U.S. patent application number 12/982435 was filed with the patent office on 2011-07-07 for novel compounds.
Invention is credited to Roger Bonnert, Stephen Brough, Andrew Davies, Timothy Luker, Thomas McInally, Ian Millichip, Garry Pairaudeau, Anil Patel, Rukhsana Rasul, Stephen Thom.
Application Number | 20110166117 12/982435 |
Document ID | / |
Family ID | 20290949 |
Filed Date | 2011-07-07 |
United States Patent
Application |
20110166117 |
Kind Code |
A1 |
Bonnert; Roger ; et
al. |
July 7, 2011 |
Novel Compounds
Abstract
The invention relates to substituted phenoxyacetic acids (I) as
useful pharmaceutical compounds for treating respiratory disorders,
pharmaceutical compositions containing them, and processes for
their preparation. ##STR00001##
Inventors: |
Bonnert; Roger;
(Loughborough, GB) ; Brough; Stephen;
(Loughborough, GB) ; Davies; Andrew;
(Loughborough, GB) ; Luker; Timothy;
(Loughborough, GB) ; McInally; Thomas;
(Loughborough, GB) ; Millichip; Ian;
(Loughborough, GB) ; Pairaudeau; Garry;
(Loughborough, GB) ; Patel; Anil; (Loughborough,
GB) ; Rasul; Rukhsana; (Loughborough, GB) ;
Thom; Stephen; (Loughborough, GB) |
Family ID: |
20290949 |
Appl. No.: |
12/982435 |
Filed: |
December 30, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10551783 |
Jul 7, 2006 |
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PCT/SE2004/000535 |
Apr 6, 2004 |
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12982435 |
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Current U.S.
Class: |
514/210.2 ;
514/210.01; 514/235.8; 514/256; 514/275; 514/311; 514/347; 514/522;
514/571; 544/122; 544/332; 544/335; 546/173; 546/293; 558/414;
562/435; 562/472 |
Current CPC
Class: |
A61P 3/10 20180101; A61P
35/00 20180101; A61P 37/04 20180101; C07C 217/80 20130101; C07C
311/29 20130101; C07D 207/02 20130101; A61P 9/00 20180101; A61P
9/12 20180101; A61P 11/02 20180101; A61P 19/02 20180101; A61P 25/28
20180101; A61P 25/00 20180101; A61P 31/12 20180101; A61P 37/02
20180101; C07C 235/42 20130101; A61P 11/06 20180101; C07D 233/52
20130101; A61P 13/08 20180101; A61P 7/02 20180101; A61P 11/14
20180101; A61P 13/02 20180101; A61P 17/02 20180101; A61P 17/04
20180101; C07D 307/80 20130101; C07D 417/04 20130101; A61P 1/00
20180101; C07C 69/94 20130101; C07C 2601/02 20170501; C07D 205/04
20130101; A61P 13/10 20180101; C07D 295/26 20130101; A61P 17/14
20180101; C07C 255/55 20130101; A61P 13/12 20180101; A61P 17/00
20180101; C07C 205/37 20130101; C07D 239/26 20130101; A61P 5/14
20180101; A61P 17/06 20180101; A61P 35/02 20180101; C07D 295/192
20130101; A61P 25/14 20180101; C07C 275/32 20130101; A61P 11/08
20180101; A61P 31/18 20180101; A61P 43/00 20180101; C07D 213/72
20130101; A61P 29/00 20180101; C07D 333/56 20130101; A61P 1/04
20180101; A61P 15/10 20180101; C07D 403/04 20130101; A61P 25/02
20180101; A61P 37/08 20180101; C07D 213/61 20130101; A61P 31/16
20180101; A61P 31/08 20180101; C07C 323/18 20130101; A61P 1/16
20180101; A61P 37/06 20180101; C07C 65/24 20130101; C07D 239/34
20130101; C07D 317/54 20130101; A61P 7/04 20180101; A61P 27/16
20180101; C07C 59/68 20130101; C07D 215/12 20130101; A61P 9/08
20180101; A61P 21/04 20180101; A61P 27/02 20180101; C07C 205/35
20130101; A61P 11/00 20180101; C07C 59/70 20130101; C07C 271/28
20130101; C07D 239/42 20130101; C07D 285/10 20130101; A61P 9/10
20180101; C07C 317/22 20130101; C07D 277/52 20130101 |
Class at
Publication: |
514/210.2 ;
562/472; 514/571; 546/173; 514/311; 558/414; 514/522; 562/435;
544/335; 514/256; 546/293; 514/347; 544/332; 514/275; 544/122;
514/235.8; 514/210.01 |
International
Class: |
A61K 31/506 20060101
A61K031/506; C07C 59/70 20060101 C07C059/70; A61K 31/192 20060101
A61K031/192; A61P 11/06 20060101 A61P011/06; A61P 11/02 20060101
A61P011/02; C07D 215/06 20060101 C07D215/06; A61K 31/47 20060101
A61K031/47; C07C 255/54 20060101 C07C255/54; A61K 31/277 20060101
A61K031/277; C07C 205/37 20060101 C07C205/37; C07D 239/26 20060101
C07D239/26; A61K 31/505 20060101 A61K031/505; C07D 213/71 20060101
C07D213/71; A61K 31/4418 20060101 A61K031/4418; C07D 239/42
20060101 C07D239/42; C07D 413/04 20060101 C07D413/04; A61K 31/5377
20060101 A61K031/5377; A61K 31/397 20060101 A61K031/397 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 7, 2003 |
SE |
0301010-5 |
Claims
1. A compound of formula (I) or a pharmaceutically acceptable salt
thereof: ##STR00183## in which: X is halogen, cyano, nitro,
S(O).sub.nR.sup.6 or C.sub.1-4alkyl which is substituted by one or
more halogen atoms; Y is selected from hydrogen, halogen, CN,
nitro, SO.sub.2R.sup.3, OR.sup.4, SR.sup.4, SOR.sup.3,
SO.sub.2NR.sup.4R.sup.5, CONR.sup.4R.sup.5, NR.sup.4R.sup.5,
NR.sup.6SO.sub.2R.sup.3, NR.sup.6CO.sub.2R.sup.6,
NR.sup.6COR.sup.3, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.1-6alkyl, the latter
four groups being optionally substituted by one or more
substituents independently selected from halogen, OR.sup.6 and
NR.sup.6R.sup.7, S(O).sub.nR.sup.6; where n is 0, 1 or 2; Z is aryl
or a ring A, where A is a six membered heterocyclic aromatic ring
containing one or more nitrogen atoms or may be a 6, 6 or 6,5 fused
bicycle containing one or more O, N, S atoms, the aryl or A rings
all being optionally substituted by one or more substituents
independently selected from hydrogen, halogen, CN, OH, SH, nitro,
COR.sup.S, CO.sub.2R.sup.6, SO.sub.2R.sup.9, OR.sup.9, SR.sup.9,
SOR.sup.9, SO.sub.2NR.sup.10R.sup.11, CONR.sup.16R.sup.11,
NR.sup.10R.sup.11, NHSO.sub.2R.sup.9, NR.sup.9SO.sub.2R.sup.9,
NR.sup.6CO.sub.2R.sup.6, NHCOR.sup.9, NR.sup.9COR.sup.9,
NR.sup.6CONR.sup.4R.sup.5, NR.sup.6SO.sub.2NR.sup.4R.sup.5, aryl,
heteroaryl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.3-C.sub.7 cycloalkyl or C.sub.1-6alkyl, the latter four
groups being optionally substituted by one or more substituents
independently selected from halogen, C.sub.3-C.sub.7 cycloalkyl,
OR.sup.6, NR.sup.6R.sup.7, S(O).sub.nR.sup.6 (where n is 0, 1 or
2), CONR.sup.6R.sup.7, NR.sup.6COR.sup.7, SO.sub.2NR.sup.6R.sup.7
and NR.sup.6SO.sub.2R.sup.7. R.sup.1 and R.sup.2 independently
represent a hydrogen atom, halogen, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.7 cycloalkyl or a
C.sub.1-6alkyl group, the latter four groups being optionally
substituted by one or more substituents independently selected from
halogen, C.sub.3-C.sub.7 cycloalkyl, NR.sup.6R.sup.7, OR.sup.6,
S(O).sub.nR.sup.6 (where n is 0, 1 or 2); or R.sup.1 and R.sup.2
together can form a 3-8 membered ring optionally containing one or
more atoms selected from O, S, NR.sup.6 and itself optionally
substituted by one or more C.sub.1-C.sub.3 alkyl or halogen;
R.sup.3 represents C.sub.3-C.sub.7 cycloalkyl or C.sub.1-6alkyl
which may be optionally substituted by one or more substituents
independently selected from halogen, C.sub.3-C.sub.7 cycloalkyl,
OR.sup.6 and NR.sup.6R.sup.7, S(O).sub.nR.sup.6 (where n=0, 1 or
2), CONR.sup.6R.sup.7, NR.sup.6COR.sup.7, SO.sub.2NR.sup.6R.sup.7
and NR.sup.6SO.sub.2R.sup.7; R.sup.4 and R.sup.5 independently
represent hydrogen, C.sub.3-C.sub.7 cycloalkyl or C.sub.1-6alkyl,
the latter two groups being optionally substituted by one or more
substituents independently selected from halogen, C.sub.3-C.sub.7
cycloalkyl, OR.sup.6 and NR.sup.6R.sup.7, S(O).sub.nR.sup.6 (where
n=0, 1 or 2), CONR.sup.6R.sup.7,
NR.sup.6COR.sup.7,SO.sub.2NR.sup.6R.sup.7 and
NR.sup.6SO.sub.2R.sup.7; or R.sup.4 and R.sup.5 together with the
nitrogen atom to which they are attached can form a 3-8 membered
saturated heterocylic ring optionally containing one or more atoms
selected from O, S(O).sub.n (where n=0, 1 or 2), NR.sup.8, and
itself optionally substituted by halogen or C.sub.1-3 alkyl;
R.sup.6 and R.sup.7 independently represents a hydrogen atom or
C.sub.1-C.sub.6 alkyl; R.sup.8 is hydrogen, C.sub.1-4 alkyl,
--COC.sub.1-C.sub.4 alkyl, CO.sub.2C.sub.1-C.sub.4alkyl or
CONR.sup.6C.sub.1-C.sub.4alkyl; R.sup.9 represents aryl,
heteroaryl, C.sub.3-C.sub.7 cycloalkyl or C.sub.1-6alkyl, the
latter two groups may be optionally substituted by one or more
substituents independently selected from halogen, C.sub.3-C.sub.7
cycloalkyl, aryl, heteroaryl OR.sup.6 and NR.sup.6R.sup.7,
S(O).sub.nR.sup.6 (where n=0, 1 or 2), CONR.sup.6R.sup.7,
NR.sup.6COR.sup.7, SO.sub.2NR.sup.6R.sup.7 and
NR.sup.6SO.sub.2R.sup.7; R.sup.10 and R.sup.11 independently
represent aryl or heteroaryl, hydrogen, C.sub.3-C.sub.7 cycloalkyl
or C.sub.1-6alkyl, the latter two groups being optionally
substituted by one or more substituents independently selected from
halogen, C.sub.3-C.sub.7 cycloalkyl, aryl, heteroaryl, OR.sup.6 and
NR.sup.6R.sup.7, S(O).sub.nR.sup.6 (where n=0, 1 or 2),
CONR.sup.6R.sup.7, NR.sup.6COR.sup.7, SO.sub.2NR.sup.6R.sup.7 and
NR.sup.6SO.sub.2R.sup.7; or R.sup.10 and R.sup.11 together with the
nitrogen atom to which they are attached can form a 3-8 membered
saturated heterocylic ring optionally containing one or more atoms
selected from O, S(O).sub.n (where n=0, 1 or 2), NR.sup.8, and
itself optionally substituted by halogen or C.sub.1-C.sub.3
alkyl.
2. A compound according to claim 1 in which X is halogen, cyano,
nitro, S(O).sub.nR.sup.6 or C.sub.1-4alkyl which is substituted by
one or more halogen atoms.
3. A compound according to claim 1 in which X is trifluoromethyl,
nitro, cyano or halogen.
4. A compound according to claim 1 in which Y is hydrogen, halogen
or C.sub.1-3alkyl.
5. A compound according to claim 1 in which Z is phenyl, pyridinyl,
pyrimidyl, naphthyl, quinolyl, benzo[b]thienyl or benzofuranyl each
optionally substituted with substituents as defined in claim 1.
6. A compound according to claim 1 in which Z is phenyl optionally
substituted with substituents as defined in claim 1.
7. A compound according to claim 1 in which both R.sup.1 and
R.sup.2 are hydrogen or one is hydrogen and the other is methyl or
ethyl or both are methyl.
8. A compound according to claim 1 selected from:
{[5-Chloro-4'-(ethylthio)biphenyl-2-yl]oxy}acetic acid,
{[5-Chloro-4'-(ethylsulfonyl)biphenyl-2-yl]oxy}acetic acid,
[(4',5-Dichlorobiphenyl-2-yl)oxy]acetic acid,
[(5-Chloro-4'-cyanobiphenyl-2-yl)oxy]acetic acid,
[(5-Chloro-4'-methoxybiphenyl-2-yl)oxy]acetic acid,
(4-Chloro-2-quinolin-8-ylphenoxy)acetic acid,
[(5-Chloro-3',4'-dimethoxybiphenyl-2-yl)oxy]acetic acid,
2'-(Carboxymethoxy)-5'-chlorobiphenyl-4-carboxylic acid,
{[5-Chloro-4'-(methylsulfonyl)biphenyl-2-yl]oxy}acetic acid,
{[5-Chloro-4'-(ethylsulfonyl)-2'-methylbiphenyl-2-yl]oxy}acetic
acid, [(5-Cyanobiphenyl-2-yl)oxy]acetic acid,
[(5-Nitrobiphenyl-2-yl)oxy]acetic acid,
{[4'-(Methylthio)-5-(trifluoromethyl)biphenyl-2-yl]oxy}acetic acid,
{[4'-(Methylsulfonyl)-5-(trifluoromethyl)biphenyl-2-yl]oxy}acetic
acid,
{[4'-(Ethylsulfonyl)-2'-methyl-5-(trifluoromethyl)biphenyl-2-yl]oxy}aceti-
c acid, (4-Chloro-2-pyrimidin-5-ylphenoxy)acetic acid,
{2-[5-(Aminosulfonyl)pyridin-2-yl]-4-chlorophenoxy}acetic acid,
[2-(2-Aminopyrimidin-5-yl)-4-chlorophenoxy]acetic acid,
trifluoroacetate salt,
[4-Chloro-2-(4-methyl-2-morpholin-4-ylpyrimidin-5-yl)phenoxy]acetic
acid, {4-Chloro-2-[2-(dimethylamino)pyrimidin-5-yl]phenoxy}acetic
acid, [4-Chloro-2-(2-morpholin-4-ylpyrimidin-5-yl)phenoxy]acetic
acid, {4-Chloro-2-[2-(methylamino)pyrimidin-5-yl]phenoxy}acetic
acid, {2-[2-(Benzylamino)pyrimidin-5-yl]-4-chlorophenoxy}acetic
acid, [4-Chloro-2-(2-piperidin-1-ylpyrimidin-5-yl)phenoxy]acetic
acid,
(4-Chloro-2-{2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}phenoxy)acetic
acid,
[[2',5-Dichloro-4'-(ethylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[2'-Chloro-4'-(ethylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-
-yl]oxy]-acetic acid,
[[5-Chloro-4'-(ethylsulfonyl)-2'-fluoro[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[4'-(Ethylsulfonyl)-2'-fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-
-yl]oxy]-acetic acid,
[[5-Chloro-4'-(ethylsulfonyl)-2'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]ox-
y]-acetic acid,
2-[[5-Chloro-4'-(ethylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-propanoic
acid,
2-[[4'-(Ethylsulfonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]-
oxy]-(2S)-propanoic acid,
2-[[4'-(Ethylsulfonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]-
oxy]-(2R)-propanoic acid,
2-[[2',5-Dichloro-4'-(ethylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-propan-
oic acid,
2-[[2'-Chloro-4'-(ethylsulfonyl)-5-(trifluoromethyl)[1,1'-biphen-
yl]-2-yl]oxy]-(2S)-propanoic acid,
2-[[4'-(Ethylsulfonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]-
oxy]-2-methyl-propanoic acid,
2-[[4'-(Ethylsulfonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]-
oxy]-butanoic acid,
[4-Chloro-2-[2-[(methylsulfonyl)(phenylmethyl)amino]-5-pyrimidinyl]phenox-
y]-acetic acid,
[4-Chloro-2-[2-[(ethylsulfonyl)(phenylmethyl)amino]-5-pyrimidinyl]phenoxy-
]-acetic acid,
[2-[2-[Acetyl(phenylmethyl)amino]-5-pyrimidinyl]-4-chlorophenoxy]-acetic
acid,
[[4'-(Ethylsulfonyl)-5-fluoro-2'-methyl[1,1'-biphenyl]-2-yl]oxy]-ac-
etic acid,
[[4'-(Ethylsulfonyl)-4,5-difluoro-2'-methyl[1,1'-biphenyl]-2-yl-
]oxy]-acetic acid,
[[4'-(Ethylsulfonyl)-3,5-difluoro-2'-methyl[1,1'-biphenyl]-2-yl]oxy]-acet-
ic acid,
[2-(2-Amino-5-methyl-3-pyridinyl)-4-(trifluoromethyl)phenoxy]-ace-
tic acid,
[[4'-Amino-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy-
]-acetic acid,
[[4'-Amino-2'-chloro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[2'-Chloro-4'-hydroxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-
-acetic acid,
[2-(2,4-Dimethoxy-5-pyrimidinyl)-4-(trifluoromethyl)phenoxy]-acetic
acid,
[[2'-Chloro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid, [[2',5-Bis(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[5'-Fluoro-2'-methoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-aceti-
c acid,
[[5'-Cyano-2'-methoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-
-acetic acid,
[[4'-Chloro-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[2',5'-Dimethyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-aceti-
c acid,
[[5'-Chloro-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-
-acetic acid,
[[2'-Fluoro-6'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[4'-Fluoro-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]--
acetic acid,
[[4'-[[(Ethylamino)carbonyl]amino]-2'-methyl-5-(trifluoromethyl)[1,1'-bip-
henyl]-2-yl]oxy]-acetic acid,
[[2'-Methyl-4'-[[(methylamino)carbonyl]amino]-5-(trifluoromethyl)[1,1'-bi-
phenyl]-2-yl]oxy]-acetic acid,
[[4'-[[(Cyclopropylamino)carbonyl]amino]-2'-methyl-5-(trifluoromethyl)[1,-
1'-biphenyl]-2-yl]oxy]-acetic acid,
[[2'-Methyl-4'-[[(propylamino)carbonyl]amino]-5-(trifluoromethyl)[1,1'-bi-
phenyl]-2-yl]oxy]-acetic acid,
[[2',4'-Dimethyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[5'-Fluoro-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]--
acetic acid,
[[4'-(Aminocarbonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]ox-
y]-acetic acid,
[[3'-Fluoro-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[2',5'-Difluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-aceti-
c acid,
[[5'-(Aminosulfonyl)-2'-chloro-5-(trifluoromethyl)[1,1'-biphenyl]--
2-yl]oxy]-acetic acid,
[[4'-Cyano-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[4'-Chloro-2'-fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]--
acetic acid,
[[2',5'-Difluoro-4'-methoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]--
acetic acid,
[[2'-fluoro-5'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[2'-Fluoro-4'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]--
acetic acid,
[[4'-Methoxy-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-aceti-
c acid,
[[4'-(Aminosulfonyl)-2',5'-difluoro-5-(trifluoromethyl)[1,1'-biphe-
nyl]-2-yl]oxy]-acetic acid,
[2-Benzo[b]thien-3-yl-4-(trifluoromethyl)phenoxy]-acetic acid,
[2-(2-Benzofuranyl)-4-(trifluoromethyl)phenoxy]-acetic acid,
[[4'-Chloro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[3'-(1-Methylethyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[3',4'-Difluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-aceti-
c acid,
[2-(1,3-Benzodioxol-5-yl)-4-(trifluoromethyl)phenoxy]-acetic acid,
[[4'-Ethyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[3'-Fluoro-5-(trifluoromethyl)[1,1':4',1''-terphenyl]-2-yl]oxy]-acetic
acid,
[[4'-(Trifluoromethoxy)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy-
]-acetic acid,
[[2',3'-Dichloro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[4'-(1,1-Dimethylethyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]ox-
y]-acetic acid,
[2-(6-Methoxy-2-naphthalenyl)-4-(trifluoromethyl)phenoxy]-acetic
acid,
[[4'-(Ethylthio)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[4'-Acetyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[2-(2-Chloro-5-methyl-4-pyridinyl)-4-(trifluoromethyl)phenoxy]-acet-
ic acid,
[[5'-(Aminosulfonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-
-2-yl]oxy]-acetic acid,
[2-(8-Quinolinyl)-4-(trifluoromethyl)phenoxy]-acetic acid,
[[3'-Cyano-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[2-[4-Methyl-6-[methyl(methylsulfonyl)amino]-3-pyridinyl]-4-(trifluoromet-
hyl)phenoxy]-acetic acid,
[[2'-Methyl-5'-(methylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]o-
xy]-acetic acid,
2'-(Carboxymethoxy)-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxylic
acid, 3-methyl ester,
2'-(Carboxymethoxy)-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic
acid, 2-methyl ester,
[[5-(Trifluoromethyl)[1,1':4',1''-terphenyl]-2-yl]oxy]-acetic acid,
[[3'-Fluoro-2',4'-dimethyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-a-
cetic acid,
[[2'-Nitro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[2'-Methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[3'-Chloro-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]--
acetic acid,
[[5-(Trifluoromethyl)[1,1':3',1''-terphenyl]-2-yl]oxy]-acetic acid,
2'-(Carboxymethoxy)-5'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxyl-
ic acid, 4-methyl ester,
[[4'-Nitro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[5-(Trifluoromethyl)-3'-[(trifluoromethyl)thio][1,1'-biphenyl]-2-yl]oxy]-
-acetic acid,
[[5-(Trifluoromethyl)-4'-[(trifluoromethyl)thio][1,1'-biphenyl]-2-yl]oxy]-
-acetic acid,
[[4'-Methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[4'-Fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[3'-Fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[3'-Methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid, [2-(3-Pyridinyl)-4-(trifluoromethyl)phenoxy]-acetic acid,
[[2'-Fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[2'-Methoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[3'-Methoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[4'-Methoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[3'-(Ethylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[3'-Propoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[4'-Propoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[2-(2-Amino-4-methyl-5-pyrimidinyl)-4-(trifluoromethyl)phenoxy]-ace-
tic acid,
[[4'-Cyano-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid, [[4',5-Bis(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid, [2-(2-Naphthalenyl)-4-(trifluoromethyl)phenoxy]-acetic acid,
[[4'-(1-Pyrrolidinylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy-
]-acetic acid,
[[4'-[(Dimethylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]ox-
y]-acetic acid,
[[4'-[[(Phenylmethyl)amino]sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-2-
-yl]oxy]-acetic acid,
[[4'-[[(2,2,2-Trifluoroethyl)amino]sulfonyl]-5-(trifluoromethyl)[1,1'-bip-
henyl]-2-yl]oxy]-acetic acid,
[[4'-[[(5-Methyl-2-thiazolyl)amino]sulfonyl]-5-(trifluoromethyl)[1,1'-bip-
henyl]-2-yl]oxy]-acetic acid,
[[4'-[(Phenylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-
-acetic acid,
[[4'-[(Diethylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy-
]-acetic acid,
[[4'-[(Cyclopropylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl-
]oxy]-acetic acid,
[[4'-(Aminosulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid,
[[4'-[(Methylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-2-y-
l]oxy]-acetic acid,
[[4'-[(4-Methyl-1-piperazinyl)sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl-
]-2-yl]oxy]-acetic acid,
[2-[4-Methyl-2-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-5-pyrimid-
inyl]-4-(trifluoromethyl)phenoxy]-acetic acid,
[2-[4-Methyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-4-(trifluorom-
ethyl)phenoxy]-acetic acid,
[2-[2-(1,1-Dioxido-2-isothiazolidinyl)-4-methyl-5-pyrimidinyl]-4-(trifluo-
romethyl)phenoxy]-acetic acid, ammonium salt,
[2-[2-(3-Hydroxy-1-azetidinyl)-4-methyl-5-pyrimidinyl]-4-(trifluoromethyl-
)phenoxy]-acetic acid,
[2-[4-Methyl-2-(4-methyl-1-piperazinyl)-5-pyrimidinyl]-4-(trifluoromethyl-
)phenoxy]-acetic acid,
[2-[4-Methyl-2-(1-pyrrolidinyl)-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy-
]-acetic acid,
[2-[2-(Dimethylamino)-4-methyl-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy]-
-acetic acid,
[2-[5-Methyl-2-[methyl(methylsulfonyl)amino]-4-pyrimidinyl]-4-(trifluorom-
ethyl)phenoxy]-acetic acid,
[2-[2-[[(Dimethylamino)sulfonyl]amino]-4-methyl-5-pyrimidinyl]-4-(trifluo-
romethyl)phenoxy]-acetic acid,
[[2'-Chloro-4'-[(methoxycarbonyl)amino]-5-(trifluoromethyl)[1,1'-biphenyl-
]-2-yl]oxy]acetic acid
[[2'-Chloro-4'-(methylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]o-
xy]-(2S)-propanoic acid,
2-[[3'-Cyano-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-propanoic
acid,
2-[[4'-[(Dimethylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-
-2-yl]oxy]-(2S)-propanoic acid,
2-[[2'-Chloro-4'-[(dimethylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-biphe-
nyl]-2-yl]oxy]-(2S)-propanoic acid,
2-[[2'-Fluoro-4'-(methylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl-
]oxy]-(2S)-propanoic acid,
[[2',5-Dichloro-4'-(methylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-propano-
ic acid,
[[5-Chloro-4'-[(dimethylamino)sulfonyl][1,1'-biphenyl]-2-yl]oxy]--
(2S)-propanoic acid,
[[2',5-Dichloro-4'-[(dimethylamino)sulfonyl][1,1'-biphenyl]-2-yl]oxy]-(2S-
)-propanoic acid,
[(5-Chloro-3'-cyano[1,1'-biphenyl]-2-yl)oxy]-(2S)-propanoic acid,
[[5-Chloro-4'-[(dimethylamino)sulfonyl]-2'-fluoro[1,1'-biphenyl]-2-yl]oxy-
]-(2S)-propanoic acid,
[[5-Chloro-4'-(4-morpholinylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-propa-
noic acid,
[[5-Chloro-2'-fluoro-4'-(methylsulfonyl([1,1'-biphenyl]-2-yl]ox-
y]-(2S)-propanoic acid,
2-[[4'-(1-Azetidinylsulfonyl)-5-chloro[1,1'-biphenyl]-2-yl]oxy]-(2S)-prop-
anoic acid,
2-[[5-Chloro-2'-methyl-4'-(1-pyrrolidinylcarbonyl)[1,1'-biphenyl]-2-yl]ox-
y]-(2S)-propanoic acid,
2-[(2',4'-Dichloro-5-cyano[1,1'-biphenyl]-2-yl)oxy]-(2S)-propanoic
acid,
2-[[5-Cyano-2'-fluoro-4'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)--
propanoic acid,
2-[(3'-Cyano-5-fluoro[1,1'-biphenyl]-2-yl)oxy]-(2S)-propanoic acid,
sodium salt,
2-[(2',4'-Dichloro-5-fluoro[1,1'-biphenyl]-2-yl)oxy]-(2S)-propanoic
acid, sodium salt,
2-[[2'-Chloro-5-fluoro-4'-(methylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)--
propanoic acid
2-[[2'-Chloro-5-fluoro-5'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-
-propanoic acid,
[[4'-(Ethylsulfonyl)-6-methyl-5-nitro[1,1'-biphenyl]-2-yl]oxy]acetic
acid,
[[5-Chloro-4'-(ethylsulfonyl)-6-methyl[1,1'-biphenyl]-2-yl]oxy]acet-
ic acid,
[[4'-(Methylsulfonyl)-2',5-bis(trifluoromethyl)[1,1'-biphenyl]-2--
yl]oxy]acetic acid,
2-[4-Chloro-2-[4-methyl-6-[methyl(methylsulfonyl)amino]-3-pyridinyl]pheno-
xy]-(2S)-propanoic acid,
2-[2-[4-Methyl-2-[(methylsulfonyl)amino]-5-pyrimidinyl]-4-(trifluoromethy-
l)phenoxy]-(2S)-propanoic acid,
[(5-Chloro-3'-cyano[1,1'-biphenyl]-2-yl)oxy]-acetic acid, and
pharmaceutically acceptable salts thereof.
9. (canceled)
10. A method of treating a disease mediated by prostaglandin D2,
which comprises administering to a patient a therapeutically
effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt as defined in claim 1.
11. A method of treating a respiratory disease, such as asthma and
rhinitis, 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 defined in
claim 1.
Description
[0001] The present invention relates to substituted phenoxyacetic
acids as useful pharmaceutical compounds for treating respiratory
disorders, pharmaceutical compositions containing them, and
processes for their preparation.
[0002] EPA 1 170 594 discloses methods for the identification of
compounds useful for the treatment of disease states mediated by
prostaglandin D2, a ligand for orphan receptor CRTH2. GB 1356834
discloses a series of compounds said to possess anti-inflammatory,
to analgesic and antipyretic activity. It has been found that
certain phenoxyacetic acids are active at the CRTH2 receptor, and
as a consequence are expected to be potentially useful for the
treatment of various respiratory diseases, including asthma and
COPD.
[0003] In a first aspect the invention therefore provides a
compound of formula (I) or a is pharmaceutically acceptable salt or
solvate thereof:
##STR00002##
in which: X is halogen, cyano, nitro, S(O).sub.nR.sup.6 or
C.sub.1-4alkyl which is substituted by one or more halogen atoms; Y
is selected from hydrogen, halogen, CN, nitro, SO.sub.2R.sup.3,
OR.sup.4, SR.sup.4, SOR.sup.3, SO.sub.2NR.sup.4R.sup.5,
CONR.sup.4R.sup.5, NR.sup.4R.sup.5, NR.sup.6SO.sub.2R.sup.3,
NR.sup.6CO.sub.2R.sup.6, NR.sup.6COR.sup.3, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.7 cycloalkyl or
C.sub.1-6alkyl, the latter four groups being optionally substituted
by one or more substituents independently selected from halogen,
OR.sup.6 and NR.sup.6R.sup.7, S(O).sub.nR.sup.6 where n is 0, 1 or
2; Z is aryl or a ring A, where A is a six membered heterocyclic
aromatic ring containing one or more nitrogen atoms or may be a 6,
6 or 6,5 fused bicycle containing one or more O, N, S atoms, the
aryl or A rings all being optionally substituted by one or more
substituents independently selected from hydrogen, halogen, CN, OH,
SH, nitro, COR.sup.S, CO.sub.2R.sup.6, SO.sub.2R.sup.9, OR.sup.9,
SR.sup.9, SOR.sup.9, SO.sub.2NR.sup.10R.sup.11,
CONR.sup.10R.sup.11, NR.sup.10R.sup.11, NHSO.sub.2R.sup.9,
NR.sup.9SO.sub.2R.sup.9, NR.sup.6CO.sub.2R.sup.6, NHCOR.sup.9,
NR.sup.9COR.sup.9, NR.sup.6CONR.sup.4R.sup.5,
NR.sup.6SO.sub.2NR.sup.4R.sup.5, aryl, heteroaryl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.7 cycloalkyl or
C.sub.1-6alkyl, the latter four groups being optionally substituted
by one or more substituents independently selected from halogen,
C.sub.3-C.sub.7 cycloalkyl, OR.sup.6, NR.sup.6R.sup.7,
S(O).sub.nR.sup.6 (where n is 0, 1 or 2), CONR.sup.6R.sup.7,
NR.sup.6COR.sup.7, SO.sub.2NR.sup.6R.sup.7 and
NR.sup.6SO.sub.2R.sup.7.
[0004] to R.sup.1 and R.sup.2 independently represent a hydrogen
atom, halogen, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.3-C.sub.7 cycloalkyl or a C.sub.1-6alkyl group, the latter
four groups being optionally substituted by one or more
substituents independently selected from halogen, C.sub.3-C.sub.7
cycloalkyl, NR.sup.6R.sup.7, OR.sup.6, S(O).sub.nR.sup.6 (Where n
is 0, 1 or 2);
or
[0005] R.sup.1 and R.sup.2 together can form a 3-8 membered ring
optionally containing one or more atoms selected from O, S,
NR.sup.6 and itself optionally substituted by one or more
C.sub.1-C.sub.3 alkyl or halogen;
[0006] R.sup.3 represents C.sub.3-C.sub.7 cycloalkyl or
C.sub.1-6alkyl which may be optionally substituted by one or more
substituents independently selected from halogen, C.sub.3-C.sub.7
cycloalkyl, OR.sup.6 and NR.sup.6R.sup.7, S(O).sub.nR.sup.6 (where
n=0, 1 or 2), CONR.sup.6R.sup.7, NR.sup.6COR.sup.7,
SO.sub.2NR.sup.6R.sup.7 and NR.sup.6SO.sub.2R.sup.7;
[0007] R.sup.4 and R.sup.5 independently represent hydrogen,
C.sub.3-C.sub.7 cycloalkyl or C.sub.1-6alkyl, the latter two groups
being optionally substituted by one or more substituents
independently selected from halogen, C.sub.3-C.sub.7 cycloalkyl,
OR.sup.6 and NR.sup.6R.sup.7, S(O).sub.nR.sup.6 (where n=0, 1 or
2), CONR.sup.6R.sup.7, NR.sup.6COR.sup.7, SO.sub.2NR.sup.6R.sup.7
and NR.sup.6SO.sub.2R.sup.7;
or
[0008] R.sup.4 and R.sup.5 together with the nitrogen atom to which
they are attached can form a 3-8 membered saturated heterocylic
ring optionally containing one or more atoms selected from O,
S(O).sub.n (where n=0, 1 or 2), NR.sup.8, and itself optionally
substituted by halogen or C.sub.1-3 alkyl;
[0009] R.sup.6 and R.sup.7 independently represents a hydrogen atom
or C.sub.1-C.sub.6 alkyl;
[0010] R.sup.8 is hydrogen, C.sub.1-4 alkyl, --COC.sub.1-C.sub.4
alkyl, CO.sub.2C.sub.1-C.sub.4alkyl or
CONR.sup.6C.sub.1-C.sub.4alkyl;
[0011] R.sup.9 represents aryl, heteroaryl, C.sub.3-C.sub.7
cycloalkyl or C.sub.1-6alkyl, the latter two groups may be
optionally substituted by one or more substituents independently
selected from halogen, C.sub.3-C.sub.7 cycloalkyl, aryl, heteroaryl
OR.sup.6 and NR.sup.6R.sup.7, S(O).sub.nR.sup.6 (where n=0, 1 or
2), CONR.sup.6R.sup.7, NR.sup.6COR.sup.7, SO.sub.2NR.sup.6R.sup.7
and NR.sup.6SO.sub.2R.sup.7;
[0012] R.sup.10 and R.sup.11 independently represent aryl or
heteroaryl, hydrogen, C.sub.3-C.sub.7 cycloalkyl or C.sub.1-6alkyl,
the latter two groups being optionally substituted by one or more
substituents independently selected from halogen, C.sub.3-C.sub.7
cycloalkyl, aryl, heteroaryl, OR.sup.6 and NR.sup.6R.sup.7, to
S(O).sub.nR.sup.6 (where n=0, 1 or 2), CONR.sup.6R.sup.7,
NR.sup.6COR.sup.7, SO.sub.2NR.sup.6R.sup.7 and
NR.sup.6SO.sub.2R.sup.7;
or
[0013] R.sup.10 and R.sup.11 together with the nitrogen atom to
which they are attached can form a 3-8 is membered saturated
heterocylic ring optionally containing one or more atoms selected
from O, S(O).sub.n (where n=0, 1 or 2), NR.sup.8, and itself
optionally substituted by halogen or C.sub.1-C.sub.3 alkyl.
[0014] Examples of aryl include phenyl and naphthyl.
[0015] Heteroaryl is defined as a 5-7 member aromatic ring or can
be 6,6- or 6,5-fused bicyclic ring optionally containing one or
more heteroatoms selected from N, S and O. The bicyclic ring may be
linked through carbon or nitrogen and may be attached through the 5
or 6 membered ring and can be fully or partially saturated.
[0016] Examples include pyridine, pyrimidine, thiazole, oxazole,
pyrazole, imidazole, furan, isoxazole, pyrrole, isothiazole and
azulene, naphthyl, indene, quinoline, isoquinoline, indole,
indolizine, benzo[b]furan, benzo[b]thiophene, 1H-indazole,
benzimidazole, benzthiazole, benzoxazole, purine, 4H-quinolizine,
cinnoline, phthalazine, quinazoline, quinoxaline,
1,8-naphthyridine, pteridine, quinolone and 1,2-methylenedioxy
benzene.
[0017] Aryl or heteroaryl groups can be optionally substituted by
one or more substituents independently selected from hydrogen,
halogen, CN, OH, SH, nitro, CO.sub.2R.sup.6, SO.sub.2R.sup.9,
OR.sup.9, SR.sup.9, SOR.sup.9, SO.sub.2NR.sup.10R.sup.11,
CONR.sup.10R.sup.11, NR.sup.10R.sup.11, NHSO.sub.2R.sup.9,
NR.sup.9SO.sub.2R.sup.9, NR.sup.6CO.sub.2R.sup.6, NHCOR.sup.9,
NR.sup.9COR.sup.9, aryl, heteroaryl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alynyl, C.sub.3-C.sub.7 cycloalkyl or
C.sub.1-6alkyl, the latter four groups being optionally substituted
by one or more substituents independently selected from halogen,
C.sub.3-C.sub.7 cycloalkyl, OR.sup.6, NR.sup.6R.sup.7,
S(O).sub.nR.sup.6 (where n is 0, 1 or 2), CONR.sup.6R.sup.7,
NR.sup.6COR.sup.7, SO.sub.2NR.sup.6R.sup.7 and
NR.sup.6SO.sub.2R.sup.7. Substituents can be present at any
suitable position, including appropriate substituents on nitrogen
atoms.
[0018] The group A is a six membered heterocyclic ring containing
one or more nitrogen atoms or may be a 6, 6 or 6,5 fused bicycle
containing one or more O, N, S atoms. Examples of suitable rings
include pyridine, pyrimidine, pyrazine, pyridazine, indole,
quinoline, isoquinoline, benzimidazole, benzthiazole, benzofuran,
benzoxazole, benzthiophene, phthalazine and quinazoline.
[0019] In the context of the present specification, unless
otherwise indicated, an alkyl or alkenyl group or an alkyl or
alkenyl moiety in a substituent group may be linear or
branched.
[0020] Heterocyclic rings as defined for R.sup.4, R.sup.5 and
R.sup.10 and R.sup.11 means saturated heterocycles, examples
include morpholine, azetidine, pyrrolidine, piperidine and
piperazine. Substituents can be present on carbon and appropriate
nitrogen atoms of said rings.
[0021] Preferably X is trifluoromethyl, nitro, cyano or halogen.
More preferably X is is trifluoromethyl, nitro, cyano, chloro or
fluoro, even more preferably X is trifluoromethyl, chloro or
fluoro. Most preferably X is trifluoromethyl or chloro.
[0022] Preferably Y is hydrogen, halogen or C.sub.1-3alkyl. More
preferably Y is hydrogen, fluoro or methyl. Most preferably Y is
hydrogen.
[0023] Preferably Z is phenyl, pyridinyl, pyrimidyl, naphthyl,
quinolyl, benzo[b]thienyl or benzofuranyl each optionally
substituted as defined above, more preferably phenyl optionally
substituted as defined above. Preferred substituents for all Z
groups include those substituents exemplified herein, in particular
halogen, C.sub.1-3alkyl, cyano, SO.sub.2R.sup.9, OR.sup.9,
SR.sup.9, CO.sub.2R.sup.6, NHSO.sub.2R.sup.9,
NR.sup.9SO.sub.2R.sup.9 and SO.sub.2NR.sup.10R.sup.11.
[0024] More preferably when Z is phenyl it is optionally
substituted by one to three, preferably one or two, substituents
selected from SEt, SO.sub.2Me, SO.sub.2Et, chloro, fluoro, cyano,
methoxy, propoxy, CO.sub.2H, methyl, ethyl, propyl, butyl, amino,
hydroxyl, NHCONHEt, NHCONHMe, NHCONHPr, NHCONH-cyclopropyl,
CONH.sub.2, SO.sub.2NH.sub.2, OCF.sub.3, COMe, CO.sub.2Me, nitro,
phenyl, SCF.sub.3, 1-pyrrolidinylsulphonyl, dimethylaminosulphonyl,
((phenylmethyl)amino)sulphonyl,
[(2,2,2-trifluoroethyl)]amino]sulphonyl,
[(5-methyl-2-thiazolyl)amino]sulphonyl,
(phenylamino)sulphonyl,(diethylamino)sulphonyl,
(cyclopropylamino)sulphonyl, aminosulphonyl,
(methylamino)sulphonyl, (4-methyl-1-piperazinypsulphonyl,
NHCO.sub.2Me, (dimethylamino)sulphonyl, 4-morpholinylsulphonyl,
1-azetidinylsulphonyl, and 1-pyrrolidinylcarbonyl.
[0025] More preferably when Z is pyridyl it is optionally
substituted by one or two groups selected from SO.sub.2NH.sub.2,
methyl, amino, chloro and NMeSO.sub.2Me.
[0026] More preferably when Z is pyrimidine it is optionally
substituted by one or two groups selected from amino, methyl,
morpholinyl, dimethylamino, methylamino, benzylamino, piperidine,
NMeSO.sub.2Me, (methylsulphonul)(benzyl)amino,
(ethylsulphonul)(benzyl)amino, acetyl(phenylmethyl)amino,
1,1-dioxido-2-isothiazolidinyl, 3-hydroxy-1-azetidinyl,
4-methyl-1-piperazinyl, 1-pyrrolidinyl and NHSO.sub.2NMe.sub.2.
[0027] When Z is naphthyl it is preferably substituted with
methoxy.
[0028] When Z is quinolyl, benzo[b]thienyl or benzofuranyl these
groups are preferably unsubstituted.
[0029] Preferably R.sup.1 and R.sup.2 are independently hydrogen or
C.sub.1-3 alkyl. More preferably both R.sup.1 and R.sup.2 are
hydrogen or one is hydrogen and the other is methyl or ethyl or
both are methyl. Most preferably both R.sup.1 and R.sup.2 are
hydrogen.
[0030] Preferred compounds of the invention include those
exemplified herein both in free base form as well as
pharmaceutically acceptable salts and solvates thereof.
[0031] 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.
[0032] The compound 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.
[0033] It will be appreciated by those skilled in the art that in
the processes of the present invention certain functional 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`, 3rd
edition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience
(1999).
[0034] Compounds of formula (I) can be prepared by reaction of a
compound of formula (II):
##STR00003##
in which X, Y and Z are as defined in formula (I) or are protected
derivatives thereof, with a compound of formula (HI):
L-CR.sup.1R.sup.2CO.sub.2R.sup.12 (III)
[0035] Where R.sup.1 and R.sup.2 are as defined in formula (I) or
are protected derivatives thereof, R.sup.12 is H or
C.sub.1-C.sub.10 alkyl group and L is a leaving group, and
optionally thereafter in any order: [0036] removing any protecting
group [0037] hydrolysing the ester group R.sup.12 to the
corresponding acid [0038] oxidation of sulphides to sulphoxides or
sulphones [0039] forming a pharmaceutically acceptable salt.
[0040] The reaction can be carried out in a suitable solvent such
as DMF using a base such as potassium carbonate or the like.
Suitable groups R.sup.12 include C.sub.1-6 alkyl groups such as
methyl, ethyl or tert-butyl. Suitable L is a leaving group such as
halo, in particular chlorine or bromine. L may also be hydroxy so
that a Mitsunobu reaction may be performed with compound (II) using
for example triphenylphosphine and diethyl azodicarboxylate.
[0041] Hydrolysis of the ester group R.sup.12 can be carried out
using routine procedures, for example treatment of methyl and ethyl
esters with aqueous sodium hydroxide, and treatment of tert-butyl
esters with acids such as trifluoroacetic acid.
[0042] Compounds of formula (II) can be prepared by reaction of a
compound of formula (IV) with a compound of formula (V) via a
Suzuki coupling reaction followed by deprotection of group R.sup.13
when R.sup.13 is not equal to H:
##STR00004## Z-L.sup.1 (V)
in which X, Y and Z are as defined in formula (I) or are protected
derivatives thereof, R.sup.13 is H or a suitable protecting group,
for example benzyl, L.sup.1 is iodide, bromide, chloride or
triflate and R.sup.14 and R.sup.15 are H or C.sub.1-C.sub.6 alkyl
groups or R.sup.14 and R.sup.15 together can form a 5 or 6 membered
ring optionally substituted by one or more C.sub.1-C.sub.3
alkyl.
[0043] The reaction can be carried out in a suitable solvent such
as dioxane using a palladium catalyst such as
[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium and a base
such as cesium fluoride, preferably at elevated temperatures.
[0044] Compounds of formula (IV) can be prepared from a compound of
formula (VI) by formation of an organometallic (VII) followed by
reaction with a borate ester, as outlined in Scheme I.
##STR00005##
in which X, Y are as defined in formula (I) or are protected
derivatives thereof, R.sup.13 is as defined in formula (IV), E is
hydrogen or halogen and M is a metal such as Na or Li. For example
when R.sup.13 is benzyl and E is bromine, butyl lithium can be used
to form the intermediate (VII) where M=Li. The reaction is
performed at -78.degree. C. in diethylether, then quenched with a
borate ester such as trimethylborate.
[0045] Compounds of formula (IV) may also be prepared by a
palladium catalysed coupling of compounds of formula (VIII) with a
suitable boronic ester, for example (LX) or (X).
##STR00006##
in which X, Y and R.sup.13 are as defined above and G is halogen or
triflate
[0046] Compounds of formula (II) may also be prepared by reaction
of a compound of formula (XI) with a compound of formula (XII)
using Suzuki coupling methodology.
##STR00007##
in which X, Y, Z, R.sup.13, L.sup.1, R.sup.14 and R.sup.15 are as
defined above and compounds of formula (XL) and (XII) can be made
using the same methodology as above.
[0047] Compounds of formula (II), where Z=heteroaryl may also be
prepared by ring synthesis, for example a compound of formula
(XIII) may be formed by reaction of a compound of formula (XIV)
with a compound of formula (XV).
[0048] X, Y and R.sup.13 are as defined above and R.sup.16 is as
defined as a substituent on Z as defined in formula (I) or are
protected derivatives thereof. The reaction can be carried out in a
solvent such as ethanol under reflux, and a base such as sodium
ethoxide can be used if compound of formula (XV) is a salt
##STR00008##
[0049] When R.sup.16 is a group S-alkyl, this may be further
elaborated by oxidation to the sulfoxide or sulphone using an
oxidizing agent such as mcpba in DCM at RT. This may then be
displaced with an appropriate nucleophile as defined for Z in
formula 1. Scheme 2;
##STR00009##
[0050] The sequence of the steps above may be changed, for example
a compound of formula (XVI) may be formed by the reaction of a
compound of formula (XVII) with a compound of formula (XII) using a
Suzuki coupling.
##STR00010##
[0051] Compounds of formula (I) may also be prepared by reaction of
a compound of formula (XVIII) in which in which X, Y, R.sup.1,
R.sup.2, R.sup.12, R.sup.14 and R.sup.15 are as defined above with
a compound of formula (V) using Suzuki coupling method as defined
above.
[0052] A compound of formula (XVIII) may be prepared by method A or
B
Method A
##STR00011##
[0054] The acid was first converted to the acid chloride, using for
example oxalylchloride in DCM at RT, then reacted with
3-methyl-3-oxetanemethanol in the presence of a base such as
triethylamine to give the ester. The oxetane ester is the
rearranged to the OBO ester using boron trifluoride diethyletherate
in DCM at -78.degree. C. to RT. Deprotonation with a base such as
sec-butyl lithium at low temperature followed by quenching with
trimethylborate gave the protected diacid which was then
deprotected using HCl then sodium hydroxide
Method B
##STR00012##
[0056] A compound of formula (IV) where R.sup.13=Bn and R.sup.14
and R.sup.15.dbd.H and pinacol can bestirred at RT in a suitable
solvent such as diethylether to give the boronate ester. The benzyl
group may be removed by hydrogenation at RT using palladium on
carbon as catalyst then alkylated with a compound of formula (III)
using a base or mitsunobu conditions. Treatment with acid such as
HCl or trifluoroacetic acid then removes the protecting groups.
[0057] In a further aspect, the present invention provides the use
of a compound of formula (I), a prodrug, pharmaceutically
acceptable salt or solvate thereof for use in therapy.
[0058] The compounds of formula (I) have activity as
pharmaceuticals, in particular as modulators of CRTh2 receptor
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 PGD.sub.2 and its metabolites. Examples of such
conditions/diseases include: [0059] (1) (the respiratory tract)
obstructive airways diseases including: asthma (such as bronchial,
allergic, intrinsic, extrinsic and dust asthma particularly chronic
or inveterate asthma (e.g. late asthma and airways
hyper-responsiveness)); chronic obstructive pulmonary disease
(COPD) (such as irreversible COPD); bronchitis (including
eosinophilic bronchitis); acute, allergic, atrophic rhinitis or
chronic rhinitis (such as rhinitis caseosa, hypertrophic rhinitis,
rhinitis purulenta, rhinitis sicca), rhinitis medicamentosa,
membranous rhinitis (including croupous, fibrinous and
pseudomembranous rhinitis), scrofoulous rhinitis, perennial
allergic rhinitis, easonal rhinitis (including rhinitis nervosa
(hay fever) and vasomotor rhinitis); nasal polyposis; sarcoidosis;
farmer's lung and related diseases; fibroid lung; idiopathic
interstitial pneumonia; cystic fibrosis; antitussive activity;
treatment of chronic cough associated with inflammation or
iatrogenic induced; [0060] (2) (bone and joints) arthrides
including rheumatic, infectious, autoimmune, seronegative,
spondyloarthropathies (such as ankylosing spondylitis, psoriatic
arthritis and Reiter's disease), Behcet's disease, Sjogren's
syndrome and systemic sclerosis; [0061] (3) (skin and eyes)
psoriasis, atopical dermatitis, contact dermatitis, other eczmatous
dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus,
bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas,
vasculitides, erythemas, cutaneous eosinophilias, chronic skin
ulcers, uveitis, Alopecia greatacorneal ulcer and vernal
conjunctivitis; [0062] (4) (gastrointestinal tract) Coeliac
disease, proctitis, eosinopilic gastro-enteritis, mastocytosis,
Crohn's disease, ulcerative colitis, irritable bowel disease;
food-related allergies which have effects remote from the gut,
(such as migraine, rhinitis and eczema); [0063] (5) (central and
peripheral nervous system) Neurodegenerative diseases and dementia
disorders (such as 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 (such as
Guillain-Barre syndrome, chronic inflammatory demyelinating
polyradiculoneuropathy, multifocal motor neuropathy), plexopathies,
CNS demyelination (such as multiple sclerosis, acute
disseminated/haemorrhagic encephalomyelitis, and subacute
sclerosing panencephalitis), neuromuscular disorders (such as
myasthenia gravis and Lambert-Eaton syndrome), spinal diorders
(such as tropical spastic paraparesis, and stiff-man syndrome),
paraneoplastic syndromes (such as cerebellar degeneration and
encephalomyelitis), CNS trauma, migraine and stroke. [0064] (6)
(other tissues and systemic disease) 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, idiopathic thrombocytopenia pupura;
post-operative adhesions, sepsis and ischemic/reperfusion injury in
the heart, brain, peripheral limbs hepatitis (alcoholic,
steatohepatitis and chronic viral), glomerulonephritis, renal
impairment, chronic renal failure and other organs [0065] (7)
(allograft rejection) acute and chronic following, for example,
transplantation of kidney, heart, liver, lung, bone marrow, skin
and cornea; and chronic graft versus host disease; [0066] (8)
Diseases associated with raised levels of PGD.sub.2 or its
metabolites. [0067] (1) (respiratory tract)--obstructive diseases
of the airways including: asthma, including bronchial, allergic,
intrinsic, extrinsic, exercise-induced, drug-induced (including
aspirin and NSAID-induced) and dust-induced asthma, both
intermittent and persistent and of all severities, and other causes
of airway hyper-responsiveness; chronic obstructive pulmonary
disease (COPD); bronchitis, including infectious and eosinophilic
bronchitis; emphysema; bronchiectasis; cystic fibrosis;
sarcoidosis; farmer's lung and related diseases; hypersensitivity
pneumonitis; lung fibrosis, including cryptogenic fibrosing
alveolitis, idiopathic interstitial pneumonias, fibrosis
complicating anti-neoplastic therapy and chronic infection,
including tuberculosis and aspergillosis and other fungal
infections; complications of lung transplantation; vasculitic and
thrombotic disorders of the lung vasculature, and pulmonary
hypertension; antitussive activity including treatment of chronic
cough associated with inflammatory and secretory conditions of the
airways, and iatrogenic cough; acute and chronic rhinitis including
rhinitis medicamentosa, and vasomotor rhinitis; perennial and
seasonal allergic rhinitis including rhinitis nervosa (hay fever);
nasal polyposis; acute viral infection including the common cold,
and infection due to respiratory syncytial virus, influenza,
coronavirus (including SARS) and adenovirus. [0068] (2) (bone and
joints) arthritides associated with or including
osteoarthritis/osteoarthrosis, both primary and secondary to e.g.
congenital hip dysplasia; cervical and lumbar spondylitis, and low
back and neck pain; rheumatoid arthritis and Still's disease;
seronegative spondyloarthropathies including ankylosing
spondylitis, psoriatic arthritis, reactive arthritis and
undifferentiated spondarthropathy; septic arthritis and other
infection-related arthopathies and bone disorders such as
tuberculosis, including Potts' disease and Poncet's syndrome; acute
and chronic crystal-induced synovitis including urate gout, calcium
pyrophosphate deposition disease, and calcium apatite related
tendon, bursal and synovial inflammation; Behcet's disease; primary
and secondary Sjogren's syndrome; systemic sclerosis and limited
scleroderma; systemic lupus erythematosus, mixed connective tissue
disease, and undifferentiated connective tissue disease;
inflammatory myopathies including dermatomyositits and
polymyositis; polymalgia rheumatica; juvenile arthritis including
idiopathic inflammatory arthritides of whatever joint distribution
and associated syndromes, and rheumatic fever and its systemic
complications; vasculitides including giant cell arteritis,
Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa,
microscopic polyarteritis, and vasculitides associated with viral
infection, hypersensitivity reactions, cryoglobulins, and
paraproteins; low back pain; Familial Mediterranean fever,
Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi
disease; drug-induced arthalgias, tendonititides, and myopathies.
[0069] (3) (skin) psoriasis, atopic dermatitis, contact dermatitis
or other eczematous dermatoses, and delayed-type hypersensitivity
reactions; phyto- and photodermatitis; seborrhoeic dermatitis,
dermatitis herpetiformis, lichen planus, lichen sclerosus et
atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus
erythematosus, pemphigus, pemphigoid, epidermolysis bullosa,
urticaria, d angioedema, vasculitides, toxic erythemas, cutaneous
eosinophilias, alopecia greata, male-pattern baldness, Sweet's
syndrome, Weber-Christian syndrome, erythema multiforme;
cellulitis, both infective and non-infective;
panniculitis;cutaneous lymphomas, non-melanoma skin cancer and
other dysplastic lesions; drug-induced disorders including fixed
drug eruptions. [0070] (4) (eyes) blepharitis; conjunctivitis,
including perennial and vernal allergic conjunctivitis; iritis;
anterior and posterior uveitis; choroiditis; autoimmune;
degenerative or inflammatory disorders affecting the retina;
ophthalmitis including sympathetic ophthalmitis; sarcoidosis;
infections including viral, fungal, and bacterial. [0071] (5)
(gastrointestinal tract) glossitis, gingivitis, periodontitis;
oesophagitis, including reflux; eosinophilic gastro-enteritis,
mastocytosis, Crohn's disease, colitis including ulcerative
colitis, proctitis, pruritis ani; coeliac disease, irritable bowel
syndrome, and food-related allergies which may have effects remote
from the gut (for example migraine, rhinitis or eczema). [0072] (6)
(abdominal) hepatitis, including autoimmune, alcoholic and viral;
fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis,
both acute and chronic. [0073] (7) (genitourinary) nephritis
including interstitial and glomerulonephritis; nephrotic syndrome;
cystitis including acute and chronic (interstitial) cystitis and
Hunner's ulcer; acute and chronic urethritis, prostatitis,
epididymitis, oophoritis and salpingitis; vulvo-vaginitis;
Peyronie's disease; erectile dysfunction (both male and female).
[0074] (8) (Allograft rejection) acute and chronic following, for
example, transplantation of kidney, heart, liver, lung, bone
marrow, skin or cornea or following blood transfusion; or chronic
graft versus host disease; [0075] (9) (CNS) Alzheimer's disease and
other dementing disorders including CJD and nvCJD; amyloidosis;
multiple sclerosis and other demyelinating syndromes; cerebral
atherosclerosis and vasculitis; temporal arteritis; myasthenia
gravis; acute and chronic pain (acute, intermittent or persistent,
whether of central or peripheral origin) including visceral pain,
headache, migraine, trigeminal neuralgia, atypical facial pain,
joint and bone pain, pain arising from cancer and tumor invasion,
neuropathic pain syndromes including diabetic, post-herpetic, and
HIV-associated neuropathies; neurosarcoidosis; central and
peripheral nervous system complications of malignant, infectious or
autoimmune processes. [0076] (10) Other auto-immune and allergic
disorders including Hashimoto's thyroiditis, Graves' disease,
Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic
purpura, eosinophilic fasciitis, hyper-IgE syndrome,
antiphospholipid syndrome. [0077] (11) Other disorders with an
inflammatory or immunological component; including acquired immune
deficiency syndrome (AIDS), leprosy, Sezary syndrome, and
paraneoplastic syndromes. [0078] (12) (Cardiovascular);
atherosclerosis, affecting the coronary and peripheral circulation;
pericarditis; myocarditis, inflammatory and auto-immune
cardiomyopathies including myocardial sarcoid; ischaemic
reperfusion injuries; endocarditis, valvulitis, and aortitis
including infective (e.g. syphilitic); vasculitides; disorders of
the proximal and peripheral veins including phlebitis and
thrombosis, including deep vein thrombosis and complications of
varicose veins. [0079] (13) (Oncology) treatment of common cancers
including prostate, breast, lung, ovarian, pancreatic, bowel and
colon, stomach, skin and brain tumors and malignancies affecting
the bone marrow (including the leukaemias) and lymphoproliferative
systems, such as Hodgkin's and non-Hodgkin's lymphoma; including
the prevention and treatment of metastatic disease and tumour
recurrences, and paraneoplastic syndromes. [0080] (14) Diseases
associated with raised levels of PGD.sub.2 or its metabolites.
[0081] 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.
[0082] Preferably the compounds of the invention are used to treat
diseases in which the chemokine receptor belongs to the CRTh2
receptor subfamily.
[0083] Particular conditions which can be treated with the
compounds of the invention are asthma, rhinitis and other diseases
in which raised levels of PGD.sub.2 or its metabolites. It is
preferred that the compounds of the invention are used to treat
asthma.
[0084] 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.
[0085] 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..sub.2-receptor agonists and oral leukotriene
receptor antagonists).
[0086] The invention further relates to combination therapies
wherein a compound of formula (I) or a pharmaceutically acceptable
salt, solvate or in vivo hydrolysable ester thereof, or a
pharmaceutical composition or formulation comprising a compound of
formula (I) is administered concurrently or sequentially or as a
combined preparation with another therapeutic agent or agents, for
the treatment of one or more of the conditions listed.
[0087] In particular, for the treatment of the inflammatory
diseases rheumatoid arthritis, psoriasis, inflammatory bowel
disease, COPD, asthma and allergic rhinitis the compounds of the
invention may be combined with agents such as tumour necrosis
factor alpha (TNF-.alpha.) inhibitors such as anti-TNF monoclonal
antibodies (for example Remicade, CDP-870 and adalimumab) and TNF
receptor immunoglobulin molecules (such as Enbrel); non-selective
cyclo-oxygenase (COX)-1/COX-2 inhibitors whether applied topically
or systemically (such as piroxicam, diclofenac, propionic acids
such as naproxen, flubiprofen, fenoprofen, ketoprofen and
ibuprofen, fenamates such as mefenamic acid, indomethacin,
sulindac, azapropazone, pyrazolones such as phenylbutazone,
salicylates such as aspirin), COX-2 inhibitors (such as meloxicam,
celecoxib, rofecoxib, valdecoxib, lurnarocoxib, parecoxib and
etoricoxib); glucocorticosteroids (whether administered by topical,
oral, intramuscular, intravenous, or intra-articular routes);
methotrexate, lefunomide; hydroxychloroquine, d-penicillamine,
auranofin or other parenteral or oral gold preparations.
[0088] The present invention still further relates to the
combination of a compound of the invention together with a
leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor
or 5-lipoxygenase activating protein (FLAP) antagonist such as;
zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175;
Abbott-85761; N-(5-substituted)-thiophene-2-allylsulfonamides;
2,6-di-tert-butylphenol hydrazones; methoxytetrahydropyrans such as
Zeneca ZD-2138; the compound SB-210661; pyridinyl-substituted
2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoline
compounds such as L-746,530; indole and quinoline compounds such as
MK-591, MK-886, and BAY x 1005.
[0089] The present invention still further relates to the
combination of a compound of the invention together with a receptor
antagonist for leukotrienes (LT)B4, LTC4, LTD4, and LTE4. selected
from the group consisting of the phenothiazin-3-1s such as
L-651,392; amidino compounds such as CGS-25019c; benzoxalamines
such as ontazolast; benzenecarboximidamides such as BBL 284/260;
and compounds such as zafirlukast, ablukast, montelukast,
pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP
45715A), and BAY x 7195.
[0090] The present invention still further relates to the
combination of a compound of the invention together with a
phosphodiesterase (PDE) inhibitor such as the methylxanthanines
including theophylline and aminophylline; and selective PDE
isoenzyme inhibitors including PDE4 inhibitors and inhibitors of
the isoform PDE4D, and inhibitors of PDE5.
[0091] The present invention still further relates to the
combination of a compound of the invention together with histamine
type 1 receptor antagonists such as cetirizine, loratadine,
desloratadine, fexofenadine, acrivastine, terfenadine, astemizole,
azelastine, levocabastine, chlorpheniramine, promethazine,
cyclizine, and mizolastine applied orally, topically or
parenterally.
[0092] The present invention still further relates to the
combination of a compound of the invention together with a
gastroprotective histamine type 2 receptor antagonist.
[0093] The present invention still further relates to the
combination of a compound of the invention with antagonists of the
histamine type 4 receptor.
[0094] The present invention still further relates to the
combination of a compound of the invention together with an
alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor
sympathomimetic agent, such as propylhexedrine, phenylephrine,
phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline
hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline
hydrochloride, xylometazoline hydrochloride, tramazoline
hydrochloride, and ethylnorepinephrine hydrochloride.
[0095] The present invention still further relates to the
combination of a compound of the invention together with
anticholinergic agents including muscarinic receptor (M1, M2, and
M3) antagonists such as atropine, hyoscine, glycpyrrrolate,
ipratropium bromide; tiotropium bromide; oxitropium bromide;
pirenzepine; and telenzepine.
[0096] The present invention still further relates to the
combination of a compound of the invention together with a
beta-adrenoceptor agonist (including beta receptor subtypes 1-4)
such as isoprenaline, salbutamol, formoterol, salmeterol,
terbutaline, orciprenaline, bitolterol mesylate, and
pirbuterol.
[0097] The present invention still further relates to the
combination of a compound of the invention together with a
chromone, including sodium cromoglycate and nedocromil sodium.
[0098] The present invention still further relates to the
combination of a compound of the invention together with an
insulin-like growth factor type I (IGF-1) mimetic.
[0099] The present invention still further relates to the
combination of a compound of the invention together with an inhaled
glucocorticoid, such as flunisolide, triamcinolone w acetonide,
beclomethasone dipropionate, budesonide, fluticasone propionate,
ciclesonide, and mometasone furoate.
[0100] The present invention still further relates to the
combination of a compound of the invention together with an
inhibitor of matrix metalloproteases (MMPs), i.e., the
stromelysins, the collagenases, and the gelatinases, as well as
aggrecanase; especially collagenase-1 (MMP-1), collagenase-2
(MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3),
stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and
MMP-12.
[0101] The present invention still further relates to the
combination of a compound of the invention together with modulators
of chemokine receptor function such as antagonists of 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
[0102] The present invention still further relates to the
combination of a compound of the invention together with a cytokine
or modulator of cytokine function, including alpha-, beta-, and
gamma-interferon; interleukins (IL) including IL1 to 15, and
interleukin antagonists or inhibitors, including agents which act
on cytokine signalling pathways.
[0103] The present invention still further relates to the
combination of a compound of the invention together with an
immunoglobulin (Ig) or Ig preparation or an antagonist or antibody
modulating Ig function such as anti-IgE (omalizumab).
[0104] The present invention still further relates to the
combination of a compound of the invention together with other
systemic or topically-applied anti-inflammatory agents including
thalidomide and derivatives, retinoids, dithranol, and
calcipotriol.
[0105] The present invention still further relates to the
combination of a compound of the invention together with an
antibacterial agent including penicillin derivatives,
tetracyclines, macrolides, beta-lactams, fluoroquinolones, and
inhaled aminoglycosides; and antiviral agents including acyclovir,
famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine,
rimantadine; ribavirin; zanamavir and oseltamavir; protease
inhibitors such as indinavir, nelfinavir, ritonavir, and
saquinavir; nucleoside reverse transcriptase inhibitors such as
didanosine, lamivudine, stavudine, zalcitabine, zidovudine;
non-nucleoside reverse transcriptase inhibitors such as nevirapine,
efavirenz.
[0106] The present invention still further relates to the
combination of a compound of the invention together with
cardiovascular agents such as calcium channel blockers,
beta-adrenoceptor blockers, angiotensin-converting enzyme (ACE)
inhibitors, angiotensin-2 receptor antagonists; lipid lowering
agents such as statins, and fibrates; modulators of blood cell
morphology such as pentoxyfylline; thrombolytics, and
anticoagulants' including platelet aggregation inhibitors.
[0107] The present invention still further relates to the
combination of a compound of the invention together with CNS agents
such as antidepressants (such as sertraline), anti-Parkinsonian
drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors
such as selegine and rasagiline, comP inhibitors such as Tasmar,
A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists,
nicotine agonists, dopamine agonists and inhibitors of neuronal
nitric oxide synthase), and anti-Alzheimer's drugs such as
donepezil, tacrine, COX-2 inhibitors, propentofylline or
metrifonate.
[0108] The present invention still further relates to the
combination of a compound of the invention together with agents for
the treatment of acute and chronic pain, including centrally and
peripherally-acting analgesics such as opioid analogues and
derivatives, carbamazepine, phenyloin, sodium valproate,
amitryptiline and other antidepressant agents, and non-steroidal
anti-inflammatory agents.
[0109] The present invention still further relates to the
combination of a compound of the invention together with
parenterally or topically-applied local anaesthetic agents such as
lignocaine.
[0110] The present invention still further relates to the
combination of a compound of the invention together with (i)
tryptase inhibitors; (ii) platelet activating factor (PAF)
antagonists; (iii) interleukin converting enzyme (ICE) inhibitors;
(iv) IMPDH inhibitors; (v) adhesion molecule inhibitors including
VLA-4 antagonists; (vi) cathepsins; (vii) MAP kinase inhibitors;
(viii) glucose-6 phosphate dehydrogenase inhibitors; (ix)
kinin-B.sub1.- and B.sub2.-receptor antagonists; (x) anti-gout
agents, e.g., colchicine; (xi) xanthine oxidase inhibitors, e.g.,
allopurinol; (xii) uricosuric agents, e.g., probenecid, is
sulfinpyrazone, and benzbromarone; (xiii) growth hormone
secretagogues; (xiv) transforming growth factor (TGF.beta.); (xv)
platelet-derived growth factor (PDGF); (xvi) fibroblast growth
factor, e.g., basic fibroblast growth factor (bFGF); (xvii)
granulocyte macrophage colony stimulating factor (GM-CSF); (xviii)
capsaicin cream; (xix) Tachykinin NK.sub1. and NK.sub3. receptor
antagonists selected from the group consisting of NKP-608C;
SB-233412 (talnetant); and D-4418; (xx) elastase inhibitors
selected from the group consisting of UT-77 and ZD-0892; (xxi)
TNF.quadrature. converting enzyme inhibitors (TACE); (xxii) induced
nitric oxide synthase inhibitors (iNOS) or (xviii) chemoattractant
receptor-homologous molecule expressed on TH2 cells, (CRTH2
antagonists) (xxiv) inhibitors of P38
[0111] The compounds of the present invention may also be used in
combination with anti-osteoporosis agents including hormonal agents
such as raloxifene, and biphosphonates such as alendronate.
[0112] The compounds of the invention may also be used in
combination with existing therapeutic agents for the treatment of
osteoarthritis. Suitable agents to be used in combination include
standard non-steroidal anti-inflammatory agents (hereinafter
NSAIDs) such as piroxicam, diclofenac, propionic acids such as
naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen,
fenamates such as mefenamic acid, indomethacin, sulindac, apazone,
pyrazolones such as phenylbutazone, salicylates such as aspirin,
COX-2 inhibitors such as celecoxib, valdecoxib, rofecoxib and
etoricoxib, analgesics, and intra-articular therapies such as
corticosteroids and hyaluronic acid derivatives, and nutritional
supplements such as glucosamine.
[0113] The compounds of the invention can also be used in
combination with existing therapeutic agents for the treatment of
cancer. Suitable agents to be used in combination include:
(i) antiproliferative/antineoplastic drugs and combinations
thereof, as used in medical oncology, such as alkylating agents
(for example cis-platin, carboplatin, cyclophosphamide, nitrogen
mustard, melphalan, chlorambucil, busulphan and nitrosoureas);
antimetabolites (for example antifolates such as fluoropyrimidines
like 5-fluorouracil and tegafur, raltitrexed, methotrexate,
cytosine arabinoside, hydroxyurea, gemcitabine and paclitaxel;
antitumour antibiotics (for example anthracyclines like adriamycin,
bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,
mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for
example vinca alkaloids like vincristine, vinblastine, vindesine
and vinorelbine and taxoids like taxol and taxotere); and
topoisomerase inhibitors (for example epipodophyllotoxins like
etoposide and teniposide, amsacrine, topotecan and camptothecins);
(ii) cytostatic agents such as antioestrogens (for example
tamoxifen, toremifene, is raloxifene, droloxifene and iodoxyfene),
oestrogen receptor down regulators (for example fulvestrant),
antiandrogens (for example bicalutamide, flutamide, nilutamide and
cyproterone acetate), LHRH antagonists or LHRH agonists (for
example goserelin, leuprorelin and buserelin), progestogens (for
example megestrol acetate), aromatase inhibitors (for example as
anastrozole, letrozole, vorazole and exemestane) and inhibitors of
5.alpha.-reductase such as finasteride; (iii) Agents which inhibit
cancer cell invasion (for example metalloproteinase inhibitors like
marimastat and inhibitors of urokinase plasminogen activator
receptor function); (iv) inhibitors of growth factor function, for
example such inhibitors include growth factor antibodies, growth
factor receptor antibodies (for example the anti-erbb2 antibody
trastuzumab and the anti-erbb1 antibody cetuximab [C225]), farnesyl
transferase inhibitors, tyrosine kinase inhibitors and
serine/threonine kinase inhibitors, for example inhibitors of the
epidermal growth factor family (for example EGFR family tyrosine
kinase inhibitors such as
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-
-amine (gefitinib, AZD1839),
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib, OSI-774) and
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoli-
n-4-amine (CI 1033)), for example inhibitors of the
platelet-derived growth factor family and for example inhibitors of
the hepatocyte growth factor family; (v) antiangiogenic agents such
as those which inhibit the effects of vascular endothelial growth
factor, (for example the anti-vascular endothelial cell growth
factor antibody bevacizumab, compounds such as those disclosed in
International Patent Applications WO 97/22596, WO 97/30035, WO
97/32856 and WO 98/13354) and compounds that work by other
mechanisms (for example linomide, inhibitors of integrin
.alpha.v.beta.3 function and angiostatin); (vi) vascular damaging
agents such as combretastatin A4 and compounds disclosed in
International Patent Applications WO 99/02166, WO00/40529, WO
00/41669, WO01/92224, WO02/01134 and WO02/08213; (vii) antisense
therapies, for example those which are directed to the targets
listed above, such as ISIS 2503, an anti-ras antisense; (viii) gene
therapy approaches, including for example approaches to replace
aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,
GDEPT (gene-directed enzyme pro-drug therapy) approaches such as
those using cytosine deaminase, thymidine kinase or a bacterial
nitroreductase enzyme and approaches to increase patient tolerance
to chemotherapy or radiotherapy such as multi-drug resistance gene
therapy; and (ix) immunotherapy approaches, including for example
ex-vivo and in-vivo approaches to increase the immunogenicity of
patient tumour cells, such as transfection with cytokines such as
interleukin 2, interleukin 4 or granulocyte-macrophage colony
stimulating factor, approaches to decrease T-cell anergy,
approaches using transfected immune cells such as
cytokine-transfected dendritic cells, approaches using
cytokine-transfected tumour cell lines and approaches using
anti-idiotypic antibodies.
[0114] 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 CRTh2 receptor activity is
beneficial.
[0115] 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.
[0116] The invention still further provides a method of treating
diseases mediated by PGD2 or its metabolites wherein the prostanoid
binds to its receptor (especially CRTh2) receptor, which comprises
administering to a patient a therapeutically effective amount of a
so compound of formula (I), or a pharmaceutically acceptable salt,
solvate or prodrug thereof, as hereinbefore defined.
[0117] The invention also provides a method of treating an
inflammatory disease, especially psoriasis, 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.
[0118] 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.
[0119] 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.
[0120] The compound of formula (I), prodrugs 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.
[0121] The present invention also provides a pharmaceutical
composition comprising a compound of formula (I), or a
pharmaceutically acceptable salt or solvate thereof, as herein
before defined, in association with a pharmaceutically acceptable
adjuvant, diluent or carrier.
[0122] 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.
[0123] The invention will now be illustrated by the following
non-limiting examples in which, unless stated otherwise:
(i) when given, .sup.1H NMR data is quoted in the form of delta
values for major diagnostic protons, given in parts per million
(ppm) relative to tetramethylsilane (TMS) as an internal standard;
(ii) mass spectra (MS): generally only ions which indicate the
parent mass are reported, and unless otherwise stated the mass ion
quoted is the positive mass ion--(M+H).sup.+; (iii) the title
compounds of the examples and methods were named using the ACD/name
and ACD/name batch (version 6.0) from Advanced Chemical Development
Inc, Canada; (iv) unless stated otherwise, reverse phase HPLC was
conducted using a Symmetry, NovaPak or Ex-Terra reverse phase
silica column; (v) solvents were dried with MgSO.sub.4 or
Na.sub.2SO.sub.4 (vi) the following abbreviations are used: [0124]
EtOAc Ethylacetate [0125] DCM Dichloromethane [0126] NMP
N-methylpyrrolidine [0127] DMF N,N-dimethylformamide [0128] THF
tetrahydrofuran [0129] mcpba 3-chloroperoxybenzoic acid (Aldrich
77% max) [0130] Pd(dppf)Cl.sub.2
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane [0131] RT room temperature
EXAMPLE 1
{[5-Chloro-4'-(ethylthio)biphenyl-2-yl]oxy}acetic acid
##STR00013##
[0132] (i) tert-Butyl (2-bromo-4-chlorophenoxy)acetate
[0133] tert-Butyl bromoacetate (2.6 ml) was added to a stirred
mixture of 4-bromo-2-chlorophenol (3 g) and potassium carbonate (62
g) in DMF (40 ml) at RT. After 16 h the reaction was partitioned
between diethylether and water, the organics separated, dried and
evaporated under reduced pressure. The residue was purified by
chromatography on silica eluting with 4% EtOAc/iso-hexane. Yield
4.05 g
[0134] .sup.1H NMR CDCl.sub.3: .delta. 7.55 (1H, d); 7.21 (1H, dd);
6.72 (1H, d); 4.57 (2H, s); 1.48 (9H, s)
(ii) tert-Butyl
{[5-chloro-4'-(ethylthio)biphenyl-2-yl]oxy}acetate
[0135] A mixture of the product from step (i) (2 g),
4-(ethylthio)phenylboronic acid (1.5 g), cesium fluoride (2 g) and
Pd(dppf)Cl.sub.2 (0.2 g) in dioxane (40 ml) was heated under reflux
for 3 h. After cooling the mixture was partitioned between
diethylether and water. The organics were separated, dried and
evaporated under reduced pressure. The residue was purified by
chromatography on silica eluting with 5% EtOAc/iso-hexane. Yield
0.92 g
[0136] MS: APCI (+ve): 379/381 (M+1)
(iii) {[5-Chloro-4'-(ethylthio)biphenyl-2-yl]oxy}acetic acid
[0137] The title compound was prepared by stirring a mixture of the
product from step (ii) (0.3 g) and trifluoroacetic acid (4 ml) in
DCM (10 ml) at RT for 5 h. The solvent was evaporated under reduced
pressure, the residue triturated with diethylether then purified by
reverse phase HPLC. Yield 0.106 g
[0138] .sup.1H NMR DMSO-d6: .delta. 13.07 (1H, s); 7.54 (2H, d);
7.35-7.33 (4H, m); 7.02 (1H, d); 4.74 (2H, s); 3.02 (2H, q); 1.27
(3H, t)
[0139] MS: APCI (-ve): 321/3 (M-1)
EXAMPLE 2
{[5-Chloro-4'(ethylsulfonyl)biphenyl-2-yl]oxy}acetic acid
##STR00014##
[0140] (i) tert-Butyl
{[5-chloro-4'-(ethylsulfonyl)biphenyl-2-yl]oxy}acetate
[0141] Mcpba (1.2 g) was added to a stirred solution of the product
from example 1 step (ii) (0.6 g) in DCM (10 ml) at RT. After 4 h,
the mixture was partitioned between DCM and aqueous sodium
metabisulphite solution, the organics separated, washed with
aqueous sodium hydrogencarbonate solution, water, dried and
evaporated under reduced pressure. Yield 0.65 g
(ii) {[5-Chloro-4'-(ethylsulfonyl)biphenyl-2-yl]oxy}acetic acid
[0142] The title compound was prepared by the method of example 1
step (iii) using the product from step (i). Yield 0.226 g
[0143] .sup.1H NMR DMSO-d6: .delta. 13.14 (1H, s); 7.92 (2H, d);
7.87 (2H, d); 7.45-7.42 (2H, m); 7.10 (1H, d); 4.79 (2H, s); 3.35
(2H, q); 1.15 (3H, t)
[0144] MS: APCI (-ve): 353/5 (M-1)
EXAMPLE 3
[(4',5-Dichlorobiphenyl-2-yl)oxy]acetic acid
##STR00015##
[0145] (i) tert-Butyl [(4',5-dichlorobiphenyl-2-yl)oxy]acetate
[0146] The subtitle compound was prepared by the method of example
1 step (ii) using the product from example 1 step (i) and
4-chlorophenylboronic acid. Yield 0.63 g
[0147] .sup.1H NMR CDCl.sub.3: .delta. 7.54-7.22 (6H, m); 6.76 (1H,
dd); 4.48 (2H, s); 1.47 (9H, s)
(ii) [(4',5-Dichlorobiphenyl-2-yl)oxy]acetic acid
[0148] The title compound was prepared by the method of example 1
step (iii) using the product from step (i). Yield 0.224 g
[0149] .sup.1H NMR DMSO-d6: .delta. 13.00 (1H, s); 7.61 (2H, d);
7.48 (2H, d); 7.41-7.36 (2H, m); 7.05 (1H, d); 4.75 (2H, s)
[0150] MS: APCI (-ve): 295/7 (M-1)
EXAMPLE 4
[(5-Chloro-4'-cyanobiphenyl-2-yl)oxy]acetic acid
##STR00016##
[0151] (i) tert-Butyl
[(5-chloro-4'-cyanobiphenyl-2-yl)oxy]acetate
[0152] The subtitle compound was prepared by the method of example
1 step (ii) using the product from example 1 step (i) and
4-cyanophenylboronic acid. Yield 0.524 g
[0153] .sup.1H NMR CDCl.sub.3: .delta. 7.70 (4H, s); 7.32-7.26 (2H,
m); 6.79 (1H, d); 4.51 (2H, s); 1.48 (9H, s)
(ii) [(5-Chloro-4'-cyanobiphenyl-2-yl)oxy]acetic acid
[0154] The title compound was prepared by the method of example 1
step (iii) using the product from step (i). Yield 0.109 g
[0155] .sup.1H NMR DMSO-d6: .delta. 13.14 (1H, s); 7.90 (2H, d);
7.80 (2H, d); 7.45-7.41 (2H, m); 7.10 (1H, d); 4.78 (2H, s)
[0156] MS: APCI (-ve): 286/8 (M-1)
EXAMPLE 5
[(5-Chloro-4'-methoxybiphenyl-2-yl)oxy]acetic acid
##STR00017##
[0157] (i) tert-Butyl
[(5-chloro-4'-methoxybiphenyl-2-yl)oxy]acetate
[0158] The subtitle compound was prepared by the method of example
1 step (ii) using the product from example 1 step (i) and
4-methoxyphenylboronic acid. Yield 0.610 g
[0159] .sup.1H NMR CDCl.sub.3: .delta. 7.54 (2H, d); 7.31-7.18 (2H,
m); 6.96 (2H, d); 6.76 (1H, d); 4.46 (2H, s); 3.84 (3H, s); 1.46
(9H, s)
(ii) [(5-Chloro-4'-methoxybiphenyl-2-yl)oxy]acetic acid
[0160] The title compound was prepared by the method of example 1
step (iii) using the product from step (i). Yield 0.119 g
[0161] .sup.1H NMR DMSO-d6: .delta. 13.08 (1H, s); 7.53 (2H, d);
7.32-7.29 (2H, m); 7.01-6.96 (3H, m); 4.72 (2H, s); 3.79 (3H,
s)
[0162] MS: APCI (-ve): 291/3 (M-1)
EXAMPLE 6
(4-Chloro-2-quinolin-8-ylphenoxy)acetic acid, trifluoroacetic acid
salt
##STR00018##
[0163] (i) tert-Butyl (4-chloro-2-quinolin-8-ylphenoxy)acetate
[0164] The subtitle compound was prepared by the method of example
1 step (ii) using the product from example 1 step (i) and
8-quinoline boronic acid. Yield 0.356 g
[0165] .sup.1H NMR CDCl.sub.3: .delta. 8.90-8.88 (1H, m); 8.18 (1H,
d); 7.85 (1H, d); 7.76 (1H, d); 7.60 (1H, t); 7.40-7.30 (3H, m);
6.87 (1H, d); 4.37 (2H, s); 1.37 (9H, s)
(ii) (4-Chloro-2-quinolin-8-ylphenoxy)acetic acid, trifluoroacetic
acid salt
[0166] The title compound was prepared by the method of example 1
step (iii) using the product from step (i). Yield 0.25 g
[0167] .sup.1H NMR DMSO-d6: .delta. 8.91-8.89 (1H, m); 8.62 (1H,
d); 8.12 (1H, d); 7.85-7.67 (3H, m); 7.46 (1H, dd); 7.38 (1H, d);
7.09 (1H, d); 4.61 (2H, s)
[0168] MS: APCI (-ve): 312/4 (M-1)
EXAMPLE 7
[(5-Chloro-3',4'-dimethoxybiphenyl-2-yl)oxy]acetic acid
##STR00019##
[0169] (i) tert-Butyl
[(5-chloro-3',4'-dimethoxybiphenyl-2-yl)oxy]acetate
[0170] The subtitle compound was prepared by the method of example
1 step (ii) using the product from example 1 step (i) and
3,4-dimethoxyphenylboronic acid. Yield 0.86 g .sup.1H NMR
CDCl.sub.3: .delta. 7.33-7.12 (4H, m); 6.93 (1H, d); 6.79 (1H, d);
4.46 (2H, s); 3.93 (3H, s); 3.92 (3H, s); 1.46 (9H, s)
(ii) [(5-Chloro-3',4'-dimethoxybiphenyl-2-yl)oxy]acetic acid
[0171] The title compound was prepared by the method of example 1
step (iii) using the product from step (i). Yield 0.32 g
[0172] .sup.1H NMR DMSO-d6: .delta. 13.08 (1H, s); 7.36-7.27 (3H,
m); 7.12-6.98 (3H, m); 4.74 (2H, s); 3.78 (6H, 2.times.s)
[0173] MS: APCI (-ve): 321/3 (M-1)
EXAMPLE 8
2'-(Carboxymethoxy)-5'-chlorobinhenyl-4-carboxylic acid
##STR00020##
[0175] The title compound was prepared by the method of example 1
step (ii) and step (iii) using the product from example 1 step (i)
and 4-carboxyphenylboronic acid. Yield 0.035 g
[0176] .sup.1H NMR DMSO-d6: .delta. 7.98-7.38 (6H, m); 7.08-7.05
(1H, m); 4.75 (2H, s)
[0177] MS: APCI (-ve): 305 (M-1)
EXAMPLE 9
{[5-Chloro-4'(methyLsulfonyl)biphenyl-2-yl]oxy}acetic acid
##STR00021##
[0179] The title compound was prepared by the method of example 1
step (ii) and example 2 using the product from example 1 step (i)
and 4-(methylthio)benzeneboronic acid. Yield 0.1 g
[0180] .sup.1H NMR DMSO-d6: .delta. 7.97-7.08 (7H, m); 4.78 (2H,
s); 3.31 (3H, bs)
[0181] MS: APCI (-ve): 339 (M-1)
EXAMPLE 10
{[5-Chloro-4'-(ethylsulfonyl)-2'methylbiphenyl-2-yl]oxy}acetic
acid
##STR00022##
[0182] (i) 4-Bromo-3-methylphenyl ethyl sulfide
[0183] Bromine (2.2 ml) was added to a solution of
1-(ethylthio)-3-methylbenzene (6.6 g) in acetic acid (20 ml) at
0.degree. C. The mixture was stirred at RT for 2 h then the solvent
removed under reduced pressure. The residue was purified by
chromatography on silica eluting with DCM. Yield 6.6 g
[0184] MS: APCI (+ve): 247/9 (M+1)
(ii)
2-[4-(Ethylthio)-2-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborol-
ane
[0185] A mixture of the product from step (i) (6.6 g),
4,45,5-tetramethyl-[1,3,2]-dioxaborolane (1.94 ml), triethylamine
(2.4 ml), palladium acetate (0.06 g) and 2-(dicyclohexylphosphino)
biphenyl (0.3 g) in dioxane (20 ml) was heated at 85.degree. C. for
2 h. The mixture was quenched with aqueous ammonium chloride
solution, extracted with diethylether, the organics dried and
evaporated under reduced pressure. The residue was purified by
chromatography on silica eluting with 50% isohexane/DCM. Yield 0.7
g
[0186] .sup.1H NMR CDCl.sub.3: .delta. 7.66 (1H, d); 7.08-7.05 (2H,
m); 2.94-2.92 (2H, q); 2.5 (3H, s); 1.43-1.27 (15H, m)
(iii)
{[5-Chloro-4'-(ethylsulfonyl)-2'-methylbiphenyl-2-yl]oxy}acetic
acid
[0187] The title compound was prepared by the method of example 1
step (ii) and example 2 using the product from step (ii) and the
product from example 1 step (i). Yield 0.035 g
[0188] .sup.1H NMR DMSO-d6: .delta. 7.79-6.99 (6H, m); 4.67 (2H,
s); 3.35 (2H, q); 2.23 (3H, s); 1.15 (3H, t)
[0189] MS: APCI (-ve): 367 (M-1)
EXAMPLE 11
[(5-Cyanobiphenyl-2-yl)oxy]acetic acid
##STR00023##
[0191] The title compound was prepared by the method of example 1
using 3-bromo-4-hydroxybenzonitrile and phenylboronic acid. Yield
0.175 g
[0192] .sup.1H NMR DMSO-d6: .delta. 13.18 (1H, s); 7.81-7.17 (8H,
m); 4.87 (2H, s)
[0193] MS: APCI (-ve): 252 (M-1)
EXAMPLE 12
[(5-Nitrobiphenyl-2-yl)oxy]acetic acid
##STR00024##
[0195] The title compound was prepared by the method of example 1
using 2-bromo-4-nitrophenol and phenylboronic acid. Yield 0.065
g
[0196] .sup.1H NMR DMSO-d6: .delta. 13.26 (1H, s); 8.23 (1H, dd);
8.12 (1H, d); 7.63 (2H, d); 7.50-7.38 (3H, m); 7.25 (1H, d); 4.94
(2H, s)
[0197] MS: APCI (-ve): 272 (M-1)
EXAMPLE 13
{[4'-(Methylthio)-5-(trifluoromethyl)biphenyl-2-yl]oxy}acetic
acid
##STR00025##
[0198] (i) 2-Iodo-4-(trifluoromethyl)phenol
[0199] Sodium iodide (3.32 g) then chloramine-T (5.91 g) were added
to a stirred solution of 4-trifluoromethylphenol (3.0 g) in DMF (30
ml) at 0.degree. C. The mixture was warmed to RT, stirred for 1 h,
diluted with dilute hydrochloric acid then extracted with
diethylether. The organic layer was washed with aqueous sodium
thiosulphate solution, dried and the solvent removed under reduced
pressure. Yield 5.25 g
[0200] MS: APCI (-ve): 287 (M-1)
(ii) {[4'-(Methylthio)-5-(trifluoromethyl)biphenyl-2-yl]oxy}acetic
acid
[0201] The title compound was prepared by the method of example 1
using the product from step (i) and 4-(methylthio)benzeneboronic
acid. Yield 0.13 g
[0202] .sup.1H NMR DMSO-d6: .delta. 13.16 (1H, s); 7.68-7.18 (7H,
m); 4.85 (2H, s); 2.51 (3H, s)
[0203] MS: APCI (-ve): 341 (M-1)
EXAMPLE 14
{[4'-(Methylsulfonyl)-5-(trifluoromethyl)biphenyl-2-yl]oxy}acetic
acid, ammonium salt
##STR00026##
[0205] The title compound was prepared by the methods of example 1
and 2 using the product from example 13 step (i) and
4-(methylthio)benzeneboronic acid. Yield 0.14 g
[0206] .sup.1H NMR DMSO-d6: .delta. 13.21 (1H, s); 8.00-7.69 (6H,
m); 7.27 (1H, d); 4.89 (2H, s); 3.27 (3H, s)
[0207] MS: APCI (-ve): 373 (M-1)
EXAMPLE 15
{[4'-(Ethylsulfonyl)-2'-nnethyl-5-(trifluoromethyl)biphenyl-2-yl]oxy}aceti-
c acid
##STR00027##
[0209] The title compound was prepared by the methods of example 1
and 2 using the product from example 13 step (i) and the product
from example 10 step (ii). Yield 0.055 g
[0210] .sup.1H NMR DMSO-d6: .delta. 7.80-7.12 (6H, m); 4.63 (2H,
s); 3.39-3.29 (2H, q); 2.23 (3H, s); 1.18-1.11 (3H, t)
[0211] MS: APCI (-ve): 401 (M-1)
EXAMPLE 16
(4-Chloro-2-pyrimidin-5-ylphenoxy)acetic acid, ammonium salt
##STR00028##
[0212] (i) Benzyl 2-bromo-4-chlorophenyl ether
[0213] Benzyl bromide (13.1 ml) was added to a stirred mixture of
2-bromo-4-chlorophenol (20.7 g) and potassium carbonate (27.6 g) in
DMF (200 ml). After 72 h, the mixture was is partitioned between
diethylether and water, the organic layer washed with water, dried
and the solvent evaporated under reduced pressure. The residue was
purified by chromatography on silica eluting with 2%
EtOAc/isohexane: Yield 18.1 g
[0214] .sup.1H NMR CDCl.sub.3: .delta. 7.55 (1H, s); 7.46-7.18 (6H,
m); 6.84 (1H, d); 5.14 (2H, s)
(ii) [2-(Benzyloxy)-5-chlorophenyl]boronic acid
[0215] A solution of butyl lithium (1.6M in hexane) (50 ml) was
added dropwise to a stirred solution of the product from step (i)
(23 g) in diethylether (300 ml) at -70.degree. C. After 1 h a
further 18 ml of butyl lithium was added, left for 0.75 h, then
trimethylborate (10 ml) added and the mixture warmed to RT and left
for 16 h. 2M Hydrochloric acid (100 ml) was added, stirred for 1 h
then the organic layer separated and extracted with aqueous sodium
hydroxide solution. The basic layer was acidified with 2M
hydrochloric acid solution, extracted with diethylether which was
dried and evaporated under reduced pressure. The residue was
triturated with iso-hexane and filtered. Yield 10.8 g
[0216] .sup.1H NMR CDCl.sub.3: .delta. 7.82 (1H, d); 7.44-7.34 (6H,
m); 6.90 (1H, d); 5.99 (2H, s); 5.12 (2H, s)
(iii) 5-[2-(Benzyloxy)-5-chlorophenyl]pyrimidine
[0217] A mixture of the product from step (ii) (0.2 g),
5-bromopyrimidine (0.16 g), sodium carbonate (0.21 g) and
tetrakistriphenylphosphine palladium (0) (0.05 g) in dioxane (6 ml)
was heated under reflux for 48 h. The mixture was partitioned
between EtOAc and water, the organics separated, dried, and
evaporated under reduced pressure. The residue was purified by
chromatography on silica eluting with 20% EtOAc/isohexane. Yield
0.283 g.
[0218] MS: APCI (+ve): 297/9 (MA-1)
(iv) 4-Chloro-2-pyrimidin-5-ylphenol
[0219] A mixture of the product from step (iii) (0.28 g), 10%
palladium on carbon (0.04 g) in ethanol (20 ml) was hydrogenated at
2 Bar for 24 h. After filtration the solvent was evaporated under
reduced pressure. Yield 0.19 g
[0220] MS: APCI (+ve): 207/9 (M+1)
(v) tert-Butyl (4-chloro-2-pyrimidin-5-ylphenoxy)acetate
[0221] The subtitle compound was prepared by the method of example
1 step (i). Yield 0.216 g
[0222] MS: APCI (+ve): 321/3 (M-1)
(vi) (4-Chloro-2-pyrimidin-5-ylphenoxy)acetic acid, ammonium salt
The title compound was prepared by the method of example 1 step
(iii). Yield 0.033 g
[0223] .sup.1H NMR DMSO-d6: .delta. 9.15 (1H, s); 9.08 (2H, s);
7.57 (1H, d); 7.44 (1H, dd); 7.10 (1H, d); 4.67 (2H, s)
[0224] MS: APCI (+ve): 265/7 (M+1)
EXAMPLE 17
{2-[5-(Aminosulfonyl)pyridin-2-yl]-4-chlorophenoxy}acetic acid
##STR00029##
[0226] The title compound was prepared by the method of example 16.
Yield 0.022 g
[0227] .sup.1H NMR DMSO-d6: .delta. 13.19 (1H, s); 9.05 (1H, s);
8.29 (1H, d); 8.21 (1H, d); 7.84 (1H, d); 7.65 (2H, s); 7.49 (1H,
dd); 7.16 (1H, d); 4.86 (2H, s)
[0228] MS: APCI (+ve): 343/5 (M+1)
EXAMPLE 18
[2-(2-Aminopyrimidin-5-yl)-4-chlorophenoxy]acetic acid,
trifluoroacetate salt
##STR00030##
[0230] The title compound was prepared by the method of example 16.
Yield 0.036 g
[0231] .sup.1H NMR DMSO-d6: .delta. 8.56 (2H, s); 7.45 (1H, d);
7.33 (1H, dd); 7.05 (1H, d); 4.76 (2H, s)
[0232] MS: APCI (+ve): 280/2 (M+1)
EXAMPLE 19
[4-Chloro-2-(4-methyl-2-morpholin-4-ylpyrimidin-5-yl)phenoxy]acetic
acid
##STR00031##
[0233] (i)
2-[2-(Benzyloxy)-5-chlorophenyl]-N-methoxy-N-methylacetamide
[0234] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(8.6 g) was added to a solution of
(2-benzyloxy-5-chlorophenyl)-acetic acid (10.6 g),
N,O-dimethylhydroxylamine hydrochloride (4.4 g),
1-hydroxybenzotriazole (6.9 g) and N,N-diisopropylethylamine (20
ml) in DMF (150 ml) and the mixture stirred at RT for 16 h, then
partitioned between z5 ethylacetate and water. The organics were
washed with 2M hydrochloric acid, water, dried, and evaporated
under reduced pressure. Yield 12.2 g
[0235] MS: APCI (+ve): 320/2 (M+1)
(ii) 1-[2-(Benzyloxy)-5-chlorophenyl]acetone
[0236] A solution of methylmagnesium chloride (3M in THF) (6 ml)
was added dropwise to a stirred solution of the product, from step
(i) (5.2 g) in THF (150 ml) at -70.degree. C. After 111 the mixture
was warmed to RT, stirred for 1 h then quenched with aqueous
ammonium chloride solution. The mixture was partitioned between
diethylether and water, the organics separated, dried, and
evaporated under reduced pressure. The residue was purified by
chromatography on silica eluting with 10% EtOAc/isohexane. Yield
2.22 g
[0237] .sup.1H NMR CDCl.sub.3: .delta. 7.40-7.30 (5H, m); 7.26-7.12
(2H, m); 6.85 (1H, d); 5.03 (2H, s); 3.67 (2H, s); 2.12 (3H, s)
(iii)
(3Z)-3-[2-(Benzyloxy)-5-chlorophenyl]-4-(dimethylamino)but-3-en-2-on-
e
[0238] A mixture of the product from step (ii) (5.72 g) and
dimethylformamide dimethyl acetal (3.5 ml) in toluene (50 ml) were
heated at 100.degree. C. for 12 h. The solvent was evaporated under
reduced pressure to give an oil, 6.37 g.
[0239] MS: APCI (+ve): 330/2 (M+1)
(iv)
5-[2-(Benzyloxy)-5-chlorophenyl]-4-methyl-2-(methylthio)pyrimidine
[0240] A solution of the product from step (iii) (4.3 g) in ethanol
(20 ml) was added to a stirred mixture of sodium ethoxide (0.98 g)
and S-methylisothiouronium sulphate (2 g) in ethanol (30 ml), and
the mixture heated under reflux for 8 h. A further 2 g of
S-methylisothiouronium sulphate and 1.18 g of sodium ethoxide were
added and heating continued for 16 h. The mixture was cooled,
partitioned between diethylether and water, the organics washed
with water, dried, and evaporated under reduced pressure. The
residue was purified by chromatography on silica eluting with 3-5%
EtOAc/isohexane.
[0241] Yield 1.84 g
[0242] MS: APCI (+ve): 357/9 (M+1)
(v)
5-[2-(Benzyloxy)-5-chlorophenyl]-4-methyl-2-(methylsulfonyl)pyrimidine
[0243] The subtitle compound was prepared by the method of example
2 step (i). Yield 0.85 g
[0244] MS: APCI (+ve): 389/91 (M+1)
(vi)
4-Chloro-2-[4-methyl-2-(methylsulfonyl)pyrimidin-5-yl]phenol
[0245] The subtitle compound was prepared by the method of example
16 step (iv). Yield 0.5 g
[0246] MS: APCI (+ve): 299/301 (M+1)
(vii) tert-Butyl
{4-chloro-2-[4-methyl-2-(methylsulfonyl)pyrimidin-5-yl]phenoxy}acetate
[0247] The subtitle compound was prepared by the method of example
1 step (i). Yield 0.65 g
[0248] MS: APCI (+ve): 413 (M+1)
(viii) tert-Butyl
[4-chloro-2-(4-methyl-2-morpholin-4-ylpyrimidin-5-yl)phenoxy]acetate
[0249] A solution of the product from step (vii) (0.15 g) and
morpholine (0.15 ml) in dioxane (3 ml) was heated at 90.degree. C.
for 24 h, cooled and the solvent evaporated under reduced pressure.
Product used crude.
[0250] MS: APCI (+ve): 420/422 (M+1)
(ix)
[4-Chloro-2-(4-methyl-2-morpholin-4-ylpyrimidin-5-yl)phenoxy]acetic
acid
[0251] The title compound was prepared by the method of example 1
step Yield 0.046 g
[0252] .sup.1H NMR DMSO-d6: .delta. 8.12 (1H, s); 7.39 (1H, dd);
7.25 (1H, d); 7.00 (1H, d); 4.71 (2H, s); 3.73-3.67 (8H, m); 2.18
(3H, s)
[0253] MS: APCI (+ve): 364/6 (M+1)
EXAMPLE 20
{4-Chloro-2-[2-(dimethylamino)pyrimidin-5-yl]phenoxy}acetic
acid
##STR00032##
[0254] (i) 5-[2-(Benzyloxy)-5-chlorophenyl]-2-chloropyrimidine
[0255] The subtitle compound was prepared by the method of example
1 step (ii) using the product from example 16 step (ii) (3.2 g) and
2-chloro-5-bromopyrimidine (2.59 g). Yield 2.43 g
[0256] MS: APCI (+ve): 331/3 (M+1)
(ii) 5-[2-(Benzyloxy)-5-chlorophenyl]-2-(propylthio)pyrimidine
[0257] Propanethiol (3.1 ml) was added to a stirred suspension of
sodium hydride (1.4 g, 60% in oil) in DMF (30 ml). After 1 hour a
solution of the product from step (i) (2.4 g) in DMF (10 ml) was
added. The reaction mixture was stirred at RT for 1 hour then
partitioned between EtOAc and water. The organics were washed with
water, brine, dried and evaporated under reduced pressure. The
residue was purified by chromatography on silica eluting with 5%
EtOAc/isohexane. Yield 1.87 g
[0258] MS: APCI(+ve) 371 (M+1)
(iii)
5-[2-(Benzyloxy)-5-chlorophenyl]-2-(propylsulfonyl)pyrimidine
[0259] The subtitle compound was prepared by the method of example
2 step (i) using the product from step (ii).
[0260] MS: APCI(+ve) 403 (M+1)
(iv) tert-Butyl
{4-chloro-2-[2-(propylsulfonyl)pyrimidin-5-yl]phenoxy)acetate
[0261] The subtitle compound was prepared by the method of example
16 step (iv) and example 1 step (i) using the product from step
(iii). Yield 1.04 g
[0262] MS: APCI(+ve) 427 (M+1)
(v) {4-Chloro-2-[2-(dimethylamino)pyrimidin-5-yl]phenoxy}acetic
acid
[0263] Dimethylamine hydrochloride (0.82 g) was added to a stirred
solution of the product from step (iv) (0.2 g) and
N,N-diisopropylethylamine (0.9 ml) in NMP (5 ml). The reaction
mixture was heated at 90.degree. C. for 6 h then diluted with
EtOAc, washed with water, brine, dried and evaporated under reduced
pressure. The residue was dissolved in DCM (10 ml) then
trifluoroacetic acid (10 ml) added and stirred for 18 h at RT. The
reaction mixture was evaporated to dryness and the residue purified
by reverse phase HPLC followed by trituration with methanol to give
a white solid. Yield 0.035 g
[0264] 1H NMR DMSO-d6: .delta. 8.60 (2H, s); 7.42 (1H, d); 7.32
(1H, dd); 7.05 (1H, d); 4.77 (2H, s); 3.16 (6H, s).
[0265] MS: APCI(-ve) 306 (M-1)
EXAMPLE 21
[4-Chloro-2-(2-morpholin-4-ylpyrimidin-5-yl)phenoxy]acetic acid
##STR00033##
[0267] The title compound was prepared from the product of example
20 step (iv) and morpholine by the method of example 20 step
(v).
[0268] 1H NMR DMSO-d6: .delta. 13.10 (1H, brs); 8.65 (2H, s); 7.45
(1H, d); 7.34 (1H, dd); 7.06 (1H, d); 4.77 (2H, s); 3.75 (4H, m);
3.67 (4H, m)
[0269] MS: APCI(-ve) 348 (M-1)
EXAMPLE 22
{4-Chloro-2-[2-(methylamino)pyrimidin-5-yl]phenoxy}acetic acid
##STR00034##
[0271] The title compound was prepared from the product of example
20 step (iv) and methylamine hydrochloride by the method of example
20 step (v).
[0272] 1H NMR DMSO-d6: .delta. 8.54 (2H, s); 7.42 (1H, d); 7.32
(1H, dd); 7.25 (1H, brs); 7.04 (1H, d); 4.76 (2H, s); 2.84 (3H,
s)
[0273] MS: APCI(-ve) 292 (M-1)
EXAMPLE 23
{2-[2-(Benzylamino)pyrimidin-5-yl]-4-chlorophenoxy}acetic acid
##STR00035##
[0275] The title compound was prepared from the product of example
20 step (iv) and benzylamine by the method of example 20 step
(v).
[0276] 1H NMR DMSO-d6: .delta. 13.09 (1H, brs); 8.54 (2H, s); 7.90
(1H, t); 7.42 (1H, d); 7.35-7.29 (5H, m); 7.22 (1H, m); 7.03 (1H,
d); 4.76 (2H, s); 4.55 (2H, d)
[0277] MS: APCI(-ve) 368 (M-1)
EXAMPLE 24
[4-Chloro-2 (2-piperidin-1-ylpyrimidin-5-yl)phenoxy]acetic acid
##STR00036##
[0279] The title compound was prepared from the product of example
20 step (iv) and piperidine by the method of example 20 step
(v).
[0280] 1H NMR DMSO-d6: .delta. 13.10 (1H, brs); 8.59 (1H, d); 7.32
(1H, dd); 7.04 (1H, d); 4.77 (2H, s); 3.79 (4H, t); 1.65 (2H, m);
1.53 (4H, m)
[0281] MS: APCI(-ve) 346 (M-1)
EXAMPLE 25
(4-Chloro-2-{2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}phenoxy)acetic
acid
##STR00037##
[0282] (i) N-(5-Bromopyrimidin-2-yl)-N-methylmethanesulfonamide
[0283] Sodium hydride (0.22 g, 60% in oil) was added to a solution
of (5-bromopyrimidin-2-yl)methylamine (0.85 g) in DMF (10 ml) at
0.degree. C. and stirred for 30 min. Methanesulphonyl chloride
(0.62 g) was added dropwise, the mixture warmed to RT and stirred
for a further zo 2 h. The reaction was quenched with water and then
extracted with EtOAc. The organics were washed with water, dried,
and evaporated under reduced pressure. The residue was purified by
chromatography on silica eluting with 1% methanol/DCM. Yield 0.42
g
[0284] MS: APCI (+ve): 266 (M+1)
(ii)
N-[5-(5-Chloro-2-hydroxyphenyl)pyrimidin-2-yl]-N-methylmethanesulfona-
mide
[0285] The subtitle compound was prepared by the method of example
1 step (ii) using the product from step (i) and
2-hydroxy-5-chloroboronic acid (0.27 g). Yield 0.2 g
[0286] MS: APCI (+ve): 314 (M+1)
(iii)
(4-Chloro-2-{2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}phenoxy)a-
cetic acid
[0287] The title compound was prepared by the method of example 1
step (i) and (iii) using the product from step (ii). Yield 0.017
g
[0288] .sup.1H NMR DMSO-d6: .delta. 13.16 (1H, s); 8.94 (2H, s);
7.57 (1H, d); 7.45-7.42 (1H, m); 7.14 (1H, d); 4.82 (2H, s); 3.55
(3H, s); 3.47 (3H, s)
[0289] MS: APCI (-ve): 370 (M-1)
EXAMPLE 26
[[2',5-Dichloro-4'-(ethylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00038##
[0290] (i) 2-Chloro-4-(ethylthio)-1-iodo-benzene
[0291] A solution of 3-chloro-4-iodo-aniline (5.6 g),
isoamylnitrite (8.8 ml) and ethyldisulphide (13.4 ml) in
acetonitrile (100 ml) was heated at 60.degree. C. for 24 h. The
solvent was removed under reduced pressure and the residue purified
by chromatography on silica eluting with 1% ethylacetate/isohexane.
Yield 4.02 g
[0292] .sup.1H NMR. CDCl.sub.3: .delta. 7.70 (1H, d); 7.36 (1H, d);
6.87 (1H, dd); 2.94 (2H, q); 1.32 (3H, t)
(ii)
[[[2',5-Dichloro-4'-(ethylthio)[1,1'-biphenyl]-2-yl]oxy]methyl]-benze-
ne
[0293] The subtitle compound was prepared by the method of example
1 step (ii) using the product from step (i) and the product from
example 16 step (ii). Yield 3.64 g
[0294] .sup.1H NMR CDCl.sub.3: .delta. 7.4 (1H, s); 7.32-7.18 (9H,
m); 6.92 (1H, d); 5.03 (2H, s); 2.99 (2H, q); 1.36 (3H, t)
(iii)
[[[2',5-Dichloro-4'-(ethylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]methyl]--
benzene
[0295] The subtitle compound was prepared by the method of example
2 step (i) using the product from step (ii). Yield 3.8 g
[0296] .sup.1H NMR CDCl.sub.3: .delta. 8.00 (1H, s); 7.81 (1H, d);
7.48 (1H, d); 7.36-7.20 (7H, m); 6.95 (1H, d); 5.04 (2H, s); 3.16
(2H, q); 1.32 (3H, t)
(iv) 2',5-Dichloro-4'-(ethylsulfonyl)-[1,1'-biphenyl]-2-ol
[0297] The subtitle compound was prepared by the method of example
16 step (iv) using the product from step (iii). Yield 2.44 g
[0298] .sup.1H NMR CDCl.sub.3: .delta. 8.03 (1H, s); 7.85 (1H, d);
7.55 (1H, d); 7.30 (1H, d); 7.16 (1H, s); 6.92 (1H, d); 5.20 (2H,
s); 3.17 (2H, q); 1.36 (3H, t)
(v)
[[2',5-Dichloro-4'-(ethylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid, ethyl ester
[0299] The subtitle compound was prepared by the method of example
1 step (i) using the product from step (iv) and ethylbromoacetate.
Yield 2.23 g
(vi)
[[2',5-Dichloro-4'-(ethylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
[0300] A mixture of the product from step (v) (2.23 g), 1M aqueous
sodium hydroxide (10 ml) and THF (20 ml) was stirred at RT for 3 h.
The mixture was acidified with 2M hydrochloric acid, extracted with
diethylether and the organics washed with water, dried, and
evaporated under reduced pressure. The residue was recrystallised
from ethylacetate/isohexane, yield 0.45 g.
[0301] .sup.1H NMR CDCl.sub.3: .delta. 13.02 (1H, s); 8.02 (1H, s);
7.89 (1H, d); 7.69 (1H, d); 7.48 (1H, dd); 7.34 (1H, d); 7.08 (1H,
d); 4.70 (2H, s); 3.44 (2H, q); 1.16 (3H, t)
[0302] MS: APCI (-ve): 387/9 (M-1)
[0303] Mpt. 163-4.degree. C.
EXAMPLE 27
[[(2'-Chlaro-4'-(ethyLsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]ox-
y]-acetic acid
##STR00039##
[0304] (i)
2-Bromo-1-(phenylmethoxy)-4-(trifluoromethyl)-benzene
[0305] The subtitle compound was prepared by the method of example
16 step (i) using 2-bromo-4-trifluoromethylphenol. Yield 58.7 g
[0306] .sup.1H NMR CDCl.sub.3: .delta. 7.83 (1H, s); 7.51-7.32 (6H,
m); 6.98 (1H, d); 5.21 (2H, s)
(ii) [2-(Phenylmethoxy)-5-(trifluoromethyl)phenyl]-boronic acid
[0307] The subtitle compound was prepared by the method of example
16 step (ii) using the product from step (i). Yield 30.7 g
[0308] .sup.1H NMR CDCl.sub.3: .delta. 8.14 (1H, d); 7.68 (1H, dd);
7.44-7.39 (5H, m); 7.05 (1H, d); 5.79 (2H, s); 5.20 (2H, s)
(iii) [2-Hydroxy-5-(trifluoromethyl)phenyl]-boronic acid
[0309] The subtitle compound was prepared by the method of example
16 step (iv) using the product from step (ii). Yield 3.54 g
(iv)
2'-Chloro-4'-(ethylthio)-5-(trifluoromethyl)-[1,1'-biphenyl]-2-ol
[0310] A mixture of palladium acetate (0.045 g) and
tri-p-tolylphosphine (0.213 g) in methanol (10 ml) was stirred at
RT for 30 min. The product from step (iii) (1 g), sodium carbonate
(1.27 g), the product from example (26) step (i) (1.19 g) and
methanol (20 ml) were added and the mixture heated under reflux for
6 h. The solvent was removed under reduced pressure and the residue
partitioned between diethylether and 2M hydrochloric acid. The
organics were separated, dried and evaporated under reduced
pressure. The residue was purified by chromatography on silica
eluting with 10% ethylacetate/isohexane. Yield 0.503 g
[0311] MS: ESI (-ve): 331/3 (M-1)
(v)
2'-Chloro-4'-(ethylsulfonyl)-5-(trifluoromethyl)-[1,1'-biphenyl]-2-ol
[0312] The subtitle compound was prepared by the method of example
2 step (i) using the product from step (iv). Yield 0.277 g
[0313] MS: ESI (-ve): 363/5 (M-1)
(vi)
[[2'-chloro-4'-(ethylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-y-
l]oxy]-acetic acid, 1,1-dimethylethyl ester
[0314] The subtitle compound was prepared by the method of example
1 step (i) using the product from step (v). Yield 0.253 g
(vii)
[[2'-Chloro-4'-(ethylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2--
yl]oxy]-acetic acid
[0315] The title compound was prepared by the method of example 1
step (iii) using the product from step (vi). Yield 0.154 g
[0316] .sup.1H NMR CDCl.sub.3: .delta. 13.12 (1H, s); 8.04 (1H, s);
7.91 (1H, d); 7.81 (1H, d); 7.72 (1H, d); 7.63 (1H, s); 7.25 (1H,
d); 4.82 (2H, s); 3.45 (2H, q); 1.17 (3H, t)
[0317] MS: APCI (-ve): 421/3 (M-1)
[0318] Mpt. 167.degree. C.
EXAMPLE 28
[[5-Chloro-4'-(ethylsulfonyl)-2'-fluoro[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00040##
[0319] (i) 1-Bromo-4-(ethylthio)-2-fluoro-benzene
[0320] Bromine (0.3 ml) was added to a solution of
1-ethylsulfanyl-3-fluoro-benzene (1 g) in chloroform (20 ml) at
0.degree. C. then warmed to RT. After 2 h the mixture was diluted
with DCM, washed with aq. sodium thiosulphate solution, dried, and
evaporated under reduced pressure. The residue was purified by
chromatography on silica eluting with 10% diethylether/iso-hexane.
Yield 1.2 g
[0321] .sup.1H NMR CDCl.sub.3: .delta. 7.44-6.93 (3H, m); 2.99-2.90
(2H, q); 1.42-1.30 (3H, t).
(ii) 1-Bromo-4-(ethylsulfonyl)-2-fluoro-benzene
[0322] The subtitle compound was prepared by the method of example
2 step (i) using the product from step (i). Yield 0.94 g
[0323] .sup.1H NMR CDCl.sub.3: 57.81-7.07 (3H, m); 3.17-3.10 (2H,
q); 1.32-1.19 (3H, t).
(iii)
[[[5-Chloro-4'-(ethylsulfonyl)-2'-fluoro[1,1'-biphenyl]-2-yl]oxy]met-
hyl]-benzene
[0324] The subtitle compound was prepared by the method of example
1 step (ii) using the product from step (ii) and the product from
example 16 step (ii). Yield 0.55 g
[0325] .sup.1H NMR CDCl.sub.3: 87.73-6.96 (11H, m); 5.09 (2H, s);
3.19-3.13 (2H, q); 1.33-1.27 (311,
(iv) 5-Chloro-4'-(ethylsulfonyl)-2'-fluoro-[1,1'-biphenyl]-2-ol
[0326] The subtitle compound was prepared by the method of example
16 step (iv) using the product from step (ii), yield 0.35 g
[0327] MS: ESI (-ve) 313 (M-1)
(v)
[[5-Chloro-4'-(ethylsulfonyl)-2'-fluoro[1,1'-biphenyl]-2-yl]oxy]-aceti-
c acid
[0328] The title compound was prepared by the method of example 1
step (i) and step (iii) using the product from step (iv), yield
0.205 g
[0329] .sup.1H NMR. DMSO-d6: .delta. 7.81-7.08 (6H, m); 4.73 (2H,
s); 3.44-3.39 (2H, q); 1.17-1.14 (3H, t).
[0330] MS: ESI (-ve) 371 (M-1)
EXAMPLE 29
[[(4'-(Ethylsulfonyl)-2'-fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]ox-
y]-acetic acid, sodium salt
##STR00041##
[0332] The title compound was prepared by the method of example 28,
yield 0.26 g.
[0333] .sup.1H NMR DMSO-d6: .delta. 7.96-7.57 (5H, m); 7.09-7.07
(1H, d); 4.31 (2H, s); 3.44-3.35 (2H, q); 1.18-1.14 (3H, t).
[0334] MS: ESI (-ve) 405 (M-1)
EXAMPLE 30
[[5-Chloro-4'-(ethylsulfonyl)-2'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy-
]-acetic acid
##STR00042##
[0335] (i) 1-Bromo-4-(ethylthio)-2-(trifluoromethyl)-benzene
[0336] Iodoethane (0.84 ml) was added to a stirred solution of
3-trifluoromethyl-thiophenol (2 g) and potassium carbonate (1.42 g)
in DMF (20 ml). After 72 h the mixture was partitioned between
diethylether and water, the organics separated, dried and
evaporated under reduced pressure. The residue was dissolved in
acetic acid (20 ml), cooled to 0.degree. C., then bromine (0.51 ml)
added. The mixture was stirred at RT for 16 h, the solvent removed
under reduced pressure and the residue purified by chromatography
on silica eluting with 25% DCM/iso-hexane. Yield 2.05 g
(ii)
5-Chloro-4'-(ethylthio)-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-ol
[0337] The subtitle compound was prepared by the method of example
1 step (ii) using the product from step (i) and
5-chloro-2-hydroxyphenyl-boronic acid, yield 0.26 g
[0338] MS: ESI (-ve) 347 (M-1)
(iii)
[[5-Chloro-4'-(ethylthio)-2'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]o-
xy]-acetic acid, 1,1-dimethylethyl ester
[0339] The subtitle compound was prepared by the method of example
1 step (i) using the product from step (ii), yield 0.26 g
[0340] MS: APCI (-ve) 389/391 (M-1) t-butyl
(iv)
[[5-Chloro-4'-(ethylsulfonyl)-2'-(trifluoromethyl)[1,1'-biphenyl]-2-y-
l]oxy]-acetic acid
[0341] The title compound was prepared by the method of example 2
step (i) and example 1 step (iii) using the product from step yield
0.045 g
[0342] .sup.1H NMR DMSO-d6: .delta. 7.62-7.01 (6H, m); 4.69-4.66
(2H, s); 4.20-4.10 (2H, q); 1.40-1.35 (3H, t).
[0343] MS: ESI (-ve) 421 (M-1)
EXAMPLE 31
2-[[5-Chloro-4'-(ethylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-propanoic
acid
##STR00043##
[0344] (i) 2-(2-Bromo-4-chlorophenoxy)-propanoic acid,
1,1-dimethylethyl ester
[0345] The subtitle compound was prepared by the method of example
1 step (i) using 2-bromo-4-chlorophenol and 2-bromopropionic acid,
tert-butyl ester, yield 1.1 g
[0346] .sup.1H NMR DMSO-d6: .delta. 7.54-7.16 (2H, m); 6.74-6.71
(1H, d); 3.70 (3H, s); 1.78-1.76 (1H, d); 1.48 (9H, s).
2-[[5-Chloro-4'-(ethylthio)[1,1'-biphenyl]-2-yl]oxy]-propanoic
acid, 1,1-dimethylethyl ester
[0347] The subtitle compound was prepared by the method of example
1 step (ii) using the product from step (i) and
4-(ethylthio)benzeneboronic acid, yield 12 g.
[0348] MS: APCI (-ve) 336 (M-1)-t-butyl
(iii)
2-[[5-Chloro-4'-(ethylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-propanoic
acid
[0349] The title compound was prepared by the method of example 2
step (i) and example 1 step (iii) using the product from step (ii),
yield 0.08 g
[0350] .sup.1H NMR DMSO-d6: .delta. 7.97-6.96 (7H, m); 4.79-4.76
(1H, m); 3.39-3.31 (2H, t); 1.39-1.37 (3H, d); 1.16-1.07 (3H,
t).
[0351] MS: ESI (-ve) 367 (M-1)
EXAMPLE 32
2-[[4'-(Ethylsulfonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]o-
xy]-(2S)-propanoic acid
##STR00044##
[0352] (i) 1-Bromo-4-(ethylsulfonyl)-2-methyl-benzene
[0353] The subtitle compound was prepared by the method of example
2 step (i) using the product from example 10 step (i), yield 4.3
g.
[0354] MS: ESI (+ve) 264 (M+1)
(ii) [2-(Phenylmethoxy)-5-(trifluoromethyl)phenyl]-boronic acid
[0355] The subtitle compound was prepared by the method of example
16 step (ii) using the product from example 27 step (i), yield 5.5
g.
[0356] .sup.1H NMR CDCl.sub.3: .delta. 8.14-7.62 (2H, m); 7.43-7.38
(5H, m); 7.01 (1H, m); 5.67 (2H, s); 5.19-5.16 (2H, s)
(iii)
[[[4'-(Ethylsulfonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-
-yl]oxy]methyl]-benzene
[0357] The subtitle compound was prepared by the method of example
1 step (ii) using the product from step (i) and (ii), yield 2.72
g.
[0358] MS: ESI (+ve) 452 (M+1+NH.sub.3)
(iv)
4'-(Ethylsulfonyl)-2'-methyl-(trifluoromethyl)-[1,1'-biphenyl]-2-ol
[0359] The subtitle compound was prepared by the method of example
16 step (iv) using the product from step (iii), yield 2.1 g.
[0360] MS: ESI (+ve) 362 (M+1+NH.sub.3)
(v)
2-[[4'-(Ethylsulfonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2--
yl]oxy]-(2S)-propanoic acid, methyl ester
[0361] Diethyl azodicarboxylate (0.14 ml) was added to a stirred
solution of the product from step (iv) (0.3 g), methyl-R-lactate
(0.083 ml) and triphenylphosphine (0.228 g) in THF (10 ml) at
0.degree. C. After 4 h, the mixture was diluted with water and
extracted with ethylacetate, the organics separated, dried and
evaporated under reduced pressure. The residue was purified by
chromatography on silica eluting with 50% diethylether/iso-hexane.
Yield 0.4 g
[0362] MS: ESI (+ve) 448 (M+1+NH.sub.3)
(vi)
2-[[4'-(Ethylsulfonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-
-yl]oxy]-(2S)-propanoic acid
[0363] A mixture of the product from step (v) (0.4 g) and lithium
hydroxide (2 equiv) in THF (10 ml) and water (10 ml) was stirred at
RT overnight. The mixture was partitioned between
ethylacetate/water, the aqueous layer was acidified with 2M
hydrochloric acid and extracted with ethyl acetate. The organic
layer was dried, evaporated under reduced pressure and the residue
purified by reverse phase HPLC. Yield 0.035 g
[0364] .sup.1H NMR DMSO-d6: .delta. 7.78-7.44 (5H, m); 7.16-7.14
(1H, d); 4.91-4.86 (1H, q); 3.30-3.25 (2H, q); 2.22 (3H, s);
1.33-1.24 (3H, d); 1.10-1.07 (3H, t).
[0365] MS: ESI (+ve) 434 (M+1+NH.sub.3)
EXAMPLE 33
2-[[4'-(Ethylsulfonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]o-
xy]-(2R)-propanoic acid, sodium salt
##STR00045##
[0367] The title compound was prepared by the method of example 32
using methyl-5-lactate, yield 0.2 g.
[0368] .sup.1H NMR DMSO-d6: .delta. 7.77-7.38 (5H, m); 7.02-7.00
(1H, d); 4.32 (1H, m); 3.39-3.25 (2H, q); 2.32 (3H, s); 1.21-1.07
(6H, d+t).
[0369] MS: ESI (+ve) 434 (M+1+NH.sub.3)
EXAMPLE 34
2-[[2',5-Dichloro-4'-(ethylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-propano-
ic acid, sodium salt
##STR00046##
[0371] The title compound was prepared by the method of example 32
step (v) and (vi) using the product from example 26 step (iv),
yield 0.18 g.
[0372] .sup.1H NMR DMSO-d6: .delta. 7.99-7.23 (5H, m); 6.93-6.91
(1H, d); 4.26-4.24 (1H, q); 3.46-3.37 (2H, q); 1.20-1.06 (6H,
d+t).
[0373] MS: ESI (-ve) 402/403 (M-1)
EXAMPLE 35
2-[[2'-Chloro-4'-(ethylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]o-
xy]-(2S)-propanoic acid
##STR00047##
[0375] The title compound was prepared by the method of example 32
step (v) and (vi) using the product from example 2 step (v), yield
0.05 g.
[0376] .sup.1H NMR DMSO-d6: .delta. 7.98-7.23 (5H, m); 6.93-6.91
(1H, d); 4.68 (1H, m); 3.20-3.15 (2H, q); 1.48-1.39 (3H, m);
1.34-1.30 (3H, t).
[0377] MS: ESI (-ve) 436 (M-1)
EXAMPLE 36
2-[[4'-(Ethylsulfonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]o-
xy]-2-methyl-propanoic acid, sodium salt
##STR00048##
[0379] The title compound was prepared by the method of example 1
step (i) and example 26 step (vi) using the product from example 34
step (iv), yield 0.18 g.
[0380] .sup.1H NMR DMSO-d6: .delta. 7.72 (1H, s); 7.71 (1H, d);
7.56 (1H, d); 7.44 (1H, d); 7.35 (1H, s); 7.10 (1H, d); 2.29 (3H,
s); 1.38 (6H, s); 1.13 (3H, t)
[0381] MS: ESI (-ve) 429 (M-1)
EXAMPLE 37
2-[[4'-(Ethylsulfonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]o-
xy]-butanoic acid, sodium salt
##STR00049##
[0383] The title compound was prepared by the method of example 1
step (i) and example 26 step (vi) using the product from example 34
step (iv), yield 0.29 g.
[0384] .sup.1H NMR DMSO-d6: .delta. 7.78 (1H, s); 7.71 (1H, d);
7.64 (1H, d); 7.41 (1H, s); 7.01 (1H, d); 4.27 (1H, brs); 3.36 (2H,
q); 2.33 (3H, brs); 1.64-1.55 (2H, m); 1.11 (3H, t); 0.66 (3H,
brs)
[0385] MS: ESI (-ve) 429 (M-1)
EXAMPLE 38
[4-Chloro-2-[2-[(methylsulfonyl)(phenylmethyl)amino]-5-pyrimidinyl]phenoxy-
]-acetic acid
##STR00050##
[0386] (i)
N-(5-Bromo-2-pyrimidinyl)-N-(phenylmethyl)-methanesulfonamide
[0387] Sodium hydride (0.1 g, 60% disp. in oil) was added to a
stirred solution of benzyl-(5-bromo-pyrimidin-2-yl)-amine (0.55 g)
in DMF (8 ml) at 0.degree. C. After 30 min methanesulphonyl
chloride (0.286 g) was added and the mixture stirred at RT for 2 h
then partitioned between ethyl acetate and water. The organics were
separated washed with water, dried and evaporated under reduced
pressure. The residue was purified by chromatography on silica
eluting with dichloromethane. Yield 0.41 g
[0388] MS: APCI (+ve) 344 (M+1)
(ii)
N-[5-(5-Chloro-2-hydroxyphenyl)-2-pyrimidinyl]-N-(phenylmethyl)-metha-
nesulfonamide
[0389] The subtitle compound was prepared by the method of example
1 step (ii) using the product from step (i) and
5-chloro-2-hydroxyphenyl-boronic acid, yield 0.25 g.
[0390] MS: APCI (+ve) 390 (M+1)
(iii)
[4-Chloro-2-[2-[(methylsulfonyl)(phenylmethylamino)-5-pyrimidinyl]ph-
enoxy]-acetic acid
[0391] The title compound was prepared by the method of example 1
step (i) and step (iii) using the product from step (ii), yield
0.07 g.
[0392] .sup.1H NMR DMSO-d6: .delta. 13.16 (1H, s); 8.93 (2H, s);
7.56 (1H, d); 7.44-7.41 (1H, m); 7.37-7.31 (4H, m); 7.27-7.23 (1H,
m); 7.12 (1H, d); 5.28 (2H, s); 4.81 (2H, s); 3.59 (3H, s).
[0393] MS: APCI (-ve): 446 (M-1)
EXAMPLE 39
[4-Chloro-2-[2-(ethylsulfonyl)(phenylmethyl)amino]-5-pyrimidinyl]phenoxy]--
acetic acid
##STR00051##
[0394] (i)
N-(5-Bromo-2-pyrimidinyl)-N-(phenylmethyl)-ethanesulfonamide
[0395] The subtitle compound was prepared by the method of example
38 step (i) using benzyl-(5-bromo-pyrimidin-2-yl)-amine and
ethanesulphonyl chloride, yield 0.31 g.
[0396] MS: APCI (+ve) 358 (M+1)
(ii)
N-[5-(5-Chloro-2-hydroxyphenyl)-2-pyrimidinyl]-N-(phenylmethyl)-ethan-
esulfonamide
[0397] The subtitle compound was prepared by the method of example
1 step (ii) using the product from step (i) and
5-chloro-2-hydroxyphenyl-boronic acid, yield 0.25 g.
[0398] MS: APCI (+ve) 404 (M+1)
(iii)
[4-Chloro-2-[2-(ethylsulfonyl)(phenylmethyl)amino]-5-pyrimidinyl]phe-
noxy]-acetic acid
[0399] The title compound was prepared by the method of example 1
step (i) and step using the product from step (ii), yield 0.13
g.
[0400] .sup.1H NMR DMSO-d6: .delta. 13.14 (1H, s); 8.92 (2H, s);
7.56 (1H, d); 7.44-7.31 (5H, m); 7.27-7.23 (1H, m); 7.12 (1H, d);
5.27 (2H, s); 4.81 (2H, s); 3.87 (2H, q); 1.25 (3H, t).
[0401] MS: APCI (-ve): 460 (M-1)
EXAMPLE 40
2-[2-[2-[Acetyl(phenylmethyl)amino]-5-pyrimidinyl]-4-chlorophenoxy]-acetic
acid
##STR00052##
[0402] (i) N-(5-Bromo-2-pyrimidinyl)-N-(phenylmethyl)-acetamide
[0403] The subtitle compound was prepared by the method of example
38 step (i) using benzyl-(5-bromo-pyrimidin-2-yl)-amine and
acetylchloride, yield 0.21 g.
[0404] MS: APCI (+ve) 306 (M-1)
(ii)
N-[5-(5-Chloro-2-hydroxyphenyl)-2-pyrimidinyl]-N-(phenylmethyl)-aceta-
mide
[0405] The subtitle compound was prepared by the method of example
1 step (ii) using the product from step (i) and
5-chloro-2-hydroxyphenyl-boronic acid, yield 0.16 g.
[0406] MS: APCI (+ve) 354 (M-1)
(iii)
[2-[2-[Acetyl(phenylmethyl)amino]-5-pyrimidinyl]-4-chlorophenoxy]-ac-
etic acid
[0407] The title compound was prepared by the method of example 1
step (i) and step (iii) using the product from step (ii), yield
0.08 g.
[0408] .sup.1H NMR DMSO-d6: .delta. 9.01 (2H, s); 7.59 (1H, d);
7.44 (1H, q); 7.30-7.18 (5H, m); 7.13 (1H, d); 5.26 (2H, s); 4.81
(2H, s); 2.45 (3H, s).
[0409] MS: APCI (+ve): 412 (M-1)
EXAMPLE 41
[[4'-(Ethylsulfonyl)-5-fluoro-2'-methyl[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00053##
[0410] (i) [4-(Ethylthio)-2-methylphenyl]-boronic acid
[0411] A 100 ml portion of a solution of the product from example
10 step (i) (120.7 g) in THF (500 ml) was added to a stirred
mixture of magnesium turnings (13.4 g) in THF (100 ml).
Dibromoethane (0.2 ml) was added, and the mixture gently refluxed
on initiation. The remaining bromide solution was added dropwise
maintaining the reaction at reflux. After addition the mixture was
allowed to cool to RT then transferred via cannula into a stirred
solution of trimethylborate (112 ml) in THF (200 ml) at 0.degree.
C. The mixture was warmed to RT, stirred for 2 h then quenched with
2M hydrochloric acid (300 ml). After stirring at RT for 18 h the
THF was removed under reduced pressure and the mixture extracted
with diethylether. The organics were separated, washed with water,
dried and evaporated under reduced pressure. The residue was
triturated with diethylether/isohexane and filtered.
[0412] Yield 53.02 g
[0413] .sup.1H NMR CDCl.sub.3: .delta. 8.08 (1H, d); 7.18 (1H, d);
7.15 (1H, s); 3.04 (2H, q); 2.76 (3H, s); 1.38 (3H, t)
(ii) (2-Bromo-4-fluorophenoxy)-acetic acid, 1,1-dimethylethyl
ester
[0414] The subtitle compound was prepared by the method of example
1 step (i).
(iii)
[[4'-(Ethylsulfonyl)-5-fluoro-2'-methyl[1,1'-biphenyl]-2-yl]oxy]-ace-
tic acid
[0415] The title compound was prepared by the method of example 27
step (iv), example 2 step (i) and example 1 step (iii) using the
products from step (i) and (ii), yield 0.045 g.
[0416] .sup.1H NMR DMSO-d6: .delta. 7.8-7.64 (2H, m); 7.42 (2H, d);
7.8-6.0 (3H, m); 4.10 (2H, s); 3.20 (2H, q); 1.18 (3H, t)
[0417] MS: APCI (-ve): 351 (M-1)
EXAMPLE 42
[[4'-(Ethylsulfonyl)-4,5-difluoro-2'-methyl[1,1'-biphenyl]-2-yl]oxy]-aceti-
c acid
##STR00054##
[0419] The title compound was prepared by the method of example 41,
yield 0.081 g.
[0420] .sup.1H NMR DMSO-d6: .delta. 7.76 (1H, s); 7.71 (1H, dd);
7.44 (1H, d); 7.23 (1H, t); 7.01-6.94 (1H, m); 4.32 (2H, s); 3.39
(2H, m); 2.25 (3H, s); 1.18 (3H, t)
[0421] MS: APCI (-ve): 369 (M-1)
EXAMPLE 43
[[4-(Ethylsulfonyl)-3,5-difluoro-2'-methyl[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00055##
[0423] The title compound was prepared by the method of example 41,
yield 0.15 g.
[0424] .sup.1H NMR DMSO-d6: .delta. 7.82-7.70 (2H, m); 7.49-7.38
(2H, m); 7.02-6.90 (1H, m); 4.40 (2H, d); 3.34 (2H, q); 1.11 (3H,
t)
EXAMPLE 44
[2-(2-Amino-5-methyl-3-pyridinyl)-4-(trifluoromethyl)phenoxy]-acetic
acid
##STR00056##
[0425] (i) [4-(Trifluoromethyl)phenoxy]-acetic acid
[0426] Sodium hydride (2.96 g, 60% disp. in oil) was added to a
stirred solution of 4-hydroxybenzo-trifluoride (10 g) in
tetrahydrofuran (150 ml) at -78.degree. C. The cooling bath was
removed, the mixture stirred for 1 h then methyl bromoacetate (7
ml) added. After 1 h, water was added, the tetrahydrofuran
evaporated off under reduced pressure and the residue partitioned
between ethyl acetate/2M hydrochloric acid. The organic layer was
evaporated under reduced pressure and the residue dissolved in
tetrahydrofuran (120 ml). Methanol (30 ml), water (30 ml) and conc.
sodium hydroxide solution (6 ml) was added and the mixture stirred
at RT overnight. The organics were removed under reduced pressure
and the residue partitioned between ethylacetate and 2M
hydrochloric acid. The organics were separated, dried and
evaporated under reduced pressure, yield 12.42 g
[0427] .sup.1H NMR DMSO-d6: .delta. 13.13 (1H, s); 7.65 (2H, d);
7.10 (2H, d); 4.80 (2H, s).
[0428] MS: APCI (-ve) 219 (M-1)
[4-(Trifluoromethyl)phenoxy]-acetic acid,
(3-methyl-3-oxetanyl)methyl ester
[0429] Oxalyl chloride (14 ml) was added to a solution of the
product from step (i) (12.42 g) and N,N-dimethylformamide (2 drops)
in dichloromethane (100 ml), and stirred at RT for 72 h. The
mixture was evaporated under reduced pressure, the residue
dissolved in dichloromethane (100 ml) then triethylamine (20 ml)
and 3-methyl-3-oxetanemethanol (17 ml) added. After 2 h the mixture
was washed with water, evaporated under reduced pressure and the
residue purified by chromatography on silica eluting with
dichloromethane, yield 14.2 g.
[0430] .sup.1H NMR DMSO-d6: .delta. 7.66 (2H, d); 7.14 (2H, d);
4.98 (2H, s), 4.34 (2H, d); 4.24 (2H, s); 4.19 (2H, d), 1.21 (3H,
s).
(iii)
4-Methyl-1-[[4-(trifluoromethyl)phenoxy]methyl]-2,6,7-trioxabicyclo[-
2.2.2]octane
[0431] Boron trifluoride diethyl etherate (1.48 ml) was added to a
solution of the product from step (ii) (14.2 g) in dichloromethane
at -78.degree. C. The cooling bath was removed, the mixture,
stirred for 3 h then triethylamine (6.2 ml) added. The mixture was
reduced to half the volume under reduced pressure then filtered.
The filtrate was evaporated under reduced pressure then the residue
purified by chromatography on silica (pre-eluted with one column
volume of neat triethylamine) eluting with dichloromethane, yield
11.1 g.
[0432] .sup.1H NMR DMSO-d6: .delta. 7.62 (2H, d); 7.14 (2H, d);
4.04 (2H, s); 3.91 (6H, s); 0.77 (3H, s).
[0433] MS: APCI (+ve) 305 (M+1)
(iv) [2-Borono-4-(trifluoromethyl)phenoxy]-acetic acid
[0434] A solution of sec-butyllithium (66 ml, 1.4M in cyclohexane)
was added dropwise over 10 min to a stirred solution of the product
from step (iii) (9.44 g) in THF (100 ml) at -78.degree. C. After 3
h the mixture was warmed to -40.degree. C. for 5 min, then cooled
to -78.degree. C. Trimethylborate (14.1 ml) was added, then after
10 min the reaction quenched with 2M hydrochloric acid. The mixture
was warmed to RT and the organic phase separated. The aqueous layer
was extracted with ethylacetate, the organics combined and
evaporated under reduced pressure. The residue was dissolved in
methanol (500 ml) then bondelut-NH.sub.2 resin(180 g) added and the
mixture swirled for 0.5 h then filtered. The resin was washed with
10% acetic acid/methanol, the washings then evaporated under
reduced pressure and dried under high vacuum. The residue was
dissolved in methanol (50 ml), tetrahydrofuran (50 ml) and
saturated aqueous sodium hydroxide solution (2 ml), left for 30 min
then 2M hydrochloric acid (50 ml) added and the organics evaporated
under reduced pressure. The residual aqueous layer was extracted
with ethylacetate, the organics separated, dried and evaporated
under reduced pressure, yield 5.05 g.
[0435] .sup.1H NMR. DMSO-d6: .delta. 8.07 (1H, s); 7.89 (1H, d);
7.75 (1H, dd); 7.14 (1H, d); 4.85 (2H, s).
[0436] MS: APCI (-ve) 263 (M-1)
(v)
[2-(2-Amino-5-methyl-3-pyridinyl)-4-(trifluoromethyl)phenoxy]-acetic
acid
[0437] A mixture of the product from step (iv) (0.1 g),
2-amino-3-bromo-5-methylpyridine (0.071 g),
tetrakis(triphenylphosphine)palladium(0) (0.046 g), sodium
carbonate (0.12 g) in methanol (2 ml) was heated in a CEM microwave
(variable wattage up to 150 W) at 100.degree. C. for 10 min. The
mixture was loaded onto SCX resin (sulphonic acid resin), flushed
with methanol then the product eluted with methanol/ammonia. The
methanol/ammonia filtrate was evaporated under reduced pressure
then loaded onto bondelut-NH.sub.2 resin. The resin was flushed
with methanol then the product eluted with methanol/acetic acid.
The methanol/acetic acid filtrate was evaporated and the residue
purified by RPHPLC. Yield 0.089 g
[0438] .sup.1H NMR DMSO-d6: .delta. 7.87 (1H, s); 7.79 (1H, d);
7.69 (1H, s); 7.63 (1H, s); 7.26 (1H, d); 4.9 (2H, s); 2.2 (3H,
s).
[0439] MS: APCI (-ve) 325 (M-1)
EXAMPLE 45-123
[0440] The following compounds were synthesised in an analogous
method to example 44
EXAMPLE 45
[[4-Amino-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00057##
[0442] .sup.1H NMR DMSO-d6: .delta. 7.62 (1H, d); 7.32 (1H, s);
7.05 (1H, d); 6.81 (1H, d); 6.47 (1H, s); 6.44 (1H, d); 4.74 (2H,
s); 1.98 (3H, s).
[0443] MS: APCI (-ve) 324 (M-1)
EXAMPLE 46
[[4'-Amino-2'-chloro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00058##
[0445] .sup.1H NMR DMSO-d6: .delta. 7.65 (1H, d); 7.4 (1H, s), 7.15
(1H, d); 7.04 (1H, d); 6.7 (1H, s); 6.56 (1H, d); 4.76 (2H, s).
[0446] MS: APCI (-ve) 344/6 (M-1)
EXAMPLE 47
[[2'-Chloro-4'-hydroxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00059##
[0448] .sup.1H NMR DMSO-d6: .delta. 9.98 (1H, s); 7.69 (1H, d);
7.44 (1H, s); 7.21 (1H, d); 7.14 (1H, d); 6.91 (1H, s); 6.80 (1H,
d); 4.76 (2H, s).
[0449] MS: APCI (-ve) 345/7 (M-1)
EXAMPLE 48
[2-(2,4-Dimethoxy-5-pyrimidinyl)-4-(trifluoromethyl)phenoxy]-acetic
acid
##STR00060##
[0451] .sup.1H NMR DMSO-d6: .delta. 8.32 (1H, s); 7.71 (1H, d);
7.63 (1H, s); 7.20 (1H, d); 4.8 (2H, s); 3.95 (3H, s); 3.87 (3H,
s).
[0452] MS: APCI (-ve) 357 (M-1)
EXAMPLE 49
[[2'-Chloro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00061##
[0454] .sup.1H NMR DMSO-d6: .delta. 7.75 (1H, d); 7.55 (1H, m),
7.50 (1H, s); 7.42 (1H, m); 7.41 (1H, d); 7.40 (1H, d); 7.19 (1H,
d); 4.78 (2H, s).
[0455] MS: APCI (-ve) 329/31 (M-1)
EXAMPLE 50
[[2',5-Bis(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00062##
[0457] .sup.1H NMR DMSO-d6: .delta. 7.83 (1H, d); 7.75 (1H, d);
7.71 (1H, d); 7.63 (1H, t); 7.44 (1H, s); 7.43 (1H, d); 4.74 (2H,
m).
[0458] MS: APCI (-ve) 363 (M-1)
EXAMPLE 51
[[5'-Fluoro-2'-methoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00063##
[0460] .sup.1H NMR DMSO-d6: .delta. 7.68 (1H, d); 7.51 (1H, s);
7.20 (1H, d); 7.17 (1H, m); 7.15 (1H, m); 7.10 (1H, d); 4.78 (2H,
s); 3.7 (3H, s).
[0461] MS: APCI (-ve) 343 (M-1)
EXAMPLE 52
[[5'-Cyano-2'-methoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00064##
[0463] .sup.1H NMR DMSO-d6: .delta. 7.87 (1H, d); 7.74 (1H, s);
7.71 (1H, d); 7.56 (1H, s); 7.29 (1H, d); 7.19 (1H, d); 4.77 (2H,
s); 3.81 (3H, s).
[0464] MS: APCI (-ve) 350 (M-1)
EXAMPLE 53
[[4'-Chloro-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00065##
[0466] .sup.1H NMR DMSO-d6: .delta. 7.71 (1H, d), 7.47 (1H, s),
7.34 (1H, d), 7.30 (1H, d), 7.24 (1H, s), 7.13 (1H, d), 4.73 (2H,
s), 2.11 (3H, s)
[0467] MS: APCI (-ve) 343/345 (M-1)
EXAMPLE 54
[[2',5'Dimethyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00066##
[0469] .sup.1H NMR DMSO-d6: .delta. 7.64 (1H, d), 7.35 (1H, s),
7.13 (1H, d), 7.07 (1H, d), 7.02 (1H, d), 6.94 (1H, s), 4.50 (2H,
s), 2.30 (3H, s), 2.08 (3H, s)
[0470] MS: APCI (-ve) 323 (M-1)
EXAMPLE 55
[[5'-Chloro-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00067##
[0472] .sup.1H NMR DMSO-d6: .delta. 7.70 (1H, d), 7.43 (1H, s),
7.38 (1H, s), 7.29 (1H, d), 7.19 (1H, d), 7.14 (1H, s), 4.70 (2H,
s), 2.14 (3H, s)
[0473] MS: APCI (-ve) 343/345 (M-1)
EXAMPLE 56
[[2'-Fluoro-6'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00068##
[0475] .sup.1H NMR. DMSO-d6: .delta. 7.71 (1H, d), 7.44 (1H, s),
7.27 (1H, q), 7.18 (1H, t), 7.11 (1H, d), 7.04 (1H, d), 4.67 (2H,
s), 2.06 (3H, s)
[0476] MS: APCI (-ve) 327 (M-1)
EXAMPLE 57
[[4'-Fluoro-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00069##
[0478] .sup.1H NMR DMSO-d6: .delta. 7.70 (1H, d), 7.42 (1H, s),
7.30 (1H, t), 7.12 (1H, d), 7.10 (1H, d), 7.04 (1H, d), 4.69 (2H,
s), 2.11 (3H, s)
[0479] MS: APCI (-ve) 327 (M-1)
EXAMPLE 58
[[4'-[[(Ethylamino)carbonyl]amino]-2'-methyl-5-(trifluoromethyl)[1,1'-biph-
enyl]-2-yl]oxy]-acetic acid
##STR00070##
[0481] .sup.1H NMR DMSO-d6: .delta. 8.49 (1H, s), 7.62 (1H, d),
7.31 (1H, s), 7.29 (1H, s), 7.24 (1H, d), 7.04 (1H, d), 7.00 (1H,
d), 6.25 (1H, t), 4.60 (2H, s), 3.10 (2H, m), 1.06 (3H, t)
[0482] MS: APCI (-ve) 395 (M-1)
EXAMPLE 59
[[2'-Methyl-4'-[[((methylamino)carbonyl]amino]-5-(trifluoromethyl)[1,1'-bi-
phenyl]-2-yl]oxy]-acetic acid
##STR00071##
[0484] .sup.1H NMR DMSO-d6: .delta. 8.52 (1H, s), 7.65 (1H, d),
7.39 (1H, s), 7.26 (1H, s), 7.26 (1H, d), 7.07 (1H, d), 7.00 (1H,
d), 6.05 (1H, d), 4.72 (2H, s), 2.09 (3H, s)
[0485] MS: APCI (+ve) 383 (M+1)
EXAMPLE 60
[[4'-[[(Cyclopropylamino)carbonyl]amino]-2'-methyl-5-(trifluoromethyl)[1,1-
'-biphenyl]-2-yl]oxy]-acetic acid
##STR00072##
[0487] .sup.1H NMR DMSO-d6: .delta. 8.33 (1H, s), 7.66 (1H, d),
7.37 (1H, s), 7.31 (1H, s), 7.26 (1H, d), 7.08 (1H, d), 7.00 (1H,
d), 6.46 (1H, s), 4.75 (2H, s), 2.54 (1H, m), 0.63 (2H, m), 0.42
(2H, m)
[0488] MS: APCI (+ve) 409 (M+1)
EXAMPLE 61
[[2'-Methyl-4'-[[(propylamino)carbonyl]amino]-5-(trifluoromethyl)[1,1'-bip-
henyl]-2-yl]oxy]-acetic acid,
##STR00073##
[0490] .sup.1H NMR DMSO-d6: .delta. 8.48 (1H, s), 7.64 (1H, d),
7.36 (1H, s), 7.30 (1H, s), 7.24 (1H, d), 7.07 (1H, d), 7.00 (1H,
d), 6.23 (1H, t), 4.68 (2H, s), 3.05 (2H, q), 2.10 (3H, s), 1.44
(2H, m), 0.88 (3H, d)
[0491] MS: APCI (+ve) 411 (M+1)
EXAMPLE 62
[[2',4'-Dimethyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00074##
[0493] .sup.1H NMR DMSO-d6: .delta. 7.63 (1H, d), 7.34 (1H, s),
7.03 (4H, m), 4.50 (2H, s), 2.32 (3H, s), 2.11 (3H, s)
[0494] MS: APCI (-ve) 323 (M-1)
EXAMPLE 63
[[5'-Fluoro-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00075##
[0496] .sup.1H NMR DMSO-d6: .delta. 7.65 (1H, d), 7.38 (1H, s),
7.29 (1H, d), 7.27 (1H, d), 7.11 (1H, d), 7.06 (1H, m), 4.40 (2H,
s), 2.13 (3H, s)
[0497] MS: APCI (-ve) 327 (M-1)
EXAMPLE 64
[[4'-(Aminocarbonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy-
]-acetic acid
##STR00076##
[0499] .sup.1H NMR DMSO-d6: .delta. (1H, s), 7.77 (1H, s), 7.70
(1H, d), 7.63 (1H, d), 7.34 (1H, s), 7.30 (1H, s), 7.25 (1H, d),
6.98 (1H, d), 4.22 (2H, s), 2.21 (3H, s)
[0500] MS: APCI (+ve) 354 (M+1)
EXAMPLE 65
[[3'-Fluoro-2'-methyl-5-(trifluoromethyl)[1,1]-biphenyl]-2-yl]oxy]-acetic
acid
##STR00077##
[0502] .sup.1H NMR DMSO-d6: .delta. 7.66 (1H, d), 7.40 (1H, s),
7.27 (1H, d), 7.24 (1H, d), 7.16 (1H, t), 7.05 (1H, d), 4.45 (2H,
s), 2.07 (3H, s)
[0503] MS: APCI (lye) 327 (M-1).
EXAMPLE 66
[[2',5'-Difluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00078##
[0505] .sup.1H NMR DMSO-d6: .delta. 7.68 (1H, d), 7.58 (1H, s),
7.53 (1H, m), 7.30 (1H, m), 7.28 (1H, m), 7.09 (1H, d), 4.44 (2H,
s)
EXAMPLE 67
[[5'-(Aminosulfonyl)-2'-chloro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy-
]-acetic acid
##STR00079##
[0507] .sup.1H NMR DMSO-d6: .delta. 7.93 (1H, d), 7.82 (1H, d),
7.76 (1H, s), 7.73 (1H, d), 7.53 (1H, s), 7.10 (1H, d), 4.38 (2H,
s)
[0508] MS: APCI (+ve) 408/410 (M+1)
EXAMPLE 68
[[4'-Cyano-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00080##
[0510] .sup.1H NMR DMSO-d6: .delta. 7.78 (1H, s), 7.71 (1H, t),
7.71 (1H, m), 7.46 (1H, s), 7.40 (1H, d), 7.11 (1H, d), 4.61 (2H,
s), 2.18 (3H, s)
[0511] MS: APCI (-ve) 334 (M-1)
EXAMPLE 69
[[4'-Chloro-2'-fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00081##
[0513] .sup.1H NMR DMSO-d6: .delta. 7.73 (1H, d), 7.60 (1H, s),
7.56 (1H, s), 7.52 (1H, d), 7.36 (1H, d), 7.17 (1H, d), 4.70 (2H,
s)
EXAMPLE 70
[[2',5'-Difluoro-4'-methoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-a-
cetic acid
##STR00082##
[0515] .sup.1H NMR DMSO-d6: .delta. 7.63 (1H, d), 7.60 (1H, m),
7.52 (1H, s), 7.19 (1H, m), 7.06 (1H, d), 4.39 (2H, s), 3.91 (3H,
s)
EXAMPLE 71
[[2'-fluoro-5'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00083##
[0517] .sup.1H NMR DMSO-d6: .delta. 7.74 (1H, d), 7.57 (1H, s),
7.25 (1H, d), 7.26 (1H, s), 7.19 (1H, d), 7.14 (1H, d), 4.85 (2H,
s), 2.35 (3H, s)
EXAMPLE 72
[[2'-Fluoro-4'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00084##
[0519] .sup.1H NMR DMSO-d6: .delta. 7.67 (1H, d), 7.46 (1H, s),
7.40 (1H, t), 7.10 (1H, d), 7.07 (1H, d), 7.07 (1H, s), 4.49 (2H,
s), 2.34 (3H, s)
EXAMPLE 73
[[4'-Methoxy-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00085##
[0521] .sup.1H NMR DMSO-d6: .delta. 7.62 (1H, d), 7.33 (1H, s),
7.08 (1H, d), 7.00 (1H, d), 6.82 (1H, s), 6.78 (1H, d), 4.45 (2H,
s), 3.80 (3H, s), 2.13 (3H, s)
EXAMPLE 74
[[4'-(Aminosulfonyl)-2',5'-difluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-y-
l]oxy]-acetic acid
##STR00086##
[0523] .sup.1H NMR DMSO-d6: .delta. 7.83 (1H, m), 7.75 (1H, d),
7.69 (1H, s), 7.63 (1H, m), 7.18 (1H, d), 4.53 (2H, s)
[0524] MS: APCI (-ve) 410 (M-1) Example 75
[2-Benzo[b]thien-3-yl-4-(trifluoromethyl)phenoxy]-acetic acid
##STR00087##
[0526] .sup.1H NMR DMSO-d6: .delta. 8.04 (1H, d), 7.87 (1H, s),
7.78 (1H, d), 7.69 (1H, d), 7.67 (1H, s), 7.38 (2H, m), 7.24 (1H,
d), 4.81 (2H, s)
[0527] MS: APCI (-ve) 351 (M-1)
EXAMPLE 76
[[(5-(Trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic acid
##STR00088##
[0529] .sup.1H NMR DMSO-d6: .delta. 7.69 (1H, d), 7.60 (3H, m),
7.41 (3H, m), 7.20 (1H, d), 4.88 (2H, s)
[0530] MS: APCI (-ve) 295 (M-1)
EXAMPLE 77
[2-(2-Benzofuranyl)-4-(trifluoromethyl)phenoxy]-acetic acid
##STR00089##
[0532] .sup.1H NMR DMSO-d6: .delta. 8.24 (1H, s), 7.85 (1H, s),
7.75 (1H, d), 7.70 (2H, d), 7.33 (3H, m), 5.07 (2H, s)
[0533] MS: APCI (-ve) 335 (M-1)
EXAMPLE 78
[[4'-Chloro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00090##
[0535] .sup.1H NMR DMSO-d6: .delta. 7.70 (1H, d), 7.64 (1H, d),
7.62 (1H, s), 7.62 (1H, d), 7.50 (1H, d), 7.50 (1H, d), 7.21 (1H,
d), 4.81 (2H, s)
[0536] MS: APCI (-ve) 329/331 (M-1)
EXAMPLE 79
[[3'-(1-Methylethyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00091##
[0538] .sup.1H NMR DMSO-d6: .delta. 7.67 (1H, d), 7.57 (1H, s),
7.48 (1H, s), 7.38 (1H, t), 7.36 (1H, d), 7.25 (1H, d), 7.20 (1H,
d), 4.85 (2H, s)
[0539] MS: APCI (-ve) 337 (M-1)
EXAMPLE 80
[[3',4'-Difluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00092##
[0541] .sup.1H NMR DMSO-d6: .delta. 7.76 (1H, d), 7.71 (1H, d),
7.65 (1H, s), 7.51 (1H, d), 7.48 (1H, s), 7.52 (1H, d), 4.89 (2H,
s)
[0542] MS: APCI (-ve) 331 (M-1)
EXAMPLE 81
[2-(1,3-Benzodioxol-5-yl)-4-(trifluoromethyl)phenoxy]-acetic
acid
##STR00093##
[0544] .sup.1H NMR DMSO-d6: .delta. 7.63 (1H, d), 7.57 (1H, s),
7.22 (1H, s), 7.16 (1H, d), 7.05 (1H, d), 6.98 (1H, d), 6.04 (2H,
s), 4.83 (2H, s)
[0545] MS: APCI (-ve) 339 (M-1)
EXAMPLE 82
[[4'Ethyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00094##
[0547] .sup.1H NMR DMSO-d6: .delta. 7.66 (1H, d), 7.58 (1H, s),
7.51 (2H, d), 7.27 (2H, s), 7.18 (1H, d), 4.86 (2H, d), 2.65 (2H,
q), 1.22 (3H, t)
[0548] MS: APCI (-ve) 363 (M-1)
EXAMPLE 83
[[3'-Fluoro-5-(trifluoromethyl)[1,1':4',1''-terphenyl]-2-yl]oxy]-acetic
acid
##STR00095##
[0550] .sup.1H NMR DMSO-d6: .delta. 7.74 (1H, d), 7.65 (2H, m),
7.60 (1H, m), 7.59 (2H, m), 7.58 (1H, m), 7.52 (2H, m), 7.43 (1H,
m), 7.12 (1H, m), 4.51 (2H, s)
[0551] MS: APCI (-ve) 389 (M-1)
EXAMPLE 84
[[4'-(Trifluoromethoxy)-5-(trifluoromethyl)[1,1']-biphenyl]-2-yl]oxy]-acet-
ic acid
##STR00096##
[0553] .sup.1H NMR DMSO-d6: .delta. 7.82 (2H, d), 7.62 (1H, d),
7.58 (1H, s), 7.41 (2H, d), 7.05 (1H, d), 4.39 (2H, s)
[0554] MS: APCI (-ve) 379 (M-1)
EXAMPLE 85
[[2',3'-Dichloro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00097##
[0556] .sup.1H NMR DMSO-d6: .delta. 7.68 (1H, d), 7.66 (1H, d),
7.47 (1H, d), 7.48 (1H, s), 7.41 (1H, t), 7.05 (1H, d), 4.26 (2H,
d)
[0557] MS: APCI (-ve) 363 (M-1)
EXAMPLE 86
[[4'-(1,1-Dimethylethyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acet-
ic acid
##STR00098##
[0559] .sup.1H NMR DMSO-d6: .delta. 7.59 (1H, d), 7.57 (2H, d),
7.51 (1H, s), 7.44 (2H, d), 7.04 (1H, d), 4.47 (2H, s)
[0560] MS: APCI (-ve) 351 (M-1)
EXAMPLE 87
[2-(6-Methyoxy-2-naphthalenyl)-4-(trifluromethyl)phenoxy]-acetic
acid
##STR00099##
[0562] .sup.1H NMR DMSO-d6: .delta. 8.07 (1H, s), 7.87 (1H, d),
7.85 (2H, s), 7.62 (2H, d), 7.34 (1H, s), 7.17 (1H, d), 7.08 (1H,
d), 4.41 (2H, s)
[0563] MS: APCI (-ve) 329/331 (M-1)
EXAMPLE 88
[[4'-(Ethylthio)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00100##
[0565] .sup.1H NMR DMSO-d6: .delta. 7.61 (2H, d), 7.59 (1H, d),
7.52 (1H, s), 7.35 (2H, d), 7.07 (1H, d), 4.50 (2H, s), 3.02 (1H,
q), 4.85 (3H, t)
[0566] MS: APCI (-ve) 335 (M-1)
EXAMPLE 89
[[4'-Acetyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00101##
[0568] .sup.1H NMR DMSO-d6: .delta. 8.02 (2H, d), 7.77 (2H, d),
7.64 (1H, s), 7.72 (1H, d), 7.23 (1H, d), 4.83 (2H, s), 2.63 (3H,
s)
[0569] MS: APCI (-ve) 337 (M-1)
EXAMPLE 90
[2-(2-Chloro-5-methyl-4-pyridinyl)-4-(trifluoromethyl)phenoxy]-acetic
acid, ammonium salt
##STR00102##
[0571] .sup.1H NMR DMSO-d6: .delta. 8.30 (1H, d), 7.75-7.66 (1H,
m), 7.49 (1H, d), 7.04 (2H, d), 4.28 (2H, s), 2.15 (3H, s)
[0572] MS: APCI (-ve) 449 (M-1)
EXAMPLE 91
[[5'-(Aminosulfonyl)-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy-
]-acetic acid, ammonium salt
##STR00103##
[0574] .sup.1H NMR DMSO-d6: .delta. 7.73-7.65 (3H, m), 7.63 (1H,
d), 7.44 (1H, d), 7.37 (1H, d), 7.01 (1H, d), 4.23 (2H, s), 2.24
(3H, s)
[0575] MS: APCI (-ve) 388 (M-1)
EXAMPLE 92
[2-(8-Quinolinyl)-4-(trifluoromethyl)phenoxy]-acetic acid, ammonium
salt
##STR00104##
[0577] .sup.1H NMR CDCl.sub.3: .delta. 8.85-8.82 (1H, m), 8.33-8.29
(1H, m), 7.95-7.91 (1H, m), 7.82-7.78 (1H, m), 7.68-7.58 (3H, m),
7.50-7.46 (1H, m), 7.14-7.10 (1H, m), 4.54 (2H, s)
[0578] MS:APCI (-ve) 346 (M-1)
EXAMPLE 93
[[3'-Cyano-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid, ammonium salt
##STR00105##
[0580] .sup.1H NMR CDCl.sub.3: .delta. 8.00 (1H, d), 7.87-7.83 (1H,
m), 7.66-7.52 (4H, m), 6.99 (1H, d), 4.68 (2H, s)
[0581] MS:APCI (-ve) 320 (M-1)
EXAMPLE 94
[2-[4-Methyl-6-[methyl(methylsulfonyl)amino]-3-pyridinyl]-4-(trifluorometh-
yl) phenoxy]-acetic acid, ammonium salt
##STR00106##
[0583] .sup.1H NMR DMSO-d6: .delta. 8.20 (1H, s), 7.71 (1H, m),
7.51-7.47 (1H, m), 7.33 (1H, s), 7.09 (1H, d), 4.52 (2H, s), 3.32
(3H, s), 3.18 (3H, d), 2.21 (3H, s)
[0584] MS:APCI (-ve) 419 (M-1)
EXAMPLE 95
[[2'-Methyl-5'-(methylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]ox-
y]-acetic acid, ammonium salt
##STR00107##
[0586] .sup.1H NMR. DMSO-d6: .delta. 7.83-7.80 (1H, m), 7.74-7.69
(2H, m), 7.55 (1H, d), 7.49 (1H, d), 7.09 (1H, d), 4.46 (2H, s),
3.23 (3H, s), 2.26 (3H, s)
[0587] MS:APCI (+ve) 406 (M+1)
EXAMPLE 96
2'(Carboxymethoxy)-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxylic
acid, 3-methyl ester
##STR00108##
[0589] .sup.1H NMR DMSO-d6: .delta. 8.15-8.13 (1H, m), 7.99-7.93
(2H, m), 7.68-7.55 (3H, m), 7.10 (1H, d), 4.46 (2H, s), 3.87 (3H,
s)
[0590] MS:APCI (-ve) 353 (M-1)
EXAMPLE 97
2'(Carboxymethoxy)-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic
acid, 2-methyl ester
##STR00109##
[0592] .sup.1H NMR DMSO-d6: .delta. 7.77 (1H, M), 7.66-7.59 (2H,
m), 7.51-7.42 (3H, m), 4.23 (2H, s), 3.59 (4H, s)
[0593] MS:APCI (-ve) 353 (M-1)
EXAMPLE 98
[[5-(Trifluoromethyl)[1,1':4',1''-terphenyl]-2-yl]oxy]-acetic
acid
##STR00110##
[0595] .sup.1H NMR DMSO-d6: .delta. 7.75-7.62 (7H, m), 7.53-7.46
(3H, m), 7.42-7.35 (1H, m), 7.21-7.15 (1H, m), 4.76 (2H, s)
[0596] MS:APCI (-ve) 371 (M-1)
EXAMPLE 99
[[3'-Fluoro-2',4'-dimethyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-ac-
etic acid
##STR00111##
[0598] .sup.1H NMR DMSO-d6: .delta.7.66-7.62 (1H, m), 7.55 (1H, d),
7.34 (2H, d), 7.16 (1H, d), 4.78 (2H, s), 2.25 (6H, d)
[0599] MS:APCI (-ve) 341 (M-1)
EXAMPLE 100
[[2'-Nitro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid, ammonium salt
##STR00112##
[0601] .sup.1H NMR DMSO-d6: .delta. 8.00 (1H, m), 7.83-7.76 (1H,
m), 7.70-7.55 (4H, m), 6.94 (1H, d), 4.08 (2H, s)
[0602] MS:APCI (-ve) 340 (M-1)
EXAMPLE 101
[[2'-Methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00113##
[0604] .sup.1H NMR DMSO-d6: .delta. 7.65-7.61 (1H, m), 7.34-7.32
(1H, m), 7.28-7.14 (4H, m), 7.02-6.98 (1H, m), 4.36 (2H, s), 2.13
(3H, s)
[0605] MS:APCI (-ve) 340 (M-1)
EXAMPLE 102
[[3'-Chloro-2'-methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00114##
[0607] .sup.1H NMR DMSO-d6: .delta. 7.72-7.66 (1H, m), 7.47-7.40
(2H, m), 7.30-7.22 (1H, m), 7.18-7.14 (1H, m), 7.10-7.06 (1H, m),
4.56 (2H, s), 2.14 (3H, s)
[0608] MS:APCI (-ve) 343 (M-1)
EXAMPLE 103
[[5-(Trifluoromethyl)[1,1':3',1''-terphenyl]-2-yl]oxy]-acetic
acid
##STR00115##
[0610] .sup.1H NMR DMSO-d6: .delta. 7.92 (1H, t), 7.76-7.72 (2H,
m), 7.68-7.59 (4H, m), 7.56-7.34 (4H, m), 7.19-7.15 (1H, m), 4.69
(2H, s)
[0611] MS:APCI (-ve) 371 (M-1)
EXAMPLE 104
2'-(Carboxymethoxy)-5'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxylic
acid, 4-methyl ester
##STR00116##
[0613] .sup.1H NMR DMSO-d6: .delta. 8.03-7.99 (2H, m), 7.82-7.79
(2H, m), 7.70-7.66 (1H, m), 7.63-7.61 (1H, m), 7.17-7.14 (1H, m),
4.62 (2H, s), 3.88 (3H, s)
[0614] MS:APCI (-ve) 353 (M-1)
EXAMPLE 105
[[4'-Nitro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00117##
[0616] .sup.1H NMR DMSO-d6: .delta. 8.30-826 (2H, m), 7.99-7.94
(2H, m), 7.75-7.67 (2H, m), 7.20 (1H, d), 4.65 (2H, s)
[0617] MS:APCI (-ve) 340 (M-1)
EXAMPLE 106
[[5-(Trifluoromethyl)-3'-[(trifluoromethyl)thio][1,1'-biphenyl]-2-yl]oxy]--
acetic acid
##STR00118##
[0619] .sup.1H NMR DMSO-d6: .delta. 8.05 (1H, s), 7.91-7.87 (1H,
m), 7.74-7.58 (4H, m), 7.17 (1H, d), 4.64 (2H, s)
[0620] MS:APCI (-ve) 395 (M-1)
EXAMPLE 107
[[5-(Trifluoromethyl)-4'-[(trifluoromethyl)thio)[1,1'-biphenyl]-2-yl]oxy]--
acetic acid
##STR00119##
[0622] .sup.1H NMR DMSO-d6: .delta. 7.79 (4H, s), 7.76-7.72 (1H,
m), 7.69-7.67 (1H, m), 7.25 (1H, d), 4.89 (2H, s)
[0623] MS:APCI (-ve) 395 (M-1)
EXAMPLE 108
[[4'Methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00120##
[0625] .sup.1H NMR DMSO-d6: .delta. 7.67-7.63 (1H, m), 7.57-7.54
(1H, m), 7.51-7.47 (2H, m), 7.25 (2H, d), 7.17 (1H, d), 4.82 (2H,
s), 2.35 (3H, s)
[0626] MS:APCI (-ve) 309 (M-1)
EXAMPLE 109
[[4'-Fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00121##
[0628] .sup.1H NMR DMSO-d6: .delta. 7.71-7.58 (4H, m), 7.31-7.18
(3H, m), 4.86 (2H, s)
[0629] MS:APCI (-ve) 314 (M-1)
EXAMPLE 110
[[3'-Fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00122##
[0631] .sup.1H NMR DMSO-d6: .delta. 7.74-7.69 (1H, m), 7.66-7.64
(1H, m), 7.53-7.42 (3H, m), 7.26-7.18 (2H, m), 4.88 (2H, s)
[0632] MS:APCI (-ve) 314 (M-1)
EXAMPLE 111
[[3'-Methyl-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00123##
[0634] .sup.1H NMR DMSO-d6: .delta. 7.70-7.63 (1H, m), 7.56 (1H,
d), 7.42-7.28 (3H, m), 7.21-7.15 (2H, m), 4.82 (2H, s), 2.34 (3H,
s)
[0635] MS:APCI (-ve) 309 (M-1)
EXAMPLE 112
[2-(3-Pyridinyl)-4-(trifluoromethyl)phenoxy]-acetic acid
##STR00124##
[0637] .sup.1H NMR DMSO-d6: .delta. 8.88 (1H, s), 8.56-8.53 (1H,
m), 8.15-8.09 (1H, m), 7.68-7.60 (2H, m), 7.48-7.42 (1H, m), 7.10
(1H, d), 4.43 (2H, s)
[0638] MS:APCI (+ve) 298 (M+1)
EXAMPLE 113
[[(2'-Fluoro-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00125##
[0640] .sup.1H NMR DMSO-d6: .delta. 8.02 (1H, d), 7.92-7.90 (1H,
m), 7.79-7.54 (4H, m), 7.28 (1H, d), 4.90 (2H, s)
[0641] MS:APCI (-ve) 313 (M-1)
EXAMPLE 114
[[(2'-Methoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00126##
[0643] .sup.1H NMR DMSO-d6: .delta. 7.59 (1H, d), 7.42 (1H, s),
7.37-7.30 (2H, m), 7.11-6.95 (3H, m), 4.42 (2H, s), 3.72 (3H,
s)
[0644] MS:APCI (-ve) 325 (M-1)
EXAMPLE 115
[[3'-Methoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00127##
[0646] .sup.1H NMR DMSO-d6: .delta. 7.62 (1H, d), 7.56-7.54 (1H,
m), 7.34 (1H, t), 7.27-7.25 (1H, m), 7.16 (1H, d), 7.11 (1H, d),
6.95-6.90 (1H, m), 4.56 (2H, s), 3.79 (3H, s)
[0647] MS:APCI (-ve) 325 (M-1)
EXAMPLE 116
[[4'Methoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00128##
[0649] .sup.1H NMR DMSO-d6: .delta. 7.62-7.54 (4H, m), 7.04 (1H,
d), 6.98 (2H, d), 4.45 (2H, s), 3.79 (3H, s)
[0650] MS:APCI (-ve) 325 (M-1)
EXAMPLE 117
[[3'-(Ethylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00129##
[0652] .sup.1H NMR DMSO-d6: .delta. 8.19-8.17 (1H, m), 8.11-8.07
(1H, m), 7.87-7.83 (1H, m), 7.73-7.64 (3H, m), 7.11 (1H, d), 4.39
(2H, s), 3.38 (2H, q), 1.14 (3H, t)
[0653] MS:APCI (-ve) 387 (M-1)
EXAMPLE 118
[[3'Propoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00130##
[0655] .sup.1H NMR DMSO-d6: .delta. 7.70-7.65 (1H, m), 7.59 (1H,
d), 7.33 (1H, t), 7.22-7.10 (3H, m), 6.95-6.91 (1H, m), 4.86 (2H,
s), 3.97 (2H, t), 1.79-1.68 (2H, m), 0.98 (3H, t)
[0656] MS:APCI (-ve) 353 (M-1)
EXAMPLE 119
[[4'-Propoxy-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00131##
[0658] .sup.1H NMR DMSO-d6: .delta. 7.65-7.61 (1H, m), 7.56-7.50
(3H, m), 7.16 (1H, d), 7.01-6.96 (2H, m), 4.85 (2H, s), 3.97 (2H,
t), 1.80-1.70 (2H, m), 0.99 (3H, t)
[0659] MS:APCI (-ve) 353 (M-1)
EXAMPLE 120
[2-(2-Amino-4-methyl-5-pyrimidinyl)-4-(trifluoromethyl)phenoxy]-acetic
acid
##STR00132##
[0661] .sup.1H NMR DMSO-d6: .delta. 7.99 (s, 1H), 7.62 (dd, 1H),
7.43 (d, 1H), 7.01 (d, 1H), 6.56 (s, 2H), 4.41 (s, 2H), 2.15 (s,
3H).
[0662] MS:APCI (+ve) 328
EXAMPLE 121
[[4'-Cyano-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00133##
[0664] .sup.1H NMR. CD.sub.3OD: .delta. 7.86-7.73 (m, 4H), 7.65
(dd, 1H), 7.60 (d, 1H), 7.14 (d, 1H), 4.66 (s, MS:APCI (+ve)
320
EXAMPLE 122
[[4',5-Bis(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00134##
[0666] .sup.1H NMR DMSO-d6: .delta. 7.90 (2H, d), 7.78 (2H, d),
7.67 (1H, d), 7.62 (1H, s), 7.10 (1H, d), 4.47 (2H, s)
[0667] MS: APCI (-ve) 363 (M-1)
EXAMPLE 123
[2-(2-Naphthalenyl)-4-(trifluoromethyl)phenoxy]-acetic acid
##STR00135##
[0669] .sup.1H NMR DMSO-d6: .delta. 8.15 (1H, s), 7.93 (4H, m),
7.67 (1H, s), 7.64 (1H, d), 7.53 (2H, m), 7.09 (1H, d), 4.44 (2H,
s)
[0670] MS: APCI (-ve) 345 (M-1)
EXAMPLE 124
[[(4'41-Pyrrolidinylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-
-acetic acid
##STR00136##
[0671] (i) 1-[(4-Bromophenyl)sulfonyl]-pyrrolidine
[0672] A solution of 4-bromobenzenesulphonyl chloride (0.5 g) and
pyrrolidine (0.284 g) in acetonitrile (5 ml) were stirred at RT for
48 h then partitioned between ethylacetate and water. The organics
were separated, washed with water, dried and evaporated under
reduced pressure. The residue was triturated with isohexane and
filtered, yield 0.5 g.
[0673] .sup.1H NMR CDCl.sub.3: .delta. 7.72-7.65 (4H, m); 3.28-3.21
(4H, m); 1.84-1.76 (4H, m)
(ii)
[[4'-(1-Pyrrolidinylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl-
]oxy]-acetic acid
[0674] The title compound was prepared by the method of example 44,
yield 0.13 g.
[0675] .sup.1H NMR CD.sub.3OD: .delta. 7.83-7.75 (m, 4H), 7.56-7.52
(m, 1H), 7.50 (d, 1H), 7.01 (d, 1H), 4.46 (s, 2H), 3.20-3.14 (m,
4H), 1.72-1.65 (m, 4H).
[0676] MS:APCI (-ve) 428.
EXAMPLE 125-134
[0677] The following compounds were synthesised in an analogous
method to example 124
EXAMPLE 125
[[4'-[(Dimethylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy-
]-acetic acid
##STR00137##
[0679] .sup.1H NMR CD.sub.3OD: .delta. 7.92-7.81 (m, 4H), 7.67-7.61
(m, 2H), 7.14 (d, 1H), 4.64 (s, 2H), 2.73 (s, 6H).
[0680] MS:APCI (+ve) 402
EXAMPLE 126
[[4'-[[(Phenylmethyl)amino]sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-2--
yl]oxy]-acetic acid
##STR00138##
[0682] .sup.1H NMR CD.sub.3OD: .delta. 7.92-7.77 (m, 4H), 7.68 (d,
1H), 7.62 (s, 1H), 7.29-7.14 (m, 6H), 4.73 (s, 2H), 4.13 (s,
2H).
[0683] MS:APCI (-ve) 464.
EXAMPLE 127
[[4'-[[(2,2,2-Trifluoroethyl)amino]sulfonyl]-5-(trifluoromethyl)[1,1'-biph-
enyl]-2-yl]oxy]-acetic acid
##STR00139##
[0685] .sup.1H NMR CD.sub.3OD: .delta. 7.93-7.79 (m, 4H), 7.64 (d,
1H), 7.59 (d, 1H), 7.12 (d, 1H), 4.64 (s, 2H), 3.63 (t, 2H).
[0686] MS:APCI (-ve) 456
EXAMPLE 128
[[4'-[[(5-Methyl-2-thiazolyl)amino]sulfonyl]-5-(trifluoromethyl)[1,1'-biph-
enyl]-2-yl]oxy]-acetic acid
##STR00140##
[0688] .sup.1H NMR CD.sub.3OD: .delta. 7.97-7.92 (m, 2H), 7.82-7.78
(m, 2H), 7.67-7.61 (m, 1H), 7.61-7.58 (m, 1H), 7.12 (d, 2H), 6.82
(d, 1H), 4.61 (s, 2H), 2.27 (d, 3H).
[0689] MS:APCI (-ve) 471
EXAMPLE 129
[[4'-[(Phenylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]--
acetic acid
##STR00141##
[0691] .sup.1H NMR CD.sub.3OD: .delta. 7.81-7.73 (m, 4H), 7.60 (dd,
1H), 7.54 (d, 1H), 7.25-7.02 (m, 6H), 4.55 (s, 2H).
[0692] MS:APCI (-ve) 450.
EXAMPLE 130
[[4'[(Diethylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]--
acetic acid
##STR00142##
[0694] .sup.1H NMR CD.sub.3OD: .delta. 7.85 (s, 4H), 7.63 (dd, 1H),
7.59 (d, 1H), 7.11 (d, 1H), 4.58 (s, 2H), 3.27 (q, 4H), 1.16 (t,
6H).
[0695] MS:APCI (-ve) 450.
EXAMPLE 131
[[4'-[(Cyclopropylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]-
oxy]-acetic acid
##STR00143##
[0697] .sup.1H NMR CD.sub.3OD: .delta. 7.95-7.84 (m, 4H), 7.64 (dd,
1H), 7.61 (d, 1H), 7.12 (d, 1H), 4.61 (s, 2H), 2.23-2.16 (m, 1H),
0.58-0.53 (m, 4H).
[0698] MS:APCI (-ve) 414.
EXAMPLE 132
[[4'-(Aminosulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-acetic
acid
##STR00144##
[0700] .sup.1H NMR CD.sub.3OD: .delta. 7.94 (d, 2H), 7.81 (d, 2H),
7.63 (dd, 1H), 7.58 (d, 1H), 7.12 (d, 1H), 4.60 (s, 2H).
[0701] MS:APCI (-ve) 374.
EXAMPLE 133
[[4'-[(Methylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]--
acetic acid
##STR00145##
[0703] .sup.1H NMR CD.sub.3OD: .delta. 7.80-7.74 (m, 4H), 7.53 (dd,
1H), 7.50 (d, 1H), 4.48 (s, 2H); 2.47 (s, 3H).
[0704] MS:APCI (-ve) 388
EXAMPLE 134
[[4'-[(4-Methyl-1-piperazinyl)sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-
-2-yl]oxy]-acetic acid
##STR00146##
[0706] .sup.1H NMR CD.sub.3OD: .delta. 7.85-7.70 (m, 4H), 7.55-7.51
(m, 1H), 7.49 (d, 1H), 7.00 (d, 1H), 4.41 (s, 2H), 3.03-2.95 (m,
4H), 2.48 (t, 4H), 2.21 (s, 3H).
[0707] MS:APCI (-ve) 457
EXAMPLE 135
[2-[4-Methyl-2-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-5-pyrimidi-
nyl]-4-(trifluoromethyl)phenoxy]-acetic acid
##STR00147##
[0708] (i) 2,5-Dibromo-4-methyl-pyrimidine
[0709] Isoamylnitrite (21 ml) was added to a stirred suspension of
5-bromo-4-methyl-2-pyrimidinamine (1.75 g) in bromoform (30 ml) and
the mixture heated at 85.degree. C. for 4 h. After cooling,
isohexane (300 ml) was added and the solution passed through a pad
of silica-gel. The silica was washed with petrol (1000 ml),
dichloromethane (200 ml) then the product eluted with ethylacetate.
The ethylacetate layer was evaporated under reduced pressure and
the residue purified by chromatography on silica eluting with 5%
diethylether/isohexane, yield 0.9 g.
[0710] .sup.1H NMR CDCl.sub.3: .delta. 8.52 (s, 1H), 2.64 (s,
3H)
[0711] MS:APCI (-ve) 249/51/53
5-Bromo-4-methyl-2-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-pyrimi-
dine
[0712] Sodium hydride (0.128 g, 60% disp. in oil) was added to a
stirred solution of 2-methyl-1,2,5-thiadiazolidine 1,1-dioxide
(0.433 g) in THF (10 ml). DMF (10 ml) was added and the mixture
heated at 80.degree. C. for 5 min then a solution of the product
from step (i) (0.8 g) in DMF (5 ml) was added. The mixture was
heated at 60.degree. C. for 10 min, poured into water (100 ml),
acidified with citric acid and extracted with ethylacetate. The
organics were evaporated under reduced pressure and the residue
purified by chromatography on silica eluting with diethylether,
yield 0.58 g.
[0713] .sup.1H NMR CDCl.sub.3: .delta. 8.50 (s, 1H), 4.05 (t, 2H),
3.45 (t, 2H), 2.87 (s, 3H), 2.58 (s, 3H).
[0714] MS:APCI (+ve) 307/9
(iii)
[2-[4-Methyl-2-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-5-py-
rimidinyl]-4-(trifluoromethyl)phenoxy]-acetic acid
[0715] The title compound was prepared by the method of example 44,
yield 0.05 g.
[0716] .sup.1H NMR CDCl.sub.3: .delta. 8.34 (s, 1H), 7.47 (dd, 1H),
7.32 (d, 1H), 6.90 (d, 1H), 4.36 (s, 2H), 4.05 (t, 2H), 3.40 (t,
4H), 2.77 (s, 3H), 2.27 (s, 3H).
[0717] MS:APCI (+ve) 447
EXAMPLE 136-137
[0718] The following compounds were synthesised in an analogous
method to example 135
EXAMPLE 136
[2-[4-Methyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-4-(trifluorome-
thyl)phenoxy]-acetic acid
##STR00148##
[0720] .sup.1H NMR CDCl.sub.3: .delta. 8.37 (s, 1H), 7.63 (dd, 1H),
7.40 (d, 1H), 6.96 (d, 1H), 4.60 (s, 2H), 3.57 (s, 3H), 3.53 (s,
3H), 2.40 (s, 3H).
[0721] MS:APCI (-ve) 418
EXAMPLE 137
[2-[2-(1,1-Dioxido-2-isothiazolidinyl)-4-methyl-5-pyrimidinyl]-4-(trifluor-
omethyl)phenoxy]-acetic acid, ammonium salt
##STR00149##
[0723] .sup.1H NMR CDCl.sub.3: .delta. 8.37 (s, 1H), 7.60 (dd 1H),
7.36 (d, 1H), 7.02 (d, 1H), 4.53 (s, 2H), 4.09 (t, 2H), 3.49 (t,
2H), 2.51 (quintet, 2H), 2.39 (s, 3H).
[0724] MS:APCI (+ve) 432.
EXAMPLE 138
[2-[2-(3-Hydroxy-1-azetidinyl)-4-methyl-5-pyrimidinyl]-4-(trifluoromethyl)-
phenoxy]-acetic acid
##STR00150##
[0725] (i) 1-(5-Bromo-4-methyl-2-pyrimidinyl)-3-azetidinol
[0726] A mixture of the product from example 135 step (i) (0.75 g),
azetidin-3-ol hydrochloride (0.66 g) and triethylamine (0.9 ml) in
ethanol (10 ml) was stirred at RT for 2 h. The solvent was removed
under reduced pressure and the residue purified by chromatography
on silica eluting with 60% diethylether/isohexane as eluant, yield
0.7 g.
[0727] .sup.1H NMR CDCl.sub.3: .delta. 8.22 (s, 1H), 4.78-4.72 (m,
1H), 4.40-4.33 (m, 2H), 3.99-3.93 (m, 2H), 2.45 (s, 3H)
(ii)
[2-[2-(3-Hydroxy-1-azetidinyl)-4-methyl-5-pyrimidinyl]-4-(trifluorome-
thyl)phenoxy]-acetic acid
[0728] The title compound was prepared in an analogous method to
example 44, yield 0.04 g.
[0729] .sup.1H NMR CD.sub.3OD: .delta. 8.09 (s, 1H), 7.64 (m, 1H),
7.43 (d, 1H), 7.08 (d, 1H), 4.71-4.64 (m, 1H), 4.61 (s, 2H),
4.41-4.34 (m, 2H), 3.96-3.91 (m, 2H), 2.25 (s, 3H).
[0730] MS:APCI (+ve) 384
EXAMPLE 139-141
[0731] The following compounds were synthesised in an analogous
method to example 138
EXAMPLE 139
[2-[4-Methyl-2-(4-methyl-1-piperazinyl)-5-pyrimidinyl]-4-(trifluoromethyl)-
phenoxy]-acetic acid
##STR00151##
[0733] .sup.1H NMR CDCl.sub.3: .delta. 8.19 (s, 1H), 7.57 (d, 1H),
7.38 (d, 1H), 6.99 (d, 1H), 4.51 (s, 2H), 4.3-3.8 (br s, 4H), 3-2.8
(br s, 4H), 2.63 (s, 3H), 2.29 (s, 3H).
[0734] MS:APCI (+ve) 411
EXAMPLE 140
[2-[4-Methyl-2-(1-pyrrolidinyl)-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy]-
-acetic acid
##STR00152##
[0736] .sup.1H NMR CD.sub.3OD: .delta. 7.95 (s, 1H), 7.36 (d, 1H),
7.59-7.54 (m, 1H), 7.01 (d, 1H), 4.65 (s, 2H), 3.50 (t, 4H), 2.15
(s, 3H), 1.96-1.91 (m, 4H).
[0737] MS:APCI (+ve) 382
EXAMPLE 141
[2-[2-(Dimethylamino)-4-methyl-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy]--
acetic acid
##STR00153##
[0739] .sup.1H NMR CD.sub.3OD: .delta. 8.05 (s, 1H), 7.67-7.63 (m,
1H), 7.44 (d, 1H), 7.10 (d, 1H), 4.75 (s, 2H), 3.20 (s, 6H).
[0740] MS:APCI (+ve) 356
EXAMPLE 142
[2-[5-Methyl-2-[methyl(methylsulfonyl)amino]-4-pyrimidinyl]-4-(trifluorome-
thyl)phentoxy]-acetic acid
##STR00154##
[0741] (i)
N-(4-Chloro-5-methyl-2-pyrimidinyl)-N-methyl-methanesulfonamide
[0742] A mixture of N-methylsulphonamide (3.35 g),
2,4-dichloro-5-methylpyrimidine (5 g) and potassium carbonate (4.3
g) in DMF (50 ml) was heated at 80.degree. C. for 4 h. The reaction
was quenched with water (200 ml) and extracted with ethylacetate.
The organics were dried, evaporated under reduced pressure and the
residue triturated with ether. The solid was filtered off
(4-isomer) and the filtrate evaporated under reduced pressure and
subjected to RPHPLC to obtain the 2-isomer, yield 0.37 g.
[0743] .sup.1H NMR CDCl.sub.3: .delta. 8.35 (s, 1H), 3.51 (s, 3H),
3.48 (s, 3H), 2.29 (d, 3H).
(ii)
[2-[5-Methyl-2-[methyl(methylsulfonyl)amino]-4-pyrimidinyl]-4-(triflu-
oromethyl)phenoxy]-acetic acid
[0744] The title compound was prepared in an analogous method to
example 44, yield 0.04 g.
[0745] .sup.1H NMR CD.sub.3OD: .delta. 8.50 (s, 1H), 7.16 (d, 1H),
7.74 (dd, 1H), 7.62 (d, 1H), 4.68 (s, 2H), 3.50 (s, 3H), 3.45 (s,
3H), 2.19 (s, 3H).
[0746] MS:APCI (+ve) 420
EXAMPLE 143
[2-[2-[[(Dimethylamino)sulfonyl]amino]-4-methyl-5-pyrimidinyl]-4-(trifluor-
omethyl)phenoxy]-acetic acid
##STR00155##
[0747] (i)
N'-(5-Bromo-4-methyl-2-pyrimidinyl)-N,N-dimethyl-sulfamide
[0748] A mixture of 5-bromo-4-methyl-2-pyrimidinamine (0.75 g) and
dimethylsulphonyl so chloride (0.43 ml) in pyridine (20 ml) was
heated at 80.degree. C. for 17 h. The solvent was removed under
reduced pressure and the residue purified by chromatography on
silica eluting with diethylether then ethylacetate. The residue was
then purified by RPHPLC, yield 0.12 g.
[0749] MS:APCI (-ve) 295/6
(ii)
[2-[2-[[(Dimethylamino)sulfonyl]amino]-4-methyl-5-pyrimidinyl]-4-(tri-
fluoromethyl)phenoxy]-acetic acid
[0750] The title compound was prepared in an analogous method to
example 44, yield 0.01 g.
[0751] .sup.1H NMR CD.sub.3OD: .delta. 8.27 (s, 1H), 7.68 (d, 1H),
7.49 (s, 1H), 7.11 (d, 1H), 4.70 (s, 2H), 2.98 (s, 6H), 2.32 (s,
3H).
[0752] MS:APCI (+ve) 435.
EXAMPLE 144
[[2'-Chloro-4'-[(methoxycarbonyl)amino]-5-(trifluoromethyl)[1,1'-biphenyl]-
-2-yl]oxy]acetic acid
##STR00156##
[0753] i)
2-Chloro-2'-(phenylmethoxy)-5'-(trifluoromethyl)-[1,1'-biphenyl]-
-4-amine
[0754] The product from example 32 step (ii) (0.5 g) and
4-bromo-3-chloroaniline (0.38 g) were dissolved in toluene (4 ml).
Ethanol (1 ml), 2M aqueous sodium carbonate (1 ml) and
Pd(PPh.sub.3).sub.4 (0.115 g) were added sequentially and the
mixture heated at reflux for 4 h. The reaction was cooled,
evaporated, dissolved in EtOAc, washed with water and brine, dried
(MgSO.sub.4) and evaporated. The residue was purified by
chromatography on silica eluting with 10% EtOAc/isohexane. Yield
0.23 g.
[0755] .sup.1H NMR DMSO-d6: .delta. 7.67 (ddd, 1H), 7.4 (d, 1H),
7.27-7.34 (m, 6H), 7.01 (d, 1H), 6.7 (d, 1H), 6.55 (dd, 1H), 5.47
(s, 2H) 5.18 (s, 2H)
ii) 4'-Amino-2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-ol
[0756] 5% Pt/C (0.088 g) was added to a solution of the product
from step (i) in ethanol (20 ml) and hydrogenated at RT and 1 bar
for 18 h. Extra Pt/C (0.1 g) was added and hydrogenated for a
further 3 h at 2 bar. The catalyst was removed by filtration and
the filtrate evaporated to leave a solid residue. The residue was
purified by chromatography on silica eluting with 50%
EtOAc/isohexane. Yield 0.083 g.
[0757] .sup.1H NMR DMSO-d6: .delta. 10.2 (s, 1H), 7.49 (d, 1H), 7.3
(d, 1H), 7.03 (d, 1H), 6.96 (d, 1H), 6.68 (d, 1H), 6.54 (dd, 1H),
5.44 (s, 2H)
iii)
[[4'-Amino-2'-chloro-5-(trifluoromethyl)-[1,1'-biphenyl]-2-yl]oxy]ace-
tic acid, 1,1-dimethylethyl ester
[0758] The subtitle compound was prepared by the method of example
1 step (i) using the product from step (ii). Yield 0.07 g. Used in
step (iv) without characterisation.
iv)
[[2'-Chloro-4'-[(methoxycarbonyl)amino]-5-(trifluoromethyl)-[1,1'-biph-
enyl]-2-yl]oxy]acetic acid, 1,1-dimethylethyl ester
[0759] The product from step (iii) (0.07 g) was dissolved in DCM (5
ml), triethylamine (0.024 ml) added, followed by methyl
chloroformate (0.013 ml) and stirred for 20 h. Further
triethylamine (0.024 ml) and methyl chloroformate (0.013 ml) were
added three times over to achieve complete reaction. The solvent
was removed by evaporation to give the crude is product which was
carried forward to step (v) without characterisation.
v)
[[2'-Chloro-4'-[(methoxycarbonyl)amino]-5-(trifluoromethyl)-[1,1'-biphe-
nyl]-2-yl]oxy]acetic acid
[0760] The title compound was prepared by the method of example 1
step (iii) using the product from step (iv).
[0761] .sup.1H NMR DMSO-d6: .delta. 9.94 (s, 1H), 7.69 (dd, 2H),
7.41-7.47 (m, 2H), 7.35 (d, 1H), 7.13 (d, 1H), 4.65 (s, 2H), 3.7
(s, 3H)
[0762] MS:APCI (-ve) 402
EXAMPLE 145
2-[[2'-Chloro-4'-(methylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]-
oxy]-(2S)-propanoic acid
##STR00157##
[0763] i) 2-Chloro-1-iodo-4-(methylthio)benzene
[0764] Sodium methanethiolate (5 g) was added to a solution of
4-fluoro-2-chloro-iodobenzene (18.3 g) and stirred for 20 h. The
mixture was poured into water, extracted with ether, washed with
brine, dried (MgSO.sub.4) and evaporated. Yield 18.5 g.
[0765] .sup.1H NMR DMSO-d6: .delta. 7.81 (d, 1H), 7.43 (dd, 1H),
6.98 (dd, 1H), 3.32 (s, 3H)
ii) 2-Chloro-1-iodo-4-(methylsulfonyl)benzene
[0766] Mcpba (8.6 g) was added portionwise to a stirred solution of
the product from step (1) (5 g) in DCM (100 ml). After 1 h, the
reaction was diluted with DCM (200 ml), washed with saturated
aqueous sodium bicarbonate, dried (MgSO.sub.4) and evaporated under
reduced pressure. Yield 3.2 g
[0767] .sup.1H NMR DMSO-d6: .delta. 8.26 (d, 1H), 8.06 (d, 1H),
7.59 (dd, 1H), 3.32 (s, 3H)
iii)
2'-Chloro-4'-(methylsulfonyl)-5-(trifluoromethyl)-[1,1'-biphenyl]-2-y-
l]oxy]methyl]benzene
[0768] The subtitle compound was prepared by the method of example
144 step (i) using the product from step (ii) and the product from
example 32 step (ii). Yield 2.2 g
[0769] .sup.1H NMR DMSO-d6: .delta. 8.11 (s, 1H), 7.95 (dd, 1H),
7.82 (d, 1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.41 (d, 1H), 7.27-7.36
(m, 5H), 5.25 (s, 2H), 3.35 (s, 3H)
iv)
2'-Chloro-4'-(methylsulfonyl)-5-(trifluoromethyl)-[1,1'-biphenyl]-2-ol
[0770] The subtitle compound was prepared by the method of example
144 step (ii) using the product from step Yield 0.95 g
[0771] .sup.1H NMR DMSO-d6: .delta. 10.72 (s, 1H), 8.08 (d, 1H),
7.93 (dd, 1H), 7.63-7.68 (m, 2H), 7.49 (d, 1H), 7.14 (d, 1H), 3.35
(s, 3H)
[0772] MS:APCI (-ve) 349
v)
2-[[2'-Chloro-4'-(methylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2--
yl]oxy]-(2S)-propanoic acid, 1,1-dimethylethyl ester
[0773] The subtitle compound was prepared by the method of example
32 step (v) using the product from step (iv) and tert-butyl
R-lactate. Yield 0.25 g.
[0774] .sup.1H NMR DMSO-d6: .delta. 8.11 (d, 1H), 7.97 (d, 1H),
7.82 (dd; 1H), 7.73 (d, 1H), 7.62 (d, 1H), 7.15 (d, 1H), 5.0 (brs,
1H), 3.36 (s, 3H), 1.36-1.39 (m, 12H)
vi)
2-[[2'-Chloro-4'-(methylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-
-yl]oxy]-(2S)-propanoic acid
[0775] The title compound was prepared by the method of example 1
step (iii) using the product from step (v). Yield 0.12 g.
[0776] .sup.1H NMR DMSO-d6: .delta. 8.09 (d, 1H), 7.95 (dd, 1H),
7.82 (s, 1H), 7.76 (dd, 1H), 7.58 (d, 1H), 7.14 (d, 1H), 4.87 (q,
1H), 3.36 (s, 3H), 1.35 (d, 3H)
[0777] MS:APCI (-ve) 421
EXAMPLE 146
2-[[3'-Cyano-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-propanoic
acid
##STR00158##
[0778] i)
4,4,5,5-Tetramethyl-2-[2-(phenylmethoxy)-5-(trifluoromethyl)phen-
yl]-1,3,2-dioxaborolane
[0779] Pinacol (1.82 g) was added to a solution of the product from
example 32 step (ii) (4.54 g) in ether (40 ml) and stirred at RT
for 20 h. The reaction was diluted with ether (100 ml), washed with
brine, dried (MgSO.sub.4) and evaporated. Yield 5.7 g.
[0780] .sup.1H NMR DMSO-d6: .delta. 7.82 (d, 1H), 7.79 (d, 1H), 7.6
(d, 2H), 7.4 (t, 2H), 7.32 (d, 1H), 7.27 (d, 1H), 5.24 (s, 2H),
1.32 (s, 12H)
ii)
2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)phe-
nol
[0781] 10% Pd/C (0.5 g) was added to a solution of the product from
step (i) in EtOAc (80 ml) and hydrogenated at RT and 1 bar for 1 h,
and for a further 3 h at 3 bar. The catalyst was removed by
filtration and the filtrate evaporated to leave a solid product.
Yield 4.2 g.
[0782] .sup.1H NMR DMSO-d6: .delta. 9.99 (d, 1H), 7.72 (s, 1H),
7.63 (d, 1H), 6.99 (d, 1H), 1.3 (d, 12H)
iii)
2-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl-
)phenoxy]-(2S)-propanoic acid, 1,1-dimethylethyl ester
[0783] The subtitle compound was prepared by the method of example
32 step (v) using the product from step (ii) and tert-butyl
R-lactate. Yield 4.0 g. The crude material was carried forward to
step (iv).
iv) 2-[2-Borono-4-(trifluoromethyl)phenoxy]-(2S)-propanoic acid
[0784] TPA (10 ml) was added to a solution of the product from step
(iii) (4.0 g) in DCM (100 ml) and stirred for 30 min. The TFA was
evaporated and the residue dissolved in a mixture of 1M
hydrochloric acid (30 ml) and acetonitrile (30 ml) After 1 h the
mixture was evaporated to dryness, dissolved in 1M sodium
hydroxide, washed with ether and adjusted to pH 2 with concentrated
hydrochloric acid. The aqueous was then extracted with ether,
washed with brine, dried (MgSO.sub.4) and evaporated. Yield 2.0 g.
The crude material was carried forward to step (v).
v)
2-[[3'-Cyano-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-propanoi-
c acid
[0785] The title compound was prepared by the method of example 144
step (i) using the product from step (iv) and
3-bromobenzonitrile.
[0786] .sup.1H NMR DMSO-d6: .delta. 8.13 (t, 1H), 8.01 (tdt, 1H),
7.85 (dt, 1H), 7.71-7.76 (m, 2H), 7.65 (dt, 1H), 7.17-7.2 (m, 1H),
5.11 (q, 1H), 1.47 (d, 3H)
[0787] MS:APCI (-ve) 334
EXAMPLE 147
2-[[4'-[(Dimethylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]o-
xy]-(2S)-propanoic acid
##STR00159##
[0789] The title compound was prepared by the method of example 144
step (i) using the product from example 146 step (iv) and
4-bromo-N,N-dimethyl-benzenesulfonamide.
[0790] .sup.1H NMR DMSO-d6: .delta. 7.95 (d, 2H), 7.83 (d, 2H),
7.77 (d, 1H), 7.73 (s, 1H), 7.21 (d, 1H), 5.14 (q, 1H), 2.69 (s,
6H), 1.51 (d, 3H)
[0791] MS:APCI (-ve) 416
EXAMPLE 148
2-[[2'-Chloro-4'-[(dimethylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-biphen-
yl]-2-yl]oxy]-(2S)-propanoic acid
##STR00160##
[0792] i) 3-Chloro-4-iodobenzenesulfonamide
[0793] A solution of sodium nitrite (3.27 g) in water was added
dropwise over 1 h to a stirred solution of 3-chloro-4-iodoaniline
(10.0 g) in a mixture of THF (120 ml) and concentrated hydrochloric
acid (50 ml) at -5 to -1.degree. C. Magnesium chloride (6.39 g) was
then added and the resulting mixture poured into a stirred solution
of acetic acid (50 ml) saturated with sulfur dioxide and containing
cuprous chloride (2.14 g). After heating at 34.degree. C. for 30
min, the mixture was poured into brine, extracted with EtOAc,
washed with aqueous sodium bicarbonate and brine, dried
(MgSO.sub.4) and evaporated. The residue was dissolved in THF (100
ml), 0.880 ammonia (100 ml) added and stirred for 2 h. The mixture
was diluted with brine, extracted with EtOAc, washed with brine,
dried (MgSO.sub.4) and evaporated. The residue was treated with
isohexane/ether (4:1) and filtered to give the subtitle
compound.
[0794] Yield 5.67 g.
[0795] .sup.1H NMR DMSO-d6: .delta. 8.18 (d, 1H), 7.92 (d, 1H),
7.56 (s, 1H), 7.47 (dd, 1H)
ii) 3-Chloro-4-iodo-N,N-dimethylbenzenesulfonamide
[0796] Sodium hydride (0.33 g) was added to a solution of the
product from step (i) (1.2 g) in DMF (25 ml) and stirred for 20
min. Methyl iodide (0.5 ml) was added dropwise and then stirred for
a further 1 h. The reaction mixture was quenched with water,
extracted with EtOAc, dried (MgSO.sub.4) and evaporated. The
residue was treated with ether to give to give the subtitle
compound as a white solid. Yield 0.45 g.
[0797] .sup.1H NMR DMSO-d6: .delta. 8.05 (d, 1H), 7.82 (d, 1H),
7.31 (dd, 1H), 2.75 (s, 6H)
iii)
2-[[2'-Chloro-4'-[(dimethylamino)sulfonyl]-5-(trifluoromethyl)[1,1'-b-
iphenyl]-2-yl]oxy]-(2S)-propanoic acid
[0798] The title compound was prepared by the method of example 144
step (i) using the product from step (ii) and the product from
example 146 step (iv). .sup.1H NMR DMSO-d6: .delta. 7.86 (t, 1H),
7.75-7.79 (m, 3H), 7.61 (d, 1H), 7.14 (d, 1H), 4.88 (q, 1H), 2.7
(s, 6H), 1.35 (d, 3H)
[0799] MS:APCI (-ve) 450
EXAMPLE 149
2-[[2'-Fluoro-4'-(methylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-yl]-
oxy]-(2S)-propanoic acid
##STR00161##
[0800] i) Trifluoromethanesulfonic acid,
2-fluoro-4-(methylsulfonyl)phenyl ester
[0801] 2-Fluoro-4-(methylsulfonyl)phenol (1.44 g) was dissolved in
DCM (20 ml), triethylamine (1.17 ml) added, followed by
trifluoromethanesulfonic anhydride (1.57 ml) and stirred for 1 h.
The solution was washed with brine, dried (MgSO.sub.4) and
evaporated to give the subtitle compound.
[0802] .sup.1H NMR CDCl.sub.3: .delta. 7.83-7.92 (m, 2H), 7.55-7.61
(m, 1H), 3.11 (s, 3H)
ii)
2-[[2'-Fluoro-4'-(methylsulfonyl)-5-(trifluoromethyl)[1,1'-biphenyl]-2-
-yl]oxy]-(2S)-propanoic acid
[0803] The title compound was prepared by the method of example 144
step (i) using the product from step (i) and the product from
example 146 step (iv).
[0804] .sup.1H NMR DMSO-d6: .delta. 7.79-7.9 (m, 3H), 7.74 (dd,
1H), 7.64 (s, 1H), 7.12 (d, 1H), 4.87 (q, 1H), 3.31 (s, 3H), 1.35
(d, 3H)
[0805] MS:APCI (-ve) 405
EXAMPLE 150
[[2',5-Dichloro-4'-(methylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-propanoi-
c acid
##STR00162##
[0806] i)
[[[2',5-Dichloro-4'-(methylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]met-
hyl]benzene
[0807] The subtitle compound was prepared by the method of example
144 step (i) using the product from example 16 step (ii) and the
product from example 145 step (ii). Yield 1.08 g.
[0808] .sup.1H NMR DMSO-d6: .delta. 8.09 (d, 1H), 7.94 (dd, 1H),
7.67 (d, 1H), 7.49 (dd, 1H), 7.22-7.34 (m, 7H), 5.14 (s, 2H), 3.35
(s, 3H)
ii) [[[2',5-Dichloro-4'-(methylsulfonyl)[1,1'-biphenyl]-2-ol
[0809] The subtitle compound was prepared by the method of example
144 step (ii) using the product from step (i). Yield 0.45 g.
[0810] .sup.1H NMR DMSO-d6: .delta. 10.04 (s, 1H), 8.06 (d, 1H),
7.91 (dd, 1H), 7.63 (d, 1H), 7.32 (dd, 1H), 7.2 (d, 1H), 6.97 (d,
1H), 3.34 (s, 3H)
iii)
[[2',5-Dichloro-4'-(methylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-pro-
panoic acid, 1,1-dimethylethyl ester
[0811] The subtitle compound was prepared by the method of example
32 step (v) using the product from step (ii) and tert-butyl
R-lactate. Yield 0.24 g.
[0812] .sup.1H NMR DMSO-d6: .delta. 8.09 (d, 1H), 7.95 (d, 1H), 7.7
(d, 1H), 7.48 (dd, 1H), 7.33 (d, 1H), 6.98 (d, 1H), 4.85 (brs, 1H),
3.35 (s, 3H), 1.37 (s, 9H), 1.32 (d, 3H) iv)
[[2',5-Dichloro-4'-(methylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-propano-
ic acid
[0813] The title compound was prepared by the method of example 1
step (iii) using the product from step Yield 0.11 g.
[0814] .sup.1H NMR DMSO-d6: .delta. 8.07 (d, 1H), 7.92 (dd, 1H),
7.81 (s, 1H), 7.42 (dd, 1H), 7.28 (d, 1H), 6.97 (d, 1H), 4.65 (q,
1H), 3.35 (s, 3H), 1.29 (d, 3H)
[0815] MS:APCI (-ve) 387
EXAMPLE 151
[[5-Chloro-4'-[(dimethylamino)sulfonyl][1,1'-biphenyl]-2-yl]oxy]-(2S)-prop-
anoic acid
##STR00163##
[0816] i)
2-[5-Chloro-2-(phenylmethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-d-
ioxaboralane
[0817] The subtitle compound was prepared by the method of example
146 step (i) using the product from example 16 step (ii). Yield 3.3
g.
[0818] .sup.1H NMR DMSO-d6: .delta. 7.27-7.64 (m, 7H), 6.85 (d,
1H), 5.09 (s, 2H), 1.36 (s, 12H)
ii)
4-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
[0819] The subtitle compound was prepared by the method of example
146 step (ii) using the product from step (i). Purified by
chromatography on silica eluting with 50% EtOAc/isohexane. Yield
1.89 g.
[0820] .sup.1H NMR DMSO-d6: .delta. 7.76-7.79 (s, 1H), 6.79-7.62
(m, 3H), 1.36 (s, 12H)
iii)
2-[4-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-(-
2S)-propanoic acid, 1,1-dimethylethyl ester
[0821] The subtitle compound was prepared by the method of example
32 step (v) using the product from step (ii) and tert-butyl
R-lactate. Yield 3.5 g. The crude material was carried forward to
step (iv).
iv) 2-(2-Borono-4-chlorophenoxy)-(2S)-propanoic acid
[0822] The subtitle compound was prepared by the method of example
146 step (iv) using the product from step (iii). Yield 2.5 g. The
crude material was carried forward to step (v).
v)
[[5-Chloro-4'-[(dimethylamino)sulfonyl][1,1'-biphenyl]-2-yl]oxy]-(2S)-p-
ropanoic acid
[0823] The title compound was prepared by the method of example 144
step (i) using the product from step (iv) and
4-bromo-N,N-dimethylbenzenesulfonamide and THF as solvent. Yield
(0.068 g).
[0824] .sup.1H NMR DMSO-d6: .delta. 8.01 (d, 2H), 7.75 (d, 2H),
7.3-7.41 (m, 2H), 6.93 (d, 1H), 4.56 (bm, 1H), 2.65 (s, 6H), 1.33
(d, 3H)
[0825] MS:APCI (-ve) 382
EXAMPLE 152
[[2',5-Dichloro-4'-[(dimethylamino)sulfonyl][1,1'-biphenyl]-2-yl]oxy]-(2S)-
-propanoic acid
##STR00164##
[0827] The title compound was prepared by the method of example 144
step (i) using the product from example 151 step (iv), the product
from example 148 step (ii) and methanol as solvent. Yield (0.08
g).
[0828] .sup.1H NMR DMSO-d6: .delta. 7.9 (bm, 1H), 7.82 (s, 1H),
7.74 (dd, 1H), 7.4 (dd, 1H), 7.26 (d, 1H), 6.92 (d, 1H), 4.34 (bm,
1H), 2.7 (s, 6H), 1.2 (d, 3H)
[0829] MS:APCI (-ve) 416
EXAMPLE 153
[(5-Chloro-3'-cyano[1,1'-biphenyl]-2-yl)oxy]-(2S)-propanoic
acid
##STR00165##
[0831] The title compound was prepared by the method of example 144
step (i) using the product from example 151 step (iv),
3-bromobenzenenitrile and THF as solvent.
[0832] .sup.1H NMR DMSO-d6: .delta. 8.25 (s, 1H), 8.06 (d, 1H),
7.79 (d, 1H), 7.63 (t, 1H), 7.4 (d, 1H), 7.33 (dd, 1H), 6.95 (d,
1H), 4.64 (q, 1H), 1.32.degree.(d, 3H)
[0833] MS:APCI (-ve) 300
EXAMPLE 154
[[5-Chloro-4'-[(dimethylamino)sulfonyl]-2'fluoro[1,1'-biphenyl]-2-yl]oxy]--
(2S)-propanoic acid
##STR00166##
[0834] i) 4-Bromo-N,N-dimethyl-3-fluorobenzenesulfonamide
[0835] The subtitle compound was prepared by the method of example
148 step (ii) using 4-bromo-3-fluorobenzenesulfonamide 1.14 g.
ii)
[[5-Chloro-4'-[(dimethylamino)sulfonyl]-2'-fluoro[1,1'-biphenyl]-2-yl]-
oxy]-(2S)-propanoic acid
[0836] The title compound was prepared by the method of example 144
step (i) using the product from step (i), the product from example
151 step (iv) and THF as solvent.
[0837] .sup.1H NMR DMSO-d6: .delta. 7.94 (t, 1H), 7.58-7.62 (m,
2H), 7.35-7.4 (m, 2H), 6.93 (d, 1H), 4.48 (q, 1H), 2.7 (s, 6H),
1.26 (d, 3H)
[0838] MS:ESI (+ve) 402
EXAMPLE 155
[[5-Chloro-4'-(4-morpholinylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-propan-
oic acid
##STR00167##
[0840] A mixture of the product from example 151 step (iv) (0.126
g), sodium carbonate (0.22 g),
4-[(4-bromophenyl)sulfonyl]morpholine (0.16 g) and Pd(dppf)Cl.sub.2
(0.03 g) in dioxane (10 ml) was heated under reflux for 4 h. The
mixture was evaporated and purified by RVBPLC (MeCN/aqNH.sub.4Cl).
Yield 0.09 g.
[0841] .sup.1H NMR DMSO-d6: .delta. 8.03 (d, 2H), 7.74 (d, 2H),
7.31-7.39 (m, 2H), 6.93 (d, 1H), 4.55 (m, 1H), 3.65 (m, 2H), 2.92
(m, 2H), 1.34 (d, 3H)
[0842] MS:APCI (-ve) 426
EXAMPLE 156
[[5-Chloro-2'-fluoro-4'-(methylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-pro-
panoic acid
##STR00168##
[0844] The title compound was prepared by the method of example 155
using the product from example 151 step (iv) and the product from
example 149 step (i).
[0845] .sup.1H NMR DMSO-d6: .delta. 7.81-7.88 (m, 3H), 7.41-7.49
(m, 2H), 7.0 (d, 1H), 4.9 (q, 1H), 3.3 (s, 3H), 1.37 (d, 3H)
[0846] MS:ESI (-ve) 371
EXAMPLE 157
2-[[4'-(1-Azetidinylsulfonyl)-5-chloro[1,1'-biphenyl]-2-yl]oxy]-(2S)-propa-
noic acid
##STR00169##
[0848] The title compound was prepared by the method of example 144
step (i) using the product from example 151 step (iv),
1-[(4-bromophenyl)sulfonyl]azetidine and THF as solvent.
[0849] Yield 0.028 g. .sup.1H NMR DMSO-d6: .delta. 7.97 (d, 2H),
7.82 (d, 2H), 7.39-7.43 (m, 2H), 7.01 (d, 1H), 4.85 (m, 1H), 3.72
(t, 4H), 2.04 (q, 2H), 1.42 (d, 3H)
[0850] MS:ESI (-ve) 394
EXAMPLE 158
2-[[5-Chloro-2'-methyl-4'-(1-pyrrolidinylcarbonyl)[1,1'-biphenyl]-2-yl]oxy-
]-(2S)-propanoic acid, sodium salt
##STR00170##
[0852] The title compound was prepared by the method of example 155
using the product from example 151 step (iv) and
1-(4-bromo-3-methylbenzoyl)pyrrolidine. Yield 0.152 g. .sup.1H NMR
DMSO-d6: .delta. 7.2-7.41 (m, 4H), 7.25 (s, 1H), 6.85 (d, 1H), 4.22
(m, 1H), 3.56 (m, 4H), 2.2 (s, 3H), 1.85 (m, 4H), 1.17 (d, 3H)
[0853] MS:APCI (-ve) 388
EXAMPLE 159
2-[(2',4'-Dichloro-5-cyano[1,1'-biphenyl]-2-yl)oxy]-(2S)-propanoic
acid
##STR00171##
[0854] i) 2-(2-Bromo-4-cyanophenoxy)-(2S)-propanoic acid
[0855] Diethyl azodicarboxylate (2.12 g) was added to a stirred
solution of 2-bromo-4-cyanophenol (2.0 g), methyl-R-lactate (1.47
g) and triphenylphosphine (2.65 g) in UV (80 ml). After 20 h, the
mixture was filtered through silica using isohexane/EtOAc as
solvent and the filtrate evaporated to dryness. The residue was
dissolved in DCM (50 ml), treated with TFA (10 ml) and stirred for
2 h. The solution was evaporated and the residue partitioned
between EtOAc and aqueous sodium bicarbonate. The aqueous was
acidified with 2M hydrochloric acid, extracted with EtOAc, dried
(MgSO.sub.4) and evaporated to give the subtitle compound.
[0856] .sup.1H NMR DMSO-d6: .delta. 7.87 (s, 1H), 7.56 (d, 1H),
6.83 (d, 1H), 4.91 (q, 1H), 1.7 (d, 3H)
[0857] MS:APCI (-ve) 270
ii)
2-[(2',4'-Dichloro-5-cyano[1,1'-biphenyl]-2-yl)oxy]-(2S)-propanoic
acid
[0858] The title compound was prepared by the method of example 16
step (iii) using the product from step (i) and
2,6-dichlorophenylboronic acid.
[0859] .sup.1H NMR DMSO-d6: .delta. 7.58-7.78 (m, 4H), 7.46 (d,
1H), 7.02 (d, 1H), 4.51 (q, 1H), 1.26 (d, 3H)
[0860] MS:APCI (-ve) 334
EXAMPLE 160
2-[[5-Cyano-2'-fluoro-4'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-p-
ropanoic acid
##STR00172##
[0862] The title compound was prepared by the method of example 16
step (iii) using the product from example 159 step (i) and
3-cyanophenylboronic acid.
[0863] .sup.1H NMR DMSO-d6: .delta. 7.81-8.04 (m, 4H), 7.56 (t,
1H), 7.18 (d, 1H), 5.1 (q, 1H), 1.4 (d, 3H)
[0864] MS:APCI (-ve) 352
EXAMPLE 161
2-[(3'-Cyano-5-fluoro[1,1'-biphenyl]-2-yl)oxy]-(2S)-propanoic acid,
sodium salt
##STR00173##
[0865] i) 2-(2-Bromo-4-fluorophenoxy)-(2S)-propanoic acid,
1,1-dimethylethyl ester
[0866] The subtitle compound was prepared by the method of example
159 step (i) using 2-bromo-4-fluorophenol (2.5 g). Yield 3.0 g.
[0867] .sup.1H NMR DMSO-d6: .delta. 7.28-7.32 (m, 1H), 6.89-6.98
(m, 1H), 6.78-6.83 (m, 1H), 4.56 (q, 1H), 1.62 (d, 3H), 1.4 (s,
9H)
ii) 2-(2-Bromo-4-fluorophenoxy)-(2S)-propanoic acid
[0868] The subtitle compound was prepared by the method of example
146 step (iv) using the product from step (i). Yield 1.2 g. Carried
forward to step (iii) without characterisation.
iii) 2-[(3'-Cyano-5-fluoro[1,1'-biphenyl]-2-yl)oxy]-(2S)-propanoic
acid, sodium salt
[0869] The title compound was prepared by the method of example 155
using the product from step (ii) and 3-cyanophenylboronic acid. The
product was dissolved in acetonitrile, treated with 1M sodium
hydroxide and evaporated to give the title compound.
[0870] .sup.1H NMR DMSO-d6: .delta. 8.4 (s, 1H), 8.13 (d, 1H), 7.75
(d, 1H), 7.6 (t, 1H), 6.9-7.2 (m, 3H), 4.4 (q, 1H), 1.28 (d,
3H)
[0871] MS:APCI (-ve) 284
EXAMPLE 162
2-[(2',4'-Dichloro-5-fluoro[1,1'-biphenyl]-2-yl)oxy]-(2S)-propanoic
acid, sodium salt
##STR00174##
[0873] The title compound was prepared by the method of example 155
using the product from example 161 step (ii) and
2,4-dichlorophenylboronic acid. The product was dissolved in
acetonitrile, treated with 1M sodium hydroxide and evaporated to
give the title compound.
[0874] .sup.1H NMR DMSO-d6: .delta. 7.66-7.72 (m, 2H), 7.43 (d,
1H), 6.86-7.11 (m, 3H), 4.18 (q, 1H), 1.2 (d, 3H).
[0875] MS:APCI (-ve) 327
EXAMPLE 163
2-[[2'-Chloro-5-fluoro-4'-(methylsulfonyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)-p-
ropanoic acid
##STR00175##
[0876] i) Benzyl 2-bromo-4-fluorophenyl ether
[0877] The subtitle compound was prepared by the method of example
16 step (i) using 2-bromo-4-fluorophenol and acetone as solvent.
Yield 27.5 g.
[0878] .sup.1H NMR DMSO-d6: .delta. 7.27-7.49 (m, 6H), 6.82-6.99
(m, 2H), 5.12
ii) [2-(Benzyloxy)-5-fluorophenyl]boronic acid
[0879] The subtitle compound was prepared by the method of example
16 step (ii) using the product from step (i). Yield 18.77 g.
[0880] .sup.1H NMR DMSO-d6: .delta. 7.9 (s, 2H), 7.0-7.5 (m, 8H),
5.14 (s, 2H)
iii)
2-[5-Fluoro-2-(phenylmethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxab-
orolane
[0881] The subtitle compound was prepared by the method of example
146 step (i) using the product from step (ii). Yield 4.1 g.
[0882] .sup.1H NMR. DMSO-d6: .delta. 7.58 (d, 1H), 7.29-7.4 (m,
3H), 7.26 (s, 1H), 7.04 (dt, 1H), 6.84 (d, 2H), 5:07 (s, 2H), 1.36
(s, 12H)
iv)
4-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
[0883] The subtitle compound was prepared by the method of example
146 step (ii) using the product from step (iii) and ethanol as
solvent.
[0884] .sup.1H NMR DMSO-d6: .delta. 7.63 (s, 1H), 7.2-7.27 (m, 1H),
7.01-7.08 (m, 1H), 6.8-6.83 (m, 1H), 1.37 (s, 12H)
v)
4-Fluoro-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-(2S-
)-propanoic acid, 1,1-dimethylethyl ester
[0885] The subtitle compound was prepared by the method of example
32 step (v) using the product from step (iv) and tert-butyl
R-lactate. Yield 2.6 g. The crude material was carried forward to
step (vi).
vi) 2-[2-Borono-4-(trifluoromethyl)phenoxy]-(2S)-propanoic acid
[0886] The subtitle compound was prepared by the method of example
146 step (iv) using the product from step (v). Yield 1.65 g.
[0887] MS:APCI (-ve) 227
vii)
2-[[2'-Chloro-5-fluoro-4'-(methylsulfonyl)[1,1'-biphenyl]-2-yl)oxy]-(-
2S)-propanoic acid
[0888] The title compound was prepared by the method of example 155
using the product from step (vi) and the product from example 145
step (ii).
[0889] .sup.1H NMR DMSO-d6: .delta. 8.06 (s, 1H), 7.86-7.93 (m,
2H), 7.03-7.23 (m, 2H), 6.9-6.97 (m, 1H), 4.43 (q, 1H), 1.24 (d,
3H)
[0890] MS:APCI (-ve) 371
EXAMPLE 164
2-[[2'-Chloro-5-fluoro-5'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]-(2S)--
propanoic acid, sodium salt
##STR00176##
[0892] The title compound was prepared by the method of example 155
using the product from example 161 step (ii) and
2-bromo-1-chloro-4-(trifluoromethyl)benzene. The product was
dissolved in acetonitrile, treated with 1M sodium hydroxide and
evaporated to give the title compound. Yield 0.07 g.
[0893] .sup.1H NMR DMSO-d6: .delta. 8.31 (bs, 1H), 7.68-7.77 (m,
2H), 7.09-7.15 (m, 2H), 6.9-6.93 (m, 1H), 4.25 (q, 1H), 1.21 (d,
3H)
[0894] MS:APCI (-ve) 361
EXAMPLE 165
[[4'-(Ethylsulfonyl)-6-methyl-5-nitro[1,1'-biphenyl]-2-yl]oxy]acetic
acid
##STR00177##
[0895] i) (2-Bromo-3-methyl-4-nitophenoxy)acetic acid, methyl
ester
[0896] Bromine (5.27 g) in acetic acid (3 ml) was added dropwise to
a solution of 3-methyl-4-nitrophenol (5.04 g) in acetic acid (43
ml) over 45 mins, and then stirred for a further 1 h. The solvent
was evaporated, water added, extracted with ether, dried
(Na.sub.2SO.sub.4) and evaporated. The crude material was dissolved
in DMF (10 ml), potassium carbonate (3.79 g) added, followed by
methyl bromoacetate (3.37 ml) and the mixture stirred at RT for 30
mins and 60.degree. C. for 2 h. The mixture was cooled and poured
into a mixture of EtOAc and water. The organic phase was separated,
washed with water, aqueous potassium carbonate and brine, dried
(Na.sub.2SO.sub.4) and evaporated. The residue was recrystallised
from toluene/isohexane. Yield 1.8 g.
[0897] .sup.1H NMR CDCl.sub.3: .delta. 7.86 (d, 1H), 6.69 (d, 1H),
4.81 (s, 2H), 3.83 (s, 3H), 2.19 (s, 3H).
(ii)
[[4'-(Ethylsulfonyl)-6-methyl-5-nitro[1,1'-biphenyl]-2-yl]oxy]acetic
acid, methyl ester
[0898] The subtitle compound was prepared by the method of example
1 step (ii) using the product from step (i) (1.78 g) and
4-(ethylthio)phenylboronic acid (1.6 g). Yield 2.59 g.
[0899] .sup.1H NMR CDCl.sub.3: .delta. 8.02 (d, 1H), 8.0 (d, 2H),
7.45 (d, 2H), 6.75 (d, 1H), 4.65 (s, 2H), 3.76 (s, 3H), 3.2 (q,
2H), 2.25 (s, 3H) 1.36 (t, 3H)
(iii)
[[4'-(Ethylsulfonyl)-6-methyl-5-nitro[1,1'-biphenyl]-2-yl]oxy]acetic
acid
[0900] The title compound was prepared by the method of example 26
step (vi) using the product from step (ii). Yield 0.22 g.
[0901] .sup.1H NMR DMSO-d6: .delta. 13.16 (bs, 1H), 8.06 (d, 1H),
7.97 (d, 2H), 7.57 (d, 2H), 7.12 (d, 1H), 4.8 (s, 2H), 3.38 (q,
2H), 2.14 (s, 3H) 1.16 (t, 3H).
[0902] MS: APCI (+ve): 412 (M+MeOH+H.sup.+)
EXAMPLE 166
[[5-Chloro-4'-(ethylsulfonyl)-6-methyl[1,1'-biphenyl]-2-yl]oxy]acetic
acid
##STR00178##
[0903] i)
[[5-Amino-4'-(ethylsulfonyl)-6-methyl[1,1'-biphenyl]-2-yl]oxy]ac-
etic acid, methyl ester
[0904] 10% Pd/C (0.15 g) was added to a solution of the product
from example 165 step (ii) in EtOAc (20 ml) was hydrogenated at RT
and 3 bar for 2 h. The mixture was filtered through celite and the
filtrate evaporated to give the sub-title compound. Yield 1.4
g.
[0905] .sup.1H NMR CDCl.sub.3: .delta. 7.95 (d, 2H), 7.48 (d, 2H),
6.7 (d, 1H), 6.65 (d, 1H), 4.4 (s, 2H), 3.71 (s, 3H), 3.51 (bs,
2H), 3.18 (q, 2H), 1.88 (s, 3H) 1.34 (t, 3H)
ii)
[[5-Chloro-4'-(ethylsulfonyl)-6-methyl[1,1'-biphenyl]-2-yl]oxy]acetic
acid, methyl ester
[0906] Cuprous chloride (0.18 g) was dissolved in acetonitrile (6
ml), isopentylamine (0.24 ml) added, followed by the dropwise
addition of a solution of the product from step (i) in acetonitrile
(6 ml). The mixture was stirred for 12 h, evaporated and purified
by chromatography on silica eluting with 30-50% ether/isohexane.
Yield 2.59 g.
[0907] .sup.1H NMR CDCl.sub.3: .delta. 7.97 (d, 2H), 7.46 (d, 2H),
7.34 (d, 1H), 6.65 (d, 1H), 4.32 (s, 2H), 3.73 (s, 3H), 3.19 (q,
2H), 2.09 (s, 3H) 1.35 (t, 3H)
iii)
[[5-Chloro-4'-(ethylsulfonyl)-6-methyl[1,1'-biphenyl]-2-yl]oxy]acetic
acid
[0908] The title compound was prepared by the method of example 26
step (vi) using the product from step (ii). Purified by RPHPLC
(MeCN/aqNH.sub.4Cl). Yield 0.07 g.
[0909] .sup.1H NMR DMSO-d6: .delta. 7.94 (d, 2H), 7.53 (d, 2H),
7.44 (d, 1H), 6.91 (d, 1H), 4.64 (s, 2H), 3.36 (q, 2H), 2.03 (s,
3H) 1.15 (t, 3H)
[0910] MS:APCI (+ve) 367 (M-1-MeOH+H.sup.+)
EXAMPLE 167
[[4'-(Methylsulfonyl)-2',5-bis(trifluoromethyl)[1,1'-biphenyl]-2-yl]oxy]ac-
etic acid
##STR00179##
[0911] i) 4-Bromo-1-(methylthio)-2-(trifluoromethyl)benzene
[0912] Isopentyl nitrite (0.67 ml) was added dropwise to a solution
of 4-bromo-2-(trifluoromethyl)aniline (1.2 g) and dimethyl sulfide
(0.45 ml) in acetonitrile (12 ml). The reaction was slowly heated
to reflux and then refluxed until gas evolution ceased. The
volatiles were evaporated, the residue absorbed onto silica and the
product eluted off with isohexane. Yield 0.8 g.
[0913] .sup.1H NMR DMSO-d6: .delta. 7.59 (dd, 2H), 7.23 (d, 1H),
2.51 (s, 3H)
ii)
4,4,5,5-Tetramethyl-2-[4-(methylthio)-3-(trifluoromethyl)phenyl]-1,3,2-
-dioxaborolane
[0914] Pd.sub.2dba.sub.3 (0.135 g) and tricyclohexylphosphine
(0.199 g) were dissolved in dioxane (20 ml) and stirred for 30 min.
Potassium acetate (0.867 g), bis(pinacolato)diboron (1.65 g) and
the product from step (i) were sequentially added and the mixture
heated at 90.degree. C. for 3 h. The reaction was cooled,
evaporated, partitioned between ether and brine, separated, dried
(Na.sub.2SO.sub.4) and evaporated. The residue was purified by
chromatography on silica eluting with 10% ether/isohexane. Yield
0.695 g.
[0915] .sup.1H NMR DMSO-d6: .delta. 7.31 (d, 2H), 2.53 (s, 3H), 1.3
(s, 12H)
iii) 2-Bromo-4-(trifluoromethyl)phenoxyacetic acid,
1,1-dimethylethyl ester
[0916] The title compound was prepared by the method of example 1
step (i) using 2-bromo-4-(trifluoromethyl)phenol.
[0917] .sup.1H NMR DMSO-d6: .delta. 6.8-7.83 (m, 3H), 4.65 (s, 2H),
1.48 (s, 9H)
iv) [[4'-(Methylthio)-2',5-bis(trifluoromethyl)
[1,1'-biphenyl]-2-yl]oxy]acetic acid, 1,1-dimethylethyl ester
[0918] The title compound was prepared by the method of example 1
step (ii) using the products from steps (ii) and Yield 0.564 g.
Carried forward to step (v) without characterisation.
v) [[4'-(Methylsulfonyl)-2',5-bis(trifluoromethyl)
[1,1'-biphenyl]-2-yl]oxy]acetic acid, 1,1-dimethylethyl ester
[0919] The product from step (iv) (0.564 g) was dissolved in 50%
aqueous acetone (10 ml), sodium bicarbonate (0.94 g) added,
followed by a solution of oxone (1.5 g) in water (nil) and stirred
for 3 h. The reaction was quenched with aqueous sodium
metabisulfite, extracted with EtOAc, washed with aqueous potassium
carbonate, dried (Na.sub.2SO.sub.4) and evaporated to give the
subtitle compound. Yield 0.32 g.
[0920] .sup.1H NMR DMSO-d6: .delta. 8.31 (d, 1H), 8.29 (s, 1H),
8.18 (dd, 1H), 7.83 (s, 1H), 7.81 (d, 1H), 7.32 (d, 1H), 4.9 (s,
2H), 3.36 (s, 2H), 1.41 (s, 9H)
vi)
[[4'-(Methylsulfonyl)-2',5-bis(trifluoromethyl)[1,1'-biphenyl]-2-yl]ox-
y]acetic acid
[0921] The title compound was prepared by the method of example 26
step (vi) using the product from step (v). Yield 0.2 g.
[0922] .sup.1H NMR DMSO-d6: .delta. 8.33 (s, 1H), 8.3 (d, 1H), 8.19
(d, 1H), 7.83 (s, 1H), 7.81 (d, 1H), 7.34 (d, 1H), 4.92 (s, 2H),
3.36 (s, 2H)
[0923] MS:APCI (-ve) 441
EXAMPLE 168
2-[4-Chloro-2-[4-methyl-6-[methyl(methylsulfonyl)amino]-3-pyridinyl]phenox-
y]-(2S)-propanoic acid
##STR00180##
[0924] i) N-(5-Bromo-4-methyl-2-pyridinyl)methanesulfonamide
[0925] 5-Bromo-4-methylpyridin-2-amine (1.56 g) was dissolved in
DCM (40 ml), trimethylamine (1.4 ml) added, followed by
methanesulfonyl chloride (1.9 g) and the mixture stirred for 20
min. The solution was washed with water, dried (MgSO.sub.4) and
evaporated. The residue was dissolved in THF, treated with TBAF,
stirred for 16 h and evaporated. The residue was purified by
chromatography on silica eluting with 27% EtOAc/isohexane. Yield
1.3 g. Carried forward to step (ii) without characterisation.
ii) N-(5-Bromo-4-methyl-2-pyridinyl)-N-methylmethanesulfonamide
[0926] The product from step (i) (2.23 g), potassium carbonate
(2.33 g) and methyl iodide (0.7 ml) were stirred in DMF (20 ml) for
20 h. The reaction was quenched with water, extracted with EtOAc,
dried (MgSO.sub.4) and evaporated. The residue was purified by
chromatography on silica eluting with 30% EtOAc/isohexane. Yield
1.5 g. Carried forward to step (ii) without characterisation.
iii)
2-[4-Chloro-2-[4-methyl-6-[methyl(methylsulfonyl)amino]-3-pyridinyl]p-
henoxy]-(2S)-propanoic acid
[0927] The title compound was prepared by the method of example 155
using the product from step (ii) and the product from example 151
step (iv). Yield 0.125 g.
[0928] .sup.1H NMR DMSO-d6: .delta. 8.18 (s, 1H), 7.26-7.44 (m,
3H), 6.94 (d, 1H), 4.8 (m, 1H), 3.32 (s, 3H), 3.2 (s, 3H), 2.2 (s,
3H), 1.32 (d, 3H)
[0929] MS:APC1 (-ve) 397
EXAMPLE 169
2-[2-[4-Methyl-2-[(methylsulfonyl)amino]-5-pyrimidinyl]-4-(trifluoromethyl-
)phenoxy]-(2S)-propanoic acid
##STR00181##
[0930] i) Potassium
N-(5-bromo-4-methyl-2-pyrimidinyl)methanesulfonamide
[0931] Methanesulfonyl chloride (0.75 ml) was added to a solution
of 5-bromo-4-methyl-2-pyrimidinamine (1.8 g) in THF (60 ml),
followed by the rapid dropwise addition of 1M potassium
tert-butoxide/THF (20 ml). After 30 min the resulting precipitate
was filtered off and dried. Yield 3.2 g.
[0932] .sup.1H NMR DMSO-d6: .delta. 8.13 (s, 1H), 2.81 (s, 3H),
2.26 (s, 3H)
ii)
N-(5-Bromo-4-methyl-2-pyrimidinyl)-N-[[2-(trimethylsilyl)ethoxy]methyl-
]methanesulfonamide
[0933] [2-(Chloromethoxy)ethyl]trimethylsilane (0.4 ml) was added
to a solution of the product from step (i) in DMF (10 ml) and
stirred for 20 min. The mixture was poured into water, extracted
with ether, washed with brine, dried (MgSO.sub.4) and evaporated.
The residue was purified by chromatography on silica eluting with
20% EtOAc/isohexane. Yield 0.53 g.
[0934] .sup.1H NMR DMSO-d6: .delta. 8.88 (s, 1H), 5.49 (s, 2H),
3.59-3.64 (m, 5H), 2.63 (s, 3H), 0.9 (t, 2H), 0.0 (t, 9H)
iii)
2-[2-[4-Methyl-2-[(methylsulfonyl)[[2-(trimethylsilyl)ethoxy]methyl]a-
mino]-5-pyrimidinyl]-4-(trifluoromethyl)phenoxy]-(2S)-propanoic
acid
[0935] The title compound was prepared by the method of example 144
step (i) using the product from step (ii) and the product from
example 146 step (iv). Carried forward to step (iv) without
characterisation.
iv)
2-[2-[4-Methyl-2-[(methylsulfonyl)amino]-5-pyrimidinyl]-4-(trifluorome-
thyl)phenoxy]-(2S)-propanoic acid
[0936] The product from step (iii) was treated with TFA (20 ml) and
stirred for 20 min. The TFA was evaporated and the residue purified
by RVBPLC (CH.sub.3CN/aqTFA).
[0937] .sup.1H NMR DMSO-d6: .delta. 8.84 (s, 1H), 7.77 (dd, 2H),
7.65 (d, 1H), 7.14 (d, 5H), 5.04 (q, 1H), 3.4 (s, 3H), 2.3 (s, 3H),
1.41 (d, 3H)
[0938] MS:APCI (-ve) 418
EXAMPLE 170
[(5-Chloro-3'-cyano[1,1'-biphenyl]-2-yl)oxy]-acetic acid
##STR00182##
[0939] (i) 5'-Chloro-2'-methoxy-[1,1'-biphenyl]-3-carbonitrile
[0940] The subtitle compound was prepared by the method of example
1 step (ii) using 3-iodobenzonitrile and 5-chloro-2-methoxyphenyl
boronic acid. Yield 0.465 g .sup.1H NMR CDCl.sub.3: .delta. 7.82
(1H, t), 7.71 (1H, dt), 7.62 (1H, dt), 7.51 (1H, t), 7.32 (2H, dd),
7.26 (1H, m), 6.93 (1H, d), 3.81 (3H, s)
(ii) 5'-Chloro-2'-hydroxy-[1,1'-biphenyl]-3-carbonitrile
[0941] A solution of boron tribromide (1M in dichloromethane, 6 ml)
was added to a stirred solution of the product from step (i) in
dichloromethane (10 ml) at 0.degree. C. After 15 min the mixture
was warmed to room temperature, stirred for 16 h then poured onto
ice. The to mixture was extracted with dichloromethane then
ethylacetate, the organics combined, dried and evaporated under
reduced pressure. The residue was purified by chromatography on
silica eluting with 30-70% diethylether/isohexane. Yield 0.415
g
[0942] .sup.1H NMR CDCl.sub.3: .delta. 7.83 (1H, s), 7.75 (1H, d),
7.68 (1H, d), 7.58 (1H, t), 7.25 (2H, m), 6.89 (1H, d), 5.00 (1H,
s)
(iii) [(5-chloro-3'-cyano[1,1'-biphenyl]-2-yl)oxy]-acetic acid,
1,1-dimethylethyl ester
[0943] The subtitle compound was prepared by the method of example
1 step (i) using the product from step (ii). Yield 0.60 g
[0944] .sup.1H NMR CDCl.sub.3: .delta. 7.90 (1H, s), 7.82 (1H, d),
7.63 (1H, d), 7.53 (1H, td), 7.28 (2H, m), 6.78 (1H, d), 4.52 (2H,
s), 1.47 (10H, s)
(iv) [(5-Chloro-3'-cyano[1,1'-biphenyl]-2-yl)oxy]-acetic acid
[0945] The title compound was prepared by the method of example 1
step (iii) using the product from step (iii). Yield 0.265 g
[0946] .sup.1H NMR DMSO-d6: .delta. 13.12 (1H, s), 8.08 (1H, s),
7.94 (1H; d), 7.82 (1H, d), 7.64 (1K t), 7.43 (2H, m), 7.10 (1H,
d), 4.78 (2H, s).
[0947] MS: APCI (-ve): 286
Pharmacological Data
Ligand Binding Assay
[0948] [.sup.3H]PGD.sub.2 was purchased from Perkin Elmer Life
Sciences with a specific activity of 100-210Ci/mmol. All other
chemicals were of analytical grade.
[0949] HEK cells expressing rhCRTh2/G.alpha.16 were routinely
maintained in DMEM containing 10% Foetal Bovine Serum (HyClone), 1
mg/ml geneticin, 2 mM L-glutamine and 1% non-essential amino acids.
For the preparation of membranes, the adherent transfected HEKcells
were grown to confluence in two layer tissue culture factories
(Fisher, catalogue number TKT-170-070E). Maximal levels of receptor
expression were induced by addition of 500 mM sodium butyrate for
the last 18 hours of culture. The adherent cells were washed once
with phosphate buffered saline (PBS, 50 ml per cell factory) and
detached by the addition of 50 ml per cell factory of ice-cold
membrane homogenisation buffer [20 mM HEPES (pH 7.4), 0.1 mM
dithiothreitol, 1 mM EDTA, 0.1 mM phenyl methyl sulphonyl fluoride
and 100 .mu.g/ml bacitracin]. Cells were pelleted by centrifugation
at 220.times.g for 10 minutes at 4.degree. C., re-suspended in half
the original volume of fresh membrane homogenisation buffer and
disrupted using a Polytron homogeniser for 2.times.20 second bursts
keeping the tube in ice at all times. Unbroken cells were removed
by centrifugation at 220.times.g for 10 minutes at 4.degree. C. and
the membrane fraction pelleted by centrifugation at 90000.times.g
for 30 minutes at 4.degree. C. The final pellet was re-suspended in
4 ml of membrane homogenisation buffer per cell factory used and
the protein content determined. Membranes were stored at
-80.degree. C. in suitable aliquots.
[0950] All assays were performed in Corning clear bottomed, white
96-well NBS plates (Fisher). Prior to assay, the HEK cells
membranes containing CRTh2 were coated onto SPA PVT WGA beads
(Amersham). For coating membranes were incubated with beads at
typically 25 .mu.g membrane protein per mg beads at 4.degree. C.
with constant agitation overnight. (The optimum coating
concentrations were determined for each batch of membranes) The
beads were pelleted by centrifugation (800.times.g for 7 minutes at
4.degree. C.), washed once with assay buffer (50 mM HEPES pH 7.4
containing 5 mM magnesium chloride) and finally re-suspended in
assay buffer at a bead concentration of 10 mg/ml.
[0951] Each assay contained 20 .mu.l of 6.25 nM [.sup.3H]PGD.sub.2,
20 .mu.l membrane saturated SPA beads both in assay buffer and
10111 of compound solution or 13,14-dihydro-15-keto prostaglandin
D.sub.2 (DK-PGD.sub.2, for determination of non-specific binding,
Cayman chemical company). Compounds and DK-PGD.sub.2 were dissolved
in DMSO and diluted in the same solvent to 100.times. the required
final concentration. Assay buffer was added to give a final
concentration of 10% DMSO (compounds were now at 10.times. the
required final concentration) and this was the solution added to
the assay plate. The assay plate was incubated at room temperature
for 2 hours and counted on a Wallac Microbeta liquid scintillation
counter (1 minute per well).
[0952] Compounds of formula (I) have an IC.sub.50 value of less
than (<) 10 .mu.M.
[0953] Specifically, example 9 has a pIC.sub.50=7.4, example 25 has
a pIC.sub.50=8.0, and example 133 has a pIC.sub.50=8.2.
* * * * *