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Definitions

• the present inyention concerns piperidine derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.
• Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a role in the maturation of cells of the immune system. Chemokines play an important r ⁇ le in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif.
• the chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C, or ⁇ ) and Cys-Cys (C- C, or ⁇ ) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
• the C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (E -8) and neutrophil-activating peptide 2 (NAP-2).
• the C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP- 1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins l ⁇ and l ⁇ (MTP-l ⁇ and MTJP-l ⁇ ). .
• chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10,.CXCR1, CXCR2, CXCR3 and CXCR4.
• G protein-coupled receptors among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10,.CXCR1, CXCR2, CXCR3 and CXCR4.
• Histamine is a basic amine, 2-(4-imidazolyl)-ethylamine, and is formed from histidine by histidine decarboxylase. It is found in most tissues of the body, but is present in high concentrations in the lung, skin and in the gastrointestinal tract. At the cellular level inflammatory cells such as mast cells and basophils store large amounts of histamine. It is recognised that the degranulation of mast cells and basophils and the subsequent release of histamine is a fundamental mechanism responsible for the clinical manifestation of an allergic process. Histamine produces its actions by an effect on specific histamine G- protein coupled receptors, which are of three main types, HI, H2 and H3.
• Histamine HI antagonists comprise the largest class of medications used in the treatment of patients with allergic disorders, especially rhinitis and urticaria. Antagonists of HI are useful in controlling the allergic response by for example blocking the action of histamine on post- capillary venule smooth muscle, resulting in decreased vascular permeability, exudation and oedema. The antagonists also produce blockade of the actions of histamine on the HI receptors on c-type nociceptive nerve fibres, resulting in decreased itching and sneezing.
• T is C(O) or S(O) 2 ;
• W is C(O) or S(O) 2 ;
• X is CH 2 , O or NH
• Y is CR 5 or N
• R 1 is optionally substituted aryl or optionally substituted heterocyclyl
• R 2 is hydrogen or C 1-6 alkyl
• R 3 is hydrogen or optionally substituted C 1-6 alkyl
• R 4 is alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heterocyclyl
• R 5 is hydrogen or C 1-6 alkyl; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, cyano, nitro, hydroxy, oxo, S(O) p R 25 , OC(O)NR 6 R 7 , NR 8 R 9 , NR 10 C(O)R ⁇ , NR 12 C(O)NR 13 R 14 , S(O) 2 NR 15 R 16 , NR 17 S(O) 2 R 18 , C(O)NR 19 R 20 , C(O)R 21 , CO 2 R 22 , NR 23 CO 2
• any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, hydroxy, nitro, S(O) q (C 1-4 alkyl), S(O) 2 NH 2 , cyano, C 1-4 alkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), CO 2 H, CO 2 (C 1-4 alkyl), NHC(O)(C 1-4 alkyl), NHS(O) 2 (C 1-4 alkyl), C(O)(C 1-4 alkyl), CF 3 or OCF 3 ; p and q are, independently, 0, 1 or 2; R 6 , R 7 , R 8 , R 9 , R 10 , R ⁇ , R 12 , R 13 , R 14 , R 15 ,
• NR 6 R 7 , NR 8 R 9 , NR 13 R 14 , NR 15 R 16 , NR 19 R 20 or N(C 1-4 alkyl) 2 may, independently, form a 4-7 membered heterocyclic ring, azetidine, pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter optionally substituted by C 1-4 alkyl on the distal nitrogen; R 25 , R 18 and R 24 are, independently, C 1-6 alkyl (optionally substituted by halogen, hydroxy or C 3-10 cycloalkyl), CH 2 (C 2-6 alkenyl),
• Suitable salts include acid addition salts such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate. Salts also include metal salts, such as alkali metal salts (for example a sodium salt).
• the compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.
• Halogen includes fluorine, chlorine, bromine and iodine.
• Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, 1-methylethyl or 1,1-dimethylethyl.
• Alkenyl is, for example, vinyl or allyl.
• Alkynyl is, for example, propargyl.
• Cycloalkyl is mono-, bi or tricyclic and is, for example, cyc ⁇ opropyl, cyclopentyl, cyclohexyl, norbornyl or camphoryl.
• the cycloalkyl ring is optionally fused to a benzene ring (for example forming a bicyclo[4.2.0]octa-l,3,5-trienyl or indanyl ring system).
• Haloalkyl is preferably CF 3 .
• Haloalkoxy is preferably OCF 3 .
• Aryl is preferably phenyl or naphthyl.
• Arylalkyl is preferably aryl(C 1-4 alkyl) for example benzyl or 2-phenyleth-l-yl.
• Heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring, optionally fused to one or more other rings, comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulfur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof.
• Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl), pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl (for example in 6-oxo-l,6-dihydro-pyridinyl), pyrimidinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl), benz[b]thienyl (also known as benzthienyl or benzthiophenyl), 2,3-dihydrobenz[b]thienyl (for example in 1,1-dioxo- 2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl, benz
• N-oxide of a compound of formula (I) is, for example, a 1-oxido- [ 1 ,4 ' ]bipiperidinyl- 1 ' -yl compound.
• the present invention provides a compound of formula (I) wherein: T is C(O) or S(O) 2 ; W is C(O) or S(O) 2 ; X is CH 2 , O or NH; Y is CR 5 or N; R 1 is optionally substituted aryl or optionally substituted heterocyclyl; R is hydrogen or C 1-6 alkyl; R 3 is hydrogen or optionally substituted C 1-6 alkyl;R 4 is alkylj optionally substituted aryl, optionally substituted aralkyl or optionally substituted heterocyclyl; R 5 is hydrogen or C 1-6 alkyl; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by: halogen, cyano, nitro, hydroxy, oxo,
• any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, hydroxy, nitro, S(O) q (C 1- alkyl), S(O) 2 NH 2 , cyano, C 1-4 alkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), CO 2 H, CO 2 (C 1-4 alkyl), .
• p and q are, independently, 0, 1 or 2; R 6 , R 7 ,R 8 , R 9 , R 10 , R ⁇ , R 12 , .
• R 13 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , R 21 , R 22 , and R 23 are, independently, hydrogen, C 1-6 alkyl (optionally substituted by halogen, hydroxy or C 3-1 o cycloalkyl), CH 2 (C 2-6 alkenyl), phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH 2 , NH(C 1-4 alkyl), NH(C 1-4 alkyl) 2 , S(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , cyano, C 1-4 alkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), C0 2 H, CO 2 (C 1- alkyl), NHC(O)(C ⁇ -4 alkyl), NHS(O) 2 (C ⁇ -4 alkyl), C(O)(C 1-4 alkyl),
• X is O.
• R 1 is phenyl substituted with one or more of fluorine, chlorine, C 1-4 alkyl (especially methyl) or C 1- alkoxy (especially methoxy).
• R 1 is phenyl optionally substituted (for example with one, two or three of) by halogen (especially fluoro or chloro), C 1-4 alkyl (especially methyl) or C 1-4 alkoxy (especially methoxy).
• R 1 is phenyl substituted by one, two or three of: fluoro, chloro, methyl or methoxy.
• R 1 is phenyl optionally substituted by halogen (especially fluoro or chloro), - alkyl (especially methyl); especially optionally substituted (for example independently with one, two or three of, especially two or three of) by fluoro, chloro or methyl.
• R 1 is 3,4- dichlorophenyl, or, additionally 2-chloro-4-fluorophenyl, 2-methyl-4-chlorophenyl, 2,4- dichloro-3-methylphenyl or 3,4-dichloro-2-methylphenyl.
• T and W are C(O) and the other is S(O) 2 .
• T is C(O).
• W is S(O) 2 .
• the compounds of formula (I) are preferably trans in terms of relative stereochemistry, that is, the piperidine ring and the T-N(R 3 )-W-R 4 group are both equatorial on the cyclohexane ring.
• Y is CH or N; especially N.
• R 2 is hydrogen or methyl; for example R 2 is hydrogen.
• R 3 is hydrogen or methyl; for example hydrogen.
• R 4 is unsubstituted phenyl, mono-substituted phenyl, unsubstituted heterocyclyl or mono-substituted heterocyclyl, the substituents being chosen from those described above.
• the present inention provides a compound of formula (I) wherein
• R 4 is aryl (for example phenyl or naphthyl; especially phenyl) optionally substituted by one or more of C 1-6 alkyl (for example methyl or ethyl), ' C 1-4 alkoxy (for example methoxy), halogen (for example chloro or fluoro), CF 3 , CN, CO 2 (C 1-4 alkyl) (for example CO 2 CH 3 ), OH, OCF 3 , S(O) 2 (C 1-4 alkyl) (for example S(O) 2 CH 3 ) or NR 8 R 9 (wherein R 8 and R 9 are, independently, hydrogen or C 1-4 alkyl); or heterocyclyl (for example imidazolyl, thienyl, tetrahydrothienyl, thiazolyl, 1,3,4-thiadiazolyl, pyridyl or dihydroisoquinolinyl) optionally substituted by oxo, halogen (for example chloro or fluor
• R 4 is phenyl optionally substituted by one or more of C 1-6 alkyl (for example methyl or ethyl), C 1-4 alkoxy (for example methoxy), halogen (for example chloro or fluoro), CF 3 , CN, CO 2 (C 1-4 alkyl) (for example CO 2 CH 3 ), OH, OCF 3 , S(O) 2 (C 1-4 alkyl) (for example S(O) 2 CH 3 ) or NR 8 R 9 (wherein R 8 and R 9 are, independently, hydrogen or C 1-4 alkyl).
• C 1-6 alkyl for example methyl or ethyl
• C 1-4 alkoxy for example methoxy
• halogen for example chloro or fluoro
• CF 3 CF 3
• CN CO 2 (C 1-4 alkyl) (for example CO 2 CH 3 ), OH, OCF 3 , S(O) 2 (C 1-4 alkyl) (for example S(O) 2 CH 3
• R 4 is substituted (especially mono-substituted) phenyl, the substituents being chosen from those described above.
• R 4 is phenyl or heterocyclyl, either of which is optionally substituted by: halo, hydroxy, nitro, cyano, oxo, amino, C 1- alkyl (itself optionally substituted by S(O) 2 (C 1-4 alkyl), S(O) 2 phenyl), C 1- alkoxy, S(O) k R 26 (wherein k is 0, 1 or 2 (preferably 2); and R 26 is C 1- alkyl, C 1- hydroxyalkyl, C 3-7 cycloalkyl(C 1- alkyl) (such as cyclopropylmethyl) or phenyl), C 1-4 haloalkylthio, C(O)NH 2 , NHS(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl) or S(O) 2 N(C 1-4 alkyl) 2 .
• R 4 is phenyl or heterocyclyl, either of which is optionally substituted by: halo, hydroxy, nitro, cyano, oxo, NR 8 R 9 (wherein R 8 and R 9 are, independently, hydrogen or C 1-6 alkyl), C 1-4 alkyl (itself optionally substituted by S(O) 2 (C 1- 4 alkyl), S(O) 2 phenyl), C 1-4 alkoxy, S(O) k R 26 (wherein k is 0, 1 or 2 (preferably 2); and R 26 is C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3 : 7 cycloalkyl(C 1- alkyl) (such as cyclopropylmethyl) or phenyl), C 1-4 haloalkylthio, C(O)NH 2 , NHS(O) 2 (Q. 4 alkyl), S(O) 2 NH 2 , S(0) 2 NH(C 1-4 alkyl) or S(O) 2
• variable R 4 is phenyl optionally substituted by: halo, hydroxy, nitro, cyano, amino, C 1-4 alkyl (itself optionally substituted by S(0) 2 (C ⁇ - 4 alkyl), S(O) 2 phenyl), C 1-4 alkoxy, S(O) k R 26 (wherein k is 0, 1 or 2 (preferably 2); and R 26 is C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3 .
• cycloalkyl(C 1-4 alkyl) (such as cyclopropylmethyl) or phenyl), C haloalkylthio, C(O)NH 2 , NHS(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl) or S(O) 2 N(C 1-4 alkyl) 2 (and these alkyl groups may join to form a ring as described for R 6 and R 7 above).
• variable R 4 is phenyl optionally substituted by: halo, hydroxy, nitro, cyano, NR 8 R 9 (wherein R 8 and R 9 are, independently, hydrogen .or C 1-6 alkyl), C 1- alkyl (itself optionally substituted by S(O) 2 (C 1-4 alkyl), S(O) 2 phenyl), C 1- alkoxy, S(O) k R 26 (wherein k is 0, 1 or 2 (preferably 2); and R 26 is C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3- ⁇ cycloalkyl(C 1-4 alkyl) (such as cyclopropylmethyl) or phenyl), C 1-4 haloalkylthio, C(O)NH 2 , NHS(O) 2 (C 1-4 alkyl), S(O) 2 NH 2 , S(O) 2 NH(C 1-4 alkyl) or S(O) 2 N(C 1-4 alkyl) 2 (and
• variable R 4 is phenyl optionally substituted by: halo, hydroxy, nitro, cyano, amino, C 1-4 alkyl (itself optionally substituted by S(O) 2 phenyl), C 1- alkoxy, S(O) k R 26 (wherein k is 0, 1 or 2; and R 26 is C 1-4 alkyl or phenyl) or C 1-4 haloalkylthio.
• variable R 4 is phenyl optionally substituted by: halo, hydroxy, nitro, cyano, NR 8 R 9 (wherein R 8 and R 9 are, independently, hydrogen or C 1-4 alkyl), C 1-4 alkyl (itself optionally substituted by S(O) 2 phenyl), C 1-4 alkoxy, S(O) k R 26 (wherein k is 0, 1 or 2; and R 26 is C 1-4 alkyl or phenyl) or C 1- haloalkylthio.
• the amine group NR 8 R 9 is, for example, mono-(C 1-4 ) alkylamino (such as NHCH 3 or NHCH 2 CH 3 ) or di-(C ⁇ -4 ) alkylamino (such as N(CH 3 ) 2 ).
• R 4 is phenyl mono-substituted with halogen (for example fluorine or chlorine), C 1-4 alkyl (for example methyl or ethyl), C 1-4 alkoxy (for example methoxy or ethoxy) or NR 8 R 9 (wherein R 8 and R 9 are, independently, hydrogen or C 1-6 alkyl; and NR 8 R 9 is especially NHCH 3 , NHCH 2 CH 3 or N(CH 3 ) 2 ).
• halogen for example fluorine or chlorine
• C 1-4 alkyl for example methyl or ethyl
• C 1-4 alkoxy for example methoxy or ethoxy
• NR 8 R 9 is especially NHCH 3 , NHCH 2 CH 3 or N(CH 3 ) 2 ).
• R 4 is phenyl substituted with halogen, alkyl or alkoxy.
• R 4 is phenyl mono-substituted with halogen (especially chlorine) or C 1- alkyl (especially methyl).
• R 5 is hydrogen.
• the present invention provides a pharmaceutically acceptable salt of a compound of formula (I), for example a metal salt ⁇ such as an alkali metal salt (for example the sodium salt) ⁇ of a compound of formula (I).
• X, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above; or a pharmaceutically acceptable salt thereof.
• the compounds of formula (Ic) are preferably trans in terms of relative stereochemistry, that is, the piperidine ring and the C(O)N(R 3 )S(0) 2 R 4 group are both equatorial on the cyclohexane ring.
• the present invention provides a compound of formula (If): wherein: X, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above; or a pharmaceutically acceptable salt thereof.
• the compounds of formula (If) are preferably trans in terms of relative stereochemistry, that is, the piperidine ring and the S(O) 2 N(R 3 )C(O)R 4 group are both equatorial on the cyclohexane ring.
• X, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above; or a pharmaceutically acceptable salt thereof.
• the compounds of formula (Ig) are preferably trans in terms of relative stereochemistry, that is, the piperidine ring and the C(O)N(R 3 )C(0)R 4 group are both equatorial on the cyclohexane ring.
• X, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above; or a pharmaceutically acceptable salt thereof.
• the compounds of formula (Ih) are preferably trans in terms of relative stereochemistry, that is the piperidine ring and the S(O) 2 N(R 3 )S(O) 2 R 4 group are both equatorial on the cyclohexane ring.
• a compound of formula (la) is, for example:
• a compound of formula (lb) is, for example: 4-(3,4-Dichlorophenoxy)-N-(4-methylbenzoyl)-[l,4'-bipiperidine]-i'-sulfonamide; 4-(3,4-dichlorophenoxy)-N-(4-fluorobenzoyl)-[l,4'-bipiperidine]-r-sulfonamide; N-(4-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[l,4'-bipiperidine]-r-sulfonamide; 4-(3,4-dichlorophenoxy)-N-(4-methylbenzoyl)-[l,4'-bipiperidine]-l'-sulfonamide; 4-(3,4-dichlorophenoxy)-N-[4-(dimethylamino)benzoyl]-[l,4'-bipiperidine]-r- sulfon
• a compound of formula (Ic) is, for example:
• a compound of formula (Id) is, for example: 4-(3 ,4-Dichlorophenoxy)-N-(2-methylbenzoyl)- [ 1 ,4'-bipiperidine]- 1 '-carboxamide;
• a compound of formula (Ie) is, for example: [4-(3 ,4-dichlorophenoxy)-N-(phenylsulfonyl)- 1 ,4'-bi ⁇ i ⁇ eridine] - 1 '-sulfonamide.
• a compound of formula (If) is, for example: Trans N-benzoyl-4-[4-(3 ,4-dichlorophenoxy)- 1 -piperidinyl]-cyclohexanesulfonamide.
• a compound of formula (Ig) is, for example: Trans N-[[4-[4-(3,4-Dichlorophenoxy)-l-piperidinyl]cyclohexyl]carbonyl]-benzamide.
• a compound of formula (Ih) is, for example:
• a compound of formula (Ic), (If), (Ig) or (Ih) where R 3 and R 5 are both hydrogen may be converted to a compound of formula (Ic), (If), (Ig) or (Ih) where R 5 is alkyl and R 3 is hydrogen by deprotonation to a dianion, for example with 2 equivalents of LDA, followed by reaction with an alkylating agent, R 5 Hal (wherein Hal is, for example chlorine).
• a compound of formula (Ic), (If), (Ig) or (Th) where R 5 is hydrogen and R 3 is not hydrogen may be converted to a compound of formula (Ic), (If), (Ig) or (Ih) where R 5 is alkyl and R 3 is not hydrogen by deprotonation, for example with 1 equivalent of LDA, followed by reaction with an alkylating agent, R 5 Hal.
• a compound of formula (I), wherein R is not hydrogen, can be prepared by alkylating a compound of formula (I), wherein R 3 is hydrogen, with a suitable alkylating agent (for example R 3 -L, wherein L is a leaving group such as triflate, a halide or a diazo group) in the presence of a suitable base (such as sodium hydride) in a suitable solvent.
• a suitable alkylating agent for example R 3 -L, wherein L is a leaving group such as triflate, a halide or a diazo group
• a suitable base such as sodium hydride
• a compound of formula (I), wherein T is C(O), W is S(O) 2 and Y is N, can be prepared by reacting a compound of formula (II) with a compound of formula (XXII).
• a compound of formula (XXII) :
• sulfonamide R 4 SO 2 NHR 3 may be prepared from a sulfonamide R 4 SO 2 NHR 3 and p-nitrophenyl chloroformate in the presence of a base, for example triethylamine and a catalyst, for example DMAP, typically at room temperature.
• a base for example triethylamine
• a catalyst for example DMAP
• a compound of formula (TJ) can be prepared by deprotecting a compound of formula (III):
• a suitable solvent such as dichloromethane
• a source of hydrogen chloride in a suitable solvent (such as dioxane).
• a compound of formula (HI), wherein R 2 is hydrogen, can be prepared by reacting a compound of formula (TV) :
• a compound of formula (HI), wherein R 2 is C 1-6 alkyl, can be prepared by reacting a compound of formula (XVII):
• a compound of formula (XVII) can be prepared by reacting a compound of formula (IV) with a compound of formula (V) in the presence of titanium tetrisopropoxide, for example in dichloroethane, followed by the addition of diethyl aluminium cyanide to a solution, for example in toluene.
• a compound of formula (I), wherein R 3 is hydrogen, T is S(O) 2 , W is C(O) and Y is N, can be prepared by reacting a compound of formula (IX): with a compound of formula (II) in the presence of a suitable base (such as triethylamine) in a suitable solvent (such as tetrahydrofuran) at a suitable temperature (such as below -60°C).
• a suitable base such as triethylamine
• a suitable solvent such as tetrahydrofuran
• a compound of formula (I), wherein R 3 is hydrogen, T is S(O) 2 , W is C(O) and Y is N, can be prepared by reacting a compound of formula (XVIII):
• a compound of formula (XVHJ) may be prepared by the reaction of a compound of formula (TJ) with sulfamide, for example in dioxan at reflux.
• a further method of preparing a compound of formula (I), wherein R 3 is hydrogen, T is S(O) 2 , W is C(O) and Y is N, is to react a compound of formula (XIX):
• a compound of formula (XIX) can be prepared from a compound of formula (II) and a compound of formula (XX):
• a compound of formula (I) wherein T and W are both S(O) 2 and Y is N, can be prepared by reacting a compound of formula (X):
• a compound of formula (X) can be prepared by reacting a compound of formula (H) with S(O) 2 Cl 2 in the presence of a suitable base (such as triethylamine).
• a compound of formula (I) wherein T and W are both S(O) 2 and Y is N can be prepared by reacting a compound of formula (XVIII) with a sulf onyl chloride R 4 SO 2 Cl in the presence of a base, for example triethylamine, preferably with dimethylaminopyridine as catalyst in a suitable solvent, for example dichloromethane, for example at room temperature.
• a base for example triethylamine
• dimethylaminopyridine as catalyst
• a suitable solvent for example dichloromethane
• a compound of formula (I) wherein T is C(O), is S(O) 2 and Y is CR 5 can be prepared by firstly hydrolysing a compound of formula (XI):
• ester is preferably a C 1-6 alkyl group
• R 4 S(O) 2 NHR 3 reacting the product so formed with R 4 S(O) 2 NHR 3 in the presence of an appropriate coupling agent (such as ethyl dimethylaminopropyl carbodiimide (EDCT), with 4-dimethylaminopyridine (DMAP) or 1- hydroxybenzotriazole (HOBT)) in a suitable solvent, for example DMF.
• an appropriate coupling agent such as ethyl dimethylaminopropyl carbodiimide (EDCT), with 4-dimethylaminopyridine (DMAP) or 1- hydroxybenzotriazole (HOBT)
• a compound of formula (XI), wherein R 2 is hydrogen, can be prepared by reductively aminating a compound of formula (XII):
• a compound of formula (XI) where R 2 is alkyl can be prepared by amino nitrile formation between compounds of formula (XTJ) and (XHJ) followed by displacement of the nitrile with a grignard reagent.
• a compound of formula (I), wherein T and W are both C(O) and Y is CH or N, can- be prepared by heating a compound of formula (XIV):
• a compound of formula (XIV) where Y is-CR 5 can be prepared . by firstly hydrolysing a compound of formula (XI) and then couplin the product so formed with an amine R 3 NH 2 in the presence of an appropriate coupling agent (such as ethyl dimethylaminopropyl carbodiimide, with 4-dimethylaminopyridine or 1- ' hydroxybenzotriazole) in a suitable solvent, for example DMF.
• an appropriate coupling agent such as ethyl dimethylaminopropyl carbodiimide, with 4-dimethylaminopyridine or 1- ' hydroxybenzotriazole
• a compound of formula (XIV) where Y is N and R 3 is H may be prepared by reaction of a compound of formula (II) with sodium cyanate in the presence of an acid, for example acetic acid.
• a compound of formula (I), wherein T is S(O) 2 , W is C(O) and Y is CR 5 , can be prepared by coupling a compound of formula (XV):
• an acid R >4 C,- O 2 H in the presence of an appropriate coupling agent (such as ethyl dimethylaminopropyl carbodiimide, 4-dimethylaminopyridine or HOBT) in a suitable solvent.
• an appropriate coupling agent such as ethyl dimethylaminopropyl carbodiimide, 4-dimethylaminopyridine or HOBT
• a compound of formula (I), wherein T and W are both S(O) 2 and Y is CH, can be prepared by coupling a compound of formula (XV) to a sulf onyl chloride R 4 S(O) 2 Cl in the presence of a base and a solvent (such as dichloromethane, N,N-dimethylformamide or tetrahydrofuran).
• a compound of formula (XV) can be prepared by reductively animating a compound of formula (XVI):
• a compound of formula (XVI) can be prepared by reacting
• a compound of formula (I) where Y is CR 5 and R 5 is not hydrogen may be prepared from a compound of formula (I) where Y is CH by reaction of the dianion (R 3 is H) or monoanion (R 3 is alkyl) (formed with a suitable base, for example LDA) with an alkylating agent (for example R 5 -L, wherein L is a leaving group such as triflate or a halide) in a suitable solvent for example THF for example at 0° or below.
• the compounds of the invention have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CCR3) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)).
• chemokine receptor especially CCR3
• immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)
• obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ ; bronchitis ⁇ such as eosinophilic bronchitis ⁇ ; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis;
• COPD chronic
• arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis;
• Epidermolysis bullosa urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis;
• (5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or (6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, my asthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle. ,
• the compounds of the invention are also HI antagonists and may be used in the treatment of allergic disorders.
• the compounds of the invention may also be used to control a sign and/or symptom of what is commonly referred to as a cold (for example a sign and/or symptom of a common cold or influenza or other associated respiratory virus infection).
• a compound of formula (I) for example a compound of formula (la), (Ib), ' (Ic), (Id), (Ie), (If), (Ig) or (Ih)), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis).
• a method for modulating chemokine receptor activity (especially CCR3 receptor activity), or antagonising HI , in a warm blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula (I) (for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)), or a pharmaceutically acceptable salt thereof or a solvate thereof.
• a compound of the formula (I) for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)
• a pharmaceutically acceptable salt thereof or a solvate thereof for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)
• the invention also provides a compound of the formula (I) (for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament.
• a compound of the formula (I) for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)
• a pharmaceutically acceptable salt thereof or a solvate thereof for use as a medicament.
• the invention provides the use of a compound of formula (I) (for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity), or antagonising HI, in a warm blooded animal, such as man).
• a compound of formula (I) for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)
• a pharmaceutically acceptable salt thereof or a solvate thereof for example modulating chemokine receptor activity (especially CCR3 receptor activity), or antagonising HI, in a warm blooded animal, such as man).
• the invention further provides the use of a compound of formula (I) (for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of: (1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ ; bronchitis ⁇ such as eosinophilic bronchitis ⁇ ; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa;
• arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as anky losing spondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis;
• asthma such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ ; or rhinitis ⁇ including acute, allergic, atrophic or chronic rhinitis, such as rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis ⁇ .
• a compound of formula (I) (for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)), or a pharmaceutically acceptable salt thereof, is useful in the treatment of asthma.
• the present invention also provides the use of a compound of formula (I) (for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of asthma or rhinitis.
• a compound of formula (I) for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)
• a pharmaceutically acceptable salt thereof for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)
• the present invention further provides a method of treating a chemokine mediated disease state (especially a CCR3 mediated disease state, especially asthma) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I) (for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)), or a pharmaceutically acceptable salt thereof or solvate thereof.
• a compound of formula (I) for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)
• a pharmaceutically acceptable salt thereof or solvate thereof for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)
• a compound of the invention or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity or antagonising HI
• said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
• the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) (for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)), or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.
• a pharmaceutically acceptable adjuvant for example a compound of formula (la), (lb), (Ic), (Id), (Ie), (If), (Ig) or (Ih)
• a pharmaceutically acceptable salt thereof or a solvate thereof active ingredient
• the present invention provides ' a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier.
• the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 w, of active ingredient, all percentages by weight being based on total composition.
• compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
• topical such as to the lung and/or airways or to the skin
• the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
• a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and lg of active ingredient.
• composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
• Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of O.Olmgkg "1 to lOOmgkg "1 of the compound, preferably in the range of O.lmgkg "1 to 20mgkg _1 of this invention, the composition being administered 1 to 4 times per day.
• the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
• the intravenous dose may be given by continuous infusion over a period of time.
• each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being - - administered 1 to 4 times per day.
• Buffers such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl ⁇ - cyclodextrin may be used to aid formulation.
• the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
• the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
• Examples 1B-1 AV are examples of compounds of formula (la) and were prepared using similar methodology to that of Example 1A. Recrystallisation was required after chromatography for several Examples.
• Example 2A N-[[4-(3,4-Dichlorophenoxy)[l,4'-bipiperidin]-l'-yl]carbonyl]- benzenemethanesulfonamide (an example of a compound of formula (la)).
• Examples 2B-2X are examples of compounds of formula (la) and were prepared using similar methodology to that of Example 2A.
• Example 3A 7V-[[4-(3 ,4-Dichlorophenoxy) [ 1 ,4'-bipiperidin]- 1 '-yl]carbonyl]-N,4-dimethyl- benzenesulfonamide (an example of a compound of formula (la) where R 3 is not hydrogen).
• Benzoyl sulfamoyl chloride (DE931225, (1955) Chemical Abstracts 1956, 50, 7861a; 248mg) was dissolved in THF (5ml) and cooled to -78°C. Triethylamine (170 ⁇ l) was added dropwise over 160s and the solution was stirred for 25 min. 4-(3,4- . Dichlorophenoxy)-l,4'-bipiperidine (Method C; 329mg) in THF (5ml) was added dropwise over 35min. Water was added then the mixture was evaporated.
• Example 5B-5E are examples of compounds of formula (la) and were prepared using similar methodology to that of Example 5 A.
• Example 6A trans 4-Chloro-N- [ [4- [4-(3 ,4-dichlorophenoxy)- 1 -piperidinyl] cyclohexyl] - carbonyl]-benzenesulfonamide (an example of a compound of formula (Ic)).
• Example 7A N-Benzoyl-4-(3,4-dichlorophenoxy)-[l,4'-bipiperidine]-l'-carboxamide (an example of a compound of formula (Id)).
• Example 8A N-(3,4-Dichlorobenzoyl)-4-(3,4-dichlorophenoxy)-[l,4'-bipiperidine]- - sulf onamide (an example of a compound of formula (lb)). 4-(3,4-Dichlorophenoxy)-[l,4'-bipi ⁇ eridine]-l'-sulfonamide (Method G, 200mg),
• Examples 8B-8F are examples of compounds of formula (lb) and were prepared using similar methodology to that of Example 8 A. Recrystallisation was required after chromatography for several Examples.
• Example 9A 4-(3 ,4-Dichlorophenoxy)-N-(4-methylbenzoyl)-[ 1 ,4'-bipiperidine]- 1 '-sulfonamide (an example of a compound of formula (lb)).
• 1,1 -Dimethylethyl[4-(3 ,4-dichlorophenoxy)- 1 ,4'-bipiperidin- 1 '- yl]sulfonylcarbamate (Method L; 400mg) and triethylamine (0.5ml) in dichloromethane (5ml) at ambient temperature were treated with 4-methylbenzoylchloride (163mg).
• Examples 9B and 9C are examples of compounds of formula (lb) and were prepared using similar methodology to that of Example 9A.
• Example 10A N-[[4-(3,4-Dichlorophenoxy)[l,4'-bipiperidin]-l'-yl]carbonyl]-4-methyl- ' benzenesulfonamide, sodium salt (an example of a compound of formula (la)).
• Examples 10B-10D are examples of compounds of formula (la) and were prepared using similar methodology to that of Example 10A.
• Example 11A 4-(3,4-Dichlorophenoxy)-N-[(l,2-dihydro-l-oxo-4-isoquinolinyl)carbonyl]-[l,4'- bipiperidine]-l '-sulfonamide (an example of a compound of formula (lb)).
• 1,1-Dimethylethyl [[4-(3,4 dichlorophenoxy)[l,4'-bipiperidin]-r-yl]sulfonyl][(l,2- dihydro-l-oxo-4-isoquinolinyl)carbonyl]-carbamate was dissolved in dichloromethane (10ml) followed by the addition of trifluoroacetic acid (3ml) and allowed to stir under nitrogen for 12 h.
• Example 13 A 4-(3 ,4-Dichlorophenoxy)-iV-(2-methyl- 1 -oxopropyl)- [ 1 ,4'-bipiperidine] - 1'- sulfonamide (an example of a compound of formula (lb)).
• Example 14A 4-(3,4-Dichlorophenoxy)-N-(2-phenylacetyl)-[l,4'-bipiperidine]-l'-sulfonamide (an example of a compound of formula (lb)).
• Example 16A 4-(3,4-Dichlorophenoxy)-N-[(4-methylphenyl)sulfonyl]-[l,4'-bipiperidine]-l'- sulfonamide sodium salt (an example of a compound of formula (Ie)).
• Example 16B (an example of a compound of formula (Ie)) was prepared using similar methodology to that of Example 16A and recrystallisation was required after chromatography.
• Step b 4-(3 ,4-Dichlorophenoxy)piperidine
• Step a 4-(3,4-Dichlorophenoxy)-[l,4']bipiperidinyl-l'-carboxylic acid tert-butyl ester 4-(3,4-Dichlorophenoxy)piperidine (1.5g) was dissolved in 1 ,2-dichloroethane (21ml). l-Boc-4-piperidone was added (1.21g) followed by NaBH(OAc) 3 (1.81g) and acetic acid (0.37g). After 18 hours at room temperature aqueous NaOH (IM) solution and diethyl ether were added.
• IM aqueous NaOH
• Step a The product of Step a was dissolved in dichloromethane (30ml) and trifluoroacetic acid (15ml) was added. After 4 hours at room temperature the solution was evaporated and the resultant gum triturated under ether to give the trifluoroacetate salt of the sub-titled product as a solid (1.15g). The free base was liberated by addition of aqueous NaOH (2M) and extraction with ethyl acetate followed by evaporation of solvent to give the sub-title compound as a solid (0.68g).
• Ethyl 4-[4-(3,4-dichlorophenoxy)-l-piperidinyl]-cyclohexanecarboxylate (0.97 g) was added to a solution of sodium ethoxide in ethanol (prepared from sodium (1.28g) and ethanol (100ml)). The solution was heated to reflux overnight. Acetic acid was added and the solvent was evaporated. Ethyl acetate, water and sodium hydroxide were added to the residue and an insoluble white solid formed which was collected by filtration and dried in vacuo to give the sub-titled compound (469mg; MS [M-Na] " (APCI-) 370/372) containing sodium acetate.
• N,N-Diethyl-2,4-dichloro-3-fiuorophenyl carbamate (8.14g) was dissolved in THF (17ml). A solution of lithium aluminium hydride (33ml of IM in THF) was added dropwise and the resulting solution was stirred overnight. Ethanol was added followed by hydrochloric acid (2M, 17ml). The resulting suspension was filtered and the solid was washed with ether. The phases were separated, the aqueous phase was extracted thrice with ether and the combined organic phases were dried (MgSO 4 ), filtered and evaporated to give the title compound (3.4g). 1H ⁇ MR ⁇ (CD 3 OD) 6.65 (IH, dd), 7.11 (IH, t)
• Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J. Immunol. Methods, 1991, 145, 105-110). The cells were resuspended at 10xl0 6 ml "1 in RPMI containing 200 IU/ml penicillin, 200 ⁇ g/ml streptomycin sulfate and supplemented with 10% HIFCS, at room temperature.
• Eosinophils 700 ⁇ l were pre-incubated for 15 mins at 37° C with 7 ⁇ l of either vehicle or compound (lOOx required final concentration in 10% DMSO).
• the chemotaxis plate (ChemoTx, 3 ⁇ m pore, Neuroprobe) was loaded by adding 28 ⁇ l of a concentration of eotaxin 0.1 to lOOnM (a selective CCR3 agonist over this concentration range) containing a concentration of a compound according to the Examples or solvent to the lower wells of the chemotaxis plate.
• the filter was then placed over the wells and 25 ⁇ l of eosinophil suspension were added to the top of the filter.
• the plate was incubated for 1 hr at 37° C in a humidified incubator with a 95% air/5% CO 2 atmosphere to allow chemotaxis.
• the medium containing cells that had not migrated, was carefully aspirated from above the filter and discarded.
• the filter was washed once with phosphate buffered saline (PBS) containing 5 mM EDTA to remove any adherent cells.
• PBS phosphate buffered saline
• Cells that had migrated through the filter were pelleted by centrifugation (300xg for 5 mins at room temperature) and the filter removed and the supernatant transferred to each well of a 96-well plate (Costar).
• the pelleted cells were lysed by the addition of 28 ⁇ l of PBS containing 0.5% Triton xlOO followed by two cycles of freeze/thawing. The cell lysate was then added to the supernatant.
• the number of eosinophils migrating was quantified according to the method of Strath et al., J. Immunol. Methods, 1985, 83, 209 by measuring eosinophil peroxidase activity in the supernatant.

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