ZA200405260B - N-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases. - Google Patents

N-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases. Download PDF

Info

Publication number
ZA200405260B
ZA200405260B ZA200405260A ZA200405260A ZA200405260B ZA 200405260 B ZA200405260 B ZA 200405260B ZA 200405260 A ZA200405260 A ZA 200405260A ZA 200405260 A ZA200405260 A ZA 200405260A ZA 200405260 B ZA200405260 B ZA 200405260B
Authority
ZA
South Africa
Prior art keywords
pyrazinyl
pyrazine
methylphenylsulfonylamino
methoxy
dichloro
Prior art date
Application number
ZA200405260A
Inventor
Andrew Baxter
Nicholas Kindon
Michael Stocks
Timothy Johnson
Bryan Roberts
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of ZA200405260B publication Critical patent/ZA200405260B/en

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

®
N-PYRAZINYL-PHENYLSULPHONAMIDES AND THEIR USE IN THE TREATMENT } OF CHEMOKINE MEDIATED DISEASES - The present invention relates to a sulphonamide compound, processes and intermediates s used in their preparation, pharmaceutical compositions containing them and their use in therapy.
Certain sulphonamide compounds are known in the art, for example see
GB2295616, US patent 2002143024, WO 01/44239, EP 749964 and Esche, J; Wojahn, H. Arch. Pharm. (1966), 299(2), 147-153.
Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small-secreted 1s molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. At the present time, the chemokine superfamily comprises three groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C), Cys-Cys (C-C) and Cys-X3-Cys (C-X3-C) families. The C-X-C and C-C families have sequence similarity and are distinguished from one another on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues. The C-X;-C family is distinguished from the other two families on the basis of having a triple amino acid insertion between the
NH-proximal pair of cysteine residues.
The C-X-C chemokines include several potent chemoattractants and activators of 2s neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils. Examples include human monocyte chemotactic proteins 1-3 (MCP-1,
MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and
Secreted), eotaxin and the macrophage inflammatory proteins 1a and 1 (MIP-1a and
MIP-18), Thymus and Activation Regulated Chemokine (TARC, CCL17) and Macrophage ’ Derived Chemokine (MDC, CCL22).
The C-X3-C chemokine (also known as fractalkine) is a potent chemoattractant and 35s activator of microglia in the central nervous system (CNS) as well as of monocytes, T cells, NK cells and mast cells.
@ ) } Studies have demonstrated that the actions of chemokines are mediated by subfamilies of ’ G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, ‘ CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 ’ s (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCRS5 (for the C-X-C family) and CX3CR1 for the C-X;-C family. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
The present invention therefore provides a compound of formula (I) and pharmaceutically acceptable salts, solvates or N-oxides thereof:
R' 0
I oH 3 6 2
RY ONT OR
(D in which:
R!, R? and R? are independently hydrogen, halogen, cyano, CF3, OCF;, OC;.s alkyl or Cy. alkyl;
R*is halogen, COR",
Ci-6 alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group; 2s Cs. alkenyloxy or C;.¢ alkynyloxy where either may be optionally substituted with hydroxy or NR™R"?;
OC,.¢ alkyl-X-C.¢ alkyl where the alkyl groups may form a 3-6 membered saturated ring;
OCigalkylR", or OC, alkyl-X-R'' where the alkyl group may form a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR'*R", SR'?, S(0).R", S(O)R" or COR";
® 3 ] OC, alkylR'S; * y R’ and R® are independently hydrogen, cyano, halogen, CO.R'?, CONRRY:
Ci.6 alkyl optionally substituted by hydroxy, NR"*R'>, or 1-3 fluorines;
Cis alkylR' or XCH(R')C)¢ alkyl or XCH(R'®)C,.¢ alkyl where the alkyl group may be optionally substituted with 1-3 groups selected from hydroxy, and NR*R"%;
NRYR"; NR'R'; X-(CH,)qNR “RY; (CH,)nNR “R'%; NHC(0)C, 6 alkyl optionally substituted by one or more hydroxy groups,
Cs.¢ alkynyl or Cs. alkenyl optionally branched and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O;
RY X-R'; X-R'%; X-CpealkylR'S; X-R'S; X-(CH,)nCO,R "2; X-(CH,)nCONRR';
X-(CHz)nR"'; X-(CHa)nCN; X-(CH,)qOR'% (CH,)nOR'%; (CHz)n-X-R''; X-(CH2)gNHC(O)NHR '?; X-(CH,)gNHC(O)R 2;
X-(CHz)qNHS(0)2R'?; X-(CH,)qNHS(O),R'}; X-Cs_galkenyl; X-C alkynyl; nis1,2,3,4o0rS5; qis 2,3,4,5 or 6;
X is NR", 0, 8, S(0), S(0)y;
R'! is an aryl group or a 5-7 membered heteraromatic ring containing 1-4 heteroatoms selected from nitrogen, oxygen or sulphur each of which can be optionally substituted by 1-3 groups selected from halogen, C(O)NR™R", C(O)OR'?, hydroxy, =O, =S, CN, NO,,
COR", NRMR", X(CH)qNR"R", (CH,)nNRR'®, (CH,)nOH, SR", S(O)R", S(O),R"
Ci. alkyl-X-Cy.¢ alkyl, C, alkyl or C, alkoxy where the alkyl group may form a 3-6 membered ring or is optionally substituted with 1-3 groups selected from hydroxy, ) halogen, NR'R"’, SR", S(O)R', S(O),R"3; :
® ‘
Rand R" are independently hydrogen or C;.¢ alkyl where the alkyl group may be substituted with 1-3 fluorine atoms or may form a saturated 3-6 membered ring; , “ R'" and R'® are independently hydrogen, C,.¢ alkyl, Cs.¢ cycloalkyl or (CH2)qOH,
S or R' and R" together with the nitrogen atom to which they are attached form a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C,.s alkyl, C,.¢ alkyl-OH, or hydroxy; and
R'®is a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen or sulphur and optionally substituted with 1-3 groups selected trom hydroxy, cyano, halogen and =0, provided that: » when R” is halogen or C,4alkoxy and R® is hydrogen, halogen, C,4alkyl,
C).alkoxy, C;.oalkylthio, trifluoromethyl or ethynyl and when one of R!, R*orR? is Cy.¢alkyl or C,salkoxy and is meta to the sulphonarnide group then the group ortho to both the sulphonamide group and the C;.¢alkyl or C,.salkoxy group is not hydrogen, e when R* is halogen or C,.salkoxy and R® is hydrogen, halogen, C)alkyl,
Ci.palkoxy, Cyalkylthio, trifluoromethyl or ethynyl and when one of R’ s R? or R3 is Cygalkyl or C,salkoxy and is ortho to the sulphonamide group then the group ortho to the C,.4Alkyl or C,.salkoxy and also meta to the sulphonamide group is not hydrogen, e when two of R', R%, R® are hydrogen and the other is a methyl group para to the sulphonamide and R? is methoxy then R? is not hydrogen or bromo, and » when R® is methyl and RS is methoxy and one of R', R? or R’ is bromo or iodo and the other two are both hydrogen, then the bromo or iodo group is not ortho to the sulphonamide group.
The term aryl includes phenyl and naphthyl. The term alkyl, whether alone or as part of another group, includes straight chain and branched chain alkyl groups. Examples of 5- to 7-membered heteroaromatic ring containing 1 to 4 heteroatoms include thienyl, furanyl, pyrrolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, oxazolyl, 3s thiazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl.
Examples of saturated 4- to 8-membered rings containing 1 to 3 heteroatoms include
® ; morpholine, piperidine and azetidine. Substituents on any rings can be present in any
E suitable ring position including suitable substituents on nitrogen atoms. “ Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will 5s be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
Preferred halogen groups for R', R? and R? are chloro, bromo and fluoro. Preferably one of R!, R? and R*is hydrogen and the other is chloro, bromo or methyl. More preferably R! and R? are chloro at the 2- and 3-positions of the phenyl ring and R*is hydrogen (i.e. 2,3- dichlorophenyl), R' and R? are chloro at the 2- and 4-positions of the phenyl ring and Ris hydrogen (i.e. 2,4-dichlorophenyl) or R' is chloro at the 2-position and R? is methyl at the 3-position of the phenyl ring and R? is hydrogen (i.e 2-chloro-3-methylphenyl). Most 1s preferably R! and R” are chloro at the 2- and 3-positions of the phenyl ring and Ris hydrogen (i.e. 2,3-dichlorophenyl).
In a further aspect the invention provides a compound of formula (I) as defined above but without the provisos where R' and R? are chloro at the 2- and 3-positions of the phenyl ring and R?is hydrogen (i.e. 2,3-dichlorophenyl), R! and R? are chloro at the 2- and 4-positions of the phenyl ring and R?is hydrogen (i.e. 2,4-dichlorophenyl) or R' is chloro at the 2- position and R? is methyl at the 3-position of the phenyl ring and R* is hydrogen (i.e 2- chloro-3-methylphenyl). 2s For the group R* examples of Cs. alkenyloxy include OCH,CH=CH,, examples of
Cs.¢ alkynyloxy include OCH,CCH, examples of OC,.¢ alkyl-O-C, alkyl include
OCH,CH;0Me, examples of OC, alkylR"! include OCH,R", and examples of
OC, alkylR'® include OCH;pyrrolidine.
Preferred groups for R* include Cy alkoxy such as methoxy, 2-furanylmethoxy, bromo, } chloro, 2-methoxyethoxy, (5-methyl-3-isoxazolyl)methoxy, 2-, 3- or 4-pyridylmethoxy, 3-pyridazinylmethoxy, methoxy, 2-(1-imidazolyl)ethoxy, (2-methyl-4-oxazolyl)methoxy and 4-methoxyphenylmethoxy. More preferably R* is methoxy.
For R>and R® examples of NR"R" includes morpholine, pyrrolidine, NMe;,
NHCH,CH,0OMe, NHMe, and the groups below:
\ A
OO
OH and OH
Examples of X-(CH2)gNR'“R"* include SCH,CH,NH, and SCH,CH,NMe; , examples of (CHpnNR'R" include CHsmorpholine, examples of X-R'? includes SMe, OMe, OEt, OH,
SO,Me, examples of X-C,alkylR' includes OCH, pyrrolidine, examples of X- (CH2)nCO,R*? includes SCH,CO,H, SCH,CO,Me, SCH,CH,CO,;Me, examples of X- (CH2)nCONR"R" includes SCH,CONH, , SCH,CONHMe, OCH,;CONEt,, examples of X-(CH2)nR" includes the groups below:
N_
N= 0) Ze N.S
W — 07 P o> \ —/ -
Examples of X-(CH2),CN, includes SCH,CN, examples of X-(CH,)qOR includes
OCH,CH,OMe, examples of (CH2)nOR "2 includes CH,OH, CH,OMe, examples of 1s X-(CH»)QNHC(O)NHR'? includes SCH,CH,NHC(O)NHEY, and examples of
X-(CH,)qNHC(O)R ? includes NHCH,CH,NHC(O)Me. Examples of NHC(O)C,. alkyl optionally substituted by one or more hydroxy groups includes NHCOCH,OH.
Preferred groups for R® include hydrogen, halogen such as bromo and chloro, phenyl,
Cp alkyl such as methyl, CH,0OH, cyano and 2-aminothanethiol. More preferably Ris hydrogen, methyl, CH,OH or halogen such bromo or chloro.
Preferred groups for R® include hydrogen, C.s alkyl, CH,OH and halogen, more preferably hydrogen, methyl, CH,OH or chloro. : In a further aspect the invention provides a compound of formula (1A):
R! 0
No
Rr’ He N Y N bg R
RYTON ORE
(IA) in which sR’, R?’and R*are independently hydrogen, halogen, cyano, CFs, OCF;, C,¢ alkenyl! or
C 1-6 alkyl;
R*is halogen, C,.¢ alkoxy or OR’;
R® and R® are independently hydrogen, halogen, C,.¢ alkoxy, Ci. alkylthio, cyano, R’,
OR’, NR’R'’, SR’, S(CH2),CO,H, S(CH2),CO,R'%, S(CH2),CONR'?R", S(CH2),R" or a 5-to 7-membered heteroaromatic or saturated ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur; nisl, 2or3;
R® and R'® are independently hydrogen, C,., alkyl optionally substituted by hydroxy, C). alkoxy or NHCOC,¢ alkyl, or R® and R' are optionally substituted aryl, C,.¢ alkyl-aryl or
Cig alkyl-R"” or R® and R" together with the nitrogen atom to which they are attached form a 4- to 8-membered saturated ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C,.¢ alkyl or C,.¢ alkyl-OH; and
R'is a 5- to 7-membered heteraromatic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C,.¢ alkyl; and
R7andR" are independently hydrogen or C,.¢ alkyl.
For compounds (IA) R', R? and R? are independently hydrogen, halogen, cyano, CF;,
OCF;, Cy alkenyl or C,.¢ alkyl, preferred halogen groups being chloro. Preferably one of
R!, R?and R*is methyl, ethenyl, cyano, chloro, fluoro, iodo or two are chloro or all three 2s are fluoro. More preferred are compounds where R' — R? together with the phenyl group to which they are attached form a 3-chloro-2-methylpheny! or a 2,3-dichlorophenyl group.
For compounds (IA) preferred groups for R* include halogen such as bromo and chloro,
C,.¢ alkoxy such as methoxy and ethoxy, C,_¢ alkyl or OR’ where R’ is CH,R'! where R"! isa 5- or 6-membered heteraromatic ring containing 1 or 2 heteroatoms.
g
More preferably R* is methoxy, halogen, such as chloro, or OR’ where R® is CH,R'! where . R'is furanyl, 5-methyl-3-isoxazolyl, pyridyl optionally substituted by methyl, pyridazinyl, pyrazinyl, 1-methyl-6-0xo-1,6-dihydro-3-pyridinyl. s For compounds (IA) preferably R’ is hydrogen, methyl, bromo, chloro, methoxy, morpholinyl, pyrrolinyl, dimethylamino, hydroxy, 2-methoxyethoxy, pyrazinyl, pyrimidinyl, O-Ph-CO,H, 2-hydroxyethylamino, 2-methoxyethylamino,
NHCH,CH,NHCOMe, cyano, 4-hydroxymethyl-1-piperidinyl, SMe, NHMe, or 2,4- difluorophenyl.
For compounds (IA) preferably Réis hydrogen or chloro.
Preferred compounds of formula (I)/(IA) include those exemplified herein both in free base form and as pharmaceutically acceptable salts.
According to the invention there is also provided a process for the preparation of compound (I) which comprises reaction of a compound of formula (II):
R5 N R4 ~N
J
R6 N NH, dn where R*, R® and R® are as defined in formula (I) or are protected derivatives thereof with a compound of formula (II): rR! i
RZ $=0
LG
Rr3 10) where R!, R? and R? are as defined in formula (I) or are protected derivatives thereof and
LG is a leaving group, and optionally thereafter
* removing any protecting groups, . » forming a pharmaceutically acceptable salt. i Preferred leaving groups LG include halogen such as chloro. Preferably the reaction s between compounds (II) and (Il) is carried out by treating compound (II) with a base such as sodium hydride or potassium tert-butoxide in a suitable solvent such as 1,2- dimethoxyethane or tetrahydrofuran.
Where R* is C,.¢ alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group; : Cs.6 alkenyloxy or Cs. alkynyloxy where either may be optionally substituted with hydroxy or NR'R!%:
OC\.6 alkyl-X-C. alkyl where the alkyl groups may form a 3-6 membered saturated ring;
OC, alkyIR"!, or OC, alkyl-X-R'! where the alkyl group may form a 3-6 membered - saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR'R"?, SR", S(0),R", S(O)R"?; or
OC. alkyIR'S; compounds of formula (IT) can be prepared by treating a compound of the formula (IV), where LG is a leaving group (such as chlorine or bromine):
RA. N_ _LG ~ 1 1
R N NH, (v) with a compound of formula (V)
R*-H
Vv) in a suitable solvent (such as 1,2-dimethoxyethane, N,N-dimethylformamide or ) tetrahydrofuran) with a suitable base such as sodium hydride or potasssium tert-butoxide at a suitable temperature such as 25°C to 60°C.
Where R” is C;.¢ alkoxy where the alkyl group may form a 3-6 membered saturated ring or . may be substituted with 1-3 fluorine atoms or a cyano group;
Ci. alkenyloxy or Cs. alkynyloxy where either may be optionally substituted with . hydroxy or NR*R">;
OC, alkyl-X-C, alkyl where the alkyl groups may form a 3-6 membered saturated ring;
OC, 6 alkyIR", or OCs alkyl-X-R" where the alkyl group may form a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR"“R"’, SR", S(O),R", S(O)R"; or
OC, alkylR'¢; compounds of formula (I) can be prepared by treating a compound of the formula (V1), where LG is a leaving group (such as chlorine or bromine): :
Ri. _N._ _LG
AN
BD bg
R N NH
0=S8=0 “0
RZ TR’ (V1) with a compound of formula (V) in a suitable solvent (such as 1,2-dimethoxyethane, N, N-dimethylformamide or tetrahydrofuran) with a suitable base such as sodium hydride or potasssium tert-butoxide at a suitable temperature such as 25°C to 60°C.
Compounds of structure (V111) can be prepared by taking a compound of formula (V1) where LG is a leaving group (such as chlorine or bromine) and protecting the sulfonamide as for example the trimethylsilyethoxymethyl ether (SEM) or methoxymethy] ether . 2s (MOM) by the standard literature methods (such as SEM-chloride or MOM-chloride) in a suitable solvent (such as tetrahydrofuran) with a suitable base (such as triethylamine) at a . suitable temperature (such as 0-20°C) to afford compound of the formula (V111):
® 1
LG. _N : 4 or rr
N Ps : R P
R® N NH Rr Nd } O0=8=0 0=8=0
R® R’ Rr’ R’ (Vi) (vi)
Compound of formula (VIII) could then be treated with compounds of formulae (1X):
R*-H (1x) where R>-H is a primary or secondary amine, thiol or alcohol as defined above (i.e. where
R’isa group containing an X moiety where X is NR'?, O or 8), in a suitable solvent (such as tetrahydrofuran or acetonitrile) with or without a suitable base (such as sodium hydride, caesium carbonate or triethylamine) at a suitable temperature ranging from 25-85°C to afford compound of the formula (X):
RA_ _N_ _R
IX
= P
R*” ON N” 0=8=0 2 R®
R
X) : The protecting group (P) can then be removed by standard methods to afford compound of formula (1).
Compounds of structure (11) or (1), where R’ is an optionally substituted aryl or heteroaryl ring as defined in the claims, can be prepared by taking a compound of formula (X1) or (VII) where LG is a suitable leaving group such as bromine, chlorine or iodine and reacting
® 12 it with an aryl or heteroaryl boronic acid such as phenyl boronic acid, a palladium catalyst . such as [1,1°-bis(diphenylphosphino)ferrocene]palladium (11) chloride, a suitable base such as caesium fluoride, sodium acetate or caesium carbonate and a suitable solvent such as i methanol or ethanol and heating between 40-80°C 4 5 4
R N R
Tr TT ~~ 6 —
R° N™ NH, R N™ “NH, (xX 4) : RL. N_ _R*
Or TX — 2
RS NT NH . RT ONT TH 0=8=0 0=S=0 1 3 3 2 R
R? R R (VID) 0)
Compounds of formula (11) and (1) where R® or R® is CO,R"® can be prepared by reacting a compound of formula (11) or (1), where R® or R® is bromine or iodine, in a suitable solvent 1s such as ROH or dioxane containing R'> OH, a suitable tertiary amine such as triethylamine, a suitable palladium catalyst such as [1,1°-bis(diphenylphosphino)ferrocene]palladium (11) chloride under an atmosphere of carbon monoxide usually at 2-10 bar, ideally at 4-6 bar and at a temperature of 70-120 °C.
Compounds of formula (11) and (1) where R® or RS is CONRMR'® can be prepared by reacting a compound of formula (11) or (1), where R® or R® is bromine or iodine, in a suitable solvent such as dioxane containing NHR'“R'%, a suitable tertiary amine such as triethylamine, a suitable palladium catalyst such as [1,1°-bis(diphenylphosphino)ferrocene]palladium (11) chloride under an atmosphere of carbon monoxide usually at 2-10 bar, ideally at 4-6 bar and at a temperature of 70-120 °C, 2s Compounds of formula (1) where R’ or R® is CH,OH can be prepared from compounds of formula (I) where R® or R®is COR" by reduction using a suitable reducing agent such as
® E lithium triethylborohydride in a suitable solvent such as tetrahydrofuran at a temperature of - 0-10°C. - Compounds of formula (1) where R® or R° is CHO can be prepared from compounds of formula (1) where R® or R® is CH,OH by oxidation using a suitable oxidising agent such as manganese dioxide or pyridinium chlorochromate (PCC) in a suitable solvent such as tetrahydrofuran or dichloromethane at a temperature of 0-50°C.
Compounds of formula (I) where R® or R® is CH(OH)R'' or CH(OH)(C1-5)alkyl can be prepared from compounds of formula (1) where R® or R® is CHO by reaction with a compound of formula (XII) where M is a metal such as magnesium or lithium in a suitable solvent such as tetrahydrofuran or diethyl ether at a temperature of 0-10°C
Cys alkylM or R''M (X11)
RA. _N_ _R ii RNS
TN O0—=s=0 : Bi 1 x i ’ <0) RON NH
R N LG
R? 3 0=8=0 “0
Rr R’ xin (XIV) (XV)
A compound of formula (XV) can be made by reacting a compound of formula (XIII), where R’ is preferrably chloro, bromo or alkoxy and LG is a suitable leaving group such as chloro or bromo, with a compound of formula (XIV) using a suitable base such as potassium carbonate or caesium carbonate in a suitable solvent such as N,N- dimethylformamide at a temperature of 40-90°C
Intermediate compounds of formula (II) and (III) can be prepared using standard chemistry : 25 or are available commercially. : It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compound may need to be protected by protecting groups. Thus, the preparation of the compound of formula (I) may involve, at an appropriate stage, the [
® y removal of one or more protecting groups. The protection and deprotection of functional
E groups is fully described in ‘Protective Groups in Organic Chemistry’, edited by J. W. F.
McOmie, Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’, 2nd edition, : T. W. Greene & P. G. M. Wuts, Wiley—Interscience (1991).
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably a basic addition salt such as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.
Certain compounds of formula (II) and (III) are believed to be novel and form a further aspect of the invention.
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably a basic addition salt such as sodium, potassium, calcium, aluminium, lithinm, magnesium, zine, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.
The compounds of formula (I) has activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CCR4) activity, and may be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals which are exacerbated or caused by excessive or unregulated production of chemokines.
Examples of such conditions/diseases include: (1) (the respiratory tract) obstructive airways diseases including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, ; intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, . atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa
® 15 (hay fever) and vasomotor rhinitis; sarcoidosis, farmer’s lung and related - diseases, fibroid lung and idiopathic interstitial pneumonia; : (2) (bone and joints) gout, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and
Reiter’s disease), Behcet's disease, Sjogren’s syndrome and systemic sclerosis; (3) (skin) pruritis, scleroderma, otitus, psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, ~~.
Alopecia areata and vernal conjunctivitis, lupus; (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, inflammatory bowel diseases such as Crohn’s disease, ulcerative colitis, ileitis and enteritis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema, (5) (central and peripheral nervous system) Neurodegenerative diseases and dementia disorders, e.g. Alzheimer’s disease, amyotrophic lateral sclerosis and other motor neuron diseases, Creutzfeldt-Jacob’s disease and other prion diseases, HIV encephalopathy (AIDS dementia complex), Huntington’s disease, frontotemporal dementia, Lewy body dementia and vascular dementia; polyneuropathies, e.g. Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, plexopathies; CNS demyelination, e.g. multiple sclerosis, acute disseminated/haemorrhagic encephalomyelitis, and subacute sclerosing panencephalitis; neuromuscular disorders, e.g. myasthenia gravis and Lambert-
Eaton syndrome; spinal diorders, e.g. tropical spastic paraparesis, and stiff-man syndrome: paraneoplastic syndromes, e.g. cerebellar degeneration and . encephalomyelitis; CNS trauma; migraine; stroke and correctum diseases such as meningitis (6) (other tissues and systemic disease) hepatitis, vasculitis, spondyloarthopathies, vaginitis, glomerulonephritis, myositis, atherosclerosis,
Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus,
® 16 systemic lupus, erythematosus, Hashimoto’s thyroiditis, type I diabetes, ; nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, and idiopathic thrombocytopenia pupura; post-operative adhesions, . and sepsis. (7) (allograft and xenograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease; (8) Cancer, carcinoma & tumour metastasis, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin, especially non-small cell lung cancer (NSCLC), malignant melanoma, prostate cancer and squamous sarcoma. Hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukemia, B cell lymphoma and Burketts lymphoma, Hodgkins Lymphoma, Acute Lymphoblastic Leukemia.
Hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia. Tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma, and other tumors, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma. (9) All diseases that result from a general inbalance of the immune system and resulting in increased atopic inflammatory reactions. (10) Cystic fibrosis, re-perfusion injury in the heart, brain, peripheral limbs and other organs. (11) Burn wounds & chronic skin ulcers 3 (12) Reproductive Diseases (e.g. Disorders of ovulation, menstruation and implantation, Pre-term labour, Endometriosis) (13) thrombosis (14) infectious diseases such as HIV infection and other viral infections, bacterial infections.
® 17
Thus, the present invention provides a compound of formula (I), or a pharmaceutically- ; acceptable salt or solvate thereof, as hereinbefore defined for use in therapy. . Preferably the compound of the invention are used to treat diseases in which the chemokine receptor belongs to the CC chemokine receptor subfamily, more preferably the target chemokine receptor is the CCR4 receptor.
Particular conditions which can be treated with the compound of the invention are asthma, rhinitis and inflammatory skin disorders, diseases in which there are raised TARC, MDC or CCR4 levels. It is preferred that the compound of the invention is used to treat asthma and rhinitis, especially asthma.
In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
In a still further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of chemokine receptor activity, particularly CCR4 activity, is beneficial.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
Co.
The invention still further provides a method of treating a chemokine mediated disease wherein the chemokine binds to a chemokine (especially CCR4) receptor, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
The invention also provides a method of treating a respiratory disease, such as athma and rhinitis, especially asthma, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.

Claims (1)

  1. PCT/SE03/00041 PS 154 Claims
    1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: R' 0 [l 3 (3 = rR” NT TR oy in which: R!, R? and R? are independently hydrogen, halogen, cyano, CFs, OCFs, OCy. alkyl or Ci. alkyl; R*is halogen, COR,
    C..¢ alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group;
    Cs.¢ alkenyloxy or Cj. alkynyloxy where either may be optionally substituted with hydroxy or NR™R";
    OC,.¢ alkyl-X-C1.6 alkyl where the alkyl groups may form a 3-6 membered saturated ring;
    OC. alkylR'!, or OC. alkyl-X-R'! where the alkyl group may form a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NRY“R", SR", S(0),R", S(O)R"* or COR";
    OC. alkylR'®; CLEAN COPY
    PCT/SE03/00041 @: and R® are independently hydrogen, cyano, halogen, CO,R'2, CONRMR";
    Ci.¢ alkyl optionally substituted by hydroxy, NRYRY, or 1-3 fluorines;
    Cy. alkylR"" or XCH(R'")C\. alkyl or XCH(R'®)Cy.s alkyl where the alkyl group may be optionally substituted with 1-3 groups selected from hydroxy, and NR'“R"; NRM“RY: N(R'R"; X-(CHy)gNR“R"’; (CH2)nNR'“R'’; NHC(O)C,.6 alky! optionally substituted by one or more hydroxy groups,
    "Cs. alkynyl or C36 alkenyl optionally branched and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O; R': XR": X-R'% X-CyealkylR'S; X-R'S; X-(CH)nCO;R'%; X-(CH2)nCONR'“R"; X-(CHpnR'"; X-(CH2)nCN; X-(CH,)qOR'2; (CHz)nOR'%; (CHy)n-X-R''; X-(CH;)gNHC(O)NHR '%; X-(CH,)qNHC(O)R'%; X-(CHz)qNHS(0);R 2; X-(CH;)gNHS(0),R"'; X-Cj. alkenyl; X-Cs.salkynyl; nis 1,2,3,40r5; qis2,3,4,50r6; X is NR", 0, S, S(0), S(O); R!! is an aryl group or a 5-7 membered heteraromatic ring containing 1-4 heteroatoms selected from nitrogen, oxygen or sulphur each of which can be optionally substituted by 1-3 groups selected from halogen, C(O)NR'R", C(O)OR'?, hydroxy, =O, =, CN, NO, COR", NR“RY, X(CH,)qNR"R", (CH;)nNR“R", (CH)nOH, SR", S(O)R", S(O).R"
    Ci. alkyl-X-C, 6 alkyl, Cy alkyl or Cy. alkoxy where the alkyl group may form a 3-6 membered ring or is optionally substituted with 1-3 groups selected from hydroxy, halogen, NRM“RY, SR", S(O)R"?, S(O).R"; R'2and R" are independently hydrogen or C.¢ alkyl where the alkyl group may be substituted with 1-3 fluorine atoms or may form a saturated 3-6 membered ring; R'" and R" are independently hydrogen, C6 alkyl, Cs. cycloalkyl or (CH;)qOH, CLEAN COPY
    PCT/SE03/00041 @- R' and R" together with the nitrogen atom to which they are attached form a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by Ci.¢ alkyl, C1. alkyl-OH, or hydroxy; and R'® is a 4-8 membered saturated rin g containing 1-3 heteroatoms selected from nitrogen, oxygen or sulphur and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O, provided that: e when R* is halogen or C;4alkoxy and RS is hydrogen, halogen, Caalkyl,
    C,.;alkoxy, Cj.zalkylthio, trifluoromethyl or ethynyl and when one R!, R? or R}is Ci. salkyl or C,.¢alkoxy and is meta to the sulphonamide group then the group ortho to both the sulphonamide group and the Cy.alkyl or C,.¢alkoxy group is not hydrogen, e when R* is halogen or Cj4alkoxy and R’ is hydrogen, halogen, Cy.4alkyl, Cy.qalkoxy,
    'C,.;alkylthio, trifluoromethyl, or ethynyl and when one of R!, R2orR%is C,.¢alky! or
    C.¢alkoxy and is ortho to the sulphonamide group then the group ortho to the C,. salkyl or Cj.¢alkoxy and also meta to the sulphonamide group is not hydrogen, e when two of R', R% R? are hydrogen and the other is a methyl group para to the sulphonamide and R* is methoxy then R’ is not hydrogen or bromo, e when R® is methyl and R*is methoxy and one of R', R2 or R? is bromo or iodo and the other two are both hydrogen, then the bromo or iodo group is not ortho to the sulphonamide group, e when R’ is methyl and R® is methoxy and one of R', R? or R® is bromo or iodo and the other two are both hydrogen, then the bromo or iodo group is not ortho to the sulphonamide group, e and the compound is nut 2-(2-phenoxyethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine 5-phenyl-2-(2-(N-phenyl-N-methylamino)ethyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine : 2-(2-(N-methyl-N-benzylamino)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(N -methyl-N-phenylamino)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-((tetrahydrofuran-2-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(cyclohexylmethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(piperidin- 1-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine : AMENDED SHEET
    PCT/SE03/00041
    9... yclopentylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(morpholin-4-yl)ethyloxy)-3-(4-methylphen ylsulfonylamino)pyrazine 2-(2-cyclopropylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-c yclohexylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(3-(piperidin-1-yl)propyloxy)-3-(4-methylphen ylsulfonylamino)pyrazine 2-(cyclopentylmethylox y)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-fl uorophenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-fluorophenylsulfon ylamino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-chlorophenylsutfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-chlorophenylsulfonyl amino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-phen ylamino)ethyloxy)-3-(4-bromophenylsulfonylamin o)pyrazine 2-(2-phenoxyethyloxy)-3-(4-bromophenylsulfon ylamino)pyrazine 2-(2-(N-methyl-N-phen ylamino)ethyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine 2-(2-phenoxyeth yloxy)-3-(4-ethylphenylsulfonylamino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine 2-(2-(N-methyl-N -phenylamino)ethyloxy)-3-(4-propylphenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-propylphenylsulfon ylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-(1 -methylethyl)phenylsulfonylamino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-(1 -methylethyl)phenylsulfonylamino)pyrazine 6-(perhydroazepin-1 -yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-cyclobutylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-cyclopentylaminocarbonyl-2-((pyridin-3 -yh)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine | . 6-cyclohexylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(pyrrolidin-1 -ybcarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(3-hydroxypyrrolidin-1 -yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine AMENDED SHEET
    PCT/SE03/00041
    7 ylpiperazin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(morpholin-4-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(thiomorpholin-4-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1,1-dimethylethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1 ,2-dimethylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1,3-dimethylbutyl)ami nocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1-meth ylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1 -ethylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- ] methylphenylsulfonylamino)pyrazine 6-(1-meth ylbutyl)aminocarbonyl-2-((pyridin-3-yl)meth yloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2,2-dimethylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-hydroxypropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-methylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-pentylami nocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-dimethylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-diethylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-methyl-N-propylamino)carbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-dipropylaminocarbonyl-2-((pyridin-3-yl)methylox y)-3-(4- methylphenylsulfonylamino)pyrazine AMENDED SHEET
    PCT/SE03/00041 outta nocarbon yl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfon ylamino)pyrazine 6-ethylaminocarbonyl-2-((pyridin-3-yl)meth yloxy)-3-(4-methylphenylsulfonylamino)pyrazine 6-(3-hydroxypiperidin-1-yl)carbonyl-2-((pyridin-3 -yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-meth yl-N-(2-methylpropyl)amino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-meth yl-N-pentylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-methyl-N-(1 -methylethyl)amino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1-methylethyl)aminocarbonyl-2-((pyridin-3 -yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-((1R)-1-methyl-2-h ydroxyethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N -ethyl-N-(2-hydroxyethylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-hydroxymeth ylpyrrolidin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-methylpiperidin-1-yl)carbonyl-2-((pyridin-3 -yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(3-methylpiperidin-1-yl)carbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(4-methylpiperidin-1 -ylcarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1,1-dimethylpropyl)aminocarbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-methylbutylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-dimethylaminoethyl)aminocarbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-hydroxyethyl)aminocarbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(3-methylbutyl)aminocarbonyl-2-((pyri din-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine AMENDED SHEET
    PCT/SE03/00041
    @:.3-dimethylaminopropylyaminocarbonyl-2-((pyridin-3-yDmethyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-hexylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazin 6-(N-meth yl-N-butylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-ethyl-N-butylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-methyl-N-(2-dimethylaminoethylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-ethyl-N-(1-methylethylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-(1-hydroxyethyl)-N-(1-methylethyl)amino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-((2R)-2-hydroxymethylpyrrolidin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N -ethy]-N-methylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-(2-hydroxyethyl)-N -propylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-carboxy-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine or 6-methoxylcarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine.
    2. A compound according to claim 1 in which one of R!, R? and R?is hydrogen and the other is chloro, bromo or methyl.
    3. A compound according to claim 1 or 2, in which R! and R*are chloro at the 2- and 3- positions of the phenyl ring and R? is hydrogen, or R! and R? are chloro at the 2- and 4- positions of the phenyl ring and R?is hydrogen, or R! is chloro at the 2-position and Ris methyl at the 3-position of the phenyl ring and R3is hydrogen.
    4. A compound according to any one of claims 1to 3 in which R* is C; alkoxy such as methoxy, 2-furanylmethoxy, bromo, chloro, 2-methoxyethoxy, (5-methyl-3- isoxazolyl)methoxy, pyridylmethoxy, 3-pyridazinylmethoxy, methoxy, 2-(1- imidazolyl)ethoxy, (2-methyl-4-oxazolyl)methoxy and 4-methoxyphenylmethoxy. AMENDED SHEET
    PCT/SE03/00041 o A compound according to any one of claims 1 to 4 in which R* is methoxy.
    6. A compound according to any one of claims 1 to 5 in which R’ is hydrogen, halogen such as bromo and chloro, phenyl,-C,.¢ alkyl such as methyl, CH,OH, cyano and 2-aminothanethiol
    7. A compound according to any one of claims 1 to 6 in which R® is hydrogen,
    C..6 alkyl, CH,OH and halogen.
    8. A compound according to claim 1 in which is: 2,3-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)-benzenesulphonamide N-(6-Chloro-3-methoxy-2-pyrazinyl)-2,3,4-tifluorobenzenesulphonamide 3-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)-2-methylbenzenesulphonamide
    2.3-Dichloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
    2.3-Dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,5-dichlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-3,5-dichlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,4-dichlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-3,4-dichlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-4-chlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-3-chlorobenzenesulphonamide N-(3-Methoxy-5-methyl-2-pyrazinyl)-2-fluorobenzenesulphonamide N-(3-Methoxy-5-methyl-2-pyrazinyl)benzenesulphonamide N-(3-Methoxy-5-methyl-2-pyrazinyl)-2-iodobenzenesulphonamide N-(3-Methoxy-5-methyl-2-pyrazinyl)-3-fluorobenzenesulphonamide 2-[[(3-Methoxy-5-methyl-2-pyrazinyl)amino]sulphonyl]benzonitrile N-(5-Bromo-3-methoxy-2-pyrazinyl)benzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)2-iodobenzenesulphonamide
    2.3-Dichloro-N-[3-(2-furanylmethoxy)-5-methyl-2-pyrazinyl Jbenzenesulphonamide
    2.3-Dichloro-N-[5-methyl-3-(5-methyl-3-isoxazolylmethoxy)-2- pyrazinyl]benzenesulphonamide
    2.3-Dichloro-N-[5-methyl-3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
    2.3-Dichloro-N-[5-methyl-3-(6-methyl-2-pyridinylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-methyl-3-(3-pyridinylmethoxy)-2-pyrazinyl Jbenzenesulphonamide 2,3-Dichloro-N-[5-methyl-3-(4-pyridinylmethoxy)-2-pyrazinyl Jbenzenesulphonamide AMENDED SHEET
    PCT/SE03/00041 @ coro N-(5-methyl-3-(3-methyl-2-pyridinylmethoxy)-2- pyrazinyl}benzenesulphonamide 2,3-Dichloro-N-[5-methyl-3-(3-pyridazin ylmethoxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-(3 -pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide N-[5 -Bromo-3-(2-pyrazinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(1-methyl-6-oxo-1,6-dihydro-3-pyridinylmethox y)-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide N-[5-Bromo-3-(3 -pyridazinylimethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(3 -pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N _[5-Bromo-3-(5-pyrimidinylmethoxy)-2-pyrazinyl}-2,3-dichlorobenzenesulphonamide N-[5-Chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Chloro-3-(5-pyrimidinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide 2-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benezenesulphonamide 4-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benezenesulphonamide N-(6-Chloro-3-methoxy-2-pyrazinyl)-2,4-dichlorobenezenesulphonamide N-(6-Chloro-3-methoxy-2-pyrazinyl)-3 ,4-dichlorobenezenesulphonamide 3-Chloro-N-(3 -methoxy-5-methyl-2-pyrazinyl)-2-methylbenezenesulphonamide 2-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide 3-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide 4-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide 2 4-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide 3 4-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide N-(5-B romo-3-methoxy-2-pyrazinyl)-2-trifiuoromethoxybenezenesulphonamide 3-Chloro-N-(5-chloro-3-methox y-2-pyrazinyl)-2-methylbenzenesulphonamide 2-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
    3.Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 4-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide N-(5-Chloro-3 -methoxy-2-pyrazinyl)-2,4-dichlorobenzenesulphonamide
    2.3-Dichloro-N-[3-methoxy-5-(4-morpholinyl)-2-pyrazinylJbenzenesulphonamide
    2.3-Dichloro-N-[3,5-dimethoxy-2-pyrazinyl]benzenesulphonamide
    2.3-Dichloro-N-[3-methoxy-5-(1 -pyrrolinyl)-2-pyrazinylJbenzenesulphonamide 3-Chloro-N-(5,6-dichloro-3-methoxy-2-p yrazinyl)-2-methylbenzenesulphonamide 2,3-Dichloro-N-(5 ,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 2-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 3-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 4-Chloro-N-(5,6-dichloro-3-methox y-2-pyrazinyl)benzenesulphonamide AMENDED SHEET
    PCT/SE03/00041 ®, 1 chior0.-(5.6.dichlore-3-methoxy-2-pyrazinylbenzenesulphonamide 3,4-Dichloro-N-(5,6-dichloro-3 -methoxy-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-(3-methoxy-5,6-dimethyl-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-(6-chloro-3 ,5-dimethoxy-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-[6-chloro-3 -methoxy-5-(4-morpholinyl)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-{6-chloro-5-(2-hydroxyethylami no)-3-methoxy-2- pyrazinyl]benzenesulphonamide
    2.3-Dichloro-N-[6-chloro-5-dimethylamino-3-methox y-2-pyrazinyl]benzenesulphonamide
    2.3-Dichloro-N-[6-chloro-3-methoxy-5-(2-methoxyethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[6-chloro-5-hydroxy-3-methox y-2-pyraziny!]benzenesulphonamide 2,3-Dichloro-N-[6-methoxy-5-([2,2’ Ibipyrazinylyl)]benzenesulphonamide 4-{5-(2,3-Dichlorobenzenesul phonylamino)-6-methoxy-2-pyrazinyloxy]benzoic acid
    2.3-Dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
    2.3-Dichloro-N-{6-chloro-3-methoxy-5-([2-methoxyeth yl)amino}-2- pyrazinyl }benzenesulphonamide N-{ 2-[3-Chloro-5-(2,3-dichlorobenzenesulphonylamino)-6-methoxy-2- pyrazinylaminoJethyl } acetamide
    2.3-Dichloro-N-[5-(4-hydroxymethyl-1-piperidinyl)-3 -methoxy-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5 _cyano-3-(3-pyridinylmethoxy)-2-pyrazinyljbenzenesulphonamide
    2.3-Dichloro-N-(6-chloro-3-methoxy-5-methylamino-2-pyrazinyl )benzenesuiphonamide 2,3-Dichloro-N-(3 -methoxy-5-methylsulphanyl-2-pyraziny!)benzenesulphonamide
    2.3-Dichloro-N-[5-(2,4-diflucrophen yl)-3-methoxy-2-pyrazinyl]benzenesulphonamide [5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]acetic acid methyl ester [5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyljacetic acid
    2.3-Dichloro-N-[5-(2-chlorobenzylsulphanyl)-3 -methoxy-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[6-chloro-5-(3-hydroxy-1 -azetidinyl)-3-methoxy-2- ~ pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-meth yl-3-(1-oxy-3-pyrazinylmethox y)-2-pyrazinylJbenzenesulphonamide
    2.3-Dichloro-N-[5-chloro-3-(4-pyridinylmethoxy)-2-pyrazinylJbenzenesulphonamide
    2.3-Dichloro-N-[5-chloro-3-(1-oxy-4-pyridinylmethox y)-2-pyrazinyl}benzenesulphonamide
    2.3-Dichloro-N-[S-chloro-3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
    2.3-Dichloro-N-[5-chloro-3-(2-methylsulphanylethoxy)-2-pyrazinyl]benzenesulphonamide N-(3-Butoxy-5-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
    2.3-Dichloro-N-[{5-chloro-3-(2-methyl-3-pyridinylmethoxy)-2- pyrazinyl]benzenesulphonamide AMENDED SHEET
    PCT/SE03/00041 ®, 1 cioro-(5-chioro-3 -(6-methyl-2-pyridinylmethoxy)-2- pyrazinyi]benzenesulphonamide 2,3-Dichloro-N-[5-chloro-3-(1-oxy-2-pyridinylmethox y)-2-pyrazinyl]benzenesulphonamide 3-Chloro-N-[5-chloro-3-(3-pyridin ylmethoxy)-2-pyrazinyl}-2-methylbenzenesulphonamide 3-Chloro-N-[5-chloro-3-(3 -pyridinylmethoxy)-2-pyrazinyl]-2-fluorobenzenesulphonamide
    2.3-Dichloro-N-[5-chloro-3-(4-methoxyphenylmethox y)-2-pyrazinyl}benzenesulphonamide N-[5 -Bromo-6-chloro-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide 2,3-Dichloro-N-[6-chloro-3-(3 -pyridinylmethoxy)-2-pyrazinyl}benzenesulphonamide 2,3-Dichloro-N-[6-chloro-3-(2-pyridinylmethoxy)-2-pyrazinylJbenzenesulphonamide N-[5-(2-Aminoethylsulphanyl)-3-(2-pyridinylmethoxy)-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide
    2.3-Dichloro-N-[5-chloro-3-(6-methoxy-3-pyridinylmethoxy)-2- pyrazinyl}benzenesulphonamide N-[3-(3-Bromophenylmethoxy)-5-chloro-2-pyrazinyl] -2,3-dichlorobenzenesulphonamide 3-[6-Chloro-3~(2,3-dichlorobenzenesulphonylamino)-2-pyrazinyloxymethyljbenzoic acid methyl ester 3-[6-Chloro-3-(2,3-dichlorobenzenesulphonylamino)-2-pyrazinyloxymethyl]benzoic acid :
    2.3-Dichloro-N-[5-chloro-3-(3-hydroxymethylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide
    2.3-Dichloro-N-[5-chloro-3-(3-methylaminomethylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-chloro-3-{ 3-([2-hydroxyethylamino]methyl)phenylmethoxy }-2- pyrazinyljbenzenesulphonamide
    2.3-Dichloro-N-[5-chloro-3-(4-hydroxymethylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide
    2.3-Dichloro-N-[{S-chloro-3- {4-([2-hydroxyethylamino]methyl)phenylmethoxy }-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-(4-h ydroxymethylphenylmethoxy)-2-pyrazinyl}benzenesulphonamide
    2.3-Dichloro-N-[5-chloro-3-(2-hydroxymethylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide 5-(2,3-Dichlorobenzenesuphonyl amino)-6-methoxypyrazine-2-carboxylic acid, methyl ester 2,3-Dichloro-N-{5-(1-hydroxy-1-methyleth yb)-3-methoxy-2-pyrazinyl}benzenesulphonamide N-[5-(2-Aminoethoxy)-3 -methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-{5-[(2-Aminoeth ylthio]-6-chloro-3-methoxy-2-pyrazinyl }-2,3- dichlorobenzenesulfonamide 3-[(5-{[(2,3-Dichlorophenyl)sulphonyljamino} -6-methoxy-2-pyrazinyl)thio]propanoic acid, methyl ester 2 3-Dichloro-N-[5-bromo-3-methox y-6-methyl-2-pyrazinyl ybenzenesulphonamide AMENDED SHEET
    PCT/SE03/00041
    ©... 5 Dichiorobenzencsulphonylaming)-6-methoxy-3-methylpyrazine-2-carboxylic aicd, methyl ester 2,3-Dichloro-N-[5-(hydroxymethyl)-3 -methoxy-6-methyl-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-[5,6-dichloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide 3-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-2-fluorobenzenesulphonamide 3-Chloro-2-fluoro-N-[3-(3-pyridinylmethoxy)-2-pyrazinyl}benzenesulphonamide 3-{[(2,3-Dichlorophenyl)sulphonyl]amino } pyrazine-2-carboxylic acid, methyl ester N-(5-Bromo-6-chloro-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide 3-Chloro-5-{[(2,3-dichlorophenyl)sulphonyl]amino }-6-methoxypyrazine-2-carboxylic acid, methyl ester 2,3-Dichloro-N-[6-chloro-5-(hydroxymethyl)-3-methoxypyrazin-2-yl]benzenesulphonamide 2,3-Dichloro-N-{3-[(6-methoxy-3-pyridinyl)methoxy]-2-pyrazinyl }benzenesulphonamide 2,3-Dichloro-N-[6-chloro-3-methoxy-5-(methox ymethyl)-2-pyrazinyl]benzenesul phonamide 2-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-3-fluorobenzenesulphonamide 2-Chloro-3 -fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide 2-Chloro-3-methoxy-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide N-[5-Bromo-3-[(25)-2-pyrrolidinylmethoxy]-2-pyrazinyl]-2,3 -dichlorobenzenesulphonamide 5-(2,3-Dichlorobenzenesulphonylamino)-6-(3-pyridinylmethoxy)pyrazine-2-carboxylic acid, methyl ester 5-{[(2,3-Dichlorophenyl)sulphonyl]amino }-6-(3-pyridinylmethoxy)-2-pyrazinecarboxamide
    2.3-Dichloro-N-[5-(4-pyridinyl)-3-(3-pyridinylmethoxy)-2-pyrazinylJbenzenesulphonamide 2,3-Dichloro-N-[5-(hydroxymethyl)-3-(3-pyridinylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-(hydrox ymethyl)-3-methoxy)-2-pyrazinyl]benzenesulphonamide 4-Amino-2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide N-(5-Allyloxy-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide 2,3-Dichloro-N-[5-(3-hydroxy-1-propyn yl)-3-methoxy-2-pyrazinyl]benzenesulphonamide N-{3-[(5-Bromo-3-pyridinyl)methoxy}-5-chloro-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide 2 3-Dichloro-N-[5-chloro-3- { [6-(hydrox ymethyl)-2-pyridinylJmethoxy }-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-{5-chloro-3-[(2-methyl-4-oxazolyl)methoxy]-2- pyrazinyl }bénzenesulphonamide 2 3-Dichloro-N-{3-[(2-methyl-4-oxazolyl)methoxy]-2-pyrazinyl }benzenesulphonamide N-[5-Bromo-3-(phen ylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-(2-c yclopropylethoxy)pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(3-thien ylmethoxy)pyrazinyl]-2,3-dichlorobenzenesulphonamide AMENDED SHEET
    PCT/SE03/00041 ® 166 N-{5-Bromo-3-[(2-methyl-3-furanyl)methoxy]-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide N-{5-Bromo-3-[(3-furanyl)methoxy]-2-pyrazinyl }-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-[(4-fluorophenyl)methoxy}-2-pyrazinyl }-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-[(3-fluorophenyl)methoxy]-2-pyrazinyl }-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-{3-(2-pyridinyl)propoxyl-2-pyrazinyl }-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(pentyloxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(propyloxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(2-methox yethoxy)-2-pyrazinyl}-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(2-ethox yethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(2-fluoroethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-[2-(1 H-imidazol-1-yl)ethoxy}-2-pyrazinyl }-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-[3-(3-pyridinyl)propoxy]-2-pyrazinyl }-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-[2-(methylamino)ethoxy]-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-[3-(4-hydroxyphenyl)propoxy]-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide N-[5-Bromo-3-(2-phenoxyethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(cyclopropylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3 -(3-phenoxypropoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide 2 3-Dichloro-N-(5-ethoxy-3-methoxy-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-[3-methoxy-5-([1,2,4]-1 -triazolyl)-2-pyrazinyl]benzenesulphonamide 2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]-N- methylacetamide 2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]acetamide 2,3-Dichloro-N-[5-(4-fluorobenzylsulphanyl)-3-methoxy-2-pyrazinylJbenzenesulphonamide
    2.3-Dichloro-N-[5-cyanomethylsulphanyl-3-methoxy-2-pyrazinyl]benzenesulphonamide 2 3-Dichloro-N-[3-methoxy-5-([1,2,4]-3-oxadiazolylmethylsulphanyl)-2- pyrazinyl]benzenesulphonamide N-[5-(2-Aminoethylsulphanyl)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide 2,3-Dichloro-N-[3-methoxy-5-(5-methyl-3-isoxazolylmethoxy))-2- pyrazinyl]benzenesulphonamide
    2.3-Dichloro-N-[5-(5-dimethylaminomethyl-2-furanylmethox y)-3-methoxy-2- pyrazinyl]benzenesulphonamide N-[5-Bromo-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2-pyrazinyl] -2,3-dichloro- benzenesulphonamide
    2.3-Dichloro-N-{5-(2-hydroxyeth ylsulphanyl)-3-methoxy-2-pyrazinyl]benzenesuiphonamide 2 3-Dichloro-N-{5-[2-(ethylureido)ethylsulphanyl]-3-methoxy-2- pyrazinyl}benzenesulphonamide AMENDED SHEET
    PCT/SE03/00041
    @. 1 chioro-(3-(5-dimethylaminomethyl-2-furan ylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[6-chloro-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2- pyrazinyl]benzenesulphonamide : 2,3-Dichloro-N-[6-chloro-3-(5-methylaminomethyl-2-furanylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-{5-chloro-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-(5-methylaminomethyl-2-furanylmethoxy)-2- pyrazinyl]benzenesulphonamide N-(5-Bromo-3-methoxypyrazinyl)-2-cyanobenzenesulphonamide N-(5-Bromo-3-methoxypyrazinyl)-2,3-dichloro-4-fluorobenzenesulphonamide 2,3-Dichloro-N-[3-methoxy-5-(4-morpholinylmethyl)-2-pyrazinyl Jbenzenesulphonamide N-(3-Allyloxy-5-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide 2,3-Dichloro-N-[5-chloro-3-(2-propynyloxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-(2-propynyloxy)-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-(5-cyano-3-methoxy-2-pyrazinyl)benzenesulphonamide
    2.3-Dichloro-N-{3-methoxy-5-[(2S)-pyrrolidin-2-ylmethoxy]-2- pyrazinyl }benzenesulfonamide hydrochloride 2,3-Dichloro-N-{6-chloro-3-methoxy-5-[(2R)-2-pyrrolidinylmethox y]-2- pyrazinyl }benzenesulphonamide Hydrochloride
    2.3-Dichloro-N-[3-methoxy-5-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide Hydrochloride 2,3-Dichloro-N-(3-methoxy-6-methyl-2-pyrazinyl)benzenesulphonamide
    2.3-Dichloro-N-[3-methoxy-5-(1H-1,2,4-triazol- 1-ylmethyl)-2- pyrazinyl]benzenesulphonamide N-(3-(5-Aminomethyl-2-furanylmethoxy)-5-chloro-2-pyrazinyl)-2,3-dichloro- benzenesulphonamide N-(3-(5-Ami nomethyl-2-furanylmethoxy)-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide 2,3-Dichloro-N-[3-methoxy-5-(2-propyn-1-yloxy)-2-pyrazinylJbenzenesulphonamide {[5-(2,3-Dichlorophenylsulfonylamino)-6-methoxy-2-pyrazinylJoxy }acetic acid, methyl ester N-[5-(2,3-Dichlorophenylsulphonylamino)-6-methoxy-2-pyrazinyl]-2-hydrox yacetamide 6-(2,3-Dichlorophenylsulphonylamino)-5-methoxy-2-pyrazinecarboxylic acid, methyl ester
    2.3-Dichloro-N-[6-(hydroxymethyl)-3-methoxy-2-pyrazinyl]benzenesulphonamide
    2.3-Dichloro-N-(5-methanesulphonyl-3-methoxy-2-pyrazinyl)benzenesulphonamide 2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinyloxy]-N,N-diethyl- acetamide AMENDED SHEET
    PCT/SE03/00041
    Qo. 5-[2-(dimethylamino)ethylsulphanyl]-3-methoxy-2- pyrazinyl }benzenesulphonamide 2,3-Dichloro-N-(5-difluoromethyl-3-methoxy-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-4-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-{5-chloro-3-[ 1-(cyclopropyl)ethoxy]-2-pyrazinyl } benzenesulphonamide 2,3-Dichloro-N-[5-chloro-3-(5-formyl-2-furanylmethoxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-chloro-3-(5-cyclopropylaminomethyl-2-furanylmethoxy)-2-pyrazinyl]- benzenesulphonamide N-[5 ,6-bis-(Hydroxymethyl)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[3-[(2-amino-4-oxazolyl)methoxy]-5-chloro-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide and pharmaceutically acceptable salts and solvates thereof. :
    9. A process for the preparation of compound (I) which comprises: (a) reaction of a compound of formula (II): RS N R4 j AN TX R6 N NH, ety) where R*, R® and R® are as defined in formula (I) or are protected derivatives thereof with a compound of formula (III): R! i R2 $=0 LG Rr? (IIT) a where R', R? and R? are as defined in formula (I) or are protected derivatives thereof and LG is a leaving group, or (b) for compounds where R* is C\.¢ alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group;
    Cs. alkenyloxy or Cs. alkynyloxy where either may be optionally substituted with hydroxy or NR"R"; AMENDED SHEET
    PCT/SE03/00041 LN alkyl-X-C.¢ alkyl where the alkyl groups may form a 3-6 membered saturated ring; OC, alkylR"", or OC, alkyl-X-R'' where the alkyl group may form a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR"“R", SR", S(0),R", S(O)R"; or
    OC. alkyIR'S; treating a compound of the formula (V1), where LG is a leaving group:
    RA. _N._ LGaN XX R N NH 0=S=0 R! RR (V1) with a compound of formula (V) in the presence of a suitable base, or (c) for compounds of structure (1), where R? is an optionally substituted aryl or heteroaryl ring as defined above, reacting a compound of formula (X1) or (VII) where LG is a leaving group with an aryl or heteroaryl boronic acid in the presence of a palladium catalyst and a suitable base at elevated temperature: 4 RA. N._ _R* TX JX BD | _ R*” TNT TNH RYN NH (o— =0 0=S=0 3 Rr? Rr3 R2 R . (V1) 0) and optionally thereafter process (a), (b) or (c) e removing any protecting groups, AMENDED SHEET
    PCT/SEQ3/00041 ¢ e converting a compound of formula (I) to a further compound of formula (I) forming a pharmaceutically acceptable salt.
    10. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
    11. A process for the preparation of a pharmaceutical composition as claimed in claim 10 which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1 with a pharmaceutically acceptable adjuvant, diluent or carrier.
    12. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof for use in therapy.
    13. A method of treating a chemokine mediated disease wherein the chemokine binds to one or more chemokine receptors, which comprises administering to a patient a therapeutically effective amount of a compound of formula (IB), or a pharmaceutically acceptable salt or solvate thereof: R! 0) I Eo 3 6 = rR ONT CR (IB) in which:
    R'. R? and R® are independently hydrogen, halogen, cyano, CFs, or Cy alkyl; R*is halogen, COR",
    C,.¢ alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a Cyano group,
    C;. alkenyloxy or Ci. alkynyloxy where either may be optionally substituted with hydroxy or NR“R"; AMENDED SHEET
    PCT/SE03/00041 ® 171 OC, alkyl-X-Cy.6 alkyl where the alkyl groups may form a 3-6 membered saturated ring;
    OC. alkylR"!, or OCa.6 alkyl-X-R'! where the alkyl group may form a 3-6 membered : saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR“RY, SR", S(0)R", S(OOR";
    OC. alkylR'%; R’ and R® are independently hydrogen, cyano, halogen, CO2R'2, CONRMRY;
    C..¢ alkyl optionally substituted by hydroxy, NR"RY, or 1-3 fluorines; Cre alkylR"! or XCH(R")C 16 alkyl or XCH(R'®)Cy. alkyl where the alkyl group may be optionally substituted with 1-3 groups selected from hydroxy, and NRUR"; NRMR'; NR')R"'; X-(CH;)qNR"R'; (CHz)nNR“R";
    Ci. alkynyl or Cs.¢ alkenyl optionally branched and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O; R': XR: X-R'%, X-CpalkylR'®; X-R'S; X-(CH)nCOR'; X-(CH)nCONRMR'; X-(CHp)nR'"; X-(CH,)nCN; X-(CH2)qOR'%; (CH-)nOR'™; (CHpn-X-R'!; X-(CH)qNHC(O)NHR '%; X-(CHz)qNHC(O)R'; X-(CH)gNHS(O)R'%; X-(CH2)gNHS(O)R''; X-Cs.salkenyl; X-Cs.qalkynyl; nis 1,2,3,4o0r5; qis2,3,4,50r6; X is NR", 0, S, S(0), S(O)z; R!! is an aryl group or a 5-7 membered heteraromatic ring containing 1-4 heteroatoms selected from nitrogen, oxygen or sulphur each of which can be optionally substituted by 1-3 groups selected from halogen, C(O)NR"“R", C(O)OR'?, hydroxy, =O, =S, CN, NO, NRU“R'S, X(CH)GNR “RY, (CH,)nNRR", (CH2)nOH, SR", S(O)R", S(O)R"
    Ci. alkyl-X-C 6 alkyl, C6 alky! or Cy. alkoxy where the alkyl group may form a 3-6 membered ring or is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR'“RY, SR", S(O)R", S(0):R"; AMENDED SHEET
    ® 172 PCT/SE03/00041 R'2and R" are independently hydrogen or Ci.6 alkyl where the alkyl group may be substituted with 1-3 fluorine atoms or may form a saturated 3-6 membered fing; R' and R" are independently hydrogen, Ci alkyl, Css cycloalkyl or (CH;)qOH, or R™ and R" together with the nitrogen atom to which they are attached form a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C16 alkyl, Cy.¢ alkyl-OH, or hydroxy; and R!S is a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen or sulphur and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O provided that the compound is not 2-(2-phenoxyethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine
    5.phenyl-2-(2-(N-phenyl-N-methylamino)ethyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-benzylamino)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(N _methyl-N-phenylamino)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-((tetrahydrofuran-2-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(cyclohexylmethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(piperidin-1-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-cyclopentylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(morpholin-4-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-cyclopropylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-cyclohexylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(3-(piperidin-1-yl)propyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine 3-(2(N-methyl-N-phenylamino)ethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine AMENDED SHEET
    PCT/SE03/00041
    @ 2-(2-phenoxyethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine
    2-(c yclopentylmethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-phen ylamino)ethyloxy)-3-(4-bromophenylsulfon ylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-bromophenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-ethylphenylsulfon ylamino)pyrazine 2-(2-phenoxyeth yloxy)-3-(4-ethylphenylsulfonylamino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-phenylami no)ethyloxy)-3-(4-propylphenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-propylphenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-(1-methylethyl)phen ylsulfonylamino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-(1 -methylethyl)phenylsulfonylamino)pyrazine 6-(perhydroazepin-1 -yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-cyclobutylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine
    6-c yclopentylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine
    6-cyclohexylaminocarbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine
    6-(pyrrolidin-1 -yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3 -(4-
    methylphenylsulfonylamino)pyrazine
    6-(3-hydroxypyrrolidin-1-yl)c arbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-
    methylphenylsulfonylamino)pyrazine
    6-(4-methylpiperazin-1-yl)carbonyl-2-((pyridin-3 -yl)methyloxy)-3-(4-
    methylphenylsulfonylamino)pyrazine
    6-(morpholin-4-yl)carbonyl-2-((pyridin-3 -yl)methyloxy)-3-(4-
    methylphenylsulfonylamino)pyrazine
    6-(thiomorpholin-4-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-
    methylphenylsulfonylamino)pyrazine
    6-(1,1-dimethylethyl)ami nocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-
    methylphenylsulfonylamino)pyrazine
    6-(1,2-dimethylpropyl)aminoc arbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-
    methylphenylsulfonylamino)pyrazine
    AMENDED SHEET
    17 PCT/SE03/0004 1
    ® 6.(1.3-dimethylbutylaminocarbonyl-2-((pyridin-3-yDmethyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1-methylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1-ethylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1-methylbutyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2,2-dimethylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-hydroxypropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-methylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-pentylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-dimethylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-diethylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-methyl-N -propylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-dipropylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-butylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 6-ethylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 6-(3-hydroxypiperidin- 1-yl)carbonyl-2-((pyridin-3-yl)meth yloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-methyl-N-(2-methylpropyl)amino)carbonyl-2-((pyridin-3-y)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N -methyl-N-pentylamino)carbonyl-2-((pyridin-3-y)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-methyl-N-(1-methylethyl)amino)carbonyl-2-((pyridin-3-y)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine AMENDED SHEET
    PCT/SE03/00041
    ® 6-(1-methylethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-((1R)-1-methyl-2-hydroxyeth yl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-ethyl-N -(2-hydroxyethylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-hydroxymethylpyrrolidin- 1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-methylpiperidin-1- yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3 -(4- methylphenylsulfonylamino)pyrazine 6-(3-methylpiperidin-1-yl)c arbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(4-methylpiperidin-1-yl)carbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1,1-dimethylpropyl)aminocarbonyl-2-((pyridin-3 -yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine - 6-(2-methylbutylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-dimethylaminoethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-hydroxyethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(3-methylbutyl)aminoc arbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(3-dimethylami nopropyl)aminocarbonyl-2-((pyridin-3-yl)methylox y)-3-(4- methylphenylsulfonylamino)pyrazine 6-hexylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazin 6-(N-meth yl-N-butylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-ethyl-N-butylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-methyl-N-(2-dimethylaminoethylamino)carbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine AMENDED SHEET
    PCT/SE03/00041
    ® 6.-(N-ethyl.N-(1-methylethylamino)carbonyl.2-((pyridin-3-ymethyloxy)-3-(d- methylphenylsulfonylamino)pyrazine 6-(N-(1-hydroxyethyl)-N-(1 -methylethyl)amino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-((2R)-2-hydroxymethylpyrrolidin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-ethyl-N-methylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-(2-hydroxyethyl)-N-propylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-carboxy-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine or 6-methox ylcarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine.
    14. Use according to claim 12 in which the chemokine receptor belongs to the CCR chemokine receptor subfamily.
    15. Use according to claim 13 or 14 in which the chemokine receptor is the CCR4 receptor.
    16. Use of a compound of formula (IB), or a pharmaceutically acceptable salt or solvate thereof, as defined in claim 13 in the manufacture of a medicament for treating an inflammatory disease in a patient suffering from, or at risk of, said disease.
    17. Use according to claim 16, wherein the disease is asthma.
    18. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for treatment of an illness, disease, disorder or condition.
    19. A substance or composition for use in a method of treatment, said substance or composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and said method comprising administering said substance or composition. AMENDED SHEET
    PCT/SE03/00041 ® 177
    20. A substance or composition for use in a method of treating a chemokine mediated disease wherein the chemokine binds to one or more chemokine receptors, said substance or composition comprising a compound of formula (IB), or a pharmaceutically acceptable salt or solvate thereof as defined in claim 11, and said method comprising administering to a patient a therapeutically effective amount of said substance or composition.
    21. A substance or composition for use in a method of treatment according to claim 18 in which the chemokine receptor belongs to the CCR chemokine receptor subfamily.
    22. A substance or composition for use in a method of treatment according to claim 18 or 19 in which the chemokine receptor is the CCR4 receptor.
    23. A substance or composition for use in a method of treating an inflammatory disease in a patient suffering from, or at risk of, said disease, said substance or composition comprising a compound of formula (IB), or a pharmaceutically acceptable salt or solvate thereof, as defined in claim 11, and said method comprising administering to the patient a therapeutically effective amount of said substance or composition.
    24. A substance or composition for use in a method of treatment according to claim 23, wherein the disease is asthma.
    25. A compound according to any one of claims 1 to 8 or claim 12, substantially as herein described and illustrated.
    26. A process according to claim 9, substantially as herein described and illustrated.
    27. A composition according to claim 10, substantially as herein described and illustrated.
    28. A process according to claim 11, substantially as herein described and illustrated. AMENDED SHEET
    PCT/SE03/00041 ® 29. Use according to any one of claims 13 to 18, substantially as herein described and . tlustrated.
    30. A substance or composition for use in a method of treatment according to any one of claims 19 to 24, substantially as herein described and illustrated.
    31. A new compound, a new process for preparing a compound, a new composition, a new process for preparing a composition, a new use of a compound as defined in any one of claims 13 to 15 or a pharmaceutically acceptable salt or solvate thereof, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
ZA200405260A 2002-01-16 2004-07-01 N-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases. ZA200405260B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
SE0200119A SE0200119D0 (en) 2002-01-16 2002-01-16 Novel compounds

Publications (1)

Publication Number Publication Date
ZA200405260B true ZA200405260B (en) 2005-10-03

Family

ID=20286679

Family Applications (1)

Application Number Title Priority Date Filing Date
ZA200405260A ZA200405260B (en) 2002-01-16 2004-07-01 N-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases.

Country Status (3)

Country Link
SE (1) SE0200119D0 (en)
UA (1) UA79255C2 (en)
ZA (1) ZA200405260B (en)

Also Published As

Publication number Publication date
UA79255C2 (en) 2007-06-11
SE0200119D0 (en) 2002-01-16

Similar Documents

Publication Publication Date Title
EP1458715B1 (en) Novel compounds
US20100081670A1 (en) N-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases
US9597317B2 (en) Substituted indazole derivatives active as kinase inhibitiors
CN107592861B (en) Fluorinated lysyl oxidase-like 2 inhibitors and uses thereof
US20120157433A1 (en) Heteroaryl Compounds as Kinase Inhibitors
AU2005300736B2 (en) Anthranilamide pyridinureas as VEGF receptor kinase inhibitors
US7572794B2 (en) Anthranilamide pyridinureas as vascular endothelial growth factor (VEGF) receptor kinase inhibitors
US20120165306A1 (en) Pyrazinylpyridines useful for the treatment of proliferative diseases
CN111936503A (en) Oxazin monoacylglycerol lipase (MAGL) inhibitors
CA2483890A1 (en) Substituted 3-amino-thieno[2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses
JP2015533177A (en) Substituted benzene compounds
KR20120092586A (en) Bipyridines useful for the treatment of proliferative diseases
JPWO2006004027A1 (en) Pyrazole derivative
US20070185163A1 (en) Imidazol derivatives of piperidine as histamine antagonists
TW200524903A (en) Quinazoline derivatives
CN102395583A (en) Isoxazole derivatives
JPWO2004094407A1 (en) 5-membered heterocyclic derivatives
JP2010515728A (en) Pyridine compounds and their use as P2Y12 antagonists (new pyridine analogue IX519)
CN110818641A (en) Pyridazine-3-formamide compound, preparation method and application thereof in medicine and pharmacology
ZA200405260B (en) N-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases.