U.S. patent application number 12/435864 was filed with the patent office on 2010-04-01 for n-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases.
Invention is credited to Andrew Baxter, Timothy Johnson, Nicholas Kindon, Bryan Roberts, Michael Stocks.
Application Number | 20100081670 12/435864 |
Document ID | / |
Family ID | 26655657 |
Filed Date | 2010-04-01 |
United States Patent
Application |
20100081670 |
Kind Code |
A1 |
Baxter; Andrew ; et
al. |
April 1, 2010 |
N-PYRAZINYL-PHENYLSULPHONAMIDES AND THEIR USE IN THE TREATMENT OF
CHEMOKINE MEDIATED DISEASES
Abstract
The invention provides N-pyrazinyl-phenyl-sulphonamides of
formula (I) for use in the treatment of chemokine mediated
diseases. Particularly inflammatory diseases, such as asthma.
##STR00001##
Inventors: |
Baxter; Andrew;
(Loughborough, GB) ; Johnson; Timothy;
(Loughborough, GB) ; Kindon; Nicholas;
(Loughborough, GB) ; Roberts; Bryan;
(Loughborough, GB) ; Stocks; Michael;
(Loughborough, GB) |
Correspondence
Address: |
MORGAN LEWIS & BOCKIUS LLP
1111 PENNSYLVANIA AVENUE NW
WASHINGTON
DC
20004
US
|
Family ID: |
26655657 |
Appl. No.: |
12/435864 |
Filed: |
May 5, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10501510 |
May 25, 2005 |
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PCT/SE03/00041 |
Jan 14, 2003 |
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12435864 |
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Current U.S.
Class: |
514/255.05 ;
514/255.06; 544/336; 544/405 |
Current CPC
Class: |
A61P 15/00 20180101;
A61P 31/18 20180101; C07D 401/04 20130101; A61P 31/04 20180101;
A61P 21/04 20180101; A61P 25/06 20180101; C07D 249/08 20130101;
C07F 7/0812 20130101; A61P 17/06 20180101; A61P 5/14 20180101; A61P
43/00 20180101; A61P 37/08 20180101; A61P 1/04 20180101; A61P 25/28
20180101; C07D 401/12 20130101; C07D 403/12 20130101; A61P 7/02
20180101; A61P 15/02 20180101; A61P 37/06 20180101; C07D 241/22
20130101; A61P 17/04 20180101; A61P 11/06 20180101; A61P 19/02
20180101; A61P 37/02 20180101; C07D 405/12 20130101; A61P 9/10
20180101; A61P 31/12 20180101; C07D 231/12 20130101; A61P 3/10
20180101; A61P 25/00 20180101; C07D 403/04 20130101; A61P 11/02
20180101; A61P 35/00 20180101; A61P 11/00 20180101; A61P 13/12
20180101; C07D 233/56 20130101; C07D 413/12 20130101; C07D 409/12
20130101; A61P 17/02 20180101; A61P 29/00 20180101; A61P 17/00
20180101; A61P 19/06 20180101; A61P 25/14 20180101 |
Class at
Publication: |
514/255.05 ;
544/405; 544/336; 514/255.06 |
International
Class: |
A61K 31/497 20060101
A61K031/497; C07D 401/12 20060101 C07D401/12; C07D 241/20 20060101
C07D241/20; A61K 31/4965 20060101 A61K031/4965; A61P 11/06 20060101
A61P011/06; A61P 37/06 20060101 A61P037/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 16, 2002 |
SE |
02001 19-6 |
Jun 17, 2002 |
SE |
0201857-0 |
Claims
1. A compound of formula (I) or a pharmaceutically acceptable salt
or solvate thereof: ##STR00261## in which: R.sup.1, R.sup.2 and
R.sup.3 are independently hydrogen, halogen, cyano, CF.sub.3,
OCF.sub.3, OC.sub.1-6 alkyl or C.sub.1-6 alkyl; R.sup.4 is halogen,
CO.sub.2R.sup.12, C.sub.1-6 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; C.sub.3-6 alkenyloxy or C.sub.3-6
alkynyloxy where either may be optionally substituted with hydroxy
or NR.sup.14R.sup.15; OC.sub.1-6 alkyl-X--C.sub.1-6 alkyl where the
alkyl groups may form a 3-6 membered saturated ring; OC.sub.1-6
alkylR.sup.11, or OC.sub.2-6 alkyl-X--R.sup.11 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.sup.14R.sup.15, SR.sup.13, S(O).sub.2R.sup.13, S(O)R.sup.13 or
COR.sup.13; OC.sub.1-6 alkylR.sup.16; R.sup.5 and R.sup.6 are
independently hydrogen, cyano, halogen, CO.sub.2R.sup.12,
CONR.sup.14R.sup.15; C.sub.1-6 alkyl optionally substituted by
hydroxy, NR.sup.14R.sup.15, or 1-3 fluorines; C.sub.1-6
alkylR.sup.11 or XCH(R.sup.11)C.sub.1-6 alkyl or
XCH(R.sup.16)C.sub.1-6 alkyl where the alkyl group may be
optionally substituted with 1-3 groups selected from hydroxy, and
NR.sup.14R.sup.15; NR.sup.14R.sup.15; N(R.sup.11)R.sup.11;
X--(CH.sub.2)qNR.sup.14R.sup.15; (CH.sub.2)nNR.sup.14R.sup.15;
NHC(O)C.sub.1-6 alkyl optionally substituted by one or more hydroxy
groups, C.sub.3-6 alkynyl or C.sub.3-6 alkenyl optionally branched
and optionally substituted with 1-3 groups selected from hydroxy,
cyano, halogen and .dbd.O; R.sup.11; X--R.sup.11; X--R.sup.12;
X--C.sub.1-6 alkylR.sup.16; X--R.sup.16;
X--(CH.sub.2)nCO.sub.2R.sup.12; X--(CH.sub.2)nCONR.sup.14R.sup.15;
X--(CH.sub.2)nR.sup.11; X--(CH.sub.2)nCN; X--(CH.sub.2)qOR.sup.12;
(CH.sub.2)nOR.sup.12; (CH.sub.2)n-X--R.sup.11;
X--(CH.sub.2)qNHC(O)NHR.sup.12; X--(CH.sub.2)qNHC(O)R.sup.12;
X--(CH.sub.2)qNHS(O).sub.2R.sup.12;
X--(CH.sub.2)qNHS(O).sub.2R.sup.11; X--C.sub.3-6 alkenyl;
X--C.sub.3-6 alkynyl; n is 1, 2, 3, 4 or 5; q is 2, 3, 4, 5 or 6; X
is NR.sup.13, O, S, S(O), S(O).sub.2; R.sup.11 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.sup.14R.sup.15, C(O)OR.sup.12, hydroxy, .dbd.O, .dbd.S, CN,
NO.sub.2, COR.sup.13, NR.sup.14R.sup.15,
X(CH.sub.2)qNR.sup.14R.sup.15, (CH.sub.2)nNR.sup.14R.sup.15,
(CH.sub.2)nOH, SR.sup.13, S(O)R.sup.13, S(O).sub.2R.sup.13,
C.sub.1-6 alkyl-X--C.sub.1-6 alkyl, C.sub.1-6 alkyl or C.sub.1-6
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.sup.14R.sup.15, SR.sup.13, S(O)R.sup.13,
S(O).sub.2R.sup.13; R.sup.12 and R.sup.13 are independently
hydrogen or C.sub.1-6 alkyl where the alkyl group may be
substituted with 1-3 fluorine atoms or may form a saturated 3-6
membered ring; R.sup.14 and R.sup.15 are independently hydrogen,
C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or (CH.sub.2)qOH, or R.sup.14
and R.sup.15 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.sub.1-6 alkyl, C.sub.1-6 alkyl-OH, or
hydroxy; and R.sup.16 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 .dbd.O, provided that: when R.sup.4 is halogen
or C.sub.1-4alkoxy and R.sup.5 is hydrogen, halogen,
C.sub.1-4alkyl, C.sub.1-2alkoxy, C.sub.1-2alkylthio,
trifluoromethyl or ethynyl and when one R.sup.1, R.sup.2, or
R.sup.3 is C.sub.1-6alkyl or C.sub.1-6alkoxy and is meta to the
sulphonamide group then the group ortho to both the sulphonamide
group and the C.sub.1-6alkyl or C.sub.1-6alkoxy group is not
hydrogen, when R.sup.4 is halogen or C.sub.1-4alkoxy and R.sup.5 is
hydrogen, halogen, C.sub.1-4alkyl, C.sub.1-2alkoxy,
C.sub.1-2alkylthio, trifluoromethyl, or ethynyl and when one of
R.sup.1, R.sup.2 or R.sup.3 is C.sub.1-6alkyl or C.sub.1-6alkoxy
and is ortho to the sulphonamide group then the group ortho to the
C.sub.1-6Alkyl or C.sub.1-6alkoxy and also meta to the sulphonamide
group is not hydrogen, when two of R.sup.1, R.sup.2, R.sup.3 are
hydrogen and the other is a methyl group para to the sulphonamide
and R.sup.4 is methoxy then R.sup.5 is not hydrogen or bromo, and
when R.sup.5 is methyl and R.sup.6 is methoxy and one of R.sup.1,
R.sup.2 or R.sup.3 is bromo or iodo and the other two are both
hydrogen, then the bromo or iodo group is not ortho to the
sulphonamide group.
2. The compound according to claim 1 in which one of R.sup.1,
R.sup.2 and R.sup.3 is hydrogen and the other is chloro, bromo or
methyl.
3. The compound according to claim 1 or in which R.sup.4 is
C.sub.1-6 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.
4. The compound according claim 1 in which R.sup.5 is hydrogen,
halogen such as bromo and chloro, phenyl, --C.sub.1-6 alkyl such as
methyl, CH.sub.2OH, cyano and 2-aminothanethiol
5. The compound according to claim 1 in which R.sup.6 is hydrogen,
C.sub.1-6 alkyl, CH.sub.2OH and halogen.
6. The compound according to claim 1 which is:
2,3-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)-benzenesulphonamide
N-(6-Chloro-3-methoxy-2-pyrazinyl)-2,3,4-trifluorobenzenesulphonamide
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]benzenesulphona-
mide
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]benzenesulpho-
namide
2,3-Dichloro-N-[5-methyl-3-(6-methyl-2-pyridinylmethoxy)-2-pyraziny-
l]benzenesulphonamide
2,3-Dichloro-N-[5-methyl-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulpho-
namide
2,3-Dichloro-N-[5-methyl-3-(4-pyridinylmethoxy)-2-pyrazinyl]benzene-
sulphonamide
2,3-Dichloro-N-[5-methyl-3-(3-methyl-2-pyridinylmethoxy)-2-pyrazinyl]benz-
enesulphonamide
2,3-Dichloro-N-[5-methyl-3-(3-pyridazinylmethoxy)-2-pyrazinyl]benzenesulp-
honamide
2,3-Dichloro-N-[3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphon-
amide
2,3-Dichloro-N-[3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonami-
de 2,3-Dichloro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
N-[5-Bromo-3-(2-pyrazinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphon-
amide
N-[5-Bromo-3-(1-methyl-6-oxo-1,6-dihydro-3-pyridinylmethoxy)-2-pyraz-
inyl]-2,3-dichlorobenzenesulphonamide
N-[5-Bromo-3-(3-pyridazinyllmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulp-
honamide
N-[5-Bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzen-
esulphonamide
N-[5-Bromo-3-(5-pyrimidinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulph-
onamide
N-[5-Chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzen-
esulphonamide
N-[5-Chloro-3-(5-pyrimidinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulp-
honamide
2-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
4-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
N-(6-Chloro-3-methoxy-2-pyrazinyl)-2,4-dichlorobenzenesulphonamide
N-(6-Chloro-3-methoxy-2-pyrazinyl)-3,4-dichlorobenzenesulphonamide
3-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)-2-methylbenzenesulphonamide
2-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benzenesulphonamide
3-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benzenesulphonamide
4-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benzenesulphonamide
2,4-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benzenesulphonamide
3,4-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benzenesulphonamide
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2-trifluoromethoxybenzenesulphonamide
3-Chloro-N-(5-chloro-3-methoxy-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-pyrazinyl]benzenesulphonami-
de 2,3-Dichloro-N-[3,5-dimethoxy-2-pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[3-methoxy-5-(1-pyrrolinyl)-2-pyrazinyl]benzenesulphonamid-
e
3-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-2-methylbenzenesulphonam-
ide
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-methoxy-2-pyrazinyl)benzenesulphonamide
2,4-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
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]benzenes-
ulphonamide
2,3-Dichloro-N-[6-chloro-5-(2-hydroxyethylamino)-3-methoxy-2-pyrazinyl]be-
nzenesulphonamide
2,3-Dichloro-N-[6-chloro-5-dimethylamino-3-methoxy-2-pyrazinyl]benzenesul-
phonamide
2,3-Dichloro-N-[6-chloro-3-methoxy-5-(2-methoxyethoxy)-2-pyrazin-
yl]benzenesulphonamide
2,3-Dichloro-N-[6-chloro-5-hydroxy-3-methoxy-2-pyrazinyl]benzenesulphonam-
ide
2,3-Dichloro-N-[6-methoxy-5-([2,2']bipyrazinyl)]benzenesulphonamide
4-[5-(2,3-Dichlorobenzenesulphonylamino)-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-methoxyethyl)amino]-2-pyrazinyl}-
benzenesulphonamide
N-{2-[3-Chloro-5-(2,3-dichlorobenzenesulphonylamino)-6-methoxy-2-pyraziny-
lamino]ethyl}acetamide
2,3-Dichloro-N-[5-(4-hydroxymethyl-1-piperidinyl)-3-methoxy-2-pyrazinyl]b-
enzenesulphonamide
2,3-Dichloro-N-[5-cyano-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphon-
amide
2,3-Dichloro-N-(6-chloro-3-methoxy-5-methylamino-2-pyrazinyl)benzene-
sulphonamide
2,3-Dichloro-N-(3-methoxy-5-methylsulphanyl-2-pyrazinyl)benzenesulphonami-
de
2,3-Dichloro-N-[5-(2,4-difluorophenyl)-3-methoxy-2-pyrazinyl]benzenesul-
phonamide
[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulp-
hanyl]acetic acid methyl ester
[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]ace-
tic 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-methyl-3-(1-oxy-3-pyrazinylmethoxy)-2-pyrazinyl]benzene-
sulphonamide
2,3-Dichloro-N-[5-chloro-3-(4-pyridinylmethoxy)-2-pyrazinyl]benzenesulpho-
namide
2,3-Dichloro-N-[5-chloro-3-(1-oxy-4-pyridinylmethoxy)-2-pyrazinyl]b-
enzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulpho-
namide
2,3-Dichloro-N-[5-chloro-3-(2-methylsulphanylethoxy)-2-pyrazinyl]be-
nzenesulphonamide
N-(3-Butoxy-5-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-(2-methyl-3-pyridinylmethoxy)-2-pyrazinyl]benz-
enesulphonamide
2,3-Dichloro-N-[5-chloro-3-(6-methyl-2-pyridinylmethoxy)-2-pyrazinyl]benz-
enesulphonamide
2,3-Dichloro-N-[5-chloro-3-(1-oxy-2-pyridinylmethoxy)-2-pyrazinyl]benzene-
sulphonamide
3-Chloro-N-[5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2-methylbenzenes-
ulphonamide
3-Chloro-N-[5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2-fluorobenzenes-
ulphonamide
2,3-Dichloro-N-[5-chloro-3-(4-methoxyphenylmethoxy)-2-pyrazinyl]benzenesu-
lphonamide
N-[5-Bromo-6-chloro-2-pyrazinyl]-2,3-dichlorobenzenesulphonamid- e
2,3-Dichloro-N-[6-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulph-
onamide
2,3-Dichloro-N-[6-chloro-3-(2-pyridinylmethoxy)-2-pyrazinyl]benzen-
esulphonamide
N-[5-(2-Aminoethylsulphanyl)-3-(2-pyridinylmethoxy)-2-pyrazinyl]-2,3-dich-
lorobenzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-(6-methoxy-3-pyridinylmethoxy)-2-pyrazinyl]ben-
zenesulphonamide
N-[3-(3-Bromophenylmethoxy)-5-chloro-2-pyrazinyl]-2,3-dichlorobenzenesulp-
honamide
3-[6-Chloro-3-(2,3-dichlorobenzenesulphonylamino)-2-pyrazinyloxym-
ethyl]benzoic acid methyl ester
3-[6-Chloro-3-(2,3-dichlorobenzenesulphonylamino)-2-pyrazinyloxymethyl]be-
nzoic acid
2,3-Dichloro-N-[5-chloro-3-(3-hydroxymethylphenylmethoxy)-2-pyr-
azinyl]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-pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-(4-hydroxymethylphenylmethoxy)-2-pyrazinyl]ben-
zenesulphonamide
2,3-Dichloro-N-[5-chloro-3-{4-([2-hydroxyethylamino]methyl)phenylmethoxy}-
-2-pyrazinyl]benzenesulphonamide
2,3-Dichloro-N-[3-(4-hydroxymethylphenylmethoxy)-2-pyrazinyl]benzenesulph-
onamide
2,3-Dichloro-N-[5-chloro-3-(2-hydroxymethylphenylmethoxy)-2-pyrazi-
nyl]benzenesulphonamide
5-(2,3-Dichlorobenzenesuphonylamino)-6-methoxypyrazine-2-carboxylic
acid, methyl ester
2,3-Dichloro-N-[5-(1-hydroxy-1-methylethyl)-3-methoxy-2-pyrazinyl]benzene-
sulphonamide
N-[5-(2-Aminoethoxy)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulphonami-
de
N-{5-[(2-Aminoethyl)thio]-6-chloro-3-methoxy-2-pyrazinyl}-2,3-dichlorob-
enzenesulfonamide
3-[(5-{[(2,3-Dichlorophenyl)sulphonyl]amino}-6-methoxy-2-pyrazinyl)thio]p-
ropanoic acid, methyl ester
2,3-Dichloro-N-[5-bromo-3-methoxy-6-methyl-2-pyrazinyl)benzenesulphonamid-
e
5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-3-methylpyrazine-2-carbo-
xylic acid, methyl ester
2,3-Dichloro-N-[5-(hydroxymethyl)-3-methoxy-6-methyl-2-pyrazinyl)benzenes-
ulphonamide
2,3-Dichloro-N-[5,6-dichloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesu-
lphonamide
3-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-2-fluorobenzenesulp-
honamide
3-Chloro-2-fluoro-N-[3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesu-
lphonamide
3-{[(2,3-Dichlorophenyl)sulphonyl]amino}pyrazine-2-carboxylic acid,
methyl ester
N-(5-Bromo-6-chloro-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamid-
e
3-Chloro-5-{[(2,3-dichlorophenyl)sulphonyl]amino}-6-methoxypyrazine-2-ca-
rboxylic acid, methyl ester
2,3-Dichloro-N-[6-chloro-5-(hydroxymethyl)-3-methoxypyrazin-2-yl]benzenes-
ulphonamide
2,3-Dichloro-N-{3-[(6-methoxy-3-pyridinyl)methoxy]-2-pyrazinyl}benzenesul-
phonamide
2,3-Dichloro-N-[6-chloro-3-methoxy-5-(methoxymethyl)-2-pyrazinyl-
]benzenesulphonamide
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-dichlorobenzen-
esulphonamide
5-(2,3-Dichlorobenzenesulphonylamino)-6-(3-pyridinylmethoxy)pyrazine-2-ca-
rboxylic acid, methyl ester
5-{[(2,3-Dichlorophenyl)sulphonyl]amino}-6-(3-pyridinylmethoxy)-2-pyrazin-
ecarboxamide
2,3-Dichloro-N-[5-(4-pyridinyl)-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzen-
esulphonamide
2,3-Dichloro-N-[5-(hydroxymethyl)-3-(3-pyridinylmethoxy)-2-pyrazinyl]benz-
enesulphonamide
2,3-Dichloro-N-[5-(hydroxymethyl)-3-methoxy)-2-pyrazinyl]benzenesulphonam-
ide
4-Amino-2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphona-
mide
N-(5-Allyloxy-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
2,3-Dichloro-N-[5-(3-hydroxy-1-propynyl)-3-methoxy-2-pyrazinyl]benzenesul-
phonamide
N-{3-[(5-Bromo-3-pyridinyl)methoxy]-5-chloro-2-pyrazinyl}-2,3-di-
chlorobenzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-{[6-(hydroxymethyl)-2-pyridinyl]methoxy}-2-pyr-
azinyl]benzenesulphonamide
2,3-Dichloro-N-{5-chloro-3-[(2-methyl-4-oxazolyl)methoxy]-2-pyrazinyl}ben-
zenesulphonamide
2,3-Dichloro-N-{3-[(2-methyl-4-oxazolyl)methoxy]-2-pyrazinyl}benzenesulph-
onamide
N-[5-Bromo-3-(phenylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulph-
onamide
N-[5-Bromo-3-(2-cyclopropylethoxy)pyrazinyl]-2,3-dichlorobenzenesu-
lphonamide
N-[5-Bromo-3-(3-thienylmethoxy)pyrazinyl]-2,3-dichlorobenzenesu-
lphonamide
N-{5-Bromo-3-[(2-methyl-3-furanyl)methoxy]-2-pyrazinyl}-2,3-dic-
hlorobenzenesulphonamide
N-{5-Bromo-3-[(3-furanyl)methoxy]-2-pyrazinyl}-2,3-dichlorobenzenesulphon-
amide
N-{5-Bromo-3-[(4-fluorophenyl)methoxy]-2-pyrazinyl}-2,3-dichlorobenz-
enesulphonamide
N-{5-Bromo-3-[(3-fluorophenyl)methoxy]-2-pyrazinyl}-2,3-dichlorobenzenesu-
lphonamide
N-{5-Bromo-3-[3-(2-pyridinyl)propoxy]-2-pyrazinyl}-2,3-dichloro-
benzenesulphonamide
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-methoxyethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonami-
de
N-[5-Bromo-3-(2-ethoxyethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonam-
ide
N-[5-Bromo-3-(2-fluoroethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphona-
mide
N-{5-Bromo-3-[2-(1H-imidazol-1-yl)ethoxy]-2-pyrazinyl}-2,3-dichlorobe-
nzenesulphonamide
N-{5-Bromo-3-[3-(3-pyridinyl)propoxy]-2-pyrazinyl}-2,3-dichlorobenzenesul-
phonamide
N-[5-Bromo-3-[2-(methylamino)ethoxy]-2-pyrazinyl]-2,3-dichlorobe-
nzenesulphonamide
N-{5-Bromo-3-[3-(4-hydroxyphenyl)propoxy]-2-pyrazinyl}-2,3-dichlorobenzen-
esulphonamide
N-[5-Bromo-3-(2-phenoxyethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonami-
de
N-[5-Bromo-3-(cyclopropylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulph-
onamide
N-[5-Bromo-3-(3-phenoxypropoxy)-2-pyrazinyl]-2,3-dichlorobenzenesu-
lphonamide
2,3-Dichloro-N-(5-ethoxy-3-methoxy-2-pyrazinyl)benzenesulphonam-
ide
2,3-Dichloro-N-[3-methoxy-5-([1,2,4]-1-triazolyl)-2-pyrazinyl]benzenes-
ulphonamide
2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]--
N-methylacetamide
2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]a-
cetamide
2,3-Dichloro-N-[5-(4-fluorobenzylsulphanyl)-3-methoxy-2-pyrazinyl-
]benzenesulphonamide
2,3-Dichloro-N-[5-cyanomethylsulphanyl-3-methoxy-2-pyrazinyl]benzenesulph-
onamide
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-dichlorobenzenesu-
lphonamide
2,3-Dichloro-N-[3-methoxy-5-(5-methyl-3-isoxazolylmethoxy))-2-p-
yrazinyl]benzenesulphonamide
2,3-Dichloro-N-[5-(5-dimethylaminomethyl-2-furanylmethoxy)-3-methoxy-2-py-
razinyl]benzenesulphonamide
N-[5-Bromo-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2-pyrazinyl]-2,3-di-
chloro-benzenesulphonamide
2,3-Dichloro-N-[5-(2-hydroxyethylsulphanyl)-3-methoxy-2-pyrazinyl]benzene-
sulphonamide
2,3-Dichloro-N-{5-[2-(ethylureido)ethylsulphanyl]-3-methoxy-2-pyrazinyl}b-
enzenesulphonamide
2,3-Dichloro-N-[3-(5-dimethylaminomethyl-2-furanylmethoxy)-2-pyrazinyl]be-
nzenesulphonamide
2,3-Dichloro-N-[6-chloro-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2-pyr-
azinyl]benzenesulphonamide
2,3-Dichloro-N-[6-chloro-3-(5-methylaminomethyl-2-furanylmethoxy)-2-pyraz-
inyl]benzenesulphonamide
2,3-Dichloro-N-[5-chloro-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2-pyr-
azinyl]benzenesulphonamide
2,3-Dichloro-N-[3-(5-methylaminomethyl-2-furanylmethoxy)-2-pyrazinyl]benz-
enesulphonamide
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]benzenesulp-
honamide
N-(3-Allyloxy-5-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonami-
de
2,3-Dichloro-N-[5-chloro-3-(2-propynyloxy)-2-pyrazinyl]benzenesulphonam-
ide
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}ben-
zenesulfonamide hydrochloride
2,3-Dichloro-N-{6-chloro-3-methoxy-5-[(2R)-2-pyrrolidinylmethoxy]-2-pyraz-
inyl}benzenesulphonamide Hydrochloride
2,3-Dichloro-N-[3-methoxy-5-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulph-
onamide 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]ben-
zenesulphonamide
N-(3-(5-Aminomethyl-2-furanylmethoxy)-5-chloro-2-pyrazinyl)-2,3-dichloro--
benzenesulphonamide
N-(3-(5-Aminomethyl-2-furanylmethoxy)-2-pyrazinyl)-2,3-dichlorobenzenesul-
phonamide
2,3-Dichloro-N-[3-methoxy-5-(2-propyn-1-yloxy)-2-pyrazinyl]benze-
nesulphonamide
{[5-(2,3-Dichlorophenylsulfonylamino)-6-methoxy-2-pyrazinyl]oxy}acetic
acid, methyl ester
N-[5-(2,3-Dichlorophenylsulphonylamino)-6-methoxy-2-pyrazinyl]-2-hydroxya-
cetamide
6-(2,3-Dichlorophenylsulphonylamino)-5-methoxy-2-pyrazinecarboxyl-
ic acid, methyl ester
2,3-Dichloro-N-[6-(hydroxymethyl)-3-methoxy-2-pyrazinyl]benzenesulphonami-
de
2,3-Dichloro-N-(5-methanesulphonyl-3-methoxy-2-pyrazinyl)benzenesulphon-
amide
2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinyloxy]-N-
,N-diethyl-acetamide
2,3-Dichloro-N-{5-[2-(dimethylamino)ethylsulphanyl]-3-methoxy-2-pyrazinyl-
}benzenesulphonamide
2,3-Dichloro-N-(5-difluoromethyl-3-methoxy-2-pyrazinyl)benzenesulphonamid-
e
2,3-Dichloro-4-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
2,3-Dichloro-N-{5-chloro-3-[1-(cyclopropyl)ethoxy]-2-pyrazinyl}benzenesul-
phonamide
2,3-Dichloro-N-[5-chloro-3-(5-formyl-2-furanylmethoxy)-2-pyrazin-
yl]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-dichlorobenzenesulp-
honamide
N-[3-[(2-amino-4-oxazolyl)methoxy]-5-chloro-2-pyrazinyl]-2,3-dich-
lorobenzenesulphonamide and pharmaceutically acceptable salts and
solvates thereof.
7. A process for the preparation of a compound of formula (I) as
claimed in claim 1 which comprises: (a) reaction of a compound of
formula (II): ##STR00262## where R.sup.4, R.sup.5 and R.sup.6 are
as defined in claim 1 or are protected derivatives thereof with a
compound of formula (III): ##STR00263## where R.sup.1, R.sup.2 and
R.sup.3 are as defined in claim 1 or are protected derivatives
thereof and LG is a leaving group, or (b) for compounds where
R.sup.4 is C.sub.1-6 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; C.sub.3-6 alkenyloxy or C.sub.3-6
alkynyloxy where either may be optionally substituted with hydroxy
or NR.sup.14R.sup.15; OC.sub.1-6 alkyl-X--C.sub.1-6 alkyl where the
alkyl groups may form a 3-6 membered saturated ring; OC.sub.1-6
alkylR.sup.11, or OC.sub.2-6 alkyl-X--R.sup.11 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.sup.14R.sup.15, SR.sup.13, S(O).sub.2R.sup.13, S(O)R.sup.13; or
OC.sub.1-6 alkylR.sup.16; treating a compound of the formula (VI),
where LG is a leaving group: ##STR00264## with a compound of
formula R.sup.4--H (V) (V) in the presence of a suitable base, or
(c) for compounds of structure (I), where R.sup.5 is an optionally
substituted aryl or heteroaryl ring as defined above, reacting a
compound of formula (XI) 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: ##STR00265##
and optionally thereafter process (a), (b) or (c) removing any
protecting groups, converting a compound of formula (I) to a
further compound of formula (I) forming a pharmaceutically
acceptable salt.
8. 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.
9. A process for the preparation of a pharmaceutical composition as
claimed in claim 8 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.
10. (canceled)
11. 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: ##STR00266## in which: R.sup.1, R.sup.2 and
R.sup.3 are independently hydrogen, halogen, cyano, CF.sub.3, or
C.sub.1-6 alkyl; R.sup.4 is halogen, CO.sub.2R.sup.12, C.sub.1-6
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;
C.sub.3-6 alkenyloxy or C.sub.3-6 alkynyloxy where either may be
optionally substituted with hydroxy or NR.sup.14R.sup.15;
OC.sub.1-6 alkyl-X--C.sub.1-6 alkyl where the alkyl groups may form
a 3-6 membered saturated ring; OC.sub.1-6 alkylR.sup.11, or
OC.sub.2-6 alkyl-X--R.sup.11 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.sup.14R.sup.15,
SR.sup.13, S(O).sub.2R.sup.13, S(O)R.sup.13; OC.sub.1-6
alkylR.sup.16; R.sup.5 and R.sup.6 are independently hydrogen,
cyano, halogen, CO2R.sup.12, CONR.sup.14R.sup.15; C.sub.1-6 alkyl
optionally substituted by hydroxy, NR.sup.14R.sup.15, or 1-3
fluorines; C.sub.1-6 alkylR.sup.11 or XCH(R.sup.11)C.sub.1-6 alkyl
or XCH(R.sup.16)C.sub.1-6 alkyl where the alkyl group may be
optionally substituted with 1-3 groups selected from hydroxy, and
NR.sup.14R.sup.15; NR.sup.14R.sup.15; N(R.sup.11)R.sup.11;
X--(CH.sub.2)qNR.sup.14R.sup.15; (CH.sub.2)nNR.sup.14R.sup.15;
C.sub.3-6 alkynyl or C.sub.3-6 alkenyl optionally branched and
optionally substituted with 1-3 groups selected from hydroxy,
cyano, halogen and .dbd.O; R.sup.11; X--R.sup.11; X--R.sup.12;
X--C.sub.1-6 alkylR.sup.16; X--R.sup.16;
X--(CH.sub.2)nCO.sub.2R.sup.12; X--(CH.sub.2)nCONR.sup.14R.sup.15;
X--(CH.sub.2)nR.sup.11; X--(CH.sub.2)nCN; X--(CH.sub.2)qOR.sup.12;
(CH.sub.2)nOR.sup.12; (CH.sub.2)n-X--R.sup.11;
X--(CH.sub.2)qNHC(O)NHR.sup.12; X--(CH.sub.2)qNHC(O)R.sup.12;
X--(CH.sub.2)qNHS(O).sub.2R.sup.12;
X--(CH.sub.2)qNHS(O).sub.2R.sup.11; X--C.sub.3-6 alkenyl;
X--C.sub.3-6 alkynyl; n is 1, 2, 3, 4 or 5; q is 2, 3, 4, 5 or 6; X
is NR.sup.13, O, S, S(O), S(O).sub.2; R.sup.11 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.sup.14R.sup.15, C(O)OR.sup.12, hydroxy, .dbd.O, .dbd.S, CN,
NO.sub.2 NR.sup.14R.sup.15, X(CH.sub.2)qNR.sup.14R.sup.15,
(CH.sub.2)nNR.sup.14R.sup.15, (CH.sub.2)nOH, SR.sup.13,
S(O)R.sup.13, S(O).sub.2R.sup.13C.sub.1-6 alkyl-X--C.sub.1-6 alkyl,
C.sub.1-6 alkyl or C.sub.1-6 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.sup.14R.sup.15, SR.sup.13,
S(O)R.sup.13, S(O).sub.2R.sup.13; R.sup.12 and R.sup.13 are
independently hydrogen or C.sub.1-6 alkyl where the alkyl group may
be substituted with 1-3 fluorine atoms or may form a saturated 3-6
membered ring; R.sup.11 and R.sup.15 are independently hydrogen,
C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or (CH.sub.2)qOH, or R.sup.14
and R.sup.15 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.sub.1-6 alkyl, C.sub.1-6 alkyl-OH, or
hydroxy; and R.sup.16 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 .dbd.O,
12. The method according to claim 11 in which the chemokine
receptor belongs to the CCR chemokine receptor subfamily.
13. The method according to claim 11 in which the chemokine
receptor is the CCR4 receptor.
14. A method of treating an inflammatory disease 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 (IB), or a pharmaceutically acceptable salt
or solvate thereof, as defined in claim 11.
15. The method according to claim 14, wherein the disease is
asthma.
Description
[0001] The present invention relates to a sulphonamide compound,
processes and intermediates used in their preparation,
pharmaceutical compositions containing them and their use in
therapy.
[0002] 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.
[0003] 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
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-X.sub.3-Cys (C--X.sub.3--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.sub.3--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.
[0004] The C--X--C chemokines include several potent
chemoattractants and activators of neutrophils such as
interleukin-8 (IL-8) and neutrophil-activating peptide 2
(NAP-2).
[0005] 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 1.alpha. and
1.beta. (MIP-1.alpha. and MIP-1.beta.), Thymus and Activation
Regulated Chemokine (TARC, CCL17) and Macrophage Derived Chemokine
(MDC, CCL22).
[0006] The C--X.sub.3--C chemokine (also known as fractalkine) is a
potent chemoattractant and activator of microglia in the central
nervous system (CNS) as well as of monocytes, T cells, NK cells and
mast cells.
[0007] 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 (for the C--C
family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C--X--C
family) and CX.sub.3CR1 for the C--X.sub.3--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.
[0008] The present invention therefore provides a compound of
formula (I) and pharmaceutically acceptable salts, solvates or
N-oxides thereof:
##STR00002##
in which:
[0009] R.sup.1, R.sup.2 and R.sup.3 are independently hydrogen,
halogen, cyano, CF.sub.3, OCF.sub.3, OC.sub.1-6 alkyl or C.sub.1-6
alkyl;
[0010] R.sup.4 is halogen, CO.sub.2R.sup.12,
[0011] C.sub.1-6 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;
[0012] C.sub.3-6 alkenyloxy or C.sub.3-6 alkynyloxy where either
may be optionally substituted with hydroxy or
NR.sup.14R.sup.15;
[0013] OC.sub.1-6 alkyl-X--C.sub.1-6 alkyl where the alkyl groups
may form a 3-6 membered saturated ring;
[0014] OC.sub.1-6 alkylR.sup.11, or OC.sub.2-6 alkyl-X--R.sup.11
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.sup.14R.sup.15, SR.sup.13, S(O).sub.2R.sup.13,
S(O)R.sup.13 or COR.sup.13;
[0015] OC.sub.1-6 alkylR.sup.16;
[0016] R.sup.5 and R.sup.6 are independently hydrogen, cyano,
halogen, CO.sub.2R.sup.12, CONR.sup.14R.sup.15;
[0017] C.sub.1-6 alkyl optionally substituted by hydroxy,
NR.sup.14R.sup.15, or 1-3 fluorines;
[0018] C.sub.1-6 alkylR.sup.11 or XCH(R.sup.11)C.sub.1-6 alkyl or
XCH(R.sup.16)C.sub.1-6 alkyl where the alkyl group may be
optionally substituted with 1-3 groups selected from hydroxy, and
NR.sup.14R.sup.15;
[0019] NR.sup.14R.sup.15; N(R.sup.11)R.sup.11;
X--(CH.sub.2)qNR.sup.14R.sup.15; (CH.sub.2)nNR.sup.14R.sup.15;
NHC(O)C.sub.1-6 alkyl optionally substituted by one or more hydroxy
groups,
[0020] C.sub.3-6 alkynyl or C.sub.3-6 alkenyl optionally branched
and optionally substituted with 1-3 groups selected from hydroxy,
cyano, halogen and .dbd.O;
[0021] R.sup.11; X--R.sup.11; X--R.sup.12;
X--C.sub.1-6alkylR.sup.16; X--R.sup.16;
X--(CH.sub.2)nCO.sub.2R.sup.12;
X--(CH.sub.2)nCONR.sup.14R.sup.15;
[0022] X--(CH.sub.2)nR.sup.11; X--(CH.sub.2)nCN;
X--(CH.sub.2)qOR.sup.12; (CH.sub.2)nOR.sup.12;
[0023] (CH.sub.2)n-X--R.sup.11; X--(CH.sub.2)qNHC(O)NHR.sup.12;
X--(CH.sub.2)qNHC(O)R.sup.12;
[0024] X--(CH.sub.2)qNHS(O).sub.2R.sup.12;
X--(CH.sub.2)qNHS(O).sub.2R.sup.11; X--C.sub.3-6 alkenyl;
X--C.sub.3-6alkynyl;
[0025] n is 1, 2, 3, 4 or 5;
[0026] q is 2, 3, 4, 5 or 6;
[0027] X is NR.sup.13, O, S, S(O), S(O).sub.2;
[0028] R.sup.11 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.sup.14R.sup.15, C(O)OR.sup.12,
hydroxy, .dbd.O, .dbd.S, CN, NO.sub.2, COR.sup.13,
NR.sup.14R.sup.15, X(CH.sub.2)qNR.sup.14R.sup.15,
(CH.sub.2)nNR.sup.14R.sup.15, (CH.sub.2)nOH, SR.sup.13,
S(O)R.sup.13, S(O).sub.2R.sup.13C.sub.1-6 alkyl-X--C.sub.1-6 alkyl,
C.sub.1-6 alkyl or C.sub.1-6 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.sup.14R.sup.15, SR.sup.13,
S(O)R.sup.13, S(O).sub.2R.sup.13;
[0029] R.sup.12 and R.sup.13 are independently hydrogen or
C.sub.1-6 alkyl where the alkyl group may be substituted with 1-3
fluorine atoms or may form a saturated 3-6 membered ring;
[0030] R.sup.14 and R.sup.15 are independently hydrogen, C.sub.1-6
alkyl, C.sub.3-6 cycloalkyl or (CH.sub.2)qOH,
[0031] or R.sup.14 and R.sup.15 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.sub.1-6 alkyl, C.sub.1-6
alkyl-OH, or hydroxy; and
[0032] R.sup.16 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 .dbd.O,
provided that: [0033] when R.sup.4 is halogen or C.sub.1-4alkoxy
and R.sup.5 is hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-2alkoxy,
C.sub.1-2alkylthio, trifluoromethyl or ethynyl and when one of
R.sup.1, R.sup.2 or R.sup.3 is C.sub.1-6alkyl or C.sub.1-6alkoxy
and is meta to the sulphonamide group then the group ortho to both
the sulphonamide group and the C.sub.1-6alkyl or C.sub.1-6alkoxy
group is not hydrogen, [0034] when R.sup.4 is halogen or
C.sub.1-4alkoxy and R.sup.5 is hydrogen, halogen, C.sub.1-4alkyl,
C.sub.1-2alkoxy, C.sub.1-2alkylthio, trifluoromethyl or ethynyl and
when one of R.sup.1, R.sup.2 or R.sup.3 is C.sub.1-6alkyl or
C.sub.1-6alkoxy and is ortho to the sulphonamide group then the
group ortho to the C.sub.1-6Alkyl or C.sub.1-6alkoxy and also meta
to the sulphonamide group is not hydrogen, [0035] when two of
R.sup.1, R.sup.2, R.sup.3 are hydrogen and the other is a methyl
group para to the sulphonamide and R.sup.4 is methoxy then R.sup.5
is not hydrogen or bromo, and [0036] when R.sup.5 is methyl and
R.sup.6 is methoxy and one of R.sup.1, R.sup.2 or R.sup.3 is bromo
or iodo and the other two are both hydrogen, then the bromo or iodo
group is not ortho to the sulphonamide group.
[0037] 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, 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 suitable ring position including
suitable substituents on nitrogen atoms.
[0038] Certain compounds of formula (I) are capable of existing in
stereoisomeric forms. It will 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.
[0039] Preferred halogen groups for R.sup.1, R.sup.2 and R.sup.3
are chloro, bromo and fluoro. Preferably one of R.sup.1, R.sup.2
and R.sup.3 is hydrogen and the other is chloro, bromo or methyl.
More preferably R.sup.1 and R.sup.2 are chloro at the 2- and
3-positions of the phenyl ring and R.sup.3 is hydrogen (i.e.
2,3-dichlorophenyl), R.sup.1 and R.sup.3 are chloro at the 2- and
4-positions of the phenyl ring and R.sup.2 is hydrogen (i.e.
2,4-dichlorophenyl) or R.sup.1 is chloro at the 2-position and
R.sup.2 is methyl at the 3-position of the phenyl ring and R.sup.3
is hydrogen (i.e 2-chloro-3-methylphenyl). Most preferably R.sup.1
and R.sup.2 are chloro at the 2- and 3-positions of the phenyl ring
and R.sup.3 is hydrogen (i.e. 2,3-dichlorophenyl).
[0040] In a further aspect the invention provides a compound of
formula (I) as defined above but without the provisos where R.sup.1
and R.sup.2 are chloro at the 2- and 3-positions of the phenyl ring
and R.sup.3 is hydrogen (i.e. 2,3-dichlorophenyl), R.sup.1 and
R.sup.3 are chloro at the 2- and 4-positions of the phenyl ring and
R.sup.2 is hydrogen (i.e. 2,4-dichlorophenyl) or R.sup.1 is chloro
at the 2-position and R.sup.2 is methyl at the 3-position of the
phenyl ring and R.sup.3 is hydrogen (i.e
2-chloro-3-methylphenyl).
[0041] For the group R.sup.4 examples of C.sub.3-6 alkenyloxy
include OCH.sub.2CH.dbd.CH.sub.2, examples of C.sub.3-6 alkynyloxy
include OCH.sub.2CCH, examples of OC.sub.1-6 alkyl-O--C.sub.1-6
alkyl include OCH.sub.2CH.sub.2OMe, examples of OC.sub.1-6
alkylR.sup.11 include OCH.sub.2R.sup.11, and examples of OC.sub.1-6
alkylR.sup.16 include OCH.sub.2pyrrolidine.
[0042] Preferred groups for R.sup.4 include C.sub.1-6 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.sup.4 is methoxy.
[0043] For R.sup.5 and R.sup.6 examples of NR.sup.14R.sup.15
includes morpholine, pyrrolidine, NMe.sub.2, NHCH.sub.2CH.sub.2OMe,
NHMe, and the groups below:
##STR00003##
[0044] Examples of X--(CH.sub.2)qNR.sup.14R.sup.15 include
SCH.sub.2CH.sub.2NH.sub.2 and SCH.sub.2CH.sub.2NMe.sub.2, examples
of (CH.sub.2)nNR.sup.14R.sup.15 include CH.sub.2morpholine,
examples of X--R.sup.12 includes SMe, OMe, OEt, OH, SO.sub.2Me,
examples of X--C.sub.1-6alkylR.sup.16 includes
OCH.sub.2pyrrolidine, examples of X--(CH.sub.2)nCO.sub.2R.sup.12
includes SCH.sub.2CO.sub.2H, SCH.sub.2CO.sub.2Me,
SCH.sub.2CH.sub.2CO.sub.2Me, examples of
X--(CH.sub.2)nCONR.sup.14R.sup.15 includes SCH.sub.2CONH.sub.2,
SCH.sub.2CONHMe, OCH.sub.2CONEt.sub.2, examples of
X--(CH.sub.2)nR.sup.11 includes the groups below:
##STR00004##
[0045] Examples of X--(CH.sub.2).sub.nCN, includes SCH.sub.2CN,
examples of X--(CH.sub.2)qOR.sup.12 includes OCH.sub.2CH.sub.2OMe,
examples of (CH.sub.2)nOR.sup.12 includes CH.sub.2OH, CH.sub.2OMe,
examples of X--(CH.sub.2)qNHC(O)NHR.sup.12 includes
SCH.sub.2CH.sub.2NHC(O)NHEt, and examples of
X--(CH.sub.2)qNHC(O)R.sup.12 includes NHCH.sub.2CH.sub.2NHC(O)Me.
Examples of NHC(O)C.sub.1-6 alkyl optionally substituted by one or
more hydroxy groups includes NHCOCH.sub.2OH.
[0046] Preferred groups for R.sup.5 include hydrogen, halogen such
as bromo and chloro, phenyl, C.sub.1-6 alkyl such as methyl,
CH.sub.2OH, cyano and 2-aminothanethiol. More preferably R.sup.5 is
hydrogen, methyl, CH.sub.2OH or halogen such bromo or chloro.
[0047] Preferred groups for R.sup.6 include hydrogen, C.sub.1-6
alkyl, CH.sub.2OH and halogen, more preferably hydrogen, methyl,
CH.sub.2OH or chloro.
[0048] In a further aspect the invention provides a compound of
formula (IA):
##STR00005##
in which
[0049] R.sup.1, R.sup.2 and R.sup.3 are independently hydrogen,
halogen, cyano, CF.sub.3, OCF.sub.3, C.sub.1-6 alkenyl or C.sub.1-6
alkyl;
[0050] R.sup.4 is halogen, C.sub.1-6 alkoxy or OR.sup.9;
[0051] R.sup.5 and R.sup.6 are independently hydrogen, halogen,
C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, cyano, R.sup.9, OR.sup.9,
NR.sup.9R.sup.10, SR.sup.9, S(CH2).sub.nCO.sub.2H,
S(CH2).sub.nCO.sub.2R.sup.12, S(CH.sub.2).sub.nCONR.sup.12R.sup.13,
S(CH2).sub.nR.sup.11 or a 5- to 7-membered heteroaromatic or
saturated ring containing 1 to 3 heteroatoms selected from
nitrogen, oxygen and sulphur;
[0052] n is 1, 2 or 3;
[0053] R.sup.9 and R.sup.10 are independently hydrogen, C.sub.1-6
alkyl optionally substituted by hydroxy, C.sub.1-6 alkoxy or
NHCOC.sub.1-6 alkyl, or R.sup.9 and R.sup.10 are optionally
substituted aryl, C.sub.1-6 alkyl-aryl or C.sub.1-6 alkyl-R.sup.11
or R.sup.9 and R.sup.10 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.sub.1-6 alkyl or C.sub.1-6 alkyl-OH;
and
[0054] R.sup.11 is a 5- to 7-membered heteraromatic ring containing
1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur and
optionally substituted by C.sub.1-6 alkyl; and
[0055] R.sup.12 and R.sup.13 are independently hydrogen or
C.sub.1-6 alkyl.
[0056] For compounds (IA) R.sup.1, R.sup.2 and R.sup.3 are
independently hydrogen, halogen, cyano, CF.sub.3, OCF.sub.3,
C.sub.1-6 alkenyl or C.sub.1-6 alkyl, preferred halogen groups
being chloro. Preferably one of R.sup.1, R.sup.2 and R.sup.3 is
methyl, ethenyl, cyano, chloro, fluoro, iodo or two are chloro or
all three are fluoro. More preferred are compounds where
R.sup.1-R.sup.3 together with the phenyl group to which they are
attached form a 3-chloro-2-methylphenyl or a 2,3-dichlorophenyl
group.
[0057] For compounds (IA) preferred groups for R.sup.4 include
halogen such as bromo and chloro, C.sub.1-6 alkoxy such as methoxy
and ethoxy, C.sub.1-6 alkyl or OR.sup.9 where R.sup.9 is
CH.sub.2R.sup.11 where R.sup.11 is a 5- or 6-membered heteraromatic
ring containing 1 or 2 heteroatoms.
[0058] More preferably R.sup.4 is methoxy, halogen, such as chloro,
or OR.sup.9 where R.sup.9 is CH.sub.2R.sup.11 where R.sup.11 is
furanyl, 5-methyl-3-isoxazolyl, pyridyl optionally substituted by
methyl, pyridazinyl, pyrazinyl,
1-methyl-6-oxo-1,6-dihydro-3-pyridinyl.
[0059] For compounds (IA) preferably R.sup.5 is hydrogen, methyl,
bromo, chloro, methoxy, morpholinyl, pyrrolinyl, dimethylamino,
hydroxy, 2-methoxyethoxy, pyrazinyl, pyrimidinyl, O-Ph-CO.sub.2H,
2-hydroxyethylamino, 2-methoxyethylamino, NHCH.sub.2CH.sub.2NHCOMe,
cyano, 4-hydroxymethyl-1-piperidinyl, SMe, NHMe, or
2,4-difluorophenyl.
[0060] For compounds (IA) preferably R.sup.6 is hydrogen or
chloro.
[0061] Preferred compounds of formula (I)/(IA) include those
exemplified herein both in free base form and as pharmaceutically
acceptable salts.
[0062] 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):
##STR00006##
where R.sup.4, R.sup.5 and R.sup.6 are as defined in formula (I) or
are protected derivatives thereof with a compound of formula
(III):
##STR00007##
where R.sup.1, R.sup.2 and R.sup.3 are as defined in formula (I) or
are protected derivatives thereof and LG is a leaving group, and
optionally thereafter [0063] removing any protecting groups, [0064]
forming a pharmaceutically acceptable salt.
[0065] Preferred leaving groups LG include halogen such as chloro.
Preferably the reaction between compounds (II) and (III) 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.
[0066] Where R.sup.4 is C.sub.1-6 alkoxy where the alkyl group may
form a 3-6 membered saturated ring or to may be substituted with
1-3 fluorine atoms or a cyano group;
[0067] C.sub.3-6 alkenyloxy or C.sub.3-6 alkynyloxy where either
may be optionally substituted with hydroxy or
NR.sup.14R.sup.15;
[0068] OC.sub.1-6 alkyl-X--C.sub.1-6 alkyl where the alkyl groups
may form a 3-6 membered saturated ring;
[0069] OC.sub.1-6 alkylR.sup.11, or OC.sub.2-6 alkyl-X--R.sup.11
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.sup.14R.sup.15, SR.sup.13, S(O).sub.2R.sup.13,
S(O)R.sup.13; or
[0070] OC.sub.1-6 alkylR.sup.16;
compounds of formula (II) can be prepared by treating a compound of
the formula (IV), where LG is a leaving group (such as chlorine or
bromine):
##STR00008##
with a compound of formula (V)
R.sup.4--H (V)
in a suitable solvent (such as 1,2-dimethoxyethane,
N,N-dimethylformamide or tetrahydrofuran) with a suitable base such
as sodium hydride or potassium tert-butoxide at a suitable
temperature such as 25.degree. C. to 60.degree. C.
[0071] Where R.sup.4 is C.sub.1-6 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;
[0072] C.sub.3-6 alkenyloxy or C.sub.3-6 alkynyloxy where either
may be optionally substituted with hydroxy or
NR.sup.14R.sup.15;
[0073] OC.sub.1-6 alkyl-X--C.sub.1-6 alkyl where the alkyl groups
may form a 3-6 membered saturated ring;
[0074] OC.sub.1-6 alkylR.sup.11, or OC.sub.2-6 alkyl-X--R.sup.11
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.sup.14R.sup.15, SR.sup.13, S(O).sub.2R.sup.13,
S(O)R.sup.13; or
[0075] OC.sub.1-6 alkylR.sup.16;
compounds of formula (I) can be prepared by treating a compound of
the formula (VI), where LG is a leaving group (such as chlorine or
bromine):
##STR00009##
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 potassium tert-butoxide
at a suitable temperature such as 25.degree. C. to 60.degree.
C.
[0076] Compounds of structure (VIII) can be prepared by taking a
compound of formula (VII) where LG is a leaving group (such as
chlorine or bromine) and protecting the sulfonamide as for example
the trimethylsilyethoxymethyl ether (SEM) or methoxymethyl ether
(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.degree. C.) to afford compound of the formula
(VIII):
##STR00010##
[0077] Compound of formula (VIII) could then be treated with
compounds of formulae (IX):
R.sup.5--H (IX)
where R.sup.5--H is a primary or secondary amine, thiol or alcohol
as defined above (i.e. where R.sup.5 is a group containing an X
moiety where X is NR.sup.13, O or S), 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.degree. C. to afford
compound of the formula (X):
##STR00011##
[0078] The protecting group (P) can then be removed by standard
methods to afford compound of formula (I).
[0079] Compounds of structure (II) or (I), where R.sup.5 is an
optionally substituted aryl or heteroaryl ring as defined in the
claims, can be prepared by taking a compound of formula (XI) or
(VII) where LG is a suitable leaving group such as bromine,
chlorine or iodine and reacting it with an aryl or heteroaryl
boronic acid such as phenyl boronic acid, a palladium catalyst such
as [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) chloride, a
suitable base such as caesium fluoride, sodium acetate or caesium
carbonate and a suitable solvent such as methanol or ethanol and
heating between 40-80.degree. C.
##STR00012##
[0080] Compounds of formula (II) and (I) where R.sup.5 or R.sup.6
is CO.sub.2R.sup.13 can be prepared by reacting a compound of
formula (II) or (I), where R.sup.5 or R.sup.6 is bromine or iodine,
in a suitable solvent such as R.sup.13OH or dioxane containing
R.sup.13OH, a suitable tertiary amine such as triethylamine, a
suitable palladium catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) chloride under
an atmosphere of carbon monoxide usually at 2-10 bar, ideally at
4-6 bar and at a temperature of 70-120.degree. C. Compounds of
formula (II) and (I) where R.sup.5 or R.sup.6 is
CONR.sup.14R.sup.15 can be prepared by reacting a compound of
formula (II) or (I), where R.sup.5 or R.sup.6 is bromine or iodine,
in a suitable solvent such as dioxane containing
NHR.sup.14R.sup.15, a suitable tertiary amine such as
triethylamine, a suitable palladium catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) chloride under
an atmosphere of carbon monoxide usually at 2-10 bar, ideally at
4-6 bar and at a temperature of 70-120.degree. C. Compounds of
formula (I) where R.sup.5 or R.sup.6 is CH.sub.2OH can be prepared
from compounds of formula (I) where R.sup.5 or R.sup.6 is
CO.sub.2R.sup.13 by reduction using a suitable reducing agent such
as lithium triethylborohydride in a suitable solvent such as
tetrahydrofuran at a temperature of 0-10.degree. C.
[0081] Compounds of formula (I) where R.sup.5 or R.sup.6 is CHO can
be prepared from compounds of formula (I) where R.sup.5 or R.sup.6
is CH.sub.2OH 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.degree. C.
[0082] Compounds of formula (I) where R.sup.5 or R.sup.6 is
CH(OH)R.sup.11 or CH(OH)(C1-5)alkyl can be prepared from compounds
of formula (I) where R.sup.5 or R.sup.6 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.degree. C.
[0083] C.sub.1-5 alkylM or R.sup.11M
##STR00013##
[0084] A compound of formula (XV) can be made by reacting a
compound of formula (XIII), where R.sup.4 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.degree. C.
[0085] Intermediate compounds of formula (II) and (III) can be
prepared using standard chemistry or are available
commercially.
[0086] 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 removal of one or more
protecting groups. The protection and deprotection of functional
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).
[0087] 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.
[0088] Certain compounds of formula (II) and (III) are believed to
be novel and form a further aspect of the invention.
[0089] 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.
[0090] 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: [0091] (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 (hay fever) and
vasomotor rhinitis; sarcoidosis, farmer's lung and related
diseases, fibroid lung and idiopathic interstitial pneumonia;
[0092] (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; [0093] (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; [0094] (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; [0095] (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-Barre
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 [0096] (6) (other tissues and systemic
disease) hepatitis, vasculitis, spondyloarthopathies, vaginitis,
glomerulonephritis, myositis, atherosclerosis, Acquired
Immunodeficiency Syndrome (AIDS), lupus erythematosus, 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. [0097] (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; [0098] (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. [0099] (9) All diseases that result from a general
inbalance of the immune system and resulting in increased atopic
inflammatory reactions. [0100] (10) Cystic fibrosis, re-perfusion
injury in the heart, brain, peripheral limbs and other organs.
[0101] (11) Burn wounds & chronic skin ulcers [0102] (12)
Reproductive Diseases (e.g. Disorders of ovulation, menstruation
and implantation, Pre-term labour, Endometriosis) [0103] (13)
thrombosis [0104] (14) infectious diseases such as HIV infection
and other viral infections, bacterial infections.
[0105] 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.
[0106] 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.
[0107] 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.
[0108] 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.
[0109] 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.
[0110] 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.
[0111] 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.
[0112] The invention also provides a method of treating a
respiratory disease, such as asthma 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.
[0113] For the above-mentioned therapeutic uses the dosage
administered will, of course, vary with the compound employed, the
mode of administration, the treatment desired and the disorder
indicated.
[0114] The compound of formula (I) and pharmaceutically acceptable
salts and solvates thereof may be used on their own but will
generally be administered in the form of a pharmaceutical
composition in which the formula (I) compound/salt/solvate (active
ingredient) is in association with a pharmaceutically acceptable
adjuvant, diluent or carrier. Depending on the mode of
administration, the pharmaceutical composition will preferably
comprise from 0.05 to 99% w (percent by weight), more preferably
from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and
even more preferably from 0.10 to 50% w, of active ingredient, all
percentages by weight being based on total composition.
[0115] The present invention also provides a pharmaceutical
composition comprising a compound is of formula (I), or a
pharmaceutically acceptable salt or solvate thereof, as
hereinbefore defined, in association with a pharmaceutically
acceptable adjuvant, diluent or carrier.
[0116] The invention further provides a process for the preparation
of a pharmaceutical composition of the invention which comprises
mixing a compound of formula (I), or a pharmaceutically acceptable
salt or solvate thereof, as hereinbefore defined, with a
pharmaceutically acceptable adjuvant, diluent or carrier.
[0117] The pharmaceutical compositions may be administered
topically (e.g. to the lung and/or airways or to the skin) in the
form of solutions, suspensions, heptafluoroalkane aerosols and dry
powder formulations; or systemically, e.g. by oral administration
in the form of tablets, capsules, syrups, powders or granules, or
by parenteral administration in the form of solutions or
suspensions, or by subcutaneous administration or by rectal
administration in the form of suppositories or transdermally.
Preferably the compound of the invention is administered
orally.
[0118] In a further aspect, the present invention provides the use
of a compound or formula (I), or a pharmaceutically acceptable salt
or solvate thereof, as hereinbefore defined in the manufacture of a
medicament for use in therapy in combination with drugs used to
treat asthma and rhinitis (such as inhaled and oral steroids,
inhaled .beta.2-receptor agonists and oral leukotriene receptor
antagonists).
[0119] The following examples illustrate the invention.
EXAMPLE 1
2,3-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)-benzenesulphonamide
##STR00014##
[0121] Sodium hydride (0.1 g of 60%) was added to
3-methoxy-5-methyl-2-pyrazinamine (0.07 g) in 1,2-dimethoxyethane
(3 mL) under nitrogen at room temperature. After 1 hour at
50.degree., 2,3-dichlorobenzenesuphonyl chloride (0.15 g) was
added. After stirring for 30 minutes, 5% aqueous citric acid was
added and the product extracted with ethyl acetate (X3). The
combined extracts were washed with saturated brine, dried
(MgSO.sub.4) and the solvent was evaporated. Chromatography on
silica eluting with dichloromethane/methanol mixtures gave the
title compound as a white solid (0.08 g).
[0122] m/e 346/8/350 (M-1.sup.+, 100%).
[0123] .sup.1H NMR (D6-DMSO) .delta. 11.27 (1H, s), 8.06 (1H, d),
7.93 (1H, d), 7.60-7.55 (1H, br s), 7.58 (1H, t), 3.87 (3H, s),
2.28 (3H, s).
EXAMPLE 2
N-(6-Chloro-3-methoxy-2-pyrazinyl)-2,3,4-trifluorobenzenesulphonamide
##STR00015##
[0125] Prepared by the method of Example 1 (reaction performed at
room temperature) using 6-chloro-3-methoxy-2-pyrazinamine (0.16 g)
and 2,3,4-trifluorobenzenesulphonyl chloride (0.25 g). Yield 0.08
g.
[0126] m/e 352/4 (M-1.sup.+, 100%).
[0127] .sup.1H NMR (D6-DMSO) .delta. 7.93-7.80 (1H, m), 7.89 (1H,
s), 7.60-7.50 (1H, m), 3.91 (3H, s).
EXAMPLE 3
3-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)-2-methylbenzenesulphonamide
##STR00016##
[0129] Prepared by the method of Example 1 (reaction performed at
room temperature) using 6-chloro-3-methoxy-2-pyrazinamine (0.16 g)
and 3-chloro-2-methylbenzenesulphonyl chloride (0.23 g). Yield 0.15
g.
[0130] m/e 346/8/50 (M-1.sup.+, 100%).
[0131] .sup.1H NMR (D6-DMSO) .delta. 8.05 (1H, d), 7.85 (1H, s),
7.75 (1H, d), 7.47 (1H, t), 3.92 (3H, s), 2.66 (3H, s).
EXAMPLE 4
2,3-Dichloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
a) 3-Bromo-6-chloro-2-pyrazinamine
##STR00017##
[0133] N-bromosuccinamide (6.9 g) was added portionwise over 0.5 h
to a stirred solution of 6-chloro-2-pyrazinamine (5.0 g) in
chloroform (200 mL) heated under reflux. After the addition was
complete the reaction mixture was allowed to cool, washed with
water and evaporated to give a 3:1 mixture of
5-bromo-6-chloro-2-pyrazinamine and the subtitle compound which
were separated by silica gel chromatography eluting with
dichloromethane. Yield 2.0 g. Used directly.
b) 6-Chloro-3-methoxy-2-pyrazinamine and
3-bromo-6-methoxy-2-pyrazinamine
##STR00018##
[0135] 3-Bromo-6-chloro-2-pyrazinamine (1.0 g), sodium methoxide (3
mL of 25% solution in methanol) and methanol (10 mL) were heated at
reflux for 3 hours. The solvent was evaporated and the residue was
dissolved in ethyl acetate and brine. The organic layer was
separated dried (MgSO.sub.4) and the solvent was evaporated to give
a mixture of the sub-title compounds (ratio 10:1). Purification was
by silica gel chromatography eluting with dichloromethane. Yield
0.5 g. Used directly.
c)
2,3-Dichloro-N-(6-Chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00019##
[0137] Prepared by the method of Example 1 (reaction performed at
room temperature) using 6-chloro-3-methoxy-2-pyrazinamine (0.24 g)
and 2,3-dichlorobenzenesulphonyl chloride (0.32 g). Yield 0.24
g.
[0138] m/e 366/8/370/2 (M-1.sup.+, 100%).
[0139] .sup.1H NMR (D6-DMSO) .delta. 8.14 (1H, d), 7.96 (1H, d),
7.89 (1H, s), 7.62 (1H, t), 3.91 (3H, s).
EXAMPLE 5
2,3-Dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00020##
[0141] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g)
and 2,3-dichlorobenzenesulphonyl chloride (0.15 g). Yield 0.05
g.
[0142] m/e 366/8/370/2 (M-1.sup.+, 100%).
[0143] .sup.1H NMR (D6-DMSO) .delta. 8.15 (1H, d), 7.93 (1H, d),
7.79 (1H, s), 7.58 (1H, t), 3.93 (3H, s).
EXAMPLE 6
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,5-dichlorobenzenesulphonamide
##STR00021##
[0145] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.2 g)
and 2,5-dichlorobenzenesulphonyl chloride (0.24 g). Yield 0.14
g.
[0146] m/e 410/2/4/6 (M-1.sup.+, 100%).
[0147] .sup.1H NMR (D6-DMSO) .delta. 8.04 (1H, d), 7.86 (1H, s),
7.73 (1H, dd), 7.66 (1H, dd), 3.91 (3H, s).
EXAMPLE 7
N-(5-Bromo-3-methoxy-2-pyrazinyl)-3,5-dichlorobenzenesulphonamide
##STR00022##
[0149] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.2 g)
and 3,5-dichlorobenzenesulphonyl chloride (0.24 g). Yield 0.012
g.
[0150] m/e 410/2/4/6 (M-1.sup.+, 100%).
[0151] .sup.1H NMR (D6-DMSO) .delta. 7.96-7.91 (4H, m), 3.93 (3H,
s).
EXAMPLE 8
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
##STR00023##
[0153] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.1 g)
and 2,3-dichlorobenzenesulphonyl chloride (0.2 g). Yield 0.045
g.
[0154] m/e 410/2/4/6 (M-1.sup.+, 100%).
[0155] .sup.1H NMR (D6-DMSO) .delta. 8.06 (1H, dd), 7.93 (1H, dd),
7.82 (1H, s), 7.57 (1H, t), 3.92 (3H, s).
EXAMPLE 9
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,4-dichlorobenzenesulphonamide
##STR00024##
[0157] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.2 g)
and 2,4-dichlorobenzenesulphonyl chloride (0.24 g). Yield 0.059
g.
[0158] m/e 410/2/4/6 (M-1.sup.+, 100%).
[0159] .sup.1H NMR (D6-DMSO) .delta. 8.07 (1H, d), 7.85 (2H, d),
7.64 (1H, dd), 3.92 (3H, s).
EXAMPLE 10
N-(5-Bromo-3-methoxy-2-pyrazinyl)-3,4-dichlorobenzenesulphonamide
##STR00025##
[0161] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.15 g)
and 3,4-dichlorobenzenesulphonyl chloride (0.15 g). Yield 0.09
g.
[0162] m/e 410/2/4/6 (M-1.sup.+, 100%).
[0163] .sup.1H NMR (D6-DMSO) .delta. 8.14 (1H, s), 8.00-7.85 (3H,
m), 3.94 (3H, s).
EXAMPLE 11
N-(5-Bromo-3-methoxy-2-pyrazinyl)-4-chlorobenzenesulphonamide
##STR00026##
[0165] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.1 g)
and 4-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.13 g.
[0166] m/e 376/8/380 (M-1.sup.+, 100%).
[0167] .sup.1H NMR (D6-DMSO) .delta. 11.3 (1H, br s), 7.97 (2H, d),
7.91 (1H, s), 7.66 (2H, d), 3.93 (3H, s).
EXAMPLE 12
N-(5-Bromo-3-methoxy-2-pyrazinyl)-3-chlorobenzenesulphonamide
##STR00027##
[0169] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.1 g)
and 3-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.14 g.
[0170] m/e 376/8/380 (M-1.sup.+, 100%).
[0171] .sup.1H NMR (D6-DMSO) .delta. 8.00-7.90 (3H, m), 7.75 (1H,
d), 7.64 (1H, t), 3.94 (3H, s).
EXAMPLE 13
N-(3-Methoxy-5-methyl-2-pyrazinyl)-2-fluorobenzenesulphonamide
##STR00028##
[0173] Prepared by the method of Example 1 using
3-methoxy-5-methyl-2-pyrazinamine and 2-fluorobenzenesulphonyl
chloride.
[0174] m/e 298 (M+1.sup.+, 100%).
[0175] .sup.1H NMR (D6-DMSO) .delta. 11.05 (1H, br s), 7.85-7.95
(1H, m), 7.65-7.75 (1H, m), 7.50-7.60 (1H, m), 7.35-7.45 (1H, m),
3.90 (3H, s), 2.30 (3H, s).
[0176] MP 150-152.degree. C.
EXAMPLE 14
N-(3-Methoxy-5-methyl-2-pyrazinyl)benzenesulphonamide
##STR00029##
[0178] Prepared by the method of Example 1 using
3-methoxy-5-methyl-2-pyrazinamine and benzenesulphonyl chloride
[0179] MP 138-139.degree. C.
EXAMPLE 15
N-(3-Methoxy-5-methyl-2-pyrazinyl)-2-iodobenzenesulphonamide
##STR00030##
[0181] Prepared by the method of Example 1 using
3-methoxy-5-methyl-2-pyrazinamine and 2-iodobenzenesulphonyl
chloride.
[0182] .sup.1H NMR (D6-DMSO) .delta. 10.75 (1H, br s), 8.05-8.15
(2H, m), 7.65-7.75 (2H, m), 7.30 (1H, dt), 3.90 (3H, s), 2.30 (3H,
s).
[0183] MP 140-141.degree. C.
EXAMPLE 16
N-(3-Methoxy-5-methyl-2-pyrazinyl)-3-fluorobenzenesulphonamide
##STR00031##
[0185] Prepared by the method of Example 1 using
3-methoxy-5-methyl-2-pyrazinamine and 3-fluorobenzenesulphonyl
chloride.
[0186] MP 95-97.degree. C.
EXAMPLE 17
2-[[(3-Methoxy-5-methyl-2-pyrazinyl)amino]sulphonyl]benzonitrile
##STR00032##
[0188] Prepared by the method of Example 1 using
3-methoxy-5-methyl-2-pyrazinamine and 2-cyanobenzenesulphonyl
chloride.
[0189] m/e 305 (M+1.sup.+, 100%).
[0190] .sup.1H NMR (D6-DMSO) .delta. 8.15 (1H, dd), 8.05 (1H, dd),
7.85 (1H, dt), 7.80 (1H, dt), 7.60 (1H, s), 3.85 (3H, s), 2.30 (3H,
s).
EXAMPLE 18
N-(5-Bromo-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00033##
[0192] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-bromo-3-methoxy-2-pyrazinamine and
benzenesulphonyl chloride
[0193] m/e 344 (M+1.sup.+, 100%).
EXAMPLE 19
N-(5-Bromo-3-methoxy-2-pyrazinyl)2-iodobenzenesulphonamide
##STR00034##
[0195] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-bromo-3-methoxy-2-pyrazinamine and
2-iodobenzenesulphonyl chloride.
[0196] m/e 470 (M+1.sup.+, 100%).
[0197] .sup.1H NMR (D6-DMSO) .delta. 11.30 (1H, br s), 8.0-8.1 (2H,
m), 7.80 (1H, s), 7.60 (1H, dt), 7.30 (1H, dt), 3.95 (3H, s).
EXAMPLE 20
2,3-Dichloro-N-[3-(2-furanylmethoxy)-5-methyl-2-pyrazinyl]benzenesulphonam-
ide
a)
N-(3-Bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
##STR00035##
[0199] Prepared by the method of Example 1 using
3-bromo-5-methyl-2-pyrazinamine (0.84 g) and
2,3-dichlorobenzenesulphonyl chloride (1.1 g). Yield 0.92 g.
b)
2,3-Dichloro-N-[3-(2-furanylmethoxy)-5-methyl-2-pyrazinyl]benzenesulpho-
namide
##STR00036##
[0201] Sodium hydride (0.04 g of a 60% dispersion in oil) was added
to furfurylalcohol (0.034 g) in 1,2-dimethoxyethane (1 mL). After 5
minutes
N-(3-Bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(Example 20 part a) (0.1 g) was added and the mixture heated at
40.degree. C. After 16 h, 5% aqueous citric acid (10 mL) was added
and the mixture extracted with ethyl acetate (2.times.50 mL). The
combined extracts were washed with brine, dried (MgSO.sub.4) and
the solvent evaporated. Chromatography on silica gel eluting with
dichloromethane gave the title compound as a white solid (0.02
g)
[0202] m/e 412 (M-1.sup.+, 100%).
[0203] .sup.1H NMR (D6-DMSO) .delta. 11.33 (1H, br s), 8.01 (1H,
d), 7.90 (1H, d), 7.70 (1H, s), 7.62 (1H, br s), 7.54 (1H, t),
6.61-6.58 (1H, m), 6.50-6.45 (1H, m), 5.33 (2H, s), 2.32 (3H,
s).
[0204] MP 127-129.degree. C.
EXAMPLE 21
2,3-Dichloro-N-[5-methyl-3-(5-methyl-3-isoxazolylmethoxy)-2-pyrazinyl]benz-
enesulphonamide
##STR00037##
[0206] Prepared by the method of Example 20 using
(5-methyl-3-isoxazolyl)methanol (0.05 g) and
N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(0.1 g). Yield 0.05 g.
[0207] m/e 429 (M+1.sup.+, 100%).
[0208] .sup.1H NMR (D6-DMSO) .delta. 11.39 (1H, br s), 8.03 (1H,
d), 7.91 (1H, d), 7.64 (1H, br s), 7.47 (1H, t), 6.33 (1H, s), 5.37
(2H, s), 2.41 (3H, s), 2.29 (3H, s).
[0209] MP 155-156.degree. C.
EXAMPLE 22
2,3-Dichloro-N-[5-methyl-3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphon-
amide
##STR00038##
[0211] Prepared by the method of Example 20 using
pyridine-2-methanol (0.05 g) and
N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(0.1 g). Yield 0.07 g.
[0212] m/e 425 (M+1.sup.+, 100%).
[0213] .sup.1H NMR (D6-DMSO) .delta. 8.57-8.54 (1H, m), 8.05 (1H,
d), 7.89 (1H, d), 7.83 (1H, dt), 7.65-7.50 (2H, m), 7.56 (1H, t),
7.35-7.30 (1H, m), 5.44 (2H, s), 2.26 (3H, s).
EXAMPLE 23
2,3-Dichloro-N-[5-methyl-3-(6-methyl-2-pyridinylmethoxy)-2-pyrazinyl]benze-
nesulphonamide
##STR00039##
[0215] Prepared by the method of Example 20 using
6-methylpyridine-2-methanol (0.05 g) and
N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(0.1 g). Yield 0.023 g.
[0216] m/e 439 (M+1.sup.+, 100%).
[0217] .sup.1H NMR (D6-DMSO) .delta. 8.05 (1H, dd), 7.89 (1H, dd),
7.70 (1H, t), 7.59 (1H, br s), 7.54 (1H, t), 7.34 (1H, d), 7.19
(1H, d), 5.39 (2H, s), 2.47 (3H, s), 2.26 (3H, s).
[0218] MP 164-165.degree. C.
EXAMPLE 24
2,3-Dichloro-N-[5-methyl-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphon-
amide
##STR00040##
[0220] Prepared by the method of Example 20 using
pyridine-3-methanol (0.05 g) and
N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(0.1 g). Yield 0.023 g.
[0221] m/e 425 (M+1.sup.+, 100%).
[0222] .sup.1H NMR (D6-DMSO) .delta. 8.74 (1H, d), 8.55 (1H, dd),
8.03 (1H, dd), 7.95-7.85 (2H, m), 7.59 (1H, br s), 7.54 (1H, t),
7.42 (1H, dd), 5.41 (2H, s), 2.29 (3H, s).
[0223] MP 160-161.degree. C.
EXAMPLE 25
2,3-Dichloro-N-[5-methyl-3-(4-pyridinylmethoxy)-2-pyrazinyl]benzenesulphon-
amide
##STR00041##
[0225] Prepared by the method of Example 20 using
pyridine-4-methanol (0.05 g) and
N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(0.1 g). Yield 0.009 g.
[0226] m/e 425 (M+1.sup.+, 100%).
[0227] .sup.1H NMR (D6-DMSO) .delta. 8.57 (2H, d), 8.05 (1H, dd),
7.89 (1H, dd), 7.60 (1H, s), 7.55 (1H, t), 7.50 (2H, d), 5.43 (2H,
s), 2.26 (3H, s).
[0228] MP 183-184.degree. C.
EXAMPLE 26
2,3-Dichloro-N-[5-methyl-3-(3-methyl-2-pyridinylmethoxy)-2-pyrazinyl]benze-
nesulphonamide
##STR00042##
[0230] Prepared by the method of Example 20 using
3-methylpyridine-2-methanol (0.05 g) and
N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(0.1 g). Yield 0.021 g.
[0231] m/e 439 (M+1.sup.+, 100%).
[0232] .sup.1H NMR (D6-DMSO) .delta. 8.36 (1H, d), 8.05 (1H, dd),
7.83 (1H, dd), 7.64 (1H, d), 7.60 (1H, br s), 7.49 (1H, t), 7.31
(1H, dd), 5.40 (2H, s), 2.33 (3H, s), 2.29 (3H, s).
[0233] MP 137-138.degree. C.
EXAMPLE 27
2,3-Dichloro-N-[5-methyl-3-(3-pyridazinylmethoxy)-2-pyrazinyl]benzenesulph-
onamide
##STR00043##
[0235] Prepared by the method of Example 20 using
pyridazine-3-methanol (0.1 g) and
N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(0.15 g). Yield 0.038 g.
[0236] m/e 424 (M-1.sup.+, 100%).
[0237] .sup.1H NMR (D6-DMSO) .delta. 11.47 (1H, br s), 9.21 (1H,
dd), 8.05 (1H, dd), 8.00-7.95 (1H, m), 7.88 (1H, d), 7.80-7.75 (1H,
m), 7.62 (1H, br s), 7.54 (1H, t), 5.65 (2H, s), 2.27 (3H, s).
[0238] MP 119-124.degree. C.
EXAMPLE 28
2,3-Dichloro-N-[3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
a) 2,3-Dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide
##STR00044##
[0240] 2,3-Dichloropyrazine (2.6 g),
2,3-dichlorobenzenesulphonamide (4.0 g) and potassium carbonate
(10.0 g) in N,N-dimethylformamide (50 mL) was heated at 75.degree.
C.
[0241] After 16 h, 5% aqueous citric acid (30 mL) was added and the
mixture extracted with ethyl acetate (2.times.100 mL). The combined
extracts were washed with brine, dried (MgSO.sub.4) and the solvent
evaporated. Chromatography on silica gel eluting with ethyl
acetate/isohexane mixtures gave the title compound (1.5 g).
b)
2,3-Dichloro-N-[3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
##STR00045##
[0243] Sodium hydride (0.05 g of a 60% dispersion in oil) was added
to pyridine-2-methanol (0.088 g) in 1,2-dimethoxyethane (3.0 mL).
After 5 minutes,
2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (0.1 g)
was added and the mixture heated at 70.degree. C. After 4 h, 5%
aqueous citric acid (10 mL) was added and the mixture extracted
with ethyl acetate (2.times.50 mL). The combined extracts were
washed with brine, dried (MgSO.sub.4) and the solvent evaporated.
Chromatography on silica gel eluting with ethyl acetate/isohexane
mixtures gave the title compound as a white solid (0.06 g).
[0244] m/e 411 (M+1.sup.+, 100%).
[0245] .sup.1H NMR (D6-DMSO) .delta. 8.57 (1H, d), 8.13 (1H, d),
7.93 (1H, d), 7.90-7.75 (2H, m), 7.75-7.65 (1H, m), 7.65-7.55 (2H,
m), 7.40-7.30 (1H, m), 5.49 (2H, s).
[0246] MP 167-168.degree. C.
EXAMPLE 29
2,3-Dichloro-N-[3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide
##STR00046##
[0248] Prepared by the method of Example 28 using
pyridine-3-methanol (0.09 g) and
2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (0.1 g).
Yield 0.042 g.
[0249] m/e 409 (M-1.sup.+, 100%).
[0250] .sup.1H NMR (CDCl.sub.3) .delta. 8.70 (1H, s), 8.65 (1H, d),
8.28 (1H, dd), 7.79 (1H, d), 7.70-7.67 (2H, m), 7.61 (1H, d),
7.40-7.35 (2H, m), 5.45 (2H, s).
[0251] MP 138-139.degree. C.
EXAMPLE 30
2,3-Dichloro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00047##
[0253] 2,3-Dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide
(Example 28 part a) (0.2 g) in 10% sodium methoxide in methanol (10
mL) was heated at 85.degree. C. After 4 h, 5% aqueous citric acid
(50 mL) was added and the mixture extracted with ethyl acetate
(2.times.150 mL). The combined extracts were washed with brine,
dried (MgSO.sub.4) and the solvent evaporated. Chromatography on
silica gel eluting with ethyl acetate/isohexane mixtures gave the
title compound as a white solid (0.12 g)
[0254] m/e 334 (M+1.sup.+, 100%).
[0255] .sup.1H NMR (D6-DMSO) .delta. 11.54 (1H, br s), 8.10 (1H,
d), 7.94 (1H, d), 7.85-7.75 (1H, m), 7.70-7.55 (1H, m), 7.59 (1H,
t), 3.90 (3H, s).
[0256] MP 183-184.degree. C.
EXAMPLE 31
N-[5-Bromo-3-(2-pyrazinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphona-
mide
a) 2,3-Dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide
##STR00048##
[0258] Prepared by the method of Example 1 (reaction performed at
room temperature) using 3,5-dibromo-2-pyrazinamine (2.9 g) and
2,3-dichloro benzenesulphonyl chloride (2.8 g). Yield 4.4 g.
b)
N-[5-Bromo-3-(2-pyrazinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulph-
onamide
##STR00049##
[0260] Sodium hydride (0.05 g of a 60% dispersion in oil) was added
to pyrazine-2-methanol (0.04 g) in 1,2-dimethoxyethane (3 ml).
After 5 minutes,
2,3-Dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide
(0.12 g) was added. After 0.5 h, 5% aqueous citric acid (10 mL) was
added and the mixture extracted with ethyl acetate (2.times.30 mL).
The combined extracts were washed with brine, dried (MgSO.sub.4)
and the solvent evaporated. Chromatography on silica gel eluting
with ethyl acetate/isohexane mixtures gave the title compound as a
white solid (0.06 g).
[0261] m/e 489 (M-1.sup.+, 100%).
[0262] .sup.1H NMR (D6-DMSO) .delta. 9.00 (1H, s), 8.66 (2H, s),
8.08 (1H, dd), 7.92 (1H, dd), 7.91 (1H, s), 7.56 (1H, t), 5.53 (2H,
s).
[0263] MP 207-209.degree. C.
EXAMPLE 32
N-[5-Bromo-3-(1-methyl-6-oxo-1,6-dihydro-3-pyridinylmethoxy)-2-pyrazinyl]--
2,3-dichlorobenzenesulphonamide
##STR00050##
[0265] Prepared by the method of Example 31 using
5-hydroxymethyl-1-methyl-1H-pyridin-2-one (0.1 g) and
2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (0.16
g). Yield 0.035 g.
[0266] m/e 521 (M+1.sup.+, 100%).
[0267] .sup.1H NMR (D6-DMSO) .delta. 8.04 (1H, dd), 7.91 (1H, dd),
7.90-7.87 (2H, m), 7.60-7.50 (2H, m), 6.42 (1H, d), 5.10 (2H, s),
3.41 (3H, s).
[0268] MP 169-170.degree. C.
EXAMPLE 33
N-[5-Bromo-3-(3-pyrazinyllmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphon-
amide
##STR00051##
[0270] Prepared by the method of Example 31 using
pyridazine-3-methanol (0.07 g) and
2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (0.15
g). Yield 0.06 g.
[0271] m/e 489 (M-1.sup.+, 100%).
[0272] .sup.1H NMR (D6-DMSO) .delta. 9.23 (1H, d), 8.08 (1H, dd),
7.99 (1H, dd), 7.92 (1H, dd), 7.91 (1H, s), 7.80 (1H, dd), 7.56
(1H, t), 5.67 (2H, s).
[0273] MP 115-120.degree. C.
EXAMPLE 34
N-[5-Bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphona-
mide
##STR00052##
[0275] Prepared by the method of Example 31 using
pyridine-3-methanol (0.44 g) and
2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (1.0
g). Yield 0.6 g.
[0276] m/e 491 (M+1.sup.+, 100%).
[0277] .sup.1H NMR (D6-DMSO) .delta. 8.78 (1H, d), 8.58 (1H, dd),
8.06 (1H, d), 7.99 (1H, dt), 7.91 (1H, d), 7.88 (1H, s), 7.55 (1H,
t), 7.55-7.50 (1H, m), 5.44 (2H, s).
[0278] MP 204-206.degree. C.
EXAMPLE 35
N-[5-Bromo-3-(5-pyrimidinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulpho-
namide
##STR00053##
[0280] Prepared by the method of Example 31 using
pyrimidine-5-methanol (0.035 g) and
2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (0.16
g). Yield 0.028 g.
[0281] m/e 490 (M-1.sup.+, 100%).
[0282] .sup.1H NMR (D6-DMSO) .delta. 9.21 (1H, s), 9.02 (2H, s),
8.07 (1H, dd), 7.92 (1H, dd), 7.91 (1H, s), 7.56 (1H, t), 5.45 (2H,
s).
[0283] MP 208-209.degree. C.
EXAMPLE 36
N-[5-Chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphon-
amide
##STR00054##
[0285] Prepared by the method of Example 31 using
pyridine-3-methanol (0.13 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.3 g). Yield 0.19 g.
[0286] m/e 447 (M+1.sup.+, 100%).
[0287] .sup.1H NMR (D6-DMSO) .delta. 8.78 (1H, s), 8.59 (1H, dd),
8.06 (1H, dd), 7.96 (1H, dt), 7.91 (1H, dd), 7.83 (1H, s), 7.55
(1H, t), 7.47 (1H, dd), 5.44 (2H, s).
[0288] MP 200-204.degree. C.
EXAMPLE 37
N-[5-Chloro-3-(5-pyrimidinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulph-
onamide
##STR00055##
[0290] Prepared by the method of Example 31 using
pyrimidine-5-methanol (0.035 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.07 g). Yield 0.015 g.
[0291] m/e 448 (M+1.sup.+, 100%).
[0292] .sup.1H NMR (D6-DMSO) .delta. 9.21 (1H, s), 9.02 (2H, s),
8.08 (1H, dd), 7.92 (1H, dd), 7.86 (1H, s), 7.56 (1H, t), 5.46 (2H,
s).
[0293] MP 205-206.degree. C.
EXAMPLE 38
2-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00056##
[0295] Prepared by the method of Example 1 (reaction performed at
room temperature) using 6-chloro-3-methoxy-2-pyrazinamine (0.1 g)
and 2-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.11 g.
[0296] m/e 332 (M-1.sup.+, 100%).
[0297] .sup.1H NMR (D6-DMSO) .delta. 8.15 (1H, d), 7.86 (1H, s),
7.70-7.50 (3H, m), 3.91 (3H, s).
[0298] MP 172-173.degree. C.
EXAMPLE 39
3-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00057##
[0300] Prepared by the method of Example 1 (reaction performed at
room temperature) using 6-chloro-3-methoxy-2-pyrazinamine (0.1 g)
and 3-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.14 g.
[0301] m/e 332 (M-1.sup.+, 100%).
[0302] .sup.1H NMR (D6-DMSO) .delta. 8.05 (1H, d), 7.93 (1H, dd),
7.90 (1H, s), 7.76 (1H, dd), 7.65 (1H, t) 3.92 (3H, s).
[0303] MP 126-127.degree. C.
EXAMPLE 40
4-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00058##
[0305] Prepared by the method of Example 1 (reaction performed at
room temperature) using 6-chloro-3-methoxy-2-pyrazinamine (0.1 g)
and 4-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.13 g.
[0306] m/e 332 (M-1.sup.+, 100%).
[0307] .sup.1H NMR (D6-DMSO) .delta. 7.99 (2H, dt), 7.89 (1H, s),
7.70 (2H, dt), 3.92 (3H, s).
[0308] MP 174-175.degree. C.
EXAMPLE 41
N-(6-Chloro-3-methoxy-2-pyrazinyl)-2,4-dichlorobenzenesulphonamide
##STR00059##
[0310] Prepared by the method of Example 1 (reaction performed at
room temperature) using 6-chloro-3-methoxy-2-pyrazinamine (0.05 g)
and 2,4-dichlorobenzenesulphonyl chloride (0.1 g). Yield 0.07
g.
[0311] m/e 368 (M-1.sup.+, 100%).
[0312] .sup.1H NMR (D6-DMSO) .delta. 8.13 (1H, d), 7.86 (1H, s),
7.85 (1H, d), 7.70 (1H, dd), 3.91 (3H, s).
[0313] MP 189-190.degree. C.
EXAMPLE 42
N-(6-Chloro-3-methoxy-2-pyrazinyl)-3,4-dichlorobenzenesulphonamide
##STR00060##
[0315] Prepared by the method of Example 1 (reaction performed at
room temperature) using 6-chloro-3-methoxy-2-pyrazinamine (0.05 g)
and 3,4-dichlorobenzenesulphonyl chloride (0.09 g). Yield 0.08
g.
[0316] m/e 368 (M-1.sup.+, 100%).
[0317] .sup.1H NMR (D6-DMSO) .delta. 8.21 (1H, s), 7.93-7.90 (3H,
m), 3.92 (3H, s).
[0318] MP 176-177.degree. C.
EXAMPLE 43
3-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)-2-methylbenzenesulphonamide
##STR00061##
[0320] Prepared by the method of Example 1 using
3-methoxy-5-methyl-2-pyrazinamine (0.1 g) and
3-chloro-2-methylbenzenesulphonyl chloride (0.19 g). Yield 0.08
g.
[0321] m/e 328 (M+1.sup.+, 100%).
[0322] .sup.1H NMR (D6-DMSO) .delta. 11.09 (1H, br s), 7.95 (1H,
d), 7.72 (1H, d), 7.54 (1H, br s), 7.41 (1H, t), 3.88 (3H, s), 2.64
(3H, s), 2.27 (3H, s).
[0323] MP 133-135.degree. C.
EXAMPLE 44
2-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benzenesulphonamide
##STR00062##
[0325] Prepared by the method of Example 1 using
3-methoxy-5-methyl-2-pyrazinamine (0.1 g) and
2-chlorobenzenesulphonyl chloride (0.15 g). Yield 0.06 g.
[0326] m/e 314 (M+1.sup.+, 100%).
[0327] .sup.1H NMR (D6-DMSO) .delta. 11.07 (1H, br s), 8.06 (1H,
d), 7.69-7.46 (4H, m), 3.90 (3H, s), 2.24 (3H, s).
EXAMPLE 45
3-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benzenesulphonamide
##STR00063##
[0329] Prepared by the method of Example 1 using
3-methoxy-5-methyl-2-pyrazinamine (0.1 g) and
3-chlorobenzenesulphonyl chloride (0.18 g). Yield 0.042 g.
[0330] m/e 314 (M+1.sup.+, 100%).
[0331] .sup.1H NMR (D6-DMSO) .delta. 10.89 (1H, br s), 7.97 (1H,
d), 7.92 (1H, d), 7.73 (1H, d), 7.65-7.58 (2H, m), 3.90 (3H, s),
2.29 (3H, s).
[0332] MP 123-125.degree. C.
EXAMPLE 46
4-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benzenesulphonamide
##STR00064##
[0334] Prepared by the method of Example 1 using
3-methoxy-5-methyl-2-pyrazinamine (0.1 g) and
4-chlorobenzenesulphonyl chloride (0.18 g). Yield 0.06 g.
[0335] m/e 314 (M+1.sup.+, 100%).
[0336] .sup.1H NMR (D6-DMSO) .delta. 10.83 (1H, br s), 7.96 (2H,
d), 7.65 (2H, d), 7.60 (1H, s), 3.88 (3H, s), 2.28 (3H, s).
[0337] MP 155-156.degree. C.
EXAMPLE 47
2,4-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benzenesulphonamide
##STR00065##
[0339] Prepared by the method of Example 1 using
3-methoxy-5-methyl-2-pyrazinamine (0.1 g) and
2,4-dichlorobenzenesulphonyl chloride (0.21 g). Yield 0.041 g.
[0340] m/e 348 (M+1.sup.+, 100%).
[0341] .sup.1H NMR (D6-DMSO) .delta. 8.05 (1H, d), 7.83 (1H, d),
7.64 (1H, dd), 7.54 (1H, br s), 3.87 (3H, s), 2.27 (3H, s).
[0342] MP 135-136.degree. C.
EXAMPLE 48
3,4-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benzenesulphonamide
##STR00066##
[0344] Prepared by the method of Example 1 using
3-methoxy-5-methyl-2-pyrazinamine (0.1 g) and
3,4-dichlorobenzenesulphonyl chloride (0.21 g). Yield 0.046 g.
[0345] m/e 348 (M+1.sup.+, 100%).
[0346] .sup.1H NMR (D6-DMSO) .delta. 10.97 (1H, s), 8.14 (1H, d),
7.91 (1H, dd), 7.88 (1H, d), 7.63 (1H, s), 3.89 (3H, s), 2.27 (3H,
s).
[0347] MP 148-149.degree. C.
EXAMPLE 49
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2-trifluoromethoxybenzenesulphonamide
##STR00067##
[0349] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.1 g)
and 2-trifluoromethoxybenzenesulphonyl chloride (0.13 g). Yield
0.097 g
[0350] m/e 428 (M-1.sup.+, 100%).
[0351] .sup.1H NMR (D6-DMSO) .delta. 8.03 (1H, dd), 7.87 (1H, s),
7.82-7.74 (1H, m), 7.60-7.52 (2H, m), 3.92 (3H, s).
[0352] MP 156-157.degree. C.
EXAMPLE 50
3-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-2-methylbenzenesulphonamide
##STR00068##
[0354] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g)
and 3-chloro-2-methylbenzenesulphonyl chloride (0.15 g). Yield
0.085 g.
[0355] m/e 346 (M-1.sup.+, 100%).
[0356] .sup.1H NMR (CDCl.sub.3) .delta. 8.17 (1H, d), 7.69 (1H, br
s), 7.64 (1H, s), 7.61 (2H, d), 7.30 (1H, t), 4.04 (3H, s), 2.73
(3H, s).
[0357] MP 150-152.degree. C.
EXAMPLE 51
2-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00069##
[0359] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g)
and 2-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.082 g.
[0360] m/e 332 (M+1.sup.+, 100%).
[0361] .sup.1H NMR (CDCl.sub.3) .delta. 8.33 (1H, d), 7.82 (1H, s),
7.64-7.62 (1H, m), 7.61 (1H, s), 7.50-7.42 (2H, m), 4.04 (3H,
s).
[0362] MP 190-192.degree. C.
EXAMPLE 52
3-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00070##
[0364] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g)
and 3-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.095 g.
[0365] m/e 332 (M+1.sup.+, 100%).
[0366] .sup.1H NMR (CDCl.sub.3) .delta. 8.14 (1H, s), 8.03 (1H, d),
7.76 (1H, s), 7.68-7.53 (2H, m), 7.46 (1H, t), 4.02 (3H, s).
[0367] MP 129-130.degree. C.
EXAMPLE 53
4-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00071##
[0369] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g)
and 4-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.05 g.
[0370] m/e 332 (M+1.sup.+, 100%).
[0371] .sup.1H NMR (CDCl.sub.3) .delta. 8.07 (2H, d), 7.75 (1H, s),
7.56 (1H, s), 7.49 (2H, d), 4.02 (3H, s).
[0372] MP 179-180.degree. C.
EXAMPLE 54
N-(5-Chloro-3-methoxy-2-pyrazinyl)-2,4-dichlorobenzenesulphonamide
##STR00072##
[0374] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g)
and 2,4-dichlorobenzenesulphonyl chloride (0.13 g). Yield 0.045
g.
[0375] m/e 368 (M-1.sup.+, 100%).
[0376] .sup.1H NMR (CDCl.sub.3) .delta. 8.27 (1H, d), 7.78 (1H, s),
7.63 (1H, s), 7.48 (1H, s), 7.43 (1H, d), 4.05 (3H, s).
[0377] MP 170-171.degree. C.
EXAMPLE 55
2,3-Dichloro-N-[3-methoxy-5-(4-morpholinyl)-2-pyrazinyl]benzenesulphonamid-
e
a)
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-{[2-(trimethylsilanyl)-
ethoxy]methyl}benzenesulphonamide
##STR00073##
[0379] A mixture of
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(Example 8) (0.40 g), diisopropylethylamine (0.26 g) and
[2-(chloromethoxy)ethyl]trimethylsilane (0.25 g) in dichloromethane
(50 mL) was stirred at room temperature. After 2 h, the solution
was washed with water, dried (MgSO.sub.4) and evaporated.
Chromatography on silica gel eluting with ethyl acetate/isohexane
mixtures gave the title compound as a white solid (0.40 g).
[0380] .sup.1H NMR (CDCl.sub.3) .delta. 8.09 (1H, s), 7.96 (1H,
dd), 7.68 (1H, dd), 7.29 (1H, t), 5.24 (2H, s), 3.92 (3H, s),
3.77-3.73 (2H, m), 0.86-0.82 (2H, m), 0.00 (9H, s).
b)
2,3-Dichloro-N-[3-methoxy-5-(4-morpholinyl)-2-pyrazinyl]benzenesulphona-
mide
##STR00074##
[0382]
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsila-
nyl)ethoxy}methyl]benzenesulphonamide (0.30 g) and morpholine (0.45
g) in acetonitrile (10 mL) was heated at 50.degree. C. After 16 h,
the solution was evaporated. Chromatography on silica gel eluting
with ethyl acetate/isohexane mixtures gave the title compound with
SEM group attached, as a white solid. The solid was dissolved in
trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL). After 2
h, the solution was evaporated. Chromatography on silica gel
eluting with ethyl acetate/isohexane mixtures gave the title
compound as a white solid (0.06 g).
[0383] m/e 417 (M-1.sup.+, 100%).
[0384] .sup.1H NMR (CDCl.sub.3) .delta. 8.17 (1H, d), 7.65 (1H, d),
7.41 (1H, s), 7.34 (1H, t), 7.16 (1H, s), 3.89 (3H, s), 3.80-3.75
(4H, m), 3.40-3.35 (4H, m).
[0385] MP 167-168.degree. C.
EXAMPLE 56
2,3-Dichloro-N-[3,5-dimethoxy-2-pyrazinyl]benzenesulphonamide
##STR00075##
[0387]
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsila-
nyl)ethoxy}methyl]benzenesulphonamide (0.30 g) in methanolic sodium
methoxide (10 mL of 0.5 molar solution) was stirred at room
temperature. After 16 h, the solution was evaporated to dryness and
dichloromethane (10 mL) and trifluoroacetic acid (10 mL) added.
After 2 h, the mixture was evaporated to dryness, dichloromethane
added and the inorganic salts removed by filtration. Chromatography
on silica gel eluting with ethyl acetate/isohexane mixtures gave
the title compound as a white solid (0.1 g).
[0388] m/e 364 (M+1.sup.+, 100%).
[0389] .sup.1H NMR (CDCl.sub.3) .delta. 8.21 (1H, d), 7.67 (1H, d),
7.50 (1H, s), 7.37 (1H, t), 7.26 (1H, s), 3.98 (3H, s), 3.87 (3H,
s).
[0390] MP 138-139.degree. C.
EXAMPLE 57
2,3-Dichloro-N-[3-methoxy-5-(1-pyrrolinyl)-2-pyrazinyl]benzenesulphonamide
##STR00076##
[0392] Prepared by the method of Example 55 using pyrrolidine (0.4
g) and
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)et-
hoxy}methyl]benzenesulphonamide (0.3 g). Yield 0.045 g.
[0393] m/e 403 (M+1.sup.+, 100%).
[0394] .sup.1H NMR (CDCl.sub.3) .delta. 8.08 (1H, d), 7.64 (1H, d),
7.30 (1H, t), 7.21 (1H, s), 6.99 (1H, s), 3.81 (3H, s), 3.40-3.35
(4H, m), 2.00-1.95 (4H, m).
[0395] MP 179-180.degree. C.
EXAMPLE 58
3-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-2-methylbenzenesulphonamid-
e
##STR00077##
[0397] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1
g) and 3-chloro-2-methylbenzenesulphonyl chloride (0.14 g). Yield
0.13 g.
[0398] m/e 381 (M-1.sup.+, 100%).
[0399] .sup.1H NMR (CDCl.sub.3) .delta. 8.25 (1H, d), 7.65 (1H, br
s), 7.62 (1H, d), 7.35 (1H, t), 4.04 (3H, s), 2.73 (3H, s).
[0400] MP 177-178.degree. C.
EXAMPLE 59
2,3-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00078##
[0402] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1
g) and 2,3-dichlorobenzenesulphonyl chloride (0.15 g). Yield 0.12
g.
[0403] m/e 402 (M-1.sup.+, 100%).
[0404] .sup.1H NMR (CDCl.sub.3) .delta. 8.31 (1H, d), 7.81 (1H, br
s), 7.72 (1H, d), 7.45 (1H, t), 4.05 (3H, s).
[0405] MP 172-173.degree. C.
EXAMPLE 60
2-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00079##
[0407] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1
g and 2-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.096
g.
[0408] m/e 367 (M-1.sup.+, 100%).
[0409] .sup.1H NMR (CDCl.sub.3) .delta. 8.39 (1H, d), 7.79 (1H, br
s), 7.58-7.45 (3H, m), 4.04 (3H, s).
[0410] MP 217-218.degree. C.
EXAMPLE 61
3-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00080##
[0412] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1
g) and 3-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.047
g.
[0413] m/e 367 (M-1.sup.+, 100%).
[0414] .sup.1H NMR (CDCl.sub.3) .delta. 8.19 (1H, s), 8.07 (1H, d),
7.61 (1H, d), 7.59 (1H, br s), 7.50 (1H, t), 4.02 (3H, s).
[0415] MP 171-172.degree. C.
EXAMPLE 62
4-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00081##
[0417] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1
g) and 4-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.09
g.
[0418] m/e 367 (M-1.sup.+, 100%).
[0419] .sup.1H NMR (CDCl.sub.3) .delta. 8.11 (2H, d), 7.57 (1H, br
s), 7.50 (2H, d), 4.02 (3H, s).
[0420] MP 186-187.degree. C.
EXAMPLE 63
2,4-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00082##
[0422] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1
g) and 2,4-dichlorobenzenesulphonyl chloride (0.15 g). Yield 0.076
g.
[0423] m/e 402 (M-1.sup.+, 100%).
[0424] .sup.1H NMR (CDCl.sub.3) .delta. 8.30 (1H, d), 7.76 (1H, br
s), 7.50 (1H, s), 7.48 (1H, d), 4.05 (3H, s).
[0425] MP 171-172.degree. C.
EXAMPLE 64
3,4-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00083##
[0427] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1
g) and 3,4-dichlorobenzenesulphonyl chloride (0.15 g). Yield 0.11
g.
[0428] m/e 402 (M-1.sup.+, 100%).
[0429] .sup.1H NMR (CDCl.sub.3) .delta. 8.30 (1H, s), 8.01 (1H, d),
7.63 (1H, d), 7.58 (1H, br s), 4.03 (3H, s).
[0430] MP 189-191.degree. C.
EXAMPLE 65
2,3-Dichloro-N-(3-methoxy-5,6-dimethyl-2-pyrazinyl)benzenesulphonamide
##STR00084##
[0432] Prepared by the method of Example 1 using
3-methoxy-5,6-dimethyl-2-pyrazinamine (0.07 g) and
2,3-dichlorobenzenesulphonyl chloride (0.12 g). Yield 0.04 g.
[0433] m/e 360 (M-1.sup.+, 100%).
[0434] .sup.1H NMR (CDCl.sub.3) .delta. 8.32 (1H, d), 7.67 (1H, s),
7.65 (1H, d), 7.39 (1H, t), 3.95 (3H, s), 2.28 (3H, s), 2.14 (3H,
s).
[0435] MP 165-166.degree. C.
EXAMPLE 66
2,3-Dichloro-N-(6-chloro-3,5-dimethoxy-2-pyrazinyl)benzenesulphonamide
a)
2,3-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsil-
yl)ethoxy]methyl}benzenesulphonamide
##STR00085##
[0437] To a stirred solution of
2,3-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
(0.68 g) in dichloromethane (20 mL) was added triethylamine (0.491
mL) followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.328 g)
and the resulting mixture was stirred at room temperature for 1 h.
The reaction mixture was poured into water (50 mL) and extracted
into ethyl acetate (3.times.20 mL). The combined extracts were
dried (MgSO.sub.4), filtered and concentrated. Chromatography on
silica gel eluting with ethyl acetate/isohexane mixtures gave the
sub-title compound as a white solid (0.74 g).
[0438] .sup.1H NMR (CDCl.sub.3) .delta. 8.02 (1H, dd), 7.70 (1H,
dd), 7.34 (1H, t), 5.22 (2H, s), 3.96 (3H, s), 3.73 (2H, dd),
0.91-0.79 (2H, m), -0.03 (9H, s).
b)
2,3-Dichloro-N-(6-chloro-3,5-dimethoxy-2-pyrazinyl)benzenesulphonamide
##STR00086##
[0440]
2,3-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethy-
lsilyl)ethoxy]methyl}benzenesulfonamide (0.10 g) was dissolved in
methanol (1.0 mL) and a solution of sodium methoxide in methanol
(0.1 mL of a 25% solution in methanol) was added. The reaction was
stirred at room temperature for 30 min and was concentrated. The
residue was dissolved in trifluoroacetic acid (2.0 mL) and was
stirred at room temperature for 30 min. The reaction mixture was
concentrated and chromatography on silica gel eluting with ethyl
acetate/isohexane mixtures gave the title compound as a white solid
(0.028 g).
[0441] m/e 397 (M-1.sup.+, 100%).
[0442] .sup.1H NMR (CDCl.sub.3) .delta. 8.26 (1H, d), 7.69 (1H, d),
7.41 (1H, t), 7.41 (1H, br s), 4.02 (3H, s), 3.91 (3H, s).
[0443] MP 163-165.degree. C.
EXAMPLE 67
2,3-Dichloro-N-[6-chloro-3-methoxy-5-(4-morpholinyl)-2-pyrazinyl]benzenesu-
lphonamide
##STR00087##
[0445]
2,3-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethy-
lsilyl)ethoxy]methyl}benzenesulphonamide (Example 66 part a) (0.10
g) was dissolved in THF (1.0 mL) and a solution of morpholine (0.05
g) in THF (0.1 mL) was added. The reaction was stirred at room
temperature for 30 min and was concentrated. The residue was
dissolved in trifluoroacetic acid (2.0 mL) and dichloromethane (2.0
mL) and was stirred at room temperature for 30 min. The reaction
mixture was concentrated and chromatography on silica gel eluting
with ethyl acetate/isohexane mixtures gave the title compound as a
white solid (0.042 g).
[0446] m/e 452 (M-1.sup.+, 100%).
[0447] .sup.1H NMR (CDCl.sub.3) .delta. 8.28 (1H, dd), 7.69 (1H,
dd), 7.49 (1H, br s), 7.43 (1H, t), 3.96 (3H, s), 3.79 (4H, dd),
3.28 (4H, dd).
[0448] MP 150-151.degree. C.
EXAMPLE 68
2,3-Dichloro-N-[6-chloro-5-(2-hydroxyethylamino)-3-methoxy-2-pyrazinyl]ben-
zenesulphonamide
##STR00088##
[0450] Prepared by the method of Example 67 using 2-aminoethanol
(0.05 g) and
2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethyls-
ilyl)ethoxy]methyl}benzenesulfonamide (0.1 g). Yield 0.015 g.
[0451] m/e 426 (M-1.sup.+, 100%).
[0452] .sup.1H NMR (D6-DMSO) .delta. 10.31 (1H, s), 7.91 (2H, dd),
7.52 (1H, t), 6.89 (1H, br s), 4.71 (1H, t), 3.63 (3H, s), 3.53
(2H, dd), 3.40 (2H, dd).
EXAMPLE 69
2,3-Dichloro-N-[6-chloro-5-dimethylamino-3-methoxy-2-pyrazinyl]benzenesulp-
honamide
##STR00089##
[0454] Prepared by the method of Example 67 using dimethylamine (5
mL of a 2M solution in tetrahydrofuran) and
2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl-
)ethoxy]methyl}benzenesulfonamide (0.1 g). Yield 0.015 g.
[0455] m/e 410 (M-1.sup.+, 100%).
[0456] .sup.1H NMR (D6-DMSO) .delta. 7.99-7.93 (2H, m), 7.56 (1H,
t), 3.74 (3H, s), 2.99 (6H, s).
[0457] MP 145-146.degree. C.
EXAMPLE 70
2,3-Dichloro-N-[6-chloro-3-methoxy-5-(2-methoxyethoxy)-2-pyrazinyl]benzene-
sulphonamide
##STR00090##
[0459] Sodium hydride (0.019 g of 60% dispersion in oil) was added
to a solution of
2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl-
)ethoxy]methyl}benzenesulfonamide (0.25 g) in 2-methoxyethanol (3.0
mL) at room temperature. After 16 h, the solvent was evaporated and
trifluoroacetic acid (2.0 mL) added. After 1 h, the reaction
mixture was concentrated and chromatography on silica gel eluting
with ethyl acetate/isohexane mixtures gave the title compound as a
white solid (0.08 g).
[0460] m/e 442 (M+1.sup.+, 100%).
[0461] .sup.1H NMR (CDCl.sub.3) .delta. 8.24 (1H, dd), 7.70 (1H,
dd), 7.41 (1H, t), 4.50-4.40 (2H, m), 3.96 (3H, s), 3.80-3.70 (2H,
m), 3.42 (3H, s).
[0462] MP 193-194.degree. C.
EXAMPLE 71
2,3-Dichloro-N-[6-chloro-5-hydroxy-3-methoxy-2-pyrazinyl]benzenesulphonami-
de
##STR00091##
[0463] tetrabutylammonium hydroxide (0.28 g of 40% aqueous
solution) was added to a solution of
2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl-
)ethoxy]methyl}benzenesulfonamide (0.25 g) in 1,2-dimethoxyethane
(3.0 mL) at room temperature. After 16 h, the solution was diluted
with ethyl acetate (20 mL). The organic solution was washed with
aqueous citric acid (10 mL) and brine, dried (MgSO.sub.4) and
evaporated. Chromatography on silica gel eluting with ethyl
acetate/isohexane mixtures gave the title compound containing the
SEM group, as a white solid (0.08 g). The solid was dissolved in
trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL) and
stirred at room temperature for 1 h. The reaction mixture was
concentrated and chromatography on silica gel eluting with ethyl
acetate/isohexane mixtures gave the title compound as a white solid
(0.027 g).
[0464] m/e 384 (M+1.sup.+, 100%).
[0465] .sup.1H NMR (CDCl.sub.3) .delta. 12.56 (1H, s), 10.87 (1H,
s), 7.96 (2H, t), 7.56 (1H, t), 3.74 (3H, s).
EXAMPLE 72
2,3-Dichloro-N-[6-methoxy-5-([2,2']bipyrazinylyl)]benzenesulphonamide
##STR00092##
[0467]
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsila-
nyl)ethoxy}methyl]benzenesulphonamide (Example 55 part a) (0.70 g),
tetrakis(triphenylphosphine)palladium(0) (0.1 g) and
2-(tributylstannanyl)pyrazine (0.50 g) in toluene (20 mL) was
heated under nitrogen at 100.degree. C. After 16 h, chromatography
on silica gel eluting with ethyl acetate/isohexane mixtures gave
the title compound protected with the SEM group as a white solid.
The solid was dissolved in trifluoroacetic acid (2.0 mL) and
dichloromethane (2.0 mL) and stirred at room temperature for 1 h.
The reaction mixture was concentrated, toluene added and
evaporated. The title compound crystallised from acetonitrile to
give a white solid (0.38 g).
[0468] m/e 410 (M-1.sup.+, 100%).
[0469] .sup.1H NMR (D6 DMSO) .delta. 9.35 (1H, s), 8.69 (1H, d),
8.67 (1H, d), 8.40 (1H, br s), 8.14 (1H, d), 7.96 (1H, d), 7.61
(1H, t), 4.07 (3H, s).
[0470] MP 199-200.degree. C.
EXAMPLE 73
4-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinyloxy]benzoic
acid
##STR00093##
[0472] 4-Hydroxybenzoic acid tert butyl ester (0.13 g),
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)et-
hoxy}methyl]benzenesulphonamide (Example 55 part a) (0.35 g) and
caesium carbonate (0.42 g) in acetonitrile (10 mL) was heated at
50.degree. C. After 12 h, the mixture was diluted with ethyl
acetate, washed with water, dried (MgSO.sub.4) and evaporated.
Chromatography on silica gel eluting with ethyl acetate/isohexane
mixtures gave the title compound protected with the SEM group and
tert butyl group as an oil. The oil was dissolved in
trifluoroacetic acid (2.0 mL) and stirred at room temperature for 3
h. The reaction mixture was concentrated, toluene added and
evaporated to give the title compound as a white solid (0.19
g).
[0473] m/e 468 (M-1.sup.+, 100%).
[0474] .sup.1H NMR (CDCl.sub.3) .delta. 8.28 (1H, d), 8.11 (2H, d),
7.80 (1H, br s), 7.71 (1H, d), 7.45 (2H, m), 7.12 (2H, d), 3.89
(3H, s).
[0475] MP 186-187.degree. C.
EXAMPLE 74
2,3-Dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
##STR00094##
[0477] Prepared by the method of Example 1 (reaction performed at
room temperature) using 3,5-dichloro-2-pyrazinamine (2.0 g) and
2,3-dichloro benzenesulphonyl chloride (2.94 g). Yield 3.0 g.
[0478] m/e 372 (M-1.sup.+, 100%).
[0479] .sup.1H NMR (D6 DMSO) .delta. 8.29 (1H, s), 8.06 (1H, dd),
7.94 (1H, dd), 7.57 (1H, t).
[0480] MP 181-182.degree. C.
EXAMPLE 75
2,3-Dichloro-N-{6-chloro-3-methoxy-5-([2-methoxyethyl)amino]-2-pyrazinyl}b-
enzenesulphonamide
##STR00095##
[0482] Prepared by the method of Example 67 using
2-methoxyethylamine (3 mL) and
2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimet-
hylsilyl)ethoxy]methyl}benzenesulphonamide (0.24 g). Yield 0.08
g.
[0483] m/e 439 (M+1.sup.+, 100%).
[0484] .sup.1H NMR (D6-DMSO) .delta. 10.33 (1H, s), 7.92 (2H, dd),
7.52 (1H, t), 7.00 (1H, s), 3.64 (3H, s), 3.47 (4H, s), 3.24 (2H,
dd).
[0485] MP 177-178.degree. C.
EXAMPLE 76
N-{2-[3-Chloro-5-(2,3-dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinyl-
amino]ethyl}acetamide
##STR00096##
[0487]
2,3-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-[{2-(trimethy-
lsilyl)ethoxy]methyl}benzenesulphonamide (Example 66 part a) (0.26
g) was dissolved in acetonitrile (1.0 mL) and
N-acetylethylenediamine (0.055 mL) and triethylamine (0.19 mL)
added. After 48 h, the reaction mixture was concentrated and
chromatography on silica gel eluting with ethyl acetate gave the
title compound protected with the SEM group, as an oil (0.13 g).
The oil was dissolved in dichloromethane (2.0 mL) and boron
trifluoride etherate (0.14 ml) added. After 2 h, ethyl acetate (20
mL) was added and the mixture washed with 5% aqueous citric acid (5
mL), dried (MgSO.sub.4) and evaporated. Chromatography on silica
gel eluting with ethyl acetate gave the title compound as a solid
(0.031 g).
[0488] m/e 470 (M+1.sup.+, 100%).
[0489] .sup.1H NMR (D6-DMSO) .delta. 10.32 (1H, s), 7.93-7.88 (2H,
m), 7.52 (1H, t), 7.10 (1H, s), 3.65 (3H, s), 3.40-3.10 (4H, m),
1.75 (3H, s).
[0490] MP 150-152.degree. C.
EXAMPLE 77
2,3-Dichloro-N-[5-(4-hydroxymethyl-1-piperidinyl)-3-methoxy-2-pyrazinyl]be-
nzenesulphonamide
##STR00097##
[0492] Prepared by the method of Example 55 using
4-(hydroxymethyl)piperidine (0.4 g) and
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)et-
hoxy]methyl}benzenesulphonamide (0.3 g). Yield 0.012 g.
[0493] m/e 447 (M+1.sup.+, 100%).
[0494] .sup.1H NMR (CDCl.sub.3) 8.14 (1H, dd), 7.65 (1H, dd), 7.33
(1H, t), 7.20 (1H, s), 4.20-4.10 (2H, m), 3.86 (3H, s), 3.60-3.50
(2H, m), 2.90-2.70 (2H, m), 1.90-1.70 (3H, m), 1.40-1.20 (3H,
m).
EXAMPLE 78
2,3-Dichloro-N-[5-cyano-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphona-
mide
##STR00098##
[0496]
N-[5-Bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenes-
ulphonamide (Example 34) (0.15 g),
tetrakis(triphenylphosphine)palladium(0) (0.04 g) and zinc cyanide
(0.03 g) in N,N-dimethylformamide (5.0 mL) was heated at 70.degree.
C. After 5 h, the mixture was diluted with ethyl acetate (30 mL)
and washed with 5% aqueous citric acid (5 mL), dried (MgSO.sub.4)
and evaporated. Chromatography on silica gel eluting with ethyl
acetate/isohexane mixtures containing 1% acetic acid gave the title
compound as a white solid (0.058 g).
[0497] m/e 436 (M+1.sup.+, 100%).
[0498] .sup.1H NMR (D6 DMSO) 8.70-7.65 (2H, m), 8.29 (1H, dd), 7.99
(1H, s), 7.78 (1H, d), 7.73 (1H, dd), 7.46 (1H, t), 7.40-7.35 (1H,
m), 5.45 (2H, s).
[0499] MP 222-224.degree. C.
EXAMPLE 79
2,3-Dichloro-N-(6-chloro-3-methoxy-5-methylamino-2-pyrazinyl)benzenesulpho-
namide
##STR00099##
[0501]
3-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethyls-
ilyl)ethoxy]methyl}benzenesulphonamide (Example 66 part a) (0.25 g)
was dissolved in methanol (1.0 mL) and methylamine (2.0 mL of 40%
aqueous solution) was added. After 16 h, the solution was
partitioned between water and ethyl acetate. The organic layer was
dried (MgSO.sub.4) and evaporated. The residue was dissolved in
dichloromethane (2.0 mL) and boron trifluoride etherate (0.25 mL)
added. After 1 h, ethyl acetate (20 mL) was added and the solution
washed with 5% aqueous citric acid (5 mL), dried (MgSO.sub.4) and
evaporated. Chromatography on silica gel eluting with ethyl
acetate/isohexane mixtures gave the title compound as a white solid
(0.05 g).
[0502] m/e 395 (M+1.sup.+, 100%).
[0503] .sup.1H NMR (D6-DMSO) .delta. 10.27 (1H, s), 7.95-7.87 (2H,
m), 7.51 (1H, dd), 7.10-7.00 (1H, m), 3.64 (3H, s), 2.84 (3H,
s).
[0504] MP 185-186.degree. C.
EXAMPLE 80
2,3-Dichloro-N-(3-methoxy-5-methylsulphanyl-2-pyrazinyl)benzenesulphonamid-
e
##STR00100##
[0506]
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-{[2-(trimethylsila-
nyl)ethoxy]methyl}benzenesulphonamide (0.30 g) and sodium
thiomethoxide (0.05 g) in acetonitrile (10 mL) was stirred at room
temperature. After 2 h, the solution was evaporated. Chromatography
on silica gel eluting with ethyl acetate/isohexane mixtures gave
the title compound with SEM group attached. The compound was
dissolved in trifluoroacetic acid (5 mL). After 2 h, toluene (20
mL) was added and the solution evaporated. Chromatography on silica
gel eluting with ethyl acetate/isohexane mixtures gave the title
compound as a white solid (0.16 g).
[0507] m/e 380 (M+1.sup.+, 100%).
[0508] .sup.1H NMR (CDCl.sub.3) 8.25 (1H, d), 7.70 (1H, s), 7.68
(1H, d), 7.52 (1H, s), 7.39 (1H, t), 4.03 (3H, s), 2.48 (3H,
s).
[0509] MP 141-142.degree. C.
EXAMPLE 81
2,3-Dichloro-N-[5-(2,4-difluorophenyl)-3-methoxy-2-pyrazinyl]benzenesulpho-
namide
a) 5-(2,4-difluorophenyl)-3-methoxy-2-pyrazinamine
##STR00101##
[0511] 5-Bromo-3-methoxy-2-pyrazinamine (0.3 g), cesium fluoride
(0.8 g), 2,4-difluorobenezeneboronic acid (0.4 g) and
[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) chloride (0.04
g) in methanol (20 mL) was heated at 70.degree. C. After 6 h, the
solvent was evaporated and the residue purified by chromatography
on silica eluting with ethyl acetate/isohexane mixtures to give the
sub-title compound (0.2 g).
b)
2,3-Dichloro-N-[5-(2,4-difluorophenyl)-3-methoxy-2-pyrazinyl]benzenesul-
phonamide
##STR00102##
[0513] Prepared by the method of Example 1 using
5-(2,4-difluorophenyl)-3-methoxy-2-pyrazinamine (0.2 g) and
2,3-dichlorobenzenesulphonyl chloride (0.2 g). Yield 0.06 g.
[0514] m/e 444 (M-1.sup.+, 100%).
[0515] .sup.1H NMR (D6-DMSO) 8.15 (1H, d), 8.05-7.95 (2H, m), 7.93
(1H, d), 7.60 (1H, t), 7.45-7.35 (1H, m), 7.30-7.20 (1H, m), 4.03
(3H, s).
[0516] MP 169-170.degree. C.
EXAMPLE 82
[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]acet-
ic acid methyl ester
##STR00103##
[0518]
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsila-
nyl)ethoxy}methyl]benzenesulphonamide (0.40 g), mercaptoacetic acid
methyl ester (0.1 g) and caesium carbonate (0.6 g) in acetonitrile
(10 mL) was stirred at room temperature. After 16 h, the solution
was diluted with dichloromethane, filtered and evaporated.
Chromatography on silica gel eluting with ethyl acetate/isohexane
mixtures gave the title compound with SEM group attached. The
compound was dissolved in trifluoroacetic acid (5 mL). After 2 h,
toluene (20 mL) was added and the solution evaporated.
Chromatography on silica gel eluting with ethyl acetate/isohexane
mixtures gave the title compound as a white solid (0.15 g).
[0519] m/e 438 (M+1.sup.+, 100%).
[0520] .sup.1H NMR (CDCl.sub.3) 8.26 (1H, dd), 7.73 (1H, s), 7.68
(1H, dd), 7.59 (1H, s), 7.41 (1H, t), 3.99 (3H, s), 3.80 (2H, s),
3.71 (3H, s).
[0521] MP 152-153.degree. C.
EXAMPLE 83
[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]acet-
ic acid
##STR00104##
[0523]
[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphan-
yl]acetic acid methyl ester (Example 82) (0.1 g) and lithium
hydroxide (0.04 g) in methanol (5 mL) and water (1 mL) was stirred
at room temperature. After 2 h, the mixture was evaporated and
saturated aqueous citric acid (5 mL) added. The white solid was
collected, washed with water and dried. Yield 0.07 g.
[0524] m/e 424 (M+1.sup.+, 100%).
[0525] .sup.1H NMR (CDCl.sub.3) 8.27 (1H, dd), 7.90 (1H, br s),
7.70 (1H, dd), 7.61 (1H, s), 7.40 (1H, t), 3.98 (3H, s), 3.80 (2H,
s).
[0526] MP 138-140.degree. C.
EXAMPLE 84
2,3-Dichloro-N-[5-(2-chlorobenzylsulphanyl)-3-methoxy-2-pyrazinyl]benzenes-
ulphonamide
##STR00105##
[0528] Prepared by the method of Example 82 using
2-chlorobenzylmercaptan (0.15 g) and
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)et-
hoxy}methyl]benzenesulphonamide (0.4 g). Yield 0.18 g.
[0529] m/e 492 (M+1.sup.+, 100%).
[0530] .sup.1H NMR (CDCl.sub.3) .delta. 8.26 (1H, dd), 7.73 (1H,
s), 7.69 (1H, dd), 7.53 (1H, s), 7.40-7.30 (3H, m), 7.20-7.10 (2H,
m), 4.39 (2H, s), 4.02 (3H, s).
[0531] MP 119-120.degree. C.
EXAMPLE 85
2,3-Dichloro-N-[6-chloro-5-(3-hydroxy-1-azetidinyl)-3-methoxy-2-pyrazinyl]-
benzenesulphonamide
##STR00106##
[0533]
2,3-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethy-
lsilyl)ethoxy]methyl}benzenesulphonamide (Example 66 part a) (0.20
g), azetidin-3-ol hydrochloride (0.082 g) and triethylamine (0.25
mL) in acetonitrile (3 mL) and water (0.5 mL) was stirred at room
temperature. After 2 h, the mixture was evaporated and triturated
with diethyl ether. The ethereal solution was evaporated and the
residue dissolved in a 1 molar solution of tetrabutylammonium
fluoride in THF (6 mL). After 16 h, the reaction mixture was
concentrated and chromatography on silica gel eluting with ethyl
acetate/isohexane mixtures gave the title compound as a white solid
(0.024 g).
[0534] m/e 442 (M+1.sup.+, 100%).
[0535] .sup.1H NMR (D6-DMSO) .delta. 10.58 (1H, s), 7.92 (2H, d),
7.54 (1H, t), 5.66 (1H, s), 4.49 (1H, s), 4.36 (2H, t), 3.88 (2H,
m), 3.67 (3H, s).
[0536] MP 93-95.degree. C.
EXAMPLE 86
2,3-Dichloro-N-[5-methyl-3-(1-oxy-3-pyrazinylmethoxy)-2-pyrazinyl]benzenes-
ulphonamide
##STR00107##
[0538]
2,3-Dichloro-N-[5-methyl-3-(3-pyridinylmethoxy)-2-pyrazinyl)benzene-
sulphonamide (Example 24) (0.2 g) and 3-chloroperbenzoic acid (0.35
g) in dichloromethane (4 mL) was stirred at room temperature. After
0.5 h, chromatography on silica gel eluting with 5% methanol in
ethyl acetate containing 1% acetic acid gave the title compound as
a white solid (0.16 g).
[0539] m/e 441 (M+1.sup.+, 100%).
[0540] .sup.1H NMR (D6-DMSO) .delta. 11.56 (1H, br s), 8.60 (1H, br
s), 8.18 (1H, dt), 8.06 (1H, dd), 7.90 (1H, dd), 7.61 (1H, br s),
7.56 (1H, t), 7.50-7.40 (2H, m), 5.36 (2H, s), 2.28 (3H, s).
[0541] MP 223-228.degree. C.
EXAMPLE 87
2,3-Dichloro-N-[5-chloro-3-(4-pyridinylmethoxy)-2-pyrazinyl]benzenesulphon-
amide
##STR00108##
[0543] Prepared by the method of Example 31b using
pyridine-4-methanol (0.4 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.4 g). Yield 0.47 g.
[0544] m/e 445 (M+1.sup.+, 100%).
[0545] .sup.1H NMR (D6-DMSO) .delta. 8.63 (2H, d), 8.08 (1H, dd),
7.91 (1H, dd), 7.83 (1H, s), 7.60 (2H, d), 7.55 (1H, t), 5.47 (2H,
s).
[0546] MP 226-229.degree. C. decomposes.
EXAMPLE 88
2,3-Dichloro-N-[5-chloro-3-(1-oxy-4-pyridinylmethoxy)-2-pyrazinyl]benzenes-
ulphonamide
##STR00109##
[0548] Prepared by the method of Example 86 using
2,3-dichloro-N-[5-chloro-3-(4-pyridinylmethoxy)-2-pyrazinyl]benzenesulpho-
namide (Example 87) (0.1 g). Yield 0.4 g.
[0549] m/e 462 (M+1.sup.+, 100%).
[0550] .sup.1H NMR (D6-DMSO) .delta. 8.27 (2H, dt), 8.07 (1H, dd),
7.92 (1H, dd), 7.85 (1H, s), 7.60 (2H, d), 7.57 (1H, t), 5.38 (2H,
s).
[0551] MP 208-211.degree. C. decomposes.
EXAMPLE 89
2,3-Dichloro-N-[5-chloro-3-(2-pyridinylmethoxy)-2-pyrazinyl]
##STR00110##
[0553] Prepared by the method of Example 31b using
pyridine-2-methanol (0.2 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.2 g). Yield 0.1 g.
[0554] m/e 445 (M+1.sup.+, 100%).
[0555] .sup.1H NMR (D6-DMSO) .delta. 8.58 (1H, dt), 8.08 (1H, dd),
7.92 (1H, dd), 7.80-7.90 (2H, m), 7.64 (1H, d), 7.56 (1H, t),
7.18-7.20 (1H, m), 5.47 (2H, s).
[0556] MP 147-148.degree. C.
EXAMPLE 90
2,3-Dichloro-N-[5-chloro-3-(2-methylsulphanylethoxy)-2-pyrazinyl]benzenesu-
lphonamide
##STR00111##
[0558] Prepared by the method of Example 31 using
2-methylsulphanylethanol (0.05 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.1 g). Yield 0.06 g.
[0559] m/e 427 (M-1.sup.+, 100%).
[0560] .sup.1H NMR (D6-DMSO) .delta. 11.50-12.00 (1H, br s), 8.09
(1H, d), 7.95 (1H, d), 7.81 (1H, s), 7.60 (1H, t), 4.47 (2H, t),
2.86 (2H, t), 2.14 (3H, s).
[0561] MP 140-141.degree. C.
EXAMPLE 91
N-(3-Butoxy-5-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
##STR00112##
[0563] Prepared by the method of Example 31 using 1-butanol (0.05
g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.1 g). Yield 0.037 g.
[0564] m/e 410 (M+1.sup.+, 100%).
[0565] .sup.1H NMR (D6-DMSO) .delta. 8.08 (1H, d), 7.96 (1H, d),
7.79 (1H, s), 7.57 (1H, t), 4.29 (2H, t), 1.60-1.75 (2H, m),
1.40-1.50 (2H, m), 0.95 (3H, t).
[0566] MP 133-134.degree. C.
EXAMPLE 92
2,3-Dichloro-N-[5-chloro-3-(2-methyl-3-pyridinylmethoxy)-2-pyrazinyl]benze-
nesulphonamide
##STR00113##
[0568] Prepared by the method of Example 31 using
(2-methyl-3-pyridinyl)methanol (0.15 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.15 g).
[0569] Yield 0.06 g
[0570] m/e 458 (M+1.sup.+, 100%).
[0571] .sup.1H NMR (D6-DMSO) .delta. 8.45 (1H, dd), 8.05 (1H, dd),
7.94 (1H, dd), 7.88 (1H, dd), 7.80 (1H, s), 7.53 (1H, t), 7.32 (1H,
dd), 5.40 (2H, s), 2.56 (3H, s).
[0572] MP 214-216.degree. C. decomposes.
EXAMPLE 93
2,3-Dichloro-N-[5-chloro-3-(6-methyl-2-pyridinylmethoxy)-2-pyrazinyl]benze-
nesulphonamide
##STR00114##
[0574] Prepared by the method of Example 31 using
(6-methyl-2-pyridinyl)methanol (0.15 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.15 g). Yield 0.06 g.
[0575] m/e 461 (M+1.sup.+, 100%).
[0576] .sup.1H NMR (D6-DMSO) .delta. 8.08 (1H, dd), 7.91 (1H, dd),
7.84 (1H, s), 7.75 (1H, t), 7.55 (1H, t), 7.42 (1H, d), 7.24 (1H,
d), 5.42 (2H, s), 2.52 (3H, s).
[0577] MP 158-159.degree. C.
EXAMPLE 94
2,3-Dichloro-N-[5-chloro-3-(1-oxy-2-pyridinylmethoxy)-2-pyrazinyl]benzenes-
ulphonamide
##STR00115##
[0579] Prepared by the method of Example 86 using
2,3-dichloro-N-[5-chloro-3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulpho-
namide (Example 89) (0.2 g). Yield 0.1 g.
[0580] m/e 462 (M+1.sup.+, 100%).
[0581] .sup.1H NMR (D6-DMSO) .delta. 8.35-8.40 (1H, m), 8.09 (1H,
dd), 7.80-7.90 (2H, m), 7.88 (1H, s), 7.58 (1H, t), 7.40-7.50 (2H,
m), 5.51 (2H, s).
[0582] MP 222-224.degree. C. decomposes.
EXAMPLE 95
3-Chloro-N-[5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2-methylbenzenesu-
lphonamide
a) 5-Chloro-3-(3-pyridinylmethoxy)-2-pyrazinamine
##STR00116##
[0584] 3,5-Dichloro-2-pyrazinamine (1.0 g) was added to a stirred
suspension of pyridine-3-methanol (1.3 g) and sodium hydride (0.70
g of 60% dispersion in oil) in 1,2-dimethoxyethane (10 mL). After
0.5 h, 5% aqueous citric acid was added and the mixture extracted
with ethyl acetate. Chromatography on silica gel eluting with ethyl
acetate/iso-hexane mixtures gave the title compound as a white
solid (0.2 g). Used directly.
b)
3-Chloro-N-[5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2-methylbenzen-
esulphonamide
##STR00117##
[0586] Prepared by the method of Example 1 (reaction performed at
room temperature) using
5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinamine (Example 95a) (0.1
g) and 3-chloro-2-methylbenzenesulphonyl chloride (0.09 g). Yield
0.012 g.
[0587] m/e 425 (M+1.sup.+, 100%).
[0588] .sup.1H NMR (D6-DMSO) .delta. 8.78 (1H, d), 8.58 (1H, dd),
7.96 (2H, dt), 7.83 (1H, s), 7.72 (1H, d), 7.46 (1H, dd), 7.40 (1H,
t), 5.44 (2H, s), 2.63 (3H, s).
[0589] MP 192-193.degree. C.
EXAMPLE 96
3-Chloro-N-[5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2-fluorobenzenesu-
lphonamide
##STR00118##
[0591] Prepared by the method of Example 1 (reaction performed at
room temperature) using
5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinamine (Example 95a) (0.1
g) and 3-chloro-2-fluorobenzenesulphonyl chloride (0.1 g). Yield
0.034 g.
[0592] m/e 429 (M+1.sup.+, 100%).
[0593] .sup.1H NMR (D6-DMSO) .delta. 8.78 (1H, d), 8.60 (1H, dd),
7.99 (1H, dt), 7.80-7.90 (3H, m), 7.48 (1H, dd), 7.40 (1H, t), 5.43
(2H, s).
[0594] MP 177-178.degree. C.
EXAMPLE 97
2,3-Dichloro-N-[5-chloro-3-(4-methoxyphenylmethoxy)-2-pyrazinyl]benzenesul-
phonamide
##STR00119##
[0596] Prepared by the method of Example 31 using
4-methoxybenzylalcohol (0.3 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.5 g). Yield 0.4 g.
[0597] m/e 475 (M+1.sup.+, 100%).
[0598] .sup.1H NMR (D6-DMSO) .delta. 8.05 (1H, dd), 7.91 (1H, dd),
7.81 (1H, s), 7.58 (1H, t), 7.42 (2H, d), 6.94 (2H, d), 5.32 (2H,
s), 3.77 (3H, s).
[0599] MP 163-164.degree. C.
EXAMPLE 98
[0600]
N-[5-Bromo-6-chloro-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
##STR00120##
[0601] Prepared by the method of Example 1 (reaction performed at
room temperature) using 3-bromo-5-chloro-2-pyrazinamine (Example
4a) (1.2 g) and 2,3-dichlorobenzenesulphonyl chloride (1.4 g).
Yield 1.5 g.
[0602] m/e 418 (M+1.sup.+, 100%).
[0603] .sup.1H NMR (D6-DMSO) .delta. 8.07 (1H, dd), 7.90-7.80 (2H,
m), 7.53 (1H, t).
[0604] MP 123-124.degree. C.
EXAMPLE 99
2,3-Dichloro-N-[6-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphon-
amide
##STR00121##
[0606] Prepared by the method of Example 31 using
pyridine-3-methanol (0.22 g) and
N-(3-bromo-6-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(Example 98) (0.2 g).
[0607] Yield 0.04 g.
[0608] m/e 445 (M+1.sup.+, 100%).
[0609] .sup.1H NMR (D6-DMSO) .delta. 8.77 (1H, br s), 8.59 (1H,
dd), 8.12 (1H, dd), 8.00 (1H, dt), 7.92 (1H, dd), 7.84 (1H, s),
7.58 (1H, t), 7.55-7.50 (1H, m), 5.44 (2H, s).
[0610] MP 203-204.degree. C.
EXAMPLE 100
2,3-Dichloro-N-[6-chloro-3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphon-
amide
##STR00122##
[0612] Prepared by the method of Example 31 using
pyridine-2-methanol (0.22 g) and N-(3-s
bromo-6-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(Example 98) (0.2 g). Yield 0.13 g.
[0613] m/e 445 (M+1.sup.+, 100%).
[0614] .sup.1H NMR (D6-DMSO) .delta. 8.56 (1H, dd), 8.15 (1H, dd),
7.94 (1H, dd), 7.90-7.80 (2H, m), 7.65-7.60 (1H, m), 7.58 (1H, s),
7.40-7.35 (1H, m), 5.48 (2H, s).
[0615] MP 201-203.degree. C.
EXAMPLE 101
N-[5-(2-Aminoethylsulphanyl)-3-(2-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichl-
orobenzenesulphonamide
a)
2,3-Dichloro-N-[5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-N-[2-trime-
thylsilanylethoxymethyl]benzenesulphonamide
##STR00123##
[0617] Prepared by the method of Example 66a using
2,3-dichloro-N-[5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulpho-
namide (Example 36) (0.5 g). Yield 0.68 g. Used directly.
b)
N-[5-(2-Aminoethylsulphanyl)-3-(2-pyridinylmethoxy)-2-pyrazinyl]-2,3-di-
chlorobenzenesulphonamide
##STR00124##
[0619] A mixture of
2,3-dichloro-N-[5-chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-N-[2-trimeth-
ylsilanylethoxymethyl]benzenesulphonamide (Example 101a) (0.68 g),
caesium carbonate (1.9 g) and 2-aminoethanethiol hydrochloride (0.2
g) in acetonitrile (5 mL) was stirred at room temperature for 5 h.
Ethyl acetate was added and the mixture washed with water and
brine. The organic layer was dried (MgSO.sub.4) and evaporated. The
residue was dissolved in trifluoracetic acid. After 1 h, toluene
was added and the mixture evaporated to dryness. HCl (1M in
dioxane) was added and the solid collected by filtration (0.2
g).
[0620] m/e 484 (M-1.sup.+, 100%).
[0621] .sup.1H NMR (D6-DMSO) .delta. 8.65 (1H, s), 8.52 (1H, d),
8.20-7.60 (2H, br s), 7.96 (1H, dd), 7.82 (1H, d), 7.62 (1H, d),
7.42-7.38 (1H, m), 7.35 (1H, t), 7.30 (1H, s), 5.24 (2H, s),
3.05-3.00 (2H, m), 2.85-2.80 (2H, m).
EXAMPLE 102
2,3-Dichloro-N-[5-chloro-3-(6-methoxy-3-pyridinylmethoxy)-2-pyrazinyl]benz-
enesulphonamide
##STR00125##
[0623] Prepared by the method of Example 31 using
(6-methoxy-3-pyridinyl)methanol (0.3 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.3 g). Yield 0.15 g.
[0624] m/e 474 (M-1.sup.+, 100%).
[0625] .sup.1H NMR (D6-DMSO) .delta. 8.32 (1H, d), 8.04 (1H, dd),
7.91 (1H, dd), 7.85-7.80 (2H, m), 7.86 (1H, d), 7.55 (1H, t), 6.86
(1H, dd), 5.33 (2H, s), 3.87 (3H, s).
EXAMPLE 103
N-[3-(3-Bromophenylmethoxy)-5-chloro-2-pyrazinyl]-2,3-dichlorobenzenesulph-
onamide
##STR00126##
[0627] Prepared by the method of Example 31b using
3-bromobenzylalcohol (1.3 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (1.1 g). Yield 1.1 g.
[0628] m/e 522 (M+1.sup.+, 100%).
[0629] .sup.1H NMR (D6-DMSO) .delta. 8.07 (1H, dd), 7.92 (1H, dd),
7.85 (1H, s), 7.78 (1H, s), 7.60-7.50 (3H, m), 7.37 (1H, t), 5.40
(2H, s).
EXAMPLE 104
3-[6-Chloro-3-(2,3-dichlorobenzenesulphonylamino)-2-pyrazinyloxymethyl]ben-
zoic acid methyl ester
##STR00127##
[0631]
N-[3-(3-Bromophenylmethoxy)-5-chloro-2-pyrazinyl]-2,3-dichlorobenze-
nesulphonamide (Example 103) (1.0 g) and
bis(triphenylphosphine)palladium dichloride (0.4 g) in methanol (15
mL) and triethylamine (7 mL) was heated at 100.degree. C. under an
atmosphere of carbon monoxide (6 barr). After 20 h, the mixture was
filtered and evaporated. The residue was dissolved in ethyl
acetate. The organic solution was washed with brine, aqueous citric
acid, dried (MgSO.sub.4) and evaporated. Chromatography on silica
gel eluting with ethyl acetate/iso-hexane mixtures gave the title
compound as a white solid (0.65 g).
[0632] m/e 503 (m+1.sup.+, 100%).
[0633] .sup.1H NMR (D6-DMSO) .delta. 8.11 (1H, s), 8.05 (1H, dd),
7.95 (1H, d), 7.90 (1H, dd), 7.84 (1H, s), 7.80 (1H, d), 7.60-7.50
(2H, m), 5.46 (2H, s), 3.88 (3H, s).
[0634] MP 175-176.degree. C.
EXAMPLE 105
3-[6-Chloro-3-(2,3-dichlorobenzenesulphonylamino)-2-pyrazinyloxymethyl]ben-
zoic acid
##STR00128##
[0636] A mixture of
3-[6-chloro-3-(2,3-dichlorobenzenesulphonylamino)-2-pyrazinyloxymethyl]be-
nzoic acid methyl ester (Example 104) (0.3 g) and lithium hydroxide
hydrate (0.2 g) in water (5 mL) and methanol (5 mL) was stirred at
room temperature. After 3 h, hydrochloric acid (2M) was added to
acidify the mixture and the solid product was collected by
filtration and dried (0.25 g).
[0637] m/e 489 (M+1.sup.+, 100%).
[0638] .sup.1H NMR (D6-DMSO) .delta. 13.10-13.00 (1H, br s),
12.00-11.80 (1H, br s), 8.10 (1H, s), 8.05 (1H, dd), 7.85-7.95 (2H,
m), 7.82 (1H, s), 7.76 (1H, d), 7.54 (2H, t), 5.46 (2H, s).
[0639] MP 218-224.degree. C. decomposes.
EXAMPLE 106
2,3-Dichloro-N-[5-chloro-3-(3-hydroxymethylphenylmethoxy)-2-pyrazinyl]benz-
enesulphonamide
a)
2,3-Dichloro-N-{5-chloro-3-[3-(tetrahydro-2-pyranyloxymethyl)phenylmeth-
oxy]-2-pyrazinyl}benzenesulphonamide
##STR00129##
[0641] Prepared by the method of Example 31 using
[3-(tetrahydro-2-pyranyloxymethyl)phenyl]methanol (1.99 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (1.0 g). Yield 1.0 g. Used directly.
b)
2,3-Dichloro-N-[5-chloro-3-(3-hydroxymethylphenylmethoxy)-2-pyrazinyl]b-
enzenesulphonamide
##STR00130##
[0643]
2,3-Dichloro-N-{5-chloro-3-[3-(tetrahydro-2-pyranyloxymethyl)phenyl-
methoxy]-2-pyrazinyl}benzenesulphonamide (Example 106a) (1.0 g) in
acetic acid (40 mL), water (10 mL) and tetrahyrofuran (20 mL) was
heated at 45.degree. C. for 16 h and the solution was evaporated to
dryness. Chromatography on silica gel eluting with ethyl
acetate/iso-hexane mixtures gave the title compound as a white
solid (0.6 g).
[0644] m/e 475 (M+1.sup.+, 100%).
[0645] .sup.1H NMR (D6-DMSO) .delta. 8.05 (1H, dd), 7.91 (1H, dd),
7.82 (1H, s), 7.55 (1H, t), 7.43 (1H, s), 7.40-7.25 (3H, m), 5.39
(2H, s), 4.52 (2H, s).
[0646] MP 162-163.degree. C.
EXAMPLE 107
2,3-Dichloro-N-[5-chloro-3-(3-methylaminomethylphenylmethoxy)-2-pyrazinyl]-
benzenesulphonamide
a)
2,3-Dichloro-N-[5-chloro-3-(3-formylphenylmethoxy)-2-pyrazinyl]benzenes-
ulphonamide
##STR00131##
[0648]
2,3-Dichloro-N-[5-chloro-3-(3-hydroxymethylphenylmethoxy)-2-pyrazin-
yl]benzenesulphonamide (Example 106) (0.6 g) and manganese dioxide
(1.0 g) in tetrahydrofuran (5 mL) was stirred at room temperature
for 16 h. The mixture was diluted with dichloromethane and filtered
through celite. The solution was evaporated to dryness and the
product crystallised from diethyl ether (0.4 g). Used directly.
b)
2,3-Dichloro-N-[5-chloro-3-(3-methylaminomethylphenylmethoxy)-2-pyrazin-
yl]benzenesulphonamide
##STR00132##
[0650] A mixture of
2,3-dichloro-N-[5-chloro-3-(3-formylphenylmethoxy)-2-pyrazinyl]benzenesul-
phonamide (Example 107a) (0.1 g), methylamine (2 mL of a 2M
solution in tetrahydrofuran) and acetic acid (0.2 mL) in methanol
(2 mL) was stirred at room temperature. After 2 h, sodium
cyanoborohydride (0.03 g) was added. After 0.5 h, water (2 mL) was
added and the mixture evaporated to dryness. Chromatography on
silica gel eluting with methanol/dichloromethane mixtures gave the
title compound as a white solid (0.035 g).
[0651] m/e 487 (M+1.sup.+, 100%).
[0652] .sup.1H NMR (D6-DMSO) .delta. 8.90-8.60 (2H, br s), 8.02
(1H, d), 7.90-7.80 (1H, m), 7.80-7.60 (1H, m), 7.59 (1H, d),
7.55-7.40 (4H, m), 5.40 (2H, s), 4.08 (2H, s), 2.59 (3H, s).
[0653] MP 167-168.degree. C.
EXAMPLE 108
2,3-Dichloro-N-[5-chloro-3-{3-([2-hydroxyethylamino]methyl)phenylmethoxy}--
2-pyrazinyl]benzenesulphonamide
##STR00133##
[0655] Prepared by the method of Example 107b using
2,3-dichloro-N-[5-chloro-3-(3-formylphenylmethoxy)-2-pyrazinyl]benzenesul-
phonamide (Example 107a) (0.1 g) and 2-aminoethanol (0.05 g). Yield
0.035 g.
[0656] m/e 517 (M+1.sup.+, 100%).
[0657] .sup.1H NMR (D6-DMSO) .delta. 9.00-8.80 (2H, br s), 7.93
(1H, d), 7.80-7.20 (7H, m), 5.28 (2H, s), 5.21 (1H, t), 4.20 (2H,
s), 3.80-3.60 (2H, m), 3.05-2.95 (2H, m).
[0658] MP 196-198.degree. C.
EXAMPLE 109
2,3-Dichloro-N-[5-chloro-3-(4-hydroxymethylphenylmethoxy)-2-pyrazinyl]benz-
enesulphonamide
##STR00134##
[0660] Prepared by the method of Examples 106a and 106b using
[4-(tetrahydro-2-pyranyloxymethyl)phenyl]methanol (2.0 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (1.0 g). Yield 0.7 g.
[0661] m/e 474 (M-1.sup.+, 100%).
[0662] .sup.1H NMR (D6-DMSO) .delta. 8.05 (1H, dd), 7.91 (1H, dd),
7.83 (1H, s), 7.55 (1H, t), 7.46 (2H, d), 7.33 (2H, d), 5.38 (2H,
s), 4.51 (2H, s).
[0663] MP 177-178.degree. C.
EXAMPLE 110
2,3-Dichloro-N-[5-chloro-3-{4-([2-hydroxyethylamino]methyl)phenylmethoxy}--
2-pyrazinyl]benzenesulphonamide
a)
2,3-Dichloro-N-[5-chloro-3-(4-formylphenylmethoxy)-2-parazinyl]benzenes-
ulphonamide
##STR00135##
[0665] Prepared by the method of Example 107a using
2,3-dichloro-N-[5-chloro-3-(4-hydroxymethylphenylmethoxy)-2-pyrazinyl]ben-
zenesulphonamide (Example 109) (0.65 g). Yield 0.64 g. Used
directly.
b)
2,3-Dichloro-N-(5-chloro-3-{4-[(2-hydroxyethylamino)methyl]phenylmethox-
y}-2-parazinyl]benzenesulphonamide
##STR00136##
[0667] Prepared by the method of Example 107b using
2,3-dichloro-N-[5-chloro-4-(3-formylphenylmethoxy)-2-pyrazinyl]benzenesul-
phonamide (Example 110a) (0.1 g) and 2-aminoethanol (0.05 g). Yield
0.028 g.
[0668] m/e 517 (M+1.sup.+, 100%).
[0669] .sup.1H NMR (D6-DMSO) .delta. 8.75 (2H, br s), 7.93 (1H,
dd), 7.61 (1H, dd), 7.54 (4H, s), 7.35 (1H, t), 7.26 (1H, s), 5.26
(2H, s), 5.18 (1H, t), 4.18 (2H, s), 3.70-3.60 (2H, m), 3.00-2.95
(2H, m).
[0670] MP 202-205.degree. C.
EXAMPLE 111
2,3-Dichloro-N-[3-(4-hydroxymethylphenylmethoxy)-2-pyrazinyl]benzenesulpho-
namide
a)
2,3-Dichloro-N-{3-[4-(tetrahydro-2-pyranyloxymethyl)phenylmethoxy]-2-py-
razinyl}benzenesulphonamide
##STR00137##
[0672] 2,3-Dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide
(Example 28a) (0.1 g),
[4-(tetrahydro-2-pyranyloxymethyl)phenyl]methanol (0.27 g) and
potassium tert-butoxide (2 mL of a 1M solution in tetrahydrofuran)
in N-methylpyrrolidinone (1 mL) was stirred at 50.degree. C. After
2 h, aqueous citric acid was added and the mixture extracted with
ethyl acetate. The organic solution was washed with water and brine
and evaporated to dryness. Used directly.
b)
2,3-Dichloro-N-[3-(4-hydroxymethylphenylmethoxy)-2-pyrazinyl]benzenesul-
phonamide
##STR00138##
[0674]
2,3-Dichloro-N-{3-[4-(tetrahydro-2-pyranyloxymethyl)phenylmethoxy]--
2-pyrazinyl}benzenesulphonamide (Example 111a) in acetic acid (10
mL), water (2.5 mL) and tetrahydrofuran (5 mL) was heated at
45.degree. C. for 16 h and the solution was evaporated to dryness.
Chromatography on silica gel eluting with ethyl acetate/iso-hexane
mixtures gave the title compound as a white solid (0.022 g).
[0675] m/e 440 (M+1.sup.+, 100%).
[0676] .sup.1H NMR (D6-DMSO) .delta. 8.08 (1H, dd), 7.91 (1H, dd),
7.90-7.70 (1H, br s), 7.70-7.60 (1H, br s), 7.55 (1H, t), 7.42 (2H,
d), 7.31 (2H, d), 5.39 (2H, s), 5.20-5.05 (1H, br s), 4.49 (2H,
s).
[0677] MP 160-161.degree. C.
EXAMPLE 112
2,3-Dichloro-N-[5-chloro-3-(2-hydroxymethylphenylmethoxy)-2-pyrazinyl]benz-
enesulphonamide
##STR00139##
[0679] 2,3-Dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74). (0.15 g), (2-hydroxymethylphenyl)methanol (0.27 g)
and potassium tert-butoxide (3 mL of a 1M solution in
tetrahydrofuran) in N-methylpyrrolidinone (2 mL) was stirred at
room temperature. After 1 h, aqueous citric acid was added and the
mixture extracted with ethyl acetate. The organic solution was
washed with water and brine and evaporated to dryness.
Chromatography on silica gel eluting with ethyl acetate/iso-hexane
mixtures gave the title compound as a white solid (0.027 g).
[0680] m/e 474 (M+1.sup.+, 100%).
[0681] .sup.1H NMR (D6-DMSO) .delta. 8.06 (1H, dd), 7.90 (1H, dd),
7.81 (1H, s), 7.60-7.40 (3H, m), 7.37 (1H, t), 7.29 (1H, t), 5.45
(2H, s), 4.64 (2H, s).
[0682] MP 145-146.degree. C.
EXAMPLE 113
5-(2,3-Dichlorobenzenesuphonylamino)-6-methoxypyrazine-2-carboxylic
acid, methyl ester
##STR00140##
[0684]
N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(Example 8) (6.5 g) and
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct (0.7 g) in methanol (30 mL) and
triethylamine (10 mL) was heated at 100.degree. C. under an
atmosphere of carbon monoxide (6 bar). After 5 h, the mixture was
filtered and evaporated. The residue was dissolved in ethyl
acetate. The organic solution was washed with brine, aqueous citric
acid, dried (MgSO.sub.4) and evaporated. Chromatography on silica
gel eluting with ethyl acetate/iso-hexane mixtures gave the title
compound as a white solid (4.8 g).
[0685] m/e 392 (M+1.sup.+, 100%).
[0686] .sup.1H NMR (D6-DMSO) .delta. 8.13 (2H, dd), 7.95 (1H, dd),
7.60 (1H, t), 3.95 (3H, s), 3.82 (3H, s).
[0687] MP 120-121.degree. C.
EXAMPLE 114
2,3-Dichloro-N-[5-(1-hydroxy-1-methylethyl)-3-methoxy-2-pyrazinyl]benzenes-
ulphonamide
##STR00141##
[0689] Methylmagnesium bromide (3 mL of a 3M solution in diethyl
ether) was added over 3 minutes to a stirred solution of
5-(2,3-dichlorobenzenesuphonylamino)-6-methoxypyrazine-2-carboxylic
acid, methyl ester (Example 113) (0.3 g) in tetrahydrofuran (10 mL)
cooled in an ice/water bath. After a further 5 minutes, aqueous
citric acid was added and the mixture extracted with ethyl acetate.
The organic solution was evaporated to dryness. Chromatography on
silica gel eluting with methanol/dichloromethane mixtures gave the
title compound as a white solid (0.15 g).
[0690] m/e 392 (M+1.sup.+, 100%).
[0691] .sup.1H NMR (D6-DMSO) .delta. 11.40-11.30 (1H, br s), 8.07
(1H, dd), 7.93 (1H, d), 7.90-7.80 (1H, br s), 7.59 (1H, t),
5.10-5.05 (1H, br s), 3.88 (3H, s), 1.39 (6H, s).
[0692] MP 192-193.degree. C.
EXAMPLE 115
N-4-[5-(2-Aminoethoxy)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulphonam-
ide
a)
2,3-Dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl)e-
thoxy-]-methyl}benzenesulphonamide
##STR00142##
[0694] Prepared by the method of Example 66a using
2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide
(Example 5) (7.0 g). Yield 9.8 g. Used directly.
##STR00143##
b)
N-[5-(2-aminoethoxy)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulphon-
amide
[0695]
2,3-Dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsil-
yl)ethoxy]methyl}benzenesulphonamide (Example 115a) (0.25 g) was
added to a mixture of ethanolamine (0.05 mL) and sodium hydride
(0.035 g of a 60% dispersion in oil) in 1,2-dimethoxyethane (15 mL)
at room temperature. After 2 h, the mixture was partitioned between
water and ethyl acetate. The organic layer was washed with brine,
dried (MgSO.sub.4) and evaporated to dryness. Chromatography on
silica gel eluting with methanol/dichloromethane mixtures gave the
title compound containing the SEM
([2-(trimethylsilyl)ethoxy]methyl) protecting group as an oil (0.14
g). Trifluoroacetic acid (1 mL) and dichloromethane (3 mL) were
added. After 0.5 h at room temperature, toluene was added and the
solution evaporated to dryness. HCl (4M in dioxane) was added and
the mixture evaporated to dryness. The product was crystallised
from diethyl ether (0.075 g).
[0696] m/e 393 (M+1.sup.+, 100%).
[0697] .sup.1H NMR (D6-DMSO) .delta. 10.90 (1H, br s), 8.07 (2H, br
s), 7.99-7.92 (2H, m), 7.56 (1H, t), 7.49 (1H, s), 4.45 (2H, t),
3.84 (3H, s), 3.25-3.20 (2H, m).
[0698] MP 200-205.degree. C.
EXAMPLE 116
N-{5-[(2-Aminoethyl)thio]-6-chloro-3-methoxy-2-pyrazinyl}-2,3-dichlorobenz-
enesulfonamide
##STR00144##
[0700] Prepared by the method of Example 101b using
2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl-
)ethoxy]methyl}benzenesulphonamide (Example 66a) (0.27 g). Yield
0.055 g.
[0701] m/e 443 (M+1.sup.+, 100%).
[0702] .sup.1H NMR (D6-DMSO) .delta. 8.09 (1H, d), 7.90 (1H, d),
7.58 (1H, t), 3.95 (3H, s), 3.33 (2H, t), 3.14 (2H, t).
[0703] MP 185-190.degree. C.
EXAMPLE 117
3-[(5-{[(2,3-Dichlorophenyl)sulphonyl]amino}-6-methoxy-2-pyrazinyl)thio]pr-
opanoic acid, methyl ester
##STR00145##
[0705] Prepared by the method of Example 101b using
2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl)eth-
oxy]methyl}benzenesulphonamide (Example 115a) (0.25 g) and
3-mercaptopropionic acid, methyl ester (0.06 mL). Yield 0.1 g.
[0706] m/e 452 (M+1.sup.+, 100%).
[0707] .sup.1H NMR (D6-DMSO) .delta. 11.35 (1H, br s), 8.03 (1H,
d), 7.93 (1H, d), 7.66 (1H, s), 7.57 (1H, t), 3.90 (3H, s), 3.58
(3H, s), 3.29 (2H, t), 2.72 (2H, t).
[0708] MP 146-148.degree. C.
EXAMPLE 118
2,3-Dichloro-N-[5-bromo-3-methoxy-6-methyl-2-pyrazinyl)benzenesulphonamide
a) 6-Methyl-2-pyrazinamine
##STR00146##
[0710] Dimethylzinc (100 mL of a 2M solution in toluene) was added
dropwise over 0.5 h to a stirred solution of
6-chloro-2-pyrazinamine (12.9 g) and
[1,3-bis(diphenylphosphino)propane]nickel(II) chloride (5.4 g) in
dioxane (200 mL) under a nitrogen atmosphere. The reaction mixture
was heated at reflux for 18 h, then cooled to room temperature and
quenched cautiously with iso-propanol (30 mL) and methanol (50 mL).
After removal of solvent in vacuo, the residue was partitioned
between dichloromethane and aqueous ammonium chloride. The organic
phase was filtered through celite, dried (MgSO.sub.4), filtered and
evaporated to give the crude product as an orange solid.
Chromatography on silica gel eluting with ethyl acetate/methanol
mixtures gave the title compound (5.1 g). Used directly.
b) 3,5-Dibromo-6-methyl-2-pyrazinamine
##STR00147##
[0712] A solution of bromine (1.85 g) in chloroform (5 mL) was
added dropwise to a stirred solution of 2-amino-6-methylpyrazine
(Example 118a) (0.6 g) in chloroform (50 mL). The reaction mixture
was stirred at room temperature for 0.5 h, then washed twice with
water, dried (MgSO.sub.4), filtered and evaporated to give the
crude product as an orange solid. Chromatography on silica gel
eluting with dichloromethane gave the title compound (0.95 g). Used
directly.
c) 5-Bromo-3-methoxy-6-methyl-2-pyrazinamine
##STR00148##
[0714] A solution of 3,5-dibromo-6-methyl-2-pyrazinamine (Example
118b) (0.9 g) was added to a solution of sodium (0.39 g) in
methanol (30 mL) was heated at reflux for 18 h. After removal of
solvent in vacuo, the residue was partitioned between water and
dichloromethane, and the organic phase dried (MgSO.sub.4), filtered
and evaporated to give the title compound as a pale yellow solid
(0.58 g).
[0715] m/e 218/220 (M+1.sup.+, 100%).
[0716] .sup.1H NMR (CDCl.sub.3) .delta. 4.70 (2H, br s), 3.97 (3H,
s), 2.40 (3H, s).
d)
2,3-Dichloro-N-[5-bromo-3-methoxy-6-methyl-2-pyrazinyl)benzenesulphonam-
ide
##STR00149##
[0718] Sodium hydride (0.5 g of a 60% dispersion in oil) was added
to a solution of 5-bromo-3-methoxy-6-methyl-2-pyrazinamine (Example
118c) (0.55 g) in N-methylpyrrolidinone (25 mL). The resultant dark
solution was stirred at room temperature for 0.5 h before a
solution of 2,3-dichlorobenzenesulphonyl chloride (0.67 g) in
N-methylpyrrolidinone (5 mL) was added dropwise. The reaction
mixture was stirred at room temperature for 3 h, then quenched with
aqueous ammonium chloride and partitioned between ethyl acetate and
aqueous ammonium chloride (.times.5). the organic phase was dried
(MgSO.sub.4), filtered and evaporated to give the crude product.
Chromatography on silica gel eluting with dichloromethane/acetic
acid (200:1) gave the title compound as a pale yellow solid (0.38
g).
[0719] m/e 424/426/428 (M-1.sup.-, 100%).
[0720] .sup.1H NMR (CDCl.sub.3) .delta. 8.29 (1H, d), 7.69 (2H, d),
7.41 (1H, t), 4.01 (3H, s), 2.27 (3H, s).
[0721] MP 146-148.degree. C.
EXAMPLE 119
5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-3-methylpyrazine-2-carboxy-
lic acid, methyl ester
##STR00150##
[0723] Prepared by the method of Example 113 using
2,3-dichloro-N-[5-bromo-3-methoxy-6-methylpyrazinyl)benzenesulphonamide
(Example 118) (0.35 g). Yield 0.27 g.
[0724] m/e 404/406 (M-1.sup.-, 100%).
[0725] .sup.1H NMR (CDCl.sub.3) .delta. 8.32 (1H, br s), 8.10 (1H,
br s), 7.70 (1H, d), 7.42 (1H, t) 4.06 (3H, s), 3.90 (3H, s), 2.50
(3H, br s).
[0726] MP 149-150.degree. C.
EXAMPLE 120
2,3-Dichloro-N-[5-(hydroxymethyl)-3-methoxy-6-methyl-2-pyrazinyl)benzenesu-
lphonamide
##STR00151##
[0728] To a stirred solution of
5-(2,3-dichlorobenzenesulphonylamino)-6-methoxy-3-methylpyrazine-2-carbox-
ylic acid, methyl ester (Example 119) (0.19 g) in tetrahydrofuran
(10 mL) under an atmosphere of nitrogen was added a solution of
lithium triethylborohydride (1.7 mL of a 1M solution in
tetrahydrofuran). The reaction mixture was stirred at room
temperature for 1 h, before quenching with aqueous ammonium
chloride and extraction into dichloromethane. The organic phase was
dried (MgSO.sub.4), filtered and evaporated to give the crude
product as a colourless oil. Chromatography on silica gel eluting
with dichloromethane/ethyl acetate/acetic acid (150:50:1) gave the
title compound as a white solid (0.38 g).
[0729] m/e 378 (M+1.sup.+, 100%).
[0730] .sup.1H NMR (CDCl.sub.3) .delta. 8.31 (1H, br d), 7.77 (1H,
br s), 7.68 (1H, d), 7.41 (1H, t), 4.55 (2H, d), 4.03 (3H, s), 3.12
(1H, br s), 2.13 (3H, br s).
[0731] MP 175-177.degree. C.
EXAMPLE 121
2,3-Dichloro-N-[5,6-dichloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesul-
phonamide
a) 5,6-Dichloro-3-(3-pyridinylmethoxy)-2-pyrazinamine
##STR00152##
[0733] To a stirred suspension of sodium hydride (1.20 g of a 60%
dispersion in oil) in dry dimethoxymethane (40 mL) was added
pyridine-3-methanol (2.18 g) in 1,2-dimethoxymethane (10 mL). The
resulting suspension was stirred at room temperature for 0.5 h and
then 3,5,6-trichloro-2-aminopyrazine (1.2 g) was added and the
mixture stirred at 70.degree. C. for 4 h. The reaction mixture was
cooled and cautiously added to water (100 mL) and neutralised with
2M hydrochloric acid. The mixture was extracted with ethyl acetate
(2.times.50 mL), dried (MgSO.sub.4), filtered and concentrated. The
residue was purified by chromatography on silical gel eluting with
ethyl acetate to afford the sub-titled compound as a white solid
(0.29 g). .sup.1H NMR (CDCl.sub.3) .delta. 8.73 (1H, s), 8.63 (1H,
d), 7.8 (1H, d), 7.35 (1H, dd), 5.42 (2H, s), 4.92 (2H, br s).
b)
2,3-Dichloro-N-[5,6-dichloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzene-
sulphonamide
##STR00153##
[0735] Prepared by the method of Example 1 (reaction performed at
room temperature) using
5,6-dichloro-3-(3-pyridinylmethoxy)-2-pyrazinamine (Example 121a)
(0.27 g) and 2,3-dichlorobenzenesulphonyl chloride (0.27 g). Yield
0.17 g.
[0736] m/e 479 (M+1.sup.+, 100%).
[0737] .sup.1H NMR (D6-DMSO) .delta. 8.8 (1H, s), 8.63 (1H, d),
8.11 (1H, d), 8.06 (1H, d), 7.58-7.52 (2H, m), 5.41 (2H, s).
EXAMPLE 122
3-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-2-fluorobenzenesulphonamide
##STR00154##
[0739] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.16 g)
and 3-chloro-2-fluorobenzenesulphonyl chloride (0.27 g). Yield 0.22
g.
[0740] m/e 354, 352 (M+1.sup.+, 100%).
[0741] .sup.1H NMR (D6-DMSO) .delta. 7.94-7.86 (2H, m), 7.82 (1H,
s), 7.43 (1H, dt), 3.92 (3H, s).
[0742] MP 156-157.degree. C.
EXAMPLE 123
3-Chloro-2-fluoro-N-[3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamid-
e
a) 3-(3-Pyridinylmethoxy)-2-pyrazinamine
##STR00155##
[0744] Prepared as for Example 121a using 3-chloro-2-aminopyrazine
(0.5 g), pyridine-3-methanol (0.42 g) and sodium hydride (0.31 g of
a 60% dispersion in oil) in N-methylpyrrolidinone (5 mL) to afford
the sub-titled compound as a solid (0.62 g).
[0745] .sup.1H NMR (CDCl.sub.3) .delta. 8.73 (1H, d), 8.60 (1H, d),
7.78 (1H, d), 7.60 (1H, d), 7.42 (1H, d), 7.32 (1H, dd), 5.43 (2H,
s), 4.77 (2H, br).
[0746] MP 120-122.degree. C.
b)
3-Chloro-2-fluoro-N-[3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphona-
mide
##STR00156##
[0748] To a stirred solution of
3-(3-pyridinylmethoxy)-2-pyrazinamine (Example 122a) (0.404 g) in
dichloromethane (5 mL) and pyridine (1 mL) was added
iso-butylchloroformate (0.3 mL) and the resulting solution stirred
for 20 hours. The reaction mixture was poured into water (20 mL)
and extracted into ethyl acetate (2.times.20 mL). The combined
extracts were dried (MgSO.sub.4), filtered and concentrated to
afford an oil (0.51 g) that was used without further purification.
A portion of the residue (0.15 g) was dissolved in
1,2-dimethoxymethane (2 mL) and sodium hydride (0.030 g of 60%
dispersion in oil) added. The resulting suspension was stirred for
15 minutes and then 3-chloro-2-fluorobenzenesulfonyl chloride
(0.137 g) in dimethoxymethane (1 mL) was added. The resulting
solution was stirred at room temperature for 6 h. The reaction
mixture was poured into water (20 mL) and extracted into ethyl
acetate (2.times.20 mL). The combined extracts were dried
(MgSO.sub.4), filtered and concentrated to afford an oil that was
dissolved into methanol (5 mL) and water (2 mL) and sodium
hydroxide (0.04 g) was added. The mixture was heated to 60.degree.
C. for 1 hour, cooled and was poured into water (20 mL) and
extracted into ethyl acetate (2.times.20 ml). The combined extracts
were dried (MgSO.sub.4), filtered and concentrated to afford an oil
that was purified by chromatography on silica gel eluting with
ethyl acetate/iso-hexane mixtures followed by ethyl acetate to
afford the title compound (0.067 g) as a white solid.
[0749] m/e 395, 397 (M+1.sup.+, 100%).
[0750] .sup.1H NMR (CDCl.sub.3) .delta. 8.69 (1H, s), 8.62 (1H, d),
8.06 (1H, t), 7.78 (1H, d), 7.68 (1H, d), 7.69-7.60 (2H, m), 7.34
(1H, dd), 7.26 (1H, dd), 5.43 (2H, s).
EXAMPLE 124
3-{[(2,3-Dichlorophenyl)sulphonyl]amino}pyrazine-2-carboxylic acid,
methyl ester
##STR00157##
[0752] To a stirred solution of 2,3-dichlorobenzenesulphonyl
chloride (0.246 g) and methyl-3-s aminopyrazine-2-carboxylate
(0.153 g) in 1,2-dimethoxymethane (3 mL) was added portionwise
sodium hydride (0.1 g of a 60% dispersion in oil) over 1 hour. The
mixture was stirred at room temperature for 20 h, was poured into
water (20 mL) and extracted into ethyl acetate (2.times.20 mL). The
combined extracts were dried (MgSO.sub.4), filtered and
concentrated to afford an oil that was purified by chromatography
on silica gel eluting with dichloromethane to afford the titled
compound (0.085 g) as a white solid.
[0753] m/e 362/364 (M+1.sup.+, 100%).
[0754] .sup.1H NMR (CDCl.sub.3) .delta. 10.97 (1H, s), 8.32 (1H,
dd), 8.31 (1H, d), 8.25 (1H, d), 7.68 (1H, dd), 7.42 (1H, t), 4.08
(3H, s).
[0755] MP 177-178.degree. C.
EXAMPLE 125
N-(5-Bromo-6-chloro-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
a) 3-Methoxy-5-bromo-6-chloro-2-pyrazinamine
##STR00158##
[0757] A stirred solution of 2-amino-6-chloropyrazine (2.0 g) and
N-bromosuccinimide (13.71 g) in chloroform (100 mL) was heated to
reflux for 20 hours. The reaction mixture was cooled and
concentrated onto silica gel (20 g) and the residue loaded onto a
column of silica gel (5 cm.times.2 cm) and the column was eluted
with dichloromethane. Concentration afforded
3,5-dibromo-6-chloro-2-aminopyrazine that was dissolved into
methanol (200 mL) and sodium methoxide (32 g of a 25% solution in
methanol) added. The reaction was heated to 70.degree. C. for 1.5
h, cooled and concentrated to approx. 50 mL capacity. The reaction
mixture was poured into water (200 mL) and the sub-titled adduct
(2.0 g) collected as an off-white solid.
[0758] m/e 235, 237 (M+1.sup.+, 100%).
b)
N-(5-Bromo-6-chloro-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonam-
ide
##STR00159##
[0760] Procedure as for Example 1 (reaction performed at room
temperature) using 3-methoxy-5-bromo-6-chloro-2-pyrazinamine
(Example 125a) (0.5 g) and 2,3-dichlorobenzenesulphonyl chloride
(2.21 g). Yield 3.2 g.
[0761] m/e 445, 447 (M-1.sup.+, 100%).
[0762] .sup.1H NMR (CDCl.sub.3) .delta. 8.32 (1H, dd), 7.79 (1H,
br), 7.72 (1H, dd), 7.45 (1H, t), 4.05 (3H, s).
[0763] MP 177-178.degree. C.
EXAMPLE 126
3-Chloro-5-{[(2,3-dichlorophenyl)sulphonyl]amino}-6-methoxypyrazine-2-carb-
oxylic acid, methyl ester
##STR00160##
[0765] Prepared by the method of Example 113 using
N-(5-bromo-6-chloro-3-methoxypyrazin-2-yl)-2,3-dichlorobenzenesulfonamide
(Example 125) (1.0 g). Yield 0.92 g.
[0766] m/e 426, 428 (M-1.sup.+, 100%).
[0767] .sup.1H NMR (CDCl.sub.3) .delta. 8.36 (1H, dd), 8.05 (1H,
br), 7.73 (1H, dd), 7.47 (1H, t), 4.09 (3H, s), 3.92 (3H, s).
[0768] MP 200-201.degree. C.
EXAMPLE 127
2,3-Dichloro-N-[6-chloro-5-(hydroxymethyl)-3-methoxypyrazin-2-yl]benzenesu-
lphonamide
##STR00161##
[0770] Prepared as for Example 120 using
3-chloro-5-{[(2,3-dichlorophenyl)sulphonyl]amino}-6-methoxypyrazine-2-car-
boxylic acid, methyl ester (Example 126) (0.105 g). Yield 0.072
g.
[0771] m/e 397, 399 (M-1.sup.+, 100%).
[0772] .sup.1H NMR (CDCl.sub.3) .delta. 8.34 (1H, dd), 7.84 (1H,
br), 7.74 (1H, dd), 7.45 (1H, t), 4.63 (2H, d), 4.07 (3H, s), 2.83
(1H, t).
[0773] MP 145-147.degree. C.
EXAMPLE 128
2,3-Dichloro-N-{3-[(6-methoxy-3-pyridinyl)methoxy]-2-pyrazinyl}benzenesulp-
honamide
##STR00162##
[0775] Prepared by the method of Example 28b using
2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example
28a) (0.338 g) and (6-methoxy-3-pyridinyl)methanol (0.21 g). Yield
0.23 g.
[0776] m/e 439, 440 (M-1.sup.+, 100%).
[0777] .sup.1H NMR (CDCl.sub.3) .delta. 8.28-8.26 (2H, m),
7.70-7.65 (3H, m), 7.60 (1H, br), 7.39 (1H, t), 6.80 (2H, d), 5.36
(2H, s), 3.97 (3H, s).
[0778] MP 187-188.degree. C.
EXAMPLE 129
2,3-Dichloro-N-[6-chloro-3-methoxy-5-(methoxymethyl)-2-pyrazinyl]benzenesu-
lphonamide
##STR00163##
[0780] To a stirred solution of
2,3-dichloro-N-[6-chloro-5-(hydroxymethyl)-3-methoxy-2-pyrazinyl]benzenes-
ulphonamide (Example 127) (0.1 g) in tetrahydrofuran (3 mL) was
added manganese dioxide (0.131 g) and the resulting suspension was
stirred for 20 h, filtered and concentrated. The residue was taken
up into methanol (3 mL) and acetic acid (0.1 mL). To this solution
was added ethylamine hydrochloride (0.081 g) and sodium
cyanoborohydride (0.051 g). The resulting mixture was stirred for
20 h and concentrated onto silical gel (1 g) and eluting with
methanol/dichloromethane mixtures to afford the titled compound
(0.029 g) as a white solid.
[0781] m/e 412, 414 (M-1.sup.+, 100%).
[0782] .sup.1H NMR (CDCl.sub.3) .delta. 8.35 (1H, dd), 7.72 (1H,
d), 7.45 (1H, t), 4.45 (2H, s), 4.05 (3H, s), 3.43 (3H, s).
[0783] MP 193-196.degree. C.
EXAMPLE 130
2-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-3-fluorobenzenesulphonamide
a)
N-(5-Chloro-3-methoxy-2-pyrazinyl)-3-fluorobenzenesulphonamide
##STR00164##
[0785] By the method outlined in Example 1 (reaction performed at
room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.798 g)
and 3-fluorobenzenesulphonyl chloride (1.17 g). Yield 0.64 g.
[0786] m/e 316 (M-1.sup.+, 100%).
b)
2-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-3-fluorobenzenesulphonamide
##STR00165##
[0788] A solution of
N-(5-chloro-3-methoxy-2-pyrazinyl)-3-fluorobenzenesulphonamide
(Example 130a) (0.159 g) in dry tetrahydrofuran (3 mL) was added to
a stirred solution of lithium di-iso-propylamide (prepared from
di-iso-propylamine (0.151 g) and n-butyl lithium (2.5M in hexanes))
in tetrahydrofuran (7.0 mL) at -78.degree. C. The resulting
solution was stirred at -78.degree. C. for 15 minutes and then
hexachloroethane (0.472 g) in tetrahydrofuran (2 mL) was added and
the mixture allowed to attain room temperature over a 5 hour
period. The reaction was quenched by the addition of 1N
hydrochloric acid (10 mL) and extracted into ethyl acetate
(2.times.20 mL). The combined extracts were dried (MgSO.sub.4),
filtered and concentrated to afford an oil that was purified by
chromatography on silica gel eluting with ethyl acetate/iso-hexane
mixtures gave the titled compound (0.086 g) as a white solid.
[0789] m/e 350, 352 (M-1.sup.+, 100%).
[0790] .sup.1H NMR (CDCl.sub.3) .delta. 8.16 (1H, dd), 7.81 (1H,
br), 7.62 (1H, s), 7.48-7.37 (2H, m), 4.06 (3H, s).
[0791] MP 159-159.5.degree. C.
EXAMPLE 131
2-Chloro-3-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
a) 3-Fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00166##
[0793] By the method outlined in Example 1 (reaction performed at
room temperature) using 3-chloro-2-pyrazinamine (1.29 g),
3-fluorobenzenesulphonyl chloride (2.13 g). The crude adduct was
reacted with a solution of sodium methoxide (10 mL of a 25%
solution in methanol) in methanol (20 mL) to afford the sub-titled
compound (2.36 g) as a solid.
[0794] m/e 284 (M+1.sup.+, 100%).
[0795] MP 142-143.degree. C.
b)
2-Chloro-3-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00167##
[0797] Prepared as for Example 130,
3-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide (Example
131a) (0.283 g), lithium di-iso-propylamide (prepared from
di-iso-propylamine (0.30 g) and n-butyl lithium (0.96 mL of a 2.5M
solution in hexanes)) and hexachloroethane (0.994 g) in anhydrous
tetrahydrofuran (20 mL) afforded the titled compound (0.092 g) as a
white solid after re-crystallisation from tent-butyl
methylether.
[0798] m/e 318, 320 (M-1.sup.+, 100%).
[0799] .sup.1H NMR (CD.sub.3OD) .delta. 8.11-8.08 (2H, m), 7.57
(1H, d), 7.57-7.50 (3H, m), 4.0 (3H, s).
[0800] MP 144-145.degree. C.
EXAMPLE 132
2-Chloro-3-methoxy-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
a) 3-Methoxy-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00168##
[0802] By the method outlined in Example 1 (reaction performed at
room temperature) using 3-chloro-2-aminopyrazine (0.83 g),
3-methoxybenzenesulfonyl chloride (1.44 g). The crude adduct was
reacted with a solution of sodium methoxide (10 mL of a 25%
solution in methanol) in methanol (20 mL) to afford the sub-titled
compound (1.41 g) as a solid.
[0803] m/e 296 (M+1.sup.+, 100%).
[0804] MP 133-134.degree. C.
b)
2-Chloro-3-methoxy-N-(3-methoxypyrazin-2-yl)benzenesulphonamide
##STR00169##
[0806] Prepared as for Example 130,
3-methoxy-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide (Example
132a) (0.295 g), lithium di-iso-propylamide (prepared from
di-iso-propylamine (0.30 g) and n-butyl lithium (0.96 mL of a 2.5M
solution in hexanes)) and hexachloroethane (0.994 g) in anhydrous
tetrahydrofuran (20 mL) afforded the titled compound (0.152 g) as a
white solid after re-crystallisation from tent-butyl
methylether.
[0807] m/e 328, 329 (M-1.sup.+, 100%).
[0808] .sup.1H NMR (CDCl.sub.3) .delta. 7.97 (1H, d), 7.92 (1H,
br), 7.65 (1H, d), 7.60 (1H, d), 7.41 (1H, t), 7.15 (1H, t), 3.99
(3H, s), 3.91 (3H, s).
[0809] MP 151-152.degree. C.
EXAMPLE 133
N-[5-Bromo-3-[(2S)-2-pyrrolidinylmethoxy]-2-pyrazinyl]-2,3-dichlorobenzene-
sulphonamide
##STR00170##
[0811] Sodium hydride (0.026 g of a 60% dispersion in oil) was
added to a mixture of
2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide
(Example 31a) (0.1 g) and 2-hydroxymethylpyrrolidine-1-carboxylic
acid tent-butyl ester (0.088 g) in 1,2-dimethoxyethane (2 mL).
After 0.5 h, the reaction mixture was partitioned between 2N
hydrochloric acid and ethyl acetate. The organic solution was dried
(MgSO.sub.4) and evaporated. Chromatography on silica gel eluting
with ethyl acetate/iso-hexane mixtures gave the title compound
protected with the BOC (tert-butoxycarbonyl) group (0.11 g) as an
oil. This product was dissolved in dichloromethane (6 mL) and
trifluoroacetic acid (2 mL). After 2 h, toluene was added and the
solution evaporated to dryness. Crystallisation from diethyl ether
gave the product as a white solid (0.083 g).
[0812] m/e 482 (M+1.sup.+, 100%).
[0813] .sup.1H NMR (D6-DMSO) .delta. 8.99 (1H, br), 8.65 (1H, br
s), 8.13 (1H, d), 7.95 (1H, d), 7.84 (1H, s), 7.59 (1H, t), 4.57
(1H, dd), 4.39 (1H, t), 4.0 (1H, br s), 3.3 (2H, d), 2.20-2.05 (1H,
m), 2.05-1.90 (2H, m), 1.85-1.75 (1H, m).
[0814] MP 199-200.degree. C.
EXAMPLE 134
5-(2,3-Dichlorobenzenesulphonylamino)-6-(3-pyridinylmethoxy)pyrazine-2-car-
boxylic acid, methyl ester
##STR00171##
[0816] Prepared as for Example 113 using
N-[5-bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphon-
amide (Example 34) (0.2 g) and bis(triphenylphosphine)palladium(II)
dichloride (0.1 g). Yield 0.14 g.
[0817] m/e 469 (M+1.sup.+, 100%).
[0818] .sup.1H NMR (D6-DMSO) .delta. 8.83 (1H, s), 8.61 (1H, d),
8.15-8.05 (3H, m), 7.90 (1H, d), 7.60-7.50 (2H, m), 5.48 (2H, s),
3.82 (3H, s).
[0819] MP 209-210.degree. C.
EXAMPLE 135
5-{[(2,3-Dichlorophenyl)sulphonyl]amino}-6-(3-pyridinylmethoxy)-2-pyrazine-
carboxamide
##STR00172##
[0821]
5-(2,3-Dichlorobenzenesulphonylamino)-6-(3-pyridinylmethoxy)pyrazin-
e-2-carboxylic acid, methyl ester (Example 134) (0.05 g) was heated
at 60.degree. C. in 7M ammonia in methanol for 4 days. The solution
was evaporated to dryness and the product crystallised from methyl
acetate. Yield 0.027 g.
[0822] m/e 453 (M-1.sup.+, 100%).
[0823] .sup.1H NMR (D6-DMSO) .delta. 8.72 (1H, s), 8.52 (1H, d),
7.99 (1H, d), 7.90 (1H, d), 7.83 (1H, s), 7.66 (1H, d), 7.56 (1H,
s), 7.45-7.35 (2H, m), 5.49 (2H, s).
[0824] MP 174-178.degree. C.
EXAMPLE 136
2,3-Dichloro-N-[5-(4-pyridinyl)-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzene-
sulphonamide
a)
[5-Bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl][(2,3-dichlorophenyl)sulpho-
nyl]carbamic acid, 2-methylpropyl ester
##STR00173##
[0826] Sodium hydride (0.045 g of a 60% dispersion in oil) was
added to
N-[5-bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphon-
amide (Example 34) (0.5 g) in 1,2-dimethoxyethane (3 mL).
Iso-butylchloroformate (0.15 mL) was added. After 2 h, the mixture
was partitioned between water and ethyl acetate. The organic layer
was dried (Na.sub.2SO.sub.4) and evaporated to yield the product
(0.65 g). Used directly.
b)
2,3-Dichloro-N-[5-(4-pyridinyl)-3-(3-pyridinylmethoxy)-2-pyrazinyl]benz-
enesulphonamide
##STR00174##
[0828]
[5-Bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl][(2,3-dichlorophenyl)su-
lphonyl]carbamic acid, 2-methylpropyl ester (Example 136a) (0.11
g), 4-tributylstannanylpyridine (0.067 g) and
tetrakis(triphenylphosphine)palladium(0) (0.05 g) in toluene (3 mL)
was heated at 95.degree. C. for 16 h. Chromatography on silica gel
eluting with ethyl acetate/ethanol mixtures gave the title compound
protected with the 2-methylpropylcarbonyl group (0.09 g). The
compound was heated at 60.degree. C. in methanol (2 mL) and 1M
sodium hydroxide (0.36 mL) for 1 h. The solution was evaporated.
Purification was by reverse phase preparative high pressure liquid
chromatography. Yield 0.015 g.
[0829] m/e 488 (M+1.sup.+, 100%).
[0830] .sup.1H NMR (D6-DMSO) .delta. 9.05 (1H, s), 8.85 (2H, d),
8.78 (1H, d), 8.62 (1H, s), 8.44-8.39 (3H, m), 8.17 (1H, dd), 7.96
(1H, dd), 7.87-7.80 (1H, m), 7.64-7.57 (1H, m), 5.74 (2H, s).
[0831] MP 210.degree. C. (dec.)
EXAMPLE 137
2,3-Dichloro-N-[5-(hydroxymethyl)-3-(3-pyridinylmethoxy)-2-pyrazinyl]benze-
nesulphonamide
##STR00175##
[0833] Lithium aluminium hydride (0.85 mL of a 1M solution in
tetrahydrofuran) was added dropwise to
5-(2,3-dichlorobenzenesulphonylamino)-6-(3-pyridinylmethoxy)pyrazine-2-ca-
rboxylic acid, methyl ester (Example 134) (0.2 g) in
tetrahydrofuran (10 mL) cooled to -65.degree. C. The reaction
mixture was allowed to warm to room temperature and stirred for 1
h. Aqueous acetic acid was added and the mixture extracted with
ethyl acetate. The organic solution was dried (MgSO.sub.4) and
evaporated. Chromatography on silica gel eluting with ethyl
acetate/methanol mixtures gave the title compound (0.08 g).
[0834] m/e 441 (M+1.sup.+, 100%).
[0835] .sup.1H NMR (D6-DMSO) .delta. 8.73 (1H, s), 8.55 (1H, d),
8.06 (1H, dd), 7.95-7.85 (2H, m), 7.65 (1H, s), 7.56 (1H, t),
7.64-7.57 (1H, m), 5.41 (2H, s), 5.36 (1H, t), 4.41 (2H, d).
EXAMPLE 138
2,3-Dichloro-N-[5-(hydroxymethyl)-3-methoxy)-2-pyrazinyl]benzenesulphonami-
de
##STR00176##
[0837] Prepared as for Example 120 using
5-(2,3-dichlorobenzenesuphonylamino)-6-methoxypyrazine-2-carboxylic
acid, methyl ester (Example 113) (0.84 g). Yield 0.5 g.
[0838] m/e 364 (M+1.sup.+, 100%).
[0839] .sup.1H NMR (D6-DMSO) .delta. 8.21 (1H, dd), 7.79 (1H, dd),
7.59 (1H, s), 7.51 (1H, t), 4.50 (2H, s), 4.01 (3H, s).
[0840] MP 160-161.degree. C.
EXAMPLE 139
N-(5-Allyloxy-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
##STR00177##
[0842] Procedure as for Example 115 using
N-(5-chloro-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-({2-[(trimethylsilyl)ox-
y]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.25 g), allyl
alcohol (0.06 g) and sodium hydride (0.035 g of a 60% dispersion in
oil) in N,N-dimethylformamide (5 mL) stirred at room temperature
for 5 days. Purification was by silica gel chromatography eluting
with ethyl acetate/iso-hexane mixtures to give the title compound
with SEM attached. Yield 0.18 g. This compound was dissolved in
dichloromethane (4 mL) and trifluoroacetic acid (1 mL). After 2 h,
toluene was added and the mixture evaporated to dryness.
Purification was by silica gel chromatography eluting with ethyl
acetate/iso-hexane mixtures to give the title compound.
Crystallised for diethyl ether/iso-hexane mixtures. Yield 0.026
g.
[0843] m/e 390 (M+1.sup.+, 100%).
[0844] .sup.1H NMR (D6-DMSO) .delta. 10.81 (1H, s), 8.0-7.9 (2H,
m), 7.53 (1H, t), 7.49 (1H, s), 6.07-7.02 (1H, m), 5.38 (1H, dd),
5.26 (1H, dd), 4.80 (2H, d), 3.82 (3H, s).
[0845] MP 120-121.degree. C.
EXAMPLE 140
2,3-Dichloro-N-{3-methoxy-5-[(pyrazinyloxy)methyl]-2-pyrazinyl}benzenesulp-
honamide
##STR00178##
[0847] Sodium hydride (0.022 g of a 60% dispersion in oil) was
added to
2,3-dichloro-N-[5-(hydroxymethyl)-3-methoxy)-2-pyrazinyl]benzenesulphonam-
ide (Example 138) (0.05 g) in N-methylpyrrolidinone (2 mL). After
0.5 h, chloropyrazine (0.013 mL) was added and the mixture heated
at 60.degree. C. for 3 h. Aqueous acetic acid was added and the
mixture extracted with ethyl acetate. The organic solution was
dried (Na.sub.2SO.sub.4) and evaporated. Chromatography on silica
gel eluting with ethyl acetate/iso-hexane mixtures gave the title
compound (0.012 g).
[0848] m/e 442 (M+1.sup.+, 100%).
[0849] .sup.1H NMR (D6-DMSO) .delta. 8.36 (1H, s), 8.23 (2H, d),
8.06 (1H, d), 7.87 (1H, d), 7.68 (1H, s), 7.54 (1H, t), 5.26 (2H,
s), 3.86 (3H, s).
[0850] MP 155.degree. C. (dec).
EXAMPLE 141
2,3-Dichloro-N-[5-(3-hydroxy-1-propynyl)-3-methoxy-2-pyrazinyl]benzenesulp-
honamide
##STR00179##
[0852] A mixture of
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)et-
hoxy}methyl]benzenesulphonamide (Example 55a) (0.52 g), propargyl
alcohol (0.223 mL), copper(I)iodide (0.05 g) and
bis(triphenylphosphine)palladium(II) chloride (0.1 g) in
triethylamine (3 mL) was stirred at room temperature and under
nitrogen for 16 h. The solvent was evaporated. Chromatography on
silica gel eluting with ethyl acetate/iso-hexane mixtures gave the
title compound containing the SEM
([2-(trimethylsilyl)ethoxy]methyl) protecting group (0.38 g). 0.074
g of this compound was dissolved in dichloromethane (2 mL) and
trifluoroacetic acid (2 mL). After 1 h the solvent was evaporated.
Chromatography on silica gel eluting with ethyl acetate/iso-hexane
mixtures gave the title compound (0.043 g).
[0853] m/e 386 (M-1.sup.+, 100%).
[0854] .sup.1H NMR (D6-DMSO) .delta. 8.07 (1H, d), 7.93 (1H, d),
7.72 (1H, s), 7.58 (1H, t), 4.29 (2H, s), 3.90 (3H, s).
EXAMPLE 142
N-{3-[(5-Bromo-3-pyridinyl)methoxy]-5-chloro-2-pyrazinyl}-2,3-dichlorobenz-
enesulphonamide
##STR00180##
[0856] Prepared by the method of Example 31 using
(5-bromo-3-pyridinyl)methanol (0.2 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.25 g). Yield 0.17 g.
[0857] m/e 523 (M-1.sup.+, 100%).
[0858] .sup.1H NMR (D6-DMSO) .delta. 8.77 (1H, d), 8.71 (1H, d),
8.28 (1H, s), 8.07 (1H, dd), 7.92 (1H, d), 7.85 (1H, s), 7.55 (1H,
t), 5.43 (2H, s).
[0859] MP 199-201.degree. C.
EXAMPLE 143
2,3-Dichloro-N-[5-chloro-3-{[6-(hydroxymethyl)-2-pyridinyl]methoxy}-2-pyra-
zinyl]benzenesulphonamide
##STR00181##
[0861] Prepared by the method of Example 31 using
2,6-bis(hydroxymethyl)pyridine (0.11 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.11 g) in N-methylpyrrolidinone (2 mL). Yield 0.043
g.
[0862] m/e 475 (M+1.sup.+, 100%).
[0863] .sup.1H NMR (D6-DMSO) .delta. 7.97 (1H, d), 7.83 (1H, t),
7.68 (1H, d), 7.43-7.35 (4H, m), 5.44 (1H, s), 5.32 (2H, s), 4.58
(2H, s).
[0864] MP 220.degree. C.
EXAMPLE 144
2,3-Dichloro-N-{5-chloro-3-[(2-methyl-4-oxazolyl)methoxy]-2-pyrazinyl}benz-
enesulphonamide
##STR00182##
[0866] Prepared by the method of Example 31b using
(2-methyl-4-oxazolyl)methanol (0.08 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.26 g). Yield 0.083 g.
[0867] m/e 449 (M+1.sup.+, 100%).
[0868] .sup.1H NMR (D6-DMSO) .delta. 8.09 (1H, s), 8.03 (1H, dd),
7.94 (1H, dd), 7.85 (1H, s), 7.55 (1H, t), 5.23 (2H, s), 2.45 (3H,
s).
[0869] MP 172-173.degree. C.
EXAMPLE 145
2,3-Dichloro-N-{3-[(2-methyl-4-oxazolyl)methoxy]-2-pyrazinyl}benzenesulpho-
namide
##STR00183##
[0871] Prepared by the method of Example 28 using
(2-methyl-4-oxazolyl)methanol (0.3 g) and
2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (0.89 g).
Yield 0.035 g.
[0872] m/e 412 (M-1.sup.+, 100%).
[0873] .sup.1H NMR (D6-DMSO) .delta. 8.06 (2H, dd), 7.92 (1H, dd),
7.85 (1H, br s), 7.70 (1H, br s), 7.56 (1H, t), 5.23 (2H, s), 2.41
(3H, s).
[0874] MP 207-209.degree. C.
[0875] Examples 146-165 were prepared using the following
procedure:
[0876] To a solution of
N-(3,5-dibromo-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(Example 31) (0.003 g) and primary alcohol (0.026 mL of a 0.5M
solution in N-methylpyrrolidinone) in N-methylpyrrolidinone (0.1
mL) was added potassium tert-butoxide (0.050 mL of a 1M solution in
tetrahydrofuran). The solution was allowed to stand for 24 hours.
The reaction mixture was diluted with acetic acid (0.010 mL) and
water (0.10 mL) and the solvents were evaporated. The residue was
redissolved in dimethylsulphoxide (0.5 mL) and purified by mass
directed high pressure liquid chromatography. The solvent was
evaporated to afford a solid.
EXAMPLE 146
N-[5-Bromo-3-(phenylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
##STR00184##
[0878] m/e 489 (M+1.sup.+, 100%).
EXAMPLE 147
N-[5-Bromo-3-(2-cyclopropylethoxy)pyrazinyl]-2,3-dichlorobenzenesulphanami-
de
##STR00185##
[0880] m/e 467 (M+1.sup.+, 100%).
EXAMPLE 148
N-[5-Bromo-3-(3-thienylmethoxy)pyrazinyl]-2,3-dichlorobenzenesulphonamide
##STR00186##
[0882] m/e 495 (M+1.sup.+, 100%).
EXAMPLE 149
N-{5-Bromo-3-[(2-methyl-3-furanyl)methoxy]-2-pyrazinyl}-2,3-dichlorobenzen-
esulphonamide
##STR00187##
[0884] m/e 493 (M+1.sup.+, 100%).
EXAMPLE 150
N-{5-Bromo-3-[(3-furanyl)methoxy]-2-pyrazinyl}-2,3-dichlorobenzenesulphona-
mide
##STR00188##
[0886] m/e 479 (M+1.sup.+, 100%).
EXAMPLE 151
N-{5-Bromo-3-[(4-fluorophenyl)methoxy]-2-pyrazinyl}-2,3-dichlorobenzenesul-
phonamide
##STR00189##
[0888] m/e 507 (M+1.sup.+, 100%).
EXAMPLE 152
N-{5-Bromo-3-[(3-fluorophenyl)methoxy]-2-pyrazinyl}-2,3-dichlorobenzenesul-
phonamide
##STR00190##
[0890] m/e 507 (M+1.sup.+, 100%).
EXAMPLE 153
N-{5-Bromo-3-[3-(2-pyridinyl)propoxy]-2-pyrazinyl}-2,3-dichlorobenzenesulp-
honamide
##STR00191##
[0892] m/e 518 (M+1.sup.+, 100%).
EXAMPLE 154
N-[5-Bromo-3-(pentyloxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
##STR00192##
[0894] m/e 469 (M+1.sup.+, 100%).
EXAMPLE 155
N-[5-Bromo-3-(propyloxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
##STR00193##
[0896] m/e 441 (M+1.sup.+, 100%).
EXAMPLE 156
N-[5-Bromo-3-(2-methoxyethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamid-
e
##STR00194##
[0898] m/e 457 (M+1.sup.+, 100%).
EXAMPLE 157
N-[5-Bromo-3-(2-ethoxyethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
##STR00195##
[0900] m/e 471 (M+1.sup.+, 100%).
EXAMPLE 158
N-[5-Bromo-3-(2-fluoroethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide
##STR00196##
[0902] m/e 445 (M+1.sup.+, 100%).
EXAMPLE 159
N-{5-Bromo-3-[2-(1H-imidazol-1-yl)ethoxy]-2-pyrazinyl}-2,3-dichlorobenzene-
sulphonamide
##STR00197##
[0904] m/e 493 (M+1.sup.+, 100%).
EXAMPLE 160
N-{5-Bromo-3-[3-(3-pyridinyl)propoxy]-2-pyrazinyl}-2,3-dichlorobenzenesulp-
honamide
##STR00198##
[0906] m/e 516 (M-1.sup.+, 100%).
EXAMPLE 161
N-[5-Bromo-3-[2-(methylamino)ethoxy]-2-pyrazinyl]-2,3-dichlorobenzenesulph-
onamide
##STR00199##
[0908] m/e 456 (M+1.sup.+, 100%).
EXAMPLE 162
N-{5-Bromo-3-[3-(4-hydroxyphenyl)propoxy]-2-pyrazinyl}-2,3-dichlorobenzene-
sulphonamide
##STR00200##
[0910] m/e 533 (M+1.sup.+, 100%).
EXAMPLE 163
N-[5-Bromo-3-(2-phenoxyethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamid-
e
##STR00201##
[0912] m/e 517 (M-1.sup.+, 100%).
EXAMPLE 164
N-[5-Bromo-3-(cyclopropylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphona-
mide
##STR00202##
[0914] m/e 453 (M+1.sup.+, 100%).
EXAMPLE 165
N-[5-Bromo-3-(3-phenoxypropoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonami-
de
##STR00203##
[0916] m/e 531 (M-1.sup.+, 100%).
EXAMPLE 166
2,3-Dichloro-N-(5-ethoxy-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00204##
[0918] Prepared as for Example 56 using
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)et-
hoxy}methyl]benzenesulphonamide (Example 55a) (0.3 g) and sodium
ethoxide (5 mL of a 0.5M solution in ethanol). Yield 0.1 g.
[0919] m/e 378 (M+1,100%).
[0920] .sup.1H NMR (CDCl.sub.3) .delta. 8.22 (1H, d), 7.65 (1H, d),
7.49 (1H, s), 7.34 (1H, t), 7.30 (1H, s), 4.24 (2H, q), 3.95 (3H,
s), 1.36 (3H, t).
[0921] MP 96-97.degree. C.
EXAMPLE 167
2,3-Dichloro-N-[3-methoxy-5-([1,2,4]-1-triazolyl)-2-pyrazinyl]benzenesulph-
onamide
##STR00205##
[0923] Prepared as for Example 101b (reaction heated at 50.degree.
C.) using
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsila-
nyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.25 g) and
[1,2,4]triazole (0.1 g). The intermediate product containing the
SEM (2-[trimethylsilyl]ethoxymethyl) group was purified by silica
gel chromatography eluting with ethyl acetate/iso-hexane mixtures.
Deprotection as for Example 101b gave the title compound. Yield
0.035 g.
[0924] m/e 401 (M+1.sup.+, 100%).
[0925] .sup.1H NMR (CDCl.sub.3) .delta. 8.92 (1H, s), 8.34 (1H, d),
8.24 (1H, s), 8.08 (1H, s), 8.01 (1H, br s), 7.72 (1H, d), 7.43
(1H, t), 4.14 (3H, t).
[0926] MP 248-249.degree. C.
EXAMPLE 168
2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]-N-
-methylacetamide
##STR00206##
[0928] Prepared as for Example 101b using
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)et-
hoxy}methyl]benzenesulphonamide (Example 55a) (0.4 g) and
2-mercapto-N-methylacetamide (0.1 g). The intermediate product
containing the SEM (2-[trimethylsilyl]ethoxymethyl) group was
purified by silica gel chromatography eluting with ethyl
acetate/iso-hexane mixtures. Deprotection as for Example 101b gave
the title compound. Yield 0.05 g.
[0929] m/e 437 (M+1.sup.+, 100%).
[0930] .sup.1H NMR (CDCl.sub.3) .delta. 8.25 (1H, dd), 7.76 (1H,
s), 7.68 (1H, dd), 7.58 (1H, s), 7.40 (1H, t), 6.62 (1H, br s),
3.99 (3H, s), 3.69 (2H, s), 2.86 (3H, d).
[0931] MP 150-152.degree. C.
EXAMPLE 169
2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]ac-
etamide
##STR00207##
[0933] Prepared as for Example 101b using
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)et-
hoxy}methyl]benzenesulphonamide (Example 55a) (0.2 g) and
2-mercaptoacetamide (0.05 g). The intermediate product containing
the SEM group was purified by silica gel chromatography eluting
with ethyl acetate/iso-hexane mixtures. Deprotection as for Example
101b gave the title compound. Yield 0.03 g.
[0934] m/e 423 (M+1.sup.+, 100%).
[0935] .sup.1H NMR (CDCl.sub.3) .delta. 7.98 (1H, dd), 7.75 (1H,
d), 7.46-7.42 (3H, m), 7.06 (1H, s), 3.83 (3H, s), 2.59 (2H,
s).
[0936] MP 163-164.degree. C.
EXAMPLE 170
2,3-Dichloro-N-[5-(4-fluorobenzylsulphanyl)-3-methoxy-2-pyrazinyl]benzenes-
ulphonamide
##STR00208##
[0938] Prepared as for Example 101b using
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-{[2-(trimethylsilanyl)et-
hoxy]methyl}benzenesulphonamide (Example 55a) (0.4 g) and
(4-fluorophenyl)methanethiol (0.13 g). The intermediate product
containing the SEM group was purified by silica gel chromatography
eluting with ethyl acetate/iso-hexane mixtures. Deprotection as for
Example 101b gave the title compound. Yield 0.2 g
[0939] m/e 474 (M+1.sup.+, 100%).
[0940] .sup.1H NMR (CDCl.sub.3) .delta. 8.25 (1H, dd), 7.73 (1H,
s), 7.67 (1H, dd), 7.51 (1H, s), 7.38 (1H, t), 7.27 (2H, m), 6.92
(2H, m), 4.24 (2H, s), 4.01 (3H, s).
[0941] MP 119-120.degree. C.
EXAMPLE 171
2,3-Dichloro-N-[5-cyanomethylsulphanyl-3-methoxy-2-pyrazinyl]benzenesulpho-
namide
##STR00209##
[0943] See example 172 for preparation.
[0944] m/e 403 (M-1.sup.+, 100%).
[0945] .sup.1H NMR (CDCl.sub.3) .delta. 8.28 (1H, dd), 7.84 (1H,
s), 7.69 (1H, dd), 7.63 (1H, s), 7.38 (1H, t), 4.11 (3H, s), 3.78
(2H, s).
[0946] MP 158-159.degree. C.
EXAMPLE 172
2,3-Dichloro-N-[3-methoxy-5-([1,2,4]-3-oxadiazolylmethylsulphanyl)-2-pyraz-
inyl]benzenesulphonamide
##STR00210##
[0948] Prepared as for Example 101b using
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)et-
hoxy}methyl]benzenesulphonamide (Example 55a) (0.4 g),
[1,2,4]-3-oxadiazolylmethanethiol (0.15 g) and cesium carbonate
(0.5 g) at room temperature for 16 h. The intermediate products
containing the SEM (2-[trimethylsilyl]ethoxymethyl) group was
purified by silica gel chromatography eluting with ethyl
acetate/iso-hexane mixtures. Deprotection as for Example 101b gave
the title compound (0.09 g) and
2,3-dichloro-N-[5-cyanomethylsulphanyl-3-methoxy-2-pyrazinyl]benzenesulph-
onamide (Example 171) (0.1 g) which were separated by silica gel
chromatography eluting with dichloromethane.
[0949] m/e 448 (M+1.sup.+, 100%).
[0950] .sup.1H NMR (CDCl.sub.3) .delta. 8.64 (1H, s), 8.26 (1H,
dd), 7.76 (1H, s), 7.67 (1H, dd), 7.57 (1H, s), 7.37 (1H, t), 4.39
(2H, s), 4.04 (3H, s).
[0951] MP 154-156.degree. C.
EXAMPLE 173
N-[5-(2-Aminoethylsulphanyl)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesul-
phonamide
##STR00211##
[0953] Prepared as for Example 101b using
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)et-
hoxy}methyl]benzenesulphonamide (Example 55a) (0.45 g) and
2-aminoethanethiol hydrochloride (0.2 g). Yield 0.03 g
[0954] m/e 409 (M+1.sup.+, 100%).
[0955] .sup.1H NMR (D6-DMSO) .delta. 8.02 (1H, dd), 7.94 (1H, dd),
7.87 (1H, s), 7.70 (1H, s), 7.58 (1H, t), 3.93 (3H, s), 3.48 (2H,
br s), 3.28 (2H, t), 3.10-3.03 (2H, m).
[0956] MP 189-190.degree. C.
EXAMPLE 174
2,3-Dichloro-N-[3-methoxy-5-(5-methyl-3-isoxazolylmethoxy))-2-pyrazinyl]be-
nzenesulphonamide
##STR00212##
[0958] Prepared as for Example 115b using
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)et-
hoxy}methyl]benzenesulphonamide (Example 55a) (0.3 g) and
(5-methyl-3-oxazolyl)methanol (0.13 g). The intermediate product
containing the SEM (2-[trimethylsilyl]ethoxymethyl) group was
purified by silica gel chromatography eluting with ethyl
acetate/iso-hexane mixtures. Deprotection as for Example 115b gave
the title compound. Yield 0.2 g
[0959] m/e 445 (M+1.sup.+, 100%).
[0960] .sup.1H NMR (CDCl.sub.3) .delta. 8.22 (1H, dd), 7.66 (1H,
dd), 7.59 (1H, s), 7.38 (2H, t), 6.01 (1H, t), 5.31 (2H, s), 3.97
(3H, s), 2.43 (3H, s).
[0961] MP 142-143.degree. C.
EXAMPLE 175
2,3-Dichloro-N-[5-(5-dimethylaminomethyl-2-furanylmethoxy)-3-methoxy-2-pyr-
azinyl]benzenesulphonamide
##STR00213##
[0963] Prepared as for Example 115b using
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)et-
hoxy}methyl]benzenesulphonamide (Example 55a) (0.3 g) and
(5-dimethylaminomethyl-2-furanyl)methanol (0.2 g). After removal of
the SEM (2-[trimethylsilyl]ethoxymethyl) group the title compound
was purified by silica gel chromatography eluting with
methanol/dichloromethane mixtures Yield 0.23 g
[0964] m/e 487 (M+1.sup.+, 100%).
[0965] .sup.1H NMR (CDCl.sub.3) .delta. 8.21 (1H, dd), 7.66 (1H,
dd), 7.37 (2H, t), 6.39 (2H, s), 5.20 (2H, s), 4.00 (3H, s), 3.84
(2H, s), 2.51 (6H, s).
[0966] MP 114-115.degree. C.
EXAMPLE 176
N-[5-Bromo-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2-pyrazinyl]-2,3-dic-
hloro-benzenesulphonamide
##STR00214##
[0968] Prepared by the method of Example 31 using
(5-dimethylaminomethyl-2-furanyl)methanol (0.2 g) and
2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide
(Example 31a) (0.2 g). Purified by silica gel chromatography
eluting with methanol/dichloromethane mixtures and recrystallised
from acetonitrile. Yield 0.058 g.
[0969] m/e 535 (M+1.sup.+, 100%).
[0970] .sup.1H NMR (D6-DMSO) .delta. 7.92 (1H, dd), 7.63 (1H, dd),
7.36 (2H, t), 6.71 (1H, d), 6.68 (1H, d), 5.22 (2H, s), 4.37 (2H,
d), 2.75 (6H, s).
[0971] MP 206-207.degree. C.
EXAMPLE 177
2,3-Dichloro-N-[5-(2-hydroxyethylsulphanyl)-3-methoxy-2-pyrazinyl]benzenes-
ulphonamide
##STR00215##
[0973] Prepared as for Example 101b using
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)et-
hoxy}methyl]benzenesulphonamide (Example 55a) (0.2 g) and
2-mercaptoethanol (0.2 g). After removal of the SEM
(2-[trimethylsilyl]ethoxymethyl) group the title compound was
purified by silica gel chromatography eluting with
methanol/dichloromethane mixtures. Yield 0.015 g
[0974] m/e 410 (M+1.sup.+, 100%).
[0975] .sup.1H NMR (CDCl.sub.3) .delta. 8.27 (1H, dd), 7.78 (1H,
s), 7.67 (1H, dd), 7.61 (1H, s), 7.39 (1H, t), 4.04 (3H, s), 3.83
(2H, t), 3.24 (2H, t).
[0976] MP 180-181.degree. C.
EXAMPLE 178
2,3-Dichloro-N-{5-[2-(ethylureido)ethylsulphanyl]-3-methoxy-2-pyrazinyl}be-
nzenesulphonamide
##STR00216##
[0978] Ethylisocyanate (0.016 g) was added to
N-[5-(2-aminoethylsulphanyl)-3-methoxy-2-pyrazinyl]-2,3-dichloro-benzenes-
ulphonamide (Example 173) (0.08 g) in dichloromethane (5 mL). After
1 h, the reaction mixture was evaporated to dryness. Purified by
silica gel chromatography eluting with methanol/dichloromethane
mixtures. Yield 0.015 g.
[0979] m/e 480 (M+1.sup.+, 100%).
[0980] .sup.1H NMR (CDCl.sub.3) .delta. 8.27 (1H, dd), 7.69 (1H,
dd), 7.56 (1H, s), 7.39 (1H, t), 4.60 (1H, br s), 4.18 (1H, br s),
4.04 (3H, s), 3.40-3.30 (2H, m), 3.30-3.2 (2H, m), 3.25-3.20 (2H,
m), 1.15 (3H, t).
EXAMPLE 179
2,3-Dichloro-N-[3-(5-dimethylaminomethyl-2-furanylmethoxy)-2-pyrazinyl]ben-
zenesulphonamide
##STR00217##
[0982] Prepared by the method of Example 28 using
(5-dimethylaminomethyl-2-furanyl)methanol (0.2 g) and
2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example
28) (0.4 g). Purified by silica gel chromatography eluting with
methanol/dichloromethane mixtures. Yield 0.2 g.
[0983] m/e 455 (M-1.sup.+, 100%). .sup.1H NMR (D6-DMSO) .delta.
7.96 (1H, dd), 7.66 (1H, dd), 7.40 (1H, t), 7.30 (1H, d), 7.24 (1H,
d), 6.65 (1H, s), 6.64 (1H, d), 5.23 (2H, s), 4.25 (2H, s), 2.66
(6H, s).
EXAMPLE 180
2,3-Dichloro-N-[6-chloro-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2-pyra-
zinyl]benzenesulphonamide
##STR00218##
[0985] Prepared by the method of Example 31 using
(5-dimethylaminomethyl-2-furanyl)methanol (0.2 g) and
N-(3-bromo-6-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(Example 98) (0.3 g). Purified by silica gel chromatography eluting
with methanol/dichloromethane mixtures. Yield 0.11 g.
[0986] m/e 491 (M+1.sup.+, 100%).
[0987] .sup.1H NMR (D6-DMSO) .delta. 8.01 (1H, dd), 7.66 (1H, dd),
7.39 (1H, t), 7.11 (1H, s), 6.69 (1H, d), 6.67 (1H, d), 5.20 (2H,
s), 4.39 (2H, s), 2.76 (6H, s).
[0988] MP 209-210.degree. C.
EXAMPLE 181
2,3-Dichloro-N-[6-chloro-3-(5-methylaminomethyl-2-furanylmethoxy)-2-pyrazi-
nyl]benzenesulphonamide
##STR00219##
[0990] Prepared by the method of Example 31 using
(5-methylaminomethyl-2-furanyl)methanol (0.3 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.4 g). Purified by silica gel chromatography eluting
with methanol/dichloromethane mixtures. Yield 0.03 g.
[0991] m/e 477 (M+1.sup.+, 100%).
[0992] .sup.1H NMR (D6-DMSO) .delta. 8.98 (2H, br), 7.92 (1H, d),
7.63 (1H, d), 7.35 (1H, t), 7.29 (1H, s), 6.67 (1H, d), 6.64 (1H,
d), 5.20 (2H, s), 4.25 (2H, s), 2.59 (3H, s).
[0993] MP 211-212.degree. C.
EXAMPLE 182
2,3-Dichloro-N-[5-chloro-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2-pyra-
zinyl]benzenesulphonamide
##STR00220##
[0995] Prepared by the method of Example 31 using
(5-dimethylaminomethyl-2-furanyl)methanol (0.3 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.4 g). Purified by silica gel chromatography eluting
with methanol/dichloromethane mixtures. Yield 0.30 g.
[0996] m/e 491 (M+1.sup.+, 100%).
[0997] .sup.1H NMR (D6-DMSO) .delta. 7.93 (1H, dd), 7.65 (1H, dd),
7.36 (1H, t), 7.32 (1H, s), 6.71 (1H, d), 6.69 (1H, d), 5.23 (2H,
s), 4.38 (2H, s), 2.75 (6H, s).
[0998] MP 209-210.degree. C.
EXAMPLE 183
2,3-Dichloro-N-[3-(5-methylaminomethyl-2-furanylmethoxy)-2-pyrazinyl]benze-
nesulphonamide
##STR00221##
[1000] Prepared by the method of Example 28 using
(5-methylaminomethyl-2-furanyl)methanol (0.2 g) and
2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example
28) (0.4 g). Purified by silica gel chromatography eluting with
methanol/dichloromethane mixtures. Yield 0.12 g.
[1001] m/e 443 (M+1.sup.+, 100%).
[1002] .sup.1H NMR (D6-DMSO) .delta. 8.99 (2H, br s), 7.95 (1H, d),
7.62 (1H, d), 7.35 (1H, t), 7.24 (1H, d), 7.15 (1H, d), 6.88 (1H,
d), 6.63 (1H, d), 5.20 (2H, s), 4.24 (2H, s), 2.58 (3H, s).
[1003] MP 198-199.degree. C.
EXAMPLE 184
N-(5-Bromo-3-methoxypyrazinyl)-2-cyanobenzenesulphonamide
##STR00222##
[1005] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.2 g)
and 2-cyanobenzenesulphonyl chloride (0.24 g). Yield 0.059 g.
[1006] m/e 369/370 (M+1.sup.+), 307/309 (100%).
[1007] .sup.1H NMR (D6-DMSO) .delta. 8.14 (1H, d), 8.09 (1H, d),
7.93-7.82 (3H, m), 3.93 (3H, s).
[1008] MP 190-191.5.degree. C.
EXAMPLE 185
N-(5-Bromo-3-methoxypyrazinyl)-2,3-dichloro-4-fluorobenzenesulphonamide
a) 2,3-Dichloro-4-fluorobenzenesulphonyl chloride
##STR00223##
[1010] Chlorosulphonic acid (12.1 mL) was added dropwise to a
solution of 2,3-dichloro-4-fluorobenzene (5.0 g) in dichloromethane
(12 mL) at -40.degree. C. The solution was allowed to slowly warm
to room temperature and was stirred for 3 days. The solution was
poured onto crushed ice/water, extracted into dichloromethane and
concentrated under reduced pressure. Purified by silica gel
chromatography eluting with dichloromethane/iso-hexane mixtures.
Yield 4.2 g
[1011] m/e 262/264 (M.sup.+), 163 (100%).
b)
N-(5-Bromo-3-methoxypyrazinyl)-2,3-dichloro-4-fluorobenzenesulphonamide
##STR00224##
[1013] Prepared by the method of Example 1 (reaction performed at
room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.2 g)
and 2,3-dichloro-4-fluorobenzenesulphonyl chloride (Example 185a)
(0.31 g). Yield 0.042 g.
[1014] m/e 430 (M-1.sup.-, 100%).
[1015] .sup.1H NMR (D6-DMSO) .delta. 8.16-8.12 (1H, m), 7.81 (1H,
s), 7.68-7.64 (1H, m), 3.92 (3H, s).
[1016] MP 208-211.degree. C.
EXAMPLE 186
2,3-Dichloro-N-[3-methoxy-5-(4-morpholinylmethyl)-2-pyrazinyl]benzenesulph-
onamide
a)
2,3-Dichloro-N-(5-formyl-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00225##
[1018] Prepared as for Example 107a using
2,3-dichloro-N-[5-(hydroxymethyl)-3-methoxy-2-pyrazinyl]benzenesulphonami-
de (Example 138) (0.6 g). Yield 0.53 g. Used directly.
b)
2,3-Dichloro-N-[3-methoxy-5-(4-morpholinylmethyl)-2-pyrazinyl]benzenesu-
lphonamide
##STR00226##
[1020] Prepared as for Example 107b using
2,3-dichloro-N-(5-formyl-3-methoxy-2-pyrazinyl)benzenesulphonamide
(Example 186a) (0.26 g) and morpholine (3.7 mL). Yield 0.057 g.
[1021] m/e 433 (M+1.sup.+, 100%).
[1022] .sup.1H NMR (D6-DMSO) .delta. 8.12 (1H, d), 7.94 (1H, d),
7.59 (1H, t), 4.20 (2H, s), 3.96 (3H, s), 3.85-3.65 (5H, m).
EXAMPLE 187
N-(3-Allyloxy-5-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
##STR00227##
[1024] Prepared by the method of Example 31 using allyl alcohol (10
mL) as solvent and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.35 g). Yield 0.32 g.
[1025] m/e 393 (M-1.sup.+, 100%).
[1026] .sup.1H NMR (D6-DMSO) .delta. 11.80 (1H, br s), 8.08 (1H,
dd), 7.96 (1H, dd), 7.82 (1H, dd), 7.58 (1H, t), 6.10-6.00 (1H, m),
5.49 (1H, dddd), 5.29 (1H, dddd), 4.86 (2H, dddd).
[1027] MP 145-146.degree. C.
EXAMPLE 188
2,3-Dichloro-N-[5-chloro-3-(2-propynyloxy)-2-pyrazinyl]benzenesulphonamide
##STR00228##
[1029] Prepared by the method of Example 31 using propargyl alcohol
(0.3 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.35 g). Yield 0.2 g.
[1030] m/e 390 (M-1.sup.+, 100%).
[1031] .sup.1H NMR (D6-DMSO) .delta. 8.08 (1H, dd), 7.95 (1H, dd),
7.86 (1H, s), 7.58 (1H, t), 5.02 (2H, d), 3.65 (1H, t).
[1032] MP 138-139.degree. C.
EXAMPLE 189
2,3-Dichloro-N-[3-(2-propynyloxy)-2-pyrazinyl)benzenesulphonamide
##STR00229##
[1034] Prepared by the method of Example 28 using propargyl alcohol
as solvent (3 mL),
2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example
28) (0.3 g) and sodium hydride (0.2 g of a 60% dispersion in oil)
at room temperature for 16 h. Yield 0.27 g.
[1035] m/e 356 (M-1.sup.+, 100%).
[1036] .sup.1H NMR (D6-DMSO) .delta. 11.67 (1H, br s), 8.10 (1H,
dd), 7.94 (1H, dd), 7.85 (1H, br), 7.72 (1H, br), 7.59 (1H, t),
5.01 (2H, d), 3.56 (1H, t).
[1037] MP 153-154.degree. C.
EXAMPLE 190
2,3-Dichloro-N-(5-cyano-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00230##
[1039] Prepared as for Example 78 using
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide
(Example 8) (0.1 g). Yield 0.034 g.
[1040] m/e 357 (M-1.sup.+, 100%).
[1041] .sup.1H NMR (D6-DMSO) .delta. 8.15 (1H, s), 8.14 (1H, dd),
7.95 (1H, dd), 7.59 (1H, t), 3.96 (3H, s).
[1042] MP 239-240.degree. C.
EXAMPLE 191
2,3-Dichloro-N-{3-methoxy-5-[(2S)-pyrrolidin-2-ylmethoxy]-2-pyrazinyl}benz-
enesulfonamide hydrochloride
##STR00231##
[1044] Procedure as for Example 115 using
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-({2-[(trimethylsilyl)oxy-
]ethoxy}methyl)benzenesulphonamide (Example 55a) (0.5 g),
tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.603
g) and sodium hydride (0.12 g of a 60% dispersion in oil) in
N-methylpyrrolidinone (20 mL). The adduct was deprotected with HCl
(4M in dioxane) to afford the titled adduct (0.241 g) as a white
solid.
[1045] m/e 433, 435 (M-HCl+.sup.+, 100%).
[1046] .sup.1H NMR (D6-DMSO) .delta. 10.92 (1H, s), 9.45 (1H, br),
8.93 (1H, br), 7.98 (1H, d), 7.93 (1H, d), 7.57 (1H, d), 7.52 (1H,
d), 4.53 (1H, dd), 4.37 (1H, dd), 3.94-3.86 (1H, m), 3.85 (3H, s),
3.22-3.18 (2H, m), 2.13-2.08 (1H, m), 1.99-1.86 (2H, m), 1.76-1.67
(1H, m).
EXAMPLE 192
2,3-Dichloro-N-{6-chloro-3-methoxy-5-[(2R)-2-pyrrolidinylmethoxy]-2-pyrazi-
nyl}benzenesulphonamide Hydrochloride
##STR00232##
[1048] Procedure as for Example 115 using
2,3-dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl-
)ethoxy]methyl}benzenesulphonamide (Example 66a) (0.29 g),
tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.15 g)
and sodium hydride (0.04 g of a 60% dispersion in oil) in
N-methylpyrrolidinone (20 mL). The adduct was deprotected with HCl
(4M in dioxane) to afford the titled adduct (0.2 g) as a white
solid.
[1049] m/e 464 (M+H.sup.+, 100%).
[1050] .sup.1H NMR (D6-DMSO) .delta. 11.24 (1H, br s), 9.46 (1H, br
s), 8.99 (1H, br s), 8.01 (1H, d), 7.96 (1H, d), 7.59 (1H, m), 4.61
(1H, dd), 4.46 (1H, dd), 3.95 (1H, br s), 3.85 (3H, s), 3.19 (2H,
br s), 2.16-2.07 (1H, br s), 2.03-1.94 (1H, br s), 1.92-1.85 (1H,
br s), 1.81-1.72 (1H, br s).
[1051] MP 200-204.degree. C.
EXAMPLE 193
2,3-Dichloro-N-[3-methoxy-5-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulpho-
namide Hydrochloride
##STR00233##
[1053] Procedure as for Example 115 using
N-(5-chloro-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-({2-[(trimethylsilyl)ox-
y]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.5 g),
pyridine-3-methanol (0.11 g) and sodium hydride (0.05 g of a 60%
dispersion in oil) in N-methylpyrrolidinone (5 mL). Yield 0.23
g.
[1054] m/e 438 (M-1.sup.+, 100%).
[1055] .sup.1H NMR (D6-DMSO) .delta. 10.9 (1H, br s), 8.7 (1H, br
s), 8.12 (1H, t), 7.99-7.92 (2H, m), 7.74 (1H, d), 7.61 (1H, s),
7.63-7.53 (2H, m), 5.54 (2H, s), 3.73 (3H, s).
[1056] MP 180-183.degree. C.
EXAMPLE 194
2,3-Dichloro-N-(3-methoxy-6-methyl-2-pyrazinyl)benzenesulphonamide
a) 3-Methoxy-6-methyl-2-pyrazinamine
##STR00234##
[1058] To a solution of 5-bromo-3-methoxy-6-methyl-2-pyrazinamine
(Example 118c) (0.8 g) and ammonium formate (0.4 g) in methanol (20
mL) was added palladium on carbon (0.2 g) and the reaction mixture
heated at reflux for 5 h. After cooling to room temperature, the
reaction mixture was filtered through a plug of celite, and the
filtrate evaporated. The residue was partitioned between
dichloromethane and water, and the organic phase dried
(MgSO.sub.4), filtered and evaporated to give the title compound as
a white solid (0.44 g).
[1059] .sup.1H NMR (D6-DMSO) .delta. 7.10 (1H, s), 6.15 (2H, br s),
3.83 (3H, s), 2.14 (3H, s).
b)
2,3-Dichloro-N-(3-methoxy-6-methyl-2-pyrazinyl)benzenesulphonamide
##STR00235##
[1061] A solution of 3-methoxy-6-methyl-2-pyrazinamine (Example
194a) (0.050 g) and 2,3-dichlorobenzenesulphonyl chloride (0.098 g)
in pyridine (0.3 mL) was stirred at room temperature for 18 h.
Solvent was evaporated to give a residue which was purified by
chromatography on silica gel eluting with dichloromethane/ethyl
acetate/acetic acid (200:4:1) giving the title compound as a pale
orange solid (0.071 g).
[1062] m/e 348/350 (M+H.sup.+, 100%).
[1063] .sup.1H NMR (D6-DMSO) .delta. 11.44 (1H, br s), 8.14 (1H,
dd), 7.92 (1H, dd), 7.65 (1H, br s), 7.61 (1H, t), 3.85 (3H, s),
2.07 (3H, br s).
[1064] MP 50-60.degree. C.
EXAMPLE 195
2,3-Dichloro-N-[3-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)-2-pyrazinyl]benz-
enesulphonamide
a)
2,3-Dichloro-N-[5-(hydroxymethyl)-3-methoxy-2-pyrazinyl]-N-{[2-(trimeth-
ylsilyl)ethoxy]methyl}benzenesulphonamide
##STR00236##
[1066] To a suspension of
2,3-dichloro-N-[5-(hydroxymethyl)-3-methoxy-2-pyrazinyl]-benzenesulphonam-
ide (1.0 g) in dichloromethane (100 mL) was added
diisopropylethylamine (0.57 mL) and 2-(trimethylsilyl)ethoxymethyl
chloride (0.58 mL). The reaction mixture was stirred at room
temperature for 0.5 h, then washed with water. The organic phase
was dried (MgSO.sub.4), filtered and evaporated to give a yellow
oil. This was purified by chromatography on silica gel eluting with
dichloromethane/ethyl acetate mixtures to give the title compound
as a colourless oil (0.8 g).
[1067] .sup.1H NMR (CDCl.sub.3) .delta. 8.04 (1H, s), 7.99 (1H, d),
7.66 (1H, d), 7.28 (1H, t), 5.27 (2H, s), 4.74 (2H, d), 3.90 (3H,
s), 3.78 (2H, m), 2.58 (1H, t), 0.85 (2H, m), 0.00 (9H, s).
b)
2,3-Dichloro-N-[3-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)-2-pyrazinyl]b-
enzenesulphonamide
##STR00237##
[1069] To a solution of
2,3-dichloro-N-[5-(hydroxymethyl)-3-methoxy-2-pyrazinyl]-N-{[2-(trimethyl-
silyl)ethoxy]methyl}benzenesulphonamide (Example 195a) (0.1 g) and
triethylamine (0.056 mL) in dichloromethane (5 mL) at 0.degree. C.
was added methanesulphonyl chloride (0.019 mL) and the reaction
mixture stirred at 0.degree. C. for 1 h and room temperature for 1
h. The solution was filtered through a plug of silica washing with
ethyl acetate and concentrated in vacuo to give a colourless oil
(0.082 g). This was dissolved in N,N-dimethylformamide (0.5 mL) and
1,2,4-triazole (0.013 g) and sodium carbonate (0.026 g) added. The
reaction mixture was heated at 60.degree. C. for 18 h, then
partitioned between ethyl acetate and saturated aqueous ammonium
chloride (5.times.). The organic phase was dried (MgSO.sub.4),
filtered and evaporated. The residue was dissolved in
trifluoroacetic acid (2 mL) and dichloromethane (2 mL). After 20
min, removal of solvent in vacuo gave a residue which was purified
by chromatography on silica gel eluting with ethyl acetate/acetic
acid mixtures to give the title compound a pale yellow solid (0.011
g).
[1070] m/e 413/415 (M-H.sup.-, 100%).
[1071] .sup.1H NMR (CDCl.sub.3) .delta. 8.27 (2H, m), 8.0 (1H, br
s), 7.94 (1H, s), 7.68 (1H, d), 7.58 (1H, br s), 7.41 (1H, t), 5.25
(2H, s), 3.97 (3H, s).
[1072] MP 95-105.degree. C.
EXAMPLE 196
N-(3-(5-Aminomethyl-2-furanylmethoxy)-5-chloro-2-pyrazinyl)-2,3-dichloro-b-
enzenesulphonamide
##STR00238##
[1074] Prepared by the method of Example 31 using
(5-aminomethyl-2-furanyl)methanol (0.2 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.3 g). Purified by silica gel chromatography eluting
with methanol/dichloromethane mixtures. Yield 0.1 g.
[1075] m/e 463 (M+1.sup.+, 100%).
[1076] .sup.1H NMR (D6-DMSO) .delta. 8.25 (2H, br s), 7.92 (1H,
dd), 7.61 (1H, dd), 7.35 (1H, t), 7.27 (1H, s), 6.66 (1H, d), 6.57
(1H, d), 5.19 (2H, s), 4.14 (2H, s).
[1077] MP 201-202.degree. C.
EXAMPLE 197
N-(3-(5-Aminomethyl-2-furanylmethoxy)-2-pyrazinyl)-2,3-dichlorobenzenesulp-
honamide
##STR00239##
[1079] Prepared by the method of Example 28 using
(5-aminomethyl-2-furanyl)methanol (0.2 g) and
2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (Example
28) (0.3 g). Purified by silica gel chromatography eluting with
methanol/dichloromethane mixtures. Yield 0.2 g.
[1080] m/e 427 (M-1.sup.+, 100%).
[1081] .sup.1H NMR (D6-DMSO) .delta. 8.40 (2H, br s), 7.96 (1H,
dd), 7.60 (1H, dd), 7.35 (1H, t), 7.24 (1H, d), 7.15 (1H, d), 6.64
(1H, d), 6.57 (1H, d), 5.20 (2H, s), 4.13 (2H, s).
[1082] MP 199-201.degree. C.
EXAMPLE 198
2,3-Dichloro-N-[3-methoxy-5-(2-propyn-1-yloxy)-2-pyrazinyl]benzenesulphona-
mide
##STR00240##
[1084] Procedure as for Example 115 using
2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-({2-[(trimethylsilyl)ox-
y]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.25 g),
propargyl alcohol (0.025 mL) and sodium hydride (0.035 g of a 60%
dispersion in oil) in N,N-dimethylformamide (5 mL). Yield 0.05
g.
[1085] m/e 388 (M+1.sup.+, 100%).
[1086] .sup.1H NMR (D6-DMSO) .delta. 10.90 (1H, s), 7.98-7.94 (2H,
m), 7.55 (1H, t), 7.51 (1H, s), 4.97 (2H, d), 3.85 (3H, s), 3.56
(1H, t).
[1087] MP 110-112.degree. C.
EXAMPLE 199
{[5-(2,3-Dichlorophenylsulfonylamino)-6-methoxy-2-pyrazinyl]oxy}acetic
acid, methyl ester
##STR00241##
[1089] Procedure as for Example 115 using
2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-({2-[(trimethylsilyl)ox-
y]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.26 g), methyl
glycolate (0.075 mL) and sodium hydride (0.035 g of a 60%
dispersion in oil) in N,N-dimethylformamide (5 mL). Yield 0.1 g
[1090] m/e 422 (M+1.sup.+, 100%).
[1091] .sup.1H NMR (D6-DMSO) .delta. 10.89 (1H, s), 7.99-7.92 (2H,
m), 7.58-7.53 (2H, m), 4.92 (2H, s), 3.75 (3H, s), 3.68 (3H,
s).
[1092] MP 185-190.degree. C.
EXAMPLE 200
N-[5-(2,3-Dichlorophenylsulphonylamino)-6-methoxy-2-pyrazinyl]-2-hydroxyac-
etamide
##STR00242##
[1094] Procedure as for Example 115 using
2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-N-({2-[(trimethylsilyl)ox-
y]ethoxy}methyl)benzenesulphonamide (Example 115a) (0.25 g),
glycolamide (0.066 g) and sodium hydride (0.035 g of a 60%
dispersion in oil) in N,N-dimethylformamide (5 mL). Yield 0.075
g.
[1095] m/e 407 (M+1.sup.+, 100%).
[1096] .sup.1H NMR (D6-DMSO) .delta. 11.23 (1H, br s), 9.77 (1H,
s), 8.36 (1H, s), 8.05 (1H, dd), 7.94 (1H, dd), 7.58 (1H, t), 4.04
(2H, s), 3.86 (3H, s).
[1097] MP 153-155.degree. C.
EXAMPLE 201
6-(2,3-Dichlorophenylsulphonylamino)-5-methoxy-2-pyrazinecarboxylic
acid, methyl ester
a) 6-chloro-3-methoxy-2-pyrazinamine
##STR00243##
[1099] A mixture of 5-bromo-6-chloro-3-methoxy-2-pyrazinamine
(Example 125a) (0.6 g), triethylamine (0.72 mL), 10% palladium on
carbon (0.05 g) and ethyl acetate (50 mL) were hydrogenated at 0.5
bar until reaction was complete as judged by hydrogen uptake. The
reaction mixture was filtered and washed with water (25 mL), dried
(MgSO.sub.4), filtered and evaporated to afford the sub-titled
compound (0.33 g). Used Directly.
b) 6-Amino-5-methoxypyrazine-2-carboxylic acid methyl ester
##STR00244##
[1101] Prepared as for Example 113 using
6-chloro-3-methoxy-2-pyrazinamine (Example 201a) (0.35 g) heated at
120.degree. C. for 3 h. Yield 0.3 g.
[1102] m/e 184 (M+1.sup.+, 100%).
c)
6-(2,3-Dichlorophenylsulphonylamino)-5-methoxy-2-pyrazinecarboxylic
acid, methyl ester
##STR00245##
[1104] Prepared by the method of Example 1 (reaction performed at
room temperature) using 6-amino-5-methoxypyrazine-2-carboxylic acid
methyl ester (Example 201b) (0.3 g) and
2,3-dichlorobenzenesulphonyl chloride (0.4 g). Yield 0.15 g.
[1105] m/e 392 (M+1.sup.+, 100%).
[1106] .sup.1H NMR (D6-DMSO) .delta. 8.39 (1H, s), 8.25 (1H, dd),
7.93 (1H, dd), 7.65 (1H, t), 3.99 (3H, s), 3.77 (3H, s).
[1107] MP 90-92.degree. C.
EXAMPLE 202
2,3-Dichloro-N-[6-(hydroxymethyl)-3-methoxy-2-pyrazinyl]benzenesulphonamid-
e
##STR00246##
[1109] Prepared as for example 120 using
6-(2,3-dichlorophenylsulphonylamino)-5-methoxy-2-pyrazinecarboxylic
acid, methyl ester (Example 201) (0.12 g). Yield 0.03 g.
[1110] m/e 364 (M+1.sup.+, 100%).
[1111] .sup.1H NMR (D6-DMSO) .delta. 11.5 (1H, br s), 8.13 (1H,
dd), 7.92 (1H, dd), 7.77 (1H, br s), 7.59 (1H, t), 5.25 (1H, br s),
4.19 (2H, s), 3.87 (3H, s).
[1112] MP 153-155.degree. C.
EXAMPLE 203
2,3-Dichloro-N-(5-methanesulphonyl-3-methoxy-2-pyrazinyl)benzenesulphonami-
de
##STR00247##
[1114] Oxone (potassium peroxymonosulphate) (0.6 g) was added to
2,3-dichloro-N-(3-methoxy-5-methylsulphanyl-2-pyrazinyl)benzenesulphonami-
de (Example 80) (0.3 g) in methanol (40 mL) and water (10 mL) and
the mixture heated at 50.degree. C. for 4 h. After cooling, the
mixture was filtered and evaporated. Purified by silica gel
chromatography eluting with ethyl acetate/iso-hexane mixtures
containing 1% acetic acid to give the title compound. Yield 0.2
g.
[1115] m/e 411 (M-1.sup.+, 100%).
[1116] .sup.1H NMR (CDCl.sub.3) .delta. 8.33 (1H, s), 8.30 (1H, s),
8.23 (1H, br s), 7.72 (1H, dd), 7.47 (1H, t), 4.14 (3H, s), 3.11
(3H, s).
[1117] MP 237-238.degree. C.
EXAMPLE 204
2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinyloxy]-N,N-die-
thyl-acetamide
##STR00248##
[1119] Prepared as for Example 115b using
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)et-
hoxy}methyl]benzenesulphonamide (Example 55a) (0.35 g) and
N,N-diethyl-2-hydroxyacetamide (0.13 g). Yield 0.2 g
[1120] m/e 463 (M+1.sup.+, 100%).
[1121] .sup.1H NMR (CDCl.sub.3) .delta. 8.22 (1H, dd), 7.68 (1H,
dd), 7.52 (1H, s), 7.46 (1H, s), 7.37 (1H, t), 4.88 (2H, s), 3.92
(3H, s), 3.38 (2H, q), 3.30 (2H, q), 1.20 (3H, t), 1.11 (3H,
t).
[1122] MP 117-118.degree. C.
EXAMPLE 205
2,3-Dichloro-N-{5-[2-(dimethylamino)ethylsulphanyl]-3-methoxy-2-pyrazinyl}-
benzenesulphonamide
##STR00249##
[1124] Prepared as for Example 101b using
N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-{[2-(trimethylsilanyl)et-
hoxy]methyl}benzenesulphonamide (Example 55a) (0.3 g) and
2-(dimethylamino)ethanthiol hydrochloride (0.2 g). Yield 0.25
g.
[1125] m/e 435 (M-1.sup.+, 100%).
[1126] .sup.1H NMR (D6-DMSO) .delta. 8.05 (1H, dd), 7.95 (1H, dd),
7.71 (1H, s), 7.58 (1H, t), 3.98 (3H, s), 3.47 (2H, m), 3.28 (2H,
m), 2.77 (6H, s).
[1127] MP 117-118.degree. C.
EXAMPLE 206
2,3-Dichloro-N-(5-difluoromethyl-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00250##
[1129] (Diethylamino)sulphur trifluoride (DAST) (0.15 g) and
2,3-dichloro-N-(5-formyl-3-methoxy-2-pyrazinyl)benzenesulphonamide
(Example 186a) (0.3 g) in dichloromethane (20 mL) was stirred at
room temperature for 4 h and then evaporated. Purified by silica
gel chromatography eluting with ethyl acetate/iso-hexane mixtures
to give the title compound. Yield 0.06 g.
[1130] m/e 382 (M-1.sup.+, 100%).
[1131] .sup.1H NMR (D6-DMSO) .delta. 8.14 (1H, dd), 7.96 (1H, dd),
7.84 (1H, s), 7.60 (1H, t), 6.80 (1H, t), 3.95 (3H, s).
[1132] MP 117-118.degree. C.
EXAMPLE 207
2,3-Dichloro-4-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00251##
[1134] Sodium hydride (0.4 g of a 60% dispersion in oil) was added
to a solution of 3-methoxy-2-pyrazinamine (0.25 g) in
N-methylpyrrolidinone (10 mL). After 0.5 h,
2,3-dichloro-4-fluorobenzenesulphonyl chloride (Example 185a) (0.63
g) was added. After 16 h at room temperature the reaction mixture
was quenched with 2M aqueous HCl, extracted with ethyl acetate,
dried (MgSO.sub.4) and evaporated. Purification was by silica gel
chromatography eluting with ethyl acetate/iso-hexane mixtures.
Yield 0.16 g.
[1135] m/e 350/352 (M-1.sup.-, 100%).
[1136] .sup.1H NMR (D6-DMSO) .delta. 8.16 (1H, dd), 7.78 (1H, br
s), 7.68 (1H, t), 7.62 (1H, br s), 3.9 (3H, s).
[1137] MP 192-194.degree. C.
EXAMPLE 208
2,3-Dichloro-N-{5-chloro-3-[1-(cyclopropyl)ethoxy]-2-pyrazinyl}benzenesulp-
honamide
##STR00252##
[1139] Prepared by the method of Example 31b using
1-(cyclopropyl)ethanol (0.1 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.1 g). Yield 0.04 g.
[1140] m/e 422 (M+1.sup.+, 100%).
[1141] .sup.1H NMR (D6-DMSO) .delta. 11.70-11.50 (1H, br s), 8.07
(1H, dd), 7.94 (1H, dd), 7.77 (1H, s), 7.59 (1H, t), 4.60-4.50 (1H,
m), 1.33 (3H, d), 1.1-1.0 (1H, m), 0.6-0.3 (4H, m).
[1142] MP 161-162.degree. C.
EXAMPLE 209
2,3-Dichloro-N-[5-chloro-3-(5-formyl-2-furanylmethoxy)-2-pyrazinyl]benzene-
sulphonamide
a) [5-(1,3-Dimethyl-2-imidazolidinyl)-2-furanyl]methanol
##STR00253##
[1144] 5-hydroxymethylfuran-2-carbaldehyde (5.0 g) and
N,N'-dimethylethane-1,2-diamine (3.8 g) in toluene (100 mL) was
heated under reflux using a Dean and Stark apparatus. After 12 h,
the toluene was evaporated to give an oil. Yield 8.3 g. Used
directly.
b)
2,3-Dichloro-N-[5-chloro-3-(5-formyl-2-furanylmethoxy)-2-pyrazinyl]benz-
enesulphonamide
##STR00254##
[1146] Prepared by the method of Example 31b (reaction heated at
60.degree. C. for 4 h) using
[5-(1,3-dimethyl-2-imidazolidinyl)-2-furanyl]methanol (2.3 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (3.0 g). The reaction was quenched with 2M
hydrochloric acid and left for 16 h. The solid product was
collected. Purified by silica gel chromatography eluting with ethyl
acetate/iso-hexane mixtures to give the title compound. Yield 2.5
g.
[1147] m/e 460 (M+1.sup.+, 100%).
[1148] .sup.1H NMR (D6-DMSO) .delta. 9.64 (1H, s), 8.06 (1H, dd),
7.94 (1H, dd), 7.87 (1H, s), 7.57 (2H, d+t), 6.93 (1H, d), 5.47
(2H, d).
EXAMPLE 210
2,3-Dichloro-N-[5-chloro-3-(5-cyclopropylaminomethyl-2-furanylmethoxy)-2-p-
yrazinyl]-benzenesulphonamide
##STR00255##
[1150] Prepared by the method of Example 107b using
2,3-dichloro-N-[5-chloro-3-(5-formyl-2-furanylmethoxy)-2-pyrazinyl]benzen-
esulphonamide (Example 209) (0.3 g) and cyclopropylamine (0.1 g).
Yield 0.1 g.
[1151] m/e 503 (M-1.sup.+, 100%).
[1152] .sup.1H NMR (D6-DMSO) .delta. 7.93 (1H, dd), 7.63 (1H, dd),
7.36 (1H, t), 7.30 (1H, s), 6.66 (1H, d), 6.63 (1H, d), 5.21 (2H,
s), 4.34 (2H, s), 2.71 (1H, m), 0.76 (4H, m).
[1153] MP 175-176.degree. C.
EXAMPLE 211
N-[5,6-bis-(Hydroxymethyl)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulph-
onamide
a)
2,3-Dichloro-N-(5,6-dicyano-3-methoxy-2-pyrazinyl)benzenesulphonamide
##STR00256##
[1155] Prepared by the method outlined in Example 1 using
5-amino-6-chloro-2,3-dicyanopyrazine (1.8 g) and
2,3-dichlorobenzenesulfonyl chloride (2.7 g). The adduct was
reacted by the method outlined in example 31b using sodium
methoxide to afford the sub-titled compound that was used
directly.
[1156] m/e 382, 383 (M-1.sup.+, 100%).
b) 5-{[(2,3-Di
chlorophenyl)sulphonyl]amino}-6-methoxypyrazine-2,3-dicarboxylic
acid, dimethyl ester
##STR00257##
[1158] The crude product from above (Example 211a) was dissolved in
10% aqueous sodium hydroxide solution and heated under reflux for
10 hours. The reaction mixture was cooled, concentrated and the
residue was treated with thionyl chloride (30 mL) and refluxed for
1 hour, cooled and concentrated, azeotroping with dry toluene. The
resulting residue was dissolved in methanol (30 mL) and allowed to
stand for 10 hours and concentrated to afford the sub-titled
compound that was used directly.
[1159] m/e 448, 450 (M-1.sup.+, 100%).
c)
N-[5,6-bis-(Hydroxymethyl)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesu-
lphonamide
##STR00258##
[1161] To a solution of
5-{[(2,3-dichlorophenyl)sulphonyl]amino}-6-methoxypyrazine-2,3-dicarboxyl-
ic acid, dimethyl ester (Example 211b, 0.5 g) dissolved in
anhydrous tetrahydrofuran (20 mL) at 0.degree. C. was added a
solution of lithium triethylborohydride (Super Hydride.RTM.) (5.55
mL of a 1M solution in tetrahydrofuran) and the resulting solution
was stirred for 1 hour. The reaction was quenched by the addition
of 1N hydrochloric acid (10 mL) and extracted into ethyl acetate
(2.times.20 mL). The combined extracts were dried (MgSO.sub.4),
filtered and concentrated to afford an oil that was purified by
chromatography on silica gel eluting with ethyl
acetate/dichloromethane mixtures to afford the titled compound
(0.201 g) as a foam.
[1162] m/e 392, 394 (M-1.sup.+, 100%).
[1163] .sup.1H NMR (CDCl.sub.3) .delta. 8.30 (1H, d), 7.91 (1H, br
s), 7.71 (1H, d), 7.46 (1H, t), 4.59 (2H, s), 4.50 (2H, s), 4.0
(3H, s).
EXAMPLE 212
N-[3-[(2-amino-4-oxazolyl)methoxy]-5-chloro-2-pyrazinyl]-2,3-dichlorobenze-
nesulphonamide
a) (4-Hydroxymethyl-2-oxazolyl)carbamic acid tent-butyl ester
##STR00259##
[1165] Prepared by the method of Example 120 using
2-{bis[(1,1-dimethylethoxy)carbonyl]amino}-4-oxazolcarboxylic acid,
ethyl ester (0.65 g) and sodium triethylborohydride (5.5 mL of a 1M
solution in tetrahydrofuran). Yield 0.24 g. Used directly.
b)
N-[3-[(2-amino-4-oxazolyl)methoxy]-5-chloro-2-pyrazinyl]-2,3-dichlorobe-
nzenesulphonamide
##STR00260##
[1167] Prepared by the method of Example 112 using
(4-hydroxymethyl-2-oxazolyl)carbamic acid tert-butyl ester (Example
212a) (0.12 g) and
2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide
(Example 74) (0.21 g). Purification was by silica gel
chromatography eluting with ethyl acetate/iso-hexane mixtures to
give the title compound with the BOC (tert-butyl carbonyl) attached
(0.11 g). This compound was dissolved in trifluoroacetic acid (1.5
mL) and dichloromethane (1.5 mL). After 2 h, the solution was
evaporated. Purification was by silica gel chromatography eluting
with ethyl acetate/iso-hexane mixtures to give the title compound.
Yield 0.08 g.
[1168] m/e 450 (M+1.sup.+, 100%).
[1169] .sup.1H NMR (D6-DMSO) .delta. 8.04 (1H, dd), 7.91 (1H, dd),
7.80 (1H, s), 7.55 (1H, t), 7.49 (1H, s), 6.71 (2H, br s), 5.10
(2H, s).
[1170] MP 137.degree. C.
Pharmacological Analysis
FMAT Whole Cell Binding Assay
Cells
[1171] CHO-K1 cells stably expressing the human recombinant CCR4
receptor (Euroscreen; Brussels, Belgium) were cultured in
NUT.MIX.F.sub.--12(HAM) medium with glutamax-1, containing 10%
(v/v) foetal bovine serum and 400 .mu.g ml.sup.-1 geneticin.
[1172] Cells were harvested at approximately 70% confluence by
treatment with a cell dissociation buffer, and seeded at
5.times.10.sup.3 cells/1000 culture medium into wells of a black
Costar clear-bottomed 96-well microtitre plates. Plates were
incubated overnight at 37.degree. C. in 5% CO.sub.2 and used the
following day.
Assay
[1173] Before use, the cell plates were washed twice with 100 .mu.l
Hanks balanced salt solution (HBSS). To each well was then added
650 of HBSS, 10 .mu.L of 10% DMSO in HBSS test compound and then 25
.mu.L of 2.8 nM FB-MDC (Applied Biosystems). This fluorescent probe
was prepared from a 10 .mu.M stock in 0.08% (v/v) TFA/16% (v/v)
acetonitrile, diluted into HBSS.
[1174] After two hours incubation in the dark at room temperature,
the plates were analysed in an FMAT8100 reader (Applied Biosystems)
to measure fluorescence that was associated with binding of FB-MDC
to the cells. Compound activity was determined as an pIC.sub.50
[log(concentration of compound that results in 50% inhibition)],
comparing fluorescence in control and background wells.
Typical Data
[1175] Fluorescence (ctrl)=1200 Fluorescence (bkg)=0
[1176] The compounds of the examples all have a pIC.sub.50 of
greater than 5.0.
[1177] Data for specific compounds is given below.
TABLE-US-00001 Mean Example 112 pIC.sub.50 9.5 Example 119
pIC.sub.50 7.2 Example 186 pIC.sub.50 6.2
* * * * *