HUP0201302A2 - IL-8 receptor antagonist cyclic guanidine derivatives - Google Patents

Abstract

The invention applies to compounds of general formula (I) - in the formula of which R is a hydroxy group, a mercapto group or a -NHSO2Rd group; R1 is preferably a hydrogen or halogen atom; nitro, cyano or alkyl; R2 is preferably an alkylene or alkenylene group, which optionally contains an oxygen, sulfur atom NR9, carbonyl, sulfinyl or sulfonyl group; Y is preferably a hydrogen or halogen atom; nitro, cyano or alkyl; m and n 1, 2 or 3 - and refers to pharmaceutical preparations for the treatment of diseases mediated by chemokine binding to the IL-8a or IL-8b receptor containing the compounds. HE

Description

PINK 0 1 302 £210

73.558/DE /'Λ''

IL-8 RECEPTOR ANTAGONIST C-IKLUSQS GUANIDINE DERIVATIVES <-77 ’t..1777771 PUBLICATION COPY

The invention relates to novel cyclic guanidine derivatives and processes for their preparation, to the use of the compounds in the treatment of diseases mediated by IL-8, GROa, GROP, GROy, NAP-2 and ENA-78, 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, or 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., 8_4, 1045 (1989); J. Schroder et al. , J. Immunol., 139, 3474 (1987); j. Schroder et al. , J. Immunol., 144, 2223 (1990); Cassatella et al., J. Immunol., 148, 3216 (1992)].

The chemokine family 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, GROy is also known as MGSAy [see for example: Richmond et al.,

J. CELL Physiology, 129, 375 (1986); and Chang et al., J. Immunol., h48, 451 (1992)]. All of the α-family chemokines have an ELR repeat immediately preceding the CXC repeat bound to the IL-8 B receptor (CXCR2).

IL-8, GROa, GROP, GROy, NAP-2 and ENA-78 stimulate a number 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 characteristic 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., 8J, 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 an 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 NAP-2 bind to and activate the seven-transmembrane, G-protein coupled family of receptors, particularly the IL-8 receptor, and 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 nonpeptide, 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-8Rβ, which has high affinity for IL-8 as well as GROα, GRO0, 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 Ι1-8β receptor. IL-8 is responsible for the recruitment of neutrophils to sites of inflammation and

For T-cell subset chemotaxis, thus in conditions accompanied by increased IL-8 production, compounds that function as inhibitors of IL-8 receptor binding would be advantageously used.

One aspect of the invention is a method for treating chemokine-mediated diseases, wherein the chemokine is a chemokine that binds to an IL-8α 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 for 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).

Compounds of general formula (I) that can be used in the solution according to the invention

and their pharmaceutically acceptable salts in the formula

R is a hydroxy, mercapto group or a group of the general formula -NHSC^Rd;

Rg is a group of the general formula -NR ₆ R ₇ , alkyl, aryl-(1-4 C alkyl) group, aryl-(2-4 C alkenyl) group, heteroaryl group, heteroaryl-(1-4 C alkyl) group, heteroaryl-(2-4 C alkenyl) group, heterocyclyl group or heterocyclyl-(1-4 C alkyl) group, wherein each of the rings containing the aryl, heteroaryl and heterocyclyl groups may be optionally substituted;

Rg and R7 independently represent a hydrogen atom or a C1-C4 alkyl group, or

R 6 and R ₇ together with the nitrogen atom to which they are attached form an optionally substituted 5-7 membered cyclic group, optionally containing one additional heteroatom selected from oxygen, nitrogen and sulfur;

R1 is independently hydrogen; halogen; nitro; cyano; alkyl (C1-10); haloalkyl (C1-10); alkenyl (C2-10); alkoxy (C1-10); haloalkoxy ( _C1-10 ); azido; hydroxy; hydroxyalkyl ( _C1-4 ); _aryl ; _aryl- ( _C1-4 )alkyl; aryloxy; aryl-(C1-4)alkoxy; heteroaryl; heteroarylalkyl; heterocyclyl; heterocyclyl-(C1-4)alkyl; heteroaryl-(C1-4)alkoxy; aryl-(C2-10 alkenyl)-group; heteroaryl-(C2-10 alkenyl)-group; heterocyclyl-(C2-10 alkenyl)-group; - (CR ₈ R ₈ )qNR ₄ R ₅ ; -(C2-10 alkenyl)-C(O)NR 4 R 5 ; -(CRgR8) _q C(O)NR ₄ R ₅ ;

- a group of the general formula (CRgRg)qC(O)NR4R10;

sulfo group; -S(O) ₃ R ₈ ; - (CR ₈ R ₈ ) _q C (0) R _n ; -(C2-10 alkenyl) -C (0) Rn; -(C2-10 alkenyl) -c (O) ORn; - (CRgR ₈ ) _q C (O) OR 12 ; - (CR ₈ R ₈ ) _q OC (O) R n ; - (CR ₈ R ₈ ) _q NR ₄ C (O) R n ;

(CR ₈ R ₈ ) _q NHS (O) 2R17í ~ (CR ₈ R ₈ ) _q S (0) 2NR4R5; 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;

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;

R ₄ and R ₅ are independently hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl, optionally substituted aryl-(C 1-4 alkyl), optionally substituted heteroaryl, optionally substituted heteroaryl-(C 1-4 alkyl), heterocyclyl, heterocyclyl-(C 1-4 alkyl), 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;

R2 is independently an alkylene group having 2-5 carbon atoms or an alkenylene group having 2-5 carbon atoms, optionally substituted up to three times independently with a halogen atom, a nitro group, a haloalkyl group having 1-4 carbon atoms, an alkyl group having 1-4 carbon atoms, an amino group, a mono- or dialkylamino group, a hydroxyl group, a alkoxy group having 1-4 carbon atoms, a group of the general formula -NRgC(O)R _a , -S(O) _m R _a , -C(O)NR ₆ R ₇ , a carboxy group, a group of the general formula -C(O)OR _a , -S(0) ₂ NR ₆ R ₇ and/or a group of _the general formula -NHS(O) ₂ R a , and which alkylene or alkenylene group, in addition to the carbon atoms, optionally independently with 1-3 groups of the general formula >NR ₉ , an oxygen atom, a carbonyl group, contains a sulfur atom, a sulfinyl or sulfonyl group; independently represents a hydrogen atom; a halogen atom; a nitro group; a cyano group; an alkyl group of 1-10 carbon atoms; a haloalkyl group of 1-10 carbon atoms; an alkenyl group of 2-10 carbon atoms; an alkoxy group of 1-10 carbon atoms; a haloalkoxy group of 1-10 carbon atoms; an azido group; a group of the general formula -(CR ₈ R ₈ ) _q S(O) _t R ₄ ; a hydroxy group; a hydroxyalkyl group of 1-4 carbon atoms; aryl group; aryl-(1-4 carbon alkyl) group; aryloxy group; aryl-(1-4 carbon alkoxy) group; heteroaryl group; heteroarylalkyl group; heteroaryl-(1-4 carbon alkoxy) group; heterocyclyl group; heterocyclyl-(C1-C4 alkyl) group; aryl-(C2-C10 alkenyl) group; heteroaryl-(C2-C10 alkenyl) group; heterocyclyl-(C2-C10 alkenyl) group; -(CR ₈ R ₈ ) _q NR ₄ R ₅ ; -(C2-C10 alkenyl)-C(0)NR ₄ R ₅ ; -(CR ₈ R ₈ ) _q C(0)NR ₄ R ₅ ;

(CRgRg) qC (0) NR4R10 group; sulfo group; -S(O)3Rq; - (CRgRg) _q C (O) Rn; -(C2-10 alkenyl)-C (0)Rn; -(C2-10 alkenyl)-C (O) ORn;

-C(O)Rn; - (CR ₈ R ₈ ) _q C(O) OR 12 ; - (CR ₈ R ₈ ) _q OC (0) Rn ;

- (CR ₈ Rg) _q NR ₄ C (0)Rn; -(CRgRg ) _q NHS (0) ₂ Rd; ~ (CRgRg ) _q S (O) 2NR4R5; or two Y groups together may form a group of the general formula -O-(CH ₂ ) _S -O- or a five- or six-membered unsaturated cyclic group;

n is 1, 2 or 3;

m is 1, 2 or 3;

Rg is hydrogen or C1-C4 alkyl;

R9 is hydrogen or C1-C4 alkyl;

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 heterocyclyl group, or an optionally substituted heterocyclyl-(C1-C4 alkyl) group;

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

R17 is C1-4 alkyl, aryl, aryl-(C1-4 alkyl), heteroaryl, heteroaryl-(C1-4 alkyl), heterocyclyl or heterocyclyl-(C1-4 alkyl), wherein each of the aryl, heteroaryl and heterocyclyl groups may be optionally substituted; and

Ra represents alkyl, aryl, aryl-(C1-C4 alkyl), heteroaryl, heteroaryl-(C1-C4 alkyl), heterocyclyl or heterocyclyl-(C1-C4 alkyl), each of which groups may be optionally substituted.

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.

Illustrative examples of compounds of formula (I) include the following compounds:

4-{[1-(2-bromophenyl)-4,5-dihydro-5-oxo-1H-2-imidazolyl]amino}-3-hydroxybenzonitrile;

N-(4-cyano-2-hydroxyphenyl)-ΛΡ-(2-bromophenyl)-N-[(chloromethyl)sulfonyl]guanidine;

N (4-cyano-2-hydroxyphenyl)-N'-(2-bromophenyl)-IV'-(2,2-dimethoxyethyl)guanidine;

4-{[1-(2-bromophenyl)-4,5-dihydro-1H-2-imidazolyl]amino}-3-hydroxybenzonitrile;

4-{[4-(2-bromophenyl)-4,5-dihydro-1,1-dioxo-1,2,4-thiadiazol-3-yl]amino}-3-hydroxybenzonitrile;

4-{[1-(2-bromophenyl)-1H-2-imidazolyl]amino}-3-hydroxybenzonitrile;

4-{[(S)-1-(2-bromophenyl)-4-isopropyl-5-oxo-4,5-dihydro-1H2 imidazolyl]amino}-3-hydroxybenzonitrile;

ethyl 3-[(S)-1-(2-bromophenyl)-2-(4-cyano-2-hydroxyanilino)-5-oxo-4,5-dihydro-1H-4-imidazolyl]propionate;

ethyl [(R)-1-(2-bromophenyl)-2-(4-cyano-2-hydroxyanilino)-5-oxo-4,5-dihydrolyl-4-imidazolyl]acetate;

4-{[(S)-1-(2,3-dichlorophenyl)-4-isopropyl-5-oxo-4,5-dihydro-1H-2-imidazolyl]-amino}-3-hydroxybenzonitrile;

4-{[(S)-1-(2,3-dichlorophenyl)-4-isobutyl-5-oxo-4,5-dihydro ^- 1-[2-imidazolyl]-amino}-3-hydroxybenzonitrile;

4-[{ (5)-1-(2, 3-dichlorophenyl)-4-[2-(methylthio)ethyl]-5-oxo-

-4,5-dihydro-lip-2-imidazolyl}-amino]-3-hydroxy-

-benzonitrile;

ethyl 3-[(S)-2-(4-cyano-2-hydroxyanilino)-1-(2,3-dichlorophenyl)-5-OXO-4,5-dihydro-1-th-4-imidazolyl]propionate;

{[(S)1-(2,3-dichlorophenyl)-4-methyl-5-oxo-4,5-dihydro-1H2-imidazolyl]amino}-3-hydroxybenzonitrile;

{[(R) ^1- (2,3-dichlorophenyl)-4-methyl-5-oxo-4,5-dihydro-1/2 imidazolyl]amino}-3-hydroxybenzonitrile; and

4-{[1-(2-bromophenyl)-4,5-dihydro-5-methoxy-1H-2-imidazolyl]amino}-3-hydroxybenzonitrile;

or pharmaceutically acceptable salts thereof.

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 C2-5 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 alkenyl group refers to a group containing 2-10 carbon atoms, straight or branched chain, with at least one double bond, unless the chain length is otherwise limited, such as, but not limited to, vinyl, 1-propenyl, allyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc.

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, quinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole and benzimidazole.

The term heterocyclic group or heterocyclyl group (alone or in any combination, such as heterocyclic-substituted alkyl or heterocyclylalkyl) refers to a group derived from a 4- to 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. Examples of compounds yielding such groups include, but are not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, thiomorpholine, and imidazolidine.

The term aralkyl, heteroarylalkyl or heterocyclic substituted alkyl as used herein refers to an alkyl group having 1-10 carbon atoms, as defined above, to which is attached an aryl group, a heteroaryl group or a heterocyclic group.

The compounds of formula (I) can be prepared by synthetic methods. Some of these methods are illustrated in the reaction schemes below. The methods illustrated in the reaction schemes provide compounds of formula (I) in which the substituents in the various variables, such as R, R1 and R2, optionally carry protecting groups corresponding to the indicated reactions. In these cases, the protecting groups are removed from the products to give the final products defined above. After the urea skeleton has been formed, further compounds of the above formulae can be prepared by interconversion of functional groups using conventional methods well known in the art.

Reaction scheme 1

a) Br2, NaOAc, HOAc; b) CuCN, DMF, reflux; c) (BOC)2O, DMAP,

TEA; d) K2CO3, MeOH; e) TEA

The desired aniline of formula 6 according to Scheme 1 can be prepared from the commercially available benzoxazolinone of formula 1. The benzoxazolinone of formula 1 is converted to the bromide of formula 2 by standard bromination conditions, for example, by reaction with bromine and sodium acetate in acetic acid. The bromide of formula 2 is then converted to the cyanide of formula 3 by conventional methods, for example, by reaction with copper (I) cyanide in refluxing N,N-dimethylformamide. The amide of formula 3 is converted to the BOC-protected compound of formula 4 by reaction with BOC anhydride and triethylamine in methylene chloride or other suitable organic solvent, and a catalytic amount of 4-(dimethylamino)pyridine under standard conditions. The oxazolinone of formula 4 is first hydrolyzed to the phenol of formula 5 under standard conditions, for example, by reacting with potassium carbonate in methanol, and then the BOC protecting group is removed by reacting with trifluoroacetic acid under standard conditions, for example, in methylene dichloride or another suitable organic solvent, resulting in the aniline of formula 6.

Reaction scheme 2

a) RNCS; b) TBSC1; c) thiophosgene; d) RNH2

The desired thiourea of formula 3 according to Scheme 2 can be prepared as shown in Scheme 2. The aniline of formula 1 is reacted with a commercially available isothiocyanate or with an isothiocyanate derived from the condensation of a commercially available amine with thiophosphogen or an equivalent of thiophosgene to give a thiourea of formula 2. The phenol of formula 2 is protected under standard conditions, for example, by reacting with (tert-butyldimethylsilyl) chloride (TBSC1) and imidazole in tetrahydrofuran or other suitable organic solvent to form the corresponding TBS ether of formula 3. According to another solution, the amine of formula 1 is converted to the isothiocyanate of formula 5, in which the phenol of formula 1 is first reacted with (tert-butyldimethylsilyl) chloride and an amine base, such as imidazole, under standard conditions, for example in tetrahydrofuran or other suitable organic solvent, to produce the protected phenol derivative of formula 4, and then the amine of formula 4 is reacted with thiophosphine in the presence of a base, such as potassium carbonate, to produce the thiourea of formula 5. The desired thiourea of general formula 3 can be prepared by reacting the isothiocyanate of formula 5 with the desired amine in a suitable solvent, such as ethanol or N,N-dimethylformamide.

Reaction scheme 3

The desired lactam of formula 3 according to Scheme 3 can be prepared by the process according to Scheme 3. The carbodiimide of formula 2 can be prepared by reacting a thiourea of formula 1 with an excess of mesyl chloride and a suitable amine base, such as triethylamine, under standard conditions, for example in an organic solvent, preferably methylene dichloride, at room temperature. The lactam of formula 3 can be prepared from the carbodiimide of formula 2 by first reacting the carbodiimide of formula 2 with the desired α-amino ester in a suitable organic solvent, such as tetrahydrofuran or acetonitrile, and then removing the (tert-butyldimethylsilyl) (TBS) protecting group under standard conditions, for example in tetrahydrofuran at 0 °C, by reacting with (tetrabutylammonium) fluoride (TBAF).

Reaction scheme 4

a) 2 aminoethanol, Hunig's base,

THF; b) TBAF, THF; c) PPh ₃ ,

DEAD, THF

The dihydroimidazole derivative of formula 3 according to reaction scheme 4 can be prepared from an alcohol of formula 2 by the method of reaction scheme 4. The guanidine of formula 2 can be prepared by reacting a carbodiimide of formula 1 with the appropriate primary amine under standard conditions, for example in a suitable organic solvent, for example acetonitrile or tetrahydrofuran, and then removing the (tert-butyldimethylsilyl) protecting group by reacting with (tetrabutylammonium) fluoride (TBAF) under standard conditions, for example in tetrahydrofuran at 0 °C. The cyclic guanidine derivative of general formula 3 can be prepared from guanidine of general formula 2 using standard Mitsunbu conditions, for example, the compound of general formula 2 is reacted with triphenylphosphine and diethyl azodicarboxylate (DEAD) in a suitable organic solvent, for example tetrahydrofuran.

Reaction scheme 5

a) chloro methanesulfonamide, Hunig base, THF; b) TBAF, THF *

NaH, DMF

The desired cyclic sulfonamide guanidine of formula 3 of Scheme 5 can be prepared from the chloride of formula 2 by the method of Scheme 5. The guanidine of formula 2 can be prepared from the carbodiimide of formula 1 by the methods of Schemes 3 and 4. In preparing the cyclic guanidine of formula 3, the chloride of formula 2 can be reacted with sodium hydride under standard alkylation conditions, for example, in a suitable solvent, such as N,N-dimethylformamide, at ambient temperature or with mild heating.

Reaction scheme 6

a) (2,2,-dimethoxyethyl)amine, Hünig base

THF; b) TBAF, THF;

c) p-toluenesulfonic acid, acetone

The imidazole derivative of formula 3 in Scheme 6 can be prepared by reacting a dimethyl acetal of formula 2 with p-toluenesulfonic acid under standard conditions, for example in a suitable organic solvent such as acetone. The guanidine of formula 2 can be prepared from the carbodiimide of formula 1 using the methods of Schemes 3 and 4.

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.

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. ^-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, g = quartet, m = multiplet, and br = broad signal.

example

Preparation of 4-{[1-(2-bromophenyl)-4,5-dihydro-5-oxo-1H-2-imidazolyl]-amino}-3-hydroxybenzonitrile a) Preparation of 4-bromo-1,2-benzoxazolinone To a solution of benzoxazoline (74 mmol) in 50 ml acetic acid cooled to 0 °C was added 7.4 g (74 mmol) of sodium acetate and 3.8 ml (74 mmol) of bromine. The reaction mixture was allowed to warm to room temperature with stirring, and after 21 hours the precipitate was filtered off and washed with water. The filtrate was concentrated under reduced pressure, and the additional solid thus obtained was filtered off and washed with water. The solids were combined to give 4-bromo-1,2-benzoxazolinone as a yellow solid (14 g, 88%). The product did not require further purification. ¹ H-NMR (DMSO-dg) δ (ppm): 7.6 (s, 1H), 7.3 (d, 1H), 7.0 (d, 1H). MS (El) m/e 212 (M ⁺ ).

b) Preparation of 4-cyano-1,2-benzoxazolinone

To a solution of 5.0 g (23 mmol) of 4-bromo-1,2-benzoxazolinone in 11 ml of N,N-dimethylformamide was added 3.6 g (39 mmol) of copper (I) cyanide. The reaction mixture was heated at 165 °C for 6.5 h, then cooled to room temperature, and 20 ml of water and 3.6 g of sodium cyanide were added. The reaction mixture was heated at 100 °C for 12 h, then extracted with ethyl acetate. The organic solutions were combined and filtered through a thin layer of silica gel, using ethyl acetate as the eluent. The filtrate was concentrated under reduced pressure to give 4-cyano-1,2-benzoxazolinone as a brown solid (1.9 g, 51%). The product did not require further purification. ¹ H-NMR (DMSO-dg) δ (ppm): 7.8 (s, 1H), 7.6 (d, 1H), 7.2 (d, 1H). b) Preparation of N-(tert-butylacetoxy)-4-cyano-1,2-benzoxazolinone

To a solution of 1.9 g (15 mmol) of 4-cyano-1,2-benzoxazolinone in 50 ml of tetrahydrofuran and cooled to 0 °C were added 2.5 ml (18 mmol) of triethylamine, 0.37 g (3.0 mmol) of 4-(dimethylamino)pyridine and 4.3 g (20 mmol) of BOC anhydride. The reaction mixture was allowed to warm to room temperature, and after 1.5 hours the reaction was quenched by adding 100 ml of water. The aqueous mixture was extracted with ethyl acetate, the organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. N-(tert-butylacetoxy)-4-cyano-1,2-benzoxazolinone was obtained as a yellow solid in an amount of 4.3 g (100% yield). The product did not require further purification. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.8 (d, 1H), 7.55 (d, 1H), 7.45 (s, 1H), 1.65 (s, 9H).

f) Preparation of N-(tert-butylacetoxy)-4-cyano-2-hydroxyaniline

To a solution of 4.3 g (16 mmol) of N-(tert-butylacetoxy)-4-cyano-1,2-benzoxazolinone in 50 ml of methanol was added 2.3 g (16 mmol) of potassium carbonate. The reaction mixture was stirred for 1.5 h and quenched with 100 ml of water. The aqueous mixture was extracted with ethyl acetate, the organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. N-(tert-butylacetoxy)-4-cyano-2-hydroxyaniline was obtained as a brown foam in an amount of 3.1 g (81 % yield). The product did not require further purification. ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.7 (d, 1H), 7.15 (s, 1H), 7.1 (d, 1H), 1.5 (s, 9H).

e) Preparation of 4-cyano-2-hydroxyaniline

To a solution of 3.1 g (13 mmol) of N-(tert-butylacetoxy)-4-cyano-2-hydroxyaniline in 100 ml of methylene chloride cooled to 0 °C was added trifluoroacetic acid, and the reaction mixture was allowed to warm to room temperature. After two and a half hours, the reaction was quenched by adding 100 ml of water, and the aqueous mixture was extracted with ethyl acetate. The organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained as a residue was purified by flash chromatography, using a 1:1 ethyl acetate/hexane solvent mixture as eluent. 4-Cyano-2-hydroxyaniline was obtained as a tan solid in an amount of 1.7 g (96% yield). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm) : 7.0 (d, 1H) ,

6.85 (s, 1H), 6.65 (d, 1H). MS (El) m/e 134 (M ⁺ ) .

f) Preparation of N-(4-cyano-2-hydroxyphenyl)-N(2-bromophenyl)-thiourea

To a solution of 1.0 g (7.5 mmol) of 4-cyano-2-hydroxyaniline in 20 ml of ethanol was added 1.0 ml (7.5 mmol) of (2-bromophenyl)isothiocyanate. The reaction mixture was stirred for 24 h and then concentrated under reduced pressure. This gave N-(4-cyano-2-hydroxyphenyl)-Ν'-(2-bromophenyl)thiourea as a yellow solid (2.0 g, 77%). The product did not require further purification. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.8 (s, 1H) , 10.1 (s, 1H) , 9.6 (s, 1H) , 8.7 (d, 1H) , 7.7 (d, 1H) , 7.6 (d, 1H) , 7.4 (t, 1H) , 7.25 (d, 1H), 7.2 (s, 1H and d, 2H). MS (El) m/e 229 (100), 348 [75 (M ⁺ ) ] , 4 62 (30), 695 (10).

g) N-{4-cyano-2-[(tert-butyldimethylsilyl)oxy]phenyl}-

Preparation of N-(2-bromophenyl)thiourea

To a solution of 3.5 g (10 mmol) of N-(4-cyano-2-hydroxyphenyl)-N'-(2-bromophenyl)thiourea in 50 ml of tetrahydrofuran and cooled to 0 °C were added 1.0 g (15 mmol) of imidazole and 1.5 g (10 mmol) of (tert-butyldimethylsilyl)chloride (TBSC1). After one hour, the reaction was quenched by adding 100 ml of water, and the aqueous mixture was extracted with ethyl acetate. The organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained as a residue was crystallized from ethyl acetate, which resulted in the formation of N-{4-cyano-2-[(tert-butyldimethylsilyl)oxy]phenyl}-N'-(2-bromophenyl)thiourea as a yellow solid in an amount of 3.9 g (84% yield).

H-NMR (400 MHz, DMS0-d ₆ ) δ (ppm): 9.9 (s, 1H) , 9.2 (s, 1H) ,

8.1 (d, 1H), 7.7 (d, 1H), 7.6 (d, 1H), 7.45 (d, 1H), 7.4 (t, 1H), 7.35 (s, 1H), 7.2 (t, 1H). MS (El) m/e 347 [100 (M ⁺ )], 175 (40), 461 (40).

h) Preparation of N-{4-cyano-2-[(tert-butyldimethylsilyl)oxy]-phenyl}-Ν'-(2-bromophenyl)-carbodiimide ³ <4 g (7.4 mmol) of N-{4-cyano-2-[(tert-butyldimethylsilyl)oxy]-phenyl}-N'-(2-bromophenyl)-thiourea prepared in 40 ml of methylene chloride and cooled to 0 °C were added 3.1 ml (22 mmol) of triethylamine, 20 mg of 4-(dimethylamino)-pyridine and 1.1 ml (15 mmol) of mesyl chloride. Twenty-five minutes later, the reaction was stopped by adding 100 ml of water, and the aqueous mixture was extracted with ethyl acetate. The organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. N-{4-cyano-2- [ (tert-butyldimethylsilyl)oxy]-phenyl}-N' - (2-bromophenyl)-carbodiimide was obtained as a yellow solid in 3.3 g (100% yield). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.7 (d, 1H), 7.45 (d, 1H), 7.4 (m, 4H), 7.15 (t, 1H).

x) Standard procedure for the preparation of diphenylguanidines.

Preparation of 4-{[1-(2-bromophenyl)-4,5-dihydro-5-oxo-1H-2-imidazolyl]-amino}-3-hydroxybenzonitrile

To a solution of 112 mg (0.26 mmol) of N-{4-cyano-2-[(tert-butyldimethylsilyl)oxy]phenyl}-N'-(2-bromophenyl)carbodiimide in 2 ml of acetonitrile were added 0.10 ml (0.57 mmol) of N,N-diisopropylethylamine and 40 mg (0.29 mmol) of glycine ethyl ester hydrochloride. After 30 minutes, the lower alkyl group was concentrated under reduced pressure. The residue was diluted with 1 ml of tetrahydrofuran and 0.1 ml of methanol, the mixture was cooled to 0 C, and 0.29 ml (0.29 mmol) of (tetrabutylammonium) fluoride was added. Five minutes later, the reaction was quenched by adding 2 ml of water, and the mixture was extracted with ethyl acetate. The organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained as a residue was purified by recrystallization from methylene chloride to give 4-{[1-(2-bromophenyl)-4,5-dihydro-5oxo-1H-2-imidazolyl]amino}-3-hydroxybenzonitrile as a tan powder (70 mg, 73%). ^Ί Η-ΝΜΗ (400 MHz, CD ₃ 0D) δ (ppm): 7.6 (1H, d) , 7.55 (1H, d) , 7.4 (1H,

s), 7.3 (2H, dd), 7.0 (2H, m). MS (EI) m/e 372 [100 (M ⁺ ) ] .

k) N-(4-cyano-2-hydroxyphenyl)-Ν'-(2-bromophenyl)-N-

- Preparation of [(chloromethyl)sulfonyl]guanidine

Using the general procedure, 105 mg (0.24 mmol) of N-{4-cyano-2-[(tert-butyldimethylsilyl)oxy]phenyl}-N'-{2-bromophenyl)carbodiimide, 45 μΐ (0.26 mmol) of N,N-diisopropylethylamine, 16 μΐ (0.26 mmol) of (2-hydroxyethyl)amine, and 0.53 mL (0.53 mmol) of (tetrabutylammonium) fluoride were reacted in 2 mL of tetrahydrofuran and 0.1 mL of methanol. As a result, 52 mg (57% yield) of N-(4-cyano-2-hydroxyphenyl)-Ν'-(2-bromophenyl)-N-[(chloromethyl)sulfonyl]guanidine was obtained as a tan powder. ¹ H-NMR (400 MHz, DMSO-dg) δ (ppm): 7.55 (2H, m), 7.2 (1H, t), 7.1 (1H, d), 7.05 (1H, s), 6.95 (1H, d), 6.85 (1H, t). MS (El) m/e 376 [100 (M ⁺ ) ] , 490 (20) .

1) Preparation of N-(4-cyano-2-hydroxyphenyl)-Ν'-(2-bromophenyl)-N-[(chloromethyl)sulfonyl]guanidine

Using the general procedure, 220 mg (0.51 mmol) of N-{4-cyano-2-[(tert-butyldimethylsilyl)oxy]phenyl}-Ν' -(2-bromophenyl)carbodiimide, 63 μΐ (0.56 mmol) of N,N-diisopropylethylamine, 72 mg (0.56 mmol) of chloromethanesulfonamide, and 0.13 mL (0.13 mmol) of (tetrabutylammonium) fluoride were reacted in 1 mL of tetrahydrofuran and 0.1 mL of methanol. As a result, 16 mg (32% yield) of N-(4-cyano-2-hydroxyphenyl)-N'-(2-bromophenyl)-N-[(chloromethyl)sulfonyl]guanidine was obtained as a tan powder. ¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 7.85 (1H, d), 7.7 (1H, d), 7.5 (1H, d), 7.4 (1H, t), 7.25 (1H, t), 7.15 (1H, d), 7.05 (1H, s), 4.7 (2H, s). MS (EI) m/e 887 [100 (Mx2)], 490 (20).

m) Preparation of N-(4-cyano-2-hydroxyphenyl)-N'-(2-bromophenyl)-2N-(2,2-dimethoxyethyl)guanidine

Using the general procedure, 250 mg (0.58 mmol) of N-{4-cyano-2- [ (tert-butyldimethylsilyl)oxy]-phenyl}-N'-(2-bromophenyl)-carbodiimide, 72 μΐ (0.64 mmol) of N, N-diisopropylethylamine, 70 μΐ (0.64 mmol) of (2,2-dimethoxyethyl)-amine and 0.70 ml (0.70 mmol) of (tetrabutylammonium) fluoride were reacted in 6 ml of tetrahydrofuran and 0.1 ml of methanol. As a result, 170 mg (70% yield) of N-(4-cyano-2-hydroxyphenyl)-Ν'(2 bromophenyl)-Λ7-(2, 2-dimethoxyethyl)-guanidine was obtained as a tan powder. '''H-NMR (400 MHz, CD ₃ OD) δ (ppm): 7.6 (1H, m) , 7.5 (1H, d) , 7.15 (1H, t), 7.1 (1H, d) , 7.0 (1H, s) , 6.9 (1H, d) , 6.8 (1H, t) , 4.45 (1H, t) 3.3 (6H, s) . MS (El) m/e 420 [100 (M ⁺ ) ] .

n) 4-{[1-(2-bromophenyl)-4,5-dihydro-1H-2-imidazolyl]-

-amino)-3-hydroxybenzonitrile preparation

To a solution of 46.2 mg (0.12 mmol) of N-(4-cyano-2-hydroxyphenyl)-Ν'-(2-bromophenyl)-N'-(2-hydroxyethyl)guanidine in 2 ml of tetrahydrofuran at room temperature were added 140 mg (0.53 mmol) of triphenylphosphine and 41 μΐ (0.26 mmol) of diethyl azodicarboxylate (DEAD). After two and a half hours, the reaction was quenched by adding 1 ml of water, and the aqueous mixture was extracted with ethyl acetate. The organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained as a residue was purified by column chromatography, using a 10:90 volume methanol/ethyl acetate solvent mixture as eluent. As a result, N-(4-cyano-2-hydroxyphenyl)-Ν'-(2-bromophenyl)-N”-(2,2-dimethoxyethyl)-guanidine was obtained as a tan powder in an amount of 28 mg (65% yield). H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.6 (1H, d) , 7.4 (2H, m) , 7.2 (1H, t), 7.0 (3H, d and s) , 3.95 (2H, t), 3.75 (2H, t) . MS (El) m/e 358 [100 (M ⁺ )].

o) Preparation of 4-{[4-(2-bromophenyl)-4,5-dihydro-1,1-dioxo-1,2,4-thiadiazol-3-yl]-amino)-3-hydroxybenzonitrile 220 mg (0.39 mmol) of N-(4-cyano-2-hydroxyphenyl)-Ν'-(2-bromophenyl)-N”-[(chloromethyl)sulfonyl]guanidine in 4 ml of N, N-dimethylformamide at room temperature was added with 20 mg (0.78 mmol). Twenty-four hours later, the reaction was quenched by adding 5 ml of water, and the aqueous mixture was extracted with ethyl acetate. The organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained as a residue was purified by column chromatography using a 75:25 volume ethyl acetate/hexane solvent mixture as eluent. As a result, 4-{[4-(2-bromophenyl)-4,5-dihydro-1,1-dioxo-1,2,4-thiadiazol-3-yl]-amino}-3-hydroxybenzonitrile was obtained as a tan powder in 100 mg (63 % yield). ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 8.1 (1H, d), 7.85 (1H, d) , 7.7 (1H, d) , 7.6 (1H, t), 7.5 (1H,

t), 7.2 (1H, d), 7.0 (1H, s), 4.75 (2H, q). MS (EI) m/e 406 [100 (M ⁺ )].

P) Preparation of 4-{[1-(2-bromophenyl)-ΙΗ-2-imidazolyl]-amino}-3-hydroxybenzonitrile

To a solution of 120 mg (0.28 mmol) of N-(4-cyano-2-hydroxyphenyl)-27'-(2-bromophenyl)-N-(2,2-dimethoxyethyl)guanidine in 1 mL of acetone at room temperature was added 1 mg of p-toluenesulfonic acid. Twenty-four hours later, the reaction was quenched by adding 5 mL of water, and the aqueous mixture was extracted with ethyl acetate. The organic solutions were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained as a residue was purified by column chromatography using ethyl acetate as eluent. As a result, 12 mg of 4-{[1-(2-bromophenyl)-ΙΗ-2-imidazolyl]-amino}-3-hydroxybenzonitrile was obtained in the form of a tan powder with a 12% yield, and 4 mg of 4-{[1-(2-bromophenyl)-4,5-dihydro-5-methoxy-1H-2-imidazolyl]-amino}-3-hydroxybenzonitrile was obtained in the form of a tan powder with a 4% yield.

{[1(2-Bromophenyl)-1H-2-imidazolyl]amino}-3-hydroxybenzonitrile; ¹ H-NMR (400 MHz, CD3OD) δ (ppm): 7.45 (2H, t), 7.35 (1H, d), 7.3 (1H, s), 7.25 (1H, d), 7.15 (1H, t), 7.1 (1H, s), 7.0 (1H, s), 6.75 (1H, t). MS (El) m/e 356 [100 (M ⁺ )].

4-{[1-(2-Bromophenyl)-4,5-dihydro-5-methoxy-1H-2-imidazo[11]-amino}-3-hydroxybenzonitrile; ¹ H-NMR (400 MHz, CD3OD) δ (ppm): 7.65 (1H, t) , 7.55 (1H, d) , 7.25 (1H, t) , 7.2 (2H, s and

d) , 7.05 (1H, d) , 6.95 (1H, t) , 5.8 (1H, d) , 3.8 (1H, dd) , 3.5 (1H, dd), 3.25 (3H, s). MS (EI) m/e 388 [100 (M ⁺ )].

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, GROa, GROP, GROy, ENA-78 or NAP-2.

The compounds of formula (I) are administered in an amount sufficient to inhibit cytokine function, particularly IL-8, GROa, GRO3, GROy, ENA-78 or NAP-2 function, to such an extent that the cytokine function is reduced to normal levels or, in some cases, to subnormal levels, thereby ameliorating or preventing the disease. In the context of the present invention, abnormal levels of IL-8, GROa, GROP, GROy, ENA-78 or NAP-2 consist of three factors: (i) an amount of free IL-8 of at least 1 picogram/milliliter; (ii) any greater than normal amount of cells associated with IL-8, GROa, GROP, GROy, ΝΑΡ-2 or ENA-78; or (iii) IL-8, GROa, GROp, GROy, ENA-78 or NAP-2 is present in greater than basal levels in cells or tissues in which IL-8, GROa, GROP, GROy, ENA-78 or NAP-2 is produced.

There are many disease states in which excessive or unregulated IL-8 production plays a role in the development or exacerbation. Chemokine-mediated diseases include, but are not limited to, the following: psoriasis, atopic dermatitis, osteoarthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, advanced respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, multiple sclerosis, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, reperfusion injury to the heart or kidney; glomerulonephritis, thrombosis, graft versus host reaction, Alzheimer's disease, allograft rejection, malaria, restenosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis, and unwanted hematopoietic stem cell release.

Such diseases are characterized by massive neutrophil infiltration, T-cell infiltration, or neovascular growth. In all of these diseases, there is increased production of IL-8, GROa, GROP, GROy, ENA-78, or NAP-2, which are responsible for neutrophil chemotaxis to the site of inflammation or directed endothelial cell growth. In contrast to other inflammatory cytokines (IL-1, TNF, and IL-6), IL-8, GROa, GROP, GROy, ENA-78, or NAP-2 have the unique property of promoting neutrophil chemotaxis, enzyme release, including elastase release, and superoxide production and activation. α-chemokines, especially type I or II, are involved in the pathogenesis of inflammatory diseases. GROa, GROP, GROy, ENA-78 or NAP-2, acting through IL-8 receptors, may promote tumor neovascularization by promoting the directed growth of endothelial cells. 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 injuries as used herein refers to open and penetrating head injuries, such as surgical or closed head trauma. The term also includes ischemic stroke, particularly ischemic stroke affecting the brain region.

Ischemic stroke can be defined as a focal neurological disorder resulting from inadequate blood supply to a specific brain area, usually due to embolism, thrombosis or local atheromatous occlusion of the vessel. In these cases, the role of inflammatory cytokines increases, so the invention also offers the possibility of treating such injuries. In the case of acute injury, relatively little treatment is required.

TNF-α is a cytokine with proinflammatory effects, including the expression of endothelial leukocyte adhesion molecule. Leukocytes infiltrate the site of ischemic brain injury, and compounds that inhibit or reduce TNF levels may be useful in the treatment of ischemic brain injury [Liu et al. , Stroke, 25 (7), 1481-1488 (1994)].

Closed head injury models and treatment with mixed 5-LO/CO agents are described in Shohami et al., J. of Vasc. & Clinical Physiology and Pharmacology, 3_ (2), 99-107 (1992). Treatment resulting in decreased edema formation was found to improve functional performance in treated animals.

The compounds of formula (I) are administered in an amount sufficient to inhibit IL-8 bound to the IL-8a or IL-θβ receptor from binding to said receptors, as evidenced by a reduction in neutrophil chemotaxis and activation. The knowledge that the compounds of formula (I) are inhibitors of IL-8 binding is based on the effects of the compounds of formula (I) in the in vitro receptor binding assays described below. The compounds of formula (I) are in some cases dual inhibitors of recombinant type I and type II IL-8 receptors. Preferably, the compounds are inhibitors of only a single 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 of the production or action of IL-1 that 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-8a or IL-8β receptor plays a role, such as, but not limited to, IL-8, GROa, GROP, GROy, 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 includes, 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. A cytokine includes, but is 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, a variety of 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, GRO0, GROy, NAP-2, ENA-78, IP-10, MIP-la, MIP-p, 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 routes of administration of 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 inside the oral cavity, or instilling the compound into the eyes, ears, or nose. In such administration, the compound does not enter the bloodstream in significant amounts. Systemic administration, in contrast, 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 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 which may optionally contain 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 agents and skin 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, inter alia, the following: hydrocarbons, such as hard, soft or liquid paraffin, glycerin, beeswax, metallic soap; adhesives; oils of natural origin, such as almond, corn, arachis (peanut), castor or olive oil; wool fat or derivatives thereof 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 agent and/or any other suitable preservative, preferably a surfactant. The solution thus obtained may be filtered and 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 agents suitable for use in drops include, but are not limited to, phenylmercury (II) nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and hexidine 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. intranasal and oral inhalation. 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 chemokine 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-ββ 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 ¹²⁵ I-IL-8 125 or Ι-GROa, and 0.5 pg/ml IL-8Ra or 1.0 pg/ml IL-8Rb membrane, 1.2 mM magnesium sulfate, 0.1 mM EDTA, 25 mM sodium chloride, and 0.03% CHAPS in 200 mM Bis-Trisporane and 0.4 mM Tris-HCl buffer. In addition, the drug or compound to be tested, previously dissolved in dimethyl sulfoxide, was used in amounts necessary for a final concentration between 0.01 nM and 100 μΜ. The assay was initiated by the addition of ¹²⁵ I-IL-8. The plate was kept at room temperature for one hour, then filtered through a glass fiber filter blocked with 1% poly(ethyleneimine) using a Tomtec apparatus. The filter was washed three times with 25 mM sodium chloride, 10 mM Tris-HCl, 1 mM magnesium sulfate, 0.5 mM EDTA, 0.03% CHAPS, pH 7.4 buffer, then dried, and radioactivity was measured using a Betaplate liquid scintillation counter. The recombinant IL-8Ra or type I receptor is also referred to as the non-permissive receptor, while the IL-8Rb or type II receptor is also referred to as the permissive receptor.

In this study, the compounds of formula (I) described in the chemical preparation examples (Examples 1-15) showed IC50 values of less than about 1 pg/ml in the IL-8 inhibition model. Of the compounds tested, the compounds of Example 112 also inhibited Gro-α binding to about the same extent.

Chemotaxis assay

The in vitro inhibitory properties of the compounds of the invention were determined using a standard neutrophil chemotaxis assay (Current Protocols in Immunology, vol. I, Suppl. 1, Unit 6.12.3.). Neutrophils were isolated from human blood using a standard method (Current Protocols in Immunology, vol. I, Suppl. 1, Unit 7.23.1.). The chemoattractants IL-8, GROa, GROp, GROy and NAP-2 were placed in the lower chamber of a 48-well chamber (Neuro Probe, Cabin John, Maryland, United States) at concentrations ranging from 0.1 nM to 100 nM. The two chambers were separated by a 5 μιη polycarbonate filter. When testing the 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. 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). Chemotaxis cells for chemokine were visually counted using a microscope. Typically, four fields were counted for each sample and the average of the counts obtained was used 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. Neutrophils were isolated from human blood using a standard procedure (Current Protocols in Immunology, vol. I, Suppl. 1, Unit 7.23.1.). 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 was 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, tumor necrosis factor mRNA expression was determined 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 a moderate (2.4 atm.) lateral fluid percussion traumatic brain injury was inflicted on the animals (n = 18) centered over the left temporoparietal cortex, or the animals (n = 18) were sham-treated (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); the 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 was performed relative 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), LC sample (105 ± 21%, p < 0.05), and LA sample (69 ± 8%, p < 0.01). Six hours after injury, an increase in TNF-α mRNA expression was also observed in the LH sample (46 ± 8%, p < 0.05), LC sample (30 ± 3%, p < 0.01), and LA sample (32 ± 8%, p < 0.01), which normalized 24 hours after injury. In the contralateral hemisphere, an increase in TNF-α mRNA expression was observed 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. In the six brains examined in sham-treated (non-injury intervention) or natural (untreated) animals, no consistent change in TNF-α mRNA expression was observed in any of the hemispheres at the mentioned 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. Because TNF-α is able to induce nerve growth factor (NGF) and stimulate 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 a moderate (2.4 atm.) lateral fluid percussion traumatic brain injury was inflicted on the animals (n - 18) by focusing on the left temporo-parietal cortex, or the animals (n = 18) were subjected 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); the 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 the 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, play a role in the post-traumatic sequelae 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 (5)

PATENT CLAIMS 1. A compound of general formula (I) (I) — in the formula of which in the formula R is a hydroxy, mercapto group or a group of the general formula -NHSO2Rd; Rd is a group of the general formula -NR5R7, alkyl group, ^aryl ( ^1-4C alkyl), aryl-(2-4C alkenyl), heteroaryl group, heteroaryl-(1-4C alkyl), heteroaryl-(2-4C alkenyl), heterocyclyl group or heterocyclyl-(1-4C alkyl), wherein each of the rings constituting the aryl, heteroaryl and heterocyclyl groups may be optionally substituted; Rg and R7 are independently hydrogen or C1-C4 alkyl, or ^R6 and _R7 together with the nitrogen atom to which they are attached form an optionally substituted 5-7 membered cyclic group, optionally containing one additional heteroatom selected from oxygen, nitrogen and sulfur; ^R 1 is independently hydrogen; halogen; nitro; cyano; alkyl (1-10C); haloalkyl (1-10C); alkenyl (2-10C); alkoxy (1-10C); haloalkoxy (1-10C); azido; hydroxy; hydroxyalkyl (1-4C); aryl; aryl-( ^1-4C ); aryloxy; aryl-(1-4C); alkoxy; heteroaryl; heteroarylalkyl; heterocyclyl; heterocyclyl-(1-4C); heteroaryl-(1-4C); aryl-(C2-C10 alkenyl) group; heteroaryl-(C2-C10 alkenyl) group; heterocyclyl-(C2-C10 alkenyl) group; - (CR8R ₈ ) _q NR ₄ R5; -(C2-C10 alkenyl)-C (O) NR4R5; -(CR ₈ R ₈ ) _q C(O)NR ₄ R ₅ ; - (CR ₈ R ₈ ) _q C(0)NR ₄ Riq group; sulfo group; -S(O) ₃ R ₈ ; - (CR ₈ R ₈ ) _q C (0) R11; -(C2-10 alkenyl)-C (0) Rn; -(C2-10 alkenyl) -C (O) ORn; - (CR ₈ R ₈ ) _q C (0) OR12; - (CR ₈ R ₈ ) _q 0C (0)Rn; - (CR ₈ R ₈ ) _q NR ₄ C (O) Rn ; - (CR ₈ R ₈ ) _q NHS (0) 2 ^r 17! ~ (CR ₈ R ₈ ) _q S (0) ₃ NR ₄ Rs group; or two ^R i groups together may form a group of the general formula -0-(0¾) ₃ -0- or a five- or six-membered 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; 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), heterocyclyl, heterocyclyl-(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 an additional heteroatom selected from oxygen, nitrogen and sulfur; ^R 2 is independently an alkylene group having 2-5 carbon atoms or an alkenylene group having 2-5 carbon atoms, optionally substituted up to three times independently with a halogen atom, a nitro group, a haloalkyl group having 1-4 carbon atoms, an alkyl group having 1-4 carbon atoms, an amino group, a mono- or dialkylamino group, a hydroxyl group, a alkoxy group having 1-4 carbon atoms, a group of the general formula -NRgC(O)R _a , -S(O) _m R _a , -C(O)NRgR ₇ , a carboxy group, a group of the general formula -C(O)OR _a , -S(0) ₂ NR ₆ R ₇ and/or a group of _the general formula -NHS(O) ₂ R a , and which alkylene or alkenylene group, in addition to the carbon atoms, optionally independently with 1-3 >NRg groups, an oxygen atom, a carbonyl group, contains a sulfur atom, a sulfinyl or a sulfonyl group; independently represents a hydrogen atom; a halogen atom; a nitro group; a cyano group; an alkyl group of 1-10 carbon atoms; a haloalkyl group of 1-10 carbon atoms; an alkenyl group of 2-10 carbon atoms; an alkoxy group of 1-10 carbon atoms; a haloalkoxy group of 1-10 carbon atoms; an azido group; a group of the general formula -(CRgRg) qS(O) tR4; a hydroxy group; a hydroxyalkyl group of 1-4 carbon atoms; aryl group; aryl-(1-4 carbon atoms alkyl) group; aryloxy group; aryl-(1-4 carbon atoms alkoxy) group; heteroaryl group; heteroarylalkyl group; heteroaryl-(1-4 carbon atoms alkoxy) group; heterocyclyl group; heterocyclyl-(1-4 carbon atoms alkyl) group; aryl-(C2-10 alkenyl) group; heteroaryl-(C2-10 alkenyl) group; heterocyclyl-(C2-10 alkenyl) group; - (CRgRg) _q NR ₄ R ₅ ; -(C2-10 alkenyl)-C (O) NR ₄ R ₅ ; -(CRgRg) _q C(O)NR ₄ R ₅ ; - (CRgRg) _q C (O) NR ₄ R ₄ q group; sulfo group; -S(O)3Rg; - (CRgRg) _q C (O) Rn; -(C2-10 alkenyl)-C (O) Rn; -(C2-10 alkenyl)-C (0) ORn; -C(O)Rn; - (CRgRg) _qC (O) _ORi2 ; - (CR ₈ R ₈ ) _q OC (O) R n ; - (CRgRg) _q NR ₄ C (0)Rn; - (CRgRg ) _q NHS (O) ₂ Rd» - (CRgRg) _q S (O) 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; Rg is hydrogen or C1-C4 alkyl; R9 is hydrogen or C1-C4 alkyl; R10 is a group of the general formula -(C1-C10 alkyl)-C(O) _2Rs ; 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 heterocyclyl group, or an optionally substituted heterocyclyl-(C1-C4 alkyl) group; R12 represents a hydrogen atom, a C1-C10 alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group; R17 is C1-4 alkyl, aryl, aryl-(C1-4 alkyl), heteroaryl, heteroaryl-(C1-4 alkyl), heterocyclyl or heterocyclyl-(C1-4 alkyl), wherein each of the ^{aryl /} heteroaryl and heterocyclyl groups may be optionally substituted; and R _a represents alkyl, aryl, aryl-(C 1-4 alkyl), heteroaryl, heteroaryl-(C 1-4 alkyl), heterocyclyl or heterocyclyl-(C 1-4 alkyl), each of which groups may be optionally substituted - and pharmaceutically acceptable salts thereof. 2. A compound according to claim 1 selected from the group consisting of: 4-{[1-(2-bromophenyl)-4,5-dihydro-5-oxo-1H-2-imidazolyl]- -amino}-3-hydroxybenzonitrile; N-(4-cyano-2-hydroxyphenyl)-Ν'-(2-bromophenyl)-N-[(chloromethyl)sulfonyl]guanidine; N-(4-cyano-2-hydroxyphenyl)-Ν'-(2-bromophenyl)-N-(2.256 -dimethoxyethyl)guanidine; 4-{[1-(2-bromophenyl)-4,5-dihydro-1H-2-imidazolyl]-amino}-3-hydroxybenzonitrile; 4-{[4-(2-bromophenyl)-4,5-dihydro-1,1-dioxo-1,2,4-thiadiazol-3-yl]amino}-3-hydroxybenzonitrile; 4-{[1-(2-bromophenyl)-1H-2-imidazolyl]amino}-3-hydroxybenzonitrile; 4-{[(3)-1-(2-bromophenyl)-4-isopropyl-5-oxo-4,5-dihydro-1H-2-imidazolyl]amino}-3-hydroxybenzonitrile; ethyl-3-[(3)-1-(2-bromophenyl)-2-(4-cyano-2-hydroxy- - anilino)-5-oxo-4,5-dihydro-1H-4-imidazolyl]-propionate; ^e ethyl-[(R)-1-(2-bromophenyl)-2-(4-cyano~2-hydroxyanilino)- - 5-OXO-4,5-dihydro-1H-4-imidazolyl]acetate; 4-{[(S)-1-(2,3-dichlorophenyl)-4-isopropyl-5-oxo-4,5-dihydro-1H-2-imidazolyl]amino}-3-hydroxybenzonitrile; 4-{[(S)-1-(2,3-dichlorophenyl)-4-isobutyl-5-oxo-4,5-dihydro ^- 1R-2-imidazolyl]amino}-3-hydroxybenzonitrile; 4 - [ { (3)-1-(2,3-dichlorophenyl)-4-[2-(methylthio)ethyl]-5-oxo- - 4,5-dihydro-11-[2-imidazolyl]amino]-3-hydroxy- - benzonitrile; ethyl-3-[(S)-2-(4-cyano-2-hydroxyanilino)-1-(2, 3-dichloro- - phenyl)-5-ΟΧΟ-4,5-dihydro-1H-4-imidazolyl]propionate; 4-{[(3)-1-(2,3-dichlorophenyl)-4-methyl-5-oxo-4, 5-dihydro-1H- - 2-imidazolyl]amino}-3-hydroxybenzonitrile; 4-{[(R)-1-(2,3-dichlorophenyl)-4-methyl-5-oxo-4,5-dihydro-1H- - 2-imidazolyl]amino}-3-hydroxybenzonitrile; and 4-{[1-(2-bromophenyl)-4,5-dihydro-5-methoxy-1H-2- - imidazolyl]amino}-3-hydroxybenzonitrile; or pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent. 4. A method for treating chemokine-mediated diseases in a mammal, wherein the chemokine binds to an IL-8a or IL-δβ receptor, comprising administering to the mammal an effective amount of a compound according to claim 1. 5. The method of claim 4, wherein the mammal suffers from a disease mediated by a chemokine selected from the group consisting of psoriasis, atopic dermatitis, osteoarthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, advanced respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, multiple sclerosis, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, reperfusion injury to the heart or kidney; glomerulonephritis, thrombosis, graft versus host reaction, Alzheimer's disease, allograft rejection, malaria, restenosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis, and unwanted hematopoietic stem cell release. The authorized person: