WO2004063192A1

WO2004063192A1 - Imidazolyl pyrimidine derivatives useful as il-8 receptor modulators

Info

Publication number: WO2004063192A1
Application number: PCT/US2004/000469
Authority: WO
Inventors: Jaap Van Der Louw; Michael H. J. Ohlmeyer; Adolph C. Bohnstedt; Koc-Kan Ho; Douglas S. Auld; Steven G. Kultgen; Andrew Laird Roughton
Original assignee: Pharmacopeia Drug Discovery, Inc.
Priority date: 2003-01-10
Filing date: 2004-01-09
Publication date: 2004-07-29

Abstract

The invention relates to compounds of the formula I, wherein R1, R2, R3 and R4 are each independently selected from H, (1-4C)alkyl, (1-4C)alkoxy, trifluoromethyl, trifluoromethoxy, halogen, amino, sulfonamide, cyano, OH and nitro; R5 is H or (1-6C)alkyl; R6 is H, (1-6C)alkyl or (1-6C)alkoxy; R7 is H or (1-6C)alkyl; R8 is (1-6C)alkyl, optionally substituted with (1-6C)alkoxy; R9 is -(CH2)nR10, wherein n is 1, 2 or 3 and R10 is selected from (1-4C)alkoxy, (1-4C)alkylthio, trifluoromethyl, (3-8C)cycloalkyl, phenyl optionally substituted with (1-4C)alkoxy, -NR11R12 and -O(CH2)2NR11R12, wherein one of R11 and R12 is (1-4C)alkoxy, the other being H or (1-4C)alkyl, or R9 is -CH2(2-7C)heterocycloalkyl, provided that when at least one heteroatom in the heterocycloalkyl moiety is nitrogen, the distance between this nitrogen and the nitrogen in 'NHR9' is at least three carbon atoms, or R9 is -(CH2)3(2-7C)heterocycloalkyl or -(CH2)2CHR13R14, wherein R13 and R14 together with the carbon atom to which they are attached, are (2-7C)heterocycloalkyl; and X is O, S or NH; or a pharmaceutically acceptable salt thereof. The compounds of the invention are Il-8 receptor modulators, in particular inhibitors thereof, and can be used for treating or preventing Il-8 receptor mediated disorders, such as atherosclerosis, inflammation, rheumatoid arthritis and related disorders.

Description

IMIDALOZYL PYRIMIDINE DERIVATIVES USEFUL AS IL-8 RECEPTOR MODULATORS

Cross Reference to Related Applications

This application claims priority from US provisional application 60/439,357, filed January 10, 2003, and is related in subject matter to US non-provisional application 10/340,398, filed January 10, 2003, and to US provisional application 60/439,362, filed January 10, 2003 . The entire disclosures of all are incorporated herein by reference.

Field of the Invention

The invention relates to chemical compounds containing the imidazolyl-2-pyrimidine nucleus, a process for the preparation of the compounds, pharmaceutical compositions containing the same, as well as the use of the compounds for the manufacture of a medicament for treating or preventing IL-8 (CXCL8) receptor mediated disorders.

Background of the Invention

Chemokines are pro-inflammatory mediators that primarily control leukocyte migration into selected tissues and upregulation of adhesion receptors. By interaction with their respective G-protein-coupled receptor (GPCR) chemokines have a profound influence on the selective recruitment of specific cell types in several inflammatory diseases.

Chemokines are members of the cytokine superfamily. They generally have low molecular weights ranging from 7 to 15 kDa and stimulate the recruitment of well defined leukocyte subtypes. Chemokines are secondary pro-inflammatory mediators that are induced by primary pro-inflammatory mediators like IL-1 and TNF. Chemokines are divided into two large families (CXC and CC) according to the organisation of the first two of four conserved cysteines in the primary molecular structure.

Actions of CXC chemokines are mediated through four cell surface receptors, CXCR1 to CXCR4, which are G protein-coupled receptors (GPCRs). IL-8 signals through CXCR1 and CXCR2 (IL-8 receptors). Pharmacological distinction between both receptors is possible since GRO, ENA78, and NAP-2 only bind CXCR2, whereas IL-8 binds both CXCR1 and CXCR2. This two-receptor system does not exist in rodents. Rodents appear to possess only the CXCR2 homologue, which is designated IL-8Rh (IL-8 receptor homologue). The phenotype of mice that lack the murine IL-8Rh resembles that of patients with leukocyte adhesion deficiency, i.e. neutrophils that fail to infiltrate tissues (Cacalano G et al., Science 265;682-684, 1994). Until recently, CXCR2 was especially regarded as a chemokine receptor inducing neutrophil activation. More recently it became clear that CXCR2 also functions on monocytes, macrophages, and T cells. Strong, recently collected, data suggest a crucial role of CXCR2 in both atherosclerosis and rheumatoid arthritis.

The process of vascular transformation that ultimately leads to atherosclerosis involves the influx of monocytes into the vascular wall. These monocytes transfer to macrophages and become loaded with large amounts of lipids. A vast amount of evidence points to a crucial role of monocytes/macrophages in the development and progress of the disease.

It was shown only recently that IL-8 and CXCR2 are important for monocyte infiltration into the vascular wall. Expression of IL-8 is induced by Ox-LDL in monocytes and is expressed in atherosclerotic plaques. IL-8 and CXCR2 signalling have been shown to be associated with atherosclerosis in vivo. In 1998 Boisvert et al. (JCI 101;353-363, 1998) showed that atherosclerosis susceptible mice (LDL-R-deficient) that were lethally irradiated and transplanted with bone marrow from mice that lack the mIL-8Rh develop less severe lesions compared to mice that receive normal bone marrow. Lesion area from these mice were reduced by a factor 2.5 and contained significantly less macrophages as compared to control recipients (Boisvert WA et ai, 1CI 101;353-363, 1998). Thus, there seems to be a role for a CXCR2 homologue in the recruitment of monocytes/macrophages. In mice, KC/GRO-α and MIP-2 are endogenous ligands for mIL-8Rh. KC/GRO-α expression was generally abundant in atherosclerotic lesions of LDLR knock-out mice (Boisvert WA et al, CI 101 ;353-363, 1998). The role of CXCR2 in atherosclerosis was further underscored by researchers from SmithKline Beecham. They reported a 40% reduction in plaque density in LDLR knock-out mice compared to placebo treated animals. Using human cells, Gerszten et al. (Nature 398, 718-723, 1999) showed that IL-8 mediates firm adhesion of human monocytes on endothelial cells (HUVECs). Furthermore, IL-8 was identified as an inducer of monocyte/macrophage migration. Thus, convincing data links IL-8 and CXCR2 through their activity on monocytes/macrophages with atherosclerosis.

The current concept of rheumatoid arthritis deals with the assumption that inflammation and joint destruction are the net results of complex cell-cell interactions. The driving force is supposed to be the (false) recognition of self-peptides by CD⁴+ T cells on the surface of various types of antigen presenting cells. Released lymphokines activate monocytes/macrophages, which respond with an increase in their cytokine (e.g. TNFα, IL-1), chemokine (e.g IL-8) and enzyme (e.g. MMFs) output. These secreted products maintain and amplify the aforementioned process and further stimulate fibroblasts and chondrocytes to release cartilage degrading enzymes (e.g. MMPs), adhesion molecules and chemotactic factors (e.g. IL-8) for new recruitment of T cells, monocytes and neutrophils to the afflicted joints. In recent years, especially the role of macrophages in the immunopathogenesis of rheumatoid arthritis has gained more and more attention, because macrophage-secreted chemokines and cytokines, together with fibroblast-derived cytokines, constitute the major part of the cytokine profile in synovial fluid and because the number of macrophages is increased considerably in the synovial tissue of rheumatoid arthritis patients at sites where cartilage degration is fulminate. The secretion pattern of monocytes/macrophages includes IL-8. In vitro stimulation of IL-8 production can be achieved by simple contact with synovial fluid taken from rheumatoid arthritis patients and, without the interference of soluble mediators, by direct contact with activated T cells (Koch et al., J. Immunol., 147, 2187-2195, 1991; Rodenburg et al, Ann Rheum. Dis., 58, 648-652, 1999). Pro-inflammatory cytokines, like TNFα, IL-1 and IL-17, which are all prominantly present in synovial fluid of arthritis patients, induce high levels of IL-8 as well as GROα production by synovial chondrocytes and fibroblasts (Pulsatelli et al, J. RheumatoL, 26, 1992-2000, 1999).

Beside a role in atherosclerosis and rheumatoid arthritis, elevated production and local concentrations of IL-8 in affected tissues have been found to be associated with a number of disease states. Chemokine (such as, but not limited to IL-8, Gro-alpha (CXCL1), Gro-beta (CXCL2), Gro-gamma (CXCL3), NAP-2 or ENA-78 (CXCL5)) mediated diseases include psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, ulcerative colitis, idiopathic pulmonary fibrosis, imTammatory bowel disease, adult respiratory distress syndrome (ARDS), Crohn's disease, stroke, meconium aspiration syndrome, cardiac and renal reperfusion injury, glomerulonephritis, graft vs. host reaction, alzheimers disease, allograft rejections, malaria, restenosis, angiogenesis, undersired hematopoietic stem cell release, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, and cancer.

As described above several diseases are associated with an increase in IL-8 production and other ligands of CXC chemokine receptors leading to chemotaxis of cells involved in the disease process. Therefore, these diseases would benefit by compounds that are inhibitors of chemokine receptor binding.

It has now been found that compounds of the formula I

wherein

R¹, R², R³ and R⁴ are each independently selected from H, (l-4C)alkyl, (l-4C)alkoxy, trifluoromethyl, trifluoromethoxy, halogen, amino, sulfonamide, cyano, OH and nitro;

R⁵ is H or (l-6C)alkyk

R⁶ is H, (l-6C)alkyl or (l-6C)alkoxy;

R⁷ is H or (l-6C)alkyl;

R⁸ is (l-6C)alkyl, optionally substituted with (l-6C)alkoxy;

R⁹ is -(CH₂)_nR¹⁰, wherein n is 1, 2 or 3 and R¹⁰ is selected from (l-4C)alkoxy, (1-

4C)alkylthio, trifluoromethyl, (3-8C)cycloalkyl, phenyl optionally substituted with

(14C)alkoxy, -NR^πR¹² and -O(CH₂)₂NR^πR¹², wherein one of R¹¹ and R¹² is (l-4C)alkoxy, the other being H or (l-4C)alkyl, or R⁹ is -CH₂(2-7C)heterocycloalkyl, provided that when at least one heteroatom in the heterocycloalkyl moiety is nitrogen, the distance between this nitrogen and the nitrogen in "NHR⁹" is at least three carbon atoms, or R⁹ is

-(CH₂)₃(2-7C)heterocycloalkyl or -(CH₂)₂CHR¹³R¹⁴, wherein R¹³ and R¹⁴ together with the carbon atom to which they are attached, are (2-7C)heterocycloalkyl; and X is O, S orNH; or a pharmaceutically acceptable salt thereof are potent IL-8 receptor modulators, in particular inhibitors thereof, having anti-inflammatory activity and interesting pharmacological properties.

The compounds of the present invention are useful for treating or preventing IL-8 receptor mediated disorders, such as atherosclerosis, inflammation, rheumatoid arthritis and related disorders. Further, the term "IL-8 receptor mediated disorders" refers to any and all disease states in which chemokines play a role (vide supra). Preferred compounds according to the invention are compounds having the structure II

II

Other preferred compounds of formula I are those, wherein R¹, R², R³ and R⁴ are each independently selected from H, (l-4C)alkyl, (l-4C)alkoxy, trifluoromethyl, trifluoromethoxy, halogen and nitro; R⁵ is H; R⁶ is (l-6C)alkyl; R⁷ is H; and R⁸ is (l-6C)alkyl.

Further prefeιτed are compounds of formula I, wherein R⁹ is -(CH₂)_nR¹⁰, wherein n is 2 or 3 and R¹⁰ is selected from (l-4C)alkoxy, trifluoromethyl, cyclopentyl, cyclohexyl, phenyl substituted with (l-4C)alkoxy, and -NR^πR¹², wherein one of R¹¹ and R¹² is (l-4C)alkoxy, the other being (l-4C)alkyl, or R⁹ is -(CH₂)₃(2-7C)heterocycloalkyl or -(CH₂)₂CHR¹³R¹⁴, wherein

R¹³ and R¹⁴ together with the carbon atom to which they are attached, are (2-

7C)heterocycloalkyl.

Most preferred are compounds wherein X is O.

The terms (l-4C)alkyl and (l-6C)alkyl mean a branched or unbranched alkyl group having 1 to 4 or 1 to 6 carbon atoms, respectively, such as methyl, ethyl, isopropyl, t-butyl and the like.

The term (l-4C)alkoxy means an alkoxy group having 1-4 carbon atoms, the alkyl moiety of which having the meaning as previously defined.

The term (3-5C)alkylene means an unbranched alkylene group having 3 to 5 carbon atoms, respectively, such as propylene. The term (3-8C)cycloalkyl means a cycloalkyi group having 3-8 carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclo-octyl. Cyclopentyl and cyclohexyl are preferred cycloalkyi groups.

The term (2-7C)heterocycloalkyl means a cyclic group having 2 or 7 carbon atoms and further containing one or two heteroatoms selected from O, S or N, such as tetrahydrofuranyl, tetrahydropyranyl and morpholinyl.

The term halogen means fluorine, chlorine, bromine or iodine. Preferred halogens are fluorine and chlorine.

In the definitions, the term substituted means: substituted by one or more substituent. Compounds according to formula I may suitably prepared as described in the following. The synthesis is started with 2,4-dichloropyrimidine or 4,6-dichloro-2- methylsulfanylpyrimidine. Substituents on the pyrimidine ring are introduced under basic conditions. Regioisomers can be separated by column cliromatography. In the final two steps the alcohol is oxidised to the carboxylic acid and the in situ formed active ester of the carboxylic acid is condensed with a range of amines to form the desired amides.

Benzofuranylimidazole building blocks used in the current invention are prepared from the corresponding phenols. The phenol is converted to a 2-formyl-benzofuran. Subsequent ether formation using 2-bromo-l, 1-diethoxyethane and cyclisation under acidic conditions yields the benzofuran-2-carbaldehyde. The aldehyde is reacted with p-tolylsulfonyl isocyanide (TosMIC), followed by heating in methanolic ammonia to give the imidazole. A further embodiment of this invention is a process for preparing a compound of formula I, comprising the introduction of the chiral centre using enantiomer pure aminoalcohol (e.g. leucinol), which after modifications on the pyrimidine ring, is oxidised to the corresponding carboxylic acid followed by amide formation. By using this synthetic sequence, racemisation of the chiral centre is avoided.

The compounds of the invention, which can be in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts may also be obtained by treating the free base of formula I with an organic or inorganic acid such as, but not limited to, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, η propionic acid, glycolic acid, maleic acid, maionic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.

Compounds of the invention may exist in solvated as well as in unsolvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

Compounds of the present invention may exist as amorphous forms, but also multiple crystalline forms may be possible. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of this invention.

The compounds of this invention possess one or more chiral carbon atoms, and may therefore be obtained as a pure enantiomer, or as a mixture of enantiomers, or as a mixture containing diastereomers. Methods for obtaining the pure enantiomers are well known in the art, e.g. crystallization of salts which are obtained from optically active acids and the racemic mixture, or chromatography using chiral columns. For diastereomers straight phase or reversed phase columns may be used.

The compounds of the invention may be administered enterally or parenterally, and for humans preferably in a daily dosage of 0.001-100 mg per kg body weight, preferably 0.01-10 mg. per kg body weight. The oral administration is generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques. Mixed with pharmaceutically suitable auxiliaries, e.g. as described in the standard reference, Gennaro et al., Remington's Pharmaceutical Sciences, (20th ed., Lippincott Williams & Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing) the compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds can also be applied in the form of a solution, suspension, emulsion, e.g. for use as an injection preparation, or as a spray, e.g. for use as a nasal spray.

For making dosage units, e.g. tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used. Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.

The invention is further illustrated by -but not limited to- the following examples.

EXAMPLES

Abbreviations

Formule I

In this part reference is made to "Ra, Rb, Re and Rd" only for explanatory reasons to generalize the procedural steps. The meaning of "X" is the same as X in the formula I of the claims.

Synthetic Overview

All non commercially available alkyl substituents on Rb are introduced on 2,4 dichloro pyrimidine using the alkyl bromine in the presence of lithium (J.Org.Chem.,1988, 53, 4137-

4140).

An aminoalcohol was reacted with 2,4-dichloro-6-methyl pyrimidine and the resulting regioisomers were separated. Subsequent reaction of the 2-chloropyrimidine isomer with a benzofuranylimidazolyl, oxidation and amide formation, afforded the final product (Scheme

1).

CI CI

Scheme 1

The synthetic methods for the benzofiiranylimidazolyl and some reagents incorporated as the Rd groups (Formula I) are outlined in Schemes 1 to 4.

Benzofuranylimidazoles used in the current invention were prepared from the corresponding phenols (Scheme 2). The phenol was converted to a 2-formyl-benzofuran Chem.Pharm.Bull.,1983, 31, 1751; Tetrahedron Lett., 1992, 33, 2179). Subsequent ether formation using 2-bromo-l,l-diethoxyethane and cyclisation under acidic conditions yielded the benzofuran-2-carbaldehyde. The aldehyde was reacted with p-totylsulfonyl isocyanide (TosMIC), followed by heating in methanolic ammonia to give the imidazole.

HOAc Mg₂SO„

_N TosMic, K_jCO-_j, EtOH O

Ra ^■ *1 ^■* Ra V-NH NH MeOH O

Scheme 2

Representative procedures for reactions shown in Schemes 1 and 2 are as follows:

2-Hydroxy-5-trifluoromethyl-benzaldehyde.

HMTA (47 gram) was added to a solution of 4-trifluoromethyl-phenol (50 gram) in TFA (650 ml). The reaction mixture was stirred for 2 hours at 80°C. At 0°C, water (355 ml) and H₂SO (9N, 190 ml) were added. The mixture was stirred at room temperature for 17 hours. The mixture was extracted three times with diethyl ether. The diethyl ether layers were combined, washed three times with HCI (4N, 500 ml), cautiously with a solution of NaOH (5N, 200 ml) until pH = 5 of the water layer, dried over sodium sulfate, filtered and evaporated. Silica gel chromatography (DCM) provided 28.5 g of the title compound.

2-(2,2-Diethoxy-ethoxy)-5-trifluoromethyl-benzaldehyde.

A solution of 2-hydroxy-5-trifluoromethyl-benzaldehyde (35 gram), 2-bromo-l,l-diethoxy- ethane (36 gram) and K₂CO₃ (39 gram) in DMSO (230 ml) was stirred at 130°C for 5 hours. The solution was taken up in water, and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Silica gel chromatography (heptane/ethyl acetate 95/5) provided 22.6 g of the title compound.

5-trifluoromethyl-benzofuran-2-carbaldehyde.

To a solution of 2-(2,2-diethoxy-ethoxy)-5-trifluoromethyl-benzaldehyde (22.6 gram) in HOAc (300 ml) was added Mg₂SO₄ (17.8 gram). The mixture was stirred for 3 hours at reflux, filtered and the solvent was removed in vacuo. Silica gel chromatography (heptane/ethyl acetate 9/1) provided 8.6 g of the title compound. MS(m/z) 215[M+H]⁺

4-(5-TrifluoromethyI-benzofuran-2-yl)-imidazoIe.

To a round-bottom flask containing 5-trifluoromethyl-benzofuran-2-carbaldehyde from above (1.51 g) was added ethanol (20 mL), followed by TosMIC (1.38 g). The mixture was stirred at room temperature for 10 min. and cat. NaCN (34 mg) was added. After an additional 30. min stirring, the solid/suspension was filtered. The solid cake was washed with cold ethanol and dried in vacuo to give the tosyloxazoline intermediate (2.16 g) as a white solid. The intermediate was added to a glass pressure vessel containing NH₃ in methanol (120 ml of a 7.0 N solution). The vessel was capped and heated to 90 °C for 14 hours. The contents were carefully cooled to 0 °C and the vessel was opened. Upon warming slowly to room temperature, most of the ammonia had dissipated. The mixture was transferred to a round- bottom flask and concentrated in vacuo. The title compound (0,56 g) was isolated from the crude mixture by flash chromatography (dichloromethane/methanol 10/1). MS(m/z) 253[M+H]⁺

(2S)-2-(6-Butyl-2-chloro-pyrimidin-4-ylamino)-4-methyl-pentan-l-oI.

A solution of 2,4-dichloro-6-butylpyrimidine (46 gram), L-leucinol (30.2 gram) and DIEA (117 ml) in dimethyl sulfoxide (90 ml) was stirred at room temperature for 17 hours. The solution was taken up in water, and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Silica gel chromatography (heptane/ethyl acetate 4/1) provided 31 g of the title compound. MS(m/z) 286[M+H]⁺

(2S)-2-{6-ButyI-2-[4-(5-trifluoromethyI-benzofuraπ-2-yl)-iιnidazoI-l-yl]-pyrimidin-4- ylamino}-4-methyI-pentan-l-ol.

A solution of (2S)-2-(6-butyl-2-chloro-pyrimidin-4-ylamino)-4-methyl-pentan-l-ol (595 mg), 4-(5-trifluoromethyl-benzofuran-2-yl)-imidazole (890 mg), K₂CO₃ (720 mg) and KF (120 mg) in DMSO (23 ml) was stirred at 115°C for 17 hours. The solution was taken up in water, and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Silica gel chromatography (heptane/ethyl acetate 4/1) provided 700 mg of the title compound.

(2S)-2-{6-Butyl-2-[4-(5-trifluoromethyl-benzofuran-2-yl)-imidazoH-yl]-pyrimidin-4- ylamino}-4-methyl-pentanoic acid. A suspension of 2-{6-butyl-2-[4-(5-trifluoromethyl-benzofuran-2-yl)-imidazol-l-yl]- pyrimidin-4-ylamino}-4-methyl-pentan-l-ol (647 mg), iodobenzene diacetate (990 mg) and TEMPO (40 mg) in dioxane/water (120 ml/40 ml) was stirred for 41 hours at room temperature. The solution was taken up in water, and extracted three times with dichloromethane. The dichloromethane layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Crystallisation (diethyl ether/heptane) provided 524 mg of the title compound. MS(m/z) 516[M+H]⁺

(2S)-2-{6-Butyl-2-[4-(5-trifluoromethyI-benzofuran-2-yI)-imidazoI-l-yl]-pyrinιidin-4- yIaminoJ-4-methyl-pentanoic acid (3-ethoxy-propyI)-amide.

A solution of 2- {6-butyl-2-[4-(5-trifluoromethyl-benzofuran-2-yl)-imidazol- 1 -yl]-pyrimidin-4- ylamino}-4-methyl-pentanoic acid (327 mg), N-methylmorpholine (70 μl) and isobutyl chloroformate (84 μL) in THF was stirred for 0.5 hour at 0°C. At room temperature 3- ethoxypropyl amine (78 μL) was added. The reaction mixture was stirred at room temperature for 0.5 hour. The solution was taken up in water, and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Silica gel chromatography (heptane/ethyl acetate 3/2) provided 340 mg of the title compound. MS(m/z) 601[M+H]⁺

1H-NMR : (CDC1₃): δ 7.1(s,Ha), 8.6(s,Hb), 8.3(s,Hc), 1.0(dd,Hd), 2.6(t,He), 1.2(t,Hf) Some Rd groups used in Scheme 1 are not commercially available. For example, 4,4,4- trifluorobutylamine was synthesized via reductive amination of 4,4,4-trifluorobutyraldehyde (Scheme 3) using a literature procedure (J. Am. Chem. Soc, 1971, 93, 2897).

NH₄OAc/ MeOH

Scheme 3

N-(3-aminopropyl)-N,O-dimethylhydroxylamine was synthesized in 2 steps by alkylation of N,O-dimethyIhydroxylamine with N-(3-bromopropyl)phthalimide (Scheme 4) followed by removal of the phthalimide protecting group with hydrazine (J. Org. Chem., 1978, 43, 2320). The procedures to prepare 2-[3-(methoxymethylamino)propyl]isoindole-l,3-dione are shown below.

2-[3-( ethoxy-methyl-amiπo)- propyl]-isoindole-1 ,3-dioπe

Scheme 4

2-[3-(Methoxymethylamino)propyl]isoindoIe-l,3-dione.

A stirred mixture of N,O-dimethylhydroxylamine hydrochloride (5.6 g), N-(3- bromopropyl)phthalimide (3.0 g), and potassium carbonate (15.5 g) was heated at 55 °C for 24 hours in DMSO. The mixture was partitioned between water and ethyl acetate. The ethyl acetate was separated and washed 3 times with brine. The ethyl acetate was evaporated to provide a 3:1 mixture of desired product and unreacted bromide. This crude material was converted to the HCI salt with 0.6 M HCI in 95% ethanol and the resulting oil was partitioned between 1 N HCI and ethyl ether. The ethyl ether portion was washed twice with 1 N HCI. The combined HCI washes were made basic with NaOH and extracted with DCM. The DCM was dried with sodium sulfate and evaporated to provide the desired product (200 mg).

Synthetic procedures for additional examples of Rd are as follows:

2-CycIopentyl-ethyIamine.

Triethylamine (2.1 mL, 15 mM) and methanesulfonyl chloride (0.85 mL, 11 mM) were added dropwise to a cold (-5 to -10 °C) solution of 2-(tetrahydro-furan-3-yl)-ethanol (1.14 g, 10 mM) in dichloromethane (15 mL). The reaction was stirred for 20 min at this temperature then, water (10 mL) was added and the reaction was stirred an additional 10 min, the aqueous phase was extracted with dichloromethane (3 x 20 mL). The combined organics were washed with 50 % aqueous HCI, sat. NaHCO₃, dried (MgSO ), filtered and concentrated to give a quantitative yield of methanesulfonic acid 2-(tetrahydro-furan-3-yl)-ethyl ester. The crude mesylate (2.03 g, 10 mM), sodium azide (3.25 g, 50 mM) and DMF were combined and heated at 80 °C for 2 hours, cooled to roomtemperature then the mixture was diluted with ethyl acetate and thoroughly washed with water (3 x 100 mL) and brine. The organics were dried, filtered and concentrated, passed through a short silica gel column eluted with 30 % ethyl acetate /hexanes to yield 3-(2-azido-ethyl)-tetrahydro-furan (1.04 g, 75 %). A catalytic amount of 10 % palladium on carbon was added to a methanolic solution of the azide (1.04 g, 7.5 mM), the reaction flask was briefly evacuated under house vacuum and H₂ was added via a balloon. The reaction was stirred at room temperature for 17 hours under an atmosphere of H₂, filtered through a plug of celite, which was thoroughly rinsed with MeOH. HCI (1 M) in Et₂O (10 mL) was added and the volatiles were removed to give the title product as the HCI salt (51% yield). ESI-MS (m/z) 114 [M+Hf.

3-Furan-3-yl-propylamine.

3-Furaldehyde (0.43 mL, 5 mM), (cyanomethyl)triphenylphosphonium chloride (1.77 g, 5.3 mmol), DBU (0.82 mL, 5.5 mmol) in toluene (50 mL) were heated at reflux for 30 min, then the reaction volume was reduced in vacuo and the entire reaction contents added to a silica gel column. Elution with 15 % ethyl acetate/hexanes gave 3-furan-3-yl-acrylonitrile (quant) as a 5:1 mixture (1H NMR) of the E/Z isomers. Raney Ni (approx 1 mL) was added to 3-furan-3-yl-acrylonitrile (0.64 g, 5.0 mmol) in THF (6 mL), the mixture was evacuated then charged with 1 arm H₂ (balloon) and stirred overnight. The mixture was recharged with -Raney Ni (1 mL) and H₂ and stirring was continued an additional 24 hours, until no starting material was evident via TLC. The, reaction contents were filtered through a celite plug, that Was thoroughly rinsed with MeOH, solvents removed to yield a product mixture containing three components (64 % yield) (MS, m/z 126.1 (MH*), 130.2, 234.1). The mixture was purified via column chromatography. Elution with 10 % MeOH7CH₂Cl₂ gave bis-(3-furan-3-yl-propyl)-amine (ESI-MS (m/z) 234 [M+H]⁴), elution with 1 % NHtOH/10 % MeOH/CH₂Cl₂ gave the title compound (ESI-MS (m/z) 126 [M+H]⁺) together with approx 10 % (1H NMR) of over reduction product 3-(tetrahydro-furan-3-yl)- propylamine (ESI-MS (m/z) 130 [M+H .

r"°

2-(Tetrahydroraran-3-yl)-ethylamine.

Freshly prepared sodium methoxide (from the reaction of 0.165 g, 7.2 mM sodium with anhydrous methanol (1 mL)) was added dropwise via double ended needle to a cooled (0 °C) solution of tetrahydrofuran-3-carboxaldehyde (0.72 g, 7.2 mM, obtained from dichloromethane extraction of commercially available tetrahydrofuran-3-carboxaIdehyde in water (50 %, 2 mL)) and mtromethane (0.39 mL, 7.2 mM) in methanol (1 mL). The reaction mixture was stirred at 0 °C for 30 min, Et₂O was added and the resulting precipitate was collected via filtration. The solid was taken up in minimal water, ice cold 25 % aq. HCI solution was added and the resulting solution was extracted with dichloromethane. The crude product was purified by column chromatography (elution with 30 % ethyl acetate / hexanes), to yield 3-(2-Nitro-vinyl)- tetrahydro-furan (0.57 g, 55 % yield).

The above vinyl-nitro compound (0.57 g, 4.0 mM)' in anhydrous Et O (5 mL) was added dropwise over 5 min via double ended needle to an ice-cold solution of LiAlH_t (8.0 mL, 1.0 M Et₂O) diluted with Et₂O (25 mL). After the addition was complete the mixture was removed from the ice bath and heated at a gentle reflux for 17 hours. The reaction mixture was recboled to 0 °C and quenched by the careful addition of water (0.3 mL), 10 % NaOH (0.45 mL) and water (0.75 mL). Celite was added to the precipitate, which was filtered and solids thoroughly rinsed with Et₂O. The collected filtrate was dried (MgS0₄) filtered, 1M HCI / Et₂O (5 mL) was added and solvents removed to yield the titled compound as the HCI salt (30 % yield). ESI-MS (m/z) 116 [M+H]⁺.

3-(Tetrahydro-furan-3-yI)-propyIamine.

To thoroughly dried ground 4A molecular sieves (5 g) was added anhydrous CH₂C1₂ (20 mL) and 4-methylmorpholine-N-oxide (ΝMO) (1.76 g, 15 mmol). The mixture was stirred at 0 °C for 15 min, then tetrahydro-3.-furanmethanol (0.96 mL, 10 mmol) and tetrapropylammonium peiruthenate (TPAP) (0.17 g, 0.5 mmol) were added and the mixture stirred for 90 min. The solvent volume was reduced and the entire reaction content was passed through a short silica gel column with Et₂O elutant to yield tetrahydro-furan-3-carbaIdehyde (approx 50 % yield, together with a dimeric product).

Wittig reaction of the crude aldehyde with (cyanomethyl)triρhenylphosphonium chloride as descibed for 3-furan-3-yl-propylamine gave 3-(tetrahydro-furan-3-yl)-acrylonitrile (3.3 mmol) as a 2:1 mixture (1H ΝMR) of the E/Z isomers after column chromatography (10 % Et₂O/CH₂Cl₂ elutant).

Hydrogenation of 3-(tetrahydro-furan-3-yl)-acrylonitrile in the presence of Raney Νi as detailed for 3-furan-3-yl)-propylamine gave the title amine (33 % yield). ESI-MS (m/z) 130 [M+H]⁺.

3-(5-Methyl-oxazol-2-yl)-propylamine.

To a mixture of 4-ført-butoxycarbonylamino-butyric acid (5 g), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (5.66 g) and triethylamine (7.47 g) in dichloromethane (80 mL) at room temperature was added 2-propynylamine (1.49 g).^' After being stirred at room temperature for 3 hours, the mixture was diluted with dichloromethane (80 mL) and washed with 0.5 M HCI (aqueous, 2X), saturated NaHCO₃ (IX) and water (IX). The dichloromethane was dried over sodium sulfate, filtered and evaporated to afford (3-prόp-2-ynylcarbamoyl- propyl)-carbamic acid tert-butyl ester (1.67g). Sodium hydride (60 mg, 60% dispersion) was added to a mixture of (3-proρ-2-ynylcarbamoyl- propyl)-carbamic acid tert-butyi ester (0.5g) and dimethylsulfoxide (10 mL) under argon. The mixture was stirred at room temperature for 4 hours. Saturated aqueous ammonium chloride (30 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (2X). Combined ethyl acetate layers were washed with water (IX), dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography (20 to 30% ethyl acetate in hexanes) to give [3-(5-methyl-oxazol-2-yl)-propyl]-carbamic acid tert- butyi ester (150 mg).

HCI in dioxane (4M, 3 mL) was added to [3-(5-methyl-oxazol-2-yl)-propyl]-carbamic acid tert-butyi ester (250mg). The mixture was stirred at room temperature for 2 hours and evaporated to dryness in vacuo to give the HCI salt of the title compound (228 mg). ESI-MS (m/z) 141 [M+H]⁺.

Tabel 1, shown below, lists representative compounds prepared according to the above described methodes.

Tabel 1

Example 44 MS(m/z) 587[M+H]^"t

Example 45 MS(m/z) 533[M+H]⁺

Example 46 MS(m/z) 535[M+H]⁺

Example 47 MS(m/z) 532[M+H]⁺

Example 48 MS(m/z) 573[M+H]⁺

Example 49 MS(m/z) 547[M+H]⁺

The oxyalkyl substituents were introduced using the potassium salt of the corresponding alcohol and 4,6-dichloro-2-methylsulfanyl-pyrimidine as the starting compound, followed by aminoalcohol introduction, oxidation of the methylsulfanyl group to the corresponding methylsulfonyl group, substitution of the methylsulfonyl group, oxidation of the alcohol to the corresponding carboxylic acid and amide formation using TBTU.

Scheme 5

Representative procedures for reactions shown in scheme 5 are as follows:

4-Chloro-6-methoxy-2-methyIsulfanyl-pyrimidine.

At 0°C, sodium (1.77 gram) was added to MeOH (30 ml) and the mixture was stirred for 0.5 hours. This solution was added dropwise to a solution of 4,6 dichloro-2-methylsulfanyl- pyrimidine (15 gram) in MeOH (75 ml) at 0°C. The reaction mixture was stirred for 1.5 hours at room temperature. The solution was taken up in water, and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. 14.6 gram of 4-chloro-6-methoxy-2- methylsulfanyl-pyrimidine was obtained as yellow crystals. MS(m/z) 191[M+H]⁺

2-(6-Methoχy-2-methylsufanyl-pyrimidin-4-yIamino)-4-methyl-pentan-l-ol.

A solution of 4-Chloro-6-methoxy-2-methylsulfanyl-pyrimidine (900 mg), KF (274 mg), K₂CO₃ (1.3 gram) and L-leucinol (830 mg) in DMSO (20 ml) was stirred at 100°C for 3 days. The solution was taken up in water, and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Silica gel chromatography (heptane/ethyl acetate 3/1) provided 747 mg of the title compound. MS(m/z) 272[M+H]⁺

2-(2-Methaαesulfonyl-6-methoxy-pyrimidin-4-yIamino)-4-methyl-pentan-l-ol.

A solution of 2-(6-methoxy-2-methylsufanyl-pyrimidin-4-yIamino)-4-methyI-pentan-l-ol (745 mg) and MCPBA (1.3 gram) in DCM (10 ml) was stirred at room temperature for 2 hours. A saturated solution of sodium thiosulfite (5 ml) was added and the mixture was stirred for 10 min. The solution was taken up in water, and extracted three times with dichloromethane. The dichloromethane layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. The title compound was obtained (850 mg) and used without further purification. MS(m/z) 304[M+H]⁺

2-{6-Methoxy-2-[4-(5-trifluoromethyl-benzofuran-2-yl)-imidazol-l-yI]-pyrimidin-4- ylamino}-4-methyI-pentan-l-ol.

A solution of 2-(2-methanesulfonyl-6-methoxy-pyrimidin-4-ylamino)-4-methyl-pentan-l-ol (880 mg), 4-(5-trifluoromethyl-benzofuran-2-yl)-imidazole (1.46 gram), KF (168 mg¹) and K₂CO₃ (1 gram) in DMSO (6 ml) was stirred at 110°C for 3 days. The solution was taken up in water, and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Silica gel chromatography (heptane/acetone 3/1) provided 635 mg of the title compound. MS(m/z) 476[M+H]⁺

2-{6-Methoχy-2-[4-(5-trifluoromethyl-benzofuran-2-yl)-imidazol-i-yl]-pyrimidin-4- yIamino}-4-methyI-pentanoic acid.

A solution of 2-{6-Methoxy-2-[4-(5-trifluoromethyl-benzofuran-2-yl)-imidazol-l-yl]- pyrimidin-4-ylamino}-4-methyl-pentan-l-ol (630 mg), iodobenzene diacetate (854 mg) and TEMPO (41 mg) in dioxane/water (16 ml/4 ml) was stirred for 17 hours at room temperature. The solution was taken up in water, and extracted three times with dichloromethane. The dichloro-methane layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Trituration with heptane/ethyl acetate provided 379 mg of the title compound. MS(m/z) 490[M+H]⁺

2-{6-Methoxy-2-[4-(5-trifluoromethyI-benzofuran-2-yl)-imidazoI-l-yl]-pyrimidin-4- ylamino}-4-methyl-pentanoic acid (3-ethoxy-prαpyl)-amide.

A solution of 2-{6-Methoxy-2-[4-(5-trifluoromethyI-benzofuran-2-yl)-imidazol-l-yl]- pyrimidin-4-ylamino}-4-methyl-pentanoic acid (375 mg), TBTU (295 mg) and DIEA (268 μL) in DCM (5 ml) was stirred for 1 hour at room temperature. The solution was taken up in water, and extracted three times with dichloromethane. The dichloro-methane layers were combined, washed with brine, dried over magnesium sulfate, filtered, and the solvents were removed in vacuo. Silica gel chromatography (DCM MeOH 97/3) provided 175 mg of the title compound. MS(m/z) 575[M+H]⁺

1H-NMR : (CDCfe): δ 7.1(s,Ha), 8.6(s,Hb), 8.2(s,Hc), 1.0(dd,Hd), 4.0(s,He), 3.5(q,Hf), 1.2(t,Hg)

Pharmacological assays

Receptor Binding Assay

Ki values of compounds of formula I were measured by means of IL-8 displacement. [¹²⁵I]- LL8 (human recombinant) was obtained from NEN-New England Nuclear, Boston, Mass. with a specific activity of 2200 Ci/mmol. All other chemicals were of analytical grade. High levels of recombinant CXCR2 receptors were expressed in Chinese hamster ovary cells as described previously (Holmes, et al., Science 253; 1278 1991). The Chinese hamster ovary membranes were homogenized according to a previously described protocol (Haour et al., J. Biol. Chem. 249; 2195-2205 1974), using a homogenization buffer of 20 mM HEPES and 10 mM EDTA adjusted to pH 8.0.

Membrane protein concentration was determined using Pierce Co. micro-assay kit using bovine serum albumin as a standard. All assays were performed in a 96-well micro plate format. Each reaction contained [¹²⁵I] IL-8 (0.1 nM) and 100 μg/mL of CXCR2 membranes in 1 % DMSO, 10 mM Tris, pH=8, 1.2 mM MgSO₄, 0.1 mM EDTA, 25 mM NaCl, 0.-03 % CHAPS. In addition, drug or compound of interest was added which had been pre-dissolved in DMSO so as to reach a final concentration of between 0.01 nM and 100 μM. The assay was initiated by addition of CXCR2 membranes to the plate. After 1 hour at room temperature the plate was harvested using a Tomtech 96-well harvester onto a glass fiber filterplate (Millipore Corporation; Multiscreen-FC, Opaque plates, 1.2 μM type C filter; cat # MAFCNOB50) pre- wet with 0.3 % polyethyleneimine and washed 3 times with 10 mM Tris pH=8, 1 mM MgSO _> 0.5 mM EDTA, 25 mM NaCl, 0.03 % CHAPS, 0.5 % BSA using 100 μL/well. 50 μl/well of Microscint20 scintillation liquid (Packard Bioscience cat #3013621) was added to each well and the plate was counted on the Packard liquid scintillation counter.

Compounds of formula I were found to exhibit inhibitory activity of Ki<1000 nM in the receptor binding assay. Preferred compounds have a Ki<100nM.

Calcium influx assay

Calcium (Ca²⁺) influx inhibition with compounds of formula I have been tested in human Acute Monocyte Leukemia (AML-193) cells and human neutrophils. AML-193 cells (ATCC: CRL-9589, Rockwell MD) were maintained in suspension at a concentration of 3xl0⁵ cells/mL in culture medium (Iscove modified Dulbecco medium (Life Technologies # 21980-065) containing 5 μg/mL transferrin and insulin, 1 % (v/v) of penicilline/streptomycine solution (Sigma), 5 μg/mL GM-CSF (R&D systems # 215-GM) and 10 % fetal calf serum (FCS) (v/v). AML-193 cells were stimulated to differentiate with all-trans-retinoic acid (ATRA) in the concentration of lxl 0^"7 M during 3-4 days. Cells were harvested and washed in Krebs buffer (120 mM NaCL 4.75 mM KCL, 1 mM KH₂PO_4, 1.44 mM MgSO₄.7H₂O, 1.1 mM CaCl₂.2H₂O, 5 mM NaHCO₃, 11 mM glucose, 25 mM Hepes adjusted to pH 7.4). The cell suspension was centrifuged at 25000 N/kg at room temperature for 6 min. The supernatant was siphoned off and The pellet was resuspended in Krebs buffer in order to obtain a suspension containing lxl0⁷cells/mL.

Human neutrophils were obtained from free-flowing blood from healthy volunteers. Blood was collected in 0.1 volume sodium citrate dihydrate in water (38 g/L) and diluted 5 times with medium (RPMI 1640 solution (Life Technologies #32404-014), 2 mM L-glutamine (Sigma #G7513) and 0.01 volume of penicilline/streptomycine solution (Sigma #P0781) + 0.1 % bovine serum albumin (Sigma #A-9418)). The neutrophils were separated by the Ficoll Paque technique. In different tubes containing 20 ml Ficoll Paque (Amersham-Pharmacia #17-1440- 03) 30 ml bloodcells were pipetted. The tubes were centrifuged at 25000 N/kg for 60 minutes at room temperature. The plasma and the lymphocytes layers were siphoned off. The red pellet was collected and adjusted to approximately 100 ml with medium in a sterile flask. An equal volume of Dextran solution (3 % w/w Dextran T500 (Amersham-Pharmacia #115977) in NaCl 0.9 %) was added and mixed with the cells. The mixture was divided into two graduated- glasses of 250 ml and the air bubles were removed. After an incubation of 30 minutes at room temperature the upper-layer containing neurophils was siphoned off and 30 ml was pipetted into Falcon tubes. The cells were centrifuged at 20000 N/kg for 6 minutes at 4° C. The supernatant was siphoned off. The pellet was shaken free from the bottom and 20 ml ice-cold NaCl 0.2 % was added and the suspension was mixed for exactly 30 sec. The red cells were lysed and the cell suspension was neutralised by adding 20 ml ice-cold NaCl 1.6 %. The cells were centrifuged again at 20000 N/kg for 6 min. at 4° C. The supernatant was siphoned off and the white pellet was resuspended in medium in order to obtain a suspension containing lxl0⁷cells/ml.

Assay: Cells were labelled with Fura-2 AM. Fifty μg of Fura-2 AM (Molecular Probes #F- 1221) was dissolved in 50 μl DMSO and subsequently 25 μl 10% w/w Pluronic F127 (Sigma #P2443) in water was added. Three μL Fura-2 AM solution was added to 1 mL cell suspension and the mixture was incubated for 30 min at 37°C. The cell suspension was centrifuged at 25000 N/kg (1200 rpm) at roomtemperature for 6 min and the cells were washed in Krebs buffer and centrifuged again. The washstep was repeated once. The pellet was resuspended in Krebs buffer in order to obtain a suspension containing lxl0⁷cells/mL. The assay was performed in a 96 well plate. Each reaction contained 40 μL celsuspension in Krebs buffer (total volume 250 μL). In addition, drug or compound of interest was added which had been pre-dissolved in DMSO so as to reach a final concentration of between 0.1 nM and 10 μM. The assay was initiated by addition of 50 μl agonist solution (final concentrations 2 nM IL-8 (R&D systems # 618-IL) or 10 nM Gro-alpha (R&D systems # 275-GR)) to each well automatically by Victor² Wallac 1420 multilabel HTS counter (PerkinElmer) equipped with a dispenser. Subsequently the responses were recorded alternating at 380 nm (excitation) and 510 (emission) for determination of unbound Fura-2 and to 340 nm (excitation) and 510 (emission) for Ca²⁺ bound Fura-2. Fifty counts were recorded for each well which took 'about 40 seconds. The ratio of fluorescence at 340 and 380 nm was calculated and concentrations were calculated using the maximum (0.67% Triton X-100) and minimum (5.6 mM EGTA) salcium response. Compounds of formula I were found to exhibit an IC50<1000 nM in the calcium influx assay. Preferred compounds have a Ki<100nM.

Claims

1. A compound of the formula I

wherein

R⁵ is H or (l-6C)alkyl;

R⁶ is H, (l-6C)alkyl or (l-6C)alkoxy;

R⁷ is H or (l-6C)alkyl;

R is (l-6C)alkyl, optionally substituted with (l-6C)alkoxy; R⁹ is chosen from

(a) -(CH₂)_nR¹⁰, wherein n is 1, 2 or 3 and R¹⁰ is selected from

(i) (l-4C)alkoxy;

(ii) (l-4C)alkylthio;

(iii) trifluoromethyl;

(iv) (3-8C)cycloalkyl;

(v) phenyl, optionally substituted with (l-4C)alkoxy;

(vi) -NR^πR¹² ; and

(vii) -O(CH₂)₂NR H¹¹τR.1¹2 wherein one of R¹¹ and R is (l-4C)alkoxy, the other being H or (1- 4C)alkyl;

(b) -CH₂(2-7C)heterocycloaIkyl, provided that when at least one heteroatom in the heterocycloalkyl moiety is nitrogen, the distance between this nitrogen and the nitrogen in "NHR⁹" is at least three carbon atoms;

(c) -(CH₂)₃(2-7C)heterocycloalkyl; and

(d) -(CH₂)₂CHR¹³R¹⁴ wherein R¹³ and R¹⁴, together with the carbon atom to which they are attached, are (2-7C)heterocycloalkyl; and X is O, S or NH; or a pharmaceutically acceptable salt thereof.

The compound of claim 1, having the structure II

II

The compound of claim 1 or 2, wherein R , R², R³ and R⁴ are each independently selected from H, (l-4C)alkyl, (l-4C)alkoxy, trifluoromethyl, trifluoromethoxy, halogen and nitro; R⁵ is H; R⁶ is (l-6C)alkyl; R⁷ is H; and R⁸ is (l-6C)alkyl.

The compound of any one of claims 1-3, wherein R is chosen from (a) -(CH₂)_nR¹⁰, wherein n is 2 or 3 and R¹⁰ is selected from

(i) (l-4C)alkoxy;

(ii) trifluoromethyl;

(iii) cyclopentyl;

(iv) cyclohexyl;

(v) phenyl substituted with (l-4C)alkoxy; and (vi) -NRⁿR¹² wherein one of R¹¹ and R¹² is (l-4C)alkoxy, the other being (1- 4C)alkyl;

(b) -(CH₂)₃(2-7C)heterocycloalkyl; and

(c) -(CH₂)₂CHR¹³R¹⁴, wherein R¹³ and R¹⁴ together with the carbon atom to wliich they are attached, are (2-7C)heterocycloalkyl.

5. The compound of any one of claims 1-4, wherein X is O.

6. A pharmaceutical composition comprising the compound of any one of claims 1 - 5 and at least one pharmaceutically suitable auxiliary.

7. The compound of any one of claims 1 - 5 for use in therapy.

8. Use of the compomid of any one of claims 1 - 5 for the manufacture of a medicament for treating or preventing IL-8 receptor mediated disorders.