EP1831210A1

EP1831210A1 - 8-aza-bicyclo[3.2.1]octane derivatives with an activity on chemokine ccr5 receptors

Info

Publication number: EP1831210A1
Application number: EP05813627A
Authority: EP
Inventors: David Cameron Pfizer Global Res. and Dev. PRYDE; Paul Anthony Pfizer Global Res. and Dev. STUPPLE
Original assignee: Pfizer Ltd Great Britain
Current assignee: Pfizer Ltd Great Britain
Priority date: 2004-12-23
Filing date: 2005-12-12
Publication date: 2007-09-12
Also published as: WO2006067584A1; JP2008525418A; CA2594602A1

Abstract

The present invention provides compounds of formula (I) R3, (I) wherein R1, R2, R3 and R4 are as defined hereinabove. The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors. Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV and genetically related retroviruses.

Description

8-AZA-BICYCLO O . 2 . 1) OCTANE DERIVATIVES WITH AN ACTIVITY ON CHEMOKINE CCR5 RECEPTORS

Chemical Compounds

This invention relates to tropane derivatives, to processes for their preparation, to compositions containing them and to their use.

More particularly, the present invention relates to the use of 8-azabicyclo[3.2.1]octane 5 derivatives in the treatment of a variety of disorders, including those in which the modulation, in particular antagonism, of chemokine CCR5 receptors is implicated. Accordingly, compounds of the invention are useful in the treatment of HIV, such as HIV-1 , and genetically related retroviral infections (and the resulting acquired immune deficiency syndrome, AIDS), inflammatory diseases, autoimmune diseases and pain. ' The name "chemokine", is a contraction of "chemotactic cytokines". The chemokines comprise a large family of proteins which have in common important structural features and which have the ability to attract leukocytes. As leukocyte chemotactic factors, chemokines play an indispensable role in the attraction of leukocytes to various tissues of the body, a process which is essential for both inflammation and the body's response to infection. Because 5 chemokines and their receptors are central to the pathophysiology of inflammatory and infectious diseases, agents which are active in modulating, preferably antagonising, the activity of chemokines and their receptors, are useful in the therapeutic treatment of such inflammatory and infectious diseases.

The chemokine receptor CCR5 is of particular importance in the context of treating 0 inflammatory and infectious diseases. CCR5 is a receptor for chemokines, especially for the macrophage inflammatory proteins (MIP) designated MIP-1α and MIP-1 β, and for a protein which is regulated upon activation and is normal T-cell expressed and secreted (RANTES).

We have now found a group of compounds that are both potent and selective modulators, in particular antagonists, of the CCR5 receptor. 5 According to a first aspect of the present invention, there is provided a compound of formula (I)

0 or a pharmaceutically acceptable salt, solvate of derivative thereof, wherein: R¹ is R⁷, OR⁷ or NR⁵R⁶ ; R² is H or C_1-6 alkyl;

R³ is phenyl substituted by 0 to 3 atoms or groups selected from C_1-6 alkyl, Ci_-6 alkylcarbonyl, Ci_-6 alkoxy, C_1-6 alkoxycarbonyl, halogen, CF₃, OH, CN, NR⁵R⁶, CO₂R⁷ or CONR⁵R⁶;

R⁴ is a moiety of partial

wherein:

Q is CR⁴²or N;

T is CR⁴³ or N

R⁴¹ is H, C_1-6 alkyl or C_1-6 fluoroalkyl;

R⁴² and R⁴³ are independently selected from H, C_1-6 alkyl, C_1-6 fluoroalkyl, or halogen; or R⁴² and R⁴³ when taken together with the atoms to which they are attached form a benzene, pyridine, pyrimidine, pyridazine or pyrazine ring, wherein the said benzene pyridine, pyrimidine, pyridazine or pyrazine ring is substituted by 0 to 3 atoms or groups selected from C_1- ₆ alkyl, C_1-6 fluoroalkyl or halogen; or form a partially saturated pyridine ring such that R⁴ is a moiety of partial formula (1.0.1)

; wherein the arrowhead denotes the point of attachment to the tropane ring;

R⁵ is H or C_1-6 alkyl; C_2-6 alkenyl; C₂.₆ alkynyl; C_3-7 cycloalkyl; a 5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturated heterocycle; wherein said alkyl, alkenyl, alkynyl and cycloalkyl are substituted by 0 to 3 atoms or groups selected from oxo, halogen, CF₃, OR⁶, CN, COR⁶, or CO₂R⁶; wherein said heterocycle contains one to three heteroatoms selected from N, O or S; and wherein said heterocycle is substituted by 0 to 3 atoms or groups selected from C_1-6 alkyl, C_1-6 alkylcarbonyl, Ci_-6 alkoxy, C_1-6 alkoxycarbonyl, halogen, CF₃, OH, CN, COR⁶, or CO₂R⁶;

R⁶ is H or C_1-6 alkyl; or, when R⁵ and R⁶ are both attached to the same N atom, NR⁵R⁶ may also represent a 5 to 7 membered, saturated, partially unsaturated or aromatic, heterocycle containing from 0 to 2 additional heteroatoms selected from O, N or S, substituted by 0 to 3 halogen atoms;

R⁷ is C_1-6 alkyl; C_2-6 alkenyl; C₂-e alkynyl; C_3-7 cycloalkyl; a 5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturated heterocycle; wherein said alkyl, alkenyl, alkynyl and cycloalkyl are substituted by 0 to 3 atoms or groups selected from oxo, halogen, CF₃, OR⁶,

CN, NR⁵R⁶, COR⁶, CO₂R⁶ or CONR⁵R⁶; wherein said heterocycle contains one to three heteroatoms selected from N, O or S; and wherein said heterocycle is substituted by O to 3 atoms or groups selected from C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkoxy, C_1-6 alkoxycarbonyl, oxo, halogen, CF₃, OH, CN, NR⁵R⁶, COR⁶, CO₂R⁶ or CONR⁵R⁶; provided that when R¹ is OR⁷ the said heterocycle is carbon bonded to the oxygen of OR⁷;

R⁸ is H or C_1-6 alkyl;

X and Y are selected from CH₂ and NR⁹ such that one of X and Y is CH₂ and the other is NR⁹; R⁹ is H; R⁷; COR⁷; CO₂R⁷; CONR⁵R⁶; SO₂R⁷; or (C_1-6 alkylene)phenyl, wherein phenyl is substituted by O to 3 atoms or groups selected from C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkoxy, C_1-6 alkoxycarbonyl, halogen, CF₃, OH, CN, NR⁵R⁶, COR⁶, CO₂R⁶ or CONR⁵R⁶.

The term "alkyl" as a group or part of a group includes straight chain and branched groups. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. T he term "C_3-C₇ cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The term halogen means fluoro, chloro, bromo or iodo. The term Ci_-6 fluoroalkyl means Ci_-6 alkyl substituted by one to three fluoro atoms.

In one embodiment, R¹ is R⁷ or OR⁷.

In yet a further embodiment, R⁷ is C_1-4alkyl optionally s ubstituted by C _1-3alkoxy; C ₃.₆ cycloalkyl substituted by O to 2 halogen atoms; or a 4 to 6-membered saturated heterocycle containing one heteroatom selected from N, O, or S, wherein said heterocycle is substituted by O to 2 atoms or groups selected from oxo, halogen, or COC_1-3alkyl.

In yet a further embodiment, R¹ is R⁷ or OR⁷ as defined above in any preceding embodiment or NR⁵R⁶ ; R⁵ is H, C_1-4alkyl, a C_3-7cylcoalkyl; R⁶ is H or C_1-6 alkyl; or R⁵ and R⁶ together with the N to which they are attached form a C_5-7 saturated, partially unsaturated or aromatic heterocycle containing one or two additional heteroatoms selected from O, N or S, substituted by O to 3 halogen.

In yet a further embodiment, R² is H.

In yet a further embodiment, R³ is phenyl optionally substituted by one fluorine atom. In yet a further embodiment, R, is: i) a moiety of partial formula (1.0.1)

); ii) a benzimidazolyl of partial formula (1.0.2)

substituted by 0 to 3 atoms or groups selected from C_1-β alkyl, C_1-6 fluoroalkyl or halogen; or iii) a triazolyl of partial formula (1.0.3)

-

(1.0.3) substituted by 0 to 3 groups selected from C_1-6 alkyl or C_1-6 fluoroalkyl.

In yet a further embodiment, R⁴ is:

In yet another embodiment R⁴ is a moiety of partial formula

wherein X and Y are as defined hereinbefore or

substituted by 0 to 3 groups selected from C_1-6 alkyl or C_1-6 fluoroalkyl.

In yet another embodiment, R⁴ is a moiety of partial formula

wherein R⁹ is as defined hereinbefore.

In yet a further embodiment, R⁸ is C_1-3alkyl. In yet a further embodiment, R⁸ is methyl. In yet a further embodiment, R⁹ is H; R⁷; COR⁷; CO₂R⁷. In yet a further embodiment, R⁹ is C alkyl , CO C_1-4 alkyl or CO₂-C_1-4 alkyl. In yet a further embodiment there is provided a compound of formula 1 as shown in the first aspect of the invention, wherein R¹ is R⁷ or OR⁷ ; R² is H;

R³ is phenyl optionally substituted by one fluorine; R⁴ is i) a moiety of partial form

Wherein X and Y are selected from CH₂ and NR⁹ such that one of X and Y is CH₂ and the other is NR⁹; or ii) a triazolyl of partial formula (1.0.3)

(1.0.3) substituted by 0 to 3 groups selected from C_1-6 alkyl or Ci_-6 fluoroalkyl;

R⁷ is C_1-4alkyi optionally substituted by C_1-3alkoxy; C_3-6 cycloalkyl substituted by 0 to 2 halogen atoms; or a 4 to 6-membered saturated heterocycle containing one heteroatom selected from N, O, or S, wherein said heterocycle is substituted by 0 to 2 atoms or groups selected from oxo, halogen, or COCi_-3alkyl.

R⁸ is methyl; and R⁹ is C_1-4alkyl, COC_1-4alkyl or CO₂C_1-4alkyl.

In yet a further embodiment, there is provided a compound of formula (I)

(D

or a pharmaceutically acceptable salt, solvate of derivative thereof, wherein:

R¹ is R⁷, OR⁷ or NR⁵R⁶ ; R² is H or C_1-6 alkyl; R³ is phenyl substituted by 0 to 3 atoms or groups selected from Ci_-6 aikyl, C_1-6 alkylcarbonyl, C_1-6 alkoxy, C_1-6 alkoxycarbonyl, halogen, CF₃, OH, CN, NR⁵R⁶, CO₂R⁷ or CONR⁵R⁶;

R⁴ is a moiety of partial

wherein:

Q is CR⁴²Or N; T is CR⁴³ or N R⁴¹ is H, C_1-6 alkyl or C_1-6 fluoroalkyl;

R⁴² and R⁴³ are independently selected from H, C_1-6 alkyl, C_1-6 fluoroalkyl, or halogen; or R⁴² and R⁴³ when taken together with the atoms to which they are attached form a benzene, pyridine, pyrimidine, pyridazine or pyrazine ring, wherein the said benzene pyridine, pyrimidine, pyridazine or pyrazine ring is substituted by 0 to 3 atoms or groups selected from Ci- β alkyl, C_1-6 fluoroalkyl or halogen; or form a partially saturated pyridine ring such that R⁴ is a moiety of partial formula (1.0.1)

wherein the arrowhead denotes the point of attachment to the tropane ring; R⁵ is H or C_1-6 alkyl; C_2-6 alkenyl; C_2-6 alkynyl; C_3-7 cycloalkyl; a 5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturated heterocycle; wherein said alkyl, alkenyl, alkynyl and cycloalkyl are substituted by 0 to 3 atoms or groups selected from oxo, halogen, CF₃, OR⁶, CN, COR⁶, or CO₂R⁶; wherein said heterocycles contain one to three heteroatoms selected f rom N ₁ O or S ; a nd w herein s aid h eterocycles a re s ubstituted b y 0 to 3 atoms or groups s elected from C _1-6 a Ikyl, C _1-6 a Ikylcarbonyl, C _1-6 a Ikoxy, C_1-6 alkoxycarbonyl, halogen, CF₃, OH, CN, COR⁶, or CO₂R⁶; R⁶ is H or C_1-6 alkyl; or, when R⁵ and R⁶ are both attached to the same N atom, NR⁵R⁶ may also represent a 5 to 7 membered, saturated, partially unsaturated or aromatic, heterocycle containing from O to 2 additional heteroatoms selected from O, N or S; R⁷ is C_1-6 alkyl; C_2-6 alkenyl; C₂.₆ alkynyl; C_3-7 cycloalkyl; a 5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturated heterocycle; wherein said alkyl, alkenyl, alkynyl and cycloalkyl are substituted by 0 to 3 atoms or groups selected from oxo, halogen, CF₃, OR⁶, CN, NR⁵R⁶, COR⁶, CO₂R⁶ or CONR⁵R⁶; wherein said heterocycles contain one to three heteroatoms selected from N, O or S; and wherein said heterocycles are substituted by O to 3 atoms or groups selected from C_1-6 aikyl, Ci_-6 alkylcarbonyl, C_1-6 alkoxy, C_1-6 alkoxycarbonyl, halogen, CF₃, OH, CN, NR⁵R⁶, COR⁶, CO₂R⁶ or CONR⁵R⁶; provided that when R¹ is OR⁷ the said heterocycles are carbon bonded to the oxygen of OR⁷;

R⁸ is H or C_1-6 alkyl; X and Y are selected from CH₂ and NR⁹ such that one of X and Y is CH₂ and the other is NR⁹;

R⁹ is H; R⁷; COR⁷; CO₂R⁷; CONR⁵R⁶; SO₂R⁷; or (C_1-6 alkylene)phenyl, wherein phenyl is substituted by O to 3 atoms on groups selected from C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkoxy, C_1-6 alkoxycarbonyl, halogen, CF₃, OH, CN, NR⁵R⁶, COR⁶, CO₂R⁶ or CONR⁵R⁶. It is to be understood that the invention covers all combinations of embodiments of the invention as described hereinabove, consistent with the definition of compounds of formula (I).

The compounds of the invention include compounds of formula (I) and pharmaceutically acceptable salts, solvates or derivatives thereof (wherein derivatives include complexes, prodrugs and isotopically-labelled compounds, as well as salts and solvates thereof). In a further embodiment, the compounds of the invention are the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, in particular the compounds of formula (I). It is to be understood that the aforementioned compounds of the invention include polymorphs and isomers thereof.

Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), incorporated herein by reference.

The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').

Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one ₍ or more of three methods:

(i) by reacting the compound of formula (I) with the desired acid; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid; or

(iii) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The salt, may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may also exist in unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995), incorporated herein by reference. Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they a re n ext to other water m olecules. I n m etal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug a nd at l east one other component a re p resent i n stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug- host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes o f n eutral m olecular c onstituents w hich a re b ound t ogether t hrough non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, ,17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference. For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975), incorporated herein by reference.

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to s uitable conditions. The m esomorphic s tate is i ntermediate between the true crystalline state and the true liquid state (either meit or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -COO^'Na⁺, -COO^"K⁺, or -SO₃-Na⁺) or non-ionic (such as -N^"N⁺(CH₃)₃) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4^th Edition (Edward Arnold, 1970), incorporated herein by reference.

All references to compounds of formula (I) include references to salts, solvates, multi- component complexes and liquid crystals thereof and to solvates, multi-component complexes and liquid crystals of salts thereof.

The compounds of the invention include compounds of formula (I) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically- labeled compounds of formula (I).

As indicated, so-called 'prodrugs' of the compounds of formula (I) are also within the scope of the invention. Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems. Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association), incorporated herein by reference.

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985). Some examples of prodrugs in accordance with the invention include:

(i) where the compound of formula (I) contains a carboxylic acid functionality (-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (I) is replaced by (C^CaJalkyl;

(ii) where the compound of formula ( I) contains a n a lcohol functionality (-OH), a n ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula I is replaced by (CrC₆)alkanoyloxymethyl; and (iii) where the compound of formula (I) contains a primary or secondary amino functionality

(-NH₂ or -NHR where R ≠ H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula I is/are replaced by (CrC₁₀)alkanoyl.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types i n a ccordance w ith t he i nvention m ay b e found i n t he aforementioned references.

Moreover, certain compounds of formula ( I) m ay t hemselves a et as prodrugs of other compounds of formula (I).

Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include:

(i) where the compound of formula (I) contains a methyl group, an hydroxymethyl derivative thereof (-CH₃ -> -CH₂OH);

(ii) where the compound of formula (I) contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH); (iii) where the' compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NR¹R² -> -NHR¹ or -NHR²); (iv) where the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHR¹ -> -NH₂); (v) where the compound of formula (I) contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and

(vi) where the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CONH₂ -> COOH). Compounds of formula (I) contain at least two asymmetric carbon atoms (the carbon atom from which R³ is a substituent and the adjacent carbon from which the methylene tropane is a substituent), and may contain one or more further asymmetric carbon atoms, and therefore exist as four or more stereoisomers. R⁴ substitution of the tropane ring in compounds of formula (I) can be in either endo- or exo- configuration, and therefore geometric cisltrans (or Z/E) isomers are possible. Where the compound contains, for example, a keto group, tautomeric isomerism ('tautomerism') may occur. It follows that a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers of the compounds of formula (I), including all optical isomers, geometric isomers and tautomeric forms as well as compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL- arginine.

Imidazole substitution of the tropane ring in the endo- configuration is preferred. Triazole substitution of the tropane ring in the exo- configuration is preferred.

Endo/exo isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography

(HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1- phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel (Wiley, New York, 1994).

The present invention also includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-f14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labelled reagent in place of the non-labelled reagent previously employed. Pharmaceutically acceptable solvates i n a ccordance w ith t he i nvention i nclude t hose wherein the solvent of crystallization may be isotopically substituted, e.g. D₂O, d₆-acetone, d₆- DMSO.

Preferred compounds of formula (I) include the compounds of Examples 1-29; and pharmaceutically acceptable salts, solvates or derivatives thereof. In the general processes, and schemes, that follow: R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and

R⁹ are as previously defined unless otherwise stated; Z is OH, or a carboxylic acid activating group such as chloro or 1 H-imidazol-1-yl; Pg is an amino protecting group, such as boc; DMF is N,N-dimethylformamide; DCM is dichloromethane; THF is tetrahydrofuran; Lg is a leaving group appropriate to aliphatic nucleophilic substitution, such as those disclosed in Jerry March, ibid, page 352 (incorporated herein by reference), including Cl, Br, I and sulfonic esters (e.g. tosylate, mesylate and triflate); WSCDI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DCC is N,N'-dicyclohexylcarbodiimide; HOAT is 1-hydroxy-7-azabenzotriazole; HOBt is 1-hydroxybenzotriazole hydrate; HBTU is O-benzotriazol-i-yl-Λ/./V.Λ/'./V- tetramethyluronium hexafluorophosphate.

According to a first process (A) compounds of formula (I) may be prepared by reacting a compound of formula (II)

with a compound of formula (III)

Conveniently, the coupling is effected under the conditions described hereinafter in connection with scheme 1 , step (c).

According to a second process (B) compounds of formula (I) wherein R¹ is NR⁵R⁶ and

R⁵ or R⁶ is H may be prepared by reacting a compound of formula (II) with an isocyanate of formula (VII) R⁵-N=C=O _(V||)

Conveniently, the coupling is effected under the conditions described hereinafter in connection with scheme 1 , step (ci).

According to a third process (C) compounds of formula (I) wherein R¹ is OR⁷ may be prepared by reacting a compound of formula (II) with a compound of formula (VIII)

Conveniently, the coupling is effected under the conditions described hereinafter in connection with scheme 1 , step (cii).

According to a fourth process (D) compounds of formula (I) may be prepared by reductive amination of an aldehyde of formula (XVI)

(XVI) with an amine of formula (V)

under conventional conditions. Conveniently, reductive amination is effected under the conditions described hereinafter in connection with scheme 1 , step (a).

According to a fifth process (E) compounds of formula (I) may be prepared by reductive amination of a nitrile of formula (XVlI)

with an amine of formula (V) under conventional conditions. Conveniently, reductive amination is effected under the conditions described hereinafter in connection with scheme 1 , step (a). According to a sixth process (F) compounds of formula (I) may be prepared by alkylation of an amine of formula (V) with a compound of formula (XVIII)

(XVlIl)

under conventional alkylation conditions. Conveniently, alkylation is effected in a suitable solvent, such as an haloalkane (e.g. DCM), an alcohol (e.g. ethanol) or an ether (e.g. THF); optionally in the presence of a base, such as an amine (e.g. triethylamine or Λ/-ethyl-Λ/,Λ/- diisopropylamine); and at from ambient to elevated temperature (e.g. reflux).

According to a further process (G) compounds of formula (I) wherein R⁴ is a moiety of partial formula (1.0.1) and X is NCOR⁷may be prepared by reacting a compound of formula (XIII) with a compound of formula (XIX)

Conveniently, the coupling is effected under the conditions described hereinafter in connection with scheme 2, step (e).

According to a further process (H) compounds of formula (I) wherein R⁴Is a moiety of partial formula (1.0.1.) and X is NR⁷may be prepared by reacting a compound of formula (XIII)

with a compound of formula (XX)

R⁷-Lg (XX)

Compounds of formula (I) wherein R⁴ is a moiety of partial formula (1.0.1 ) may also be prepared from compounds of formula (XIII) according to transformations described in WO 03/08954 (in particular processes A-F and L therein pp7-17).

A person skilled in the art will appreciate that compounds of formula (I) wherein Y is NR⁹ may be prepared by processes directly analogous to those described above wherein X is NR⁹. Schemes that further illustrate general methods for the preparation of compounds of formula (I), and intermediates thereto, follow. It will be appreciated by those skilled in the art that certain of the procedures described in the schemes for the preparation of compounds of formula (I) or intermediates thereto may not be applicable to some of the possible substituents.

It will be further appreciated by those skilled in the art that it may be necessary or desirable to carry out the transformations described in the schemes in a different order from that described, or to modify one or more of the transformations, to provide the desired compound of formula (I).

It will be still further appreciated by those s killed i n the a rt that, as i llustrated i n the schemes that follow, it may be necessary or desirable at any stage in the synthesis of compounds of formula (I) to protect o ne o r m ore s ensitive g roups i n t he m olecule s o a s t o prevent undesirable side reactions. In particular, it may be necessary or desirable to protect amino groups. The protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See, for example, those described in 'Protective Groups in Organic Synthesis' by Theodora W Green and Peter G M Wuts, third edition, (John Wiley and Sons, 1999), in particular chapter 7, pages 494-653 ("Protection for the Amino Group"), incorporated herein by reference, which also describes methods for the removal of such groups.

The a mino p rotecting g roups b oc, m ethylformate, b enzyl a nd a cetyl a re o f particular use in the preparation of compounds of formula (I) and intermediates thereto.

Scheme 1

(H)

With specific reference to scheme 1 , the transformations depicted therein may be effected as follows: (a) Compounds of formula (IV) are prepared by reductive amination of an aldehyde of formula

(VI) by an amine of formula (V). Conveniently, the reaction is carried out in the presence of an acid, such as organic acid (e.g. acetic acid); in a solvent, such as a haloalkane (e.g. DCM) or an ether (e.g. THF); using an alkali metal hydride reducing agent, such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride; and at ambient temperature.

(b) When the protecting group is benzyl its removal is conveniently effected by a transition metal catalyst (e.g. 20% (w/w) palladium on carbon), either hydrogen gas or ammonium formate in a suitable solvent, such as an alcohol (e.g. ethanol or methanol); and from ambient temperature to reflux.

(c) The acid/amine coupling is conveniently effected using an amine of formula (II) and an acid chloride/alkyl chloroformate of formula (III); an excess of an acid acceptor, such as triethylamine or Λ/-ethyl-Λ/,Λ/-diisopropylamine; a solvent, such as a haloalkane (e.g. DCM) or an ether (e.g. THF); and at ambient temperature. Alternatively, the acid/amine coupling is effected using an acid of formula (III) activated by reagents such as WSCDI or DCC and HOBt or HOAt; an excess of an acid acceptor such as triethylamine or Λ/-ethyl-Λ/,Λ/-diisopropylamine; a solvent, such as a haloalkane (e.g. DCM) or an ether (e.g. THF); and at ambient temperature. c(i) Alternatively, compounds of formula (I) wherein R¹ is NR⁵R⁶ and R⁵ or R⁶ is H can be conveniently prepared by treatment of an amine of formula (II) with an isocyanate of formula

(VII) in a suitable solvent, such as a haloalkane (e.g. dichlorom ethane) or an ether (e.g. THF) at ambient to elevated temperature (e.g 50 ⁰C) c(ii) Compounds of formula (I) wherein R¹ is OR⁷ can be conveniently prepared by treatment of an amine of formula (II) with a suitable carbamoyl chloride of formula (VIII), an excess of an acid acceptor, such as triethylamine or /V-ethyl-Λ/,Λ/-diisopropyIamine; a solvent, such as a haloalkane (e.g. DCM) or an ether (e.g. THF); and at a mbient temperature. T he carbamoyl chloride can itself be prepared by treatment of an amine with triphosgene or phosgene in a suitable solvent such as a haloalkane (e.g. dichloromethane) or an ether (e.g. THF) at reduced (e.g. 0 ⁰C) to ambient temperature. It will be appreciated by those skilled in the art that one or more of the transformations described in the scheme 1 may be carried out in a different order from that described, or may be modified, in order to provide the desired compound of formula (I).

Compounds of formula (I) wherein R⁴ is a moiety of partial formula (1.0.1) may be prepared by the transformations depicted in scheme 2, Scheme 2

(d) When the protecting group is methyl formate its removal is conveniently effected by the use of an aqueous metal hydroxide solution (e.g. sodium hydroxide) in a suitable organic solvent such as an alcohol (e.g. propan-2-ol); and at elevated temperature (up to reflux).

Alternatively removal of a methyl formate protecting group can be conveniently effected by the use of trimethylsilyliodide in a suitable organic solvent, such as a haloalkane (e.g. DCM) or an ether (e.g. THF); at ambient to elevated temperature (e.g. 50 ⁰C).

(e) Compounds of formula (X) can be conveniently prepared from compounds of formula (Xl) by the transformations described in WO 03/084954 (in particular process A-F & L therein, pp7-

17). In particular compounds of formula (X) may be prepared using an amine of formula (Xl) and an acid chloride/alkyl chloroformate of formula (XIX) according to the conditions described with respect to Scheme 1 , step (c).

Furthermore, compounds of formula (X) where R⁹ is R⁷ can be conveniently prepared by reductive amination by an amine of formula (Xl) with an aldehyde/ketone, in the presence of an acid, such as organic acid (e.g. acetic acid); in a solvent, such as a haloalkane (e.g. DCM) or an ether (e.g. THF); using an alkali metal hydride reducing agent, such as sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride; and at ambient temperature. Alternatively alkylation of a compound of formula (Xl) can be effected by use of an alkyl halide or alkyl sulfonate of formula (XX), in the presence of a base, such as an inorganic base (e.g. potassium carbonate); optionally in the presence of an metal iodide salt (e.g. potassium iodide); an organic solvent (e.g. DMF or NMP); and at ambient temperature to elevated temperature (up to 100⁰C). Step (f) may be carried out according to the conditions described with respect to scheme 1 , step (b).

Step (g) may be carried out according to the conditions described with respect to scheme 1 , step (c).

In a variation of scheme 2, compounds of formula (I) may be prepared by carrying out steps (d) to (g) in a different order, for example in the order (f), (g), (d), (e).

Compounds of formula (XII) are of analogous structure to compounds of formula (IV), or intermediates thereto, and may be prepared by analogous methods.

Compounds of formulae (III), (V), (Vl), (XVII), (XVIII), (XIX) and (XX) are either known compounds or may be prepared by conventional chemistry; see, for example WO00/038680, WO01/90106 (especially pages 5-19) and WO03/084954 (especially pages 7-17) incorporated herein by reference.

Pyrrolidines of formula (Vl) can be prepared by methods previously described in the literature, e.g. US2002/0198178 incorporated herein by reference. Tropanes of formula (V) can also be prepared by methods previously described in the literature (WO00/038680, WO03/084954 and WO01/90106).

The compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives are useful because they have pharmacological activity in animals, including humans. More particularly, they are useful in the treatment of a disorder in which the modulation, in particular antagonism, of CCR5 receptors is implicated. Disease states of particular interest include HIV, retroviral infections genetically related to HIV, AIDS, inflammatory diseases, autoimmune diseases and pain. The compounds of this invention may be used for treatment of respiratory disorders, including adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, sarcoidosis, farmer's lung, nasal polyposis, fibroid lung or idiopathic interstitial pneumonia. Other conditions that may be treated are those triggered, affected or are in any other way correlated with T-cell trafficking in different organs. It is expected that the compounds of this invention may be useful for the treatment of such conditions and in particular, but not limited to, conditions for which . a correlation with CCR5 or CCR5 chemokines has been established, and more particularly, but not limited to, the following: multiple sclerosis; Behcet's disease, Sjogren's syndrome or systemic sclerosis; arthritis, such as rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis; and graft rejection, in particular, but not limited to, solid organ transplants, such as heart, lung, liver, kidney and pancreas transplants (e.g. kidney and lung allografts), and graft versus host rejection; inflammatory bowel disease, including Crohn's disease and ulcerative colitis; inflammatory lung conditions; endometriosis; renal diseases, such as glomerular disease (e.g. glomerulonephritis); fibrosis, such as liver, pulmonary and renal fibrosis; encephalitis, such as HIV encephalitis; chronic heart failure; myocardial infarction; hypertension; stroke; ischaemic heart disease; atherosclerotic plaque ; restenosis; obesity; psoriasis; atopic dermatitis; CNS diseases, such as AIDS related dementias and Alzheimer's disease; anaemia; chronic pancreatitis; Hashimoto's thyroiditis; type I diabetes; cancer, such as non-Hodgkin's lymphoma, Kaposi's sarcoma, melanoma and breast cancer; pain, such as nociceptive pain and neuropathic pain (e.g. peripheral neuropathic pain); and stress response resulting from surgery, infection, injury or other traumatic insult.

Infectious diseases where modulation of the CCR5 receptor is implicated include acute and chronic hepatitis B Virus (HBV) and hepatitis C Virus (HCV) infection; bubonic, septicemic, and pneumonic plague; pox virus infection, such as smallpox; toxoplasmosis infection; mycobacterium infection; trypanosomal infection such as Chagas' Disease; pneumonia; and cytosporidiosis.

For a recent review of possible applications of chemokines and chemokine receptor blockers see Cascieri, M.A., and Springer, M.S., "The chemokine/chemokine receptor family: potential and progress for therapeutic intervention", Curr. Opin. Chem. Biol., 4(4), 420-7 (August 2000).

Accordingly, in another aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof for use as a medicament. In another aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, for the treatment of a disorder in which the modulation of CCR5 receptors is implicated.

In another aspect the invention provides the use of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate or derivative thereof, in the manufacture of a medicament for the treatment of a disorder in which the modulation of CCR5 receptors is implicated.

In another aspect the invention provides a method of treatment of a disorder in which the modulation of CCR5 receptors is implicated which comprises administering to a patient in need thereof (e.g a human patient or an animal patient) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof.

The compounds of the invention are useful in the treatment of the diseases, disorders or conditions mentioned above; diseases of particular interest include HIV, retroviral infections genetically related to HIV, AIDS, inflammatory diseases, autoimmune diseases and pain.. For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.

In another aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, for the treatment of a respiratory disorder including adult respiratory d istress syndrome (ARDS), b ronchitis, chronic b ronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, sarcoidosis; farmer's lung, nasal polyposis, fibroid lung or idiopathic interstitial pneumonia

In another aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, for the treatment of multiple sclerosis, Behcet's disease, Sjogren's syndrome, systemic sclerosis, rheumatoid arthritis or graft rejection.

In another aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, for the treatment of inflammatory bowel d isease; e ndometriosis; type I diabetes; renal diseases; fibrosis such as liver fibrosis; chronic pancreatitis; inflammatory lurig conditions; encephalitis; chronic heart failure; myocardial infarction; ischaemic heart disease; psoriasis; stroke; obesity; CNS diseases; anaemia; restenosis; atherosclerotic plaque; atopic dermatitis; chronic pancreatitis; Hashimotos thyroiditis; cancer; pain; or stress response resulting from surgery, infection, injury or other traumatic insult. In another aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, for the treatment of HBV, HCV, plague, pox virus, toxoplasmosis, mycobacterium, trypanosomal, pneumonia, or cytosporidiosis.

In another aspect the invention provides the use of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate or derivative thereof, for the manufacture of a medicament for the treatment of a disorder in which the modulation of CCR5 receptors is implicated. In another aspect the invention provides a method of treatment of a mammalian disorder in which the modulation of CCR5 receptors is implicated which comprises treating said mammal with an effective amount of a compound of formula (I) or with a pharmaceutically acceptable salt, solvate or derivative thereof. The compounds of the invention may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or in any combination thereof).

Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions a nd m ethods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995). The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981- 986 by Liang and Chen (2001).

For tablet dosage forms, depending on dose, the drug may make up from 0.1 wt% to 80 wt%, more typically from 1 wt% to 60 wt%, such as 5 wt% to 50 wt%,- of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 0.1 wt% to 25 wt%, more typically from 0.5 wt% to 20 wt%, such as 1 wt% to 15 wt%, of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, calcium carbonate and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents m ay comprise from 0.2 wt% to 5 wt% of the tablet, and glidants may comprise from 0.2 wt% to 1 wt% of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavours, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 1 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.

Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.

The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).

Solid formulations for o ral administration m ay be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

The compounds of the invention may also be administered directly into the blood stream, i nto m uscle, o r i nto a n internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the compound. Examples of such formulations include drug- coated stents and PGLA microspheres.

The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, s ponges, fibres, bandages and m icroemulsions. L iposomes m ay also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1,1,2-tetrafluoroethane or 1,1,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound comprising, for example, ethanol (optionally, aqueous ethanol) or a suitable alternative agent ifor dispersing, solubiiising, or extending release of the compound, the propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

Capsules (made, for example, from gelatin or HPMC)_/ blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A s uitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1μg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1μl to 100μl. A typical formulation may comprise a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration. Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid) (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from 1μg to 10mg of the compound of the invention. The overall daily dose will typically be in the range 1μg to 200mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, vaginal ring or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate. As described hereinabove, the compounds of the invention can also be applied topically to mucosa, such as vaginal and rectal mucosa. Typical formulations for this purpose include gels, creams, ointments, foams, wafers, implants and sponges.

Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural' administration include ointments, biodegradable (e.g. a bsorbable g el s ponges, collagen) a nd n on-biodegradable (e.g. s ilicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.

The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration. Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an a uxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

Inasmuch as it may desirable to administer a compound of the invention in combination with another therapeutic agent, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound of the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions.

Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

For administration to human patients, having a weight of about 65 to 70kg, the total daily dose of a compound of the invention is typically in the range 1 to 10,000mg, such as 10 to

1 ,000mg, for example 25 to 500mg, depending, of course, on the mode of administration, the age, condition and weight of the patient, and will in any case be at the ultimate discretion of the physician. The total daily dose may be administered in single or divided doses.

Accordingly in another aspect the invention provides a pharmaceutical composition including a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers. The compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives have the advantage that they are more selective, have a more rapid onset of action, are more potent, are better absorbed, are more stable, are more resistant to metabolism, have a reduced 'food effect', have an improved safety profile or have other more desirable properties

(e.g. with respect to solubility or hygroscopicity) than the compounds of the prior art.

The compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives may be administered alone or as part of a combination therapy. Thus included within the scope of the present invention are embodiments comprising co-administration of, and compositions which contain, in addition to a compound of the invention, one or more additional therapeutic agents.

Such multiple drug regimens, often referred to as combination therapy, may be used in the treatment and prevention of any of the diseases or conditions mediated by or associated with CCR5 chemokine receptor modulation, particularly infection by human immunodeficiency virus, HIV. The use of such combination therapy is especially p ertinent with respect to the treatment and prevention of infection and multiplication of the human immunodeficiency virus, HIV, and related pathogenic retroviruses within a patient in need of treatment or one at risk of becoming such a patient. The ability of such retroviral pathogens to evolve within a relatively short period of time into strains resistant to any monotherapy which has been administered to said patient is well known in the literature. A recommended treatment for HIV is a combination drug treatment called Highly Active Anti-Retroviral Therapy, or HAART. HAART combines three or more HIV drugs. Thus, the methods of treatment and pharmaceutical compositions of the present invention may employ a compound of the invention in the form of monotherapy, but said methods and compositions may also be used in the form of combination therapy in which one or more compounds of the invention are co-administered in combination with one or more additional therapeutic agents such as those described in detail further herein.

The therapeutic agents that may be used in combination with the compounds of the present invention include, but are not limited to, those useful as HIV protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), CCR5 antagonists, agents which inhibit the interaction of gp120 with CD4, other agents which inhibit the entry of HIV into a target cell, inhibitors of HIV integrase, RNaseH inhibitors, prenylation inhibitors, maturation inhibitors which act by interfering with production of the HIV capsid protein, compounds useful as anti-infectives, and others as described below.

It will be appreciated by a person skilled in the art, that a combination drug treatment, as described herein above, may comprise two or more compounds having the same, or different, mechanism of action. Thus, by way of illustration only, a combination may comprise a compound of the invention and: one or more NRTIs; one or more NRTIs and a Pl; one or more NRTIs and another CCR5 antagonist; a Pl; a Pl and an NNRTI; an NNRTI; and so on.

Examples of PIs include, but are not limited to, amprenavir (141W94), CGP-73547, CGP-61755, D MP-450 ( mozenavir), n elfinavir, ritonavir, saquinavir (invirase), lopinavir, TMC- 126, atazanavir, palinavir, GS-3333, KN 1-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, ABT-378, DMP-450, AG-1776, MK-944, VX- 478, indinavir, tipranavir, TMC-114, DPC-681 , DPC-684, fosamprenavir calcium (Lexiva), benzenesulfonamide derivatives disclosed in WO 03/053435, R-944, Ro-03-34649, VX-385, GS-224338, OPT-TL3, PL-100, PPL-100, SM-309515, AG-148, DG-35-VIII, DMP-850, GW- 5950X, KNI-1039, L-756423, LB-71262, LP-130, RS-344, SE-063, UIC-94-003, Vb-19038, A- 77003, BMS-182193, BMS-186318, SM-309515, JE-2147, GS-9005.

Examples of NRTIs include, but are not limited to, abacavir, GS-840, lamivudine, adefovir dipivoxil, beta-fluoro-ddA, zalcitabine, didanosine, stavudine, zidovudine, tenofovir disoproxii fumarate, amdoxovir (DAPD), SPD-754, SPD-756, racivir, reverset (DPC-817), MIV-

210 (FLG), beta-L-Fd4C (ACH-126443), MIV-310 (alovudine, F LT), d OTC, DAPD, e ntecavir,

GS-7340, emtricitabine (FTC).

Examples of NNRTIs include, but are not limited to, efavirenz, HBY-097, nevirapine,

TMC-120 (dapivirine), TMC-125, etravirine, delavirdine, DPC-083, DPC-961 , capravirine, rilpivirine, 5-{[3,5-Diethyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}isophthalonitrile or pharmaceutically a cceptable s alts, s olvates o r d erivatives t hereof; GW-678248, GW -695634,

MIV-150, calanolide, and tricyclic pyrimidinone derivatives as disclosed in WO 03/062238.

Examples of CCR5 antagonists include, but are not limited to, TAK-779, SC-351125, SCH-C (ancriviroc), SCH-D (vicriviroc), maraviroc, PRO-140, aplaviroc, AMD-887 CMPD-167, methyl 1 -enc/o-{8-[(3S)-3-(acetylamino)-3-(3-fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2- methyl-4,5,6,7-tetrahydro-1 /-/-imidazo[4,5-c]pyridine-5-carboxylate or pharmaceutically acceptable salts, solvates or derivatives thereof, methyl 3-enofo-{8-[(3S)-3-(acetamido)-3-(3- fluorophenyl)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-4,5,6,7-tetrahydro-3/-/-imidazo[4,5- c]pyridine-5-carboxylate o r p harmaceutically a cceptable s alts, s olvates o r derivatives thereof, ethyl 1-eπc/o-{8-[(3S)-3-(acetylamino)-3-(3-fluoropheny!)propyl]-8-azabicyclo[3.2.1]oct-3-yl}-2- methyl-4,5,6,7-tetrahydro-1 H-imidazo[4,5-c]pyridine-5-carboxylate or pharmaceutically acceptable salts, solvates or derivatives thereof, and Λ/-{(1 S)-3-[3-enc/o-(5-lsobutyryl-2-methyl- 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-(3- fluorophenyl)propyl}acetamide) or pharmaceutically acceptable salts, solvates or derivatives thereof. \

Examples of entry and fusion inhibitors include, but are not limited to, BMS-806, BMS- 488043, 5-{(1 S)-2-[(2R)-4-Benzoyl-2-methyl-piperazin-1 -yl]-1 -methyl-2-oxo-ethoxy}-4-methoxy- pyridine-2-carboxylic acid methylamide and 4-{(1S)-2-[(2R)-4-Benzoyl-2-methyl-piperazin-1-yl]- 1-methyl-2-oxo-ethoxy}-3-methoxy-N-methyl-benzamide, enfuvirtide (T-20), SP-01A, T1249, PRO 542, AMD-3100, soluble CD4, compounds disclosed in JP 2003171381 , and compounds disclosed in JP 2003119137.

Examples of inhibitors of HIV integrase include, but are not limited to, L-000870810 GW- 810781 , 1 ,5-naphthyridine-3-carboxamide derivatives disclosed in WO 03/062204, compounds disclosed in WO 03/047564, compounds disclosed in WO 03/049690, and 5-hydroxypyrimidine- 4-carboxamide derivatives disclosed in WO 03/035076.

Examples of p renylation inhibitors include, but are not limited to, HMG CoA reductase inhibitors, such as statins (e.g. atorvastatin).

Examples of maturation inhibitors include 3-O-(3'3'-dimethylsuccinyl) betulic acid (otherwise known as PA-457) and alphaHGA. Anti-infectives that may be used in combination with the compounds of the present invention include antibacterials and antifungals. Examples of antibacterials include, but are not limited to, atovaquone, azithromycin, clarithromycin, trimethoprim, trovafloxacin, pyrimethamine, daunorubicin, clindamycin with primaquine, fluconazole, pastill, ornidyl, eflornithine pentamidine, rifabutin, spiramycin, intraconazole-R51211 , trimetrexate, daunorubicin, recombinant human erythropoietin, recombinant human growth hormone, megestrol acetate, testerone, and total enteral nutrition. Examples of antifungals include, but are not limited to, anidulafungin, C31G, caspofungin, DB-289, fluconazaole, itraconazole, ketoconazole, micafungin, posaconazole, and voriconazole. There is also included within the scope the present invention, combinations of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, together with one or more additional therapeutic agents independently selected from the group consisting of:

- Proliferation inhibitors, e.g. hydroxyurea. - Immunomodulators, such as AD-439, AD-519, alpha interferon, AS-101 , bropirimine, acemannan, CL246.738, EL10, FP-21399, gamma interferon, granulocyte macrophage colony stimulating factor (e.g. sargramostim), IL-2, immune globulin intravenous, IMREG-1 , IMREG-2, imuthiol diethyl dithio carbamate, alpha-2 interferon, methionine-enkephalin, MTP-PE, remune, rCD4, recombinant soluble human CD4, interferon alfa-2, SK&F106528, soluble T4 thymopentin, tumor necrosis factor (TNF), tucaresol, recombinant human interferon beta, interferon alfa n-3.

- Tachykinin receptor modulators (e.g. NK1 antagonists) and various forms of interferon or interferon derivatives.

- Other chemokine receptor agonists/antagonists such as CXCR4 antagonists (e.g AMD070 and AMD3100) or CD4 antagonists (e.g. TNX-355).

- Agents which substantially inhibit, disrupt or decrease viral transcription or RNA replication such as inhibitors of tat (transcriptional trans activator) or nef (negative regulatory factor).

- Agents which substantially inhibit, disrupt or decrease translation of one or more proteins expressed by the virus (including, but not limited to, down regulation of protein expression or antagonism of one or more proteins) other than reverse transcriptase, such as Tat or Nef.

- Agents which influence, in particular down regulate, CCR5 receptor expression; chemokines that induce CCR5 receptor intemalisation such MIP-1α, MIP-1 β, RANTES and derivatives thereof; examples of such agents include, but are not limited to, immunosupressants, such as calcineurin inhibitors (e.g. tacrolimus and cyclosporin A); steroids; agents which interfere with cytokine production or signalling, such as Janus Kinase (JAK) inhibitors (e.g. JAK-3 inhibitors, including 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}- 3-oxo-propionitrile) and pharmaceutically acceptable salts, solvates or derivatives thereof; cytokine antibodies (e.g. antibodies that inhibit the interleukin-2 (IL-2) receptor, including basiliximab and daclizumab); - Agents which interfere with cell activation or cell cycling, such as rapamycin.

In addition to the requirement of therapeutic efficacy, which may necessitate the use of therapeutic agents in addition to the compounds of the invention, there may be additional rationales which compel or highly recommend the use of a combination of a compound of the invention and another therapeutic agent, such as i n the treatment of d iseases o r conditions which directly result from or indirectly accompany the basic or underlying CCR5 chemokine receptor modulated disease or condition. For example, where the basic CCR5 chemokine receptor modulated disease or condition is HIV infection and multiplication it may be necessary or at least desirable to treat Hepatitis C Virus (HCV), Hepatitis B Virus (HBV), Human Papillomavirus (HPV), neoplasms, and other conditions which occur as the result of the immune-compromised state of the patient being treated. Other therapeutic agents may be used with the compounds of the invention, e.g., in order to provide immune stimulation or to treat pain and inflammation which accompany the initial and fundamental HIV infection.

Accordingly, therapeutic agents for use in combination with the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives also include: -

- Agents u seful i n t he t reatment of h epatitis, s uch a s i nterferons, p egylated i nterferons (e.g. peginterferon alfa-2a and peginterferon alfa-2b), long-acting interferons (e.g. albumin-interferon alfa); TLR7 inhibitors; reverse transcriptase i nhibitors, s uch a s I amivudine a nd e mtricitabine; IMP dehydrogenase inhibitors such as ribavirin and viramidine; polymerase inhibitors (including NS5B polymerase inhibitors) such as valopicitabine, HCV-086, HCV-796 purine nucleoside analogues as disclosed in WO 05/009418, and imidazole derivatives as disclosed in WO 05/012288; alpha glucosidase inhibitors such as celgosivir; interferon enhancers such as EMZ- 702; serine protease inhibitors such as B1LN-2061 , SCH-6, VX-950, aza-peptide-based macrocyclic derivatives as disclosed in WO 05/010029 and those disclosed in WO 05/007681; caspase inhibitors such as IDN-6566; HCV replicon inhibitors such as arylthiourea derivatives as disclosed in WO 05/007601.

- Agents useful in the treatment of AIDS related Kaposi's sarcoma, such as interferons, daunorubicin, doxorubicin, paclitaxel, metallo-matrix proteases, A-007, bevacizumab, BMS- 275291 , halofuginone, interleukin-12, rituximab, porfimer sodium, rebimastat, COL-3.

- Agents useful in the treatment of cytomegalovirus (CMV), such as fomivirsen, oxetanocin G, cidofovir, cytomegalovirus immune globin, foscarnet sodium, lsis 2922, valacyclovir, valganciclovir, ganciclovir.

- Agents useful in the treatment of herpes simplex virus (HSV), such as acyclovir, penciclovir, famciclovir, ME-609.

Further combinations for use according to the invention include combination of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof with a CCR1 antagonist, such as BX-471 ; a beta adrenoceptor agonist, such as salmeterol; a corticosteroid agonist, such fluticasone propionate; a LTD4 antagonist, such as montelukast; a muscarinic antagonist, such as tiotropium bromide; a PDE4 inhibitor, such as cilomilast or roflumilast; a COX-2 inhibitor, such as celecoxib, valdecoxib or rofecoxib; an alpha-2-delta ligand, such as gabapentin or pregabalin; a beta-interferon, such as REBIF; a TNF receptor modulator, such as a TNF-alpha inhibitor (e.g. adalimumab). There is also included within the scope the present invention, combinations of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, together with one or more additional therapeutic agents which slow down the rate of metabolism of the compound of the invention, thereby leading to increased exposure in patients. Increasing the exposure in such a manner is known as boosting. This has the benefit of increasing the efficacy of the compound of the invention or reducing the dose required to. achieve the same efficacy as an unbόosted dose. The metabolism of the compounds of the invention includes oxidative processes carried out by P450 (CYP450) enzymes, particularly CYP 3A4 and conjugation by UDP glucuronosyl transferase and sulphating enzymes: ^" Thus, among the agents that may be used to increase the exposure of a patient to a compound of the present invention are those that can act as inhibitors of at least one isoform of the cytochrome P450

(CYP450) enzymes. The isoforms of CYP450 that may be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4. Suitable agents that may be used to inhibit CYP 3A4 include, but are not limited to, ritonavir, saquinavir or ketoconazole.

In the above-described combinations, the compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof and other therapeutic agent(s) may be administered, in .terms of dosage forms, either separately or in conjunction with each other; and in terms of their time of administration, either simultaneously or sequentially. Thus, the administration of one component agent may be prior to, concurrent with, or subsequent to the administration of the other component agent(s). Accordingly, in a further aspect the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof and one or more additional therapeutic agents.

It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment. The i nvention i s i llustrated by the following Examples a nd P reparations i n which the following further abbreviations may be used: h = hour min = minute

LRMS = low resolution mass spectrum HRMS = high resolution mass spectrum

APCI = atmospheric pressure chemical ionisation

ESI = electrospray ionisation

NMR = nuclear magnetic resonance tic - thin layer chromatography ^{

Me = methyl

Example 1 i-fO-encfoV.δ-irOSΛSVI-acetyl^-phenylpyrrolidin-a-yllmethylVδ-azabicyclora.Σ.iloct-S-vO-δ- isobutyryl-2-methyl-4,5,6,7-tetrahvdro-1H-imidazor4,5-cipyridine

To a stirred solution of ^((S-enc/oJ-δ-t^SS^SVI-acetyl^-phenylpyrrolidin-S-yllmethylJ-δ- azabicyclop^.iloct-S-yl^-methyl^.δ.θ.T-tetrahydro-i /-/-imidazo[4,5-c]pyridine (Example 2δ, 70mg, 0.16 mmol) in dichloromethane (1ml) was added diisopropylethylamine (30μl, 0.17 mmol) followed by isobutyryl chloride (17μl, O.iδmmol). After 1δ hours the mixture was diluted with dichloromethane (5ml) and 10% aqueous K₂CO₃ solution (3ml). The mixture was passed through a phase separation cartridge and the organic component was concentrated. The crude product mixture was purified by silica gel column chromatography eluting with dichloromethaneimethanokconcentrated aqueous ammonia (97:3:0.3 then 96:4:0.4, by volume) to give the title compound as a white solid (46mg, 56%). LRMS (atmospheric pressure chemical ionisation): m/z 51 δ [MH⁺].

¹H NMR (400MHz, CD₃OD) 1.06 (3H, d), 1.14 (3H, d), 1.47-1.60 (4H, m), 1.35-2.05 (2H, m), 2.07 and 2.14 (3H, 2 x s), 2.23-2.45 (7H, m), 2.55-2.60 (3H, m), 2.91-3.57 (6H, m), 3.77-3.87 (2H, m), 3.91-4.04 (2H, m), 4.27-4.41 (1 H, m), 4.42-4.48 (2H, m), 7.21-7.29 (1H, m), 7.31-7.36 (4H, m). Found C₁ 66.43; H, δ.57; N, 12.78. C₃₁H₄₃N₅O₂-I ^H₂O requires C, 68.44; H, 8.51 ; N, 12.87.

Examples 2-20 were prepared according to the method described above in Example 1 using the appropriate acid chloride/chloroformate and the amine as specified. Example 2 Prepared using the amine of Preparation

ionisation): m/z 522 [MH⁺].

Found C, 66.68; H, 7.90; N, 12.92.

C_3OH₄₀N₅FO₂-H₂O requires C₁ 66.77; H₁

7.84; N, 12.98.

Example 3 Prepared using the amine from

Preparation 10, 5-Acetyl-2-methyl-1-((3- enc/o)-8-{[(3R,4S)-4-phenylpyrrolidin-3- yl]methyl}-8-azabicyclo[3.2.1 ]oct-3-yl)-

4,5,6,7-tetrahydro-1H-imidazo[4,5- c]pyridine. LRMS (atmospheric pressure chemical ionisation): m/z 504 [MH⁺].

Found C, 68.37; H, 8.43; N, 13.14.

C₃oH₄iN₅0₂.1.25H₂0 requires C, 68.38; H,

8.34; N, 13.29.

Example 4 Prepared using the amine from

Preparation 10, 5-Acetyl-2-methyl-1-((3- encfo)-8-{[(3R,4S)-4-phenylpyrrolidin-3- yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-

4,5,6,7-tetrahydro-1H-imidazo[4,5- cjpyridine. LRMS (atmospheric pressure chemical ionisation): m/z 518 [MH⁺].

Found C, 68.14; H, 8.61 ; N, 12.69.

C₃₁ H₄₃N₅O₂.1.59H₂O requires C, 68.15; H,

8.52; N, 12.82. Prepared using the amine from

4,5,6,7-tetrahydro-1H-imidazo[4,5- φyridine.

LRMS (atmospheric pressure chemical ionisation): m/z 516 [MH⁺].

Found C, 69.59; H, 8.25; N, 12.84.

C_3IH₄₁N₅O₂-LOSH₂O requires C, 69.58; H,

8.13; N, 13.05.

Example 6 Prepared using the amine from

Preparation 10, 5-Acetyl-2-methyl-1 -((3- encto)-8-{[(3R,4S)-4-phenylpyrrolidin-3- yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-

4,5,6,7-tetrahydro-1H-imidazo[4,5- c]pyridine. LRMS (atmospheric pressure chemical ionisation): m/z 518 [MH⁺].

Found C, 68.73; H, 8.38; N, 12.79.

C₃₁ H₄₃N₅O₂.1.32H₂O requires C, 68.76; H,

8.50; N, 12:53.

Example 7 Prepared using the amine from

4,5,6,7-tetrahydro-1 H-imidazo[4,5- cjpyridine.

LRMS (atmospheric pressure chemical ionisation): m/z 490 [MH⁺].

Found C, 67.00; H, 8.30; N, 13.24.

C₂₉H₃₉N₅O₂.1.68H₂O requires C, 66.99; H,

8.21 ; N, 13.47. Example 8 Prepared using the amine from

Methyl 1 -((3-encfo)-8-f K3S,4S)-1 -acetyl-4- Preparation 8, Methyl 2-methyl-1-((3- phenylpyrrolidin-3-vπmethyl)-8- enofo)-8-{[(3R,4S)-4-phenylpyrrolidin-3- azabicvclor3.2.1loct-3-yl)-2-methyl-1 , 4.6.7- yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)- tetrahvdro-δWmidazol^.δ-clpyridine-δ- 1,4,6,7-tetrahydro-5H-imidazo[4,5-

chemical

N, 13.11. C, 66.22; H,

Prepared using the amine from Example

28, 1 -((3-enαfo)-8-{[(3S,4S)-1 -Acetyl-4- phenylpyrrolidin-3-yl]methyl}-8- azabicyclo[3.2.1 ]oct-3-yl)-2-methyl-

4,5,6,7-tetrahydro-1H-imidazo[4,5- c]pyridine.

LRMS (atmospheric pressure chemical ionisation): m/z 504 [MH⁺].

Found C, 67.87; H, 8.39; N, 13.14.

C₃₀H₄₁N₅O₂-LSI H₂O requires C, 67.87; H,

8.36; N, 13.19.

Prepared using the amine from

Preparation 7, Methyl 1-((3-enofo)-8-

{[(3R,4S)-4-(3-fluorophenyl)pyrrolidin-3- yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-1 ,4,6,7-tetrahydro-5/-/-imidazo[4,5- c]pyridine-5-carboxylate. LRMS (atmospheric pressure chemical ionisation): m/z 524 [MH⁺].

Found C, 62.76; H, 7.14; N, 12.35.

C₂₉H₃₈N₅FO₃. 0.75 H₂O requires C, 62.74;

H, 7.53; N, 12.61. Prepared using the amine from

Preparation 14, 5-Acetyl-1-((3-encfo)-8-

{[(3R,4S)-4-(3-fluorophenyl)pyrrolidin-3- yl]methyl}-8-azabicyclo[3.2.1 ]oct-3-yl)-2- methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5- c]pyridine.

LRMS (atmospheric pressure chemical ionisation): m/z 536 [MH⁺].

Found C, 67.89; H, 8.00; N, 12.79.

C₃iH₄₂N₅FO₂.0.71 H₂O requires C, 67.88;

H, 7.98; N, 12.77.

Example 12 Prepared using the amine from

Preparation 14, 5-Acetyl-1-((3-encfo)-8-

{[(3f?,4S)-4-(3-fluorophenyl)pyrrolidin-3- yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-4,5,6,7-tetrahydro-1AV-imidazo[4,5- c]pyridine.

LRMS (atmospheric pressure chemical ionisation): m/z 523 [MH⁺].

Found C, 67.67; H, 7.89; N, 12.92.

C₃₀H₄₀N₅FO₂-H₂O requires C, 66.67; H,

7.84; N, 12.98.

Prepared using the amine from

Preparation 14, 5-Acetyl-1-((3-encfo)-8-

{[(3f?,4S)-4-(3-fluorophenyl)pyrrolidin-3- yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5- φyridine.

LRMS (atmospheric pressure chemical ionisation): m/z 536 [MH⁺].

Found C, 67.89; H, 8.00; N, 12.79.

C₃₁H₄₂N₅FO₂.O.7I H₂O requires C, 67!88;

H, 7.98; N, 12.77. Prepared using the amine from

Preparation 14, 5-Acetyl-1-((3-enofo)-8-

{[(3R,4S)-4-(3-fluorophenyl)pyrrolidin-3-, yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- methyl-4,5,6,7-tetrahydro~1H-imidazo[4,5- cjpyridine.

LRMS (atmospheric pressure chemical ionisation): m/z 534 [MH⁺].

Found C, 67.49; H, 7.72; N, 12.66.

C₃₁ H₄₀N₅FO₂. H₂O requires C, 67.49; H,

7.67; N, 12.69.

Prepared using the amine from

Preparation 12, 1-((3-enofo)-8-{[(3R,4S)-4-

(3-Fluorophenyl)pyrrolidin-3-yl]methyl}-8- azabicyclo[3.2.1]oct-3-yl)-5-isopropyl-2- methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5- φyridine. .LRMS (atmospheric pressure chemical ionisation): m/z 508 [MH⁺].

Found C, 68.89; H, 8.37; N, 13.36.

C₃₀H₄₂N₅FO-H₂O requires C, 68.54; H,

8.44; N, 13.32.

Prepared using the amine from

Preparation 22, 5-Ethyl-1-((3-encfo)-8-

{[(3R,4S)-4-(3-fluorophenyl)pyrrolidin-3- yl]m ethyi}-8-azabicyclo[3.2.1 ]oct-3-yl )-2- methyl-4,5,6,7-tetrahydro-1/-/-imidazo[4,5- c]pyridine. LRMS (atmospheric pressure chemical ionisation): m/z 495 [MH⁺]. Example 17 Prepared using the amine from

Preparation 8, Methyl 2-methyl-1-((3- e/7ofo)-8-{[(3R,4S)-4-phenylpyrrolidin-3- yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-

1 ,4,6,7-tetrahydro-5/-/-imidazo[4,5- c]pyridine-5-carboxylate.

LRMS (atmospheric pressure chemical ionisation): m/z 522 [MH⁺].

Found C, 65.20; H, 7.64; N, 12.98.

C₂₉H₃₅N₅O₄-OJIH₂O requires C, 65.17; H,

7.62; N, 13.10.

Example 18 Prepared using the amine from

Preparation 10, 5-Acetyl-2-methyl-1-((3- enofo)-8-{[(3f?,4S)-4-phenylpyrrolidin-3- yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-

4,5,6,7-tetrahydro-i H-imidazo[4,5- cjpyridine.

LRMS (atmospheric pressure chemical ionisation): m/z 506 [MH⁺].

Found C, 66.70; H, 7.94; N₁ 13.31.

C₂₉H₃₅N₅O₃.1.02H₂O requires C, 66.47; H,

7.89; N, 13.36.

Example 19 Prepared using the amine from

Preparation 11 , (3-exo)-3-(3-lsopropyl-5- methyl-4H-1 ,2,4-triazol-4-yl)-8-{[(3R,4S)-

4-phenylpyrrolidin-3-yl]methyl}-8- azabicyclo[3.2.1]octane.

LRMS (atmospheric pressure chemical ionisation): m/z 464 [MH⁺].

Found C, 68.73; H, 8.38; N, 12.79.

C₃₁H₄₃N₅O₂.1.32H₂O requires C, 68.76; H,

8.50; N, 12.53.

Prepared using the amine from

4-phenylpyrrolidin-3-yl]meihyl}-8- azabicyclo[3.2.1]octane. LRMS (atmospheric pressure chemical ionisation): m/z 436 [MH⁺].

Example 21 Prepared using the amine from

Preparation 8, Methyl 2-methyl-1-((3- encfo)-8-{[(3R,4S)-4-phenylpyrrolidin-3- yl]methyi}-8-azabicyclo[3.2.1]oct-3-yl)-

1 ,4,6,7-tetrahydro-5H-imidazo[4,5- c]pyridine-5-carboxylate._ ■

LRMS (atmospheric pressure chemical ionisation): m/z 536 [MH⁺].

Found C, 65.58; H, 7.74; N, 12.64.

C₃oH₄₁N₅0₄.0.8H₂0 requires C, 65.50; H,

7.74; N, 12.64. Example 22

O-exoVS-tfOSΛSVI-^Λ-difluorocvclohexyπcarbonyll^-phenylpyrrolidin-S-yllmethvπ-S-O- isopropyl-δ-methvMH-I .ΣΛ-triazoM-vO-δ-azabicycloP^.iloctane

To a stirred solution of 4,4-difluorocyclohexanecarboxylic acid (30mg, 0.18mmol) in dichloromethane (1 ml) was added 1 -hydroxybenzotriazole monohydrate (27mg, 0.20mmol), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride salt (38mg, 0.20mmol), triethylamine (28μl, 0.20mmol) and finally the amine from Preparation 11 (3-exo)-3-(3-lsopropyl- 5-methyl-4H-1 ,2,4-triazol-4-yl)-8-{[(3f?,4S)-4-phenylpyrrolidin-3-yl]methyl}-8- azabicyclo[3.2.1]octane (66rhg, O.Ummol) and the reaction mixture was stirred at room temperature. After 18 hours the mixture was diluted with dichloromethane (5ml) and 10% aqueous potassium carbonate solution (2ml). The organic component was separated and concentrated. The crude product mixture was purified by silica gel column chromatography eluting with dichloromethane:methanol:concentrated aqueous ammonia (95:5:0.5, by volume) to give the title compound as a white solid (32mg, 35%). LRMS (atmospheric pressure chemical ionisation): m/z 540 [MH⁺].

Examples 23-26 were prepared according to the method described above in Example 22 using the appropriate carboxylic acid and the amine as specified.

Example 23 Prepared using the amine from

Preparation 11 , (3-exo)-3-(3-lsopropyl-5- methyl-4H-1 ,2,4-triazol-4-yl)-8-{[(3R4S)-

4-phenylpyrrolidin-3-yl]methyl}-8- azabicyclo[3.2.1]octane. e LRMS (atmospheric pressure chemical ionisation): m/z 494 [MH⁺]. Prepared using the amine from

Preparation 11, (3-exo)-3-(3-lsopropyl-5- methyl-4tf-1 ,2,4-triazol-4-yl)-8-{[(3R,4S)-

4-phenylpyrrolidin-3-yl]methyl}-8- azabicyclo[3.2.1]octane.

LRMS (atmospheric pressure chemical ionisation): m/z 512 [MH⁺].

Found C, 66.01; H, 7.71; N, 13.22.

C₂₅H₃₅F₂N₅O.0.89H₂O requires C, 66.01 ;

H, 7.75; N, 13.27.

Example 25 Prepared using the amine from

Preparation 9, 2-Methyl-1-((3-enofo)-8-

{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}-

8-azabicyclo[3.2.1]oct-3-yl)-1H- benzimidazole.

LRMS (atmospheric pressure chemical ionisation): m/z 526 [MH⁺].

Found C, 69.52; H₁ 7.41 ; N, 12.62.

C₃₂H₃₉N₅O₂-LSH₂O requires C, 69.54; H,

7.66; N, 12.67

Prepared using the amine from

Preparation 9, 2-Methyl-1-((3-e/7cfo)-8-

{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}-

8-azabicyclo[3.2.1]oct-3-yl)-1H- benzimidazole.

LRMS (atmospheric pressure chemical ionisation): m/z 561 [MH⁺].

Found C, 64.25; H, 7.06; N, 9.50.

C₃₂H₄₀N₄O₃S.2H₂O requires C, 64.40; H,

7.43; N, 9.39

Example 27

O-exoVδ-^OSΛSVI-^Λ-difluoropiperidin-i-vDcarbonvn^-phenylpyrrolidin-S-yllmethvD-S-O- isopropyl-δ-methvMH-I .ΣΛ-triazoM-vO-δ-azabicycloβ^.πoctane

-To a stirred solution 4,4-difluoropiperidine hydrochloride salt (66mg, 0.42 mmol) and triethylamine (117μl, 0.84mmol) in dichloromethane (1ml) at 0 ⁰C was added triphosgene (44mg, 0.15mmol). The reaction mixture was allowed to slowly warm to room temperature. After 2 hours a solution of the hydrochloride salt of the amine from Preparation 11 (3-exo)-3-(3- lsopropyl-5-methyl-4H-1 ,2,4-triazol-4-yl)-8-{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}-8- azabicyclo[3.2.1]octane (100mg, 0.25mmol) and triethylamine (58μl, 0.42mmol) in dichloromethane (1ml) was added and the reaction mixture was stirred at room temperature. After 18 hours the mixture was diluted with dichloromethane (5ml) and washed with 10% aq potassium carbonate solution (3ml). The orgainic component was separated, d ried (MgSO₄) and concentrated. The crude product mixture was purified by silica gel column chromatography eluting with dichloromethane :methanol:concentrated aqueous ammonia (98:2:0.2, by volume) to give the title compound as a white solid (57mg, 42%). LRMS (atmospheric pressure chemical ionisation): m/z 541 [MH⁺]. Found C, 64.31 ; H, 7.97; N, 14.94. C₃₀H₄₂F₂N₆O-LOgH₂O requires C, 64.31 ; H, 7.95; N, 15.00.

Examples 28 1-((3-endo)-8-(r(3S,4S)-1-acetyl-4-phenylpyrrolidin-3-yllmethylV8-azabicvclor3.2.noct-3-yl)-2- methyl-4,5,6,7-tetrahvdro-1/-/-imidazof4,5-clpyridine

To a stirred solution of the carbamate from Example 8 Methyl 1-((3-encfo)-8-{[(3S,4S)-1-acetyl- 4-phenylpyrrolidin-3-yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 ,4,6,7-tetrahydro-5H- imidazo[4,5-c]pyridine-5-carboxylate (300mg, 0.59mmol) in dichloromethane (10ml) was added trimethylsilyl iodide (253μl, 1.77mmol) and the reaction mixture was heated at reflux. After 6 hours a second portion of trimethylsilyl iodide was added (253μl, 1.77mmol) and the mixture was again heated at reflux. After a further 18 hours a third portion of trimethylsilyl iodide was added (253μl, 1.77mmol) and the mixture was again heated at reflux for a further 3 hours. After cooling to room temperature methanol (2ml) was added added and the mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane (30ml) and saturated aqueous NaHCO₃ solution (15ml). The organic component was separated, dried (MgSO₄) and concentrated. The crude product mixture was purified by silica gel column chromatography eluting with dichloromethane:methanol:concentrated aqueous ammonia (98:2:0.2 then 90:10:1 , by volume) to give the title compound as a white solid (170mg, 64%).

LRMS (atmospheric pressure chemical ionisation): m/z 448 [MH⁺].

Example 29 1-((3-endo)-8-(r(3S,4S)-1-acetyl-4-phenylpyrrolidin-3-vnmethylV8-azabicvclor3.2.1loct-3-yl)-2,5- dimethyl-4,5,6.7-tetrahvdro-1/-/-imidazof4,5-clpyridine

Example 29 was isolated as a by-product during the purification of Example 28 1-((3-e/?c/o)-8- {[(3S,4S)-1-acetyl-4-phenylpyrrolidin-3-yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7- tetrahydro-1 H-imidazo[4,5-c]pyridine and was isolated as a white solid (43mg, 16%).

LRMS (atmospheric pressure chemical ionisation): m/z 462 [MH⁺].

Found C, 67.73; H, 8.58; N, 13.83. C₂₈H₃₅N₅CLSSH₂O requires C, 67.75; H, 8.70; N, 14.11. ^"

Preparation 1

(3R4S)-1-Benzyl-4-phenylpyrrolidine-3-carbaldehvde

To a stirred solution of oxalyl chloride (1.6ml, 19mmol) in dichloromethane (70 ml) at -78⁰C was added DMSO (1.99ml, 28mmol). After 10 minutes 1-benzyl-3-(R)-hydroxymethyl-4-(S)- phenylpyrrolidine (US2002/0198178, page 31 ; 2.5g, 9mmol) in DCM (10 ml) was added dropwise. After 30 minutes di-isopropylethylamine (16ml, 93mmol) was added dropwsie. After warming to room temperature the mixture was diluted with water (50ml) and extracted with dichloromethane (50ml). The organic layer was separated, washed with brine (30ml), dried and concentrated to give a yellow oil (2.5g) which was used without further purification. LRMS (APCI+): m/z [MH⁺] 266.

Preparation 2

(3f?,4S)-1-Benzyl-4-(3-fluorophenyl)pyrrolidine-3-carbaldehvde

The title compound was prepared according to the method described in Preparation 1 using 1- benzyl-3-(R)-hydroxymethyl-4-(S)-(3-fluorophenyl)pyrrolidine (US2002/0198178, page 31 ). LRMS (APCI+): m/z [MH⁺] 284.

Preparation 3

Methyl 1-((3-enc/o)-8-(r(3f?,4S)-1-benzyl-4-(3-fluorophenyl)pyrrolidin-3-vnmethyl)-8- azabicyclo|^'3.2.1]oct-3-yl)-2-methyl-1 ,4,6.7-tetrahvdro-5/-/-imidazor4.5-ciPyridine-5-carboxylate

To a stirred solution of the aldehyde from Preparation 2 (3R,4S)-1-Benzyl-4-(3- fluorophenyl)pyrrolidine-3-carbaldehyde (2.4g, δ.δmmol) in dichloromethane (20ml) at room temperature was added m ethyl 1 -(endo-8-azabicyclo[3.2.1]oct-3yl)2-methyl-4,5,6,7-tetrahydro- 1 H-imidazo[4,5-c]pyridine-5-carboxylate (WO03/084954, Preparation 49; 2.Og, 6.58mmol). Sodium triacetoxyborohydride (1.8g, 8.6mmol) was added followed by acetic acid (0.38ml, δ.δmmol) and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution (20ml). The aqueous component was separated and extracted with dichloromethane (50 ml). The organic components were combined, dried over MgSO₄, filtered and concentrated. The crude product mixture was purified by silica gel column chromatography eluting with dichloromethane:methanol:concentrated aqueous ammonia (98:2:0.2 then 95:5:0.5, by volume) to give the title compound as a yellow oil (3.1g, 81%). LRMS (atmospheric pressure chemical ionisation): m/z 572 [MH⁺]. Found C, 71.43; H, 7.40; N, 12.25. C₃₄H₄₂N₅FO₂. 0.5 H₂O requires C, 70.32; H, 7.46; N, 12.06.

Preparations 4-6 were prepared according to the method described in Preparation 3 using the aldehydes from Preparations 1 or 2 as appropriate and the amine as specified.

Preparation 4 , Amine: WO03/084954, Preparation 49.

Methyl 1 -«3-eπcfo)-8-ffl3R.4SV1 -benzyl-4- phenylpyrrolidin-3-yl]methylV8- LRMS: m/z [MH⁺] 554 azabicvclor3.2.1loct-3-yl)-2-methyl-1 , 4,6,7- tetrahvdro-5/-/-imidazor4,5-clpyridine-5- carboxylate

Preparation 5 Amine: WO2000038680, Preparation 53

1 -((3-βncfoV8-f IT3R4SV1 -Benzyl-4- phenylpyrrolidin-3-yllmetrιyll-8- azabicvclor3.2.11oct-3-yl)-2-methyl-1 H-

LRMS: m/z [MH⁺] 491 benzimidazole

Preparation 6 Amine: WO01/90106, Preparation 25.

(3-exo)-8-(r(3/^:?,4S)-1-Benzyl-4-phenylpyrrolidin- 3-vnmethyl)-3-(3-isopropyl-5-methyl-4H-1 ,2,4- LRMS: m/z [MH⁺] 354 triazol-4-yl)-8-azabicvclor3.2.1lbctane

Preparation 7

Methyl 1-((3-eπcyo)-8-(r(3f?,4S)-4-(3-fluoroprienyl)pyrrolidin-3-yl1methyl)-8-azabicvclor3.2.noct-3- yl)-2-methyl-1,4,6,7-tetrahvdro-5H-imidazor4,5-clpyridine-5-carboxylate

To a stirred solution of the /V-benzyl pyrrolidine from Preparation 3 Methyl 1-((3-endo)-8- {[(SR^SJ-i-benzyl^^S-fluorophenylJpyrrolidin-S-yπmethyl^δ-azabicyclop.a.iloct-S-yl)^- methyl-I ^.ΘJ-tetrahydro-δW-imidazo^.δ-clpyridine-S-carboxylate (1.17g, 2.04mmol) in ethanol (20ml) was added ammonium formate (2.52g, 40.8mmol) followed by palladium on carbon (20% w/w; 120mg). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was heated at 5O⁰C for 4 hours. Further portions of the palladium on carbon (20% w/w; 20mg) and ammonium formate were added (1.0g, 15.9mmol) and the mixture was heated at 5O⁰C for 6 hours. After cooling to room temperature the reaction mixture was filtered through Arbocel, the filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane:methanol:concentrated aqueous ammonia (90:10:1 , by volume) to give the title compound as a colourless oil (0.45g, 46%). LRMS (atmospheric pressure chemical ionisation): m/z 482 [MH⁺].

Preparations 8-11 were prepared according to the method described in Preparation 7 using the pyrrolidine as specified.

Preparation 8 Pyrrolidine from P reparation 4 , M ethyl 1-

Methyl 2-methyl-1 -W3-enctoV8-f K3R4SV4- ((3-encfo)-8-{[(3R,4S)-1 -benzyl-4- phenylpyrrolidin-3-yllmethyl)-8- phenylpyrrolidin-3-yl]methy!}-8- imidazof4,5-cipyridine-5-carboxylate 1 ,4,6,7-tetrahydro-5H-imidazo[4,5- c]pyridine-5-carboxylate

LRMS: m/z [MH⁺] 464

((3-

Preparation 10 Pyrrolidine from Preparation 20, 5-Acetyl- 5-Acetyl-2-metrιyl-1-((3-endoV8-(r(3R.4S)-4-

1 -((3-enc/o)-8-{[(3/^:?,4S)r1 -benzyl-4- phenylpyrrolidin-3-yllmethvD-8- phenylpyrrolidin-3-yl]niethyl}-8- azabicvcloβ^.iioct-S-ylH.δ.ej-tetrahvdro-i/-/- azabicyclo[3.2.1]oct-3-yl)-2-methyl- imidazof4,5-clpyridine

4,5,6,7-tetrahydro-1H-imidazo[4,5-

-

Preparation 11 Pyrrolidine from Preparation 6, (3-exo)-8-

(3-exo)-3-(3-lsopropyl-5-methyl-4H-1,2,4-triazor- {[(3R,4S)-1-Benzyl-4-phenylpyrrolidin-3- 4-yl)-8-(r(3f?₁4S)-4-phenylpyrrolidin-3-vπmethyl)- yl]methyl}-3-(3-isopropyl-5-methyl-4H-

_;.

Preparation 14 Pyrrolidine from Preparation 19, 5-Acetyl- 5-Acetyl-1-((3-encto)-8-(r(3R.4S)-4-(3-

1 -((3-enc/o)-8-{[(3R,4S)-1 -benzyl-4-(3- fluorophenyl)pyrrolidin-3-vnmethyl)-8- fluorophenyl)pyrrolidin-3-yl]methyl}-8- azabicvclor3.2.noct-3-yl)-2-methyl-4,5,6,7- azabicyclo[3.2.1]oct-3-yl)-2-methyl- tetrahvdro-1H-imidazor4,5-clpyridine

4_I5,6,7-tetrahydro-1H-imidazo[4,5- c]pyridine

LRMS: m/z [MH⁺] 466

tyl-

Preparation 16

1-((3-encfoV8-(r(3f?,4S)-1-benzyl-4-(3-fluoroprienyl)pyrrolidin-3-yl1methylV8-azabicvclor3.2.1loct-

3-yl)-2-methyl-4,5,6,7-tetrahvdro-1H-imidazof4.5-cipyridine

To a stirred solution the carbamate from Preparation 3 Methyl 1-((3-endo)-8-{[(3R,4S)-1-benzyl- 4-(3-fluorophenyl)pyrrolidin-3-yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 ,4,6,7-tetrahydro- 5H-imidazo[4,5-c]pyridine-5-carboxylate (1.1g, 1.9mmol) in propan-2-ol (8ml) was added 2M aqueous NaOH (10ml). The reaction mixture was heated at reflux for 3 days. After cooling to room temperature the mixture was diluted with water (20ml) and extracted with dichloromethane (3 x 20ml). The organic components were combined, dried (MgSO₄), filtered and concentrated. The crude product mixture was purified by silica gel column chromatography eluting with dichloromethane:methanol:concentrated aqueous ammonia (90:10:1 , by volume) to give the title compound as a white foam (O.δg, 62%). LRMS (atmospheric pressure chemical ionisation): m/z 514 [MH⁺]. Found C, 71.81 ; H, 7.92; N, 12.96. C₃₂H₄₀FN₅. 0.25 H₂O requires C, 71.68; H, 7.92; N, 13.06%.

Preparation 17 was prepared according to the method described in Preparation 16 using the carbamate of Preparation 4, Methyl 1-((3-e/7cfo)-8-{[(3R,4S)-1-benzyl-4-phenylpyrrolidin-3- yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1 ,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5- carboxylate.

Preparation 17

1 -((3-enctoV8-M3R4S)-1 -Benzyl-4- LRMS: m/z [MH⁺] 496 phenylpyrrolidiπ-3-yllmetrιyl}-8- azabicvclof3.2.1loct-3-yl)-2-methyl-4,5,6,7- tetrahvdro-1H-imidazof4,5-clpyridine

Preparation 18

1-((3-enc/o)-8-(r(3R,4S)-1-benzyl-4-(3-fluorophenyl)pyrrolidin-3-yllmethyl)-8-azabicvclor3.2.11oct-

3-yl)-2-methyl-5-propionyl-4,5,6,7-tetrahvdro-1H-imidazor4,5-clpyridine

To a stirred solution of the imidazopiperidine from Preparation 16 1-((3-enofo)-8-{[(3R,4S)-1- benzyl-4-(3-fluorophenyl)pyrrolidin-3-yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7- tetrahydro-1H-imidazo[4,5-c]pyridine (315mg, 0.61 mmol) in dichloromethane (5 ml) was added triethylamine (0.10ml, 0.74mmol) followed by acetyl chloride (64 μl, 0.74mmol). After 1 hour the mixture was diluted with aqueous potassium carbonate solution (10% w/v; 3ml) and dichloromethane and then passed through a phase separation cartridge. The organic component was concentrated and purified by silica gel column chromatography eluting with dichloromethaneimethanohconcentrated aqueous ammonia (95:5:0.5, by volume) to give the title compound as a colourless oil which formed a white foam (309mg, 89%).

LRMS (atmospheric pressure chemical ionisation): m/z 570 [MH⁺].

Found C, 71.88; H, 7.82; N, 11.92. C₃₅H₄₄FN₅O. H₂O requires C, 71.52; H, 7.89; N, 11.91 %.

Preparations 19-20 were prepared according to the method described in Preparation 18 using the amine as specified.

Preparation 19 Amine from Preparation 16, 1-((3-encto)-

5-Acetyl-1 -((3-er>Gto)-8-(r(3R.4S)-1 -benzyl-4-(3- 8-{[(3R,4S)-1 -benzyl-4-(3- fluorophenvDpyrrOlidin-3-yl]methyl)-8- fluorophenyl)pyrrolidin-3-yl]methyl}-8- azabicvclor3.2.11oct-3-yl)-2-methyl-4,5,6,7- azabicyclo[3.2.1]oct-3-yl)-2-methyl- tetrahydro-1H-imidazof4,5-clpyridine 4,5,6,7-tetrahydro-1 AV-imidazo[4,5- ^'

Preparation 20 , Amine from Preparation 17, 1-((3-encfo)-

5-Acetyl-1 -((3-e/?cfo)-8-ffl3R4S)-1 -benzyl-4- 8-{[(3R,4S).-1-Benzyl-4-phenylpyrrolidin-3- phenylpyrrolidin-3-yl1methyl>-8- yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-2- azabicvclor3.2.1]oct-3-yl)-2-methyl-4,5,6,7- methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5- tetrahydro-1Wmidazor4,5-clpyridine c]pyridine

Preparation 21 1-((3-endo)-8-ir(3R4S)-1-Benzyl-4-(3-fluorophenvπpyrrolidin-3-yl]methylV8- azabicvclor3.2.11oct-3-y|^')-5-isopropyl-2-methyl-4.5.6,7-tetrahvdro-1H-imidazor4.5-clpvridine

To a stirred solution of the tropane from Preparation 16 1-((3-endo)-8-{[(3f?,4S)-1-benzyl-4-(3- fluorophenyl)pyrrolidin-3-yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-1H- imidazo[4,5-c]pyridine (330mg, 0.64mmol) in dichloromethane (5ml) was added acetone (57μl, 0.77mol), acetic acid (37μl, 0.64mmol) and sodium triacetoxyborohydride (204mg, 0.96mmol).After stirring at room temperature for 16 hours more acetic acid (100μl, 1.75mmol) and sodium triacetoxyborohydride (100mg, 0.47mmol) were added. The reaction mixture was stirred at 50 ⁰C for 48 hours, during which time acetone (5 x 100μl, 5 x 1.36mmol) and dichloromethane (5 x 2 ml) were added. The reaction mixture was quenched by addition of 10% aqueous potassium carbonate solution (10ml) and extracted with dichloromethane (2 x 20ml). The combined organic components were dried (MgSO₄), filtered and concentrated. The crude product mixture was purified by silica gel column chromatography eluting with dichloromethane:methanol:concentrated aqueous ammonia (98:2:0.2, ,95:5:0.5, 90:10:1 then 80:20:1 by volume) to give the title compound as a yellow oil (188mg, 53%). LRMS (atmospheric pressure chemical ionisation): m/z 557 [MH⁺].

Preparation 22

5-ethyl-1-((3-enQfo)-8-{f(3R,4S)-4-(3-fluorophenyl)pyrrolidin-3-yllmethyl}-8-azabicyclof3.2.1loct-

3-vO-2-methyl-4,5,6,7-tetrahvdro-1 H-imidazor4,5-clpyridine

To a stirred solution of the tropane from Preparation 14 5-Acetyl-1-((3-endo)-8-{[(3R,4S)-4-(3- fluorophenyl)pyrrolidin-3-yl]methyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-4,5,6,7-tetrahydro-1H- imidazo[4,5-c]pyridine (85mg, 0.18mmol) in THF (5ml) was added BH₃-THF complex (0.5ml of a 1.0M solution in THF). The reaction mixture was heated at reflux for 88 hours during which time more BH₃-THF complex (2.0ml of a 1.0M solution in THF) was added in portions. After cooling to room temperature the mixture was diluted by dropwise addition of 2M HCI (10ml) and the mixture was heated at 80 ⁰C for 4 hours. After cooling to room temperature 10% aqueous K₂CO₃ solution was carefully added (20ml). The THF was removed under reduced pressure and the aqueous mixture was extracted with dichloromethane (2 X 15ml). The organic components were combined passed through a phase separation cartridge. The organic solution was concentrated and the residue was purified by silica gel column chromatography eluting with dichloromethane:methanol:concentrated aqueous ammonia (98:2:0.2, 95:5:0.5, 90:10:1 then 80:20:1 by volume) to give the title compound as a colourless oil (29mg, 35%). LRMS (atmospheric pressure chemical ionisation): m/z 452 [MH⁺].

Biological Data

. The ability of the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives to modulate chemokine receptor activity is demonstrated by methodology known in the art, such as by using the assay for CCR5 binding following procedures disclosed in Combadiere et al., J. Leukoc. Biol., 60, 147-52 (1996); and/or by using the intracellular calcium mobilisation assays as described by the same authors. Cell lines expressing the receptor of interest include those naturally expressing the receptor, such as PM- 1 , or IL-2 stimulated peripheral b lood lymphocytes ( PBL), o r a cell e ngineered to express a recombinant receptor, such as CHO, 300.19, L1.2 or HEK-293.

All the Examples, when tested using the assay for intracellular calcium mobilisation according to Combadiere et al (ibid) were potent antagonists with IC₅₀ values of less than 10μM.

The pharmacological activity of the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives is further demonstrated using a gp160 induced cell-cell fusion assay to determine the IC₅₀ values of compounds against HIV-1 fusion. The gp160 induced cell-cell fusion assay uses a HeLa P4 cell line and a CHO-Tat10 cell line.

The HeLa P4 cell line expresses CCR5 and CD4 and has been transfected with HIV-1 LTR-β-Galactosidase. The media for this cell line is Dulbecco modified eagle's medium(D- MEM) (without L-glutamine) containing 10% foetal calf serum (FCS), 2mM L-glutamine penicillin/streptomycin (Pen/Strep; 100U/mL penicillin + 10mg/mL streptomycin), and 1μg/ml puromycin.

The CHO cell line is a Tat (transcriptional trans activator)-expressing clone from a CHO JRR17.1 cell line that has been transfected with pTat puro plasmid. The media for this cell line is rich medium for mammalian cell culture originally developed at Roswell Park Memorial Institute R PM11640 (without L-glutamine) containing 10% FCS, 2mM L-glutamine, 0.5 mg/ml Hygromycin B and 12μg/ml puromycin. The CHO JRR17.1 line expresses gp160 (JRFL) and is a clone that has been selected for its ability to fuse with a CCR5/CD4 expressing cell line.

Upon cell fusion, Tat present in the CHO cell is able to transactivate the HIV-1 long terminal repeat (LTR) present in the HeLa cell leading to the expression of the β-Galactosidase enzyme. This expression is then measured using a Fluor Ace™ β-Galactosidase reporter assay kit (Bio-Rad cat no. 170-3150). This kit is a quantitative fluorescent assay that determines the level of expression of β-galactosidase using 4-methylumbelliferul-galactopyranoside (MUG) as substrate. β-Galactosidase hydrolyses the fluorogenic substrate resulting in release of the fluorescent molecule 4-methylumbelliferone (4MU). Fluorescence of 4-methylumbelliferone is then measured on a fluorometer using an excitation wavelength of 360nm and emission wavelength of 460nm.

Compounds that inhibit fusion will give rise to a reduced signal and, following solubilisation in an appropriate solvent and dilution in culture medium, a dose-response curve for each compound can be used to calculate IC₅₀ values. All the compounds of the Examples of the invention have IC₅₀ values, according to the above method, of less than 15OnM. The compounds of Examples 4, 7, 15, 22 and 25 have, respectively, IC₅₀ values of 18pM, 556pM, 5.1 nM, 6.7nM and 5.7 nM.

Claims

1. A compound of formula (I)

or a pharmaceutically acceptable salt, solvate of derivative thereof, wherein:

R¹ is R⁷, OR⁷ or NR⁵R⁶ ;

R² is H or C_1-6 alky!;

R³ is phenyl substituted by 0 to 3 atoms or groups selected from C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkoxy, C_1-6 alkoxycarbonyl, halogen, CF₃, OH, CN; NR⁵R⁶, CO₂R⁷ or CONR⁵R⁶; R⁴ is a moiety of partial

wherein:

Q is CR⁴²Or N; T is CR⁴³ or N

R⁴¹ is H, C_1-6 alkyl or C_1-6 fluoroalkyl;

R⁴² and R⁴³ are independently selected from H, C_1-6 alkyl, C_1-6 fluoroalkyl, or halogen; or R⁴² and R⁴³ when taken together with the atoms to which they are attached form a benzene, pyridine, pyrimidine, pyridazine or pyrazine ring, wherein the said benzene pyridine, pyrimidine, pyridazine or pyrazine ring is substituted by 0 to 3 atoms or groups selected from C_1- e alkyl, C_1-6 fluoroalkyl or halogen; or form a partially saturated pyridine ring such that R⁴ is a moiety of partial formula (1.0.1 ) wherein the arrowhead denotes the point of attachment to the tropane ring;

R⁵ is H or C_1-6 alkyl; C_2-6 alkenyl; C_2-6 alkynyl; C_3-7 cycloalkyl; a 5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturated heterocycle; wherein said alkyl, alkenyl, alkynyl and cycloalkyl are substituted by 0 to 3 atoms or groups selected from oxo, halogen, CF₃, OR⁶, CN, COR⁶, or CO₂R⁶; wherein said heterocycles contain one to three heteroatoms selected from N ₁ O o r S ; a nd w herein s aid h eterocycles a re s ubstituted b y O to 3 atoms or groups s elected from C _1-6 a Ikyl, C _1-6 a Ikylcarbonyl, C i._B a Ikoxy, C_1-6 alkoxycarbonyl, halogen, CF₃, OH, CN, COR⁶, or CO₂R⁶; ^■ • R⁶ is H or C_1-6 alkyl; or, when R⁵ and R⁶ are both attached to the same N atom, NR⁵R⁶ may also represent a

5 to 7 membered, saturated, partially unsaturated or aromatic, heterocycle containing from O to 2 additional heteroatoms selected from O, N or S, substituted by O to 3 halogen atoms;

R⁷ is C_1-6 alkyl; C_2-6 alkenyl; C_2-6 alkynyl; C_3-7 cycloalkyl; a 5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturated heterocycle; wherein said alkyl, alkenyl, alkynyl and cycloalkyl are substituted by O to 3 atoms or groups selected from oxo, halogen, CF₃, OR⁶,

CN, NR⁵R⁶, COR⁶, CO₂R⁶ or CONR⁵R⁶; wherein said heterocycle contains one to three heteroatoms selected from N, O or S; and wherein said heterocycle is substituted by O to 3 atoms or groups selected from C_1-6 alkyl, C_1-6 alkylcarbonyl. C^e alkoxy, C_1-6 alkoxycarbonyl, oxo, halogen, CF₃, OH, CN, NR⁵R⁶, COR⁶, CO₂R⁶ or CONR⁵R⁶; provided that when R¹ is OR⁷ the said heterocycle is carbon bonded to the oxygen of OR⁷;R⁸ is H or C_1-6 alkyl;

X and Y are selected from CH₂ and NR⁹ such that one of X and Y is CH₂ and the other is NR⁹;

R⁹ is H; R⁷; COR⁷; CO₂R⁷; CONR⁵R⁶; SO₂R⁷; or (C_1-6 alkylene)phenyl, wherein phenyl is substituted by O to 3 atoms or groups selected from C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkoxy, C_1-

₆ alkoxycarbonyl, halogen, CF₃, OH, CN, NR⁵R⁶, COR⁶, CO₂R⁶ or CONR⁵R⁶.

2. A compound as claimed in claims 1 wherein R¹ is R⁷ or OR⁷.

3. A compound as claimed in any of claims 1 or 2 wherein R² is H.

4. A compound as claimed in any of the preceding claims wherein R³ is phenyl optionally substituted by one fluorine atom.

5. A compound as claimed in any preceding claim wherein R⁴ is: i) a moiety of partial form

ii) a benzimidazolyl of partial formula (1.0.2)

substituted by 0 to 3 atoms or groups selected from C_1-6 alkyl, C_1-6 fluoroalkyl or halogen; or iii) a triazolyl of partial formula (1.0.3)

' substituted by 0 to 3 groups selected from C_1-6 alkyl or Ci_-6 fluoroalkyl.

6. A compound as claimed in any preceding claim wherein R⁴ is:

7. A compound as claimed in claim 5 wherein R⁴ is a moiety of formula 1.01 or 1.03 .

8. A compound as claimed in any preceding claim wherein R⁷ is C^alkyl optionally substituted by C_1-3alkoxy; C₃.₆cycloalkyl substituted by 0 to 2 halogen atoms; or a 4 to 6- membered saturated heterocycle containing one heteroatom selected from N, O, or S, wherein said heterocycle is substituted by 0 to 2 atoms selected from oxo, halogen, or COC1-3alkyl

9. A compound as claimed in any preceding claim wherein R⁸ is C_halky!.

10. A compound as claimed in any preceding claim wherein R⁸ is methyl.

11. A compound as claimed in any preceding claim wherein R⁹ is H; R⁷; COR⁷; CO₂R⁷.

12. A compound as claimed in any claim 11 wherein R⁹ is C_1-4 alkyl, CO C_1-4 alkyl or CO₂C_1-4 alkyl.

13. A pharmaceutical composition including a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, according to any preceding claim, together with one or more pharmaceutically acceptable excipients, diluents or carriers.

14. A pharmaceutical composition as claimed in claim 13 including one or more additional therapeutic agents.

15. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 12 for use as a medicament.

16. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 12 for the treatment of a disorder in which the modulation of CCR5 receptors is implicated.

17. A compound according to claim 16 wherein the disorder is HIV, a retroviral infection genetically related to HIV, AIDS, an inflammatory disease, autoimmune disease and pain.

18. A compound .according to claim 16 wherein the disorder is multiple sclerosis, rheumatoid arthritis, or graft rejection.

19. A compound according to claim 16 wherein the disorder is inflammatory bowel disease; endometriosis; type I diabetes; renal diseases; fibrosis; liver fibrosis; chronic pancreatitis; inflammatory lung conditions; encephalitis; chronic heart failure; myocardial infarction; ischaemic heart disease; psoriasis; stroke; obesity; CNS diseases; anaemia; restenosis; atherosclerotic plaque; atopic dermatitis; Hashimoto's thyroiditis; chronic pancreatitis; cancer; pain; or stress response resulting from surgery, infection, injury or other traumatic insult.

20. A compound according to claim 16 wherein the disorder is HBV, HCV, plague, pox^' virus, toxoplasmosis, mycobacterium, trypanosomal, pneumonia, or cytosporidiosis.

21. Use of a compound of formula (I) or of a pharmaceutically acceptable salt, solvate or derivative thereof according to any one of claims 1 to 12 for the manufacture of a medicament for the treatment of a disorder in which the modulation of CCR5 receptors is implicated.

22. A method of treatment of a mammal suffering from a disorder in which the modulation of CCR5 receptors is implicated which comprises treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 12.

23. A compound of formula (I)

(D

or a pharmaceutically acceptable salt, solvate of derivative thereof, wherein:

R¹ is R⁷, OR⁷ or NR⁵R⁶ ; R² is H or C_1-6 alkyl;

R³ is phenyl substituted by 0 to 3 atoms or groups selected from C_1-6 alkyl, Ci_-6 alkylcarbonyl, C_1-6 alkoxy, C_1-6 alkoxycarbonyl, halogen, CF₃, OH, CN, NR⁵R⁶, CO₂R⁷ or CONR⁵R⁶;

R⁴ is a moiety of partial formula (1.0) wherein:

Q is CR⁴²Or N; T is CR⁴³ or N

R⁴¹ is H, C_1-6 alkyl or C_1-6 fluoroalkyl;

R⁴² and R⁴³ are independently selected from H, C_1-6 alkyl, C_1-6 fluoroalkyl, or halogen; or R⁴² and R⁴³ when taken together with the atoms to which they are attached form a benzene, pyridine, pyrimidine, pyridazine or pyrazine ring, wherein the said benzene pyridine, pyrimidine, pyridazine or pyrazine ring is substituted by 0 to 3 atoms or groups selected from C_1- β alkyl, C_1-6 fluoroalkyl or halogen; or form a partially saturated pyridine ring such that R⁴ is a moiety of partial formula (1.0.1 )

wherein the arrowhead denotes the point of attachment to the tropane ring; R⁵ is H or C_1-6 alkyl; C_2-6 alkenyl; C_2-6 alkynyl; C_3-7 cycloalkyl; a 5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturated heterocycle; wherein said alkyl, alkenyl, alkynyl and cycloalkyl are substituted by 0 to 3 atoms or groups selected from oxo, halogen, CF₃, OR⁶, CN, COR⁶, or CO₂R⁶; wherein said heterocycles contain one to three heteroatoms selected f rom N ₁ O o r S ; a nd w herein s aid h eterocycles a re s ubstituted b y O to 3 atoms or groups s elected from C _1-6 a Ikyl, C _1-6 a Ikylcarbonyl, C _1-6 a Ikoxy, C_1-6 alkoxycarbonyl, halogen, CF₃, OH, CN, COR⁶, or CO₂R⁶; ^' R⁶ is H or C_1-6 alkyl; or, when R⁵ and R⁶ are both attached to the same N atom, NR⁵R⁶ may also represent a 5 to 7 membered, saturated, partially unsaturated or aromatic, heterocycle containing from O to 2 additional heteroatoms selected from O, N or S;

R⁷ is C_1-6 alkyl; C_2-6 alkenyl; C_2-6 alkynyl; C_3-7 cycloalkyl; a 5 or 6-membered aromatic heterocycle; or a 4 to 7-membered saturated heterocycle; wherein said alkyl, alkenyl, alkynyl and cycioalkyl are substituted by O to 3 atoms or groups selected from oxo, halogen, CF₃, OR⁶, CN, NR⁵R⁶, COR⁶, CO₂R⁸ or CONR⁵R⁶; wherein said heterocycles contain one to three heteroatoms selected from N, O or S; and wherein said heterocycles are substituted by O to 3 atoms or groups selected from C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkoxy, Ci_-6 alkoxycarbonyl, halogen, CF₃, OH, CN, NR⁵R⁶, COR⁶, CO₂R⁶ or CONR⁵R⁶; provided that when R¹ is OR⁷ the said heterocycles are carbon bonded to the oxygen of OR⁷;R⁸ is H or C_1-6 alkyl;

R⁹ is H; R⁷; COR⁷; CO₂R⁷; CONR⁵R⁶; SO₂R⁷; or (C_1-6 alkylene)phenyl, wherein phenyl is substituted by O to 3 atoms or groups selected from C_1-6 alkyl, Ci_-6 alkylcarbonyl, C_1-6 alkoxy, C_1-6 alkoxycarbonyl, halogen, CF₃, OH, CN, NR⁵R⁶, COR⁶, CO₂R⁶ or CONR⁵R⁶.