IMIDAZOPYRIDINE DERIVATIVES AS DUAL HISTAMINE (H1) AND PLATELET ACTIVATING FACTOR (PAF) ANTAGONISTS

Abstract: Compounds of formula (II), wherein D is for example a group of formula (X), are dual H1/PAF antagonists.

Description: IMIDAZOPYRIDINE DERIVATIVES AS DUAL HISTAMINE (HI) AND PLATELET ACTIVATING FACTOR (PAF) ANTAGONISTS This invention relates to compounds which are dual histamine (Hi) and platelet activating factor (PAF) antagonists, to therapeutic compositions containing such compounds, and to methods for their preparation. Background to the Invention Potent H*ι antagonists of various structural types are known, and are useful in treating the symptoms of inflammatory conditions such as allergic rhinitis, and allergic conditions of the skin, which are mediated at least in part by the release of histamine. However, in such conditions, in which histamine release plays a causative role, there may be other mechanisms at work which are not inhibited by treatment with an H-i antagonist alone. For example PAF is released directly from cell membranes and mediates a range of potent and specific effects on target cells resulting in a wide variety of physiological responses, including hypotension, thrombocytopenia, bronchoconstriction, circulatory shock, increased vascular permeability (oedema/erythema), and accumulation of inflammatory cells in the lower airways. There is therefore a need for agents which have dual H-i and PAF antagonistic activity for the improved treatment of conditions mediated by histamine and PAF release. Such conditions include allergic rhinitis, sinusitis, asthma, dermatitis, psoriasis, urticaria, anaphylactic shock, conjunctivitis, pruritis, inflammatory bowel disease and colitis. International patent application WO-A-92/03423 (British Bio-technology) discloses a series of compounds which are potent antagonists of PAF. The compounds there disclosed are of the general formula (I) with the various substituents A 1 ( A2, B and R-R 7 being as defined in the publication itself. Other patent publications which disclose compounds with PAF antagonist activity are EP-B-0404797 (Searle), EP-A-0260613 (Searle), WO 89/08653 (Searle), WO 91/17162 (Pfizer), and WO 92/03422, WO 92/18503, WO 93/02080, WO 93/16075, WO 93/14072 and WO 93/14069 (all British Biotech). US patent 2,712020, European patent applications EP-A-085959 and EP-A- 133534 (Wellcome Foundation Ltd); EP-A-270818 (Schering Corporation); and United States patent application 4,254,129 (Richardson Merrell Inc.) all disclose compounds which are potent Hi antagonists. Patent applications WO-A-92/14734 (Pfizer); WO-A-92/00293, WO-A-89/10363, WO-A-93/20080, WO-93/20063, WO-A-93/23400, WO-A-93/02C81 ( all Schering); WO-A-94/08581 (Toray); EP-A-515158 (Schering); EP-A-463873 and EP-A- 549364 (Sankyo); EP-A-577957 (Uriach); EP-A-339978, and Japanese patent application published under no 4-226993 (Yoshitomi) all disclose compounds which possess both histamine (H*j) and PAF antagonist activity. Brief Descriotion of the Invention The invention makes available a class of compounds with some of the structural features of the potent PAF antagonists of WO-A-92/03423, and some of the structural features of certain known H- * antagonists, united in a single molecule in such a way as to provide a desirable balance of H-* and PAF antagonist activity. The class includes compounds which are active when administered by the oral route. Detailed Description of the Invention According to the present invention there is provided a compound of formula (II) wherein A represents =N-, =CH- or =CR1-, wherein Ri represents hydrogen, C Cβ alkyl, C2- C- 6 alkenyl, halogen, -CN, -CO 2 H, -CO 2 (CrC 6 alkyl), -CONH 2 , -CHO, -CH 2 OH, - CF 3 , C C 6 alkoxy, C C 6 alkylsulphanyl, C C 6 alkylsulphinyl, C r C 6 alkylsulphonyl, -NH 2 , -NHCOCH 3 , or -NO 2 ; provided that when A represents =N- the resulting imidazo[4,5-c]pyridinyl bicyclic ring system may be optionally substituted in the 4- and/or 6-positions by methyl; R represents hydrogen, C C 6 alkyl, C 2 -C 6 alkenyl, halogen or Cι-C 6 alkoxy; R2 represents hydrogen, C Cβ alkyl, C ∑ -Cε alkenyl, C Cβ alkoxy, C Cβ alkylsulphanyl, cyclopropyl, C Cβ hydroxyalkyl, (CrC 6 alkyl) 2 N-, (C C 6 alkyl) N(C r C 6 alkyl)- or -CF 3 ; R3 represents hydrogen, CrCε alkyl, C2-C 6 alkenyl, C2-C6 alkynyl, -CO2(C C6 alkyl), d-C 6 alkoxy, C C 6 alkylsulphanyl, (d-C 6 alkoxy)(C C 6 alkyl)-, (CrC 6 alkylsulphanyl)(CrC 6 alkyl)-, (phenyl)(C r C 6 alkyl)-, or phenylsulphanyl; R 4 represents hydrogen, C Cε alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C Cε alkylcarbonyl, -CO 2 (C C 6 alkyl), (phenyl)CrC 6 alkylcarbonyl-, -C(=O)O-(C C 6 alkyl)-(phenyl), (Cι-C 6 alkoxy)(C C 6 alkyl)-, (C C 6 alkylsulphanyl)(C r C 6 alkyl)-, -(C C 6 alkyl)-C(=O)O-(C r C 6 alkyl), (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, or a group of formula (III) wherein h is 0 or an integer from 1 to 3, and each of R6 and R 7 is independently hydrogen, C Cβ alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, -CN, -CO 2 H, - CO 2 (CrC 6 alkyl), -CONH 2 , -CONH(C C 6 alkyl), -CON(C C 6 alkyl) 2 , -CHO, - CH 2 OH, -CF 3 , C C 6 alkoxy, C C 6 alkylsulphanyl, Cι-C 6 alkylsulphinyl, C C 6 alkylsulphonyl, -NH 2 , or -NHCOCH 3 ; R5 represents hydrogen, halogen, CrC & alkyl optionally substituted with one or more halogen atoms, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C C 6 alk l)-C(=O)O-(CrC 6 alkyl), (C C 6 a.koxy)C C 6 alkyl, (C C 6 alkylsulphanyl)C r C 6 alkyl, -(C C 6 alkyl)N(CrC 6 alkyl) 2 , (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, ((C 3 - C 8 )cycloalkyl)Cι-C 6 alkyl, ((C 4 -C 8 )cycloalkenyl)Cι-C 6 alkyl, ((C 3 -C 8 )cycloalkyl)-O- (C C 6 alkyl), ((C 4 -C 8 )cycioalkenyl)-O-(CrC 6 alkyl), ((C 3 -C 8 )cycloalkyl)-S-(Cι-C 6 aikyl), ((C4-C8)cycloalkenyl)-S-(CrC6 alkyl), a side chain of a naturally occurring amino acid, or a group of formula (III) as defined above; B represents a bond, or a straight saturated or unsaturated hydrocarbon chain of from 1 to 6 carbon atoms which may additionally include from 1 to 3 non-adjacent hetero atoms or groups selected from -O-, -S-, -N(R 4 )- wherein R 4 is as defined above, -S(O)-, -S(O 2 )-, and -S(O 2 )N(R 4 )- wherein R 4 is as defined above, and in which one or more carbon atoms of the chain may be substituted by oxo, hydroxy, C1-C4 alkyl, phenyl, or -phenyl(Ci-C 4 alkyl); D represents a group of formula (IV), (V), (VI), (VII) or (VIIA) wherein R8 and R9 are the same or different and each represents an optionally substituted divalent phenylene group or an optionally substituted 5-6 membered monocyclic divalent heteroarylene group containing at least one nitrogen, oxygen or sulphur atom, wherein any optional substituents are selected from C Cβ alkyl, C 2 -C 6 alkenyl, HOOC-(C 2 -Cβ alkenyl), halogen or C Cβ alkoxy groups, and X and Y are independently hydrogen or when taken together in groups (IV), (V), (VI) or (VIIA) represent a divalent group selected from -CH2CH 2 -, -CH=CH-, -CH 2 0- and - COCH2-; and R10 and R11 are independently C-i-Cβ alkyl or together with the nitrogen atom to which they are attached form a non-aromatic 5-7 membered heterocyclic ring; provided that when D is a group IV, V, VI or VIIA in which R β and R9 are both phenylene groups and substituents X and Y are other than a divalent group selected from -CH 2 CH 2 -, -CH=CH-, -CH 2 O- and -COCH 2 -, then the group B does not include a carbonyl group bonded directly to D; or a pharmaceutically or veterinarily acceptable acid addition salt or hydrate thereof. Hereafter in this specification the term "compound" includes "salt" or "hydrate" unless the context requires otherwise. As used herein the term "halogen" or its abbreviation "halo" means fluoro, chloro, bromo or iodo. As used herein the term "C Cβ alkyl" refers to straight chain or branched chain hydrocarbon groups having from one to six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl. As used herein the term "C 2 -C 6 alkenyl" refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one double bond, of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl and 2-methyl-2- propenyl. As used herein the term "C 2 -C6 alkynyl" refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1 -propynyl, 1- and 2- butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl and 5-hexynyl. As used herein the term "C Cβ alkoxy" refers to straight chain or branched chain alkoxy groups having from one to six carbon atoms. Illustrative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert- butoxy, pentoxy, neopentoxy and hexoxy. As used herein the term "C Cβ alkylsulphanyl" refers to straight chain or branched chain alkylsulphanyl groups having from one to six carbon atoms. Illustrative of such alkyl groups are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, neopentylthio and hexylthio. The terms "C-i-Cβ alkylsulphinyl" and "CrCβ alkylsulphonyl" refer to the corresponding sulphinyl and sulphonyl groups respectively. As used herein, the term "C 3 -C 8 cycloalkyl" refers to an alicyclic group having from 3 to 8 carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. As used herein, the term "C 4 -C 8 cycloalkenyl" refers to an alicyclic group having from 4 to 8 carbon atoms and having in addition one or more double bonds. Illustrative of such cycloalkenyl groups are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. As used herein, the term "side chain of a naturally occurring amino acid" includes the side chains of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glycine, histidine, 5-hydroxylysine, 4-hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, α-aminoadipic acid, α-amino-n-butyric acid, 3,4- dihydroxyphenylalanine, homoserine, α-methylserine, ornithine, pipecolic acid, and thyroxine. The amino acid side chains may be protected; for example the carboxyl groups of aspartic acid, glutamic acid and α-aminoadipic acid may be esterified (for example as a C Cβ alkyl ester), the amino groups of lysine, ornithine, 5- hydroxylysine, 4-hydroxyproline may be converted to amides (for example as a COC-rCβ alkyl amide) or carbamates (for example as a C(=O)OC-ι-C 6 alkyl or C(=O)OCH 2 Ph carbamate), the hydroxyl groups of 5-hydroxylysine, 4- hydroxyproline, serine, threonine, tyrosine, 3,4-dihydroxyphenylalanine, homoserine, α-methylserine and thyroxine may be converted to ethers (for example a C*ι-C 6 alkyl or a (CrCβ alkyl)phenyl ether) or esters (for example a C(=O)C-|-C 6 alkyl ester) and the thiol group of cysteine may be converted to thioethers (for example a C-ι-C- 6 alkyl thioether) or thioesters (for example a C(=O)C*|-C 6 alkyl thioester). The stereochemistry at the carbon atom to which the amino acid side chain is attached may be either D or L. As used herein, the term "non-aromatic 5 to 7 membered heterocyclyl" refers to a non-aromatic monocyclic heterocyclic group having from 5 to 7 ring atoms wherein the heteroatom(s) are selected from O, S and N. Illustrative of such are pyrolyl, furanyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyrrolidinyl, pyrimidinyl, morpholinyl, and piperizinyl. As used herein, the term "divalent phenylene" group means a benzene ring in which two of the ring carbon atoms, for example two adjacent ring carbon atoms, have unsatisfied valencies. As used herein, the term "divalent heteroarylene" group means an aromatic heterocyclic ring in which two of the ring atoms, for example two adjacent ring atoms, have unsatisfied valencies. In compounds of this invention, the presence of several asymmetric carbon atoms gives rise to diastereoisomers, each of which consists of two enantiomers, with the appropriate R or S stereochemistry at each chiral centre. The invention is understood to include all such diastereoisomers, their optically active enantiomers and mixtures thereof. The term "pharmaceutically or veterinarily acceptable acid addition salt" refers to a salt prepared by contacting a compound of formula (I) with an acid whose anion is generally considered suitable for human or animal consumption. Examples of pharmaceutically and/or veterinarily acceptable acid addition salts include the hydrochloride, sulphate, phosphate, acetate, propionate, lactate, maleate, succinate and tartrate salts. In the compounds of the invention, the group B is believed to function as a flexible linker between the two halves of the molecule. As depicted in formula (II), the grouping to the left of linker group B is primarily responsible for the PAF antagonist activity of the compounds, and the group D to the right is primarily responsible for its H-i activity. The invention is based at least in part on the finding of the present inventors that linking the two halves by a flexible linker of the kind defined above enables the molecule to orient itself for interaction with the PAF receptor without the Hi antagonist moiety D interfering unduly with that interaction, and vice versa with respect to the H*ι receptor. The linker group B may, for example, have the formula -(CH 2 )j-, -CO-, -COX(CH 2 ) r , -COX(CH 2 )iYCO-, -COX(CH 2 )iY(CH 2 ) j -, -(CH 2 )XCO-, -COX(CH 2 )jY(CH 2 )ZCO-, -CO(CH 2 ) r , -(CH 2 )X(CH 2 ) r , -(CH 2 )X(CH 2 )iY(CH 2 ) r , -(CH 2 )X(CH 2 )iYCO-, -(CH 2 )XCO(CH 2 )i-, -X(CH 2 ) , -S(CH 2 ) r , -SO(CH 2 ) r , -SO 2 (CH 2 )i-, or -SO 2 X(CH 2 )i-, wherein X, Y and Z independently represent -O- or -NR 4 - where R 4 is as defined above in formula (II), and i and j are independently 0 or an integer from 1 to 6, provided that no more than 6 carbon atoms are present in the linear chain represented by the foregoing formulae, and provided that where both X and Y are present in the linker group B then i is an integer from 1 to 6. In the foregoing formulae one or more carbon atoms of the linear chain may be substituted by hydroxy, C 1 -C 4 alkyl, phenyl, or -phenyl(C*ι-C 4 alkyl). Preferred compounds of formula (II) include those in which, independently or in any compatible combination: A is =N-; R represents hydrogen; R2 represents methyl; R3 represents hydrogen; R4 represents hydrogen, a -Ci-Cβ alkyl (for example methyl, ethyl or iso- propyl) group, a -C 2 -C6 alkenyl (for example allyl) group, a C3-C 8 cycloalkyl (for example cyclohexyl, cyclopentyl, cyclopropyl) group, a (CrCβ alkoxy)(C-|- Cβ alkyl)- group (for example 1-ethoxymethyl-3-methylbut-1-yl), a -(d-Cβ alkyl)-C(=O)O-(C*ι-C6 alkyl) group (for example 1 -ethoxycarbonyl-3-methylbut- 1 -yl), or a group of formula (III) above; R5 represents hydrogen, a C-i-Cβ alkyl (for example methyl, ethyl, n-butyl, i- butyl, sec-butyl or t-butyl) group, a C 2 -Ce alkenyl (for example allyl) group, a (C Cβ alkyl)C3-Cβ cycloalkyl (for example cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl) group, a side chain of a naturally occurring amino acid (for example the side chain of leucine, isoleucine, phenylalanine, valine, tryptophan, methionine or tyrosine) or a group of formula (III) above; 1 1 in those cases where a group of formula (III) is present, R6 represents a hydrogen atom, a CrCβ alkyl (for example methyl) group, a halogen (for example fluorine, chlorine or bromine) atom, a CF 3 group or a C-i-Cβ alkoxy (for example methoxy) group; and R 7 represents a hydrogen atom or a Ci-Cε alkoxy (for example methoxy) group; the group B may be a bond, or -CO-, -CH 2 -, -CH 2 CH 2 , -CH 2 OCO-, - CH 2 OCOCH 2 - , -COO(CH2)2θCH 2 CH2-, -CONH(CH 2 ) -, -COOCH 2 -, - COO(CH 2 ) 2 -, -COO(CH 2 ) 3 -, -CH 2 OCH 2 CO-, -CH 2 OCH 2 CH 2 -, -COOCH(4-tert- butylphenyl)(CH 2 ) 3 , -COOCH(CH 3 )(CH 2 ) 3 , -CH 2 NHCOCH 2 -, -CH 2 NHCO-; in the group D, the groupings -R β -X and -R9-Y may be independently a phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 2-pyridyl, or 6-[2- carboxyethenyl]pyrid-2-yl group; or the group D may be of formula (VIII), (IX) or (X): the latter group (X) being presently preferred. Specific presently preferred compounds of the invention are: N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L- leucine-2-(4-benzhydryl-piperazin-1 -yl)-ethyl ester, N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L- leucine-3-(4-benzhydryl-piperazin-1 -yl)-propyl ester, 4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1.2-b]-pyridin-11-ylidene)-1-(N- methyl-N-4-{1 H-2-methylimidazo[4,5-c]pyridinylmethyl}-phenylsulphonyl-L-leucyl)- piperidine amide, (E)-3-(6-[Pyrrolidino-1 -{4-tolyl}prop-1 E-enyl]-2-pyridyl)acrylic acid, N-methyl-N-4- (1 H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L-leucyl ester, N-(S)-(1 -Ethoxymethyl-3-methylbutyl)-N-{(E)-3-(6-[3-pyrrolidino-1 -{4-tolyl}-prop-1 E- enyl]-pyridin-2-yl)-prop-2-en-1 -yl}-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)- phenylsulphonamide, and (S)-4-Methyl-2-([4-1H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonyl]- (E)-{3-[6-(3-pyrrolidin-1 -yl-{4-tolyl}-prop-1 E-enyl]-prop-2-en-1 -yl}-amino)-pentanoic acid ethyl ester, and pharmaceutically or veterinarily acceptable acid addition salts or hydrates thereof Additional specific compounds of the invention include: N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine- 2-(2-{4-[4-(chlorophenyl)-phenyl-methyl]-piperazin-1-yl}-ethoxy)-ethyl ester, N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine- 2-(4-[1 , 1 -dimethylethyl]phenyl)-4-(hydrσxydipheπylmethyl)-1 -piperidinebutyl ester, N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine- 2-(4-benzhydryl-piperazin-1-yl)-ethylamide, 4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1.2-b]-pyridin-11-ylidene)-1-(N- methyl-N-4-{1 H-2-methylimidazo[4,5-c]pyridinylmethyl}-phenylsulphonyl-L-leucinol)- piperidine carbamate, (4-Benzhydrylpiperazin-1 -yl)-acetic acid, N-methyl-N-4-(1 H-2-methylimidazo[4,5-c]- pyridinylmethyl)-phenylsulphonyl-L-leucyl ester, N-Methyl-N-(S)-(1 -[4-benzhydrylpiperazin-1 -yl]-methyl-3-methyl-butyl)-N-4-(1 H-2- methylimidazo[4,5c]pyridinylmethyl)-phenylsulphonamide, N-Methyl-N-(S)-(1-aminomethyl-[{4-benzhydrylpiperazin-1-yl}-acetamide]-3-methyl- butyl)-N-4-(1 H-2-methylimidazo[4,5-c]-pyridinylmethyl)-phenylsulphonamide, N-(S)-(4-Methyl-2-{methyl-[4-(1H-2-methyl-imidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonyl]-amino}-pentyl)-3-[6-(3-pyrrolidin-1-yl-p-tolyl-prop-1E-enyl)-pyridin- 2-yl] acrylamide, 2-[4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]ρyridin-11-ylidene)- piperidin-1 -yl]-N-(4-methyl-2-{methyl-[4-(1 H-2-methylimidazo[4,5-c]pyridin-1 - ylmethyl)-phenylsulphonyl]-amino}-pentyl)-acetamide, N-[1 -{(4-Chlorobenzhydryl)-piperazin-1 -ylmethyl}-3-methyl-butyl]-N-methyl-4-(1 H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide, N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L- leucine-2-(4-{8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11- ylidene}piperidin-1 -yl)-ethyl ester, N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L- leucine-(R,S)-5-(4-benzhydrylpiperazin-1 yl)-2-pentyl ester, 4-Methyl-2-{methyl-[4-(2-methyl-imidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonyl]- aminoj-pentanoic acid-(E)-3-(6-[3-pyrrolidino-1 -{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)- prop-2-en-1-yl ester, N-(1-{2-[4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -ylidene)- piperidin-1-yl]-2-oxo-ethoxymethyl}-3-methyl-butyl)-N-methyl-4-(1 H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide, N-{2-[4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -ylidene)- piperidin-1 -yl]-2-oxo-ethyl}-N-(S)-(1 -ethoxymethyl-3-methylbutyl)-4-(1 H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide, N-(2-{[4-(R,S)-(4-Chlorophenyl)-ρhenyl-methyl]piperazin-1-yl}ethyl)-N-(S)-(1 - ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5-c]pyridin-1ylmethyl)- phenylsulphonamide, N-(2-{[3-(R,S)-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-methylamino}ethyl)-N-(S)-(1- ethoxymethyl-3-methylbutyl)-4-(1H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonamide, N-(3-{[3-(R,S)-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-methylamino}propyl)-N-(S)-(1- ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonamide, N-(3-{[4-(R,S)-(4-Chlorophenyl)-phenyl-methyl]piperazin-1-yl}propyl)-N-(S)-(1 - ethoxymethyl-3-methylbutyl)-4-(1H-2-methylimidazo[4,5-c]pyridin-1ylmethyl)- phenylsulphonamide, N-Cyclohexyl-N-{(E)-3-(6-[3-pyrrolidiπo-1-{4-tolyl}-prop-tE-enyl]-pyridin-2-yl)-prop-2- en-1 -yl}-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonamide, N-Methyl-N-{(E)-3-(6-[3-pyrrolidino-1 -{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)-prop-2-en- 1 -yl}-4-(1 H-2-methyiimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonamide, and pharmaceutically or veterinarily acceptable acid addition salts or hydrates thereof. Compounds of the invention of general formula (II) may be prepared by standard techniques of organic synthesis. In considering specific synthetic routes which may be employed, it is convenient to simplify the depiction of general formula (II) as formula (MA): Q-B-D (HA) wherein B and D are as defined in formula (II) and Q represents the grouping wherein A, and R-R5 are as defined in formula (II). It is also convenient to categorise compounds of the invention of formula (II) according to the identity of the first few atoms of the linker group B, counting the atom to which grouping Q is joined as position 1 , the adjacent atom of the linker chain as position 2, and so on. Route 1 Compounds of the invention in which linker B commences -C(O)O- may be prepared by esterification of an acid of formula (XI) QCO 2 H (XI) with an alcohol of formula (XII) HO-B1-D (XII) wherein D is as defined in formula (II) and B is the residue of linker B (as defined in formula (II)) commencing at position 3. The esterification may be facilitated by using a carbodiimide condensing agent, such as 3-dimethylaminopropyl-1-ethyl- carbodiimide. Alternatively an activated derivative of the acid (XI) may be employed for the esterification, such as the acid chloride or pentafluorophenyl ester. Dimethylaminopyridine added to the reaction mixture may facilitate the esterification reaction and increase yield. Route 2 Compounds of the invention in which linker B commences -C(O)N(R 4 )- wherein R 4 is as defined in formula (II) may be prepared by amidation of an acid of formula (XI) QCO 2 H (XI) with an amine of formula (XIII) HN(R 4 )-B1-D (XIII) wherein D is as defined in formula (II) and B is the residue of linker B (as defined in formula (II)) commencing at position 3. The amidation, like the esterification reaction of Route 1 , may be facilitated by using a carbodiimide condensing agent or by the use of an activated derivative of the acid (XI). Route 3 Compounds of the invention in which linker B commences -CH 2 OC(O)- may be prepared by esterification with an alcohol of formula (XIV) QCH 2 OH (XIV) of an acid of formula (XV) HOOC-B1-D (XV) wherein D is as defined in formula (II) and B1 is the residue of linker B (as defined in formula (II)) commencing at position 4. The comments made in relation to the esterification conditions in Route 1 apply here also. Route 4 Compounds of the invention in which linker B is -CH 2 - and group D is of formula (IV), (V), (VI) or (VIIA) may be prepared by condensation of an alcohol of formula (XIV) QCH 2 OH (XIV) with an amine of formula (XVI) H-D (XVI) The alcohol (XIV) preferably participates in the condensation reaction as the mesylate, formed from the reaction of the alcohol (XIV) with methyl sulphonyl chloride in the presence of a tertiary amine. Route 5 Compounds of the invention in which linker B commences -CH 2 NHC(O)- may be prepared by amidation with an amine of formula (XVII) QCH 2 NH 2 (XVII) of an acid of formula (XV) HOOC-B1-D (XV) wherein D is as defined in formula (II) and B> is the residue of linker B (as defined in formula (II)) commencing at position 4. The comments made in relation to the amidation conditions in Route 2 apply here also. The carbonyl group in position 3 of the linker B of the product of the foregoing reaction may be reduced to form the corresponding compounds of the invention in which linker B commences - CH 2 NHCH 2 -. Route 6 Compounds of the invention in which linker B commences -CH 2 NH- may be prepared by reaction of an amine of formula (XVII) QCH 2 NH 2 (XVII) with an aldehyde of formula (XVIII) HCO-B1-D (XVIII) wherein D is as defined in formula (II) and B1 is the residue of linker B (as defined in formula (II)) commencing at position 4. The reaction preferably takes place in the presence of a suitable reducing agent such as sodium cyaπoborohydride. 18 Route 7 Compounds of the invention of formula (II) may also be prepared by a process comprising reaction of a diamino compound of formula (XIX) wherein A, R, R3-R5, B and D are as defined in formula (II), with a acid of formula (XX) R2COOH (XX) or an activated derivative thereof. This reaction is analagous to that described previously in WO 92/03423, and further details of suitable activated derivatives of acid (XX) and process conditions may be found therein. Route 8 Compounds of the invention in which D is a group of formula (VII) as defined above and B is a bond may be prepared by reaction of a sulphonamide of formula (XXI) with an acetate of formula (XXII) in the presence of a palladium(O) catalyst, such as tetrakis(triphenylphosphine)palladium(0) 19 CH 3 COOCH 2 D (XXII) Sulphonamides of formula (XXI) may be prepared using procedures analogous to those reported in WO 92/03423 or WO 92/03422. The starting acid (XI) for routes 1 and 2 above may be prepared by hydrolysis under acidic conditions of a corresponding ester (prepared as previously described in WO 92/03423). The starting alcohol (XIV) for routes 3 and 4 above may be prepared by reduction, for example using lithium aluminium hydride, of a corresponding ester (prepared as previously described in WO 92/03423). The starting amine (XVII) for routes 5 and 6 above may be prepared by reaction of a mesylate of the alcohol (XIV) with sodium azide followed by hydrogenation over a palladium catalyst. In addition to the above routes, compounds of the invention may be prepared by other methods and techniques analogous to those known in the art for compounds having similar structural features, and by analogy with the methods and techniques used in the specific preparative examples below. As mentioned above, the invention makes available a class of compounds having a desirable balance of H-i and PAF antagonist activity. Accordingly in another aspect, this invention concerns: (i) a method of management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by histamine and/or PAF in mammals, in particular in humans, which method comprises administering to the mammal an effective amount of a compound as defined with respect to formula (II) above, or a pharmaceutically acceptable salt thereof; and (ii) a compound as defined with respect to formula (II) for use in human or veterinary medicine, particularly in the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by histamine and or PAF; and „ IΛ Λ „ ΛMnι PCT/GB95/01878 WO 96/05201 20 (iii) the use of a compound as defined with respect to formula (II) in the preparation of an agent for the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by histamine and/or PAF. Diseases or conditions mediated by histamine and/or PAF, but which probably include contributions from both agents, include hypotension, thrombocytopenia, bronchoconstriction, circulatory shock, increased vascular permeability (oedema/erythema), allergic rhinitis, sinusitis, asthma, dermatitis, psoriasis, urticaria, anaphylactic shock, conjunctivitis, pruritis, inflammatory bowel disease and colitis. According to a further aspect of the invention there is provided a pharmaceutical or veterinary formulation comprising a compound of general formula (II) and a pharmaceutically and/or veterinarily acceptable carrier. One or more compounds of general formula (II) may be present in association with one or more non-toxic pharmaceutically and/or veterinarily acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general formula (II) may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium 21 stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally- occuring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening 22 agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparations. These compositions may be preserved by the addition of an anti- oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present. Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical application to the skin compounds of the invention may be made up into a cream, ointment, jelly, solution or suspension etc. Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British Pharmacopoeia. For topical applications to the eye, compounds of the invention may be made up into a solution or suspension in a suitable sterile aqueous or non-aqueous vehicle. Additives, for instance buffers, preservatives including bactericidal and fungicidal agents, such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorohexidine, and thickening agents such as hypromellose may also be included. Compounds of the invention may be administered parenterally in a sterile medium. The drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. Compounds of the invention may be used for the treatment of the respiratory tract by nasal or buccal administration of, for example, aerosols or sprays which can disperse the pharmacologic al active ingredient in the form of a powder or in the form 24 of drops of a solution or suspension. Pharmaceutical compositions with powder- dispersing properties usually contain, in addition to the active ingredient, a liquid propellant with a boiling point below room temperature and, if desired, adjuncts, such as liquid or solid non-ionic or anionic surfactants and/or diluents. Pharmaceutical compositions in which the pharmacological active ingredient is in solution contain, in addition to this, a suitable propellant, and furthermore, if necessary, an additional solvent and or a stabiliser. Instead of the propellant, compressed air can also be used, it being possible for this to be produced as required by means of a suitable compression and expansion device. Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 71 g per patient per day). For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 1.0 mg to about 3.5 g per patient per day). The dosage employed for the topical administration will, of course, depend on the size of the area being treated. For the eyes each dose will be typically in the range from 0.1 to 10 mg of the drug. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the 25 particular disease undergoing therapy. The following examples illustrate the invention, but are not intended to limit the scope in any way. The following abbreviations have been used in the examples:- DCM - Dichloromethane MPLC - Medium Pressure Liquid Chromatography DMF - Dimethylformamide THF - Tetrahydrofuran DIBAL - Diisobutylaluminium hydride DMSO - Dimethylsulphoxide Column chromatography was performed with flash grade silica gel. 1H-NMR and 13C-NMR were recorded either on a Bruker AC-250 spectrometer at 250 MHz and 62.5 MHz respectively or on a Bruker AMX-500 spectrometer at 500MHz and 125.72 MHz respectively. CDCI 3 was used as a solvent and internal reference and spectra are reported as δ ppm from TMS. Example 1 N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L- leucine-2-(2-{4-[4-(chlorophenyl)-phenyl-methyl]-piperazin-1-yl}-ethoxy)-ethyl ester. 26 (a) N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridylmethyl)-phenylsulphonyl-L- leucine (675mg, 1.6mmol)(WO-92 03423) was dissolved in DCM (15ml) and treated with pentafluorophenol (239mg, 1.9mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (360mg, 1.9mmol) and N-methylmoφholine (380μl, 3.5mmol). After stirring at room temperature for 3.5 hours the reaction mixture was partitioned with saturated sodium bicarbonate. The organic layer was separated, washed with brine and dried over sodium sulphate. Filtration and evaporation of solvent under reduced pressure provided the pentafluorophenylester as a colourless oil. The residue was taken up in DCM (15ml) and treated with 2-{4-[4- (chlorophenyl)-phenylmethyl]-piperazin-1-yl}-ethoxyethanol dihydrochloride (700mg, 1.6mmol) and imidazole (320mg, 4.7mmol). The reaction was stirred overnight at room temperature. The reaction mixture was partitioned between DCM and 10% citric acid. The organic layer was separated, washed with saturated sodium bicarbonate and brine and dried over sodium sulphate. The crude product was purified by MPLC on a silica gel column with a gradient elution 5-7% methanol in DCM over 40 minutes and a flow rate of 60 ml min. Product containing fractions were combined and solvent removed under reduced pressure to provide N-methyl- N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethylphenylsulphonyl-L-leucine-2-(2-{4-[4- (chlorophenyl)-phenyl-methyl]-piperazin-1-yl}-ethoxy)-ethyl ester as a yellow oil (648mg, 52%). 1H-NMR; δ (CDCI 3 ), 8.99 (1H, s), 8.31 (1H, d, J=5.6Hz), 7.69 (2H, d, J=8.4Hz), 7.34- 7.06 (12H, m), 5.32 (2H, s), 4.63-4.57 (1H, m), 4.16 (1 H, s), 3.89-3.79 (2H, m), 3.45- 3.34 (6H, m), 2.77 (3H, s), 2.53 (3H, s), 2.49-2.29 (8H, m), 1.64-1.50 (3H, m), 0.87 (3H, d, J=5.8Hz) and 0.86 (3H, d, J=5.8Hz). 13 C-NMR; δ (CDCI 3 ). 170.7, 153.2, 142.0, 141.8, 141.2, 140.0, 139.7, 139.5, 139.1 , 132.3, 129.0, 128.4, 128.1, 127.7, 127.0, 126.6, 104.6, 75.2, 68.8, 68.2, 63.6, 57.5, 57.0, 53.7, 51.5, 50.1 , 46.7, 38.0, 29.7, 24.3, 22.8 and 20.9. Example 2 N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L- leucine-2-(4-[1 ,1-dimethylethyl]phenyl)-4-(hydroxydiphβnylmethyl)-1-piperidinebutyl ester. N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridylmethyl)-phenylsulphonyl-L-leucine (675mg, 1.6mmol) was reacted via a pentafluorophenyl ester derivative using conditions described in example 1 but using 4-[1 ,1-dimethylethyl]phenyl)-4- (hydroxydiphenylmethyl)-l-piperidinebutanol (755mg, 1.6mmol) in place of 2-{4-[4- (chlorophenyl)-phenylmethyl]-piperazin-1-yl}-ethoxyethanol dihydrochloride. Following column chromatography on silica gel, eluting with 3% methanol/DCM, N- methyl-N-4-(1 H-2-methylimidazo[4,5-cJpyridinylmethyl)-phenylsulphonyl-L-leucine- 2-(4-[1 ,1-dimethylethyl]phenyl)-4-(hydroxydiphenylmethyl)-1 -piperidinebutyl ester was obtained as a white foam and a 2:1 mixture of diastereoisomers (at the 1 ,1- 28 dimethylethylphenyl methyl group, 625mg, 45%). 1 H-NMR; δ (CDCI 3 ), 8.99 (0.66H.S), 8.94 (0.33H.S), 7.73 (0.66H, d, J 8.3Hz), 7.54- 7.48 (5.33H, m), 7.31-6.81 (13H,m), 5.49-5.44 (1 H, m), 5.36 (0.66H, s), 5.26 (1.33H, d, J 3.7 Hz), 4.72-4.67 (1 H, m), 2.96-2.82 (2H, m), 2.78 (1H, s), 2.73 (2H, s), 2.57 (1 H,s), 2.52 (2H, s), 2.52-2.35 (1 H, m), 2.30-2.25 (2H, m), 2.07-1.89 (2H, m), 1.78- 1.24 (11 H, m), 1.28 (3H, s), 1.26 (6H, s) and 0.97-0.92 (6H,m). 1 3C-NMR; δ (CDCI 3 ), 170.2, 170.6, 153.4, 151.0, 146.1 , 142.0, 141.7, 140.1 , 139.7, 139.4, 138.8, 136.9, 135.5, 128.1 , 127.9, 126.6, 126.5, 126.3, 125.8, 125.2, 125.1 , 104.7, 79.2, 76.7, 76.4, 57.6, 57.4, 57.1 , 53.8, 53.7, 46.8, 44.0, 38.0, 37.6, 34.4, 34.2, 33.9, 31.7, 29.7, 29.5, 26.0, 24.3, 22.9, 22.6, 22.4, 21.0 and 13.8. Example 3 N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine- 2-(4-benzhydryl-piperazin-1 -yl)-ethyl ester. (a) 2-(4-Benzhydryl-piperazine)-ethan-1 -ol 2-Bromoethanol (7.8g, 62.4mmol) was added to a solution of benzhydrylpiperazine in dry THF (150ml). The reaction mixture was stirred at room temperature overnight. THF was removed under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulphate, filtered and solvent removed to leave 2- (4-benzhydryl-piperazine)-ethan-1-ol as a colourless oil (8.2g, 44%). 1H-NMR; δ (CDCI 3 ), 7.42 (4H, d, J=7.3Hz), 7.27 (4H, m), 7.18 (2H, m), 4.23 (1 H, s), 3.60 (2H, t, J=5.5Hz), 2.85 (1 H, bs) and 2.55-2.44 (10H, bm). (b) N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L- leucine-2-(4-benzhydryl-piperazin-1 -yl)-ethyl ester. N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L-leucine (1.0g, 2.33mmol) was dissolved in DCM (25ml) and treated with N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (446mg, 2.33mmol), 2- (4-benzhydryl-piperazine)-ethan-1-ol (688mg, 2.33mmol) and dimethylaminopyridine (284mg, 2.33mmol). The reaction was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and saturated sodium bicarbonate. The organic layer was separated and washed with brine dried over magnesium sulphate, filtered and concentrated. The crude product was purified by column chromatography using silica gel and eluting with 3-10% methanol/DCM. Product containing fractions were combined and solvent removed to provide as a white foam N-methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)- phenylsulphonyl-L-leucine-2-(4-benzhydryl-piperazin-1 -yl)-ethyl ester (660mg, 40%). 1H-NMR; δ (CDCI 3 ), 9.06 (1 H, bs), 8.39 (1 H, bs), 7.75 (2H, d, J=8.2Hz), 7.40 (4H, d, J=7.7Hz), 7.28-7.25 (4H, m), 7.19-7.12 (5H, m), 5.36 (2H, s), 4.65-4.62 (1 H, m), 4.20 (1 H, s), 3.98-3.91 (2H, m), 2.81 (3H, s), 2.57 (3H, s), 2.43-2.39 (8H, m), 1.87 (2H, bs), 1.62-1.54 (3H, m) and 0.93 (6H, t, J=2.5Hz). 13C-NMR; δ (CDCI 3 ), 170.8, 153.2, 142.5, 142.2, 142.1 , 140.1 , 139.8, 139.6, 139.4, 128.5, 128.3, 127.9, 127.0, 126.6, 104.6, 76.1 , 62.0, 57.2, 56.2, 53.5, 51.7, 46.8, 38.1 , 29.8, 24.4, 23.0, 21.2 and 14.0. Example 4 N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L- leucine-3-(4-benzhydryl-piperazin-1 -yl)-propyl ester. (a) 3-(4-Benzhydryl-piperazine)-propan-1 -ol Benzhydrylpiperazine (14.7g, 58.3mmol) was reacted with 3-bromopropanol (8.1 g, 58.3mmol) using conditions described for example 3(a). 3-(4-Benzhydryl- piperazine)-propan-1-ol was produced as a colourless oil (12.4g, 69%). 1 H-NMR; δ (CDCI 3 ), 7.48-7.25 (10H, m), 4.22 (1H, s), 3.78 (2H, t),2.69-2.35 (10H, m) and 1.72 (2H, m). (b) N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L- leucine-3-(4-benzhydryl-piperazin-1 -yl)-propyl ester. N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine (1.0g, 2.33mmol) was reacted using conditions described for example 3(b) with 4- benzhydrylpiperazine-1-propanol (722mg, 2.33mmol) to provide N-methyl-N-4-(1H- 31 2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine-3-(4-benzhydryl- piperazin-1-yl)-propyl ester as a white foam (234mg, 14%). 1H-NMR; δ(CDCI 3 ), 9.01 (1H,s), 8.33 (1H, d, J=5.6Hz), 7.71 (2H, d, J=8Hz), 7.39 (4H.d,J=7.8Hz), 7.38-7.09 (9H, m), 5.31 (2H, d, J=3Hz), 4.61-4.58 (1H, m), 4.20 (1H,s), 3.87-3.77 (2H, m), 2.79 (3H, s), 2.54 (3H, s), 2.41 (8H, bs), 2.26 (2H,t, J=7.4Hz), 1.63-1.55 (5H, m) and 0.99-0.90 (6H, m). 13 C-NMR; δ(CDCI 3 ), 170.9, 153.3, 142.6, 142.1, 142.0, 140.2,139.8, 139.7, 139.3, 128.4, 128.2, 127.9, 126.9, 126.6, 104.7, 76.1, 63.4, 57.1, 54.7, 53.4, 51.8, 46.8, 38.1, 29.8, 25.8, 24.4, 23.0, 21.0 and 14.0. Example 5 N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L- leucine-2-(4-benzhydryl-piperazin-1-yl)-ethylamide. (a) (4-Benzyhydryl-piperazin-1 -yl)-acetonitrile Benzhydrylpiperazine (20g, 79mmol) was taken up in dry DCM (100ml) and treated with triethylamine (11ml, 79mmol) and bromoacetonitrile (7.7ml, 110mmol). The reaction was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and water. The organic layer was separated, washed with water.dried over magnesium sulphate and filtered. Solvent was removed under reduced pressure and the residue recrystallised from ethyl acetate to yield (4- benzhydryl-piperazin-1-yl)-acetonitrile as a white solid (19g, 82%). 1H-NMR; δ (CDCI 3 ), 7.48-7.44 (4H, m), 7.34-7.17 (6H, m), 4.27 (1 H,m), 3.51 (2H, s), 2.66-2.62 (4H,m), 2.49 (4H, bs). (b) 2-(4-Benzhydryl-piperazine)-ethylamine (4-Benzyhydryl-piperazin-1-yl)-acetonitrile (19g, 65mmol) was taken up in dry THF (150ml) and cooled in an ice/water bath. Lithium aluminium hydride (7.4g, 195mmol) was added slowly over 40 minutes and the reaction allowed to stir at room temperature overnight. The reaction mixture was treated dropwise with water (7.4ml), 15% sodium hydroxide solution (7.4ml) and more water (22.2ml). The resulting precipitate was filtered off through sodium sulphate and silica. Removal of solvent under reduced pressure gave 2-(4-benzhydryl-piperazine)-ethylamine (19g, 99%). 1H-NMR; δ (CDCI 3 ), 7.45-7.41 (4H, m), 7.30-7.14 (6H,m), 4.22 (1H, s), 2.77 (2H, t, J=6.3Hz), 2.47-2.27 (10H, m). (c) N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L- leucine-2-(4-benzhydryl-piperazin-1 -yl)-ethylamide. N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethylphenylsulphonyl-L-leucine (435mg, 1.01 mmol) was taken up in DMF (10ml) and cooled in an ice/water bath. Hydroxybenzotriazole (177mg, 1.31 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (232mg, 1.21 mmol) and 2-(4-benzhydryl- piperazine)-ethylamine (298mg, 1.01 mmol) were added with stirring. The reaction was allowed to warm to ambient temperature and stirred for 48 hours. DMF was removed under vaccuum and the residue partitioned between ethyl acetate and sodium bicarbonate. The organic layer was separated and washed with brine before drying over sodium sulphate. The product was purified by flash chromatography on silica-gel, eluting with 10% methanol/DCM. Product containing fractions were combined and solvent removed to yield N-methyl-N-4-(1 H-2-methylimidazo[4,5-c]- pyridinylmethyl)phenylsulphonyl-L-leucine-2-(4-benzhydryl-piperazin-1-yl)- ethylamide as a white foam (374mg, 0.53mmol). 1H-NMR; δ (CDCI 3 ), 9.06 (1H, s), 8.39 (1 H, d, J=5.6Hz), 7.79 (2H, m), 7.41 (5H, d, J=7.6Hz), 7.26 (3H, t, J=7.5Hz), 7.15 (5H, m), 6.63 (1H, bs), 5.39 (2H, s), 4.32 (1 H, t, J=7.5Hz), 4.21 (1H, s), 3.23 (2H, dd, J=3.4, 5.0Hz), 2.80 (3H, s), 2.59 (3H, s), 2.58-2.42 (1 OH, bm), 1.70 (1 H, m), 1.32 (1 H, m), 1.15 (1H, m), and 0.78 (6H, dd, J=5.0, 6.5Hz). 13C-NMR; δ (CDCI 3 ), 169.6, 153.2, 142.8, 142.3, 142.2, 140.1 , 139.9, 139.8, 139.6, 128.6, 128.4, 128.2, 128.1, 127.9, 126.9, 126.7, 126.6, 104.5, 76.2, 57.7, 56.1 , 53.1, 53.0, 52.5, 51.8, 46.8, 37.1 , 36.1 , 169.6, 153.2, 142.8, 142.3, 142.2, 140.1 , 139.9, and 14.0. Example 6 4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1.2-b]-pyridin-11 -ylidene)-1 -(N- methyl-N-4-{1H-2-methylimidazo[4,5-c]pyridinylmethyl}-phenylsulphonyl-L-leucyl)- piperidine amide. 34 N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethylphenylsulphonyl-L-leucine (215mg, O.δmmol) was converted to the pentafluorophenol derivative using the procedure described for example 1 (a). The pentafluorophenylester was dissolved in DCM (15ml) and treated with 4-(8-chloro-5,6-dihydro-11 H-benzo[5,6]- cyclohepta[1 ,2-b]pyridin-11-ylidene)piperidine (150mg, O.δmmol). The reaction mixture was stirred overnight at room temperature before partitioning between DCM and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulphate and concentrated. The product was purified by column chromatography on silica gel and eluting with 3-5% methanol/DCM. Product containing fractions were combined and solvent removed under reduced pressure to provide 4-(8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1.2-b]-pyridin-11 - ylidene)-1-(N-methyl-N-4-{1H-2-methylimidazo[4,5-c]pyridinylmethyl}- phenylsulphonyl-L-leucyl)-piperidine amide as a white foam (151 mg, 42%). 1H-NMR; δ (CDCI 3 ), 9.01 , 8.98 (1 H, 2s), 8.39-8.34 (2H, m), 7.73-7.65 (2H, m), 7.46- 7.41 (1 H, m), 7.24-7.03 (7H, m), 5.40, 5.36 (2H, 2s), 4.94-4.89 (1 H, m), 4.02-3.70 (2H, m), 3.52-2.94 (3H, m), 2.94-2.69 (2H, m), 2.89, 2.83 (3H, 2s), 2.65-2.04 (4H, m), 2.57, 2.54 (3H, 2s), 1.72-1.36 (2H, m), 1.27-0.96 (2H, m) and 0.88-0.79 (6H, m). 13C-NMR; δ (CDCI 3 ), 168.2, 156.6, 153.2, 146.7, 142.1 , 142.0, 140.1 , 139.8, 139.2, 137.6, 136.1 , 134.9, 133.2, 133.1 , 130.3, 129.0, 126.6, 126.2, 122.3, 104.6, 53.3, 53.1 , 46.8, 46.3, 43.0, 37.2, 31.6, 31.5, 30.3, 24.8, 22.4, 22.2, 21.9 and 13.9. Example 7 4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1.2-b]-pyridin-11 -ylidene)-1 -(N- methyl-N-4-{1 H-2-methylimidazo[4,5-c]pyridinylmethyl}-phenylsulphonyl-L-leucinol)- piperidine carbamate. N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L- leucinol (200mg, 0.48mmol) was stirred in acetonitrile (4ml) at room temperature and treated with N,N'-disuccinimidyl carbonate (185mg, 0.72mmol) and triethylamine (200μl, 1.44mmol). After 4 hours solvent was removed under reduced pressure and the solvent partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated to yield a white foam. A solution of this mixed carbonate in DCM (2ml) was added to a solution of 4-(8-chloro-5,6-dihydro-11 H-benzo[5,6]- cyclohepta[1 ,2-b]pyridin-11-ylidene)piperidine (170mg, 0.57mmol) and triethylamine (100μl, 0.72mmol). The reaction was stirred at room temperatue overnight before diluting with DCM and partitioning with saturated sodium bicarbonate. The organic 36 layer was separated, washed with brine, dried over sodium sulphate, filtered and solvent removed. The crude product was purified by MPLC using a siica gel column and a gradient elution of 6.5-7.5% methanol/DCM in 40 minutes with a flow rate of 70ml/minute. Product contaning fractions were combined and solvent removed to yield 4-(8-chloro-5,6-dihydro-11 H-benzo[5,6]-cyclohepta[1.2-b]-pyridin-11 -ylidene)- 1-(N-methyl-N-4-{1 H-2-methylimidazo[4,5-c]-pyridinylmethyl}-phenylsulphonyl-L- leucinol)-piperidine carbamate as a white foam (304mg,87%). 1H-NMR; δ (CDCI 3 ), 9.04 (1H, s), 8.37 (2H, m), 7.77 (2H, d, J=8.1 Hz), 7.42 (1H, d, J=7.3 Hz), 7.06-7.15 (7H, m), 5.38 (2H, s), 4.20-4.35 (1 H, m), 3.90-4.10 (2H, m), 3.70- 3.90 (2H, m), 3.07-3.47 (4H, m), 2.70-3.06 (2H, m), 2.65 (3H, s), 2.58 (3H, s), 2.25- 2.55 (4H, m), 1.12-1.46 (3H, m) and 0.75-0.85 (6H, bd). 13C-NMR; δ (CDCI3), 167.6, 157.2, 154.8, 153.2, 149.6, 146.7, 142.3, 140.9, 140.3, 140.0, 139.6, 137.8, 137.4, 137.3, 134.4, 133.3, 133.0, 130.5, 129.0, 128.0, 126.8, 126.2, 122.2, 104.6, 64.2, 54.4, 46.9, 45.0, 37.9, 31.8, 31.6, 30.7, 30.5, 28.3, 24.6, 22.9, 22.3 and 13.9. Example 8 (E)-3-(6-[Pyrrolidino-1 -{4-tolyl}prop-1 E-enyl]-2-pyridyl)acrylic acid, N-methyl-N-4- (1H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L-leucyl ester. 37 N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethylphenylsulphonyl-L-leucinol (253mg, 0.61 mmol) was dissolved in DCM (10ml) and treated with N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (140mg, 0.73mmol), (E)-3- (6-[pyrrolidino-1-{4-tolyl}prop-1E-enyl]-2-pyridyl)acrylic acid (acrivastine) (211mg, 0.61 mmol) and dimethylaminopyridine (3mg). The reaction was stirred at room temperature overnight and directly added to a silica gel column for purification. Elution with 5% methanol/DCM and removal of solvent under reduced pressure yielded (E)-3-(6-[pyrrolidino-1-{4-tolyl}prop-1E-enyl]-2-pyridyl)acrylic acid, N-methyl- N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L-leucyl ester as a pale brown foam (199mg, 44%). 1H-NMR; δ (CDCI 3 ), 9.02 (1 H, d, J=0.7Hz), 8.33 (1 H, d, J=5.7Hz), 7.82 (2H, d, J=8.4Hz), 7.59 (1H, d, J=2.8Hz), 7.58 (1H, t, J=3.6Hz), 7.10 (11 H, m), 5.26 (2H, s), 4.38 (1H, m), 4.13 (1H, dd, J=11.9, 7.4Hz), 4.04 (1H, dd, J=11.8, 4.8Hz), 3.26 (2H, d, J=6.8Hz), 2.79 (3H, s), 2.59 (4H, m), 2.50 (3H, s), 2.40 (3H, s), 1.82 (4H, m), 1.51 (1 H, m), 1.36 (1H, m), 1.25 (1 H, m), 0.95 (3H, d, J=2.8Hz) and 0.93 (3H, d, J=2.9Hz). 13C-NMR; δ (CDCI 3 ), 166.3, 158.2, 153.3, 151.6, 144.2, 142.2, 142.1 , 140.4, 140.2, 139.8, 139.6, 137.3, 137.2, 134.8, 129.6, 129.3, 128.1 , 126.8, 123.2, 123.1 , 121.3, 104.6, 64.1 , 54.7, 54.1 , 54.0, 46.7, 38.0, 28.6, 24.4, 23.5, 23.1 , 22.0, 21.2 and 13.9. „ Λ ,„„, PCT/GB95/01878 WO 96/05201 38 Example 9 (4-Benzhydrylpiperazin-1 -yl)-acetic acid, N-methyl-N-4-(1 H-2-methylimidazo[4,5-c]- pyridinylmethyl)-phenylsulphonyl-L-leucyl ester. (a) (4-Benzhydrylpiperazin-1-yl)-acetic acid, methyl ester. Methylbromoacetate (2.75g, 1 βmmol) was added dropwise to a solution of benzhydrylpiperazine (4.5g, 18mmor) in THF (150ml). The reaction was stirred for 30 minutes at room temperature and a white precipitate formed. THF was removed under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate solution and water before drying over magnesium sulphate, filtration and removal of solvent to leave (4-benzhydrylpiperazin-1-yl)- acetic acid, methyl ester as a pale brown oil (2.80g, 48%). 1H-NMR; δ (CDCI 3 ) 7.42 (4H, d), 7.37 (4H, m), 7.18 (2H, m), 4.25 (1H, s), 3.70 (3H, s), 3.24 (2H, s), 2.66 (4H, bs) and 2.48 (4H, bs). (b) (4-Benzhydrylpiperazin-1 -yl)-acetic acid. An aqueous solution of lithium hydroxide (486mg, 11.58mmol, 2ml water) was added to a solution of (4-benzhydrylpiperazin-1-yl)-acetic acid, methyl ester (2.5g, 39 7.72mmol) in a 5:1 mixture of THF/water (20ml). The reaction was stirred at room temperature overnight. THF was removed under reduced pressure. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was separated and neutralised to pH7 with 1 M HCl. A white gelatinous precipitate of (4- benzhydrylpiperazin-1-yl)-acetic acid was formed which was collected by filtration and dried (1.10g, 46%). 1 H-NMR; δ (CDCI 3 ), 7.45 (4H, d, J 7.5Hz), 7.29 (4H, t, J=7.4Hz), 7.21 (2H, m), 4.39 (1H, s), 3.60 (2H, s), 3.33 (4H, bs), 2.67 (4H, bs). (c) (4-Benzhydrylpiperazin-1-yl)-acetic acid, N-methyl-N-4-(1H-2-methylimidazo[4,5- c]-pyridinylmethyl)-phenylsulphonyl-L-leucyl ester. N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L- leucinol (800mg, 1.92mmol), (4-benzhydrylpiperazin-1-yl)-acetic acid (595mg, 1.92mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (368mg, 1.92mmol) and dimethylaminopyridine (235mg, 1.92mmol) were dissolved in DCM (30ml) and allowed to stand at room temperature overnight. The reaction mixture was partitioned between DCM and brine. The organic layer was separated, dried over magnesium sulphate, filtered and solvent removed to leave a white foam. The product was isolated by chromatography on silica-gel using 4% methanol/DCM as θluant. Product containing fractions were combined and solvent removed to provide (4-benzhydrylpiperazin-1-yl)-acetic acid, N-methyl-N-4-(1 H-2-methylimidazo[4,5-c]- pyridinylmethyl)-phenylsulphonyl-L-leucyl ester as a white foam (510mg, 38%). 1H-NMR; δ (CDCI 3 ), 9.04 (1 H, s), 8.38 (1H, d, J=5.5Hz), 7.78 (2H, d, J=8.3Hz), 7.28 (4H, m), 7.45 (4H, d), 7.15 (5H, m), 5.42 (2H, s), 4.27 (1H, m), 4.23 (1H, s), 4.03 (1H, dd, J=11.7 and 8.2Hz), 3.96(1 H, dd, J=11.7 and 4.5Hz), 3.19 (2H, d, J=2.1 Hz), 2.60 (3H, s), 2.59 (4H, bs), 2.59 (3H, s). 2.45 (4H, bs), 1.37 (1H, m), 1.18 (2H, t, J=7.0Hz) and 0.86 (6H, m). 13C-NMR; δ (CDCI 3 ), 170.0, 153.2, 142.3, 142.2, 140.4, 140.2, 139.6, 128.4, 128.1 , 40 127.9, 126.9, 126.7, 104.6, 76.1 , 63.1 , 58.9, 53.7, 53.1 , 51.6, 46.8, 37.6, 28.2, 24.4, 22.9, 22.1 and 14.0. Example 10 N-Methyl-N-(S)-(1 -[4-benzhydrylpiperazin-1 -yl]-methyl-3-methyl-butyl)-N-4-(1 H-2- methylimidazo[4,5c]pyridinylmethyl)-phenylsulphonamide. (a) N-Methyl-N-(S)-(1-methyl-O-methanesulphonate-3-methyl-butyl)-N-4-(1 H-2- methylimidazo[4,5c]-pyridinylmethyl)-phenylsulphonamide. N-Methyl-N-4-(1 H-2-methylimidazo[4,5c]pyridinylmethyl)-phenylsulphonyl-L-leucinol (890mg, 2.1 mmol) was dissolved in THF (30ml) and treated with triethylamine (0.33ml, 2.5mmol) and methane sulphonylchloride. After 30 minutes solvent was removed under reduced pressure and the residue partitioned between DCM and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over sodium sulphate, filtered and solvent removed to leave N- Methyl-N-(S)-(1-methyl-O-methanesulphonate-3-methyl-butyl)-N-4-(1 H-2- methylimidazo[4,5c]-pyridinylmethyl)-phenylsulphonamide as a yellow foam (1.02g, 96%). 1H-NMR; δ (CDCI 3 ), 9.05 (1H, s), 8.40 (1H, d, J 5.7Hz), 7.81 (2H, d, J==8.3Hz), 7.26 (1H, d, J=6.5Hz), 7.16 (2H, d, J 8.2Hz), 5.44 (2H, s), 4.34-4.30 (1H, m ), 4.06-3.98 (2H, m), 2.91 (3H, s), 2.72 (3H, s), 2.64 (3H, s), 1.54-1.50 (1H, m), 1.43-1.34 (1H, m), 1.24-1.18 (1H, m) and 0.91 (6H, t , J=2.6Hz). (b) N-Methyl-N-(S)-(1-[4-benzhydrylpiperazin-1-yl]-methyl-3-methyl-butyl)-N-4-(1H- 2-methylimidazo[4,5c]pyridinylmethyl)-phenylsulphonamide. N-Methyl-N-(S)-(1-methyl-O-methanesulphonate-3-methyl-butyl)-N-4-(1 H-2- methylimidazo[4,5c]-pyridinylmethyl)-phenylsulphonamide (300mg, 0.61 mmol) in THF (20ml) was added to a stirred solution of 1 -benzhydryl-piperazine (306mg, 1.21 mmol) and triethylamine (0.1ml, 0.71 mmol) in THF (30ml). The reaction mixture was heated under reflux for 3 days. Solvent was removed under reduced pressure and the residue partitioned between DCM and water. The organic layer was separated, dried over sodium sulphate and concentrated. Purification by column chromatography on silica gel, eluting with 5% methanol/DCM yielded N-methyl-N- (S)-(1 -[4-benzhydrylpiperazin-1-yl]-methyl-3-methyl-butyl)-N-4-(1 H-2- methylimidazo[4,5c]pyridinylmethyl)-phenylsulphonamide as a white foam (234mg, 59%). 1H-NMR; δ (CDCI 3 ), 9.03 (1 H, s), 8.34 (1 H, d, J=5.5Hz), 7.90-7.29 (2H, m), 7.46-7.32 (4H, m), 7.30-6.99 (9H, m), 5.30 (2H, s), 4.21-4.06 (1H, m), 4.13 (1H, s), 2.55 (3H, s), 2.53 (3H, s), 2.51-2.07 (10H, m), 1.59-1.40 (1 H, m), 1.33-1.20 (2H, m) and 0.82 (6H, d, J=6.6Hz). 13C-NMR; δ (CDCI 3 ), 153.2, 142.5, 142.0, 141.8, 140.6, 140.1 , 139.7, 139.2, 128.3, 128.2, 127.6, 126.7, 126.4, 104.6, 76.1, 60.0, 53.6, 52.3, 51.7, 46.6, 39.7, 27.6, 24.4, 23.1 , 21.7 and 13.8. Example 11 N-Methyl-N-(S)-(1-aminomethyl-[{4-benzrιydrylpiperaLεin-1-yl}-acetamide]-3-methyl- butyl)-N-4-(1 H-2-methylimidazo[4,5c]-pyridinylmethyl)-phenylsulphonamide. 42 (a) N-Methyl-N-(S)-(1 -azidomethyl-3-methyl-butyl)-N-4-(1 H-2-methylimidazo[4,5c]- pyridinylmethyl)-phenylsulphonamide. N-Methyl-N-(S)-(1-methyl-O-methanesulphonate-3-methyl-butyl)-N-4-(1H-2- methylimidazo[4,5c]-pyridinylmethyl)-phenylsulphonamide (850mg, 1.7mmol) was dissolved in DMF (15ml), treated with sodium azide (144mg, 2.2mmol) and heated at 1000C for 6 hours. The reaction mixture was partitioned between diethylether and brine. The organic layer was separated, dried over sodium sulphate, filterd and solvent removed to yield N-methyl-N-(S)-(1-azidomethyl-3-methyl-butyl)-N-4-(1 H-2- methylimidazo[4,5c]-pyridinylmethyl)-phenylsulphonamide as a colourless oil (476mg, 63%). 1H-NMR; δ (CDCI 3 ), 9-02 (1 H, d, J= 2.9Hz), 8.36 (1 H, m), 7.79 (2H, m), 7.14 (3H, m), 5.39 (2H, s), 4.12-4.06 (1 H, m), 3.20-3.16 (2H, m), 2.68 (3H, s), 2.56 (3H, S), 1.51- 1.42 (1 H, m), 1.33-1.25 (1 H, m), 1.19-1.15 (1 H, m), 0.86 (3H, d, J =3.3Hz) and 0.84 (3H, d, J= 3.4Hz. (b) N-Methyl-N-(S)-(1 -aminomethyl-3-methyl-butyl)-N-4-(1 H-2-methylimidazo[4,5c]- pyridinylmethyl)-phenylsulphonamide A solution of N-methyl-N-(S)-(1 -azidomethyl-3-methyl-butyl)-N-4-(1 H-2- methylimidazo[4,5c]-pyridinylmethyl)-phenylsulphonamide (310mg, 0.70mmol) in ethanol (25ml) was treated with palladium on charcoal catalyst (50mg, 10% Pd/C) 43 and stirred under an atmosphere of hydrogen for 90 minutes. The catalyst was removed by filtration and solvent evaporated under reduced pressure to yield N- Methyl-N-(S)-(1 -aminomethyl-3-methyl-butyl)-N-4-(1 H-2-methylimidazo[4,5c]- pyridinylmethyl)-phenylsulρhonamide as a white foam (285mg, 98%). 1H-NMR; δ (CDCI 3 ), 9.04 (1H, s), 8.37 (1 H, d, J=5.6Hz), 7.81 (2H, d, J=8.3Hz), 7.16 (2H, d, J=8.4Hz), 7.13 (1H, d, J=5.9Hz), 5.40 (2H, s), 3.96-3.91 (1H, m), 2.76 (1 H, dd, J=13.7, 4.44Hz), 2.67 (3H, s), 2.64 (1 H, dd, J=13.7, 4.1 Hz), 2.59 (3H, s), 1.32- 1.27 (1H, m), 1.17-1.12 (1H, m), 0.97-0.92 (1H, m), and 0.74 (6H, t, J=6.2Hz). 13C-NMR; δ (CDCI 3 ), 152.5, 142.2, 142.1 , 128.2, 126.8, 104.6, 57.8, 46.4, 42.3, 38.5, 28.0, 24.6, 22.7 and 15.5. (c) N-Methyl-N-(S)-(1 -aminomethyl-[{4-benzhydrylpiperazin-1 -yl}-acetamide]-3- methyl-butyl)-N-4-(1 H-2-methylimidazo[4,5c]-pyridinylmethyl)-phenylsulphonamide. A solution of (4-benzhydrylpiperazin-1-yl)-acetic acid (180mg, 0.58mmol), pentafluorophenol (106mg, 0.58mmol) and N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (111mg, 0.58mmol) in DCM (15ml) was stirred at room temperature for 30 minutes. A solution of N-methyl-N-(S)-(1 -aminomethyl-3- methyl-butyl)-N-4-(1 H-2-methylimidazo[4,5c]-pyridinylmethyl)-phenylsulphonamide (200mg, 0.48mmol) in DCM (5ml) was added to the reaction mixture which was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and 1M sodium carbonate. The organic layer was separated and washed with brine before drying over magnesium sulphate. Filtration and concentration gave a colourless oil. The product was purified by column chromatography on silica-gel eluting with 5% methanol/DCM. Product containing fractions were combined and solvent removed to yield N-methyl-N-(S)-(1-aminomethyl-[{4-benzhydrylpiperazin-1- yl}-acetamide]-3-methyl-butyl)-N-4-(1 H-2-methylimidazo[4,5c]-pyridinylmethyl)- phenylsulphonamide as a white solid (45mg, 13%). 1H-NMR; δ (CDCI 3 ), 9.03 (1H, s), 8.36 (1 H, d, J=5.5Hz), 7.56 (2H, d, J=8.3Hz), 7.56 44 (1H, t, J=7.56Hz), 7.39 (4H, d, J=7.3Hz), 7.26-7.21 (4H, m), 7.15-7.10 (5H, m), 5.36 (2H, s), 4.23 (1H, s), 4.04-4.01 (1H, m), 3.31-3.24 (1H, m), 3.21-3.05 (1H, m), 3.02 (2H, d, J=5.4Hz), 2.63 (3H, s), 2.59 (4H, bm), 2.56 (3H, s), 2.54-2.40 (4H, bm), 1.23-1.18 (1H, m), 1.15-1.09 (1H, m), 0.98-0.92 (1H, m), 0.72 (3H, d, J=3.5Hz), and 0.71 (3H, d, J=3.6Hz). 13 C-NMR; δ (CDCI 3 ), 171.1 , 153.3, 142.7, 142.2, 142.1 , 140.3, 140.2, 139.8, 139.6, 128.4, 128.0, 127.8, 126.9, 126.8, 104.6, 76.0, 61.4, 54.8, 53.9, 51.9, 46.8, 39.6, 38.8, 27.8, 24.6, 22.6, 22.6 and 14.0. Example 12 N-(S)-(4-Methyl-2-{methyl-[4-(1 H-2-methyl-imidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonyl]-amino}-pentyl)-3-[6-(3-pyrrolidin-1-yl-p-tolyl-prop-1 E-enyl)-pyridin- 2-yl] acrylamide. Using a procedure similar to that described for example 11 , N-methyl-N-(S)-(1- aminomethyl-3-methyl-butyl)-N-4-(1H-2-methylimidazo[4,5c]-pyridin-1-ylmethyl)- benzeπesulphoπamide (1.00g, 2.41mmol) was coupled to (E)-3-(6-[pyrrolidino-1-{4- 45 tolyl}prop-1 E-enyl]-2-pyridyl)acrylic acid (0.92g, 2.65mmol) to provide N-(S)-(4- methyl-2-{methyl-[4-(1H-2-methyl-imidazo[4,5-c]pyridin-1-ylmethyl)- benzenesulphonyl]-amino}-pentyl)-3-[6-(3-pyrrolidin-1 -yl-p-tolyl-prop-1E-enyl)- pyridin-2-yl] acrylamide as a pink solid (106mg, 4.5%). iH-NMR; δ (CDCI 3 ), 9.00 (1H, s), 8.33 (1H, d, J=5.5Hz), 7.91 (2H, d, J=8.3Hz), 7.66 (1H, m), 7.50 (3H, m), 7.27 (1H, d, J=7.7Hz), 7.20 (1H, d, J=7.5Hz), 7.16 (3H, d, J=8.3Hz), 7.09 (3H, d, J=7.9Hz), 7.03 (1H, d, J=5.6Hz), 6.83 (1H, d, J=7.7Hz), 5.22 (2H, s), 4.16 (1H, m), 3.61 (2H, d, J=7.0Hz), 3.30 (2H, m), 2.99 (4H, br m), 2.78 (3H, s), 2.49 (3H, s), 2.43 (3H, s), 1.97 (4H, br m), 1.54 (1H, m), 1.29 (2H, m) and 0.87 (6H, t, J=6.2Hz). 13C-NMR; δ (CDCI 3 ), 166.0, 155.8, 153.4, 152.4, 144.8, 142.0, 141.8, 140.3, 140.2, 139.7, 139.4, 138.2, 137.6, 137.5, 137.4, 133.2, 129.6, 129.6, 129.3, 128.2, 127.0, 124.1, 122.4, 104.8, 55.1 , 54.4, 54.2, 53.7, 53.6, 46.8, 40.6, 39.0, 28.0, 24.5, 23.3 and 13.9. Example 13 2-[4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11-ylidene)- piperidin-1 -yl]-N-(4-methyl-2-{methyl-[4-(1 H-2-methylimidazo[4,5-c]pyridin-1 - ylmethyl)-phenylsulphonyl]-amino}-pentyl)-acetamide. 46 (a) Methyl-[4-{8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 - ylidene}-piperidin1 -yljacetate Methylbromoacetate (0.17ml, 1.77mmol) was added dropwise to a solution of 4-{8- chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -ylidene}-piperidine (0.50g, 1.61 mmol) and triethylamine (0.45ml, 3.22mmol) in THF (15ml) under an inert atmosphere. The reaction was left to stir for 18 hours. THF was removed under reduced pressure and the product purified by column chromatography on silica gel, eluting with 5% methanol/DCM. Product containing fractions were combined and solvent removed under reduced pressure to yield methyl-[4-{8-chloro-5,6-dihydro- 11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -ylidene}-piperidin-1 -yljacetate as an orange solid (550mg, 90%). 1H-NMR; δ (CDCI 3 ), 8.40 (1 H, m), 7.42 (1 H, m), 7.09 (4H, m), 3.71 (3H, s), 3.37 (2H, m), 3.24 (2H, s), 2.79 (4H, m), 2.57 (1H, m), 2.47 (1H, m), and 2.37 (4H, m). 13C-NMR; δ (CDCI 3 ), 170.9, 157.5, 146.6. 139.5, 138.1 , 137.7, 137.2, 133.4, 133.0, 132.7, 130.8, 128.9, 126.0, 122.1 , 59.3, 54.6, 51.7, 31.8, 31.4, 30.8 and 30.5. (b) 4-{8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyrid-11 -ylidene}- piperidin-1 -ylacetic acid Using the procedure described for example 9(b), methyl-[4-{8-chloro-5,6-dihydro- 11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -ylidene}-piperidin-1 -yljacetate (460mg, 1.19mmol) was hydrolysed to provide 4-{8-chloro-5,6-dihydro-11 H-benzo[5,6]- cyclohepta-[1 ,2-b]-pyridin-11-ylidene}piperidin-1-ylacetic acid as a yellow glass (440mg, 99%). 1H-NMR; δ (MeOD), 8.31 (1 H, d, J=4.9Hz), 7.65 (1 H, d, J=7.7Hz), 7.2 (4H, m), 3.41 (2H, m), 3.31 (2H, s), 3.05 (2H, s), 2.86 (2H, m), 2.55 (4H, m), 2.46 (1H, m) and 2.31 (1H, m). 47 1 3C-NMR; δ (MeOD), 158.4, 147.0, 141.2, 139.5, 138.4, 138.0, 135.9, 134.2, 131.7, 130.3, 127.0, 124.1 , 62.3, 55.2, 55.2, 32.6, 32.0, 30.6 and 30.5. (c) 2-[4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -ylidene)- piperidin-1-yl]-N-(4-methyl-2-{methyl-[4-(1H-2-methylimidazo[4,5-c]pyridin-1- ylmethyl)-phenylsulphonyl]-amino}-pentyl)-acetamide. Using a procedure similar to that described for example 11 (c), 4-(8-chloro-5,6- dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-]pyridin-11 -ylidene}piperidin-1 -ylacetic acid (445mg, 1.19mmol) was coupled to N-methyl-N-(S)-(1-aminomethyl-3-methyl-butyl)- N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonamide (459mg, 108mmol) to provide 2-[4-(8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2- b]pyridin-11 -ylidene)-piperidin-1 -yl]-N-(4-methyl-2-{methyl-[4-(1 H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonyl]-amino}-pentyl)-acetamide as an off white solid (264mg, 32%). 1H-NMR; δ (CDCI 3 ), 8.98 (1H, s), 8.31 (2H, m), 7.70 (2H, d, J=8.3Hz), 7.66 (1H, dd, J=10.2, 5.0Hz), 7.35 (1 H, d, J=7.1Hz), 7.05 (7H, m), 5.33 (2H, s), 4.00 (1H, m), 3.25 (4H, m), 2.94 (2H, m), 2.74 (4H, m), 2.60 (3H, d, J=1.1Hz), 2.53 (3H, s), 2.52 (1H, m), 2.43 (1H, m), 2.28 (4H, m), 1.12 (2H, m), 0.88 (1H, m) and 0.66 (6H, m). 13C-NMR; δ (CDCI 3 ), 171.3, 171.2, 157.5, 153.2, 146.6, 142.2, 142.1 , 140.4, 140.3, 140.1 , 139.8, 139.6, 139.5, 138.1 , 138.0, 137.7, 137.3, 133.4, 132.9, 132.6, 130.8, 128.9, 128.0, 126.8, 126.0, 122.1 , 104.6, 61.3, 55.5, 55.4, 54.9, 54.7, 46.8, 39.7, 39.6, 38.9, 38.9, 31.8, 31.4, 30.9, 30.8, 27.8 and 22.6. Example 14 N-[1 -{(4-Chlorobenzhydryl)-piperazin-1 -ylmethyl}-3-methyl-butyl]-N-methyl-4-(1 H-2- 48 methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide. Following the procedure described for example 10, N-methyl-N-(S)-(1-methyl-0- methanesulphonate-3-methyl-butyl)-N-4-(1 H-2-methylimidazo[4,5c]-pyridinylmethyl)- phenylsulphonamide (300mg, 0.61 mmol) was reacted with 4- chlorobenzhydrylpiperazine (350mg, 1.22mmol) to provide N-[1-{(4- chlorobenzhydryl)-piperazin-1-ylmethyl}-3-methyl-butyl]-N-methyl-4-(1 H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide as a white solid (39mg, 9%). 1H-NMR; δ (CDCI 3 ), 9.08 (1 H, s), 8.41 (1H, dd, J=1.3, 5.6Hz), 7.91 (2H, dd, J=1.2, 8.4Hz), 7.36-7.08 (12H, m), 5.40 (2H, s), 4.16 (2H, m), 2.61 (3H, s), 2.58 (3H, s), 2.42 (8H, brs), 2.23 (1H, m), 2.15 (1H, m), 1.50 (1H, m), 1.25 (2H, m), and 0.86 (6H, m). 13C-NMR; δ (CDCI 3 ), 153.3, 142.2, 140.9, 140.2, 139.9, 139.2, 132.5, 129.2, 128.6, 128.5, 127.8, 127.2, 126.5, 104.6, 75.5, 60.1 , 53.6, 52.2, 51.7, 46.8, 39.6, 27.7, 24.5, 23.3, 21.8 and 14.0. Example 15 N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine- 2-(4-{8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 - ylidene}piperidin-1 -yl)-ethyl ester. (a) Ethyl-(4-{8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]-pyridin-11 - ylidenejpiperidinl -yljacetate 2-Bromoethyl acetate (267mg, 1.6mmol) was added dropwise to a stirred solution of 4-{8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 - ylidenejpiperidine (500mg, 1.6mmol) in THF (12ml) and the reaction stirred at room temperature overnight. THF was removed under reduced pressure and the residue partitioned between ethylacetate and saturated sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulphate, filtered and solvent removed to leave a white solid. The product was purified by column chromatography on silica gel eluting with 5% methanol/DCM. Product containing fractions were combined and solvent removed to yield ethyl-(4-{8-chloro-5,6-dihydro-11H- benzo[5,6]cyclohepta[1 ,2-b]pyridin-11-ylidene}piperidin-1-yl)acetate as a white solid (214mg, 34%) 1H-NMR; δ (CDCI 3 ), 8.40 (1H, dd, J=4.6, 1.3Hz), 7.43 (1H, dd, J=7.6, 1.6Hz), 7.15- 7.07 (4H, m), 4.23-4.15 (2H, m), 3.44-3.33 (2H, m), 2.87-2.76 (4H, m), 2.63 (2H, t, J=6.0Hz), 2.56-2.18 (6H, m), 2.05 (3H, s). (b) 4-{8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 - ylidene}piperidin-1 -yl-ethanol An aqueous solution of potassium carbonate (299mg, 2.16mmol, 5ml water) was added to a solution of ethyl-(4-{8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta-[1 ,2- b]pyridin-11-ylidene}piperidin-1-yl)acetate (214mg, 0.54mmol) in methanol (20ml). The reaction was stirred at room temperature for 24 hours followed by 3 hours at 800C. Methanol was removed under reduced pressure and the residue partitioned between DCM and brine. The crude product was purified by chromatography on silica gel using a gradient elution of 5% methanol in DCM. Product containing fractions were combined and solvent evaporated to leave 4-{8-chloro-5,6-dihydro- 11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11-ylidene}-piperidin-1 -yl-ethanol as a white solid (136mg, 71%). 1H-NMR; δ (CDCI 3 ), 8.40 (1H, dd, J=4.9, 1.5Hz), 7.44 (1 H, dd, J=7.7, 1.2Hz), 7.16- 7.09 (4H, m), 3.65 (2H, t, J=5.2Hz), 3.44-3.33 (2H, m), 2.88-2.80 (4H, m), 2.61-2.54 (3H, m), 2.54-2.37 (5H, m). (c) N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L- leucine-2-(4-{8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11- ylidene}piperidin-1 -yl)-ethyl ester. Following a procedure similar to that described for example 3(b), N-methyl-N-4-(1 H- 2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L-leucine (198mg, 0.46mmol) was coupled to 4-{8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2- b]pyridin-11 -ylidene}-piperidin-1 -yl-ethanol (135mg, 0.38mmol) to yield N-methyl-N- 4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine-2-(4-{8- chloro-5,6-dihydro-11 H-benzo[5,6-cyclohepta[1 ,2-b]pyridin-11 -ylidene}piperidin-1 - yl)-ethyl ester as a white solid (32mg, 11%). 1H-NMR; δ (CDCI 3 ), 9.02 (1H, s), 8.39-8.35 (2H, m), 7.76 (2H, d, J=8.4Hz), 7.43 (1 H, m), 7.15-7.08 (7H, m), 5.38 (2H, d, J=2.8Hz), 4.65-4.62 (1 H, m), 3.97-3.87 (2H, m), 3.43-3.32 (2H, m), 2.87-2.76 (1 H, m), 2.83 (3H, s), 2.68-2.64 (2H, m), 2.58 (3H, s), 2.48-2.26 (7H, m), 2.17-2.05 (2H, m), 1.64-1.55 (3H, m) and 0.93 (6H, d, J=4.6Hz). 13 C-NMR; δ (CDCI 3 ), 170.8, 157.3, 153.3, 146.6, 142.2, 142.1 , 140.2, 139.8, 139.6, 139.5, 139.4, 137.9, 137.7, 137.4, 133.4, 133.0, 132.7, 130.7, 128.9, 128.3, 126.6, 126.0, 122.2, 104.7, 62.0, 57.2, 56.1, 55.0, 54.9, 54.8, 46.9, 38.1 , 31.7, 31.4, 30.8, 30.6, 29.8, 29.7, 24.4 and 14.0. Example 16 N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L- leucine-(R,S)-5-(4-benzhydrylpiperazin-1 yl)-2-pentyl ester. (a) 5-(4-Benzhydrylpiperazin-1-yl)-2-pentanone ethylene ketal A solution of 5,chloro-2-pentanone (2.00g,12.2mmol), benzhydrylpiperazine (3.70g, 14.6mmol), sodium iodide (10mg) and potassium carbonate (3.36g, 24.3mmol) in acetone (40ml) was heated under reflux for 18 hours. Acetone was removed under reduced pressure. Dichloromethane was added to the residue and the undissolved inorganic salts removed by filtration. The product was purified by column chromatography on silica gel eluting with 4% methanol/DCM. Product containing fractions were combined and solvent removed to yield 5-(4-benzhydrylpiperazin-1- yl)-2-pentanone ethylene ketal as a colourless oil (1.54g, 33%). 1 H-NMR; δ (CDCI 3 ), 7.41 (4H, d, J=7.5Hz), 7.27-7.25 (4H, m), 7.19-7.16 (2H, m), 4.23 (1H, s), 3.96-3.89 (4H, m), 2.67-2.40 (10H, m), 1.91-1.78 (4H, m), 1.31 (3H, s). (b) 5-(4-Benzhydrylpiperazin-1 -yl)-2-pentanone A solution of 5-(4-benzhydrylpiperazin-1-yl)-2-pentanone ethylene ketal (1.10g, 2.9mmol) in THF (25ml) was treated with concentrated hydrochloric acid (2ml) and stirred at room temperature overnight. The reaction mixture was evaporated to dryness before partitioning between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated to yield 5-(4-benzhydrylpiperazin-1-yl)-2-pentanone as a colourless oil (716mg, 80%). 1 H-NMR; δ (CDCI 3 ), 7.41 (4H, J=7.4Hz), 7.28-7.24 (4H, m), 7.19-7.16 (2H, m), 4.20 (1H, m), 2.56-2.34 (10H, m), 2.32 (2H, t, J=7.2Hz), 2.14 (3H, s), 1.78-1.72 (2H, m). (c) (RS)-5-(4-Benzhydrylpiperazin-1 -yl)-2-pentanol Lithium aluminium hydride (97mg, 2.56mmol) was taken up in dry THF (15ml) and stirred under an inert atmosphere at -780C. 5-(4-Benzhydrylpiperazin-1-yl)-2- pentanone (717mg, 2.13mmol) as a solution in THF (35ml) was added dropwise. The reaction was stirred at -78°C for 15 minutes before allowing to warm to room temperature. After a total reaction time of 30 minutes the reaction was quenched with a 15% aqueous solution of sodium hydroxide (25ml). The reaction mixture was filtered through Kieselguhr gel and partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulphate, filtered and solvent removed under reduced pressure to yield (RS)-5-(4-benzhydrylpiperazin-1-yl)-2- pentanol as a white powder (686mg, 95%). 1H-NMR; δ (CDCI 3 ), 7.40 (4H, d, J=7.9Hz), 7.27-7.24 (4H, m), 7.18-7.15 (2H, m), 4.20 (1H, s), 3.69-3.66 (1H, m), 2.80-2.20 (10H, m), 1.81-1.55 (4H, m), 1.15 (3H, d, J=6.1 Hz). (d) N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L- leucine-(R,S)-5-(4-benzhydrylpiperazin-1 yl)-2-pentyl ester. Following a procedure similar to that described for example 3(b) N-methyl-N-4-(1 H- 2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine (1.05g, 2.44mmol) was coupled to (RS)-5-(4-benzhydrylpiperazin-1-yl)-2-pentanol (0.69g, 2.03mmol) to yield N-methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl) phenylsulphonyl-L- leucine-(R,S)-5-(4-benzhydrylpiperazin-1yl)-2-pentyl ester as a white solid (612mg, 40%). 1H-NMR; δ (CDCI 3 ), 9.05 (1H, d, J=4.7Hz), 8.38 (1H, m), 7.77 (2H, m), 7.40 (3H, d, J=7.6Hz), 7.26 (4H, m), 7.18-7.12 (6H, m), 5.44-5.23 (2H, m), 4.68-4.58 (2H, m), 3.40 (1H, s), 2.82 (3H, m), 2.59 (3H, m), 2.49-2.13 (5H, m), 1.92-1.52 (8H, m), 1.42-1.14 (4H, m), 1.01-0.96 (3H, m), and 0.95-0.92 (6H, m). 13C-NMR; δ (CDCI 3 ), 170.6, 142.6, 142.2, 142.1 , 139.8, 139.6, 128.4, 128.3, 127.9, 126.9, 126.7, 126.6, 104.6, 76.2, 72.0, 71.9, 58.1 , 57.3, 57.1 , 53.4, 51.8, 46.9, 38.1 , 38.0, 33.4, 29.8, 24.4, 21.0, 19.7, 19.6 and 14.0. Example 17 4-Methyl-2-{methyl-[4-(2-methyl-imidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonyl]- amino}-pentanoic acid-(E)-3-(6-[3-pyrrolidino-1 -{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)- prop-2-en-1-yl ester. 54 (a) Methyl-(E)-3-(6-[3-pyrrolidin-1 -yl-{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)-acrylate A solution of (E)-3-(6-[3-pyrrolidin-1-yl-{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)-acrylic acid (2.04g, 5.9mmol) in methanol (50ml) was treated with concentrated hydrochloric acid (10ml) and stirred at room temperature for 6 days. The reaction was neutralised with sodium hydrogen carbonate and solvent removed under reduced pressure. DCM was added to the filtrate and inorganic solids removed by filtration. Concentration of the filtrate under reduced pressure yielded methyl-(E)-3-(6-[3- pyrrolidin-1-yl-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-acrylate as a pink foam (1.98g, 93%). 1 H-NMR; δ (CDCI 3 ), 7.70 (1 H, d, J=15.7Hz), 7.57 (1 H, t, J=7.7Hz), 7.30 (1 H, t, J=7.6Hz), 7.25 (2H, d, J=8.3Hz), 7.17 (1H, d, J=7.2Hz), 7.10 (2H, dt, J=8.2, 1.8Hz), 6.96 (1 H, d, J=15.6Hz), 6.93 (1 H, d, J=7.9Hz), 3.83 (3H, s), 3.65 (2H, brs), 2.85 (4H, brm), 2.41 (3H, s), 2.04 (4H, brm). (b) (E)-3-(6-[3-Pyrrolidino-1 -{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)-prop-2-en-1 -ol A solution of methyl-(E)-3-(6-[3-pyrrolidin-1-yl-{4-tolyl}-prop-1 E-enyl]-pyridin-2- yl)acrylate (1.98g, 5.47mmol) in dry THF (100ml) was cooled to -78°C and treated under an inert atmosphere with a solution of DIBAL (1M in toluene, 16.4ml, 16.4mmol). After stirring for 3 hours at -78<*>C more DIBAL was added (11ml, 11 mmol) and the reaction allowed to warm to room temperature. Following a total reaction time of 24 hours the reaction was quenched with water (0.5ml). The reaction mixture was partitioned between DCM and water. The aqueous layer was separated, acidified (20ml, 1M HCl) and extracted with DCM. The organic extracts were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure to yield (E)-3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2- yl)-prop-2-en-1-ol as an off white solid (1.69g, 93%). 1H-NMR; δ (CDCI 3 ), 7.40 (1 H, t, J=7.9Hz), 7.19 (2H, d, J=7.8Hz), 7.16 (1 H, t, J=7.3Hz), 7.08 (1H, d, J=7.7Hz), 7.01 (2H, d, J=7.9Hz), 6.96 (1 H, dt, J=15.7, 5.0Hz), 6.69 (1 H, d, J=15.7Hz), 6.66 (1 H, d, J=7.8Hz), 4.36 (2H, dd, J=5.0, 1.4Hz), 3.58 (2H, d, J=7.2Hz), 3.04 (4H, br s), 2.36 (3H, s) and 1.96 (4H, br s). 13C-NMR; δ (CDCI 3 ), 155.8, 154.7, 146.6, 137.9, 136.9, 134.8, 133.8, 129.5, 129.4, 129.3, 129.1 , 121.1 , 120.8, 62.6, 53.0, 52.8, 29.6, 23.4, 23.4 and 21.2. (c) 4-Methyl-2-{methyl-[4-(2-methyl-imidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonylj-aminoj-pentanoic acid-(E)-3-(6-[3-pyrrolidino-1 -{4-tolyl}-prop-1 E- enyl]-pyridin-2-yl)-prop-2-en-1 -yl ester. Following a procedure similar to that described for example 3(b), N-methyl-N-4-(1H- 2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine (300mg, 0.70mmol) was coupled to (E)-3-(6-[3-pyrrolidino-1 -{4-tolyl}-prop-1E-enyl]-pyridin-2- yl)-prop-2-en-1-ol (194mg, 0.58mmol) to yield 4-methyl-2-{methyl-[4-(2-methyl- imidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonyl]-amino}-pentanoic acid-(E)-3-(6- [3-pyrrolidino-1-{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)-prop-2-en-1-yl ester as a pink foam (108mg, 25%). 1H-NMR; δ (CDCI 3 ), 8.98 (1H, s), 8.31 (1H, d, J=5.2Hz), 7.75 (2H, d, J=8.3Hz), 7.51 (1H, t, J=7.8Hz), 7.24 (3H, m), 7.14 (4H, m), 7.04 (2H, d, J=7.9Hz), 6.79 (1 H, d, J=7.8Hz), 6.72-6.68 (1H, dt, J=15.8, 5.7Hz), 6.54 (1H, d, J=15.8Hz), 5.40 (2H, d, J=2.3Hz), 4.71 (1H, t, J=9.5Hz), 4.47 (2H, m), 3.68 (2H, d, J=7.2Hz), 2.92 (4H, m), 2.85 (3H, s), 2.55 (3H, s), 2.39 (3H, s), 2.01 (4H, m), 1.65 (3H, m) and 0.96 (6H, m). 13C-NMR; (CDCI 3 ), 170.5, 155.8, 153.7, 153.6, 140.3, 140.0, 139.8, 139.1 , 138.3, 137.2, 133.3, 132.7, 129.7, 129.2, 128.2, 127.5, 126.8, 121.8, 121.1 , 104.8, 64.4, 57.3, 53.2, 52.8, 46.9, 38.1 , 29.9, 24.4, 23.3, 23.0, 21.2 and 14.0. Example 18 N-(1 -{2-[4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -ylidene)- piperidin-1 -yl]-2-oxo-ethoxymethyl}-3-methyl-butyl)-N-methyl-4-(1H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide. (a) (4-Methyl-2-{methyl-[4-(1 H-2-methyl-imidazo[4,5-c]pyridin-1 -ylmethyl)- phenylsulphonyl]-amino}-pentyloxy)-acetic acid tert-butyl ester. A solution of N-methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)- phenylsulphonyl-L-leucinol (2.00g, 4.80mmol) in dry DMF (30ml) was treated with sodium hydride (127mg, 5.28mmol, 60% dispersion in oil) under an inert atmosphere and stirred for 30 minutes at room temperature. The reaction mixture was cooled to QOC and ferf-butylbromoacetate (775μl, 4.48mmol) added. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. Solvent was removed under reduced pressure and the residue resuspended in DCM before washing with saturated sodium bicarbonate solution and brine. The organic solution was dried over sodium sulphate, filtered and concentrated to leave a red oil. The product was purified by chromatography on silica gel eluting with 4-6% methanol/DCM. Product containing fractions were combined and solvent removed to yield (4-methyl-2-{methyl-[4-(1H-2-methyl-imidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonyl]-amino}-pentyloxy)-acetic acid tert-butyl ester as an orange foam (480mg, 19%). 1H-NMR; δ (CDCI 3 ), 9.04 (1 H, s), 8.38 (1H, d, J=5.6Hz), 7.85 (2H, d, J=8.3Hz), 7.14 (1 H, d, J=5.6Hz), 7.12 (2H, d, J=8.3Hz), 5.40 (2H, s), 4.22-4.19 (1 H, m). 3.69 (2H, m), 3.46-3.36 (2H, m), 2.74 (3H, s), 2.59 (3H, s), 1.56-1.45 (1H, m), 1.43 (9H, s), 1.38- 1.19 (2H, m), 0.89 (3H, d, J=5.1Hz), 0.88 (3H, d, J=5.3Hz). (b) N-(1 -{2-[4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -ylidene)- piperidin-1-yl]-2-oxo-ethoxymethyl}-3-methyl-butyl)-N-methyl-4-(1H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide. A solution of (4-methyl-2-{methyl-[4-(1 H-2-methyl-imidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonyl]-amino}-pentyloxy)-acetic acid tert-butyl ester (325mg, 0.61 mmol) in DCM (8ml) was cooled to O°C and treated with trif luoroacetic acid (2ml). The reaction was stored at 5°C for 18 hours before concentrating under reduced pressure. The resulting white foam was coupled to 4-(8-chloro-5,6-dihydro-11H- benzo[5,6]cyclohepta[1 ,2-b]pyrid-11 -ylidene)piperidine (208mg, 0.67mmol) using a procedure similar to that described for example 6 to yield N-(1-{2-[4-(8-chloro-5,6- dihydro-benzo[5,6]-cyclohepta[1 ,2-b]pyridin-11 -ylidene)-piperidin-1 -yl]-2-oxo- ethoxymethyl}-3-methyl-butyl)-N-methyl-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 - ylmethyl}-phenylsulphonamide as a white foam (214mg, 42%). 1H-NMR; δ (CDCI 3 ), 9.01 (1H, d, J=8.0Hz), 8.38 (2H, m), 7.81 (2H, m), 7.45 (1H, d, J=7.7Hz), 7.18-7.08 (7H, m), 5.38 (2H, s), 4.18 (1H, t, J=3.3Hz), 4.04-3.89 (3H, m), 3.55 (1 H, m), 3.45-3.32 (4H, m), 3.16-3.05 (2H, m), 2.90-2.78 (2H, m), 2.70 (3H, s), 2.58 (3H, s), 2.47 (1H, m), 2.33 (3H, m), 1.48 (1H, m), 1.31-1.17 (2H, m), and 0.86 (6H, m). 13C-NMR; δ (CDCI 3 ), 167.0, 156.7, 153.3, 146.7, 142.2, 140.5, 140.2, 139.8, 139.5, 139.3, 137.7, 137.5, 137.4, 136.3, 134.9, 133.4, 133.1 , 130.3, 129.0, 128.3, 126.5, 126.3, 122.4, 104.7, 71.9, 70.0, 54.6, 46.8, 45.6, 42.9, 37.7, 31.6, 31.2, 31.0, 30.4, 30.2, 28.6, 24.4, 23.1, 22.0, 14.0. Example 19 (S)-N-{1-[2-(4-Benzhydryl-piperazin-1 -yl)-ethoxymethyl]-3-methyl-butyl}-methyl-4- (1 H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide. (a) N-[1 -(2-Hydroxy-ethoxymethyl)-butyl]-N-methyl-4-(1 H-2-methyl-imidazo[4,5- c]pyridin-1 -ylmethyl)-phenylsulphonamide Lithium aluminium hydride was taken up in dry THF (25ml), cooled to -78<>C and treated under an inert atmosphere with a solution of tert-butyl-[N-methyl-N-4-(1 H-2- methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L-leucinol-O-acetate (1.00g, 1.88mmol) in THF (10ml). The reaction mixture was stirred at -780C for 15 minutes before warming to ambient temperature. After a total reaction time of 40 minutes the reaction was cooled to -780C and quenched with sodium hydroxide solution (5ml, 15%). The reaction mixture was filtered through Kieselguhr gel and partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulphate, filtered and solvent removed to yield N-[1-(2-hydroxy- ethoxymethyl)-butyl]-N-methyl-4-(1 H-2-methyl-imidazo[4,5-c]pyridin-1 -ylmethyl)- phenylsulphonamide as a yellow oil (838mg, 97%). 1 H-NMR; δ (CDCI 3 ), 9.03 (1 H, s), 8.38 (1H, d, J=5.6Hz), 7.81 (2H, d, J=8.5Hz), 7.18 (1 H, d, J=5.9Hz), 7.13 (2H, d, J=8.2Hz), 5.40 (2H, s), 4.31-4.28 (1 H, m), 3.57-3.27 (6H, m), 2.61 (3H, s), 2.60 (3H, s), 1.55-1.51 (1 H, m), 1.35-1.28 (1 H, m), 1.15-1.11 (1 H, m), 0.92 (3H, d, J=6.6Hz), 0.89 (3H, d, J=6.6Hz). (b) Methanesulphonic acid 2-(4-methyl-2-{methyl-imidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonyl]-amino}-pentyloxy)ethyl ester. A solution of N-[1-(2-hydroxy-ethoxymethyl)-butyl]-N-methyl-4-(1 H-2-methyl- imidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide (830mg, 1.80mmol) in DCM (15ml), stirred under an inert atmosphere at 00C, was treated with triethylamine (264mg, 3.6mmol) and methane sulphonylchloride (309mg, 2.7mmol). The reaction was allowed to warm to room temperature and stirred for 18 hours before partitioning between DCM and 1M HCl. The organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to yield methanesulphonic acid 2-(4-methyl-2-{methyl-imidazo[4,5-c]pyridin-1- ylmethyl)-phenylsulphonyl]-amino}-pentyloxy)ethyl ester as a yellow oil (882mg, 91%). 1H-NMR; δ (CDCI 3 ), 9.01 (1H, s), 8.47 (1H, d, J=6.4Hz), 7.90 (1H, d, J=6.4Hz), 7.81 (2H, d, J=8.3Hz), 7.21 (2H, d, J=8.4Hz), 5.67 (2H, s), 4.25-4.17 (1H, m), 4.09 (2H, t, J=4.4Hz), 3.57-3.53 (1 H, m), 3.48-3.42 (1 H, m), 3.31 (2H,d, J=6.7Hz), 3.02 (3H, s), 2.71 (3H, s), 2.66 (3H, s), 1.62-1.58 (1 H, m), 1.38-1.32 (1 H, m), 1.18-1.10 (1H, m), 0.92 (3H, d, J=6.6Hz), 0.90 (3H, d, J=6.8Hz). (c) (S)-N-{1 -[2-(4-Benzhydryl-piperazin-1 -yl)-ethoxymethyl]-3-methyl-butyl}-methyl-4- (1H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide A solution of methanesulphonic acid 2-(4-methyl-2-{methyl-imidazo[4,5-c]pyridin-1 - ylmethyl)-phenylsulphonyl]-amino}-pentyloxy)ethyl ester (440mg, 0.82mmol), benzhydrylpiperazine (414mg, 1.64mmol), triethylamine (100mg, 0.98mmol) and sodium iodide (20mg) in THF (30ml) was heated under reflux for 96 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between DCM and water. The organic layer was separated, dried over sodium sulphate, filtered and concentrated to leave a yellow gum. The product was purified by column chromatography on silica gel eluting with 5% methanol/DCM. Product containing fractions were combined and solvent removed to yield (S)-N-{1- [2-(4-Benzhydryl-piperazin-1-yl)-ethoxymethyl]-3-methyl-butyl}-methyl-4-(1H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide as a yellow glass (188mg, 33%). 1H-NMR; δ (CDCI 3 ), 9.04 (1H, s), 8.38 (1 H, d, J=5.7Hz), 7.80 (2H, m), 7.41 (4H, m), 7.29-7.25 (4H, m), 7.19-7.10 (5H, m), 5.37 (2H, s), 4.20 (1H, s), 4.13 (1H, m), 3.43- 3.32 (2H, m), 3.31-3.27 (2H, m), 2.68 (3H, s), 2.58 (3H, s), 2.43 (1 OH, brs), 1.48 (1 H, m), 1.29-1.17 (2H, m), and 0.85 (6H, m). 13C-NMR; δ (CDCI 3 ), 142.6, 142.2, 142.2, 140.6, 140.2, 139.8, 139.2, 128.5, 128.4, 127.9, 126.9, 126.4, 104.6, 76.2, 71.6, 68.7, 57.4, 54.6, 53.8, 51.7, 46.8, 37.8, 24.4, 23.1 , 22.1 and 14.0. Examples 20-25 were synthesised using (S)-(1-ethoxymethyl-3-methylbutyl)-4-(1 H- 2-methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide, the synthesis of which is described in international patent application WO 92/03422. Example 20 N-{2-[4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -ylidene)- piperidin-1 -yl]-2-oxo-ethyl}-N-(S)-(1 -ethoxymethyl-3-methylbutyl)-4-(1 H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide. (a) {(S)-(1 -Ethoxymethyl-3-methylbutyl)-[4-(1 H-2-methylimidazo[4,5-c]pyridin-1 - ylmethyl)-phenylsulphonyl]-amino}-acetic acid tert butyl ester. A solution of (S)-(1-ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5- c]pyridin-1 -ylmethyl)-phenylsulphonamide (5.00g, 11.61 mmol) in anhydrous DMF (50ml) under an inert atmosphere was treated with sodium hydride (557mg, 60% in oil, 13.93mmol) and stirred at room temperature for 30 minutes. The reaction mixture was cooled in an ice-water bath and tett-butylbromoacetate added. After warming to room temperature the reaction was stirred for 18 hours. DMF was removed under reduced pressure. The residue was resuspended in DCM and washed with saturated aqueous sodium bicarbonate and brine, before drying over magnesium sulphate, filtration and concentration to a red oil. The product was purified by column chromatography on silica gel eluting with 4-5% methanol/DCM. Product containing fractions were combined and solvent removed to yield {(S)-(1-ethoxymethyl-3- methylbutyl)-[4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonyl]- amino}-acetic acid tert butyl ester as an orange foam (4.95g, 78%). 1H-NMR; δ (CDCI 3 ), 9.03 (1 H, s), 8.37 (1H, d, J=5.5Hz), 7.91 (2H, d, J=8.3Hz), 7.13 (3H, m), 5.38 (2H, s), 3.97 (2H, d, J=3.9Hz), 3.70 (1H, m), 3.40 (1H, dd, J=3.9, 9.8Hz), 3.33 (1 H, dd, J=4.7, 9.8Hz), 3.31-3.22 (2H, m), 2.58 (3H, s), 1.49-1.45 (1 H, m), 1.43 (9H, s), 1.42-1.38 (1 H, m), 1.23-1.18 (1H, m), 1.01 (3H, t, J=7.0Hz), 0.93 (3H, d, J=6.5Hz) and 0.69 (3H, d, J=6.4Hz). 13C-NMR; δ (CDCI 3 ), 169.0, 153.3, 142.1 , 140.8, 140.2, 139.8, 139.5, 128.9, 126.4, 104.7, 81.5, 71.5, 66.4, 55.2, 46.9, 45.8, 38.4, 27.9, 24.2, 22.5, 22.4, 14.9 and 14.0. (b) N-{2-[4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 - ylidene)-piperidin-1 -yl]-2-oxo-ethyl}-N-(S)-(1 -ethoxymethyl-3-methylbutyl)-4-(1 H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide. {(S)-(1 -Ethoxymethyl-3-methylbutyl)-[4-(1 H-2-methylimidazo [4,5-c]pyridin-1 - ylmethyl)-phenylsulphonyl]-amino}-acetic acid tert butyl ester (500mg, 0.92mmol) was taken up in DCM (8ml), cooled to O ' C and treated with trifluoroacetic acid (2ml). The reaction was stored at O ' C for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue azeotroped with DCM. The resulting carboxylic acid was taken up in a mixture of DCM/DMF (20ml/2ml), cooled to O ' C and treated with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (230mg, 1.20mmol), N-methylmorpholine (303μl, 2.76mmol) and pentafluorophenol (221 mg, 1.20mmol). The resulting solution was allowed to stir at room temperature for 4 hours before the addition of 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta[1 ,2- b]pyridin-11-ylidene)piperidine (286mg, 0.92mmol). The reaction was stirred at room temperature for 150 hours. Solvent was removed under reduced pressure. The residue was taken up in DCM and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulphate, filtered and evaporated. The product was purified by column chromatography on silica gel, eluting with 4-5% methanol/DCM. Product containing fractions were combined and solvent removed to yield N-{2-[4-(8-chloro-5,6-dihydro-1 1H- benzo[5,6]cyclohepta[1 ,2-b]pyridin-11-ylidene)-piperidin-1 -yl]-2-oxo-ethyl}-N-(S)-(1 - ethoxymethyl-3-methylbutyl)-4-( 1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)- phenylsulphonamide as a white foam (267mg, 37%). O 96/05201 63 1H-NMR; δ (CDCI 3 ), 9.04 (1H, s), 8.40 (1H, d, J=3.9Hz), 8.37 (1H, d, J=5.6Hz), 8.01 (2H, d, J=8.5Hz), 7.45 (1H, d, J=7.7Hz), 7.18-7.10 (7H, m), 5.38 (2H, s), 4.28 (2H, m), 4.08-3.86 (1 H, m), 3.69 (2H, m), 3.45-3.03 (8H, bm), 2.89-2.79 (2H, bm), 2.59 (3H, s), 2.50-2.30 (4H, bm), 1.51-1.38 (2H, m), 1.25 (1 H, m), 1.03-0.96 (3H, m) and 0.72 (6H, m). 13C-NMR; δ (CDCI 3 ), 167.2, 167.1 , 156.8, 156.6, 153.3, 146.7, 142.2, 142.1 , 140.8, 140.6, 140.2, 139.8, 139.5, 139.4, 137.6, 137.5, 137.4, 136.4, 134.8, 133.4, 133.3, 133.1 , 130.4, 129.3, 129.0, 126.3, 122.4, 104.7, 71.3, 71.1, 66.3, 55.5, 55.4, 46.9, 45.7, 45.6, 45.5, 43.3, 43.2, 38.4, 38.3, 31.6, 31.5, 31.0, 30.8, 30.7, 30.3, 30.1 , 24.4 and 14.0. Example 21 N-(2-{[4-(R,S)-(4-Chlorophenyl)-phenyl-methyl]piperazin-1-yl}ethyl)-N-(S)-(1- ethoxymethyl-3-methylbutyl)-4-(1H-2-methylimidazo[4,5-c]pyridin-1ylmethyl)- phenylsulphonamide. (a) N-(S)-(1 -Ethoxymethyl-3-methylbutyl)-N-(2-hydroxyethyl)-4-(1 H-2- methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonamide. Lithium aluminium hydride (418mg, 11.01 mmol) was taken up in anhydrous THF (10ml) and stirred at -78 ' C under an inert atmosphere. A solution of {(S)-(1- ethoxymethyl-3-methylbutyl)-[4-(1 H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonyl]-amino}-acetic acid tert butyl ester (2.00g, 3.67mmol) in THF (40ml) was added dropwise to the cooled solution. The mixture was stirred at -78 ' C for 15 minutes and allowed to warm to ambient temperature. After a total reaction time of 30 minutes the reaction was cooled to -78 ' C before quenching with a 15% aqueous solution of sodium hydroxide (5ml). After warming to room temperature more sodium hydroxide solution was added (15ml) and a gelatinous precipitate formed. The suspension was filtered through keiselguhr and concentrated under vacuum to yield N-(S)-(1 -ethoxymethyl-3-methylbutyl)-N-(2-hydroxyethyl)-4-(1H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide as a yellow foam (1.53g, 88%). 1H-NMR; δ (CDCI 3 ), 9.06 (1H, d, J=0.7Hz), 8.39 (1H, d, J=5.6Hz), 7.86 (2H, d, J=8.3Hz), 7.16-7.14 (3H, m), 5.41 (2H, s), 4.00-3.97 (1 H, m), 3.78-3.74 (1 H, m), 3.66- 3.61 (1 H, m), 3.51-3.26 (6H, m), 2.61 (3H, s), 1.51-1.47 (1 H, m), 1.38-1.29 (2H, m), 1.00 (3H, t, J=7.0Hz) and 0.85 (6H, t, J=6.1 Hz). (b) N-(S)-(1 -Ethoxymethyl-3-methylbutyl)-N-(2-ethyl-O-methanesulphonate)-4-(1 H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide. A solution of N-(S)-(1 -ethoxymethyl-3-methylbutyl)-N-(2-hydroxyethyl)-4-(1 H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide (1.52g, 3.20mmol) and triethylamine (893μl, 6.40mmol) in dry DCM was stirred under an inert atmosphere at O ' C. Methanesulphonyl chloride (372μl, 4.80mmol) was added dropwise and the reaction allowed to warm to ambient temperature. After a total reaction time of 4 hours the reaction was partitioned between DCM and water. The organic layer was separated, washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure to a yellow foam (1.77g, 100%). 1 H-NMR; δ (CDCI 3 ), 9.04 (1H, s), 8.38 (1 H, d, J=5.5Hz), 7.83 (2H, d, J=8.3Hz), 7.16- 7.13 (3H, m), 5.40 (2H, s), 4.41-4.30 (2H, m), 3.98-3.92 (1H, m), 3.50-3.36 (2H, m), 3.32-3.20 (4H, m), 3.02 (3H, s), 2.60 (3H, s), 1.51-1.45 (1H, m), 1.36-1.31 (1H, m), 1.22-1.16 (1 H, m), 0.93 (3H, t, J=7.0Hz) and 0.83 (6H, t, J=6.4Hz). (c) N-(2-{[4-(R,S)-(4-Chlorophenyl)-phenyl-methyl]piperazin-1 -yl}ethyl)-N-(S)-(1 - ethoxymethyl-3-methylbutyl)-4-(1H-2-methylimidazo[4,5-c]pyridin-1ylmethyl)- phenylsulphonamide. A solution of N-(S)-(1-ethoxymethyl-3-methylbutyl)-N-(2-ethyl-O-methane- sulphonate)-4-(1 H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide (94mg, 0.17mmol), 4-chlorobenzhydrylpiperazine (98mg, 0.34mmol), triethylamine (29μl, 0.20mmol) and sodium iodide (catalytic) in THF (15ml) was heated under reflux for 180 hours. THF was removed under reduced pressure. The residue was resuspended in DCM, washed with water (x3), dried over sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by column chromatography on silica gel eluting with 3% methanol/DCM. Product containing fractions were combined and solvent removed to yield N-(2-{[4-(R,S)-(4- chlorophenyl)-phenyl-methyl]piperazin-1-yl}ethyl)-N-(S)-(1-ethoxymethyl-3- methylbutyl)-4-(1H-2-methylimidazo[4,5-c]pyridin-1ylmethyl)-phenylsulphonamide as a white solid (80mg, 65%). 1H-NMR; (CDCI3), 9.04 (1H, s), 8.38 (1H, d, J=5.5Hz), 7.83 (2H, d, J=8.2Hz), 7.34 (4H, m), 7.27-7.10 (8H, bm), 5.38 (2H, s), 4.19 (1 H, s), 3.93 (1 H, m), 3.28-3.15 (6H, m), 2.65 (2H, bs), 2.59 (3H, s), 2.51 (6H, bs), 2.38 (2H, bs), 1.50 (1 H, m), 1.28 (2H, m), 0.89 (3H, t, J=6.9Hz) and 0.82 (6H, m). 13C-NMR; δ (CDCI 3 ), 142.1 , 142.0, 141.1 , 139.8, 139.2, 132.5, 129.1 , 128.6, 128.5, 127.8, 127.2, 126.4, 104.6, 75.3, 71.3, 66.3, 58.7, 56.1 , 53.7, 51.5, 46.8, 41.2, 39.6, 24.4, 22.8, 22.3, 14.9 and 14.0. Example 22 N-(2-{[3-(R,S)-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-methylamino}ethyl)-N-(S)-(1- ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonamide. Using reaction conditions described for example 21 (c) N-(S)-(1-ethoxymethyl-3- methylbutyl)-N-(2-ethyl-O-methane-sulphonate)-4-(1 H-2-methylimidazo[4,5- c]pyridin-1-ylmethyl)-phenylsulphonamide (400mg, 0.72mmol) was reacted with N- methyl-(R,S)-3-(4-chlorophenyl)-3-(pyridin-2-yl)propylamine (378mg, 1.45mmol) to yield N-(2-{[3-(R,S)-(4-chlorophenyl)-3-pyridin-2-yl-propyl]-methylamino}ethyl)-N- (S)-(1 -ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)- phenylsulphonamide (143mg, 28%). 1H-NMR; δ (CDCI 3 ), 9.03 (1 H, s), 8.51 (1 H, dd, J=5.1 , 1.3Hz), 8.36 (1 H, d, J=5.6Hz), 7.76 (2H, d, J=7.9Hz), 7.53 (1 H, td, J=7.7, 1.7Hz), 7.27-7.25 (2H, m), 7.21 (2H, d, J=8.4Hz), 7.12-7.05 (5H, m), 5.36 (2H, s), 4.09 (1 H, t, J=7.6Hz), 3.90-3.87 (1H, m), 3.24-3.05 (6H, m), 2.61-2.56 (1H, m), 2.58 (3H, s), 2.47-2.42 (1 H, m), 2.40-2.35 (1 H, m), 2.29-2.27 (2H, m), 2.21 (3H, s), 2.18-2.12 (1H, m), 1.49-1.45 (1H, m), 1.28-1.22 (1 H, m), 1.20-1.14 (1 H, m), 0.88 (3H, td, J=6.9, 4.9Hz), 0.80-0.79 (3H, m) and 0.79- 0.78 (3H, m). 13 C-NMR; δ (CDCI 3 ), 162.9, 153.3, 149.3, 142.2, 142.1 , 142.0, 141.2, 140.1 , 139.8, 139.2, 136.5, 132.1 , 129.4, 128.6, 128.5, 126.4, 122.7, 121.5, 104.6, 71.3, 66.2, 58.0, 56.0, 55.6, 50.2, 46.8, 42.5, 41.9 and 14.0. Example 23 N-(3-{[3-(R,S)-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-methylamino}propyl)-N-(S)-(1 - ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonamide. (a) N-Allyl-N-(S)-(1 -ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5- c]pyridin-1 -ylmethyl)-phenylsulphonamide. A solution of (S)-(1 -ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5- c]pyridin-1-ylmethyl)-phenylsulphonamide (5.00g, 11.61 mmol) in dry DMF (75ml), under an inert atmosphere was treated with sodium hydride (560mg, 13.94mmol). The reaction was stirred at room temperature for 30 minutes before the addition of allyl bromide (1ml, 11.61 mmol). After stirring for 18 hours solvent was removed under reduced pressure and the residue was partitioned between DCM and brine. The aqueous layer was back extracted with DCM. The organic layers were combined, dried over magnesium sulphate, filtered and concentrated to a dark red oil. The product was purified by column chromatography on silica gel eluting with 5- 10% methanol/DCM. Product containing fractions were combined and solvent removed to yield N-allyl-N-(S)-(1-ethoxymethyl-3-methylbutyl)-4-(1 H-2- methylimidazo-[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide as a red oil (5.9g, 100%). 1H-NMR; δ (CDCI 3 ), 9.05 (1 H, s), 8.38 (1 H, d, J=6Hz), 7.85 (2H, d, J=10Hz), 7.13 (1H, d, J=7Hz), 7.11 (2H, d, J=10Hz), 5.79-5.70 (1 H, m), 5.39 (2H, s), 5.15 (1 H, d, J=16Hz), 5.03 (1 H, d, J=12Hz), 4.08-4.02 (1H, m), 3.80 (2H, d, J=7Hz), 3.33-3.18 (4H, m), 2.60 (3H, s), 1.59-1.51 (1 H, m), 1.43-1.38 (1 H, m), 1.28-1.23 (1 H, m), 0.92 (3H, t, J=7Hz), 0.86 (6H, d, J=6Hz). (b) N-(S)-(1 -Ethoxymethyl-3-methylbutyl)-N-(3-hydroxypropyl)-4-(1 H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide. N-Allyl-N-(S)-(1 -ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 - ylmethyl)-phenylsulphonamide (4.00g, 8.50mmol) was taken up in dry THF (75ml) under an inert atmosphere. A solution of 9-borabicyclo[3,3,1]nonane (25ml, 0.5M in THF, 12.5mmol) was added and the reaction heated at 80 * C for 18 hours. The reaction was quenched by the sequential addition of ethanol (6ml), sodium hydroxide solution (6M, 2ml) and hydrogen peroxide solution (4ml, 30%). THF was removed in a stream of argon and the residue partitioned between DCM and brine. The organic layer was separated, washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to yield N-(S)-(1- ethoxymethyl-3-methylbutyl)-N-(3-hydroxypropyl)-4-(1 H-2-methylimidazo[4,5- c]pyridin-1-ylmethyl)-phenylsulphonamide as a yellow oil (1.8g, 43%). 1 H-NMR; δ (CDCI 3 ), 9.03 (1 H, s), 8.38 (1H, d, J=6Hz), 7.82 (2H, d, J=9Hz), 7.12- 7.10 (3H, m), 5.39 (2H, s), 3.96-3.90 (1H, m), 3.74-3.65 (2H, m), 3.35-3.19 (6H, m), 2.60 (3H, s), 1.90-1.43 (3H, m), 1.37-1.26 (2H, m), 0.92 (3H, t, J=7Hz), 0.82 (6H, t, J=8Hz). (c) N-(S)-(1 -Ethoxymethyl-3-methylbutyl)-N-(3-propyl-O-methane-sulphonate)-[4- (1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonamide. A solution of N-(S)-(1 -ethoxymethyl-3-methylbutyl)-N-(3-hydroxypropyl)-4-(1 H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide (1.8g, 3.68mmol) in dry DCM (50ml) was cooled in an ice-water bath and treated with triethylamine (1.0ml, 7.37mmol) and methanesulphonyl chloride (0.43ml, 5.53mmol) under an inert atmosphere. The reaction was stirred at room temperature for 18 hours before partitioning with brine. The organic layer was separated, washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to a yellow oil. The product was purified by column chromatography on silica gel eluting with 5-15% methanol/DCM. Product containing fractions were combined and solvent removed to yield N-(S)-(1-ethoxymethyl-3-methylbutyl)-N-(3-propyl-O-methane- sulphonate)-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonamide as a pale yellow oil (0.80g, 38%). 1H-NMR; δ (CDCI 3 ), 8.96 (1H, s), 8.30 (1H, d, J=5.5Hz), 7.74 (2H, d, J=9Hz), 7.11 (1 H, d, J=6Hz), 7.09 (2H, d, J=9Hz), 5.35 (2H, s), 4.19 (2H, t, J=6Hz), 3.90-3.86 (1 H, m), 3.25-3.12 (6H, m), 2.96 (3H, s), 2.54 (3H, s), 2.06-1.40 (3H, m), 1.31-1.26 (1 H, m), 1.19-1.13 (1 H, m), 0.87 (3H, t, J=6Hz), 0.77 (3H, t, J=7Hz), 0.76 (3H, d, J=7Hz). (d) N-(3-{[3-(R,S)-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-methylamino}propyl)-N- (S)-(1 -ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)- phenylsulphonamide. N-(S)-(1-Ethoxymethyl-3-methylbutyl)-N-(3-propyl-O-methane-sulphonate)-4-(1H-2- methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphoπamide (400mg, 0.71 mmol) was coupled to N-methyl-(R,S)-3-(4-chlorophenyl)-3-(pyridin-2-yl)propylamine (370mg, 1.41 mmol) using conditions described for example 21 (c). N-(3-{[3-(R,S)-(4- Chlorophenyl)-3-pyridin-2-yl-propyl]-methylamino}propyl)-N-(S)-(1-ethoxymethyl-3- methylbutyl)-4-(1 H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide was isolated following chromatography as a yellow oil (173mg, 34%). 1H-NMR; δ (CDCI 3 ), 9.04 (1 H, s), 8.54 (1 H, d, J=4.0Hz), 8.36 (1 H, d, J=5.7Hz), 7.82 (2H, d, J=8.3Hz), 7.54 (1 H, td, J=7.6, 1.9Hz), 7.27-7.21 (4H, m), 7.12-7.07 (5H, m), 5.37 (2H, s), 4.08 (1 H, t, J=7.5Hz), 3.94 (1 H, quintet, J=6.7Hz), 3.28-3.22 (3H, m), 3.22-3.15 (1 H, m), 3.15-3.05 (2H, m), 2.58 (3H, s), 2.47-2.10 (9H, bm), 1.84-1.64 (2H, bm), 1.51 (1 H, septet, J=6.6Hz), 1.33-1.22 (2H, m), 0.91 (3H, td, J=7.0, 1.0Hz), 0.82 (3H, d, J=6.7Hz) and 0.81 (3H, d, J=6.2Hz). 13C-NMR; δ (MeOD), 162.6, 155.3, 148.6, 141.8, 141.0, 140.8, 140.6, 140.3, 139.7, 139.1 , 137.3, 132.0, 129.2, 128.3, 128.0, 127.0, 122.9, 121.8, 106.0, 70.9, 65.8, 56.0, 55.1 , 54.3, 50.3, 46.3, 41.9, 40.8, 39.3, 31.1 , 27.9, 24.2, 21.9, 21.2, 13.9 and 12.4. Example 24 N-(3-{[4-(R,S)-(4-Chlorophenyl)-phenyl-methyl]piperazin-1 -yl}propyl)-N-(S)-(1 - ethoxymethyl-3-methylbutyl)-4-(1H-2-methylimidazo[4,5-c]pyridin-1ylmethyl)- phenylsulphonamide. N-(S)-(1 -Ethoxymethyl-3-methylbutyl)-N-(3-propyl-0-methane- sulphonate)-4-(1 H-2- methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonamide (400mg, 0.71 mmol) was coupled to 4-chlorobenzhydrylpiperazine (405mg, 1.41 mmol) using conditions described for example 21 (c). N-(3-{[4-(R,S)-(4-Chlorophenyl)-phenyl- methyl]piperazin-1 -yl}propyl)-N-(S)-(1 -ethoxymethyl-3-methylbutyl)-[4-(1 H-2- methylimidazo[4,5-c]pyridin-1ylmethyl)-phenylsulphonamide was isolated following chromatography as a colourless glass (221 mg, 41%). 1H-NMR; δ (CDCI 3 ), 9.05 (1 H, d, J=0.8Hz), 8.38 (1H, d, J=5.4Hz), 7.81 (2H, d, J=8.3Hz), 7.36-7.34 (4H, m), 7.28-7.22 (4H, m), 7.18 (1 H, t, J=7.3Hz), 7.12-7.11 (1 H, m), 7.09 (2H, m), 5.37 (2H, s), 4.18 (1H, s), 3.96-3.91 (1H, m), 3.29-3.16 (4H, m), 3.16-3.06 (2H, m), 2.59 (3H, s), 2.60-2.20 (9H, m), 1.95-1.86 (1 H, bs), 1.86-1.76 (1 H, m), 1.76-1.67 (1 H, m), 1.53-1.46 (1 H, m), 1.33-1.24 (2H, m), 0.92 (3H, t, J=6.8Hz) and 0.83-0.80 (6H, m). 13C-NMR; δ (CDCI 3 ), 153.3, 142.2, 142.1 , 142.0, 141.4, 141.3, 140.1 , 139.8, 139.1 , 132.5, 129.2, 128.6, 128.5, 128.4, 127.8, 127.1 , 126.3, 104.7, 75.4, 71.4, 66.2, 56.1 55.7, 53.3, 51.8, 46.8, 42.5, 39.8, 28.2, 24.5, 22.8, 22.3, 14.9 and 13.9. Example 25 N-(S)-(1-Ethoxymethyl-3-methylbutyl)-N-{(E)-3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1 E- enyl]-pyridin-2-yl)-prop-2-en-1 -yl}-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)- phenylsulphonamide. (a) (E)-3-(6-[3-Pyrrolidino-1 -{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)-prop-2-en-1 -yl acetate. Pyridine (110μl, 1.36mmol) was added to a solution of (E)-3-(6-[3-pyrrolidino-1-{4- tolyl}-prop-1 E-enyl]-pyridin-2-yl)-prop-2-en-1-ol (227mg, 0.68mmol, example 17(b)) in DCM (3ml) under an inert atmosphere. Acetyl chloride (72μl, 1.02mmol) was added and the reaction stirred for 18 hours at room temperature. The reaction mixture was partitioned between DCM and brine. The organic layer was separated, dried over sodium sulphate, filtered and concentrated under vacuum to leave a brown oil. The product was purified by column chromatography on silica gel eluting with 5% methanol/DCM. Product containing fractions were combined and solvent removed to yield (E)-3-(6-[3-pyrrolidino-1 -{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)-prop-2- en-1 -yl acetate as a brown gum (184mg, 73%). 1H-NMR; (CDCI 3 ), 7.49 (1 H, t, J=7.8Hz), 7.24 (2H, d, J=7.9Hz), 7.18-7.11 (2H, m), 7.06 (2H, d, J=7.9Hz), 6.91 -6.66 (3H, m), 4.79 (2H, dd, J=5.4, 0.7Hz), 3.72 (2H, m), 3.20 (4H, bm), 2.40 (3H, s), 2.12 (3H, s), 2.11-2.02 (4H, m). (b) N-(S)-(1 -Ethoxymethyl-3-methylbutyl)-N-{(E)-3-(6-[3-pyrrolidino-1 -{4-tolyl}-prop- 1 E-enyl]-pyridin-2-yl)-prop-2-en-1 -yl}-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 - ylmethyl)-phenylsulphonamide. Sodium hydride (17mg, 60% oil, 0.42mmol) was added to a solution of (S)-(1- ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonamide (173mg, 0.4mmol) in a mixture of THF/DMF (3/1 , 4ml) under an inert atmosphere. (E)-3-(6-[3-Pyrrolidino-1 -{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)-prop- 2-en-1-yl acetate (100mg, 0.27mmol) was taken up in THF (2ml), treated with tetrakis(triphenylphosphine)palladium(0) (16mg, 0.014mmol) and stirred at room temperature for 1 hour. The solution was transferred by cannula to the reaction mixture which was then heated at 60 * C for 48 hours. The reaction mixture was concentrated under reduced pressure to a brown oil. The residue was taken up in DCM, washed with saturated sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated. The product was purified by column chromatography on silica gel, eluting with a gradient of 2-50% methanol/DCM. Product containing fractions were combined and solvent removed to yield N-(S)-(1- ethoxymethyl-3-methylbutyl)-N-{(E)-3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1 E-enyl]- pyridin-2-yl)-prop-2-en-1 -yl}-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)- phenylsulphonamide as a brown gum (94mg, 47%). 1H-NMR; δ (MeOD), 8.83 (1 H, s), 8.27 (1H, d, J=5.7Hz), 7.85 (2H, d, J=8.4Hz), 7.51 (2H, m), 7.27 (4H, m), 7.14 (1 H, d, J=7.7Hz), 7.08 (2H, d, J=8.0Hz), 6.99 (1 H, t, J=7.1 Hz), 6.67 (1H, m), 6.62 (2H, d, J=15.9Hz), 5.60 (2H, s), 4.10 (1 H, m), 4.02 (2H, d, J=6.1 Hz), 3.53 (2H, d, J=7.1 Hz), 3.22 (4H, m), 2.91 (4H, bm), 2.60 (3H, s), 2.39 (3H, s), 1.89 (4H, br m), 1.62 (1 H, m), 1.48 (1 H, m), 1.25 (1 H, m), 0.86 (6H, m) and 0.79 (3H, d, J=6.7Hz). 13C-NMR; δ (MeOD), 156.7, 155.3, 154.4, 145.1 , 141.1 , 141.0, 140.7, 140.2, 139.7, 139.1 , 137.7, 136.9, 134.2, 132.4, 131.7, 129.3, 129.1 , 129.0, 129.0, 128.2, 126.9, 124.1 , 121.0, 119.8, 106.0, 70.9, 65.8, 56.2, 53.5, 53.4, 46.4, 45.2, 24.0, 22.7, 22.0, 21.0, 19.9, 14.0 and 12.5. Example 26 N-Cyclohexyl-N-{(E)-3-(6-[3-pyrrolidino-1 -{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)-prop-2- en-1 -yl}-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonamide. (a) N-Cyclohexyl-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenyl sulphonamide. N-Cyclohexyl-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenyl sulphonamide was prepared using a procedure analogous to that described for the regioselective synthesis of S-(1 -ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5-c]pyridin- 1-ylmethyl)-phenylsulphonamide in the international patent application WO 92/03422. 1H-NMR; δ (CDCI 3 ), 9.05 (1 H, d, J=0.7Hz), 8.39 (1 H, d, J=5.5Hz), 7.84 (2H, d, J=8.5Hz), 7.17-7.13 (3H, m), 5.30 (2H, s), 4.75 (1 H, bd, J=6.9Hz), 3.17-3.14 (1 H, m), 2.60 (3H, s), 1.88-1.50 (6H, m), 1.26-1.06 (4H, m). (b) N-Cyclohexyl-N-{(E)-3-(6-[3-pyrrolidino-1 -{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)- prop-2-en-1 -yl}-4-(1 H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonamide N-Cyclohexyl-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenyl sulphonamide (494mg, 1.29mmol) was coupled to (E)-3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1 E-enyl]- pyridin-2-yl)-prop-2-en-1 -yl acetate (400mg, 1.07mmol) using the procedure described for example 25(b) to yield N-cyclohexyl-N-{(E)-3-(6-[3-pyrrolidino-1-{4- tolyl}-prop-1 E-enyl]-pyridin-2-yl)-prop-2-en-1 -yl}-4-(1 H-2-methylimidazo[4,5- c]pyridin-1-ylmethyl)-phenylsulphonamide as a white foam (215mg, 29%). 1 H-NMR; δ (CDCI 3 ), 9.02 (1 H, s), 8.34 (1 H, d, J=5.5Hz), 7.80 (2H, d, J=8.3Hz), 7.43 (1 H, t, J=7.8Hz), 7.24-7.04 (9H, m), 6.74-6.57 (3H, m), 5.39 (2H, s), 4.01 (2H, d, J=5.1 Hz), 3.74-3.66 (1 H, m), 3.48 (2H, d, J=7.1Hz), 2.94-2.87 (4H, m), 2.55 (3H, s), 2.40 (3H, s), 1.91 (4H, bs), and 1.75-0.98 (10H, m). 13C-NMR; δ (CDCI 3 ). 156.5, 154.2, 153.4, 142.2, 142.1 , 141.8, 140.3, 139.9, 139.5, 137.7, 136.8, 134.4, 132.2, 132.0, 129.5, 128.0, 126.9, 121.2, 120.2, 104.8, 58.4, 54.0, 53. 6, 46.9, 45.3, 31.9, 26.1 , 25.2 and 14.1. Example 27 N-Methyl-N-{(E)-3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)-prop-2-en- 1 -y|}-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonamide. (a) N-Methyl-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenyl sulphonamide. N-Methyl-4-(1 H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide was prepared using a procedure analogous to that described for the regioselective synthesis of S-(1 -ethoxymethyl-3-methylbutyl)-[4-(1 H-2-methylimidazo[4,5-c]pyridin- 1-ylmethyl)-phenylsulphonamide in the international patent application WO 92/03422. 1H-NMR; δ (CDCI 3 ), 9.07 (1H, s), 8.40 (1 H, d, J=6.8Hz), 7.85 (2H, d, J=8.9Hz), 7.16 (3H, m), 5.42 (2H, s), 4.95 (1 H, m), 2.70 (3H, d, J=5.5Hz), 2.61 (3H, s). (b) N-Methyl-N-{(E)-3-(6-[3-pyrrolidino-1 -{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)-prop-2- en-1 -yl}-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonamide. N-Methyl-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonamide (381 mg, 1.21 mmol) was coupled to (E)-3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1 E-enyl]- pyridin-2-yl)-prop-2-en-1-yl acetate (300mg, O.βOmmol) using the procedure described for example 25(b) to yield N-methyl-N-{(E)-3-(6-[3-pyrrolidino-1-{4-tolyl}- prop-1 E-enyl]-pyridin-2-yl)-prop-2-en-1 -yl}-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 - ylmethyl)-phenylsulphonamide as a pale brown solid (226mg, 44%). 1H-NMR; δ (MeOD), 8.75 (1 H, s), 8.19 (1 H, d, J=5.8Hz), 7.72 (2H, d, J=8.3Hz), 7.48 (1 H. t, J=7.8Hz), 7.41 (1 H, d, J=6.0Hz), 7.20 (5H, m), 6.98 (2H, d, J=8.1Hz), 6.90 (1H, t, J=7.2Hz), 6.73 (1 H, d, J=7.2Hz), 6.56 (2H, m), 5.55 (2H, s), 3.74 (2H, m), 3.68 (2H, d, J=7.2Hz), 3.10 (4H, m), 2.63 (3H, s), 2.51 (3H, s), 2.29 (3H, s) and 1.89 (4H, m). 13C-NMR; δ (MeOD), 157.7, 156.9, 155.6, 148.3, 142.5, 142.2, 142,2, 141.1 , 140.5, 139.5, 138.7, 138.6, 135.1 , 134.3, 130.6, 129.5, 128.6, 122.9, 122.6, 122.0, 107.3, 54.5, 54.3, 53.1 , 49.8, 49.5, 47.7, 35.3, 24.0, 21.3 and 13.8. Example 28 (S)-4-Methyl-2-([4-1H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonyl]- (E)-{3-[6-(3-pyrrolidin-1-yl-{4-tolyl}-prop-1 E-enyl]-prop-2-enyl}-amino)-pentanoic acid ethyl ester. Sodium hydride (35mg, 60% oil, 0.88mmol) was added to a solution of (S)-4-Methyl- 2-([4-1 H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonyl]-amino)- pentanoic acid ethyl ester (381 mg, 0.86mmol) in a mixture of THF/DMF (3/1 , 15ml) under an inert atmosphere. (E)-3-(6-[3-Pyrrolidino-1-{4-tolyl}-prop-1 E-enyl]-pyridin- 2-yl)-prop-2-en-1-yl acetate (213mg, 0.57mmol) was taken up in a mixture of THF/DMF (3/1 , 5ml), treated with tetrakis(tripheπylphosphine)palladium(0) (35mg, 0.03mmol) and stirred at room temperature for 1 hour. The solution was transferred by cannula to the reaction mixture which was then heated at 60 * C for 48 hours. The reaction mixture was concentrated under reduced pressure to a brown oil. The residue was taken up in DCM, washed with saturated sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated. The product was purified by column chromatography on silica gel, eluting with a gradient of 2-20% methanol/DCM. Product containing fractions were combined and solvent removed to yield (S)-4-methyl-2-([4-1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)- phenylsulphonyl]-(E)-{3-[6-(3-pyrrolidin-1-yl-{4-tolyl}-prop-1 E-enyl]-prop-2-enyl}- amino)-pentanoic acid ethyl ester as a yellow/brown solid (188mg, 44%). 1H-NMR; δ (CDCI 3 ), 8.57 (1 H, s), 8.39 (1 H, d, J=5.6Hz), 7.77 (2H, d, J=8.33Hz), 7.60 (1 H, dd, J=5.5, 0.8Hz), 7.40 (1H, 1H, t, J=7.8Hz), 7.17 (4H, m), 7.06 (4H, m), 6.65 (3H, m), 5.43 (2H, s), 4.57 (1H, ), 4.10 (1H, ), 3.95 (1H, ), 3.82 (2H, m), 3.28 (2H, d), 2.66 (4H, m), 2.56 (3H, s), 2.36 (3H, s), 1.79 (4H, m), 1.68 (3H, m), 0.98 (3H, t, J=7.0Hz), 0.92 (3H, d, J=6.0Hz) and 0.81 (3H, d, J=6.1 Hz). 13C-NMR; δ (CDCI 3 ), 171.0, 157.1 , 155.0, 153.9, 147.7, 142.9, 142.2, 139.9, 139.7, 137.1 , 136.5, 134.8, 132.7, 132.1 , 130.8, 129.5, 129.1 , 128.3, 127.6, 126.6, 120.9, 119.4, 113.9, 61.0, 58.1 , 54.1 , 53.6, 47.2, 46.9, 38.9, 24.2, 23.4, 22.5, 21.1 and 13.7. Pharmacology Example 1 Histamine Induced Bronchoconstriction in the Anaesthetised Guinea Pig Following oral administration of test compound or vehicle by oral gavage, male Dunkin-Hartley guinea pigs (350-400g) were anaesthetised by intraperitoneal injection of 60mgkg-ι sodium pentobarbitone (Sagatal, May & Baker UK). Through a midline incision of the neck, the trachea was cannulated and connected to a small animal respirator (Harvard, UK). Animals were artificially ventilated at a rate of 30 breaths per minute with a tidal volume of 8-10ml to give a resting tracheal inflation pressure of 15mmHg as measured by a physiological pressure transducer (type P23XL, Spectramed USA) connected to a side arm of the respiratory circuit. A jugular vein was cannulated for the administration of propranolol and for the infusion of histamine. A carotid artery was cannulated for the measurement of arterial blood pressure via a physiological pressure transducer (type P23XL, Spectramed USA). Blood pressure and tracheal inflation pressure were recorded on a thermal array chart recorder (type TA4000, Gould Electronics UK). Following a suitable equilibration period, propranolol (1 mgkg-ι i.v. & 3mgkg-ι s.c. Sigma Chemical Co. UK) was administered to inhibit any resulting catecholamine release following histamine administration. Histamine infusion (10μgkg-imin-ι at a rate of 10mlhr-ι using a perfusion pump type Perfuser securer FT, B. Braun Germany) was started at the one hour time point following oral administration of the test compound or vehicle. Changes in tracheal inflation pressure and blood pressure of drug treated animals were compared with changes from vehicle treated animals and ED 50 values determined. One dose of test compound was investigated per animal. Results Example ED δ o mgkg-i, p.o. 6 6.5 8 0.16 25 0.50 Pharmacology Example 2 PAF Induced Bronchoconstriction in the Anaesthetised Guinea Pig Following oral administration of test compound or vehicle, male Dunkin-Hartley guinea pigs (350-400g) were anaesthetised by intraperitoneal injection of 60mgkg- sodium pentobarbitone (Sagatal, May & Baker UK). Through a midline incision of the neck, the trachea was cannulated and connected to a small animal respirator (Harvard, UK). Animals were artificially ventilated at a rate of 30 breaths per minute with a tidal volume of 8-10ml to give a resting tracheal inflation pressure of 15mmHg as measured by a physiological pressure transducer (type P23XL, Spectramed USA) connected to a side arm of the respiratory circuit. A jugular vein was cannulated for the administration of a bolus dose of propranolol and for the later administration of bolus PAF. A carotid artery cannulated for the measurement of arterial blood pressure via a physiological pressure transducer (type P23XL, Spectramed USA). Blood pressure and tracheal inflation pressure were recorded on a thermal array chart recorder (type TA4000, Gould Electronics UK). Propranolol (1mgkg-ι i.v. & 3mgkg-ι s.c. Sigma Chemical Co. UK) was administered 10 minutes before PAF in order to prevent the broπchodilatory activity of catecholamines which may be released in response to PAF administration. PAF (100ngkg-ι i.v. bolus) was administered at the one hour time point following oral administration of the test compound or vehicle. Changes in tracheal inflation pressure and blood pressure of drug treated animals were compared with changes from vehicle treated animals and percentage inhibition determined. One dose of test compound was investigated per animal. Results Example %lnhibition at 10mgkg-ι, p.o. 6 40 8 46 25 50 Pharmacology Example 3 Inhibition of [3H]-Pyrilamine Binding to Histamine-1 Receptors on Hela-S3 Cells The inhibition of [3H]-pyrilamine binding to histamine-1 receptors on Hela-S3 cells (American Type Culture Collection) was determined by isotopic labelling and filtration techniques. A suspension of the cells in buffer (25ml, 0.5% Bovine Serum Albumin, 0.1% sodium azide, phosphate buffered saline (PBS)) was centrifuged at 1000 rpm for 5 minutes in a JOUAN CR 422 centrifuge, collected, resuspended in buffer (25ml) and spun again. The cells were counted using a haemocytometer and resuspended in buffer to provide a final concentration of 4.5X106 cells mM. A portion of the Hela-S3 cell suspension (1 ml) was added to each assay tube containing 25μl of vehicle (50% DMSO/buffer) or 25μl of solution containing test compound (dissolved in DMSO and diluted with sufficient PBS to give a final test concentration of 1μM) and 25μl of [3H]-pyrilamine (supplied by Amersham International and diluted with PBS to 3nM). The tubes were mixed and incubated at 37 * C for 30 minutes. The tubes were then spun at 4"C at 2000 rpm for 2 minutes. The supernatant was removed and the cells resuspended in buffer (repeated x2). The cells were suspended in 300μl of a 2:1 solution of 1 M sodium hydroxide and 1% sodium dodecyl sulphate. The tubes were left overnight before the contents were tranferred to a scintillation vial, treated with 10ml, OPTIPHASE MP scintillation fluid (OPTIPHASE MP is a trade mark) and the radioactivity counted in a scintillation counter. Non-displacable binding (NDB) was determined using Astemizole (5 X 10-5 M) in place of test compounds. Defining the counts for total binding from the vehicle control sample as "TB" and the counts for total binding with antagonist as TBA" the percentage specific binding (%SB) can be determined from the following equation. %SB = (TBA - NDB) X100 % (TB - NDB) Results Example % Specific Binding at 1μM 2 57 4 34 6 79 17 47 23 33 25 55 Pharmacology Example 4 Inhibition of PAF-lnduced Platelet Aggregation Male New Zealand White rabbits (3.0 - 3.5 kg) were anaesthetised by intravenous administration of sodium pentobarbitone, 18mg.ml-ι, via a marginal ear vein. The trachea was exposed and connected to a respiratory pump (Havard UK) to provide artificial ventilation. A carotid artery was exposed and cannulated and the animal was exsanguinated. Whole blood was collected in a syringe containing tri-sodium citrate (3.8% w/v) to a ratio of 1 part citrate:9 parts blood. Collected blood was centrifuged at 180 x g for 15 minutes at room temperature (21 * C) to prepare platelet-rich plasma (PRP). The remaining blood was then centrifuged at 1800 x g for 10 minutes at room temperature to obtain platelet poor plasma (PPP). Platelet count of the PRP was measured using a Technicon H1 blood cell differential analyser (Bayer Diagnostics UK) and adjusted with PPP to obtain a final platelet count of 500,000 platelets per μl of plasma, this being the normal physiological platelet count for rabbits. Corrected PRP was left to equilibrate at room temperature for 30 minutes before use. Aggregation studies were carried out using 4-channel aggregometer (PAP-4C, BioData USA) as follows: 400 μl aliquots of PRP were placed in siliconised cuvettes and incubated to 37'C for 1 to 2 minutes in the heating block of the aggregometer. Baseline (100% aggregation) was set up using PPP (500 μl in a siliconised cuvette). The PRP was placed into a measuring well of the aggregometer, and a stir bar was added. The sample was stirred at 1000 φm. The machine was activated to set the 0% aggregation level. Test compound or vehicle (50 μl) was added to the PRP, where any effects on the baseline was noted. PAF (100 ng.ml-1 as 50 μl aliqout) was added to the PRP 3 minutes after test compound or vehicle. Aggregation was measured for a further 4 minutes after PAF addition and the maximum aggregation over the 4 minutes was recorded. The investigation of different concentrations of test compound was performed in triplicate. Data were expressed as 0% aggregation of the sample and test compound data were compared to vehicle data to obtain % inhibition of the PAF- induced aggregation from which IC5 0 values could be determined. PAF was made up in sterile saline (NaCl 0.9% w/v) containing BSA (0.25% w/v) from an initial stock solution (10 mg.mH in EtOH). Test compounds were made up as 1 x 10-3M stock solutions in sterile saline containing molar equivalents of 1 N HCl (v/v) or in DMSO. Results Example PAF-lnduced Platelet Aggregation ICso (nM) 2 2100 4 190 6 252 17 115 23 300 25 420

Claims: Claims 1. A compound of formula (II) wherein A represents =N-, =CH- or =CR 1 -, wherein Ri represents hydrogen, C-i-Cβ alkyl, C2- C 6 alkenyl, halogen, -CN, -CO 2 H, -Cθ2(C C 6 alkyl), -CONH 2 , -CHO, -CH 2 OH, -CF 3 , C Cβ alkoxy, C Cβ alkylsulphanyl,- d-Cβ alkylsulphinyl, C Cε alkylsulphonyl, -NH 2 , -NHCOCH 3 , or -NO2; provided that when A represents =N- the resulting imidazo[4,5- cjpyridinyl bicyclic ring system may be optionally substituted in the 4- and/or 6- positions by methyl; R represents hydrogen, Ci-Cε alkyl, C2-C6 alkenyl, halogen or C Cε alkoxy; R2 represents hydrogen, CrC 6 alkyl, C -C 6 alkenyl, d-C 6 alkoxy, C C 6 alkylsulphanyl, cyclopropyl, C Cβ hydroxyalkyl, (CrC 6 alkyl) N-, (Cι-C 6 alkyl) N(C r C 6 alkyl)- or -CF 3 ; R3 represents hydrogen, C Cβ alkyl, C2-C 6 alkenyl, C 2 -C 6 alkynyl, -CO 2 (C C6 alkyl), C C 6 alkoxy, C C 6 alkylsulphanyl, (Cι-C 6 alkoxy)(C C 6 alkyl)-, (Cι-C 6 alkylsulphanyl)(CrC6 alkyl)-, (phenyl)(C r C6 alkyl)-, or pheπylsulphanyl; R4 represents hydrogen, Ci-Cε alkyl, C 2 -C6 alkenyl, C2-C 6 alkynyl, d-Cβ alkylcarbonyl, -CO (C -C 6 alkyl), (phenyl)CrC 6 alkylcarbonyl-, -C(=O)O-(C C 6 alkyl)-(phenyl), (Cι-C 6 alkoxy)(d-C 6 alkyl)-, (C C 6 alkylsulphanyl)(d-C 6 alkyl)-, -(Cι-C 6 alkyl)-C(=O)O-(Cι-C 6 alkyl), (C 3 -C 8 )cycloalkyl. (C 4 -C 8 )cycloalkenyl, or a group of formula (III) wherein h is 0 or an integer from 1 to 3, and each of R6 and R? is independently hydrogen, C C 6 alkyl, C -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, -CN, -CO 2 H, -CO (d- C 6 alkyl), -CONH 2 . -CONH(Cι-C 6 alkyl), -CON(d-C 6 alkyl) 2 , -CHO, -CH 2 OH, -CF 3 , d-Cβ alkoxy, CrC 6 alkylsulphanyl, CrC 6 alkylsulphinyl, d-Cβ alkylsulphonyl, -NH , or -NHCOCH 3 ; R5 represents hydrogen, halogen, Ci-Ce alkyl optionally substituted with one or more halogen atoms, C -C 6 alkenyl, C 2 -C 6 alkynyl, (C C 6 alkyl)-C(=O)O-(C r C 6 alkyl), (Cι-C 6 alkoxy)Cι-C 6 alkyl, (C C 6 alkylsulphanyl)C C 6 alkyl, -(C Ce alkyl)N(Cι-C 6 alkyl) 2 , (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, ((C 3 -C 8 )cycloalkyl)C 1 -C 6 alkyl, ((C - C 8 )cycloalkenyl)CrC 6 alkyl, ((C 3 -C 8 )cycloalkyl)-O-(Cι-C 6 alkyl), ((C 4 - C 8 )cycloalkenyl)-O-(Cι-C 6 alkyl), ((C 3 -C 8 )cycloalkyl)-S-(Cι-C 6 alkyl), ((C 4 - C 8 )cycloalkenyl)-S-(CrC 6 alkyl), a side chain of a naturally occurring amino acid, or a group of formula (III) as defined above; B represents a bond, or a straight saturated or unsaturated hydrocarbon chain of from 1 to 6 carbon atoms which may additionally include from 1 to 3 non-adjacent hetero atoms or groups selected from -O-, -S-, -N(R 4 )- wherein R 4 is as defined above, -S(O)-, -S(O )-, and -S(O 2 )N(R 4 )- wherein R 4 is as defined above, and in which one or more carbon atoms of the chain may be substituted by oxo, hydroxy, Cι-C alkyl, phenyl, or -phenyl(C C alkyl); D represents a group of formula (IV), (V), (VI), (VII) or (VIIA) wherein R β and R9 are the same or different and each represents an optionally substituted divalent phenylene group or an optionally substituted 5-6 membered monocyclic divalent heteroarylene group containing at least one nitrogen, oxygen or sulphur atom, wherein any optional substituents are selected from C C 6 alkyl, C 2 -C 6 alkenyl, HOOC-(C 2 -C 6 alkenyl), halogen or CrCβ alkoxy groups, and X and Y are independently hydrogen or when taken together in groups (IV), (V), (VI) or (VIIA) represent a divalent group selected from -CH 2 CH 2 -, -CH=CH-, -CH2O- and -COCH 2 - ; and Rio and R11 are independently Ci-Ce alkyl or together with the nitrogen atom to which they are attached form a non-aromatic 5-7 membered heterocyclic ring; provided that when D is a group IV, V, VI or VIIA in which R β and R9 are both phenylene groups and substituents X and Y are other than a divalent group selected from -CH 2 CH 2 -, -CH=CH-, -CH 2 O- and -COCH -, then the group B does not include a carbonyl group bonded directly to D; or a pharmaceutically or veterinarily acceptable acid addition salt or hydrate thereof. 2. A compound as claimed in claim 1 wherein the group B has the formula -(CH 2 )i-- -CO-, -COX(CH 2 )r. -COX(CH 2 )iYCO-, -COX(CH 2 )iY(CH2) j - , -(CH 2 )XCO-, -COX(CH 2 )iY(CH 2 )ZCO-, -CO(CH 2 )j-, -(CH 2 )X(CH 2 )i-, -(CH 2 )X(CH 2 )iY(CH 2 ) r , -(CH 2 )X(CH 2 )jYCO-, -(CH 2 )XCO(CH 2 )j-, -X(CH 2 ) r , -S(CH 2 ) r , -SO(CH 2 ) r , -SO 2 (CH2)r, or -SO 2 X(CH2)r, wherein X, Y and Z independently represent -O- or - NR 4 - where R 4 is as defined above in formula (II), and i and j are independently 0 or an integer from 1 to 6, provided that no more than 6 carbon atoms are present in the linear chain represented by the foregoing formulae, and provided that where both X and Y are present in the linker group B then i is an integer from 1 to 6. 3. A compound as claimed in claim 1 or claim 2 wherein A is =N- . 4. A compound as claimed in any of the preceding claims wherein R2 represents methyl. 5. A compound as claimed in any of the preceding claims wherein R3 represents hydrogen. 6. A compound as claimed in any of the preceding claims wherein R 4 represents hydrogen, a -Cι-C 6 alkyl (for example methyl, ethyl or iso-propyl) group, a -C 2 -C 6 alkenyl (for example allyl) group, a C 3 -C 8 cycloalkyl (for example cyclohexyl, cyclopentyl, cyclopropyl) group, a (d-C 6 alkoxy)(Cι-C 6 alkyl)- group (for example 1 - ethoxymethyl-3-methylbut-1-yl), a -(Ci-Ce alkyl)-C(=0)O-(Cι-C 6 alkyl) group (for example 1-ethoxycarbonyl-3-methylbut-1-yl), or a group of formula (III) as defined in claim 1 ; 7. A compound as claimed in claim 6 wherein R 4 represents methyl, ethyl, iso- propyl, allyl, cyclohexyl, cyclopentyl, cyclopropyl, 1-ethoxymethyl-3-methylbut-1-yl, or 1 -ethoxycarbonyl-3-methylbut-1 -yl. 8. A compound as claimed in any of the preceding claims wherein R5 represents hydrogen, a Ci-Ce alkyl (for example methyl, ethyl, n-butyl, i-butyl, sec-butyl or t- butyl) group, a C 2 -Cβ alkenyl (for example allyl) group, a (Ci-Ce alkyl)C 3 .C 8 cycloalkyl (for example cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl) group, a side chain of a naturally occurring amino acid (for example the side chain of leucine, isoleucine, phenylalanine, valine, tryptophan, methionine or tyrosine) or a group of formula (III) as defined in claim 1. 9. A compound as claimed in claim 8 wherein R5 represents methyl, ethyl, n- butyl, i-butyl, sec-butyl, t-butyl, allyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl or the side chain of leucine, isoleucine, phenylalanine, valine, tryptophan, methionine or tyrosine. 10. A compound as claimed in any of the preceding claims wherein a group of formula (III) is present and R6 represents a hydrogen atom, a C Cβ alkyl (for example methyl) group, a halogen (for example fluorine, chlorine or bromine) atom, a CF 3 group or a Ci-Ce alkoxy (for example methoxy) group; and R? represents a hydrogen atom or a Ci-Ce alkoxy (for example methoxy) group; 11. A compound as claimed in claim 10 wherein R6 represents a hydrogen atom, methyl, fluorine, chlorine, bromine, CF 3 , or methoxy, and R? represents a hydrogen atom or methoxy. 12. A compound as claimed in any of the preceding claims wherein the group B is a bond, or -CO-, -CH 2 -, -CH 2 CH 2 , -CH 2 OCO-, -CH 2 OCOCH 2 - , - COO(CH 2 )2OCH 2 CH2-. -CONH(CH 2 ) 2 -. -COOCH 2 -, -COO(CH 2 ) 2 -, -COO(CH 2 ) 3 -, - CH 2 OCH 2 CO-, -COOCH(4-tert-butylphenyl)(CH 2 ) 3 -, -CH 2 OCH 2 CH 2 -,- COOCH(CH 3 )(CH 2 )3-, -CH 2 NHCOCH 2 -. or -CH 2 NHCO-; 13. A compound as claimed in any of the preceding claims wherein in the group D, the groupings -R 8 -X and -R9-Y independently represent a phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-methylphenyl, 2-pyridyl, or 6-[2- carboxyethenyl]pyrid-2-yl group. 14. A compound as claimed in any of the preceding claims wherein the group D has formula (VIII), (IX) or (X): (X) 15. A compound as claimed in claim 1 selected from the group consisting of N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L- leucine-2-(4-benzhydryl-piperazin-1 -yl)-ethyl ester, N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L- leucine-3-(4-benzhydryl-piperazin-1 -yl)-propyl ester, 4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1.2-b]-pyridin-11 -ylidene)-1 -(N- methyl-N-4-{1 H-2-methylimidazo[4,5-c]pyridinylmethyl}-phenylsulphonyl-L-leucyl)- piperidine amide, (E)-3-(6-[Pyrrolidino-1 -{4-tolyl}prop-1 E-enyl]-2-pyridyl)acrylic acid, N-methyl-N-4- ( 1 H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L-leucyl ester, N-(S)-(1-Ethoxymethyl-3-methylbutyl)-N-{(E)-3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1 E- enyl]-pyridin-2-yl)-prop-2-en-1 -yl}-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)- phenylsulphonamide, and (S)-4-Methyl-2-([4-1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonyl]- (E)-{3-[6-(3-pyrrolidin-1 -yl-{4-tolyl}-prop-1 E-enyl]-prop-2-en-1 -yl}-amino)-pentanoic acid ethyl ester, and pharmaceutically or veterinarily acceptable acid addition salts or hydrates thereof. 16. A compound as claimed in claim 1 selected from the group consisting of N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L- leucine-2-(2-{4-[4-(chlorophenyl)-phenyl-methyl]-piperazin-1 -yl}-ethoxy)-ethyl ester, N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine- 2-(4-[1 ,1-dimethylethyl]phenyl)-4-(hydroxydiphenylmethyl)-1-piperidinebutyl ester, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonyl-L- leucine-2-(4-benzhydryl-piperazin-1-yl)-ethylamide, 4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1.2-b]-pyridin-11 -ylidene)-1 -(N- methyl-N-4-{1 H-2-methylimidazo[4,5-c]pyridinylmethyl}-phenylsulphonyl-L-leucinol)- piperidine carbamate, (4-Benzhydrylpiperazin-1-yl)-acetic acid, N-methyl-N-4-(1 H-2-methylimidazo[4,5-c]- pyridinylmethyl)-phenylsulphonyl-L-leucyl ester, N-Methyl-N-(S)-(1 -[4-benzhydrylpiperazin-1 -yl]-methyl-3-methyl-butyl)-N-4-(1 H-2- methylimidazo[4,5-c]pyridinylmethyl)-phenylsulphonamide, N-Methyl-N-(S)-(1-aminomethyl-[{4-benzhydrylpiperazin-1-yl}-acetamide]-3-methyl- butyl)-N-4-(1 H-2-methylimidazo[4,5c]-pyridinylmethyl)-phenylsulphonamide, N-(S)-(4-Methyl-2-{methyl-[4-(1 H-2-methyl-imidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonyl]-amino}-pentyl)-3-[6-(3-pyrrolidin-1 -yl-p-tolyl-prop-1 E-enyl)-pyridin- 2-yl] acrylamide, 2-[4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11-ylidene)- piperidin-1 -yl]-N-(4-methyl-2-{methyl-[4-(1 H-2-methylimidazo[4,5-c]pyridin-1 - ylmethyl)-phenylsulphonyl]-amino}-pentyl)-acetamide, N-[1 -{(4-Chlorobenzhydryl)-piperazin-1 -ylmethyl}-3-methyl-butyl]-N-methyl-4-(1 H-2- methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonamide, N-Methyl-N-4-(1 H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L-leucine- 2-(4-{8-chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 - ylidene}piperidin-1 -yl)-ethyl ester, N-Methyl-N-4-(1H-2-methylimidazo[4,5-c]pyridinylmethyl)phenylsulphonyl-L- leucine-(R,S)-5-(4-benzhydrylpiperazin-1 yl)-2-pentyl ester, 4-Methyl-2-{methyl-[4-(2-methyl-imidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonyl]- aminoj-pentanoic acid-(E)-3-(6-[3-pyrrolidino-1 -{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)- prop-2-en-1-yl ester, N-(1 -{2-[4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -ylidene)- piperidin-1-yl]-2-oxo-ethoxymethyl}-3-methyl-butyl)-N-methyl-4-(1 H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide, N-{2-[4-(8-Chloro-5,6-dihydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -ylidene)- piperidin-1 -yl]-2-oxo-ethyl}-N-(S)-(1 -ethoxymethyl-3-methylbutyl)-4-(1 H-2- methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide, N-(2-{[4-(R,S)-(4-Chlorophenyl)-phenyl-methyl]piperazin-1-yl}ethyl)-N-(S)-(1- ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5-c]pyridin-1ylmethyl)- phenylsulphonamide, N-(2-{[3-(R,S)-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-methylamino}ethyl)-N-(S)-(1- ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)- phenylsulphonamide, N-(3-{[3-(R,S)-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-methylamino}propyl)-N-(S)-(1- ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)- phenylsulphonamide, N-(3-{[4-(R,S)-(4-Chlorophenyl)-phenyl-methyl]piperazin-1-yl}propyl)-N-(S)-(1- ethoxymethyl-3-methylbutyl)-4-(1 H-2-methylimidcizo[4,5-c]pyridin-1ylmethyl)- phenylsulphoπamide, N-Cyclohexyl-N-{(E)-3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1 E-enyl]-pyridin-2-yl)-prop-2- en-1 -yl}-4-(1 H-2-methylimidazo[4,5-c]pyridin-1 -ylmethyl)-phenylsulphonamide, N-Methyl-N-{(E)-3-(6-[3-pyrrolidino-1 -{4-tolyl}-prop-1 E-enylj-pyridin-2-yl)-prop-2-en- 1-yl}-4-(1 H-2-methylimidazo[4,5-c]pyridin-1-ylmethyl)-phenylsulphonamide, and pharmaceutically or veterinarily acceptable acid addition salts or hydrates thereof. 17. A method of management of diseases or conditions mediated by histamine and/or PAF in mammals, in particular in humans, which method comprises administering to the mammal an effective amount of a compound as claimed in any of claims 1 to 16, or a pharmaceutically or veterinarily acceptable salt thereof. 18 A compound as claimed in any of claims 1 to 16, or a pharmaceutically or veterinarily acceptable salt thereof, for use in human or veterinary medicine, particularly in the management of diseases or conditions mediated by histamine and/or PAF. 19. The use of a compound as claimed in any of claims 1 to 16, or a pharmaceutically or veterinarily acceptable salt thereof, in the preparation of an agent for the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by histamine and/or PAF. 20. A method as claimed in claim 17, a compound for use as claimed in claim 18, or the use as claimed in claim 19, wherein the disease or condition is hypotension, thrombocytopenia, bronchoconstriction, circulatory shock, increased vascular permeability (oedema/erythema), allergic rhinitis, sinusitis, asthma, dermatitis, psoriasis, urticaria, anaphylactic shock, conjunctivitis, pruritis, inflammatory bowel disease and colitis. 95 21. A pharmaceutical or veterinary formulation comprising a compound as claimed in any of claims 1 to 16 and a pharmaceutically and/or veterinarily acceptable carrier. 22. A process for the preparation of a compound as claimed in claim 1 , which process comprises: (i) (for compounds in which linker B as defined in formula (II) commences - C(O)O-) esterification of an acid of formula (XI) QCO 2 H (XI) with an alcohol of formula (XII) HO-B1-D (XII) wherein Q represents the grouping wherein A, and R-R5 are as defined in formula (II), D is as defined in formula (II) and Bi is the residue of linker B (as defined in formula (II)) commencing at position 3, or (ii) (for compounds in which linker B as defined in formula (II) commences - C(O)N(R 4 )- wherein R 4 is as defined in formula (II) ) amidation of an acid of formula (XI) QCO 2 H (XI) with an amine of formula (XIII) HN(R )-B1-D (XIII) wherein D is as defined in formula (II) and B1 is the residue of linker B (as defined in formula (II)) commencing at position 3, or (iii) (for compounds in which linker B as defined in formula (II) commences - CH OC(O)-) esterification with an alcohol of formula (XIV) QCH 2 OH (XIV) of an acid of formula (XV) HOOC-B1-D (XV) wherein D is as defined in formula (II) and B 1 is the residue of linker B (as defined in formula (II)) commencing at position 4, or (iv) (for compounds in which linker B as defined in formula (II) is -CH - and group D is of formula (IV), (V), (VI) or (VIIA) ) by condensation of an alcohol of formula (XIV) QCH 2 OH (XIV) with an amine of formula (XVI) H-D (XVI), or (v) (for compounds in which linker B as defined in formula (II) commences - CH 2 NHC(O)- ) amidation with an amine of formula (XVII) QCH 2 NH 2 (XVII) of an acid of formula (XVII) HOOC-B1-D (XV) wherein D is as defined in formula (II) and B1 is the residue of linker B (as defined in formula (II)) commencing at position 4, and {for compounds in which linker B commences -CH 2 NHCH 2 - ) reduction of the carbonyl group in position 2 of the linker B of the product of the foregoing reaction, or (vi) (for compounds in which linker B as defined in formula (II) commences - CH2NH- ) reaction of an amine of formula (XVII) QCH 2 NH 2 (XVII) with an aldehyde of formula (XVIII) HCO-B1-D (XVIII) wherein D is as defined in formula (II) and B 1 is the residue of linker B (as defined in formula (II)) commencing at position 3, or (vii) reaction of a diamino compound of formula (XIX) wherein A, R, R3-R5, B and D are as defined in formula (II), with a acid of formula (XX) R2COOH (XX) or an activated derivative thereof, or (viii) (for compounds in which D is a group of formula (VII) and B is a bond) by reaction of a sulphonamide of formula (XXI) (XXI) wherein A, R, R2 -R 4 are as defined in formula (II) with an acetate of formula (XXII) CH 3 COOCH 2 D (XXII) in the presence of a palladium(O) catalyst.

Inventors: AYSCOUGH ANDREW PAUL, BOWLES STEPHEN ARTHUR, MILLER ANDREW, WHITTAKER MARK, AYSCOUGH, ANDREW, PAUL, BOWLES, STEPHEN, ARTHUR, MILLER, ANDREW, WHITTAKER, MARK
Applicants: AYSCOUGH ANDREW PAUL, BOWLES STEPHEN ARTHUR, BRITISH BIOTECH PHARM, MILLER ANDREW, WHITTAKER MARK, AYSCOUGH, ANDREW, PAUL, BOWLES, STEPHEN, ARTHUR, BRITISH BIOTECH PHARMACEUTICALS LIMITED, MILLER, ANDREW, WHITTAKER, MARK
Application year: 1995
Main classification: C07D471
IPC codes: C07D471