —w, Π (I) and their pharmaceutically acceptable salts can be used, the formula of which is

Z is cyano, -ORn, -C(0)NR15R16, -R16,

a group of the general formula -C(O)Rn, -C(O)ORn or -S(O)2R17;

R is a functional group having an ionizable hydrogen atom and a pKa value of at most 10;

R1 is independently hydrogen; halogen; nitro; cyano; C1-10 alkyl; C1-10 haloalkyl; C2-10 alkenyl; C1-10 alkoxy; C1-10 haloalkoxy; azido; -(CReRe)qS(O)tR4; hydroxy; C1-4 hydroxyalkyl; aryl; aryl-(C1-4 alkyl)-group; aryloxy; aryl-(C1-4 alkoxy)-group; heteroaryl; heteroarylalkyl; heterocyclic; C1-4 alkyl substituted with heterocyclic; heteroaryl-(C1-4 alkoxy)-group; aryl-(C2-10 alkenyl) group; heteroaryl-(C2-10 alkenyl) group; heterocyclic substituted C2-10 alkenyl group; -(CReRe)qNR4Rs; -(C2-10 alkenyl)-C(O)NR ₄ R ₅ ; - (CReRe) _q C (0)NR4R5; - (CReRs) qC (0)NR4R10 group; sulfo group; -S(O)3Re;

- (CReRe) qC (0)Rn; -(C2-10 alkenyl) -C (0) Rn; -(C2-10 alkenyl)-C(0)OR11; - (CReRe) qC (O) OR12; - (CReRe) qOC(O)Rn; - (CReRe) _q NR ₄ c (0) Rn; - (CReRe) qNHS (0) 2R19; - (CReRe) qS (0) 2NR4R5; or two R1 groups together may form a group of the general formula -O-(CH2)s ^_ O- or a five- or six-membered, saturated or unsaturated cyclic group;

q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

t is 0, 1 or 2;

s has the value 1, 2 or 3;

v is 0 _z 1, 2, 3 or 4;

R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl-(C1-4 alkyl), optionally substituted heteroaryl, optionally substituted heteroaryl-(C1-4 alkyl), heterocyclic, C1-4 alkyl substituted with heterocyclic, or

R4 and R5 together with the nitrogen atom to which they are attached form a 5-7 membered cyclic group optionally containing an additional heteroatom selected from oxygen, nitrogen and sulfur;

Y is hydrogen; halogen; nitro; cyano; C1-10 alkyl; C1-10 haloalkyl; C2-10 alkenyl; C1-10 alkoxy; C1-10 haloalkoxy; azido; - (CRgRe)qS(0)tR4J hydroxy; C1-4 hydroxyalkyl; aryl; aryl-(C1-4 alkyl) group; aryloxy; aryl-(C1-4 alkoxy) group; heteroaryl; heteroarylalkyl; heteroaryl-(C1-4 alkoxy) group; heterocyclic; heterocyclic substituted C1-4 alkyl; aryl-(C2-10 alkenyl) group; heteroaryl-(C2-C10 alkenyl) group; heterocyclic substituted C2-C10 alkenyl group;

- (CR5Re) _qNR4R5 ; -(C2-10 alkenyl)-C(O)NR4R5;

- (CR8R8)qC(0)NR4R5; - (CR ₈ Rs)qC(0)NR4R10 group; sulfo group; -S(0)3Rs; - (CReRs)qC(0)Rn; -(C2-10 alkenyl)-C(0)Rn; -(C2-10 alkenyl) -C(0)ORn; -C(0)Rn; -(CR8R8)qC(O)ORi2;

-(CR ₈ R 8 )qOC(O) R 1i ; - (CRsRe)qNR ₄ C(0)Rn; -(CR ₈ R 8 )qNHS(O) ₂ Rd;

- a group of the general formula (CR5Re)qS(0)2NR4R5; or two Y groups together may form a group of the general formula -O-(CH2) _s -O- or a five- or six-membered unsaturated cyclic group;

n is 1, 2 or 3;

m is 1, 2 or 3;

R 6 and R 7 independently represent a hydrogen atom or a C 1-4 alkyl group, or

Rg and R7 together with the nitrogen atom to which they are attached form a 5-7 membered cyclic group optionally containing an additional heteroatom selected from oxygen, nitrogen and sulfur;

R 5 represents a hydrogen atom or a C 1-4 alkyl group;

R10 is a group of the general formula -(C1-10 alkyl)-C(O) _2Rs ;

Rn represents a hydrogen atom, a C1-C4 alkyl group, an optionally substituted aryl group, an optionally substituted aryl-(C1-C4 alkyl) group, an optionally substituted heteroaryl group, an optionally substituted heteroaryl-(C1-C4 alkyl) group, an optionally substituted heterocyclic group, or an optionally substituted C1-C4 alkyl group substituted with an optionally substituted heterocyclic group;

R12 represents a hydrogen atom, a C1-C10 alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group;

R13 and R14 are independently hydrogen or optionally substituted C1-4 alkyl, or one of R13 and R14 is optionally substituted aryl;

R15 and R16 independently represent hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl-(C1-4 alkyl), optionally substituted heteroaryl, optionally substituted heteroaryl-(C1-4 alkyl), heterocyclic, C1-4 alkyl substituted with heterocyclic, or

R15 and R16 together with the nitrogen atom to which they are attached form a 5-7 membered cyclic group optionally containing one further heteroatom selected from oxygen, nitrogen and sulfur;

R17 is a C1-4 alkyl group, a group of the general formula -NR15R16, -ORn, an optionally substituted aryl group, an optionally substituted aryl-(C1-4 alkyl) group, an optionally substituted heteroaryl group, an optionally substituted heteroaryl(C1-4 alkyl) group, a heterocyclic group or a C1-4 alkyl group substituted with a heterocyclic group;

R18 is an optionally substituted C1-4 alkyl group, an optionally substituted aryl group, an optionally substituted aryl-(C1-4 alkyl) group, an optionally substituted heteroaryl group, an optionally substituted heteroaryl-(C1-4 alkyl) group, a heterocyclic group, or a C1-4 alkyl group substituted with a heterocyclic group;

R19 is C1-4 alkyl, aryl, aralkyl, heteroaryl, heteroaryl-(C1-4 alkyl), heterocyclic, or C1-4 alkyl substituted with heterocyclic, each of which is optionally substituted;

Rd is a group of the general formula -NReR?, alkyl, aryl-(C1-C4 alkyl), aryl-(C2-C4 alkenyl), heteroaryl, heteroaryl-(C1-C4 alkyl), heteroaryl-(C2-C4 alkenyl), heterocyclic group or C1-C4 alkyl group substituted with heterocyclic group, wherein the alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl groups are optionally substituted;

W meaning

group of formula;

E' means, if applicable

lags (*)

Ri

or a group of general formula, where the points of attachment of the chila ring are indicated;

Meaning of Wi

group of general formula;

This report, if applicable

port, where asterisks (*) indicate the connection points of the ring.

The compounds of formula (I) may also be used in the veterinary treatment of non-human mammals that require inhibition of IL-8 or other chemokines binding to IL-8a or IL-δβ receptors. Examples of chemokine-mediated diseases that can be treated therapeutically or prophylactically in animals include, for example, those conditions listed in the Methods of Treatment section.

In the compounds of general formula (I), W represents a

The E' ring with the attachment point marked with an asterisk (*) is optionally present. If not present, the ring is a phenyl group substituted with a R1 group. The E' ring may be substituted with a R1 group in any saturated or unsaturated ring. For the purposes of the invention, the E' ring is substituted only in the unsaturated ring(s).

In the compounds of formula (I), R suitably represents a functional group which provides an ionizable hydrogen atom with a pKa value of up to 10, preferably from about 3 to 9, more preferably from about 3 to 7. Such functional groups include, but are not limited to, hydroxy, carboxy, mercapto, -SR2, -OR2, -NH-C(O)R _a , -C(O)NR6<R7«, -NHS (O) 2Rb, -S(0)2NHR _c , -NHC(X2)NHRb or a tetrazolyl group, where X2 is oxygen or sulfur, preferably oxygen. Preferably, the functional group is other than sulfo and is attached directly to the backbone or as a substituent of the aryl, heteroaryl or heterocyclic group, such as in the group -SR2 or -OR2. More preferably, R is a hydroxy, mercapto group or a group of the general formula -NHS(O)2Rb.

Suitably, R2 is a substituted aryl, heteroaryl or heterocyclic group having a functional group providing an ionizable hydrogen atom with a pKa value of up to 10.

Suitably, Rg* and _R7 ' are hydrogen, C1-4 alkyl, aryl, aryl-(C1-4 alkyl), aryl-(C2-4 alkenyl), heteroaryl, heteroaryl-(C1-4 alkyl), heteroaryl-(C2-4 alkenyl), heterocyclic, heterocyclic-substituted C1-4 alkyl, or heterocyclic-substituted C2-4 alkenyl, each of which may be optionally substituted with 1-3 atoms and/or groups selected from: halogen; nitro; C1-4 haloalkyl, such as trifluoromethyl; C1-4 alkyl, such as methyl; a C1-C4 alkoxy group, for example a methoxy group; a group of the general formula -NR9C(0)R _a ; a group of the general formula -C(O)NRgR7 ; a sulfo group; or a (C1-C4 alkoxy)carbonyl group, with the proviso that only one of Re· and R?» may be a hydrogen atom, and both may not be hydrogen atoms.

Suitably, R and R are independently hydrogen or C1-C4 alkyl, or R and R together with the nitrogen atom to which they are attached form a 5-7 membered cyclic group, optionally containing one further heteroatom selected from oxygen, nitrogen and sulphur. The heterocycle may be optionally substituted as defined above.

Suitably, R _a is aryl, aryl-(C 1-4 alkyl), heteroaryl, heteroaryl-(C 1-4 alkyl), heterocyclic or C 1-4 alkyl substituted with heterocyclic, each of which may be optionally substituted as defined below.

Suitably, Rb is a group of the general formula -NR6R7, alkyl, aryl, aryl-(1-4C alkyl), aryl-(2-4C alkenyl), heteroaryl, heteroaryl-(1-4C alkyl), heteroaryl-(2-4C alkenyl), heterocyclic, heterocyclic-substituted C1-4 alkyl, heterocyclic-substituted C2-4 alkenyl, or camphoryl, wherein each of the foregoing groups may be optionally substituted with 1-3 atoms and/or groups selected from the following: halogen; nitro; haloalkyl of 1-4C, for example trifluoromethyl; alkyl of 1-4C, for example methyl; C1-4 alkoxy, for example methoxy; -NRgC(O)R _a ; -C(O)NReR7 ; sulfo; or (C1-4 alkoxy)carbonyl. Rb is preferably optionally substituted phenyl, benzyl or styryl. When Rb is a heteroaryl, Rb is preferably optionally substituted thiazolyl, optionally substituted thienyl or optionally substituted quinolyl.

Suitably, Rg is hydrogen or C1-4 alkyl, preferably hydrogen. Preferably, when the substituent is -NRgC(O) _R a , R a _is preferably alkyl, for example methyl.

Suitably, R _c represents a hydrogen atom, an alkyl, aryl, aryl-(C 1-4 alkyl), aryl-(C 2-4 alkenyl), heteroaryl, heteroaryl-(C 1-4 alkyl), heteroaryl-(C 2-4 alkenyl), heterocyclic group, a heterocyclic substituted C 1-4 alkyl group, or a heterocyclic substituted C 2-4 alkenyl group, wherein each of the foregoing groups may be optionally substituted with 1-3 atoms and/or groups selected from the following: halogen atom; nitro group; haloalkyl group of C 1-4 atoms; alkyl group of C 1-4 atoms; alkoxy group of C 1-4 atoms; -NR gC(O)R _a ; -C(O)NR gR7 group; sulfo; or (C1-C4 alkoxy)carbonyl; wherein R9 is hydrogen or C1-C4 alkyl. Preferably, _Rc is optionally substituted phenyl.

It will be apparent to the skilled person that when R is -OR2 or -SR2, the aryl group must contain the required ionizable hydrogen atom. The aryl group may also be optionally substituted with 1 to 3 atoms and/or groups selected from the following: halogen, nitro, haloalkyl (C1-4), alkyl (C1-4), alkoxy (C1-4), hydroxy, mercapto, -C(O)NRgR7, -NH-C(O)R _a , -NHS(O)2Rb, -S(O)2NReR7, -C(O)ORe and/or tetrazolyl.

In the compounds of formula (I), R1 is suitably independently hydrogen; halogen; nitro; cyano; C1-10 alkyl, for example methyl, ethyl, isopropyl or propyl; C1-10 haloalkyl, for example trifluoromethyl; C2-10 alkenyl; C1-10 alkoxy, for example methoxy or ethoxy; C1-10 haloalkoxy, for example trifluoromethoxy; azido; -(CRsRe)qS(0) _tR4 , where t is 0, 1 or 2; hydroxy; C1-4 hydroxyalkyl, for example hydroxymethyl or hydroxyethyl; aryl, for example phenyl or naphthyl; aryl-(C1-4 alkyl), for example benzyl; aryl-(C2-C10 alkenyl group; aryloxy group, for example phenoxy group; aryl-(C1-C4 alkoxy) group, for example benzyloxy group; heteroaryl group; heteroarylalkyl group; heteroaryl-(C2-C10 alkenyl) group; heteroaryl-(C1-C4 alkoxy) group; heterocyclic substituted C2-C10 alkenyl group; - (CRgRe)qNR4Rs; - (CRgRg)qC(0)NR4R5; - (CReRe)qC(O)NR4R10 group; sulfo group; -S(0)3Re group; - (CReRe )qC(0)Rn group; -(C2-10 alkenyl)-C(O)Rn; -(C2-10 alkenyl)-C(0)ORn; -C(0)Rn; - (CReRe)qC(0)OR12; - (CReRe)qOC(0)Rn; - (CR8Re)qNR4C(O)Rn; - (CReRe)qNHS(0)2R19; -(CReRe)qS(0)2NR4R5; or two R1 groups together may form a group of the general formula -O-(CH2) _s -O- or a five- or six-membered unsaturated cyclic group; where s is 1, 2 or 3. The groups containing aryl, heteroaryl and heterocyclic groups may optionally be substituted as follows.

Suitably, q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

If R1 forms an alkylenedioxy bridge, the value of s is preferably 1. If R1 forms a further unsaturated ring, the ring is preferably a six-membered ring resulting in a naphthylene ring system, which may optionally be substituted 1-3 times with the substituents listed for the R1 group.

Suitably, R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl-(C1-4 alkyl), optionally substituted heteroaryl, optionally substituted heteroaryl-(C1-4 alkyl), heterocyclic, heterocyclic-substituted C1-4 alkyl, or R4 and R5 together with the nitrogen atom to which they are attached form a 5-7 membered cyclic group, optionally containing a further heteroatom selected from oxygen, nitrogen and sulphur.

Suitably, R 5 is independently hydrogen or C 1-4 alkyl.

Suitably, R10 is a group of the general formula -(C1-10 alkyl)-C(O)2-8, for example carboxymethyl or (methoxycarbonyl)methyl.

Suitably, Rn is hydrogen, C1-4 alkyl, aryl, aryl-(C1-4 alkyl), heteroaryl, heteroaryl-(C1-4 alkyl), heterocyclic, or C1-4 alkyl substituted with a heterocyclic.

Suitably, R12 is hydrogen, C1-C10 alkyl, optionally substituted aryl or optionally substituted aralkyl.

Suitably R19 is C1-4 alkyl, aryl, aralkyl, heteroaryl, heteroaryl-(C1-4 alkyl), heterocyclic or C1-4 alkyl substituted with heterocyclic, wherein the aryl, heteroaryl and heterocyclic groups may be optionally substituted.

Preferably, R1 is halogen, cyano, nitro, trifluoromethyl, -C(O)NR4R5, -alkenyl-C(O)NR4R5, -C(O)R4R10, -alkenyl-C(O)OR12, heteroaryl, heteroarylalkyl, heteroarylalkenyl or -S(O)NR4R5, and preferably R4 and R5 are each hydrogen or one is phenyl. R1 is preferably in the 4-position of the phenyl.

When R is hydroxy, mercapto or -NHSO2Rb, R1 is preferably in the 3,4 position when 3, 4 or double substituted. The substituent is suitably an electron withdrawing group. When R is hydroxy, mercapto or -NHSO2Rb, R1 is preferably nitro, halogen, cyano, trifluoromethyl or -C(O)NR4Rs.

When R is a carboxyl group, R 1 is preferably a hydrogen atom, or R 1 is preferably in the 4-position, more preferably a trifluoromethyl group or a chlorine atom.

In the compounds of formula (I), R13 and R14 are suitably independently hydrogen, optionally substituted straight or branched C1-4 alkyl, or one of R13 and R14 is optionally substituted aryl; and v is 0, 1, 2, 3 or 4.

When R13 or R14 represents an optionally substituted alkyl group, the alkyl group may carry 1 to 3 atoms and/or groups selected from the following as substituents: halogen atom; haloalkyl group having 1 to 4 carbon atoms, for example trifluoromethyl group; hydroxy group; hydroxy group having 1 to 4 carbon atoms

-alkyl group; C1-C4 alkoxy group, for example methoxy or ethoxy group; C1-C10 haloalkoxy group; -S(O)tR4 group; aryl group; -NR4R5;

-NHC(O)R4; -C(O)NR4R5; or -C(O)ORe.

In the compounds of general formula (I), Wi suitably represents

group with a general formula.

The E ring with the attachment point marked with an asterisk (*) is optionally present. If not present, the ring is a phenyl group substituted with a Y group. The E ring may be substituted with a Y group in any saturated or unsaturated ring. For the purposes of the invention, the E ring is substituted only in the unsaturated ring(s).

Suitably, Y is hydrogen; halogen; nitro; cyano; C1-10 alkyl; C1-10 haloalkyl; C2-10 alkenyl; C1-10 alkoxy; C1-10 haloalkoxy; azido; -(CRsRe)qS(0) _tR4 /'hydroxy; C1-4 hydroxyalkyl; aryl; aryl-(C1-4 alkyl)-group; aryloxy; aryl-(C1-4 alkoxy)-group; heteroaryl; heteroarylalkyl;

heteroaryl-(C1-C4 alkoxy) group; heterocyclic group; heterocyclic substituted C1-C4 alkyl group; aryl-(C2-C10 alkenyl) group; heteroaryl-(C2-C10 alkenyl) group; heterocyclic substituted C2-C10 alkenyl group; - (CRsRs)qNR4Rs; -(C2-C10 alkenyl)-C(0)NR4R5; - (CRgRe)qC(0)NR4R5; - (CRgRe)qC(0)NR4R10 group; sulfo group; -S(O)3R8; - (CRgRs)qC(0) Rn; -(C2-C10 alkenyl)-C(0)Rn; -(C2-10 alkenyl)-C (0) ORn; -C(0)Rn; - (CR8R8)qC(O)ORi2; - (CReRe) qOC (0) Rn; - (CReR8)qNR4C(O)Rn; - (CReRe) qNHS (0) 2Rd; “ (CReRs) qS (0) 2NR4R5; or two Y groups together may form a group of the general formula -O-(CH2) s ^- O~ or a five- or six-membered unsaturated cyclic group; where the groups containing aryl, heteroaryl and heterocyclic groups may be optionally substituted.

When Y forms an alkylene dioxy bridge, the value of s is preferably 1. When R1 forms a further unsaturated ring, the ring is preferably a six-membered ring resulting in a naphthylene ring system. The naphthylene group may optionally be substituted with 1 to 3 other Y groups as defined above. The various aryl, aralkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclic, heterocyclic-substituted alkyl groups and heterocyclic-substituted alkenyl groups indicated above may optionally be substituted as defined below.

Suitably, Rd is a group of the general formula -NRgR?, alkyl, aryl, aryl-(C1-4 alkyl), aryl-(C2-4 alkenyl), heteroaryl, heteroaryl-(C1-4 alkyl), heteroaryl-(C2-4 alkenyl), heterocyclic, heterocyclic-substituted C1-4 alkyl or heterocyclic-substituted C2-4 alkenyl, wherein the aryl, aralkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclic, heterocyclic-substituted alkyl and heterocyclic-substituted alkenyl groups may be optionally substituted as defined below.

Y is preferably a halogen atom, a C1-C4 alkoxy group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted arylalkoxy group, an optionally substituted heteroarylalkoxy group, a methylenedioxy group, a group of the general formula -NR4R5, a C1-C4 alkylthio group, arylthio, a haloalkoxy group, an optionally substituted C1-C4 alkyl group or a hydroxyalkyl group. Y is more preferably one or two halogen atoms, one or two alkoxy groups, methylenedioxy, aryl or alkyl groups, more preferably these substituents are in the 2'-position or the 2',3'-position.

Although the Y substituents may be located at any of the 5 possible ring positions, when R is hydroxy, mercapto or -NHSO2Rb, preferably

Y occurs singly and is either in the 2' or 3' position, while the 4' position remains unsubstituted. If the ring is disubstituted, when R is hydroxy, mercapto or -NHSOzRb, the substituents are preferably in the 2' or 3' position of the monocyclic ring. Although both R1 and Y may be hydrogen, preferably at least one of the rings is substituted, preferably both rings are substituted.

Preferably, when Z is cyano, W is phenyl, R is hydroxy, v is 0, and Wi is phenyl, then (Y) _n — where n is 1 or 2 — is other than a phenyl group substituted by halogen, trifluoromethyl, trifluoromethoxy, carboxy, alkoxycarbonyl, (aryloxy)carbonyl, carbamoyl, cyano, alkyl, alkoxy, hydroxy, nitro, hydroxymethyl, sulfamoyl, amino, aryloxy, alkylcarbonyl, arylcarbonyl, (alkylcarbonyl)oxy or (arylcarbonyl)oxy, monosubstituted in the 3'-position or disubstituted in the 3', 5'-position of the phenyl group.

Also preferably, when Z is cyano, v is 0, W is phenyl, R is hydroxy, and Wi is phenyl, then (Y) _n — where n is 1 — is other than a 2-substituted arylalkyl group or an arylalkenyl group (optionally substituted with alkyl).

In the compounds of formula (I), Z is suitably a cyano group, -ORn, -C(0)NR15R16, -R18, -C(0)Rn, -C(0)ORn or -S(O)2R17.

.:. .:. .:. : .1.

- 23 Suitably, R15 and R16 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl-(C1-4 alkyl), optionally substituted heteroaryl, optionally substituted heteroaryl-(C1-4 alkyl), heterocyclic, C1-4 alkyl substituted with heterocyclic, or R15 and R16 together with the nitrogen atom to which they are attached form a 5-7 membered cyclic group, optionally containing a further heteroatom selected from oxygen, nitrogen and sulphur.

R17 is suitably a C1-4 alkyl group, a group of the general formula -NR15R16, -OR11, an optionally substituted aryl group, an optionally substituted aryl-(C1-4 alkyl) group, an optionally substituted heteroaryl group, an optionally substituted heteroaryl-(C1-4 alkyl) group, an optionally substituted heterocyclic group or an optionally substituted C1-4 alkyl group substituted with an optionally substituted heterocyclic group.

R1 suitably represents an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aryl-(C1-C4)alkyl group, an optionally substituted heteroaryl group, an optionally substituted heteroaryl-(C1-C4)alkyl group, an optionally substituted heterocyclic group, or an optionally substituted C1-C4 alkyl group substituted with an optionally substituted heterocyclic group.

Unless otherwise indicated, the term optionally substituted as used herein refers to substitution with the following atoms and/or groups: halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxyalkyl having 1-10 carbon atoms; alkoxy having 1-10 carbon atoms, such as methoxy or ethoxy; -S(0) _m (C1-10alkyl) where m' is 0, 1 or 2, such as methylthio, methylsulfinyl or methylsulfonyl; optionally mono- or di-substituted amino, such as -NR4R5; -NHC(O)R4; -C(O)NR4Rs; carboxy; -S(O)2NR4Rs; -NHS(O)2R21; an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl or tert-butyl; a haloalkyl group having 1 to 10 carbon atoms, such as trifluoromethyl; an optionally substituted aryl group, such as phenyl; an optionally substituted aralkyl group, such as benzyl or phenethyl; an optionally substituted heterocyclic group; an alkyl group optionally substituted with a substituted heterocyclic group; an optionally substituted heteroaryl group; an optionally substituted heteroarylalkyl group; wherein said aryl, heteroaryl or heterocyclic groups may themselves be substituted with one or two substituents selected from the following atoms and/or groups: halogen; hydroxy; hydroxyalkyl; alkoxy group having 1 to 10 carbon atoms; -S(0) _m <(C1-C10 alkyl); optionally mono- or di-substituted amino, for example -NR4R5; -C1-C10 alkyl; -C1-C10 haloalkyl, for example trifluoromethyl.

Suitably, R21 is C1-4 alkyl, aryl, aryl-(C1-4 alkyl), heteroaryl, heteroaryl-(C1-4 alkyl), heterocyclic or C1-4 alkyl substituted with heterocyclic.

Suitable pharmaceutically acceptable salts are well known to those skilled in the art. Such salts include, for example, acid addition salts with inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of the compounds of formula (I) can also be prepared with a pharmaceutically acceptable cation, for example, in cases where a substituent contains a carboxy group. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include, for example, alkali metal, alkaline earth metal, ammonium and quaternary ammonium ions.

The term halogen or halogen atom refers to chlorine, fluorine, bromine, and iodine atoms.

The term C1-10 alkyl group or alkyl group, unless otherwise limited in chain length, refers to a straight or branched chain alkyl group containing 1-10 carbon atoms, such as, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, etc.

The term cycloalkyl as used herein refers to a ring group preferably having 3 to 8 carbon atoms, such as, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, etc.

The term alkenyl group refers to a group containing 2-10 carbon atoms, straight or branched chain, with at least one double bond, such as, but not limited to, vinyl, 1-propenyl, allyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc., unless the chain length is otherwise limited.

The term aryl group refers to phenyl and naphthyl groups.

The term heteroaryl group (alone or in any combination, such as heteroaryloxy or heteroarylalkyl) refers to a group derived from a 5- to 10-membered aromatic ring system containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and/or sulfur. Examples of compounds yielding such groups include, but are not limited to, pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, and benzimidazole.

The term heterocyclic group (alone or in any combination, such as an alkyl group substituted with a heterocyclic group) refers to a group derived from a 4-10 membered saturated or partially unsaturated ring system containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and/or sulfur in one or more rings. Compounds yielding such groups include, but are not limited to, the following: pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran and imidazolidine.

The term "aralkyl", "heteroarylalkyl" or "heterocyclic substituted alkyl" as used herein refers to an alkyl group having 1 to 4 carbon atoms, as defined above, to which an aryl group, a heteroaryl group or a heterocyclic group is attached.

The term sulfinyl refers to the S(O) oxide of the corresponding sulfide, while the term sulfonyl refers to the fully oxidized S(O)2 derivative of the corresponding sulfide.

As used herein, the term "two R1 groups (or two Y groups) together form a five- or six-membered, unsaturated cyclic group" refers to the formation of a naphthylene ring system or a phenyl group having a five- or six-membered, partially unsaturated ring fused to the phenyl group, such as a 6-carbon cycloalkene, such as cyclohexene, or a 5-carbon cycloalkene, such as cyclopentene.

Examples of compounds of formula (I) include the following derivatives:

N-(2-hydroxy-4-nitrophenyl)-N'-(2-chlorophenyl)-N-cyanoguanidine;

N-(2-hydroxy-4-nitrophenyl)-Ν’-(2-chlorophenyl)-N-cyanoguanidine;

N-(4-cyano-2-hydroxyphenyl)-N'-phenyl-N-cyanoguanidine;

N-(2-bromophenyl)-N'-(4-cyano-2-hydroxyphenyl)-N'-cyanoguanidine;

N-(4-cyano-2-hydroxyphenyl)-Ν'-(2,3-dichlorophenyl)-N-cyanoguanidine;

N-(2-bromophenyl)-Ν'-(4-cyano-2-hydroxy-3-propylphenyl)-N-cyanoguanidine;

N-(2-bromophenyl)-Ν’-(4-cyano-2-hydroxy-3-isobutylphenyl)-N”-cyanoguanidine;

N-(2-bromophenyl)-N'-(3-bromo-4-cyano-2-hydroxyphenyl)-N'-'-cyanoguanidine;

N-(4-cyano-2-hydroxy-3-propylphenyl)-Ν'-(2,3-dichlorophenyl)-N"-cyanoguanidine;

N-(3-bromo-4-cyano-2-hydroxyphenyl)-Ν'-[2,3-(methylenedioxy)phenyl]-N'-cyanoguanidine;

N-(2-chlorophenyl)-Ν'-(4-cyano-2-hydroxy-3-propylphenyl)-N-cyanoguanidine;

N-(2-bromophenyl)-Ν'-[4-cyano-2-hydroxy-3-(methoxycarbonyl)phenyl]-N-cyanoguanidine.

The compounds of the invention may be in the form of stereoisomers, regioisomers or diastereoisomers. The compounds may contain one or more asymmetric carbon atoms and thus may exist in racemic or optically active forms. All such compounds are within the scope of the invention.

The compounds of formula (I) can be prepared by synthetic methods. Some of these methods are illustrated in the following reaction schemes. The methods illustrated in the reaction schemes can be used to obtain compounds of formula (I) in which the substituents in the various variables, such as R, R1 and Ar, optionally carry protecting groups corresponding to the indicated reactions. In these cases, the protecting groups are removed from the products to obtain the final products defined above. After the urea skeleton has been formed, further compounds of the above formulae can be prepared by methods commonly used for the interconversion of functional groups, which are well known in the art. The reaction schemes are illustrative in nature and for the sake of simplicity refer only to the preparation of compounds of formula (I).

Production processes

The title compounds can be prepared from thiuronium salts of general formula 2 (Scheme 1). R’ corresponds to the group of general formula - (R13R14)v~Wi as defined in general formula (I). In the reaction schemes, W is shown as a substituted phenyl group.

··· ·J· « ···

Reaction scheme 1

a) Na, EtOH, cyanamide; b) EDC*HC1

According to Scheme 1, the thiuronium salt of formula 2 can be prepared by reacting sodium cyanamide with a commercially available isothiocyanate of formula 1 (if the isothiocyanate is not readily available, the compound can be prepared by reacting the desired amine with thiophosgene in the presence of a base, such as sodium bicarbonate). The thiuronium salt of formula 2 is then condensed with the appropriate substituted aniline in the presence of a coupling agent, such as 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC-HCl) or acidified to form the cyanothiourea and then reacted.

Alternatively (Scheme 2), the compound of formula £ can be prepared by reacting a commercially available (Aldrich) diphenylcyanocarbomidate of formula 5 with an amine to form an O-phenylisourea of formula 6, which is then

According to the method of Atwal [Atwal, K. S., Tetrahedron Letters, 35, 8085 (1994)], the corresponding substituted aniline is reacted in the presence of trimethylaluminum. Compounds in which R* is an alkyl group can be prepared by heating the corresponding substituted alkylamines without the use of a catalyst.

Reaction scheme 2

a) acetonitrile, heating; b) AlMea

Alternatively, the title compound can be prepared using a protected ortho-substituted aniline of formula 8 (Scheme 3) (see U.S. Patent Application Serial No. 60/020655, filed June 27, 1996, International Patent Application WO 96/25157, and U.S. Patent Application Serial No. 08/701299, filed August 21, 1996). An ortho-substituted aniline of general formula 7 is pre-protected (e.g. with a tert-butyldimethylsilyl, allyl, benzyl, methoxymethyl or other suitable group) by reacting the ortho-substituted aniline with the appropriate alkyl or silyl halide in an aprotic solvent in the presence of a suitable base such as cesium carbonate, potassium carbonate or imidazole. The protected ortho-substituted aniline can also be prepared by reacting an ortho-substituted nitrobenzene of general formula 9 with a reagent suitable for forming a suitable protecting group under well-known conditions [see, for example: Greene, T., Protecting Groups in Organic Synthesis, Wiley # Sons, New York (1981)], and then reducing the protected ortho-substituted nitro compound to the corresponding aniline with tin(II) chloride in ethanol, or by palladium-catalyzed hydrogenation, or with lithium aluminum hydride in an aportic solvent.

X « nitrogen, oxygen or sulfur atom

The protected ortho-substituted aniline of formula 8 is converted with thiophosgene to an isothiocyanate, which is then reacted with the anion of formula ZNH ^- formed from the amine of formula ZNH ₂ with a base, such as sodium hydride [Z is as defined in formula (I)]. The thio anion thus obtained is reacted with an alkylating agent, such as methyl iodide, to give a thioimidate of formula 10 (Scheme 4).

Reaction scheme 4

son 14

a) C1CSC1, NaHCO ₃ ; b) ZNH ^- ; c) Today

The thioimidate 10 can be converted to the title compound 4 by reaction with the amine R'NH ₂ (Scheme 5). The reaction can be accelerated by adding a metal salt with a high affinity for sulfur, such as mercury(II) oxide or silver acetate, to the reaction mixture, or by oxidizing the sulfur atom with dimethyloxirane to provide a better leaving group. Finally, the phenol protecting group is removed by standard methods to give the title compound 4.

Reaction scheme 5

a) R'NH ₂ ; b) deprotection

In a further embodiment, the title compound can be prepared by reacting a protected carbodiimide of formula 11 (Scheme 6) with the _ZNH2 amine with a base, such as sodium hydride, to form the ^ZNH- anion, or the original _NH2Z amine (Z is cyano) and a tertiary amine base, such as N-ethyldiisopropylamine (Hünig's base), triethylamine, N,N-diisopropylethylamine, N,N-dimethylbenzylamine, or N,N-dimethylisopropylamine, under conditions where the nucleophile is present in large excess and where the reaction is carried out as quickly as possible after removal of the protecting group, with careful monitoring of the reaction. Other suitable bases, such as secondary amines such as pyridine and amino-substituted pyridine derivatives, may also be used for the said purpose. When Z is a cyano group, suitable solvents include, but are not limited to, the following aprotic solvents: acetonitrile; halogenated solvents such as chloroform and methylene dichloride; ethylene glycol dimethyl ether, dioxane, N,N-dimethylformamide and dimethyl sulfoxide; and mixtures thereof. The ··· ··· ·/·

- 35 solvent is preferably acetonitrile. It will be apparent to those skilled in the art that the choice of solvents is determined by the solubility of the cyano derivative compound. In the case of compounds in which Z is other than cyano, while aprotic solvents are preferred, it will be apparent to those skilled in the art that other suitable solvents, such as protic solvents such as alkanols, may also be used.

When Z is cyano, the reaction is preferably carried out at a temperature range of about -10°C to about 100°C, more preferably at a temperature range of about 10°C to about 50°C, most preferably at about room temperature, i.e. at a temperature range of about 20°C to about 30°C.

The protecting group of the protected R group can be removed by methods known in the art. For example, if the protecting group is an allyl derivative, the protecting group can be removed by palladium(0)-catalyzed deallylation.

Reaction scheme 6

a, b or c d

R

a) ZNH ^- (ZNH2 + NaH) , if Z - -OR, -COOEt, -CHO, RNHSO2-, ArNHSO2-; b) ZNH2-HC1, if Z - -OH; c) ZNH2 and NR3, if Z - -CN; d) deprotection

Carbodiimide 11 can be prepared from thiourea 12a (Scheme 7) by reacting thiourea 12a with a tertiary amine base and phosgene, or by reacting a thiourea 12a or a urea 12b in carbon tetrachloride with triphenylphosphine and triethylamine.

The carbodiimide can also be prepared by reacting a thiourea of formula 12a with an excess of methanesulfonyl chloride, for example an excess of 2 or more equivalents, in the presence of a tertiary amine base, such as N-ethyldiisopropylamine (Hünig's base), triethylamine, N,N-diisopropylethylamine, N,N-dimethylbenzylamine or N,N-dimethylisopropylamine, preferably triethylamine. The reaction can be carried out in any halogenated solvent, for example methylene dichloride, chloroform or carbon tetrachloride. The reaction is conveniently carried out at a temperature range of about -30°C to about 80°C, preferably about -10°C to about 50°C, more preferably about 0°C to room temperature [see Fell, J. B., Coppola, J. B., Syn. Communications, 25, 43 (1995)].

Reaction scheme 7

a) phosgene, EtaN; b) PhaP, Ccl4, EtaN; c) MsCl, EtN

Thiourea or urea is prepared according to the process described in U.S. Patent Application Serial No. 60/020655, filed June 27, 1996. Thiourea of formula 12a (Scheme 8) can also be prepared by reacting the protected ortho-substituted aniline with two equivalents of a suitable base, such as sodium hydride, potassium hydride, calcium hydride, and then reacting the anion with a commercially available isothiocyanate of the formula Wi-NCS, where Wi is as defined in formula (I). The reaction is carried out in aprotic solvents or halogenated solvents, preferably N,N-dimethylformamide. The reaction is conveniently carried out at a temperature range of about -10°C to about 50°C.

If the desired isothiocyanate is not readily available, the compound can be prepared by reacting an appropriate aniline with thiophosgene and a suitable base, such as sodium bicarbonate.

Reaction scheme 8

a, b

the

a) base; b) R’NCS

The invention further relates to novel compounds of general formula (II) which

Wi-N=C=N-W (ii) in which W and Wi are as defined for general formula (I) and W contains an optionally protected R (R) group as defined for compounds of general formula (I).

The invention further relates to novel compounds of general formula (III) which

W]-NH-C(S)-NH-W (III) in which W and Wj are as defined for general formula (I) and W contains an optionally protected R (R) group as defined for compounds of general formula (I).

The protected (R) versions of the compounds of formula (I) are also within the scope of the invention.

It is noted that the guanidine functional group can exist in a number of different tautomeric forms, such as Wi-N-C(=NZ)-NW, • ♦ · · .í. ’ ZN=C (NWi)-NW and Wi-N-C (=NW)-NZ, all of which are within the scope of the invention.

Pharmaceutically acceptable salts of the compounds of formula (I) may be prepared by known methods, for example by reacting the free compound with an appropriate amount of an acid or base in a suitable solvent.

In the examples, temperatures are given in degrees Celsius (°C). Unless otherwise indicated, mass spectra were recorded using a VG Zaf mass spectrometer using the fast atom bombardment method. ¹ H-NMR spectra were recorded using a Bruker AM 250 or AM 400 spectrometer at a field strength of 250 MHz or 400 MHz. Multiplicities are indicated by the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad signal.

During flash chromatography separations, Merck Silica gel 60 (230 - 400 mesh) adsorbent was used.

SYNTHETIC EXAMPLES

The invention is described in more detail in the following section through examples of the preparation of the compounds. The preparation examples are illustrative only and do not limit the scope or extent of the invention. Temperature values are given in degrees Celsius (°C). All solvents are of the highest possible purity. Unless otherwise indicated, all reactions were carried out under anhydrous conditions under an argon atmosphere.

• · · you

n. ? ,f.

Example 1

Preparation of N-(2-hydroxy-4-nitrophenyl)-Ν'-(2-chlorophenyl)-2T*-cyanoguanidine

a) N-(2-Chlorophenyl)-N-cyanothiourea sodium salt

1.64 g (71.3 mmol) of sodium was dissolved in ethanol. After gas evolution had ceased, 1.685 g (40 mmol) of cyanamide was added to the solution. The reaction mixture was stirred for 15 min, then 7.21 g (42.66 mmol) of (2-chlorophenyl) isothiocyanate was added. The reaction mixture was refluxed for 6 h, then cooled and diluted with methylene chloride. The white precipitate formed was filtered off and dried. 8.26 g of N-(2-chlorophenyl)-^T'-cyanothiourea sodium salt were obtained in 87.5 % yield. MS (ES ⁺ ) m/e 210, 212 [M+H] ⁺ .

b) N-(2-Hydroxy-4-nitrophenyl)-Ν'-(2-chlorophenyl)-ΔT-cyano-

-guanidine

To a solution of 234 mg (1 mmol) of N-(2-chlorophenyl)-N-cyanothiourea sodium salt and 156 mg (1 mmol) of 2-hydroxy-3-nitroaniline in 2 ml of anhydrous N _t N-dimethylformamide under argon atmosphere was added 384 mg (2 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC-HCl), the reaction mixture was stirred at room temperature for 4 days, then partitioned between ethyl acetate and 1 M hydrochloric acid solution. The organic solutions were combined, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The red oil obtained as a residue was chromatographed on silica gel, eluting with a 3:97 acetone/chloroform solvent mixture. 30 mg of a shiny yellow solid was isolated in 9% yield, which was recrystallized from tert-butyl methyl ether to give the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 10.93 (s, 1H), 8.53 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.8 Hz, 2H), 7.38-750 (m, 2H), 7.22 (s, 1H), 7.08 (t, 1H). IR (KBr) 2181 cm' ¹ . MS (ES~) m/e 330 [MH]". Melting point: 163-164 °C.

Example 2

Preparation of N-(2-hydroxy-4-nitrophenyl)-2Γ-(2-bromophenyl)-N”-cyanoguanidine

a) 1-(Allyloxy)-5-cyano-2-nitrobenzene

A mixture of 3.0 g (18.9 mmol) of 5-cyano-2-nitrophenol, 1.82 ml (21.0 mmol) of allyl bromide, 7.39 g (22.7 mmol) of cesium carbonate and 20 ml of N,N-dimethylformamide was stirred at room temperature under an argon atmosphere for 18 hours. The reaction mixture was then partitioned between tert-butyl methyl ether and water. The phases were separated and the aqueous layer was extracted with tert-butyl methyl ether three more times. The organic solutions were combined, washed twice with water and then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure. As a result, 3.89 g of the title compound was obtained in 100% yield. ¹ H-NMR (400 MHz, CDCl3) δ (ppm): 7.87 (d, J = 8.5 Hz, 1H), 7.35 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H), 7.35 (d, J = 1.5 Hz, 1H), 6.02 (m,

1H), 5.52 (d, 1H), 5.43 (d, 1H), 4.73 (dd, J = 3.6 Hz, J = 1.2 Hz, 2H).

b) 2-(Allyloxy)-4-cyanoaniline

A mixture of 3.6 g (17.46 mmol) of 1-(allyloxy)-5-cyano-2-nitrobenzene, 19.7 g (87.3 mmol) of stannous chloride and 100 ml of ethanol was stirred overnight at room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between 5% by weight aqueous sodium bicarbonate solution and ethyl acetate. The mixture was filtered to remove the tin salts, and the aqueous phase was extracted with ethyl acetate four more times. The organic solutions were combined, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The 2.82 g brown solid obtained as a residue was recrystallized from tert-butyl methyl ether/hexane solvent system to give the title compound as a pale brown solid in an amount of 2.63 g (93% yield). MS (ES ⁺ ) m/e 175 [M+H] ; MS (ES ) m/e 173 [MH]'.

c) N-[2-(Allyloxy)-4-cyanophenyl]-Ν'-(2-bromophenyl)thiourea

240 mg (6.0 mol) of a 60% by weight dispersion of sodium hydride in mineral oil was washed with hexane, and then a solution of 522 mg (3 mmol) of 2-(allyloxy)-4-cyanoaniline in 1.5 ml of N,N-dimethylformamide was added to a suspension of sodium hydride in 10 ml of N,N-dimethylformamide cooled to 0 °C. The mixture was stirred under argon for 15 min at 0 °C, and then (2-bromophenyl)isothiocyanate was added dropwise. The reaction mixture was stirred at room temperature for 1 h, and then the reaction was stopped by adding 0.5 M aqueous sodium dihydrogen phosphate solution. The mixture was extracted with ethyl acetate, the organic solutions were combined, washed with water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product obtained as a residue was recrystallized from methanol to give the title compound as a white solid (911 mg, 78%). MS (ES ⁺ ) m/e 388, 390 [M+H].

d) N-[2-(Allyloxy)-4-cyanophenyl]-Ν'-(2-bromophenyl)-

-carbodiimide

To a solution of 900 mg (2.32 mmol) of N-[2-(allyloxy)-4-cyanophenyl]-N’-(2-bromophenyl)thiourea and 1 ml (6.95 mmol) of triethylamine in methylene chloride under argon and cooled to 0 °C was added dropwise 360 μΐ (4.64 mmol) of methanesulfonyl chloride while stirring. The reaction mixture was stirred at 0 °C for 15 min; thin layer chromatography showed no more starting material. The reaction mixture was chromatographed on silica gel using methylene chloride as eluent. The title compound was obtained as a yellow solid in an amount of 1.2 g (> 100 % yield). The product was used in the next reaction without further purification.

e) N- [2-(Allyloxy)-4-cyanophenyl]-Ν'-(2-bromophenyl)-N-

-cyanoguanidine

560 mg (13.33 mmol) cyanamide and 2.6 ml N-ethyldiisopropyl44

-amine in acetonitrile was added dropwise with stirring a solution of 600 mg (1.69 mmol) of N- [2-(allyloxy)-4-cyanophenyl]-Ν’ -(2-bromophenyl)carbodiimide in 30 ml of acetonitrile. The reaction mixture was stirred at room temperature for 15 min, then the solvent was removed under reduced pressure. The residue was hydrolyzed with 0.5 M aqueous sodium dihydrogen phosphate solution, and the aqueous mixture was extracted with ethyl acetate. The organic solutions were combined, washed with 0.5 M aqueous sodium dihydrogen phosphate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. 500 mg of crude product was isolated as a tan solid. The crude product was chromatographed on silica gel, eluting with 50:50 ethyl acetate/hexane, to afford 455 mg of the title compound in 95% yield. MS (ES) m/e 394, 396 [M-H]~.

f) N-(2-Hydroxy-4-nitrophenyl)-Ν'-(2-bromophenyl)-AT-cyanoguanidine

To a mixture of 100 mg (0.25 mmol) of N-[2-(allyloxy)-4-cyanophenyl]-N'-(2-bromophenyl)-N-cyanoguanidine, 20 mg (0.52 mmol) of sodium [tetrahydridoborate](1-) and 3 ml of tetrahydrofuran at room temperature was added 21 mg (7 mol%) of tetrakis(triphenylphosphine)palladium(0). The reaction mixture was stirred at room temperature until the starting compound disappeared from the thin layer chromatogram. The reaction mixture was then partitioned between ethyl acetate and 0.5 M aqueous sodium dihydrogen45 phosphate solution. The organic solutions were combined, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The 100 mg of a brown solid obtained as a residue was subjected to column chromatography on silica gel using a 5:95 methanol/chloroform solvent mixture as eluent. The 64 mg of a pale yellow solid thus isolated was recrystallized from chloroform to give 42 mg of the title compound in 47% yield. ^Ή-ΝΜΚ (400 MHz, DMSO-d ₆ ) 6 (ppm): 10.93 (s, 1H), 9.57 (s, 1H), 8.74(s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 7.8 Hz, 2H), 7.50-7.42 (m, 2H), 7.30-7.26 (m, 2H 7.17 (s, 1H), 7.08 (t, 1H). IR (KBr) 2224, 2193 cm' ¹ . MS (ES~) m/e 354, 356 [MH]. MS (ES ⁺ ) m/e 356, 358 [M+H] ⁺ . Melting point: 175-176 °C.

Example 3

Preparation of N-(4-cyano-2-hydroxyphenyl)-Ν'-phenyl-N”-cyanoguanidine

a) 5-Cyano-1-(methoxymethoxy)-2-nitrobenzene

260 mg (6.5 mmol) of a 60 wt% dispersion of sodium hydride in mineral oil was washed with hexane, and then a solution of 978 mg (5.96 mmol) of 5-cyano-2-nitrophenol in 10 ml of tetrahydrofuran was added dropwise at room temperature to a suspension of sodium hydride in 5 ml of tetrahydrofuran. The solution turned bright orange, and a large amount of precipitate formed. The suspension was stirred at room temperature for 15 min, and then (methoxymethyl) bromide was added dropwise. The reaction mixture was stirred at room temperature for 18 h, after which the yellow mixture was partitioned between tert-butyl methyl ether and water. The aqueous phase was extracted three times with tert-butyl methyl ether, the organic solutions were combined, washed four times with 5% aqueous sodium bicarbonate solution, then once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The title compound was obtained as a pale yellow solid in an amount of 1.05 g (85% yield). Ir-NMR (400 MHz, CDCl3) δ (ppm): 7.84 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 1.4 Hz, 1H), 7.35 (dd, J = 8.4 Hz, J = 1.5 Hz, 1H), 5.34 (s, 2H), 3.55 (s, 3H).

b) 4-Cyano-2-(methoxymethoxy)aniline

A mixture of 0.5 g (2.4 mmol) of 5-cyano-1-(methoxymethoxy)-2-nitrobenzene, 0.05 g of 10 wt% palladium/carbon catalyst and 50 ml of ethyl acetate was stirred at room temperature under atmospheric pressure of hydrogen for 72 h. The reaction mixture was then filtered through celite to remove the catalyst, the filtrate was evaporated, and the residue was chromatographed on silica gel using a 25:75 (v/v) ethyl acetate/hexane mixture as eluent. 250 mg of the title compound was obtained in 58 % yield. MS (ES ⁺ ) m/e 179 [M+H] ⁺ .

c) N-[4-Cyano-2-(methoxymethoxy)-N-phenyl-N"-cyanoguanidine

The title compound was prepared according to the procedures of steps c)-e) of Example 1, except that in this case phenyl isothiocyanate was used instead of (2-bromophenyl) isothiocyanate and 2-(methoxymethoxy)-4-cyanoaniline was used instead of 2-(allyloxy)-4-cyanoaniline. The desired product was obtained in 24% overall yield. IR (KBr) 2226, 2198 cm ¹ . MS (ES~) m/e 320 [MH]”.

d) N-(4-Cyano-2-hydroxyphenyl)-Ν'-phenyl-N-cyano-guanidine mg (0.146 mmol) N- [4-cyano-2-(methoxymethoxy)-Ν'-phenyl-N-cyano-guanidine in 20 ml ethyl acetate was added 10 ml 6 M hydrochloric acid solution, the reaction mixture was stirred for 3 hours at room temperature, then another 5 ml 6 M hydrochloric acid solution was added and stirring was continued for another 2 hours. After that, the reaction mixture was diluted with ethyl acetate, the aqueous phase was extracted five times with ethyl acetate, the organic solutions were combined, dried over anhydrous sodium sulfate and evaporated under vacuum. The 64 mg crude product obtained as a residue was recrystallized from tert-butyl methyl ether to give the title compound as a white solid (2 mg, 5% yield). ¹ H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H), 9.12 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.55 (d, J - 1.2 Hz, 1H), 7.49 (dd, J = 1.2 Hz, J 8.1 Hz, 1H), 7.36 (m, 4H), 7.18 (m, 1H). IR (KBr) 2233, 2192 cm ^-1 . MS (ES ⁺ ) m/e 278 [M+H] ⁺ . MS ( ^ES- ) m/e 276 [MH]. Melting point: 270-271 °C.

Example 4 Preparation of N-(4-cyano-2-hydroxyphenyl)-Ν'-(2,3-dichlorophenyl)-1T'-cyanoguanidine

The title compound was prepared according to the procedures of steps a)-e) of Example 1, except that (2,3-dichlorophenyl)isothiocyanate was used instead of (2-bromophenyl)isothiocyanate. The desired product was obtained in 17% overall yield. IR (KBr) 2231, 2197 cm . MS (ES ⁺ ) m/e 346, 348, 350 [M+H] ⁺ . MS (ES ^- ) m/e 344, 346, 347, 348 [MH] ^- . Melting point: 155-156 °C.

Example 5

Preparation of N-(2-bromophenyl)-Ν'-(4-cyano-2-hydroxy-3-propylphenyl)-N'-cyanoguanidine

a) 2-Amino-5-cyano-6-(prop-1-en-3-yl)-phenol

1.88 g (1.29 mmol) of the product from step b) of Example 2 was added with 20 ml of N, N-dimethylaniline under an argon atmosphere, and the reaction mixture was kept in an oil bath at 175 °C for 3.5 hours. The solvent was then removed under vacuum and the residue was recrystallized from tert-butyl methyl ether containing 10-20% methylene dichloride and hexane. As a result, the title compound was obtained as a pure solid in an amount of 1.67 g (89% yield). MS (ES ⁺ ) m/e 175 [M+H] ⁺ . MS (ES) m/e 173 [MH]”.

b) 2-Amino-5-cyano-6-propylphenol

A mixture of 0.5 g (2.4 mmol) of 2-amino-5-cyano-6-(prop-1-en-3-yl)-phenol, 0.05 g of 10 wt% palladium/carbon catalyst and 50 ml of ethyl acetate was stirred under atmospheric pressure of hydrogen at room temperature for 2 h. The reaction mixture was then filtered through celite to remove the catalyst and the filtrate was evaporated. The title compound was obtained as a pale pink solid in an amount of 1.2 g (78 % yield). MS (ES ) m/e 177 [M+H] . MS (ES ) m/e 175

[M-H] .

c) N-(2-Bromophenyl)-Ν'-(4-cyano-2-hydroxy-3-propylphenyl)-N-cyanoguanidine

The title compound was prepared according to the procedures of steps a)-e) of Example 2, except that in this case 2-amino-5cyano-6-propylphenol was used instead of 5-cyano-2-nitrophenol. The desired product was obtained in 37% overall yield. ¹ H-NMR (400 MHz, DMSO-d6) δ (ppm) : 9.72 (s, 1H), 9.45 (s, 1H), 8.66 (s, 1H), 7.71 (d, J = 7.0 Hz,

1H), 7.56 (d, J = 8.4 Hz, 1H), 7.45 (m, 2H)/7.28 (d, J = 8.4

Hz, 1H), 7.26 (t, 1H), 2.76 (t, J - 7.5, 2H), 1.55 (hextet, J = 7.6, 2H), 0.93 (t, J - 7.3, 3H). IR (KBr) 2224, 2184 cm ^-1 . MS (ES ⁺ ) m/e 398, 400 [M+H] ⁺ . MS (ES ^- ) m/e 396, 398 [MH].

Example 6

Preparation of N-(4-cyano-2-hydroxy-3-propylphenyl)-N’-(2,3-dichlorophenyl)-JT’-cyanoguanidine

The title compound was prepared according to the procedures of steps b)-e) of Example 1, except that in this case (2,3-dichlorophenyl)isothiocyanate was used instead of (2-bromophenyl)isothiocyanate and 2-(allyloxy)-4-cyano-3-propylaniline was used instead of 2-(allyloxy)-4-cyano-3-propylaniline. The desired product was obtained in 7% overall yield. IR (KBr) 2236, 2182 cm ^-1 . MS (ES ⁺ ) m/e 388, 390, 391 [M+H] ⁺ . MS (ES~) m/e 386, 388, 390 [MH]". Melting point: 143-147 °C.

Example 7

Preparation of N-(2-chlorophenyl)-Ν'-(4-cyano-2-hydroxy-3-propylphenyl)-N-cyanoguanidine

The title compound was prepared according to the procedures of Example 1, steps b) -e), except that in this case (2-chloro-phenyl)-isothiocyanate was used instead of (2-bromo-phenyl)-isothiocyanate, and 2-(allyl-oxy)-4-cyano-3-propyl-aniline was used instead of 2-(allyl-oxy)-4-cyano-3-propyl-aniline. The desired product was obtained in 26% overall yield. IR (KBr) 2225, 2187 cm* ¹ . MS (ES ⁺ ) m/e 354, 356 [M+H] ⁺ . MS (ES ) m/e 352/ 354 [MH]. Melting point: 159-160 °C.

Example 8

Preparation of IT-(2-bromophenyl)-Ν'-(4-cyano-2-hydroxy-3-isobutylphenyl)-N-cyanoguanidine

The title compound was prepared according to the procedures of Example 4, steps a)-c), except that 3-bromo-2-methyl-1-propene was used instead of allyl bromide. The desired product was obtained in 16% overall yield. IR (KBr) 2231, 2189 cm ¹ . MS (ES ⁺ ) m/e 412, 414 [M+H] ⁺ . MS (ES~) m/e 410, 412 [MH] .

Example 9

Preparation of N-(2-bromophenyl)-Ν'-(3-bromo-4-cyano-2-hydroxyphenyl)-N'-cyanoguanidine

a) 2-Bromo-3-hydroxy-4-nitrobenzonitrile

To a solution of 3.03 g (18.4 mmol) of 3-hydroxy-4-nitrobenzonitrile in 660 ml of hexamethylenetetramine was added 9.91 g (26.0 mmol) of hydrogen tribromide (1:1). The solution was stirred at room temperature for one week, then acidified with 1 M hydrochloric acid and extracted with a 1:1 ethyl acetate/hexane solvent mixture. The organic solutions were combined, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The solid obtained as a residue was chromatographed on silica gel, eluting with a 1:1 hexane/ethyl acetate solvent mixture. 1.47 g of the desired product was obtained in 35.0 % yield. MS (ES~) m/e 241, 243 [M-H].

b) N-(2-Bromophenyl)-N*-(3-br6m-4-cyano-2-hydroxyphenyl)-N-cyanoguanidine

The title compound was prepared according to the procedures of steps a)-e) of Example 2, except that 2-bromo-3-hydroxy-4-nitrobenzonitrile was used instead of 5-cyano-2-nitrophenol. After chromatographic purification, the desired product was obtained in a total yield of 44% and after recrystallization in a total yield of 15%. Off-white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.66 (s, 1H), 9.56 (s, 1H), 8.92 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.48-7.41 (m, 3H), 7.26 (t, 1H). IR (KBr) 2228, 2186 cm ^-1 . MS (ES ⁺ ) m/e 434, 436, 438 [M+H] ⁺ . MS (ES-) m/e 432, 434, 436 [MH]". Melting point: 142°C.

Example 10

Preparation of N-(3-bromo-4-cyano-2-hydroxyphenyl)-Ν’-[2,3-(methylenedioxy)phenyl]-N”-cyanoguanidine

The title compound was prepared according to the procedures of Example 8, steps a)-b), except that [2,3-(methylenedioxy)phenyl]isothiocyanate was used instead of (2-bromophenyl)isothiocyanate. The title compound was obtained in 14% overall yield. IR (KBr) 2230, 2196 cm ^-1 . MS (ES ⁺ ) m/e 400, 402 [M+H] ⁺ . MS (ES ^- ) m/e 398, 400 [MH]~. Melting point: 164-165°C.

Example 11

Preparation of N-(2-bromophenyl)-N-[4-cyano-2-hydroxy-3-(methoxycarbonyl)phenyl]-N-cyanoguanidine

a) Methyl 2,6-dihydroxybenzoate

A mixture of 10.00 g (333.3 mmol) of 80 wt% sodium hydride dispersion in mineral oil and 45 ml of N,N-dimethylformamide was cooled to 0 °C under an argon atmosphere, and then a solution of 48.88 g (317.1 mmol) of 2,6-dihydroxybenzoic acid in 50 ml of N,N-dimethylformamide was slowly added over 45 min. The mixture was stirred for 45 min, and then 21.0 ml (337 mmol) of methyl iodide was added over 20 min. The resulting solution was stirred at room temperature for 70 h, then diluted with methylene dichloride, and the solution was filtered through a silica gel pad. The silica gel was washed with methylene dichloride, and the solvent was evaporated from the filtrate. 35.22 g of the desired product were obtained in 66.1% yield. ¹ H-NMR (250 MHz, DMSO-d ₆ ) δ (ppm): 9.91 (s, 2H), 7.09 (t, J = 1.2 Hz, J = 2.5 Hz, 1H), 6.37 (d, J = 1, 1 Hz, 2H), 3.78 (s, 3H).

b) Methyl 2-(benzyloxy)-6-hydroxybenzoate

To a solution of 20.00 g (118.9 mmol) of methyl 2,6-dihydroxybenzoate in 100 ml of N,N-dimethylformamide under an argon atmosphere, 3.9144 g (130.5 mmol) of 80% sodium hydride dispersion in mineral oil were added first, followed by 25.5 ml (214.5 mmol) of benzyl bromide. The solution was heated at 701 °C for 20 hours, then cooled, and saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, the organic solutions were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated from the filtrate. The solid obtained as a residue was chromatographed on silica gel using a 95:5 hexane/ethyl acetate solvent mixture as eluent. 16.71 g of the desired product was obtained in 54.4% yield. MS (ES“) m/e 257 [M-H]“.

c) Methyl 2-(benzyloxy)-6-cyanobenzoate

To a solution of 2.730 g (10.6 mmol) of methyl 2-(benzyloxy)-6-hydroxybenzoate in 28.5 ml of methylene chloride and cooled to 0 °C under an argon atmosphere were added 4.5424 g (12.7 mmol) of N-phenyl-(trifluoromethanesulfonimide) and 1.62 ml (11.6 mmol) of triethylamine. The reaction mixture was warmed to room temperature, stirred for 14 hours, and then diluted with diethyl ether. The solution was washed with water, 5% by weight aqueous sodium hydroxide solution, and saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated. 4.476 g of crude triflate was obtained in 108% yield. ¹ H-NMR (250 MHz, CDCl 3 ) δ (ppm): 7.35 (m, 6H), 6.95 (m, 2H), 5.16 (s, 2H), 3.94 (s, 3H).

• · » · 55 -

e) Methyl 6-cyano-2-hydroxy-3-nitrobenzoate

To a suspension of 1.1428 g (6.45 mmol) of methyl 6-cyano-2-hydroxybenzoate and 21 ml of acetic anhydride cooled to 0 °C was added dropwise 0.41 ml (6.44 mmol) of concentrated nitric acid. The reaction mixture was allowed to warm to room temperature, while all the starting materials dissolved. The solution was stirred for 36 h, then poured into water, and the aqueous mixture was extracted with ethyl acetate. The organic solutions were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The solid obtained as a residue was chromatographed on silica gel, using a 70:30:1 hexane/ethyl acetate/acetic acid solvent mixture as the eluent. 0.50 g of the desired product was obtained in a yield of 35.7%. MS (ES) m/e 221 [M-H].

f) Methyl 3-amino-6-cyano-2-hydroxybenzoate

To a solution of 402 mg (1.81 mmol) of methyl 6-cyano-2-hydroxy-3-nitrobenzoate in 40 mL of ethyl acetate under argon was added 0.23 g of 10 wt% palladium/carbon catalyst. The flask was flushed with hydrogen, and the reaction mixture was stirred under balloon pressure of hydrogen for 2 h at room temperature. The flask was then flushed with argon, and the solution was filtered through celite. The solvent was evaporated from the filtrate to give the desired product (334 mg, 96.0 % yield). MS (ES ) m/e 192 [M-H] .

g) N-(2-Bromophenyl)-Ν'-[4-cyano-2-hydroxy-3-(methoxy-

-carbonyl)phenyl]-N-cyanoguanidine

The title compound was prepared according to the procedures of steps a)-e) of Example 2, except that methyl 3-amino-6-cyano-2-hydroxybenzoate was used instead of 5-cyano-2-nitrophenol, and the desired product was obtained in a total yield of 19%. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 11.08 (s, 1H), 9.69 (s, 1H), 8.89 (s, 1H), 7.99 (d, J = 8.40 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.50-7.42 (m, 3H), 7.28 (t, 1H). IR (KBr) 2228, 2186 cm ^-1 . IR (KBr) 2225, 2177 cm ^-1 . MS (ES”) m/e 412, 414 [MH]. Melting point: 210-211 °C. ✓

TREATMENT PROCEDURES

The compounds of formula (I) and their pharmaceutically acceptable salts can be used in the manufacture of pharmaceutical compositions for the prophylactic or therapeutic treatment of diseases in humans or other mammals which are aggravated or caused by excessive or unregulated IL-8 cytokine production by mammalian cells, such as monocytes and/or macrophages, or other chemokines that bind to the IL-8a or IL-δβ receptor, also known as type I or type II receptor.

Accordingly, the invention provides a method for treating chemokine-mediated diseases, wherein the chemokine is a chemokine that binds to an IL-8α or IL-δβ receptor, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In particular, the chemokine is IL-8, GROα, 6Η0β, GROγ, ENA-78 or NAP-2.

The compounds of formula (I) are administered in an amount sufficient to enhance cytokine function, particularly IL-8,

T-cell infiltration or neovascular growth. In all of these diseases, there is increased production of IL-8, GROa, GROP, GROy or NAP-2, which are responsible for neutrophil chemotaxis to the site of inflammation or directional endothelial cell growth. In contrast to other inflammatory cytokines (IL-1, TNF and IL-6), IL-8, GROa, GROP, GROy or NAP-2 have the unique property of promoting neutrophil chemotaxis, enzyme release, including elastase release, and superoxide production and activation. α-Chemokines, and in particular GROa, GROP, GROy or NAP-2, acting through IL-8 type I or II receptors, may promote neovascularization of tumors by promoting directional endothelial cell growth. Accordingly, inhibition of IL-8-induced chemotaxis or activation may directly reduce neutrophil infiltration.

Recently, chemokines have been shown to play a role in the treatment of HIV infections [Littleman et al., Nature, 661 (1996); and Koup et al., Nature, 667 (1996)].

The invention provides the opportunity to treat acute central nervous system injuries through the chemokine receptor antagonist compounds of general formula (I), and also to prevent central nervous system injuries in individuals at increased risk of central nervous system injuries.

The term central nervous system injury as used herein refers to open and penetrating head injury, such as surgical or closed head trauma. The term also includes ischemic stroke, particularly cerebral injury. Compounds of formula (I) are inhibitors of IL-8 binding, based on the effects of compounds of formula (I) in in vitro receptor binding assays described below. Compounds of formula (I) are dual inhibitors of recombinant type I and type II IL-8 receptors. Preferably, the compounds are inhibitors of only one receptor, more preferably the type II receptor.

As used herein, the term IL-8-mediated disease or condition refers to any and all disease states in which IL-8, GROa, GROP, GROy, ENA-78 or NAP-2 plays a role, either through the production of IL-8, GROa, GROP, GROy, NAP-2 or ENA-78 itself, or through the release of other monokines, such as IL-1, IL-6 or TNF, among others. Accordingly, an IL-8-mediated disease state also includes, for example, a disease state in which IL-1 is the primary component, the production or action of which is accomplished or secreted in response to IL-8.

The term chemokine-mediated disease or condition as used herein refers to any and all disease states in which a chemokine that binds to an IL-8α or IL-δβ receptor plays a role, such as, but not limited to, IL-8, GROα, GROP, GROγ, NAP-2, or ENA-78. This includes a disease in which IL-8 plays a role, either through the production of IL-8 itself or through IL-8 causing the release of other monokines, such as, but not limited to, IL-1, IL-6, or TNF. Accordingly, an IL-8-mediated disease state is also contemplated, for example, a disease state in which IL-1 is the primary component of the production or action of IL-1 that is accomplished or secreted in response to IL-8.

The term cytokine as used herein includes any secreted polypeptide that affects the functional activity of cells and is a molecule that modifies cell-cell interactions in immune, inflammatory or hematopoietic responses. Cytokines include, but are not limited to, monokines and lymphokines, regardless of the cell that produces them. For example, a monokine is typically produced and secreted by a mononuclear cell, such as a macrophage and/or a monocyte. However, many other cells also produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes and B lymphocytes. Lymphokines are typically produced by lymphocyte cells. Examples of cytokines include, but are not limited to, interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α), and tumor necrosis factor-beta (TNF-β).

The term chemokine as used herein includes any secreted polypeptide that affects the functional function of cells in a manner similar to that of cytokines as defined above and is a molecule that modulates cell-cell interactions in immune, inflammatory or hematopoietic responses. Chemokines are primarily secreted across cell transmembranes; chemokines cause chemotaxis and activation of specific white blood cells and leukocytes, neutrophils, monocytes, macrophages, T cells, B cells, endothelial cells and smooth muscle cells. Examples of chemokines include, but are not limited to, the following: IL-8, GROa, GROP, GROy, NAP-2, ENA-78, IP-10, MΙΡ-Ια, MΙΡ-β, PF4, and MCP 1, 2 and 3.

For the pharmaceutical use of the compounds of formula (I), the compounds are formulated into pharmaceutical compositions according to standard pharmaceutical practice. The invention also includes a pharmaceutical composition comprising an effective, non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.

The compounds of formula (I), their pharmaceutically acceptable salts and pharmaceutical compositions containing the compounds may be administered by any of the conventional methods for administering active ingredients, for example, orally, topically, parenterally or by inhalation. The compounds of formula (I) may be administered in conventional dosage forms which may be prepared by admixing a compound of formula (I) with a standard pharmaceutical carrier according to conventional formulation techniques. The compounds of formula (I) may also be administered in conventional dosage forms in combination with a second known pharmaceutically active compound. In the formulation techniques, the ingredients may be mixed, granulated and compressed or dissolved according to the desired formulation. It is to be noted that the form and nature of the pharmaceutically acceptable carrier or diluent will be determined by the amount of active ingredient to be employed, the route of administration chosen and other well-known circumstances. The carrier must be acceptable in the sense that the carrier must be compatible with the other ingredients of the composition and not deleterious to the recipient.

The pharmaceutical carrier employed may be, for example, solid or liquid. Examples of solid carriers include, but are not limited to, lactose, gypsum, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, etc. Examples of liquid carriers include, but are not limited to, sugar syrup, peanut oil, olive oil, etc. Similarly, the carrier or diluent may also contain a time-delaying agent well known in the art, such as glyceryl monostearate or glyceryl distearate alone or in combination with a wax.

A wide variety of pharmaceutical forms may be used. For example, if a solid carrier is used, the composition may be tableted, placed in a hard gelatin capsule, administered in the form of a powder or pellet, or in the form of a wafer or lozenge. The amount of solid carrier may vary widely, but is preferably from about 25 mg to about 1 g. If a liquid carrier is used, the composition may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid (e.g., ampoule), or nonaqueous liquid suspension.

The compounds of formula (I) may also be administered topically; topical administration is a non-systemic form of administration. This involves applying a compound of formula (I) externally to the epidermis or within the oral cavity, or instilling the compound into the eyes, ears, and nose. In such administration, the compound does not enter the bloodstream in significant amounts. In contrast, systemic administration includes oral, intravenous, intraperitoneal, and intramuscular administration.

Compositions suitable for topical administration include liquid or semi-solid compositions such as liniments, lotions, creams, ointments or pastes which are capable of penetrating the skin to reach the site of inflammation, and drops suitable for administration to the eyes, ears and nose. For topical administration, the amount of active ingredient based on the weight of the composition is between 0.001% and 10% by weight, for example 1-2% by weight. The composition may contain up to 10% by weight of active ingredient, but preferably the concentration of active ingredient in the composition is less than 5% by weight, more preferably between 0.1% and 1% by weight.

The lotions of the invention are suitable for application to the skin or to the eyes. An ophthalmic lotion may consist of a sterile aqueous solution, optionally containing a bactericidal agent. Such a preparation may be prepared in a manner similar to that used for the formulation of drops. Lotions or liniments for application to the skin may also contain drying and cooling agents, such as alcohol or acetone, and/or a humectant, such as glycerine or an oil, such as castor oil or arachis oil (peanut oil).

The creams, ointments and pastes according to the invention are semi-solid preparations for the external application of the active ingredient. They can be prepared by mixing the active ingredient, either in finely divided or powdered form, alone or as a solution or suspension in an aqueous or non-aqueous liquid, with a fatty or non-fatty base using a suitable apparatus. The said base may contain, for example, the following: hydrocarbons, such as hard, soft or liquid paraffin, glycerin, beeswax, metallic soap; adhesive; oil of natural origin, such as almond, corn, arachis (peanut), castor or olive oil; wool fat or its derivatives or a fatty acid, such as stearic acid or oleic acid, together with an alcohol, such as propylene glycol, or a macrogel. The composition may also contain suitable surfactants, such as an anionic, cationic or nonionic surfactant, such as a sorbitan ester or a poly(oxyethylene) derivative thereof. The composition may also contain suspending agents, such as natural gums, cellulose derivatives or inorganic materials, such as silicic acids, and other ingredients, such as lanolin.

The drops according to the invention may consist of sterile aqueous or oily solutions or suspensions which may be prepared by dissolving the active ingredient in a suitable aqueous solution containing a bactericidal and/or fungicidal active ingredient and/or any other suitable preservative, preferably a surfactant. The solution thus obtained may be filtered and then placed in a suitable container which is then sealed and sterilized in an autoclave or at 98-100°C for 30 minutes. Alternatively, the solution may be sterilized by filtration and the resulting solution filled into the container under aseptic conditions. Examples of bactericidal and fungicidal active ingredients suitable for use in drops include, but are not limited to, phenylmercury(II) nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Solvents suitable for preparing oily solutions include glycerin, diluted alcohol, and propylene glycol.

The compounds of formula (I) may be administered parenterally, i.e. intravenously, intramuscularly, subcutaneously, intranasally, intrarectally, intravaginally or intraperitoneally. Preferred routes of parenteral administration include subcutaneous and intramuscular administration. Dosage forms suitable for such administration may be prepared using conventional methods. The compounds of formula (I) may also be administered by inhalation, e.g. intranasally and orally. Dosage forms suitable for such administration, e.g. aerosol formulations and dosage forms, may be prepared using conventional methods.

In all methods of use of the compounds of formula (I) described herein, the daily oral dose is from about 0.01 mg to about 80 mg per kilogram of body weight. The daily parenteral dose is from about 0.001 mg to about 80 mg per kilogram of body weight. The daily topical dose is preferably from about 0.1 mg to about 150 mg, administered one to four times per day, preferably two or three times per day. The daily inhalation dose is preferably from about 0.01 mg to about 1 mg per kilogram of body weight. It will be apparent to those skilled in the art that the optimum amount and frequency of individual administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition to be treated, the form, route and site of administration, and the condition of the patient to be treated. Such optimum values may be determined by conventional methods. It is also apparent to one skilled in the art that the optimal regimen, i.e., the number of doses to be administered per day, and the number of days of treatment, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, can be determined by one skilled in the art using conventional treatment determination tests.

The invention is described in more detail in the following section through biological examples. The biological examples are illustrative only and do not limit the scope or extent of the invention.

BIOLOGICAL EXAMPLES

The IL-8 and GROa inhibitory effects of the compounds of the invention were determined by the following in vitro assay.

Receptor binding assays

The experiment was performed using 2000 Ci/mmol specific activity human recombinant [I]IL-8 (Amersham Corp., Arlington Heights, Illinois, United States) and GROa (NEN - New England Nuclear). All other chemicals were of analytical grade. Large amounts of recombinant human IL-8a and IL-δβ receptors were expressed individually in golden hamster ovary cells as known (Holmes et al., Science, 253, 1278 (1991)). Golden hamster ovary membranes were homogenized as known (Haour et al., J. Biol. Chem. , 249, 2195-2205 (1974)). The only difference from the known solution was that the homogenization buffer was replaced with a buffer containing 10 mM Tris-HCl, 1 mM magnesium sulfate, 0.5 mM EDTA (ethylenediaminetetraacetic acid), 1 mM MPMSF (α-toluenesulfonyl fluoride), 0.5 mg/liter Leupeptin, pH 7.5. The membrane protein concentration was determined using a Pierce Co. microassay kit (kit) using bovine serum albumin as a standard. All assays were performed in 96-well microplates. Each reaction mixture contained the following components: 0.25 nM I-IL-8 or ¹²⁵ I-GROa, and 0.5 ug/ml IL-8Ra or 1.0 μg/ml IL-8Rb membrane, in 200 mM Bis-Trisporane and 0.4 mM Tris-HCl buffer containing 1.2 mM magnesium sulfate, 0.1 mM EDTA, 25 mM sodium chloride, and 0.03% CHAPS. In addition to the above, the drug or compound to be tested, previously dissolved in dimethyl sulfoxide, was added.

John, Maryland, United States of America). The two chambers were separated by a 5 μm polycarbonate filter. When testing compounds of the invention, the compounds were mixed with the cells (0.001-1000 nM) immediately before the cells were placed in the upper chamber. The cells were incubated in a humidified incubator containing 5% carbon dioxide for approximately 45-90 minutes. At the end of the incubation period, the polycarbamate membrane was removed, the upper side was washed, and the membrane was stained with Diff Quick (Baxter Products, McGaw Park, Illinois, United States of America). Cells chemotactically for the chemokine were counted visually using a microscope. Typically, four fields were counted for each sample, and the numbers thus obtained were averaged to obtain the average number of migrated cells. All samples were tested in triplicate and all compounds were tested at least four times. Certain cells were not treated with a compound of the invention (positive control); these cells showed the maximal chemotactic response. When a negative (unstimulated) control was required, no chemokine was added to the lower chamber. The difference between the positive control and the negative control indicates the chemotactic activity of the cells.

Elastase release assay

The compounds of the invention were also tested for their ability to inhibit elastase release from human neutrophils. Human blood was prepared in a standard manner (Current Protocols in Immunology, vol. I,

Suppl. 1, Unit 7.23.1.) neutrophils were isolated. PMN cells (0.88-10 ⁶ ) were suspended in Ringer's solution (NaCl 118, KC1 4.56, NHCO3 25, KH2PO4 1.03, glucose 11.1, HEPES 5 mM, pH 7.4) and 50 μΐ of the suspension were placed in each well of a 96-well plate. 50 μΐ (0.001-1000 nM) of test compound, 50 μΐ (20 μg/ml) of Cytochalasin Bt and 50 μΐ of Ringer's buffer were added to the plate. The cells were incubated at 37 °C, 5% CO2, and 95% relative humidity, and IL-8, GROa, GROp, GROy, and NAP-2 were added to the cells at final concentrations ranging from 0.01 to 1000 nM. After 45 min, the plates were centrifuged at 800 g for 5 min, and 100 μΐ of supernatant was removed from each well. The supernatant was transferred to a second 96-well plate, and a solution of an artificial elastase substrate [MeOSuc-Ala-Ala-Pro-Val-AMC (Nova Biochem, La Jolla, California, USA)] in phosphate-buffered saline was added to the wells at a final concentration of 6 μg/ml. The plates were immediately placed in a fluorescent 96-well plate reader (Cytofluor 2350, Millipore, Bedford, Massachusetts, USA) and data were collected every three minutes as described previously [Nakajima et al., J. Biol. Chem., 254, 4027 (1979)]. The amount of elastase released from PMN cells was calculated by measuring the rate of MeOSuc-Ala-Ala-Pro-Val-AMC degradation.

TNF-α testing in traumatic brain injury

In this study, we determined the mRNA expression of tumor necrosis factor in specific brain regions following experimentally induced lateral fluid percussion traumatic brain injury (TBI) in rats. Adult Sprague-Dawley rats (n = 42) were anesthetized with 60 mg/kg intraperitoneal sodium pentobarbital, and then we inflicted a moderate (2.4 atm.) lateral fluid percussion traumatic brain injury (n = 18) centered over the left temporoparietal cortex, or we subjected the animals (n = 18) to sham treatment (anesthesia and no injury). The animals were killed by decapitation at 1, 6, and 24 hours after the injury, the brains were removed, and tissue samples were prepared from the following parts: left (injured) parietal cortex (LC); the same part of the contralateral right cortex (RC); the cortex adjacent to the injured parietal cortex (LA); the corresponding adjacent area in the right cortex (RA); the left hippocampus (LH); and the right hippocampus (RH). Total RNA was isolated, Northern-blot hybridization was performed, and relative quantification was performed with respect to a TNF-α positive control RNA (macrophage = 100%). One hour after injury, a significant increase in TNF-α mRNA expression was observed in the traumatized hemisphere in the LH sample (104 ± 17% of the positive control, p < 0.05 compared to sham), in the LC sample (105 ± 21%, p < 0.05), and in the LA sample (69 ± 8%, p < 0.01). Six hours after injury, we observed an increase in TNF-α mRNA expression in the LH sample (46 ± 8%, p < 0.05), the LC sample (30 ± 3%, p < 0.01), and the LA sample (32 ± 8%, p < 0.01), which returned to normal 24 hours after injury. In the contralateral hemisphere, we observed an increase in TNF-α mRNA expression one hour after injury in the RH sample (46 ± 2%, p < 0.01), the RC sample (4 ± 3%), and the RA sample (22 ± 8%), six hours after injury in the RH sample (28 ± 11%), the RC sample (7 ± 5%), and the RA sample (26 ± 6%), but no abnormal values were observed in this area 24 hours after injury. No consistent changes in TNF-α mRNA expression were observed in any of the six brains examined in sham-operated (non-injury) or natural (untreated) animals at the aforementioned time points. These results indicate that TNF-α mRNA expression is transiently altered in specific brain regions, including specific brain regions of the non-traumatized hemisphere, following parasagittal fluid percussion brain injury. Since TNF-α is capable of inducing nerve growth factor (NGF) and stimulating the release of other cytokines from activated astrocytes, posttraumatic changes in TNF-α gene expression play a significant role in the acute and regenerative response to CNS trauma.

IL-β mRNA central nervous system injury model

In this study, we determined the mRNA expression of interleukin-ΐβ (IL-Ιβ) in specific brain regions following experimentally induced lateral fluid percussion traumatic brain injury (TBI) in rats. Adult Sprague-Dawley rats (n = 42) were anesthetized with 60 mg/kg intraperitoneal sodium pentobarbital, and then we induced a moderate (2.4 atm.) lateral fluid percussion traumatic brain injury (n = 18) centered over the left temporoparietal cortex, or we subjected the animals (n = 18) to sham treatment (anesthesia and no injury). Animals were sacrificed by decapitation at 1, 6, and 24 hours after the procedure, brains were removed, and tissue samples were prepared from the following areas: left (injured) parietal cortex (LC); the same part of the contralateral right cortex (RC)/cortex adjacent to the injured parietal cortex (LA); the corresponding adjacent area in the right cortex (RA); left hippocampus (LH); and right hippocampus (RH). Total RNA was isolated, Northern-blot hybridization was performed, and relative quantification of IL-Ιβ mRNA in brain tissue was performed based on the percentage radioactivity of IL-Ιβ positive macrophage RNA located on the same gel. One hour after brain injury, a significant and significant increase in IL-Ιβ mRNA expression was observed in the traumatized hemisphere in the LC sample (20.0 ± 0.7% of positive control, n = 6, p < 0.05 compared to sham), in the LH sample (24.5 ± 0.9%, p < 0.05), and in the LA sample (21.5 ± 3.1%, p < 0.05). Six hours after injury, even higher values were observed in the LC sample (4.0 ± 0.4%, n = 6, p < 0.05) and in the LH sample (5.0 ± 1.3%, p < 0.05). In sham-treated (non-injury intervention) or natural (untreated) animals, no IL-Ιβ mRNA expression was observed in any of the areas examined.

These results indicate that IL-Ιβ mRNA expression is transiently regionally stimulated in specific brain regions following traumatic brain injury (TBI) with parasagittal fluid percussion. These regional changes in cytokines, including IL-1β, may play a role in the post-traumatic pathological or regenerative consequences of brain injury.

The above description fully describes the invention, including the preferred embodiments. Modifications and improvements of the embodiments described in detail are also within the scope of the invention. In our opinion, a person skilled in the art can use the invention to its full extent based on the above description. The examples are illustrative only and do not limit the scope or scope of the invention in any way. The scope or scope of the invention is defined by the appended patent claims.

Claims (36)

PATENT CLAIMS 1. A compound of general formula (I) has .ZN Λ ^W— NH (CR ₁₃ R, ₄ )v —W, Π (i> — in the formula of which Z is cyano, -ORn, -C(0)NR15R16, -R18/ a group of the general formula -C(O)Rn, -C(O)ORn or -S(O)2R17; R is a functional group having an ionizable hydrogen atom and a pKa value of at most 10; R1 is independently hydrogen; halogen; nitro; cyano; C1-10 alkyl; C1-10 haloalkyl; C2-10 alkenyl; C1-10 alkoxy; C1-10 haloalkoxy; azido; - (CRgRs) _qS (0)tR4; hydroxy; C1-4 hydroxyalkyl; aryl; aryl-(C1-4 alkyl) group; aryloxy; aryl-(C1-4 alkoxy) group; heteroaryl; heteroarylalkyl; heterocyclic; C1-4 alkyl substituted with heterocyclic; heteroaryl-(C1-4 alkoxy) group; aryl-(C2-10 alkenyl)-group; heteroaryl-(C2-10 alkenyl)-tube77 port; heterocyclic substituted C2-10 alkenyl group; - (CR ₈ R ₈ ) _q NR4Rs; -(C2-10 alkenyl)-C(O)NR ₄ Rs; - (CR ₈ R ₈ ) _q C (0) NR4R5; - (CR ₈ R ₈ ) _q C (0) NR4R10 group; sulfo group; -S(O)3R ₈ ; - (CR ₈ R ₈ ) _q C (0) Rn; -(C2-10 alkenyl) -C (0) Rn; -(C2-10 alkenyl)-C(0)OR11; - (CR ₈ R ₈ ) qC (0) OR12; - (CR ₈ R ₈ )qOC(O)Rn; - (CR ₈ R ₈ ) _q NR ₄ C (O) Rn; -(CR ₈ R ₈ ) _q NHS(O) ₂ R19; - (CR ₈ R ₈ ) qS (0) 2NR4R5; or two R1 groups together may form a group of the general formula -0-(CH2)s-0- or a five- or six-membered, saturated or unsaturated cyclic group; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; t is 0, 1 or 2; s has the value 1, 2 or 3; v is 0, 1, 2, 3 or 4; R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl-(C1-4 alkyl), optionally substituted heteroaryl, optionally substituted heteroaryl-(C1-4 alkyl), heterocyclic, C1-4 alkyl substituted with heterocyclic, or R ₄ and R 5 together with the nitrogen atom to which they are attached form a 5-7 membered cyclic group optionally containing an additional heteroatom selected from oxygen, nitrogen and sulfur; Y is hydrogen; halogen; nitro; cyano; C1-10 alkyl; C1-10 haloalkyl; C2-10 alkenyl; C1-10 alkoxy; C1-10 haloalkoxy; azido; - (CR ₈ Re) _g S (0) tR4>hydroxy; C1-4 hydroxyalkyl; aryl; aryl-(C1-4 alkyl) group; aryloxy; aryl-(C1-4 alkoxy) group; heteroaryl; heteroarylalkyl; heteroaryl-(C1-4 alkoxy) group; heterocyclic; heterocyclic substituted C1-4 alkyl; aryl-(C2-10 alkenyl) group; heteroaryl-(C2-C10 alkenyl) group; heterocyclic substituted C2-C10 alkenyl group; - (CRsRe)qNR4Rs; -(C2-10 alkenyl)-C(O)NR4R5; - (CReRe) qC (0) NR4R5; - (CReRe) qC (0) NR4R10 group; sulfo group; -S(O)3Re; - (CReRe) qC (0) Rm -(C2-10 alkenyl)-C(0)Rn; -(C2-10 alkenyl) -C(0) ORn; -C(0)Rn; - (CRsRs) qC (0) OR12; - (CRsR8)qOC(O)Rn; - (CRsRs)qNR4C (0)Rn; - (CRsRe)qNHS (O) 2 Rd/ - (CRsRe)qS (0) 2NR4R5; or two Y groups together may form a group of the general formula -O-(CH2) _S ~O- or a five- or six-membered unsaturated cyclic group; n is 1, 2 or 3; m is 1, 2 or 3; R 6 and R 7 are independently hydrogen or 1-4 Λ. 4. ? a carbon alkyl group, or R ₆ and R 7 together with the nitrogen atom to which they are attached form a 5-7 membered cyclic group, optionally containing an additional heteroatom selected from oxygen, nitrogen and sulfur; Re represents a hydrogen atom or a C1-C4 alkyl group; R10 is a group of the general formula -(C1-C10 alkyl)-C(O)2R8; R11 represents a hydrogen atom, a C1-C4 alkyl group, an optionally substituted aryl group, an optionally substituted aryl-(C1-C4 alkyl) group, an optionally substituted heteroaryl group, an optionally substituted heteroaryl-(C1-C4 alkyl) group, an optionally substituted heterocyclic group, or a C1-C4 alkyl group optionally substituted with a substituted heterocyclic group; R12 represents a hydrogen atom, a C1-C10 alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group; R13 and R14 are independently hydrogen or optionally substituted C1-4 alkyl, or one of R13 and R14 is optionally substituted aryl; R15 and R16 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl-(C1-4 alkyl), each optionally substituted; Rd is a group of the general formula -NRgR?, alkyl, aryl-(C1-C4 alkyl), aryl-(C2-C4 alkenyl), heteroaryl, heteroaryl-(C1-C4 alkyl), heteroaryl-(C2-C4 alkenyl), heterocyclic group or C1-C4 alkyl group substituted with heterocyclic group, wherein the alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl groups are optionally substituted; W meaning This group of formula; meaning where applicable a group of formula, where the asterisks (*) indicate the points of attachment of the ring; Meaning of Wi group of general formula; This report, if applicable The use of a compound, wherein the asterisks (*) indicate the points of attachment of the ring — or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of chemokine-mediated diseases in a mammal, wherein the chemokine binds to an IL-8a or IL-δβ receptor. 2. The use according to claim 1, wherein the ionizable hydrogen atom has a pKa value of 3-10. 3. The use according to claim 2, wherein R is a hydroxy, carboxy, mercapto group, -SR2, -OR2, -NH-C(O)R _a , -C(O)NR ₆ R ₇ , -NHS(O)2Rb/ -S(O)2NHR _C , a group of the general formula -NHC(X2)NHRb or a tetrazolyl group; where R ₂ is a substituted aryl, heteroaryl or heterocyclic group having a functional group providing an ionizable hydrogen atom with a pKa value of up to 10; Re and R7' are hydrogen, C1-4 alkyl, aryl, aryl-(C1-4 alkyl), aryl-(C2-4 alkenyl), heteroaryl, heteroaryl-(C1-4 alkyl), heteroaryl-(C2-4 alkenyl), heterocyclic, heterocyclic-substituted C1-4 alkyl, or heterocyclic-substituted C2-4 alkenyl, each of which may be optionally substituted with 1-3 atoms and/or groups selected from the following: halogen; nitro; C1-4 haloalkyl, such as trifluoromethyl; C1-4 alkyl, such as methyl; C1-4 alkoxy, such as methoxy; -NRgC(O)R _a ; -C(O)NRgR7 a group; sulfo group; or (C1-C4 alkoxy)carbonyl group, with the proviso that only one of Rg· and R7* may be hydrogen, and both may not be hydrogen; R _a represents alkyl, aryl, aryl-(C 1-4 alkyl), heteroaryl, heteroaryl-(C 1-4 alkyl), heterocyclic group or C 1-4 alkyl group substituted with heterocyclic group, each of which may be optionally substituted; R _b is a group of the general formula -NRgR7, alkyl, aryl, aryl-(C1-4 alkyl), aryl-(C2-4 alkenyl), heteroaryl, heteroaryl-(C1-4 alkyl), heteroaryl-(C2-4 alkenyl), heterocyclic group, heterocyclic substituted C1-4 alkyl, heterocyclic substituted C2-4 alkenyl, or camphoryl, wherein each of the foregoing groups may optionally be substituted with 1-3 substituents selected from the following atoms and/or groups: halogen atom; nitro group; C1-4 haloalkyl group; C1-4 alkyl group; C1-4 alkoxy group; -NR9C(0)R _a ; a group of the general formula -C(O)NReR7; a sulfo group; or a (C1-C4 alkoxy)carbonyl group; R9 is hydrogen or C1-C4 alkyl; R _c represents an alkyl, aryl group, aryl-(C 1-4 alkyl) group, aryl-(C 2-4 alkenyl) group, heteroaryl group, heteroaryl-(C 1-4 alkyl) group, heteroaryl-(C 2-4 alkenyl) group, heterocyclic group, heterocyclic substituted C 1-4 alkyl group or heterocyclic substituted C 2-4 alkenyl group, wherein each of the foregoing groups may be optionally substituted with 1-3 substituents selected from the following atoms and/or groups: halogen atom, nitro group, C 1-4 haloalkyl group, C 1-4 alkyl group, C 1-4 alkoxy group; -NR9C(O)R _a ; -C(O)NRgR7 a group of general formula 85; a sulfo group; or a (C1-C4 alkoxy)carbonyl group; and X ₂ represents an oxygen or sulfur atom. 4. Use according to claim 3, wherein the R2 group may optionally be substituted with 1-3 atoms and/or groups selected from the following: halogen atom, nitro group, C1-4 haloalkyl group, C1-4 alkyl group, C1-4 alkoxy group, hydroxy-, mercapto group, -C(O)NRgR7, -NH-C(O)Ra, -NHS(0)2Rb/ -S(O)2NR6R7, -C(O)ORe group and/or tetrazolyl group. 5. The use according to claim 3, wherein R is a hydroxyl group, a group of the general formula -NHS(O)2Rb or a carboxy group. 6. The use according to claim 1, wherein R1 is a halogen atom, a cyano, a nitro, a trifluoromethyl group, a group of the general formula -C(O) _NR4R5 , -alkenyl-C(ONR4R5, -C(O)R4R10, -alkenyl-C(0)OR12, a heteroaryl, heteroarylalkyl, heteroarylalkenyl group or a group of the general formula -S(O) _NR4R5 . 7. The use according to claim 1, wherein Y is a halogen atom, a C1-4 alkoxy group, an optionally substituted aryl group, an optionally substituted arylalkoxy group, a methylenedioxy group, a group of the general formula -NR4R5, a C1-4 alkylthio group, arylthio, a haloalkoxy group, an optionally substituted C1-4 alkyl group or a hydroxyalkyl group. 8. The use according to claim 1, wherein R is a hydroxy, mercapto or -NHS(O)2Rb group, and R1 is substituted with an electron-withdrawing group at the 3-position, the 4-position or the 3,4-position, respectively. 9. The use according to any one of claims 1-8, wherein the mammal suffers from a disease mediated by a chemokine selected from the group consisting of psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, advanced respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, stroke, reperfusion injury to the heart or kidney, glomerulonephritis, thrombosis, graft versus host reaction, Alzheimer's disease or allograft rejection. 10. A compound of general formula (I) is í ^z w—NH^N—(CR ₁₃ R,Jv —W, H (I) — in the formula of which Z is a cyano group, -ORn, -C(0)NR15R16, -R18/ a group of the general formula -C(O)Rn, -C(O)ORn or -S(O)2R17; R is a functional group having an ionizable hydrogen atom and a pKa value of at most 10; R1 is independently hydrogen; halogen; nitro; cyano; C1-10 alkyl; C1-10 haloalkyl; C2-10 alkenyl; C1-10 alkoxy; C1-10 haloalkoxy; azido; -(CReRe)qS(0)tR4; hydroxy; C1-4 hydroxyalkyl; aryl; aryl-(C1-4 alkyl) group; aryloxy; aryl-(C1-4 alkoxy) group; heteroaryl; heteroarylalkyl; heterocyclic; C1-4 alkyl substituted with heterocyclic; heteroaryl-(C1-4 alkoxy) group; aryl-(C2-10 alkenyl) group; heteroaryl-(C2-10 alkenyl) group; heterocyclic substituted C2-10 alkenyl group; - (CReRe)qNRíRs; -(C2-10 alkenyl)-C(0)NR4R5; - (CReRe)qC(O)NR4Rs; - (CReRe)qC(0)NR4R10 group; sulfo group; -S(O)3Re; - (CReRe) qC (0) R11; -(C2-10 alkenyl) -C (0) Rn; -(C2-10 alkenyl)-C(0)OR11; - (CReRe)qC(0)OR12; - (CReRe) qOC(O)Rn; - (CReRe) qNR ₄ C(0)Rn; -(CR ₈ R8)qNHS(O) ₂ Ri9; - (CReRe) qS (0) 2NR4R5; or two R1 groups together may form a group of the general formula -O-(CH ₂ ) _S ^_ O ^- or a five- or six-membered, saturated or unsaturated cyclic group; q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; t is 0, 1 or 2; s has the value 1, 2 or 3; v has the value 0, 1, 2, 3 or 4; R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl-(C1-4 alkyl), optionally substituted heteroaryl, optionally substituted heteroaryl-(C1-4 alkyl), heterocyclic, C1-4 alkyl substituted with heterocyclic, or R4 and R5 together with the nitrogen atom to which they are attached form a 5-7 membered cyclic group optionally containing an additional heteroatom selected from oxygen, nitrogen and sulfur; Y is hydrogen; halogen; nitro; cyano; C1-10 alkyl; C1-10 haloalkyl; C2-10 alkenyl; C1-10 alkoxy; C1-10 haloalkoxy; azido; - (CReRs) qS (0) _t R4; hydroxy; C1-4 hydroxyalkyl; aryl; aryl-(C1-4 alkyl) group; aryloxy; aryl-(C1-4 alkoxy) group; heteroaryl; heteroarylalkyl; heteroaryl-(C1-4 alkoxy) group; heterocyclic; heterocyclic substituted C1-4 alkyl; aryl-(C2-10 alkenyl) group; heteroaryl-(C2-C10 alkenyl) group; heterocyclic substituted C2-C10 alkenyl group; - (CR ₈ R ₈ ) _q NR 4 R s ; -(C2-10 alkenyl)-C(O)NR4R5; - (CR ₈ R ₈ ) _q C (0) NR4R5; - (CR ₈ R ₈ ) _q C (0)NR4Rio group; sulfo group; -S(O)3R ₈ ; - (CR ₈ R ₈ ) qC (0) Rn; -(C2-10 alkenyl)-C(0)R11; -(C2-10 alkenyl) -C (0) OR11; -C(0)Rn; -(CR ₈ R ₈ ) _q C(O)ORi ₂ ; - (CR ₈ R ₈ ) _q 0C (0) Rn; - (CR ₈ R ₈ ) _q NR ₄ C (O) R n ; -(CR ₈ R ₈ ) _q NHS(O) ₂ R _d ; - a group of the general formula (CR ₈ R ₈ ) _q S(0) ₂ NR 4 R s ; or two Y groups together may form a group of the general formula -0-(CH ₂ ) _s -0- or a five- or six-membered unsaturated cyclic group; n is 1, 2 or 3; m is 1, 2 or 3; r ₆ and R 7 are independently hydrogen or C 1-4 alkyl, or r ₆ and R 7 together with the nitrogen atom to which they are attached form a 5-7 membered cyclic group optionally containing an additional heteroatom selected from oxygen, nitrogen and sulfur; R ₈ represents a hydrogen atom or a C 1-4 alkyl group; R10 is a group of the general formula -(C1-10 alkyl)-C(O) _2R8 ; R11 represents a hydrogen atom, a C1-C4 alkyl group, an optionally substituted aryl group, an optionally substituted aryl-(C1-C4 alkyl) group, an optionally substituted heteroaryl group, an optionally substituted heteroaryl-(C1-C4 alkyl) group, an optionally substituted heterocyclic group, or optionally 90 is a C1-4 alkyl group substituted with a substituted heterocyclic group; R12 represents a hydrogen atom, a C1-C10 alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group; R13 and R14 are independently hydrogen or optionally substituted C1-4 alkyl, or one of R13 and R14 is optionally substituted aryl; R15 and R16 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl-(C1-4 alkyl), optionally substituted heteroaryl, optionally substituted heteroaryl-(C1-4 alkyl), heterocyclic, C1-4 alkyl substituted with heterocyclic, or R15 and R16 together with the nitrogen atom to which they are attached form a 5-7 membered cyclic group optionally containing one further heteroatom selected from oxygen, nitrogen and sulfur; r ₁₇ is a C 1-4 alkyl group, a group of the general formula -NR 15 R 16 Z -OR n , an optionally substituted aryl group, an optionally substituted aryl-(C 1-4 alkyl) group, an optionally substituted heteroaryl group, an optionally substituted heteroaryl(C 1-4 alkyl) group, a heterocyclic group or a C 1-4 alkyl group substituted with a heterocyclic group; r ₁₈ represents an optionally substituted C 1-4 alkyl group, an optionally substituted aryl group, an optionally substituted aryl-(C 1-4 alkyl) group, an optionally substituted heteroaryl group, an optionally substituted heteroaryl-(C 1-4 alkyl) group, a heterocyclic group or a C 1-4 alkyl group substituted with a heterocyclic group; R19 is C1-4 alkyl, aryl, aralkyl, heteroaryl, heteroaryl-(C1-4 alkyl), heterocyclic, or C1-4 alkyl substituted with heterocyclic, each of which is optionally substituted; Rd is a group of the general formula -NRgR?, alkyl, aryl-(C1-C4 alkyl), aryl-(C2-C4 alkenyl), heteroaryl, heteroaryl-(C1-C4 alkyl), heteroaryl-(C2-C4 alkenyl), heterocyclic group or C1-C4 alkyl group substituted with heterocyclic group, wherein the alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl groups are optionally substituted; W meaning Group of formula 92; E’ means, if applicable lags (*) indicate the connection points of the ring; Meaning of Wi group of general formula; This report, if applicable powder, where the asterisks (*) indicate the points of attachment of the ring — or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 10, wherein the ionizable hydrogen atom has a pKa value of 3-10. 12. A compound according to claim 10, wherein R is a hydroxy, carboxy, mercapto group, a group of the general formula -SR2, -OR2, -NH-C(O)R _a , -C(O)NRgR ₇ , “NHS (O) ₂ *b, -S (0) 2NHR _C , -NHC(X2)NHRb or a tetrazolyl group; where R ₂ is a substituted aryl, heteroaryl or heterocyclic group having a functional group providing an ionizable hydrogen atom with a pKa value of up to 10; Rg' and R ₇ ' are hydrogen, C1-4 alkyl, aryl, aryl-(C1-4 alkyl), aryl-(C2-4 alkenyl), heteroaryl, heteroaryl-(C1-4 alkyl), heteroaryl-(C2-4 alkenyl), heterocyclic, heterocyclic-substituted C1-4 alkyl, or heterocyclic-substituted C2-4 alkenyl, each of which may be optionally substituted with 1-3 atoms and/or groups selected from the following: halogen; nitro; C1-4 haloalkyl, such as trifluoromethyl; C1-4 alkyl, such as methyl; C1-4 alkoxy, such as methoxy; -NRgC(O)R _a ; -C(0)NRgR ₇ a group; sulfo group; or (C1-4 alkoxy)carbonyl group, with the proviso that only one of Rg' and R ₇ > is a 94 can mean a hydrogen atom, both cannot mean a hydrogen atom; R _a represents alkyl, aryl, aryl-(C 1-4 alkyl), heteroaryl, heteroaryl-(C 1-4 alkyl), heterocyclic group or C 1-4 alkyl group substituted with heterocyclic group, each of which may be optionally substituted; R _b is a group of the general formula -NRgR?, alkyl, aryl, aryl-(C1-4 alkyl), aryl-(C2-4 alkenyl), heteroaryl, heteroaryl-(C1-4 alkyl), heteroaryl-(C2-4 alkenyl), heterocyclic, heterocyclic-substituted C1-4 alkyl, heterocyclic-substituted C2-4 alkenyl, or camphoryl, wherein each of the foregoing groups may optionally be substituted with 1-3 substituents selected from the following atoms and/or groups: halogen; nitro; C1-4 haloalkyl; C1-4 alkyl; C1-4 alkoxy; -NRgC(O)R _a ; a group of the general formula -C(O)NR6R7; a sulfo group; or a (C1-C4 alkoxy)carbonyl group; Rg is hydrogen or C1-C4 alkyl; R _c is alkyl, aryl, aryl-(C1-C4 alkyl), aryl-(C2-C4 alkenyl), heteroaryl, heteroaryl-(C1-C4 alkyl), heteroaryl-(C2-C4 alkenyl), heterocycle 95 salt group, heterocyclic substituted C1-4 alkyl group or heterocyclic substituted C2-4 alkenyl group, wherein each of the foregoing groups may be optionally substituted with 1-3 substituents selected from the following atoms and/or groups: halogen atom, nitro group, C1-4 haloalkyl group, C1-4 alkyl group, C1-4 alkoxy group; -NR9C(0)R _a ; -C(O)NRgR7 group; sulfo group; or (C1-4 alkoxy)carbonyl group; and X ₂ represents an oxygen or sulfur atom. 13. A compound according to claim 12, wherein the R2 group may optionally be substituted with 1-3 groups and/or groups selected from the following: halogen atom, nitro group, C1-4 haloalkyl group, C1-4 alkyl group, C1-4 alkoxy group, hydroxy-, mercapto group, -C(0)NRgR7, -NH-C(O)R _a , -NHS(O)2Rb/ -S(O) _2NR6R7 , -C(O)OR8 group and/or tetrazolyl group. 14. A compound according to claim 12, wherein R is hydroxy, -NHS(O)2Rb, or carboxy. 15. A compound according to claim 10, wherein R1 is halogen, cyano, nitro, trifluoromethyl, -C(O) _NR4R5 , -alkenyl-C(0) _NR4R5 , -C(0) _R4R10 , -alkenyl-C(0)OR12, heteroaryl, heteroarylalkyl, heteroarylalkenyl or -S(0) _NR4R5 96 groups. 16. A compound according to claim 10, wherein Y is halogen, C1-4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylenedioxy, -NR4R5, C1-4 alkylthio, arylthio, haloalkoxy, optionally substituted C1-4 alkyl or hydroxyalkyl. 17. A compound according to claim 10, wherein R is hydroxy, mercapto or -NHS(O) _2Rb , and R1 is substituted with an electron withdrawing group at the 3-position, the 4-position or disubstituted at the 3,4-position, respectively. 18. A compound according to claim 10 selected from the group consisting of: N-(2-hydroxy-4-nitrophenyl)-Ν'-(2-chlorophenyl)-N-cyanoguanidine; N-(2-hydroxy-4-nitrophenyl)-Ν'-(2-bromophenyl)-N-cyanoguanidine; N-(4-cyano-2-hydroxyphenyl)-N*-phenyl-N-cyanoguanidine; N-(2-bromophenyl)-Ν'-(4-cyano-2-hydroxyphenyl)-N-cyanoguanidine; N-(4-cyano-2-hydroxyphenyl)-Ν'-(2,3-dichlorophenyl)-N-cyanoguanidine; N-(2-bromophenyl)-Ν'-(4-cyano-2-hydroxy-3-propylphenyl)-N"-cyanoguanidine; N-(2-bromophenyl)-Ν'-(4-cyano-2-hydroxy-3-isobutylphenyl)97-N-cyanoguanidine; N-(2-bromophenyl)-N'-(3-bromo-4-cyano-2-hydroxyphenyl)-N'-cyanoguanidine; N-(4-cyano-2-hydroxy-3-propylphenyl)-N'-(2,3-dichlorophenyl)-N-cyanoguanidine; N-(3-bromo-4-cyano-2-hydroxyphenyl)-N'-[2,3-(methylenedioxy)phenyl]-N-cyanoguanidine; N-(2-chlorophenyl)-Ν'-(4-cyano-2-hydroxy-3-propylphenyl)-N-cyanoguanidine; N-(2-bromophenyl)-N'-[4-cyano-2-hydroxy-3-(methoxycarbonyl)phenyl]-N'-cyanoguanidine; or a pharmaceutically acceptable salt thereof. 19. A pharmaceutical composition comprising a compound according to any one of claims 10-18 and a pharmaceutically acceptable carrier or diluent. 20. A process for the preparation of a compound of general formula (I) according to claim 10, characterized in that a compound of general formula (II) is Wj-N=C=N-W (II) __ in which W and Wi are as defined in formula (I) and W contains a protected R (R) group as defined in compounds of formula (I) — with an amine of formula ZNH2 — in which Z is as defined in compounds of formula (I) — or its anion or salt and a base can react to form a compound of formula (I) A compound of general formula 98 is obtained, and then, if desired, the protecting group is removed from the product. 21. The process of claim 20, _wherein the base is a tertiary amine base. 22. The process according to claim 21, wherein the base is N-ethyldiisopropylamine or triethylamine. 23. The method of claim 20, wherein the solvent is an aprotic solvent. 24. The process of claim 23, wherein the solvent is acetonitrile. 25. The process of claim 20, wherein the reaction temperature is between about -10°C and about 50°C. 26. The process according to claim 20, characterized in that Z is a cyano group, the base is N,N-diisopropylethylamine, the solvent is acetonitrile and the cyanamide is used in large excess. 27. The process of claim 20, wherein the protecting group is removed from the R group by palladium(0)-catalyzed desallylation. 28. A process for preparing a compound of general formula (II) as defined in claim 20. W|-N=C=N-W (II) — in which formula W and Wi have the general meaning of (I) 99 is defined in the case of compounds of general formula (I), and W contains a protected R (R”) group as defined in the case of compounds of general formula (I), characterized in that a compound of general formula (III) is prepared W]-NH-C(S)-NH-W (III) — in which W and Wi are as defined for general formula (I) and W contains a protected R (R”) group as defined for compounds of general formula (I) — can be reacted with an excess of methanesulfonyl chloride in the presence of a tertiary amine base. 29. The process of claim 28, wherein the base is triethylamine. 30. The process of claim 28, wherein the solvent is methylene dichloride. 31. The process of claim 28, wherein the reaction temperature is between about -10°C and about 50°C. 32. Process for preparing a compound of formula (III) W]-NH-C(S)-NH-W (III) __ in which W and Wi are as defined for the general formula (I) and W contains a protected R (R) group as defined for the compounds of the general formula (I), characterized in that a W-NH2 is formed by - A compound of formula 100 — in which W is as defined in formula (I) — is reacted with a corresponding isothiocyanate of formula Wi-NCS in an aprotic or halogenated solvent in the presence of two or more equivalents of base. 33. The process of claim 32, wherein the base is sodium hydride, potassium hydride or calcium hydride. 34. The method of claim 32, wherein the solvent is an aprotic solvent. 35. The process of claim 34, wherein the aprotic solvent is N,N-dimethylformamide, dioxane or toluene. 36. The process of claim 32, wherein the reaction temperature is between about -10°C and about 50°C. The authorized person: Phone: 34-24-950, Fax: 34-24-32?