U.S. patent application number 13/047280 was filed with the patent office on 2011-10-27 for novel compounds.
Invention is credited to Roger Bonnert, Mark Robert Dickinson, Rukhsana Mohammed.
Application Number | 20110263614 13/047280 |
Document ID | / |
Family ID | 33492578 |
Filed Date | 2011-10-27 |
United States Patent
Application |
20110263614 |
Kind Code |
A1 |
Bonnert; Roger ; et
al. |
October 27, 2011 |
Novel compounds
Abstract
The present invention relates to substituted indoles useful as
pharmaceutical compounds for treating respiratory disorders.
Inventors: |
Bonnert; Roger;
(Loughborough, GB) ; Mohammed; Rukhsana; (Muscat,
OM) ; Dickinson; Mark Robert; (Loughborough,
GB) |
Family ID: |
33492578 |
Appl. No.: |
13/047280 |
Filed: |
March 14, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12397618 |
Mar 4, 2009 |
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13047280 |
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10558228 |
Nov 22, 2005 |
7687535 |
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PCT/SE2004/000808 |
May 25, 2004 |
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12397618 |
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Current U.S.
Class: |
514/256 ;
514/312; 514/339; 514/378; 514/397; 514/406; 514/414; 514/418;
544/333; 546/153; 546/277.7; 548/247; 548/312.1; 548/364.7;
548/466; 548/484 |
Current CPC
Class: |
A61P 27/16 20180101;
A61P 31/16 20180101; C07D 403/04 20130101; A61P 11/06 20180101;
A61P 11/02 20180101; C07D 401/04 20130101; C07D 405/04 20130101;
C07D 409/04 20130101; A61P 29/00 20180101; A61P 11/08 20180101;
C07D 413/04 20130101; C07D 403/12 20130101; A61P 11/00 20180101;
C07D 401/12 20130101; A61P 11/16 20180101; C07D 209/30 20130101;
A61P 43/00 20180101 |
Class at
Publication: |
514/256 ;
548/484; 544/333; 546/153; 548/312.1; 548/466; 548/247; 546/277.7;
548/364.7; 514/418; 514/312; 514/397; 514/414; 514/378; 514/339;
514/406 |
International
Class: |
A61K 31/404 20060101
A61K031/404; C07D 403/10 20060101 C07D403/10; C07D 215/36 20060101
C07D215/36; C07D 403/12 20060101 C07D403/12; C07D 409/10 20060101
C07D409/10; C07D 413/10 20060101 C07D413/10; C07D 401/10 20060101
C07D401/10; A61K 31/506 20060101 A61K031/506; A61K 31/475 20060101
A61K031/475; A61K 31/4178 20060101 A61K031/4178; A61K 31/422
20060101 A61K031/422; A61K 31/4439 20060101 A61K031/4439; A61K
31/4155 20060101 A61K031/4155; A61P 11/06 20060101 A61P011/06; A61P
31/16 20060101 A61P031/16; C07D 209/40 20060101 C07D209/40 |
Foreign Application Data
Date |
Code |
Application Number |
May 27, 2003 |
SE |
0301569-0 |
Aug 27, 2003 |
SE |
0302305-8 |
Claims
1. A compound of formula (I) or a pharmaceutically acceptable salt
or solvate thereof: ##STR00047## in which: R.sup.1 is one or more
substituents independently selected from NR.sup.4SO.sub.2R.sup.5,
NR.sup.4CO.sub.2R.sup.6, NR.sup.4COR.sup.6,
NR.sup.4SO.sub.2NR.sup.5R.sup.6, NHSO.sub.2R.sup.5,
NHCO.sub.2R.sup.6, NHCOR.sup.6, NHCONR.sup.4,
NHSO.sub.2NR.sup.5R.sup.6, or heteroaryl, the latter which may be
optionally substituted by halogen, CN, OR.sup.7, C.sub.1-3 alkyl
(which may be optionally substituted by halogen atoms); R.sup.2 is
hydrogen, halogen, CN, SO.sub.2R.sup.4 or CONR.sup.5R.sup.6,
CH.sub.2OH, CH.sub.2OR.sup.4 or C.sub.1-7alkyl, the latter group
being optionally substituted by one or more substituents
independently selected from halogen atoms, OR.sup.8 and
NR.sup.5R.sup.6, S(O).sub.xR.sup.7 where x is 0, 1 or 2; R.sup.3 is
aryl or heteroaryl each of which is optionally substituted by one
or more substituents independently selected from hydrogen, halogen,
CN, OH, SO.sub.2R.sup.4, OR.sup.4, SR.sup.4, SOR.sup.4,
SO.sub.2NR.sup.5R.sup.6, CONR.sup.5R.sup.6, NR.sup.5R.sup.6,
NHSO.sub.2R.sup.4, NHCOR.sup.4, NHCO.sub.2R.sup.4,
NR.sup.7SO.sub.2R.sup.4, NR.sup.7CO.sub.2R.sup.4,
NR.sup.7COR.sup.4, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-6 alkyl, the latter three groups being optionally
substituted by one or more substituents independently selected from
halogen atoms, OR.sup.8 and NR.sup.5R.sup.6, S(O).sub.xR.sup.7
where x is 0, 1 or 2; R.sup.4 represents aryl, heteroaryl, or
C.sub.1-6alkyl all of which may be optionally substituted by one or
more substituents independently selected from halogen atoms, aryl,
heteroaryl, OR.sup.10, OH, NR.sup.11R.sup.12, S(O).sub.xR.sup.13
(where x is 0, 1 or 2), CONR.sup.14R.sup.15, NR.sup.14COR.sup.15,
SO.sub.2NR.sup.14R.sup.15, NR.sup.14SO.sub.2R.sup.15, CN, nitro;
R.sup.5 and R.sup.6 independently represent a hydrogen atom, a
C.sub.1-6 alkyl group, or an aryl, or a heteroaryl, the latter
three of which may be optionally substituted by one or more
substituents independently selected from halogen atoms, aryl,
OR.sup.8 and NR.sup.14R.sup.15, CONR.sup.14R.sup.15,
NR.sup.14COR.sup.15, SO.sub.2NR.sup.14R.sup.15;
NR.sup.14SO.sub.2.sup.15; CN, nitro, C.sub.1-3 alkyl (which may be
optionally substituted by halogen atoms; or R.sup.5 and R.sup.6
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.x where x is 0, 1 or 2,
NR.sup.16, and itself optionally substituted by C.sub.1-3 alkyl;
R.sup.7 and R.sup.13 independently represent a C.sub.1-C.sub.6,
alkyl, an aryl or a heteroaryl group, all of which may be
optionally substituted by halogen atoms; R.sup.8 represents a
hydrogen atom, C(O)R.sup.9, C.sub.1-C.sub.6 alkyl (optionally
substituted by halogen atoms or aryl) an aryl or a heteroaryl group
(optionally substituted by halogen); each of R.sup.9 R.sup.10,
R.sup.11, R.sup.12, R.sup.14, R.sup.15, independently represents a
hydrogen atom, C.sub.1-C.sub.6 alkyl, an aryl or a heteroaryl group
(all of which may be optionally substituted by halogen atoms); and
R.sup.16 is hydrogen, C.sub.1-4 alkyl, COC.sub.1-C.sub.4 alkyl or
COYC.sub.1-C.sub.4alkyl where Y is O or NR.sup.7.
2. A compound according to claim 1 in which R.sup.1 is
NHSO.sub.2R.sup.4 or NH(CO)R.sup.4 or heteroaryl (the latter being
optionally substituted by a C.sub.1-3 alkyl group).
3. A compound according to claim 1 or 2 in which R.sup.2 is C.sub.1
alkyl.
4. A compound according to claim 3 in which R.sup.3 is phenyl
optionally substituted with halogen or methyl sulfone.
5. A compound according to claim 1 selected from:
4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid;
3-[(4-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indo-
le-1-acetic acid;
3-[(4-chlorophenyl)thio]-2-methyl-4-(5-pyrimidinyl)-1H-indole-1-acetic
acid;
3-[(4-chlorophenyl)thio]-2-methyl-4-pyrazinyl-1H-indole-1-acetic
acid;
3-[(2-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indo-
le-1-acetic acid;
3-[(3-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-a-
cetic acid;
3-[(4-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-a-
cetic acid;
3-[(3-methoxyphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1--
acetic acid;
3-[(4-methoxyphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1--
acetic acid;
3-[(2-trifluoromethylphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-i-
ndole-1-acetic acid;
3-[(8-Quinolinyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-ace-
tic acid;
3-[(2-(methylethyl)phenyl)thio]-2-methyl-4-[(methylsulfonyl)amin-
o]-1H-indole-1-acetic acid;
5-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid;
4-(acetylethylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1--
acetic acid;
3-[(4-chlorophenyl)thio]-4-[cyclopropylcarbonyl)amino]-2-methyl-1H-indole-
-1-acetic acid;
4-(benzoylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid;
4-(acetylamino)-3-[(3-chlorophenyl)thio]-2-methyl-1H-indole-1-aceti-
c acid;
3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)sulfonyl]amino]-2-meth-
yl-1H-indole-1-acetic acid;
3-[(4-chlorophenyl)thio]-2-methyl-4-[[(1-methyl-1H-imidazol-4-yl)sulfonyl-
]amino]-1H-indole-1-acetic acid;
3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)acetyl]amino]-2-methyl-1H-ind-
ole-1-acetic acid;
4-(acetylamino)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-a-
cetic acid;
4-(acetylamino)-3-[(2-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid;
4-(acetylamino)-2-methyl-3-[[4-(ethylsulfonyl)phenyl]thio]-1H-indol-
e-1-acetic acid;
3-[[(4-chlorophenyl)thio]-4-Methylamino)carbonyl]amino]-2-methyl-1H-indol-
e-1-acetic acid;
3-[[4-(methylsulfonyl)phenyl]thio]-4-(5-pyrimidinyl)-1H-indole-1-acetic
acid
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-4-(2-thiophenyl)-1H-indo-
le-1-acetic acid
4-(3,5-dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-
-1H-indole-1-acetic acid
4-(3-furanyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-ace-
tic acid
2-methyl-4-[(methylsulfonyl)amino]-3-[[4-(methylsulfonyl)phenyl]t-
hio]-1H-indole-1-acetic acid
2-methyl-5-[(methylsulfonyl)amino]-3-[[3-(methylsulfonyl)phenyl]thio]-1H--
indole-1-acetic acid
2-methyl-5-[(methylsulfonyl)amino]-3-[[2-(methylsulfonyl)phenyl]thio]-1H--
indole-1-acetic acid
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(5-pyrimidinyl)-1H-indole-1-
-acetic acid
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-thiophenyl)-1H-indole-1--
acetic acid
5-(3,5-dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-
-1H-indole-1-acetic acid
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-pyridinyl)-1H-indole-1-a-
cetic acid
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(1H-pyrazol-4-yl)-
-1H-indole-1-acetic acid
4-(acetylamino)-3-[(4-cyanophenyl)thio]-2-methyl-1H-indole-1-acetic
acid and pharmaceutically acceptable salts and solvates
thereof.
6. A compound of formula (I) according to any one of claims 1 to 5
for use in therapy.
7. 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 claims 1 to 5.
8. A method of treatment according to claim 7 wherein the disease
is asthma or rhinitis.
9. 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 the treatment of a disease
mediated by CRTh2.
10. Use according to claim 9 where the disease is asthma.
11. A process for the preparation of a compound of formula (I) or a
pharmaceutically acceptable salt or solvate thereof which comprises
reaction of a compound of formula (II): ##STR00048## in which
R.sup.1, R.sup.2 and R.sup.3 are as defined in formula (I) or are
protected derivatives thereof, with a compound of formula (IIA):
L-CH.sub.2CO.sub.2R.sup.17 (IIA) where R.sup.17 is an alkyl group
and L is a leaving group such as a halogen atom, in the presence of
a base, and optionally thereafter in any order: removing any
protecting group hydrolysing the ester group R.sup.17 to the
corresponding acid forming a pharmaceutically acceptable salt or
solvate.
12. A compound of formula (II) as defined in claim 11.
Description
[0001] The present invention relates to substituted indoles useful
as 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. U.S. Pat. No.
5,486,525 discloses a series of indoles said to possess PAF
antagonist activity. It has now surprisingly been found that
certain indole acetic 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 pharmaceutically acceptable salt and
solvates thereof:
##STR00001##
in which: R.sup.1 is one or more substituents independently
selected from NR.sup.4SO.sub.2R.sup.5, NR.sup.4CO.sub.2R.sup.6,
NR.sup.4COR.sup.6, NR.sup.4SO.sub.2NR.sup.5R.sup.6,
NHSO.sub.2R.sup.5, NHCO.sub.2R.sup.6, NHCOR.sup.6, NHCONR.sup.4,
NHSO.sub.2NR.sup.5R.sup.6, or heteroaryl, the latter which may be
optionally substituted by halogen, CN, OR.sup.7, C.sub.1-3 alkyl
(which may be optionally substituted by halogen atoms); R.sup.2 is
hydrogen, halogen, CN, SO.sub.2R.sup.4 or CONR.sup.5R.sup.6,
CH.sub.2OH, CH.sub.2OR.sup.4 or C.sub.1-4alkyl, the latter group
being optionally substituted by one or more substituents
independently selected from halogen atoms, OR.sup.8 and
NR.sup.5R.sup.6, S(O).sub.xR.sup.7 where x is 0, 1 or 2; R.sup.3 is
aryl or heteroaryl each of which is optionally substituted by one
or more substituents independently selected from hydrogen, halogen,
CN, OH, SO.sub.2R.sup.4, OR.sup.4, SR.sup.4, SOR.sup.4,
SO.sub.2NR.sup.5R.sup.6, CONR.sup.5R.sup.6, NR.sup.5R.sup.6,
NHSO.sub.2R.sup.4, NHCOR.sup.4, NHCO.sub.2R.sup.4,
NR.sup.7SO.sub.2R.sup.4, NR.sup.7CO.sub.2R.sup.4,
NR.sup.7COR.sup.4, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-6 alkyl, the latter three groups being optionally
substituted by one or more substituents independently selected from
halogen atoms, OR.sup.8 and NR.sup.5R.sup.6, S(O).sub.xR.sup.7
where x is 0, 1 or 2; R.sup.4 represents aryl, heteroaryl, or
C.sub.1-6alkyl all of which may be optionally substituted by one or
more substituents independently selected from halogen atoms, aryl,
heteroaryl, OR.sup.10, OH, NR.sup.11R.sup.12, S(O).sub.xR.sup.13
(where x is 0, 1 or 2), CONR.sup.14R.sup.15, NR.sup.14COR.sup.15,
SO.sub.2NR.sup.14R.sup.15, NR.sup.14SO.sub.2R.sup.15, CN, nitro;
R.sup.5 and R.sup.6 independently represent a hydrogen atom, a
C.sub.1-6 alkyl group, or an aryl, or a heteroaryl, the latter
three of which may be optionally substituted by one or more
substituents independently selected from halogen atoms, aryl,
OR.sup.8 and NR.sup.14R.sup.15, CONR.sup.14R.sup.15,
NR.sup.14COR.sup.15, SO.sub.2NR.sup.14R.sup.15,
NR.sup.14SO.sub.2R.sup.15; K CN, nitro, C.sub.1-3 alkyl (which may
be optionally substituted by halogen atoms; or R.sup.5 and R.sup.6
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.x, where x is 0, 1 or 2,
NR.sup.16, and itself optionally substituted by C.sub.1-3 alkyl;
R.sup.7 and R.sup.13 independently represent a C.sub.1-C.sub.6,
alkyl, an aryl or a heteroaryl group, all of which may be
optionally substituted by halogen atoms; R.sup.8 represents a
hydrogen atom, C(O)R.sup.9, C.sub.1-C.sub.6 alkyl (optionally
substituted by halogen atoms or aryl) an aryl or a heteroaryl group
(optionally substituted by halogen); each of R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.14, R.sup.15, independently represents a
hydrogen atom, C.sub.1-C.sub.6 alkyl, an aryl or a heteroaryl group
(all of which may be optionally substituted by halogen atoms); and
R.sup.16 is hydrogen, C.sub.1-4 alkyl, COC.sub.1-C.sub.4 alkyl or
COYC.sub.1-C.sub.4alkyl where Y is O or NR.sup.7.
[0004] 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, branched or
cyclic.
[0005] Aryl groups as defined herein can be phenyl or naphthyl.
[0006] Heteroaryl is defined as a 5-7 membered aromatic ring or can
be 6,6- or 6,5-fused bicyclic, each ring containing one or more
heteroatoms selected from N, S and O. 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.
[0007] When R.sup.5 and R.sup.6 together with the nitrogen atom to
which they are attached can form a 3-8 membered saturated
heterocylic ring, examples include morpholine, thiomorpholine,
azetidine, imidazolidine, pyrrolidine, piperidine and piperazine.
Substituents can be present on carbon or appropriate nitrogen atoms
of such rings.
[0008] Suitably R.sup.1 is one or more substituents independently
selected from NR.sup.4SO.sub.2R.sup.5, NR.sup.4CO.sub.2R.sup.6,
NR.sup.4COR.sup.6, NR.sup.4SO.sub.2NR.sup.5R.sup.6,
NHSO.sub.2R.sup.5, NHCO.sub.2R.sup.6, NHCOR.sup.6, NHCONR.sup.4,
NHSO.sub.2NR.sup.5R.sup.6, or heteroaryl, the latter which may be
optionally substituted by halogen, CN or OR.sup.7.
[0009] Suitably R.sup.1 is one or more substituents independently
selected from NR.sup.4SO.sub.2R.sup.5, NR.sup.4CO.sub.2R.sup.6,
NR.sup.4COR.sup.6, NR.sup.4SO.sub.2NR.sup.5R.sup.6,
NHSO.sub.2R.sup.5, NHCO.sub.2R.sup.6, NHCOR.sup.6,
NHSO.sub.2NR.sup.5R.sup.6, or heteroaryl, the latter which may be
optionally substituted by halogen, CN or OR.sup.7.
[0010] Preferably R.sup.1 is NR.sup.4COR.sup.64, NHSO.sub.2R.sup.4,
NHCOR.sup.6 or a heteroaryl group.
[0011] More preferably R.sup.1 is NHSO.sub.2Me or NR.sup.4COMe,
NHCONHalkyl, NR.sup.4COcyclopropyl, NHSO.sub.2heteroaryl,
NHSO.sub.2NMe.sub.2, NHCONR.sup.4, a 5-6 membered heteroaromatic
group containing 1-2 heteroatoms. Most preferably R.sup.1 is
NHSO.sub.2Me or NR.sup.4COMe, NHCONHalkyl, dimethyoxazole,
pyrimidine or pyrazine. Even more preferably R.sup.1 is NHCOMe.
[0012] The R.sup.1 groups can be present at any suitable position
on the indole ring. Preferably the R.sup.1 group(s) is (are) at the
5-position and/or 4-position.
[0013] Preferably R.sup.2 is C.sub.1-6alkyl or hydrogen, more
preferably C.sub.1-6alkyl or hydrogen, still more preferably methyl
or hydrogen. Most preferably R.sup.2 is methyl.
[0014] Preferably R.sup.3 is quinolyl or phenyl, the latter is
optionally substituted by halogen, alkoxy, SO.sub.2R.sup.4, more
preferably the phenyl group is substituted by chloro, methoxy,
methylsulfone or ethylsulfone.
[0015] Substituents can be present on any suitable position of an
R.sup.3 group. Preferably, if R.sup.3 is phenyl the substituents
is/are present at the 2, 3 and 4-positions. Most preferably a
single substituent is present at the 4-position.
[0016] Preferred compounds of the invention include: [0017]
4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid; [0018]
3-[(4-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-a-
cetic acid; [0019]
3-[(4-chlorophenyl)thio]-2-methyl-4-(5-pyrimidinyl)-1H-indole-1-acetic
acid; [0020]
3-[(4-chlorophenyl)thio]-2-methyl-4-pyrazinyl-1H-indole-1-acetic
acid; [0021]
3-[(2-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-ind-
ole-1-acetic acid; [0022]
3-[(3-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-a-
cetic acid; [0023]
3-[(4-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-a-
cetic acid; [0024]
3-[(3-methoxyphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1--
acetic acid; [0025]
3-[(4-methoxyphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1--
acetic acid; [0026]
3-[(2-trifluoromethylphenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-i-
ndole-1-acetic acid; [0027]
3-[(8-Quinolinyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-ace-
tic acid; [0028]
3-[(2-(methylethyl)phenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-ind-
ole-1-acetic acid; [0029]
5-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid; [0030]
4-(acetylethylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid; [0031]
3-[(4-chlorophenyl)thio]-4-[cyclopropylcarbonyl)amino]-2-methyl-1H-indole-
-1-acetic acid; [0032]
4-(benzoylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid; [0033]
4-(acetylamino)-3-[(3-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid; [0034]
3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)sulfonyl]amino]-2-methyl-1H-i-
ndole-1-acetic acid; [0035]
3-[(4-chlorophenyl)thio]-2-methyl-4-[[(1-methyl-1H-imidazol-4-yl)sulfonyl-
]amino]-1H-indole-1-acetic acid; [0036]
3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)acetyl]amino]-2-methyl-1H-ind-
ole-1-acetic acid; [0037]
4-(acetylamino)-2-methyl-3-[(4-(methylsulfonyl)phenyl]thio]-1H-indole-1-a-
cetic acid; [0038]
4-(acetylamino)-3-[(2-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid; [0039]
4-(acetylamino)-2-methyl-3-[[(4-(ethylsulfonyl)phenyl]thio]-1H-indole-1-a-
cetic acid; [0040]
3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)carbonyl]amino]-2-methyl-1H-i-
ndole-1-acetic acid; [0041]
3-[[(4-(methylsulfonyl)phenyl]thio]-4-(5-primidinyl)-1H-indole-1-acetic
acid [0042]
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-4-(2-thiophenyl)-1H-indole-1--
acetic acid [0043]
4-(3,5-dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-
-1H-indole-1-acetic acid [0044]
4-(3-furanyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-ace-
tic acid [0045]
2-methyl-4-[(methylsulfonyl)amino]-3-[[4-(methylsulfonyl)phenyl]thio]-1H--
indole-1-acetic acid [0046]
2-methyl-5-[(methylsulfonyl)amino]-3-[[3-(methylsulfonyl)phenyl]thio]-1H--
indole-1-acetic acid [0047]
2-methyl-5-[(methylsulfonyl)amino]-3-[[2-(methylsulfonyl)phenyl]thio]-1H--
indole-1-acetic acid [0048]
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(5-pyrimidinyl)-1H-indole-1-
-acetic acid [0049]
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-thiophenyl)-1H-indole-1--
acetic acid [0050]
5-(3,5-dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-
-1H-indole-1-acetic acid [0051]
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-pyridinyl)-1H-indole-1-a-
cetic acid [0052]
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(1H-pyrazol-4-yl)-1H-indole-
-1-acetic acid [0053]
4-(acetylamino)-3-[(4-cyanophenyl)thio]-2-methyl-1H-indole-1-acetic
acid and pharmaceutically acceptable salts and solvates
thereof.
[0054] 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.
[0055] The compound of formula (I) above may be converted to a
pharmaceutically acceptable salt or solvate thereof, preferably a
basic addition salt such as ammonium, 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. Preferred salts include sodium and ammonium
salts.
[0056] 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).
[0057] In a further aspect the invention provides a process for the
preparation of a compound of formula (I) or a pharmaceutically
acceptable salt or solvate thereof which comprises reaction of a
compound of formula (II):
##STR00002##
in which R.sup.1, R.sup.2 and R.sup.3 are as defined in formula (I)
or are protected derivatives thereof, with a compound of formula
(IIA):
L-CH.sub.2CO.sub.2R.sup.17 (IIA)
where R.sup.17 is an alkyl group and L is a leaving group such as a
halogen atom, in the presence of a base, and optionally thereafter
in any order: [0058] removing any protecting group [0059]
hydrolysing the ester group R.sup.17 to the corresponding acid
[0060] forming a pharmaceutically acceptable salt or solvate.
[0061] The reaction can be carried out in a suitable solvent such
as THF using a base such as sodium hydride or the like. Suitable
groups R.sup.17 include C.sub.1-6 alkyl groups such as methyl,
ethyl or tertiary-butyl. Suitable L is a leaving group such as
halo, in particular bromo Preferably the compound of formula (IIA)
is ethyl, methyl or tertiary-butyl bromoacetate.
[0062] Hydrolysis of the ester group R.sup.17 can be carried out
using routine procedures, for example by stirring with aqueous
sodium hydroxide or trifluoroacetic acid.
[0063] It will be appreciated that certain functional groups may
need to be protected using standard protecting groups. The
protection and deprotection of functional groups is for example,
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).
[0064] Compounds of formula (II), in which R.sup.1 is NRSO.sub.2R
or NRC(O)R can be from compounds of formula by reaction with an
acylating reagent such as acetyl chloride or sulfonyl chloride.
##STR00003##
[0065] Compounds of formula (III) can be prepared from compounds of
formula (IV) by reduction using a hydrogen and a suitable catalyst,
preferably, the catalyst used is palladium or platinum on activated
carbon in the presence of a polar solvent such as ethanol.
##STR00004##
[0066] Compounds of formula (IV) can be prepared from compounds of
formula (V) and (VI)
##STR00005##
in which R.sup.1, R.sup.2 and R.sup.3 are as defined in formula
(I).
[0067] Preferably the reaction is carried out in a suitable
solvent, such as dichloromethane or THF, using a chlorinating agent
such as sulfonyl chloride or tert-butyl hypochlorite..sup.1
[0068] Compounds of formulae (V) and (VI) are commercially
available or can be prepared using standard chemistry well known in
the art.
[0069] Certain compounds of formula (I) can be prepared from
compounds of formula (VII) where X=halogen, preferably bromine or
iodine, by reaction with organostannanes (Stille couplings) or
boronic acids (Suzuki couplings) using palladium catalysis.
Preferably the catalysts used are tetrakis palladium
triphenylphosphine(0), or palladium(II) acetate in the presence of
a phosphine ligand such as tri-ortho tolyl phosphine, in a suitable
solvent such as toluene or methanol at 80.degree. C. The group
R.sup.17 is subsequently hydrolysed as outlined previously.
##STR00006##
[0070] Compounds of formula (VII) are prepared from compounds of
formula (II) with compounds of formula (IIA) as outlined
previously:
##STR00007##
[0071] Compounds of formula (II), where X is halogen are prepared
by reacting a compound of formula (VIII) with a compound of formula
(VI):
##STR00008##
in which R.sup.1, R.sup.2 and R.sup.3 are as defined in formula
(I).
[0072] Compounds of formula (II) can be prepared by reacting a
compound of formula (IX) with a compound of formula (X), with
subsequent hydrolysis of the ester as outlined previously for the
synthesis of compounds of formula (I):
##STR00009##
in which R.sup.1, R.sup.2 and R.sup.3 or protected derivatives
thereof, are as defined in formula (I). The reaction is carried out
in a suitable solvent in the presence of a halogen, preferably
iodine at room temperature, in a polar aprotic solvent, for example
DMF. Compounds of formula (IX) and (X) are commercially available
or can be prepared by methods well known in the art.
[0073] 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.
[0074] A compound of the invention, or a pharmaceutically
acceptable salt thereof, can be used in the treatment of: [0075]
(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. [0076] (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.
[0077] (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, 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.
[0078] (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. [0079] (5) (gastrointestinal tract) glossitis,
gingivitis, periodontitis; oesophagitis, including reflux;
eosinophilic gastro-enteritis, mastocytosis, Crohn's disease,
colitis including ulcerative colitis, proctitis, pruritic ani;
coeliac disease, irritable bowel syndrome, and food-related
allergies which may have effects remote from the gut (for example
migraine, rhinitis or eczema). [0080] (6) (abdominal) hepatitis,
including autoimmune, alcoholic and viral; fibrosis and cirrhosis
of the liver; cholecystitis; pancreatitis, both acute and chronic.
[0081] (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). [0082] (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; [0083] (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 HTV-associated
neuropathies; neurosarcoidosis; central and peripheral nervous
system complications of malignant, infectious or autoimmune
processes. [0084] (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. [0085] (11) Other disorders with an inflammatory or
immunological component; including acquired immune deficiency
syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic
syndromes. [0086] (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. [0087] (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. [0088] (14) Diseases
associated with raised levels of PGD.sub.2 or its metabolites.
[0089] 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.
[0090] Preferably the compounds of the invention are used to treat
diseases in which the chemokine receptor belongs to the CRTh2
receptor subfamily.
[0091] 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.
[0092] In a further aspect, the present invention provides the use
of a compound of formula (I), or a pharmaceutically acceptable salt
or solvate thereof, as hereinbefore defined in the manufacture of a
medicament for use in therapy in particular for the treatment of a
disease mediated by CRTh2 such as asthma or rhinitis.
[0093] 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.
[0094] Preferably the compounds of the invention are used to treat
diseases in which the chemokine receptor belongs to the CRTh2
receptor subfamily.
[0095] 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.
[0096] The invention further relates to combination therapies
wherein a compound of formula (I) or a pharmaceutically acceptable
salts, solvate or in vivo hydrolysable ester thereof, or a
pharmaceutical composition or formulation comprising a compound of
formula (I) is administered concurrently or sequentially with
therapy and/or an agent for the treatment of any one of asthma,
allergic rhinitis, cancer, COPD, rheumatoid arthritis, psoriasis,
inflammatory bowel diseases, osteoarthritis or osteoporosis.
[0097] 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 TNF-.alpha.
inhibitors such as anti-TNF monoclonal antibodies (such as
Remicade, CDP-870 and D.sub.2E.sub.7.) and TNF receptor
immunoglobulin molecules (such as Enbrel.reg.), non-selective
COX-1/COX-2 inhibitors (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 meloxicam, celecoxib,
rofecoxib, valdecoxib and etoricoxib) low dose methotrexate,
lefunomide; ciclesonide; hydroxychloroquine, d-penicillamine,
auranofin or parenteral or oral gold.
[0098] 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-alkylsulfonamides;
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.
[0099] The present invention still further relates to the
combination of a compound of the invention together with a receptor
antagonist for leukotrienes LTB.sub.4, LTC.sub.4, LTD.sub.4, and
LTE.sub.4. selected from the group consisting of the
phenothiazin-3-ones 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.
[0100] The present invention still further relates to the
combination of a compound of the invention together with a PDE4
inhibitor including inhibitors of the isoform PDE4D.
[0101] The present invention still further relates to the
combination of a compound of the invention together with a
antihistaminic H.sub.1. receptor antagonists such as cetirizine,
loratadine, desloratadine, fexofenadine, astemizole, azelastine,
and chlorpheniramine.
[0102] The present invention still further relates to the
combination of a compound of the invention together with a
gastroprotective H.sub.2. receptor antagonist.
[0103] The present invention still further relates to the
combination of a compound of the invention together with an
.alpha..sub.1- and .alpha..sub.2-adrenoceptor agonist
vasoconstrictor sympathomimetic agent, such as propylhexedrine,
phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline
hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline
hydrochloride, xylometazoline hydrochloride, and
ethylnorepinephrine hydrochloride.
[0104] The present invention still further relates to the
combination of a compound of the invention together with
anticholinergic agents such as ipratropium bromide; tiotropium
bromide; oxitropium bromide; pirenzepine; and telenzepine.
[0105] The present invention still further relates to the
combination of a compound of the invention together with a
.beta..sub.1- to .beta..sub.4-adrenoceptor agonists such as
metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol,
formoterol, salmeterol, terbutaline, orciprenaline, bitolterol
mesylate, and pirbuterol; or methylxanthanines including
theophylline and aminophylline; sodium cromoglycate; or muscarinic
receptor (M1, M2, and M3) antagonist.
[0106] 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.
[0107] The present invention still further relates to the
combination of a compound of the invention together with an inhaled
glucocorticoid with reduced systemic side effects, such as
prednisone, prednisolone, flunisolide, triamcinolone acetonide,
beclomethasone dipropionate, budesonide, fluticasone propionate,
and mometasone furoate.
[0108] 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-12.
[0109] The present invention still further relates to the
combination of a compound of the invention together with other
modulators of chemokine receptor function such as 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.
[0110] The present invention still further relates to the
combination of a compound of the invention together with antiviral
agents such as Viracept, AZT, aciclovir and famciclovir, and
antisepsis compounds such as Valant.
[0111] The present invention still further relates to the
combination of a compound of the invention together with
cardiovascular agents such as calcium channel blockers, lipid
lowering agents such as statins, fibrates, beta-blockers, Ace
inhibitors, Angiotensin-2 receptor antagonists and platelet
aggregation inhibitors.
[0112] 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.
[0113] 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) 1 MPDH 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,
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.sub.1 and NK.sub.3 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.alpha. converting enzyme inhibitors (TACE); (xxii) induced
nitric oxide synthase inhibitors (iNOS) or (xxiii) chemoattractant
receptor-homologous molecule expressed on TH2 cells.
[0114] The compounds of the present invention may also be used in
combination with osteoporosis agents such as roloxifene,
droloxifene, lasofoxifene or fosomax and immunosuppressant agents
such as FK-506, rapamycin, cyclosporine, azathioprine, and
methotrexate;
[0115] 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
NSAID's) 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 intraarticular therapies such as
corticosteroids and hyaluronic acids such as hyalgan and synvisc
and P2X7 receptor antagonists.
[0116] 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:
[0117] (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
(Taxol.RTM.); 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
camptothecin);
[0118] (ii) cytostatic agents such as antioestrogens (for example
tamoxifen, toremifene, 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;
[0119] (iii) Agents which inhibit cancer cell invasion (for example
metalloproteinase inhibitors like marimastat and inhibitors of
urokinase plasminogen activator receptor function);
[0120] (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
[Herceptin.TM.] 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)quinazolin-4-amine
(CI 1033)), for example inhibitors of the platelet-derived growth
factor family and for example inhibitors of the hepatocyte growth
factor family;
[0121] (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
[Avastin.TM.], 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);
[0122] (vi) vascular damaging agents such as Combretastatin A4 and
compounds disclosed in International Patent Applications
WO99/02166, WO00/40529, WO00/41669, WO01/92224, WO02/04434 and
WO02/08213;
[0123] (vii) antisense therapies, for example those which are
directed to the targets listed above, such as ISIS 2503, an
anti-ras antisense;
[0124] (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
[0125] (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.
[0126] 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.
[0127] 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.
[0128] 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
compound of formula (I), or a pharmaceutically acceptable salt,
solvate or prodrug thereof, as hereinbefore defined.
[0129] 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.
[0130] 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.
[0131] 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.
[0132] 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.
[0133] 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.
[0134] 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.
[0135] The invention will now be illustrated by the following
non-limiting examples in which, unless stated otherwise:
(i) the title and sub-titled compounds of the examples and methods
were named using the ACD labs/name program (version 6.0) from
Advanced Chemical Development Inc, Canada; (ii) unless stated
otherwise, reverse phase preparative HPLC was conducted using a
Symmetry, NovaPak or Ex-Terra reverse phase silica column; (iii)
Flash column chromatography refers to normal phase silica
chromatography (iv) solvents were dried with MgSO.sub.4 or
Na.sub.2SO.sub.4 (v) Evaporations were carried out by rotary
evaporation in vacuo and work-up procedures were carried out after
removal of residual solids such as drying agents by filtration;
(vi) Unless otherwise stated, operations were carried out at
ambient temperature, that is in the range 18-25.degree. C. and
under an atmosphere of an inert gas such as argon or nitrogen;
(vii) yields are given for illustration only and are not
necessarily the maximum attainable; (viii) the structures of the
end-products of the formula (I) were confirmed by nuclear
(generally proton) magnetic resonance (NMR) and mass spectral
techniques; proton magnetic resonance chemical shift values were
measured on the delta scale and peak multiplicities are shown as
follows: s, singlet; d, doublet; t, triplet; m, multiplet; br,
broad; q, quartet, quin, quintet; (ix) intermediates were not
generally fully characterised and purity was assessed by thin layer
chromatography (TLC), high-performance liquid chromatography
(HPLC), mass spectrometry (MS), infra-red (IR) or NMR analysis; (x)
mass spectra (MS): generally only ions which indicate the parent
mass are reported 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; (xi) the following abbreviations are used:
M.p.=melting point THF=tetrahydrofuran EtOAc=ethyl acetate
MCPBA=meta chloroperbenzoic acid AMY=N,N-dimethyl formamide
MgSO.sub.4=magnesium sulfate Na.sub.2SO.sub.4=sodium sulfate
NaHCO.sub.3=sodium hydrogen carbonate
EXAMPLE 1
##STR00010##
[0136]
4-(Acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-aceti-
c acid
i) 3-[(4-chlorophenyl)thio]-2-methyl-4-nitro-1H-indole
[0137] To a stirred solution of 3-nitroaniline (8 g) in THF (700
ml) cooled to -78.degree. C. was added tert-butyl hypochlorite (6.3
g) dropwise over 5 minutes. The reaction was allowed to warm to
-65.degree. C. over 20 minutes before
1-[4-chlorophenyl)thio]-2-propanone (11.6 g) was added as a
solution in THF (20 ml). After 2 hours triethylamine (8.1 ml) was
added and the reaction allowed to warm to room temperature. 2M HCl
(aq) was added to the reaction mixture before concentration in
vacuo. The residue was slurried in methanol and the solid which
precipitated isolated by filtration to give the sub-title compound
(5.8 g).
[0138] .sup.1H NMR (DMSO-d6) .delta. 12.55 (s, 1H), 7.76 (dd, 1H),
7.63 (dd, 1H), 7.31-7.22 (m, 3H), 6.91 (dd, 2H), 2.47 (s, 3H)
ii) 3-[(4-chlorophenyl)thio]-2-methyl-4-nitro-1H-indole-acetic
acid, ethyl ester
[0139] To a stirred suspension of sodium hydride, 60% dispersion in
mineral oil, (0.85 g) in THF (100 ml) was added the product from
part (i) (5.6 g) as a solution in THF (50 ml). After stirring at
room temperature for 30 minutes ethyl bromoacetate (2.3 ml) was
added dropwise over 10 minutes. After 2 hours the reaction was
concentrated in vacuo, the residue dissolved in ethyl acetate,
washed with water, brine, dried (MgSO.sub.4) and concentrated in
vacuo. Recrystallisation from ethanol gave the sub-title compound
(5 g).
[0140] .sup.1H NMR (DMSO-d6) .delta. 7.97 (dd, 1H), 7.65 (dd, 1H),
7.35 (t, 1H), 7.26 (dt, 2H), 6.92 (dt, 2H), 5.40 (s, 2H), 4.19 (q,
2H), 2.45 (s, 3H), 1.22 (t, 3H).
iii) 4-amino-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-acetic
acid, ethyl ester
[0141] A suspension of the product from part (ii) (2.25 g) in
ethanol (170 ml) was stirred in the presence of 5% Pt/C (0.5 g)
under 2 bar pressure of H.sub.2. After stirring overnight the
catalyst was removed by filtration and the filtrates concentrated
in vacuo. Purification by flash column chromatography (14%
EtOAc/hexane as eluent) to give the sub-title compound (1.4 g).
[0142] .sup.1H NMR (DMSO-d6) .delta. 7.30 (dd, 2H), 7.00 (dt, 2H),
6.85 (t, 1H), 6.68 (dd, 1H), 6.23 (dd, 1H), 5.33 (s, 2H), 5.09 (s,
2H), 4.16 (q, 2H), 2.33 (s, 3H), 1.21 (t, 3H).
3-[(4-chlorophenyl)thio]-4-(ethylamino)-2-methyl-1H-indole-1-acetic
acid, ethyl ester was also isolated as a by product from the
reaction (0.33 g).
[0143] .sup.1H NMR (DMSO-d6) .delta. 7.32 (dd, 2H), 7.01 (dd, 2H),
6.95 (t, 1H), 6.73 (d, 1H), 6.16 (d, 1H), 5.70 (t, 1H), 5.11 (s,
2H), 4.16 (q, 2H), 3.05 (dt, 2H), 2.34 (s, 3H), 1.21 (t, 3H), 1.02
(t, 3H).
iv)
4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-acetic
acid, ethyl ester
[0144] To a solution of the product from part (iii) (0.5 g) in
dichloromethane (10 ml) was added triethylamine (0.18 ml) and
acetyl chloride (0.1 ml), the reaction was stirred at room
temperature for 30 minutes. The mixture was then adsorbed onto
silica gel and purified by column chromatography (33% EtOAc/hexane
as eluent) to give the sub-title compound (0.52 g).
[0145] .sup.1H NMR (DMSO-d6) .delta. 9.51 (s, 1H), 7.46 (d, 1H),
7.34-7.27 (m, 3H), 7.11 (t, 1H), 6.97 (d, 2H), 5.24 (s, 2H), 4.18
(q, 2H), 2.39 (s, 3H), 1.86 (s, 3H), 1.21 (t, 3H).
v)
4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-acetic
acid
[0146] To a solution of the product from part (iv) (0.31 g) in THF
(10 ml) was added a 1M solution of NaOH (aq) (0.75 ml). The
reaction was stirred overnight at room temperature. The reaction
mixture was concentrated in vacuo and the residue
dissolved/suspended in water. The pH was adjusted to 2 using dilute
HCl (aq) and the solid which precipitated isolated by filtration.
Recrystallisation from acetonitrile gave the title compound (0.16
g).
[0147] .sup.1H NMR (DMSO-d6) .delta. 13.21 (s, 1H), 9.51 (s, 1H),
7.46 (d, 1H), 7.33-7.27 (m, 3H), 7.11 (t, 1H), 6.98 (d, 2H), 5.12
(s, 2H), 2.39 (s, 3H), 1.85 (s, 3H).
[0148] APCI+ [M+H] 389
[0149] M.p. dec>266.degree. C.
EXAMPLE 2
##STR00011##
[0150]
3-[(4-Chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indo-
le-1-acetic acid
i)
3-[(4-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-
-acetic acid, ethyl ester
[0151] To a solution of the product from Example 1 part (iii) (0.5
g) in dichloromethane (10 ml) were added triethylamine (0.18 ml)
and methane sulfonyl chloride (0.1 ml), and the reaction was
stirred at room temperature for 2 hours before heating at reflux
overnight. The dichloromethane was removed in vacuo, acetonitrile
added (10 ml) and the reaction was heated to 60.degree. C. for 5
hours. The mixture was adsorbed onto silica gel and purified by
column chromatography (33% EtOAc/hexane as eluent) to give the
sub-title compound (0.44 g).
[0152] .sup.1H NMR (DMSO-d6) .delta. 8.80 (s, 1H), 7.39 (d, 1H),
7.32 (d, 2H), 7.20-7.07 (m, 2H), 6.97 (d, 2H), 5.27 (s, 2H), 4.18
(q, 2H), 2.74 (s, 3H), 2.38 (s, 3H), 1.22 (t, 3H).
ii)
3-[(4-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole--
1-acetic acid
[0153] The title compound was prepared by the method of Example 1
part (v), using the product from part (i).
[0154] .sup.1H NMR (DMSO-d6) .delta. 13.25 (s, 1H), 8.80 (s, 1H),
7.39 (d, 1H), 7.32 (m, 2H), 7.16 (t, 1H), 7.09 (d, 1H), 6.98 (dt,
2H), 5.15 (s, 2H), 2.73 (s, 3H), 2.38 (s, 3H).
[0155] APCI- [M-H] 423
[0156] M.p. dec>243.degree. C.
EXAMPLE 3
##STR00012##
[0158]
3-[(4-Chlorophenyl)thio]-2-methyl-4-(5-pyrimidinyl)-1H-indole-1-ace-
tic acid
i) 4-bromo-3-[4(-chlorophenyl)thio]-2-methyl-1H-indole
[0159] 3-bromophenyl hydrazine hydrochloride (15.34 g) in water (80
ml) was added to a suspension of 1-[(4-chlorophenyl)thio]acetone
(13.77 g) in acetonitrile (200 ml) and stirred overnight at room
temperature and then concentrated in vacuo. The residue was
partitioned between aqueous sodium hydrogen carbonate and
dichloromethane. The organic phase was washed with brine, dried
(MgSO.sub.4) and concentrated in vacuo. The residual oil was
treated with acetic acid (70 ml) and heated at 80.degree. C.
overnight. The reaction mixture was poured into water, basified
with aqueous sodium hydroxide and extracted with EtOAc (twice). The
combined organics were washed (brine), dried (MgSO.sub.4) and
concentrated in vacuo.
[0160] The mixture was purified by flash column chromatography (40%
EtOAc/hexane as eluent) to give the sub-title compound (4.43
g).
[0161] .sup.1H NMR (DMSO-d6) .delta. 7.31 (s, 1H), 7.30 (d, 2H),
7.13 (dt, 2H), 7.02 (t, 1H), 6.94 (dt, 2H), 2.52 (s, 3H).
ii) 4-bromo-3-[(4-chlorophenyl)thio]-2-methyl-1-1H-indole-1-acetic
acid, 1,1-dimethylethyl ester
[0162] The sub-title compound was prepared by the method of Example
1 part (ii) using the product of part (i) and t-butyl bromoacetate.
The product was purified using column chromatography (10%
EtOAc/hexane as eluent).
[0163] .sup.1H NMR (CDCl.sub.3: .delta. 7.31 (dd, 1H), 7.21 (dd,
1H), 7.14-7.10 (m, 2H), 7.05 (t, 1H), 6.94-6.91 (m, 2H), 4.77 (s,
2H), 2.49 (s, 3H), 1.43 (s, 9H).
iii)
3-[(4-chlorophenyl)thio]-2-methyl-4-(5-pyrimidinyl)-1H-indole-1-aceti-
c acid, 1,1-dimethylethyl ester
[0164] To a solution/suspension of the product of part (ii) (500
mg) in toluene (4 ml) was added ethanol (1 ml),
5-pyrimidinyl-boronic acid (133 mg), 2M sodium carbonate (1.5 ml)
and finally tetrakis(triphenylphosphine)palladium (0), (125 mg).
The mixture was heated at 100.degree. C. for 3 days. Purification
by column chromatography (eluent 2:1 Hexane:EtOAc) gave the
sub-title compound as an orange solid (140 mg).
[0165] .sup.1H NMR (DMSO-d6) .delta. 8.99 (s, 1H), 8.57 (s, 2H),
7.68 (d, 1H), 7.10 (dd, 2H), 6.99 (d, 1H), 7.30 (dt, 1H), 6.46 (dd,
2H), 5.21 (s, 2H), 2.42 (s, 3H), 1.45 (s, 9H).
iii)
3-[(4-chlorophenyl)thio]-2-methyl-4-(5-pyrimidinyl)-1H-indole-1-aceti-
c acid
[0166] The title compound was prepared by the method of Example 1
part (v) using the product from step (iii), with purification by
reverse phase hplc (MeCN/NH.sub.3(aq) as eluent).
[0167] .sup.1H NMR (DMSO-d6) .delta. 8.99 (s, 1H), 8.57 (s, 2H),
7.69 (d, 1H), 7.29 (t, 1H), 7.10 (m, 2H), 6.98 (d, 1H), 6.47 (m,
2H), 5.19 (s, 2H), 2.43 (s, 3H). APCI-[M-H] 408
EXAMPLE 4
##STR00013##
[0168]
3-[(4-Chlorophenyl)thio]-2-methyl-4-pyrazinyl-1H-indole-1-acetic
acid
i) 3-[(4-chlorophenyl)thio]-2-methyl-4-pyrazinyl-1H-indole-1-acetic
acid, 1,1-dimethylethyl ester
[0169] To a solution of the product from Example 3 part (ii) (0.4
g) in toluene (4 ml) was added 2-tributylstannylpyrazine (0.32 g)
and tetrakis(triphenylphosphine)palladium (0) (0.1 g). The reaction
mixture was heated to 80.degree. C. for 18 hours. The mixture was
adsorbed onto silica and purified using column chromatography (33%
EtOAc/hexane as eluent) to give the sub-title compound (160
mg).
[0170] .sup.1H NMR (DMSO-d6) .delta. 8.52 (d, 1H), 8.47 (d, 1H),
8.41 (t, 1H), 7.68 (d, 1H), 7.30 (t, 1H), 7.13-7.09 (m, 3H), 6.55
(m, 2H), 5.21 (s, 2H), 2.40 (s, 3H), 1.44 (s, 9H).
ii)
3-[(4-chlorophenyl)thio]-2-methyl-4-pyrazinyl-1H-indole-1-acetic
acid
[0171] The title compound was prepared by the method of Example 1
part (v), with purification by preparative hplc (MeCN/NH.sub.3(aq)
as eluent).
[0172] .sup.1H NMR (DMSO-d6) .delta. 8.50 (d, 1H), 8.45 (d, 1H),
8.41 (dd, 1H), 7.56 (dd, 1H), 7.22 (dd, 1H), 7.13-7.09 (m, 2H),
7.04 (dd, 1H), 6.58 (dt, 2H), 4.68 (s, 2H), 2.38 (s, 3H) APCI-
[M-H] 408
EXAMPLE 5
##STR00014##
[0173]
3-[(2-Chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indo-
le-1-acetic acid
i) 2-methyl-5-nitro-1H-indole-1-acetic acid, ethyl ester
[0174] 2-Methyl-5-nitro-1H-indole (5.3 g) was dissolved in dimethyl
formamide (20 ml) and to it added sodium hydride (1.2 g) for the
mixture to be stirred for 1 hour. Ethyl bromoacetate (6.8 g) was
added all at once and a precipitate started to form. The mixture
was quenched with 1% aqueous acetic acid and the precipitate
collected by filtration and washed thoroughly with water,
triturated with diethyl ether and dried under vacuum to give pure
sub-title product (6.2 g).
[0175] .sup.1H NMR (DMSO-d6) .delta. 8.45 (d, 1H), 7.96 (dd, 1H),
7.59 (d, 1H), 6.56 (s, 1H), 5.21 (s, 2H), 4.16 (q, 2H), 2.37 (s,
3H), 1.19 (t, 3H).
[0176] APCI- [M-H] 263
ii) 5-amino-2-methyl-1H-indole-1-acetic acid, ethyl ester
[0177] A suspension of 2-methyl-5-nitro-1H-indole-1-acetic acid,
ethyl ester (6.2 g) in ethanol (600 ml) in the presence of 10%
palladium on charcoal (0.6 g) was stirred under a hydrogen
atmosphere at 3 bar for 4 hours. The mixture was filtered through
celite and the filtrate evaporated to give the sub-title compound
as a pink viscous oil (5.3 g). APCI- [M-H] 233
iii) 2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-acetic acid,
ethyl ester
[0178] Methanesulfonyl chloride (1.15 g) was added to a solution of
5-amino-2-methyl-1H-indole-1-acetic acid, ethyl ester (2.3 g) in
triethylamine (1.7 ml) and dichloromethane (20 ml) at 0.degree. C.
a pink viscous oil for a pink viscous oil for and stirred at
20.degree. C. for 1 hour. Water was added and the mixture extracted
with dichloromethane, dried (Na.sub.2SO.sub.4) and evaporated to
give the crude solid. This was purified by chromatography using
silica (40:1 dichloromethane/ethyl acetate as eluent) to give the
sub-title compound as a pink solid (1.4 g).
[0179] .sup.1H NMR (DMSO-d6) .delta. 9.23 (s, 1H), 7.30 (m, 2H),
6.94 (dd, 1H), 6.23 (s, 1H), 5.03 (s, 2H), 4.14 (q, 2H), 2.85 (s,
3H), 2.31 (s, 3H), 1.19 (t, 3H). APCI- [M-H] 311
iv)
3-[(2-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole--
1-acetic acid, ethyl ester
[0180] 2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-acetic acid,
ethyl ester (0.31 g) and 2-chlorobenzenethiol (0.27 g) were
dissolved in dimethyl formamide (3 ml) followed by addition of
iodine 0.30 g) for the whole to be stirred at room temperature
overnight. The mixture was poured into aqueous sodium thiosulphate
(50 ml) and the resultant white precipitate collected by filtration
and rinsed with water, dried under vacuum to be recrystallised from
ethanol. The crystals were harvested and rinsed with isohexane and
dried under vacuum to give the sub-title compound (0.20 g)
[0181] .sup.1H NMR (DMSO-d6) .delta. 9.34 (s, 1H), 7.55 (d, 1H),
7.45 (m, H), 7.21 (d, 1H), 7.23-7.06 (m, 311), 6.44 (m, 1H), 5.26
(s, 2H), 4.18 (q, 2H), 2.83 (s, 3H), 2.38 (s, 3H), 1.22 (t, 3H).
APCI- [M-H] 453/455
v)
3-[(2-chlorophenyl)thio]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-
-acetic acid
[0182] The title compound was prepared by the method of Example 1
part (v) except that recrystallisation was not required. (0.10
g)
[0183] .sup.1H NMR (DMSO-d6) .delta.13.25 (s, 1H), 9.33 (s, 1H),
7.54 (d, 1H), 7.45 (dd, 1H), 7.21 (d, 1H), 7.08 (m, 3H), 6.45 (d,
1H), 5.13 (s, 2H), 2.83 (s, 3H), 2.38 (s, 3H). APCI- [M-H]
425/427
[0184] M.p. 212.degree. C.
EXAMPLE 6
##STR00015##
[0185] 3-[(3-Chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)
amino]-1H-indole-1-acetic acid
i)
3-[(3-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-
-acetic acid, ethyl ester
[0186] The sub-title compound was prepared by the method of Example
5 part (iv) using the product of Example 5 part (iv) and
3-chlorobenzenethiol (0.34 g).
[0187] APCI- [M-H] 453/455
ii)
3-[(3-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole--
1-acetic acid
[0188] The title compound was prepared by the method of Example 5
part (v) using the product from Example 6 part (i).
[0189] .sup.1H NMR (DMSO-d6) .delta. 13.25 (s, 1H), 9.33 (s, 1H),
7.46 (d, 1H), 7.21 (m, 2H), 7.11 (dd, 1H), 7.07 (dd, 1H), 6.95 (m,
2H), 4.88 (s, 2H), 2.82 (s, 3H), 2.39 (s, 3H).
[0190] APCI+ [M+H] 425/427
[0191] M.pt. 224.degree. C.
EXAMPLE 7
##STR00016##
[0192]
3-[(4-Chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indo-
le-1-acetic acid
i)
3-[(4-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-
-acetic acid, ethyl ester
[0193] The sub-title compound was prepared by the method of Example
5 part (iv) using the product of Example 5 part (iv) and
4-chlorobenzenethiol.
[0194] APCI- [M-H] 453/455
ii)
3-[(4-chlorophenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole--
1-acetic acid
[0195] The title compound was prepared by the method of Example 5
part (v) using the product from part (i).
[0196] .sup.1H NMR (DMSO-d6) .delta. 13.25 (s, 1H), 9.37 (s, 1H),
7.57 (d, 1H), 7.23 (d, 2H), 7.22 (d, 1H), 7.07 (dd, 1H), 6.96 (d,
2H), 5.11 (s, 2H), 2.82 (s, 3H), 2.39 (s, 3H).
[0197] APCI+ [M+H] 425/427
[0198] M.p. 214.degree. C.
EXAMPLE 8
##STR00017##
[0199]
3-[(3-Methoxyphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-ind-
ole-1-acetic acid
i)
3-[(3-methoxyphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole--
1-acetic acid, ethyl ester
[0200] The sub-title compound was prepared by the method of Example
5 part (iv) using the product of Example 5 part (iv) and
3-methoxybenzenethiol APCI- [M-H] 449
ii)
3-[(3-methoxyphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-
-1-acetic acid
[0201] The title compound was prepared by the method of Example 5
part (v) using the product from part (i).
[0202] .sup.1H NMR (DMSO-d6) .delta. 13.25 (s, 1H), 9.34 (s, 1H),
7.50 (d, 1H), 7.26, d, 1H, 7.08 (t, 1H), 7.06 (dd, 1H), 6.64 (dd,
1H), 6.55 (d, 1H), 6.47 (d, 1H), 5.11 (s, 2H), 3.62 (s, 3H), 2.82
(s, 3H), 2.40 (s, 3H).
[0203] APCI- [M-H] 421
[0204] M.p. 292.degree. C.
EXAMPLE 9
##STR00018##
[0205]
3-[(4-Methoxyphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-ind-
ole-1-acetic acid
i)
3-[(4-methoxyphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole--
1-acetic acid, ethyl ester
[0206] The sub-title compound was prepared by the method of Example
5 part (iv) using the product of Example 5 part (iv) and
4-methoxybenzenethiol.
[0207] APCI- [M-H] 449
ii)
3-[(4-methoxyphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-
-1-acetic acid
[0208] The title compound was prepared by the method of Example 5
part (v) using the product from part (i).
[0209] .sup.1H NMR (DMSO-d6) .delta. 13.25 (s, 1H), 9.33 (s, 1H),
7.46 (d, 1H), 7.03 (d, 1H), 7.04 (dd, 1H), 7.00 (d, 2H), 6.81 (d,
2H), 5.07 (s, 2H), 3.67 (s, 3H), 2.83 (s, 3H), 2.42 (s, 3H).
[0210] APCI+ [M+H] 421
[0211] M.p. 215.degree. C.
EXAMPLE 10
##STR00019##
[0212]
3-[(2-Trifluoromethylphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino-
]-1H-indole-1-acetic acid
i) 3-[(2-trifluoromethylphenyl)thio]-2-methyl-54(methyl
sulfonyl)amino]-1H-indole-1-acetic acid, ethyl ester
[0213] The sub-title compound was prepared by the method of Example
5 part (iv) using the product of Example 5 part (iv) and
2-trifluoromethylbenzenethiol.
[0214] APCI- [M-H] 487
ii)
[(2-trifluoromethylphenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H--
indole-1-acetic acid
[0215] The title compound was prepared by the method of Example 5
part (v) using the product from part (i).
[0216] .sup.1H NMR (DMSO-d6) .delta. 13.25 (s, 1H), 9.35 (s, 1H),
7.72 (d, 1H), 7.54 (d, 1H), 7.36 (t, 7.24 (t, 1H), 7.22 (s, 1H),
7.11 (dd, 1H), 6.73 (d, 1H), 5.12 (s, 2H), 2.82 (s, 3H), 2.40 (s,
3H).
[0217] APCI- [M-H] 459
[0218] M.p. 207.degree. C.
EXAMPLE 11
##STR00020##
[0219]
3-[(8-Quinolinyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-
-1-acetic acid
i)
3-[(8-quinolinyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1-a-
cetic acid, ethyl ester
[0220] The sub-title compound was prepared by the method of Example
5 part (iv) using the product of Example 5 part (iv) and
8-quinolinthiol.
[0221] APCI- [M-H] 470
ii)
3-[(8-quinolinyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-indole-1--
acetic acid
[0222] The title compound prepared by the method of Example 5 part
(v) using the product from part (i).
[0223] .sup.1H NMR (DMSO-d6) .delta. 13.25 (s, 1H), 9.29 (s, 1H),
8.99 (dd, 1H), 8.38 (d, 1H), 7.65 (m, 2H), 7.54 (d, 1H), 7.30 (t,
1H), 7.20 (s, 1H), 7.11 (dd, 1H), 6.68 (d, 1H), 5.14 (s, 2H), 2.80
(s, 3H), 2.40 (s, 3H).
[0224] APCI+ [M+H] 442
[0225] M.p. 257.degree. C.
EXAMPLE 12
##STR00021##
[0226]
3-[(2-(Methylethyl)phenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]--
1H-indole-1-acetic acid
i)
3-[(2-(2-methylethyl)phenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1H-
-indole-1-acetic acid, ethyl ester
[0227] The sub-title compound was prepared by the method of Example
5 part (iv) using the product of Example 5 part (iv) and
2-(2-methylethyl)benzenethiol.
[0228] APCI- [M-H] 461
ii)
3-[(2-(2-methylethyl)phenyl)thio]-2-methyl-5-[(methylsulfonyl)amino]-1-
H-indole-1-acetic acid
[0229] The title compound was prepared by the method of Example 5
part (v) using the product from part (i).
[0230] .sup.1H NMR (DMSO-d6) .delta. 13.25 (s, 1H), 9.33 (s, 1H),
7.49 (d, 1H), 7.27 (d, 1H), 7.22 (d, 1H), 7.06 (m, 2H), 6.89 (t,
1H), 6.50 (dd, 1H), 5.10 (s, 2H), 3.50 (m, 1H), 2.81 (s, 3H), 2.39
(s, 3H), 1.33 (s, 3H), 1.31 (s, 3H).
[0231] APCI+ [M+H] 433
[0232] M.p. 160.degree. C.
EXAMPLE 13
##STR00022##
[0233]
5-(Acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-aceti-
c acid
i) 5-(acetylamino)-2-methyl-1H-indole-acetic acid, ethyl ester
[0234] Acetyl chloride (0.10 g) was added to a solution of the
product from Example 5 part ii) (0.28 g) in dichloromethane (10 ml)
and triethylamine (0.2 ml) at 0.degree. C. and left to stir at
20.degree. C. for 1 hour. Water was added and the mixture extracted
with dichloromethane, dried (Na.sub.2SO.sub.4) and purified by
column chromatography (eluting with 1:1 iso-hexane/ethyl acetate)
to give the sub-title compound as a pink powder (0.19 g).
[0235] .sup.1H NMR (DMSO-d6) .delta. 9.69 (s, 1H), 7.73 (d, 1H),
7.22 (d, 1H), 7.12 (dd, 1H), 6.18 (s, 1H), 5.00 (s, 2H), 4.13 (q,
2H), 2.30 (s, 3H), 2.02 (s, 3H), 1.20 (t, 3H).
[0236] APCI- [M-H] 275
ii)
5-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-acetic
acid, ethyl ester
[0237] The sub-title compound was prepared by the method of Example
5 part (iv) using the product from part (i) (0.19 g) and
4-chlorobenzenethiol (0.20 g). The mixture was poured into aqueous
sodium thiosulphate, extracted with ethyl acetate, washed with
water, dried (Na.sub.2SO.sub.4) and evaporated. The residue was
recrystallised from ethanol to give the sub-title compound as a
pink solid (0.13 g).
[0238] .sup.1H NMR (DMSO-d6) .delta. 9.80 (s, 1H), 7.67 (d, 1H),
7.43 (d, 1H), 7.36 (dd, 1H), 7.27 (d, 2H), 6.94 (d, 2H), 5.20 (s,
2H), 4.16 (q, 2H), 2.39 (s, 3H), 1.98 (s, 3H), 1.21 (t, 3H).
[0239] APCI- [M-H] 417/419
iii)
5-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-acetic
acid
[0240] The title compound was prepared by the method of Example 5
part (v) using the product from part (ii).
[0241] .sup.1H NMR (DMSO-d6) .delta. 13.25 (s, 1H), 9.79 (s, 1H),
7.67 (d, 1H), 7.42 (d, 1H), 7.34 (dd, 1H), 7.27 (d, 2H), 6.96 (d,
2H), 5.07 (s, 2H), 2.39 (s, 3H), 1.98 (s, 3H).
[0242] APCI+ [M+H] 389/391
[0243] M.p. 247.degree. C.
EXAMPLE 14
##STR00023##
[0244]
4-(Acetylethylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1--
acetic acid
i)
3-[(4-chlorophenyl)thio]-4-(ethylamino)-2-methyl-1H-indole-1-acetic
acid, ethyl ester
[0245] The sub-title compound was prepared by the method of Example
1 part (iv) using the by-product from Example 1 part (iii).
[0246] .sup.1H NMR (DMSO-d6) .delta. 7.53 (d, 1H), 7.22-7.18 (m,
3H), 6.91-6.87 (m, 3H), 5.21 (s, 2H), 4.19 (q, 2H), 4.01 (m, 1H),
2.92-2.81 (m, 1H), 2.41 (s, 3H), 1.31 (s, 3H), 1.21 (t, 3H), 0.91
(t, 3H)
ii)
4-(acetylethylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-ace-
tic acid
[0247] The title compound was prepared by the method of Example 1
part (v) and the product from part (i).
[0248] .sup.1H NMR (DMSO-d6) .delta. 7.55 (d, 1H), 7.22 (dt, 2H),
7.18 (t, 1H), 6.89-6.86 (m, 3H), 4.99 (s, 2H), 2.77 (m, 1H), 4.02
(m, 1H), 2.39 (s, 3H), 1.28 (s, 3H), 0.91 (t, 3H).
APCI+ [M+H] 417
EXAMPLE 15
##STR00024##
[0249]
3-[(4-Chlorophenyl)thio]-4-[cyclopropylcarbonyl)amino]-2-methyl-1H--
indole-1-acetic acid
i)
3-[(4-chlorophenyl)thio]-4-[cyclopropylcarbonyl)amino]-2-methyl-1H-indo-
le-1-acetic acid, ethyl ester
[0250] The sub-title compound was prepared by the method of Example
1 part (iv) using the product from Example 1 part (iii) and
cyclopropylcarbonyl chloride.
[0251] .sup.1H NMR (DMSO-d6) .delta. 9.74 (s, 1H), 7.49 (d, 1H),
7.43-7.26 (m, 3H), 7.10 (t, 1H), 6.98 (m, 2H), 5.24 (s, 2H), 4.18
(q, 2H), 2.40 (s, 3H), 1.53 (m, 1H), 1.18 (t, 3H), 0.64 (m,
4H).
ii)
3-[(4-chlorophenyl)thio]-4-[cyclopropylcarbonyl)amino]-2-methyl-1H-ind-
ole-1-acetic acid
[0252] The sub-title compound was prepared using the method of
Example 1 part (v) and the product from part (i).
[0253] .sup.1H NMR (DMSO-d6) .delta. 9.58 (s, 1H), 7.60 (d, 1H),
7.28-7.22 (m, 3H), 7.09 (t, 1H), 7.02 (m, 2H), 5.03 (s, 2H), 2.41
(s, 3H), 1.50 (m, 1H), 0.68 (m, 4H)
[0254] APCI- [M-H] 413
[0255] M.p. 183-185.degree. C.
EXAMPLE 16
##STR00025##
[0256]
4-(Benzoylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acet-
ic acid
i)
4-(benzoylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid, ethyl ester
[0257] The sub-title compound was prepared by the method of Example
1 part (iv) using the product from Example 1 part (iii) and benzoyl
chloride.
[0258] .sup.1H NMR (DMSO-d6) .delta. 10.25 (s, 1H), 7.84 (d, 1H),
7.75 (m, 2H), 7.59 (m, 1H), 7.50 (m, 2H), 7.40 (d, 1H), 7.21 (m,
3H), 6.88 (m, 2H), 5.28 (s, 2H), 4.19 (q, 2H), 2.40 (s, 3H), 1.17
(t, 3H).
ii)
4-(benzoylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid
[0259] The title compound was prepared using the method of Example
1 part (v) and the product from part (i).
[0260] .sup.1H NMR (DMSO-d6) .delta. 10.26 (s, 1H), 7.86 (d, 1H),
7.75 (dt, 2H), 7.58 (m, 1H), 7.50 (m, 2H), 7.36 (dd, 1H), 7.21 (dt,
2H), 7.17 (t, 1H), 6.90 (dt, 2H), 5.03 (s, 2H), 2.40 (s, 3H).
[0261] APCI- [M-H] 449
[0262] M.pt 213-215.degree. C.
EXAMPLE 17
##STR00026##
[0263]
4-(Acetylamino)-3-[(3-chlorophenyl)thio]-2-methyl-1H-indole-1-aceti-
c acid
i) 4-(acetylamino)-2-methyl-1H-indole-1-acetic acid, ethyl
ester
[0264] Thiosalicylic acid was added to a solution of the product
from Example 1 part (iv) (474 mg) in trifluoroacetic acid (10 ml)
was added thiosalicylic acid (351 mg) and the resulting suspension
was heated to 60.degree. C. for 4 hours. The mixture was
concentrated in vacuo and the residue dissolved in EtOAc and washed
with NaHCO.sub.3 (aq), brine, dried (MgSO.sub.4) and evaporated to
give crude material. Purification by column chromatography (50%
EtOAc/hexane as eluent) gave the sub-title compound (0.13 g).
[0265] .sup.1H NMR (DMSO-d6) .delta. 9.51 (s, 1H), 7.54 (d, 1H),
7.07 (d, 1H), 6.96 (t, 1H), 6.50 (s, 1H), 5.02 (s, 2H), 4.14 (q,
2H), 2.33 (d, 3H), 2.12 (s, 3H), 1.20 (t, 3H).
ii)
4-(acetylamino)-3-[(3-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid
[0266] The sub-title compound was prepared by the method of Example
5 part (iv) using the product from part (i) (0.11 g) and
3-chlorobenzenethiol (0.048 g), then purified by preparative hplc
(eluent MeCN/NH.sub.3(aq)) to give the title compound (70 mg).
[0267] .sup.1H NMR (DMSO-d6) .delta. 9.49 (s, 1H), 7.43 (d, 1H),
7.29 (d, 1H), 7.24 (t, 1H), 7.14 (dd, 1H), 7.08 (t, 1H), 6.97-6.95
(m, 2H), 4.96 (s, 2H), 2.38 (s, 3H), 1.86 (s, 3H).
[0268] APCI- [M-H] 387
EXAMPLE 18
##STR00027##
[0269]
3-[(4-Chlorophenyl)thio]-4-[[(dimethylamino)sulfonyl]amino]-2-methy-
l-1H-indole-1-acetic acid
i)
3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)sulfonyl]amino]-2-methyl-1H-
-indole-1-acetic acid, ethyl ester
[0270] Triethylamine (55 .mu.l) and dimethylsulfamoyl chloride (43
.mu.l) were added to a solution of the product from Example 1 part
(iv) (150 mg) in acetonitrile (5 ml). The mixture was heated at
reflux for 24 hours, adsorbed onto silica and purified using column
chromatography (33% EtOAc/hexane as eluent) to give the sub-title
compound (95 mg).
[0271] .sup.1H NMR (DMSO-d6) .delta. 8.80 (s, 1H), 7.35-7.29 (m,
3H), 7.13 (t, 1H), 7.07 (dd, 1H), 6.99 (dt, 2H), 5.25 (s, 2H), 4.18
(q, 2H), 2.56 (s, 6H), 2.37 (s, 3H), 1.21 (t, 3H).
ii)
3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)sulfonyl]amino]-2-methyl-1-
H-indole-1-acetic acid
[0272] The title compound was prepared using the method of Example
1 part (v) and the product from part (i).
[0273] .sup.1H NMR (DMSO-d6) .delta. 8.79 (s, 1H), 7.31 (m, 2H),
7.14 (dd, 1H), 7.04-6.99 (m, 4H), 4.51 (s, 2H), 2.54 (s, 6H), 2.34
(s, 3H).
[0274] APCI- [M-H] 452
EXAMPLE 19
##STR00028##
[0275]
3-[(4-Chlorophenyl)thio]-2-methyl-4-[[(1-methyl-1H-imidazol-4-yl)su-
lfonyl]amino]-1H-indole-1-acetic acid
i)
3-[(4-chlorophenyl)thio]-2-methyl-4-[[(1-methyl-1H-imidazol-4-yl)sulfon-
yl]amino]-1H-indole-1-acetic acid, ethyl ester
[0276] Triethylamine (75 .mu.l) and
1-methyl-1H-imidazole-4-sulfonyl chloride (96 mg) were added to a
solution of the product from Example 1 part (iii) (0.2 g) in
acetonitrile (20 ml) and the mixture was heated at reflux
overnight, cooled, adsorbed onto silica and purified using column
chromatography (70% EtOAc/hexane as eluent) to give the sub-title
compound as an oil (245 mg).
[0277] .sup.1H NMR (DMSO-d6) .delta. 9.17 (s, 1H), 7.73 (d, 1H),
7.63 (d, 1H), 7.32 (dt, 2H), 7.24 (dd, 1H), 7.08-7.02 (m, 2H), 6.98
(dt, 2H), 5.20 (s, 2H), 4.15 (q, 2H), 3.60 (s, 3H), 2.33 (s, 3H),
1.17 (t, 3H).
ii)
3-[(4-chlorophenyl)thio]-2-methyl-4-[[(1-methyl-1H-imidazol-4-yl)sulfo-
nyl]amino]-1H-indole-1-acetic acid
[0278] The title compound was prepared using the method of Example
1 part (v) and the product from part (i).
[0279] .sup.1H NMR (DMSO-d6) .delta. 9.16 (s, 1H), 7.73 (d, 1H),
7.62 (d, 1H), 7.31 (dt, 2H), 7.22 (dd, 1H), 7.08-7.02 (m, 2H), 6.99
(dt, 2H), 5.01 (s, 2H), 3.59 (s, 3H), 2.32 (s, 3H).
[0280] APCI- [M-H] 489
EXAMPLE 20
##STR00029##
[0281]
3-[(4-Chlorophenyl)thio]-4-[[(dimethylamino)acetyl]amino]-2-methyl--
1H-indole-1-acetic acid
i)
3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)acetyl]amino]-2-methyl-1H-i-
ndole-1-acetic acid, ethyl ester
[0282] The sub-title compound was prepared by the method of Example
1 part (iv) using the product from Example 1 part (iii) and
(dimethylamino)-acetyl chloride, hydrochloride. The product was
purified using column chromatography (33% EtOAc/hexane as
eluent).
[0283] .sup.1H NMR (DMSO-d6) .delta. 10.77 (s, 1H), 8.15 (d, 1H),
7.35-7.27 (m, 3H), 7.13 (t, 1H), 6.97 (d, 2H), 5.25 (s, 2H), 4.17
(q, 2H), 2.94 (s, 2H), 2.38 (s, 3H), 2.10 (s, 6H), 1.21 (t,
3H).
ii)
3-[(4-chlorophenyl)thio]-4-[[(dimethylamino)acetyl]amino]-2-methyl-1H--
indole-1-acetic acid
[0284] The title compound was prepared using the method of Example
1 part (v) and the product from part (i).
[0285] .sup.1H NMR (DMSO-d6) .delta. 10.76 (s, 1H), 8.10 (d, 1H),
7.30 (dt, 2H), 7.17 (d, 1H), 7.05 (t, 1H), 6.98 (dd, 2H), 4.66 (s,
2H), 2.93 (s, 2H), 2.35 (s, 3H), 2.09 (s, 6H).
[0286] APCI- [M-H] 430
EXAMPLE 21
##STR00030##
[0287]
4-(Acetylamino)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indo-
le-1-acetic acid
i) 4-(methylsulfonyl)benzenethiol
[0288] 1-fluoro-4-(methylsulfonyl)benzene and sodium bisulphide (10
g) were heated in NMP (10 ml) at 80.degree. C. for 2 h. The mixture
was poured into water, washed with EtOAc, acidified with,
concentrated hydrochloric acid and extracted with EtOAc. The
organics were washed with water, dried (MgSO.sub.4) and evaporated
to give the sub-title compound, which was used in the next step
without characterisation.
ii)
4-(acetylamino)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole--
1-acetic acid, ethyl ester
[0289] The sub-title compound was prepared by the method of Example
5 part (iv) using the product from part (i) and the product from
Example 17 part (i), and purified by chromatography (50%
EtOAc/hexane increasing to 66% EtOAc/hexane as eluent) to give the
sub-title compound.
[0290] .sup.1H NMR (DMSO-d6) .delta. 9.45 (s, 1H), 7.72 (dt, 2H),
7.38 (d, 1H), 7.32 (d, 1H), 7.16-7.11 (m, 3H), 5.27 (s, 2H), 4.19
(q, 2H), 3.14 (s, 3H), 2.38 (s, 3H), 1.82 (s, 3H), 1.22 (t,
3H).
iv)
4-(acetylamino)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole--
1-acetic acid
[0291] The title compound was prepared using the method of Example
1 part (v) and the product from part (ii).
[0292] .sup.1H NMR (DMSO-d6) .delta. 9.44 (s, 1H), 7.72 (dd, 2H),
7.38 (d, 1H), 7.31 (d, 1H), 7.17-7.10 (m, 3H), 5.14 (s, 2H), 3.14
(s, H), 2.38 (s, 3H), 1.82 (s, 3H).
[0293] APCI- [M-H] 431
EXAMPLE 22
##STR00031##
[0294]
4-(Acetylamino)-3-[(2-chlorophenyl)thio]-2-methyl-1H-indole-1-aceti-
c acid
4-(acetylamino)-3-[(2-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid
[0295] The title compound was prepared by the method of Example 5
parts (iv) and using the product from Example 17 part (i) and
2-chlorothiophenol, and purified by column chromatography (33%
EtOAc/hexane as eluent). The resulting product was treated as
outlined in example 1 part (v) to give the title compound.
[0296] .sup.1H NMR (DMSO-d6) .delta. 9.43 (s, 1H), 7.46 (dd, 1H),
7.37 (dd, 2H), 7.14-7.05 (m, 3H), 6.42 (dd, 1H), 5.14 (s, 2H), 2.37
(s, 3H), 1.81 (s, 3H)
[0297] APCI+ [M+H] 389
EXAMPLE 23
##STR00032##
[0298]
4-(Acetylamino)-2-methyl-3-[[4-(ethylsulfonyl)phenyl]thio]-1H-indol-
e-1-acetic acid
i)
4-(acetylamino)-2-methyl-3-[[4-(ethylsulfonyl)phenyl]thio]-1H-indole-1--
acetic acid
[0299] The title compound was prepared by the method of Example 5
part (iv) using the product from Example 17 part (i) and
4-(ethylsulfonyl)benzenethiol. The product was purified by
preparative hplc (eluent MeCN/NH.sub.3(aq)).
[0300] .sup.1H NMR (DMSO-d6) .delta. 9.41 (s, 1H), 7.66 (d, 2H),
7.30 (d, 2H), 7.17 (d, 2H), 7.08 (t, 1H), 4.85 (s, 2H), 3.20 (q,
2H), 2.37 (s, 3H), 1.78 (s, 3H), 1.05 (t, 3H).
[0301] APCI- [M-H] 445
EXAMPLE 24
##STR00033##
[0302]
3-[(4-Chlorophenyl)thio]-4-[[(ethylamino)carbonyl]amino]-2-methyl-1-
H-indole-1-acetic acid
i)
3-[(4-chlorophenyl)thio]-4-[[(ethylamino)carbonyl]amino]-2-methyl-1H-in-
dole-1-acetic acid, ethyl ester
[0303] Ethyl isocyanate (32 .mu.l) was added to a solution of the
product from Example 1 part (iii) (150 mg) in dichloromethane (10
ml). The reaction was stirred at room temperature for 4 days before
heating at reflux for 24 hours. The mixture was adsorbed onto
silica and purified using column chromotography (33% EtOAc/hexane
increasing to 50% EtOAc/hexane as eluent) to give sub-title
compound (150 mg).
[0304] .sup.1H NMR (DMSO-d6) .delta. 8.37 (s, 1H), 7.57 (d, 1H),
7.28 (dt, 2H), 7.12 (dd, 1H), 7.06-6.98 (m, 3H), 6.81 (t, 1H), 5.19
(s, 2H), 4.17 (q, 2H), 2.98 (dt, 2H), 2.37 (s, 3H), 1.21 (t, 3H),
0.96 (t, 3H)
ii)
3-[(4-chlorophenyl)thio]-4-[[(ethylamino)carbonyl]amino]-2-methyl-1H-i-
ndole-1-acetic acid
[0305] The title compound was prepared using the method of Example
1 part (v) and the product from part (i).
[0306] .sup.1H NMR (DMSO-d6) .delta. 8.39 (s, 1H), 7.53 (dd, 1H),
7.26 (dt, 2H), 7.04-6.94 (m, 4H), 6.76 (t, 1H), 4.56 (s, 2H), 2.98
(dt, 2H), 2.34 (s, 3H), 0.95 (t, 3H).
[0307] APCI+ [M+H] 418
EXAMPLE 25
##STR00034##
[0308]
3-[[4-(Methylsulfonyl)phenyl]thio]-4-(5-pyrimidinyl)-1H-indole-1-ac-
etic acid
i) 4-bromo-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole
[0309] The sub-title compound was prepared by the method of Example
5 part (iv) using the product from Example 21 part (i) (0.89 g) and
4-bromoindole (0.96 g). The residue was purified by chromatography
(50% EtOAc/hexane as eluent) to give the sub-title compound (1.3
g).
[0310] .sup.1H NMR (DMSO-d6) .delta. 12.18 (s, 1H), 7.93 (s, 1H),
7.73 (d, 2H), 7.56 (d, 1H), 7.29 (d, 1H), 7.17 (d, 2H), 7.12 (t,
1H), 3.14 (s, 3H)
ii) 4-bromo-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic
acid
[0311] Sodium t-butoxide (1.37 g) was added to a solution of the
product from part (i) (2.4 g) in DMF (20 ml) and the mixture
stirred for 15 minutes. Ethyl bromoacetate (0.86 ml) was added and
the mixture stirred for a further 30 minutes. 1M sodium hydroxide
(10 ml) was then added and the mixture stirred for 2 hours. The
mixture was diluted with water (200 ml), washed with EtOAc (50 ml),
acidified with 2M hydrochloric acid and the resulting solid
filtered off and dried to give the sub-titled compound (2.5 g).
[0312] .sup.1H NMR (DMSO-d6) .delta. 7.86 (s, 1H), 7.73 (d, 2H),
7.50 (d, 1H), 7.28 (d, 1H), 7.19 (d, 2H), 7.11 (t, 1H), 4.73 (s,
2H), 3.14 (s, 3H)
iii)
3-[[4-(methylsulfonyl)phenyl]thio]-4-(5-pyrimidinyl)-1H-indole-1-acet-
ic acid
[0313] The product from part (ii) (0.4 g), phenylboronic acid (0.17
g), tetrakis(triphenylphosphine) palladium (100 mg) and 2M aqueous
sodium hydrogen carbonate (2 ml) were dissolved in ethanol (10 ml)
and heated at reflux for 8 hours. The mixture was cooled to room
temperature, diluted with EtOAc (100 ml), washed with water and
brine. The organic solution was dried (MgSO.sub.4), filtered and
evaporated in vacuo and the residue purified by hplc to give the
title compound (190 mg).
[0314] .sup.1H NMR (DMSO-d6) .delta. 8.93 (s, 1H), 8.58 (s, 1H),
7.93 (s, 1H), 7.70 (d, 1H), 7.52 (d, 2H), 7.37 (t, 1H), 7.03 (d,
1H), 6.70 (d, 2H), 5.15 (s, 2H), 3.12 (s, 3H)
[0315] APCI- [M-H] 438
EXAMPLE 26
##STR00035##
[0316]
2-Methyl-3-[[4-(methylsulfonyl)phenyl]thio]-4-(2-thiophenyl)-1H-ind-
ole-1-acetic acid
i) 1-[[4-(methylsulfonyl)phenyl]thio]acetone
[0317] The product from Example 21 part (i) (3.4 g) was dissolved
in acetone (100 ml), potassium carbonate (3.0 g) added, followed by
the dropwise addition of chloroacetone (1.5 ml). The mixture was
stirred at room temperature for 20 hours, concentrated, partitioned
between EtOAc and water, dried (MgSO.sub.4) and evaporated. The
residue was purified by chromatography (50% EtOAc/hexane as eluent)
to give the sub-title compound (2.6 g).
[0318] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.84 (d, 2H), 7.43
(d, 2H), 3.81 (s, 2H), 3.06 (s, 3H), 2.34 (s, 3H)
[0319] APCI- [M-H] 243
[0320] M.p. 95-7.degree. C.
ii)
4-bromo-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole
[0321] The sub-title compound was prepared by the method of Example
3 part (i) using the product from part (i) (1.6 g) and
3-bromophenyl hydrazine hydrochloride (1.47 g). The product was
purified by using chromatography (30% EtOAc/hexane as eluent) to
give the sub-title compound (0.5 g).
[0322] .sup.1H NMR (CDCl.sub.3) .delta. 8.41 (s, 1H), 7.68 (d, 2H),
7.54 (s, 1H), 7.32 (d, 1H), 7.25 (d, 1H), 7.10 (d, 2H), 3.00 (s,
3H), 2.50 (s, 3H)
[0323] APCI- [M-H] 394
iii)
4-bromo-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-aceti-
c acid, 1,1-dimethylethyl ester
[0324] The sub-title compound was prepared by the method of Example
1 part (ii) using the product of part (i) and t-butylbromoacetate.
The product was purified using chromatography (50% EtOAc/hexane as
eluent) to give the sub-title compound (0.5 g).
[0325] APCI+ [M+H] 510
iv)
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-4-(2-thiophenyl)-1H-indole-
-1-acetic acid, 1,1-dimethylethyl ester
[0326] A mixture of palladium acetate (24 mg), tri-ortho
tolylphosphine (64 mg) and methanol (6 ml) were stirred under
nitrogen for 10 minutes. The product of part (ii) in methanol (10
ml) was added, followed by sodium carbonate (1.12 g) and
thiophene-2-boronic acid (0.68 g). After stirring for 45 minutes at
80.degree. C. further palladium acetate (24 mg) and tri-ortho
tolylphosphine (64 mg) in methanol (1 ml) was added, followed by
thiophene-2-boronic acid (0.2 g) and toluene (5 ml), the reaction
mixture was stirred at 80.degree. C. for 1 hour. The reaction
mixture was concentrated in vacuo, water was added and the mixture
extracted with dichloromethane. The organic layer was dried
(MgSO.sub.4) then concentrated in vacuo. The residue was dissolved
in methanol and treated with sodium hydroxide (5 ml). After one
hour the reaction mixture was concentrated in vacuo, then purified
by reverse phase HPLC to give the title compound (160 mg).
[0327] .sup.1H NMR (DMSO-d6) .delta. 7.58 (m, 3H), 7.38 (d, 1H),
7.18 (t, 1H), 6.99 (d, 1H), 6.87 (m, 3H), 6.78 (s, 1H), 4.98 (s,
2H), 3.11 (s, 3H), 2.38 (s,
[0328] APCI- [M-H] 456
EXAMPLE 27
##STR00036##
[0329]
4-(3,5-Dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl-
]thio]-1H-indole-1-acetic acid
[0330] Prepared by the method of Example 26 part (iv) using the
product of Example 26 part (ii) and
3,5-dimethylisoxazolyl-4-boronic acid. The product was purified
using reverse phase preparative chromatography (eluent
MeCN/NH.sub.3(aq)) to give the title compound (6 mg).
[0331] .sup.1H NMR (DMSO-d6) .delta. 7.61 (d, 1H), 7.46 (d, 2H),
7.17 (t, 1H), 6.82 (d, 2H), 6.75 (d, 1H), 4.57 (s, 2H), 3.32 (s,
3H), 1.9 (s, 3H), 1.11 (s, 6H)
[0332] APCI- [M-H] 469
EXAMPLE 28
##STR00037##
[0333]
4-(3-Furanyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-
-1-acetic acid
i)
4-(3-furanyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-a-
cetic acid, ethyl ester
[0334] The sub-title compound was prepared by the method of Example
26 part (iv) using the product of Example 27 part (i) and
furan-3-boronic acid. The product was used without characterisation
in part (ii).
ii)
4-(3-furanyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1--
acetic acid
[0335] The title compound was prepared by the method of Example 1
part (v) using the product from part (i). The product was purified
using hplc (eluent MeCN/NH.sub.3(aq)) to give the title compound
(60 mg).
[0336] .sup.1H NMR (DMSO-d6) .delta. 7.41-7.63 (m, 5H), 7.17 (t,
1H), 6.9-6.96 (m, 3H), 6.36 (s, 1H), 5.18 (s, 2H), 3.18 (s, 3H),
2.4 (s, 3H)
[0337] APCI- [M-H] 440
EXAMPLE 29
##STR00038##
[0338]
2-Methyl-4-[(methylsulfonyl)amino]-3-[[4-(methylsulfonyl)phenyl]thi-
o]-1H-indole-1-acetic acid
i) 2-methyl-4-[(methylsulfonyl)amino]-1H-indole-1-acetic acid
[0339] Thiosalicylic acid (0.35 g) was added to a solution of the
product from Example 2 part (i) (0.47 g) in TFA (10 ml). The
mixture was stirred at room temperature for 1 hour and then heated
at 60.degree. C. for 4 hours. The TFA was evaporated and the
residue dissolved in EtOAc. The organics were washed with aqueous
sodium bicarbonate and brine, dried (MgSO.sub.4) and evaporated.
The residue was purified using chromatography (50% EtOAc/hexane as
eluent) to give the sub-title compound (0.16 g).
[0340] .sup.1H NMR (DMSO-d6) .delta. 9.4 (s, 1H), 7.19 (d, 1H),
6.95-7.04 (m, 2H), 6.53 (d, 1H), 5.04 (s, 2H), 4.15 (q, 2H), 2.91
(s, 3H), 2.32 (d, 3H), 1.21 (t, 3H)
ii)
2-methyl-4-[(methylsulfonyl)amino]-3-[[4-(methylsulfonyl)phenyl]thio]--
1H-indole-1-acetic acid, ethyl ester
[0341] The sub-title compound was prepared by the method of Example
5 part (iv) using the product from part (i) and the product from
Example 21 part (i).
[0342] .sup.1H NMR (DMSO-d6) .delta. 8.76 (s, 1H), 7.74 (dd, 2H),
7.44 (d, 1H), 7.07-7.21 (m, 4H), 5.29 (s, 2H), 4.19 (q, 2H), 3.14
(s, 3H), 2.76 (s, 3H), 2.36 (s, 3H), 1.22 (t, 3H)
iii)
2-methyl-4-[(methylsulfonyl)amino]-3-[[4-(methylsulfonyl)phenyl]thio]-
-1H-indole-1-acetic acid
[0343] The title compound was prepared by the method of Example 1
part (v) using the product from part (ii) and the recrystallised
from ethanol to give the title compound as a pale pink solid (75
mg).
[0344] .sup.1H NMR (DMSO-d6) .delta. 8.78 (s, 1H), 7.74 (d, 2H),
7.44 (d, 1H), 7.13-7.2 (m, 3H), 7.08 (d, 1H) 5.15 (s, 2H), 3.14 (s,
3H), 2.76 (s, 3H), 2.36 (s, 3H)
[0345] APCI+ [M+H] 469
EXAMPLE 30
##STR00039##
[0346]
2-Methyl-5-[(methylsulfonyl)amino]-3-[[3-(methylsulfonyl)phenyl]thi-
o]-1H-indole-1-acetic acid
i) O-[3-(methylsulfonyl)phenyl]carbamothioic acid, dimethyl
ester
[0347] Sodium hydride (0.33 g) was added to a solution of
3-(methylsulfonyl)phenol in DMF (10 ml) and stirred for 30 minutes.
Dimethylcarbamothioic chloride (1.1 g) was added and the reaction
heated at 80.degree. C. for 4 hours. The mixture was poured into
aqueous ammonium chloride, extracted with EtOAc, washed with water,
dried (MgSO.sub.4) and evaporated in vacuo. The residue was
purified using chromatography (30-50% ether/hexane as eluent) to
give the sub-title compound (1.3 g).
[0348] .sup.1H NMR (DMSO-d6) .delta. 7.82 (dd, 1H), 7.69 (t, 1H),
7.59 (t, 1H), 7.39 (dd, 1H), 3.47 (s, 3H), 3.37 (s, 3H), 3.08 (s,
3H)
[0349] APCI+ [M-H] 260
ii) S-[3-(methylsulfonyl)phenyl]carbamothioic acid, dimethyl
ester
[0350] The product from part (i) (1.1 g) was dissolved in
N,N-dimethylaniline (3 ml) and heated at 220.degree. C. for 8
hours. The mixture was cooled, poured into 2M hydrochloric acid and
extracted with EtOAc. The organics were washed with 2M hydrochloric
acid and water, dried (MgSO.sub.4) and evaporated in vacuo. The
oily residue was treated with ether to give the sub-title compound
as a white solid (0.9 g).
[0351] .sup.1H NMR (DMSO-d6) .delta. 8.07 (d, 1H), 7.94 (dd, 1H),
7.79 (dd, 1H), 7.59 (t, 1H), 3.04-3.12 (m, 6H), 3.07 (s, 3H)
[0352] APCI+ [M+H] 260
iii) 3-(methylsulfonyl)benzenethiol
[0353] The product from part (ii) (0.9 g) was suspended in 2M
sodium hydroxide (70 ml) and heated at reflux for 1.5 h to give a
brown solution. The solution was cooled, extracted with EtOAc,
dried (MgSO.sub.4) and evaporated to give the sub-title compound
(0.45 g).
[0354] .sup.1H NMR (DMSO-d6) .delta. 7.84 (m, 1H), 7.7 (m, 1H),
7.52 (m, 1H), 7.44 (t, 1H), 3.67 (s, 1H), 3.06 (s, 3H)
[0355] APCI- [M-H] 187
iv)
2-methyl-5-[(methylsulfonyl)amino]-3-[[3-(methylsulfonyl)phenyl]thio]--
1H-indole-1-acetic acid, ethyl ester
[0356] The sub-title compound was prepared by the method of Example
5 part (iv) using the product from part (iii) (0.22 g) and the
product from Example 5 part (iii) and recrystallised from
ethanol.
[0357] .sup.1H NMR (DMSO-d6) .delta. 7.58 (m, 2H), 7.34 (m, 2H),
7.18 (t, 2H), 6.28 (s, 1H), 4.89 (s, 2H), 4.25 (q, 2H), 3.06 (s,
3H), 2.96 (s, 3H), 2.49 (s, 3H), 1.28 (t, 3H)
[0358] APCI- [M+NH.sub.4] 514
[0359] M.p. 176-8.degree. C.
v)
2-methyl-5-[(methylsulfonyl)amino]-3-[[3-(methylsulfonyl)phenyl]thio]-1-
H-indole-1-acetic acid
[0360] The title compound was prepared by the method of Example 1
part (v) using the product from part (iv). The basic solution was
adjusted to pH5 with 0.5M hydrochloric acid and the resulting
precipitate filtered off and dried to give the title compound (0.19
g).
[0361] .sup.1H NMR (DMSO-d6) .delta. 9.35 (s, 1H), 7.61 (m, 1H),
7.57 (d, 1H), 7.53 (d, 1H), 7.46 (t, 1H), 7.24 (d, 1H), 7.18 (m,
1H), 7.08 (dd, 1H), 5.05 (s, 2H), 3.17 (s, 3H), 2.82 (s, 3H), 2.41
(s, 3H)
[0362] APCI+ [M+NH.sub.4] 469
[0363] M.p. 233-6.degree. C.
EXAMPLE 31
##STR00040##
[0365]
2-Methyl-5-[(methylsulfonyl)amino]-3-[[2-(methylsulfonyl)phenyl]thi-
o]-1H-indole-1-acetic acid
i) 1-fluoro-2-(methylsulfonyl)benzene
[0366] A solution of oxone (17 g) in water (85 ml) was added to a
solution of 2-fluorothioanisole in acetonitrile (85 ml) and the
mixture stirred at room temperature for 20 hours. The mixture was
concentrated, extracted with EtOAc, washed with water, dried
(MgSO.sub.4) and evaporated to give the sub-title compound (5.9
g).
[0367] .sup.1H NMR (DMSO-d6) .delta. 7.98 (t, 1H), 7.66 (m, 1H),
7.35 (t, 1H), 7.26 (t, 1H), 3.23 (s, 3H)
ii) 2-(methylsulfonyl)benzenethiol
[0368] The sub-title compound was prepared by the method of Example
26 part (i) using the product from part (i) (5.4 g).
[0369] .sup.1H NMR (DMSO-d6) 8.05 (d, 1H), 7.46 (m, 2H), 7.35 (m,
1H), 4.84 (s, 1H), 3.21 (s, 3H)
[0370] APCI- [M-H] 187
iii)
2-methyl-5-[(methylsulfonyl)amino]-3-[[2-(methylsulfonyl)phenyl]thio]-
-1H-indole-1-acetic acid, ethyl ester
[0371] The sub-title compound was prepared by the method of Example
5 part (iv) using the product from part (ii) (1.3 g) and the
product from Example 5 part (iii) (0.6 g). The product was purified
using chromatography (50-67% EtOAc/hexane as eluent) to give the
sub-title compound (0.18 g).
[0372] .sup.1H NMR (DMSO-d6) .delta. 8.05 (d, 1H), 7.16-7.27 (m,
4H), 6.77 (dd, 1H), 6.33 (s, 1H), 4.9 (s, 2H), 4.26 (q, 2H), 3.44
(s, 3H), 2.88 (s, 3H), 2.5 (s, 3H), 1.21 (t, 3H)
[0373] APCI- [M+NH.sub.4] 514
[0374] M.p. 174-7.degree. C.
v)
2-methyl-5-[(methylsulfonyl)amino]-3-[[2-(methylsulfonyl)phenyl]thio]-1-
H-indole-1-acetic acid
[0375] Prepared by the method of Example 1 part (v) using the
product from part (iii). The basic solution was adjusted to pH5
with 0.5M hydrochloric acid and the resulting precipitate filtered
and dried to give the title compound.
[0376] .sup.1H NMR (DMSO-d6) 9.38 (s, 1H), 7.92 (dd, 114), 7.53 (d,
1H), 7.39 (m, 1H), 7.31 (m, 1H), 7.16 (d, 1H), 7.10 (dd, 1H), 6.75
(dd, 1H), 5.11 (s, 2H), 3.51 (s, 3H), 2.81 (s, 2.41 (s, 3H).
[0377] APCI+ [M+NH.sub.4] 486
[0378] M.p. 227-30.degree. C.
EXAMPLE 32
##STR00041##
[0379]
2-Methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(5-pyrimidinyl)-1H-in-
dole-1-acetic acid
i)
5-bromo-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole
[0380] The sub-title compound was prepared by the method of Example
3 part (i) using the product from Example 26 part (i) (2.5 g) and
4-bromophenyl hydrazine hydrochloride (2.3 g). The reaction mixture
was evaporated to half volume and the resulting precipitate
filtered off, washed with ether and dried to yield the sub-title
compound (2.2 g).
[0381] .sup.1H NMR (DMSO-d6) .delta. 12.04 (s, 1H), 7.73 (d, 2H),
7.4 (m, 2H), 7.27 (dd, 1H), 7.14 (d, 2H), 3.14 (s, 3H), 2.45 (s,
3H)
[0382] APCI- [M-H] 394
ii)
5-bromo-2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-1H-indole-1-acetic
acid, ethyl ester
[0383] The sub-title compound was prepared by the method of Example
1 part (ii) using the product of part (i) and the product was
purified using chromatography (33-50% EtOAc/hexane as eluent).
[0384] .sup.1H NMR (DMSO-d6) 7.71 (d, 2H), 7.64 (d, 1H), 7.34 (dd,
1H), 7.16 (d, 1H), 7.1 (d, 2H), 4.88 (s, 2H), 4.24 (q, 2H), 3.0 (s,
3H), 2.47 (s, 3H) 1.29 (t, 3H)
[0385] APCI+ [M+H] 482
iii)
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(5-pyrimidinyl)-1H-indo-
le-1-acetic acid, ethyl ester
[0386] The sub-title compound was prepared by the method of Example
3 part (iii) using the product of part (ii) and
pyrimidine-5-boronic acid. Carried forward to part (iii) without
characterisation.
iv)
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(5-pyrimidinyl)-1H-indol-
e-1-acetic acid
[0387] The title compound was prepared by the method of Example 1
part (v) using the product from part (iii). The basic solution was
adjusted to pH5 with 0.5M hydrochloric acid and the resulting
precipitate filtered off and dried to give the title compound (21
mg).
[0388] .sup.1H NMR (DMSO-d6) 9.38 (s, 1H), 9.09 (s, 2H), 7.71-7.79
(m, 4H), 7.64 (dd, 1H), 7.17 (d, 2H), 5.23 (s, 2H), 3.12 (s, 3H)
2.45 (s, 3H)
[0389] APCI+ [M+H] 454
[0390] M.p.>290.degree. C.
EXAMPLE 33
##STR00042##
[0391]
2-Methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(2-thiophenyl)-1H-ind-
ole-1-acetic acid
i)
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-thiophenyl)-1H-indole--
1-acetic acid, ethyl ester
[0392] The sub-title compound was prepared by the method of Example
3 part (iii) using the product of part (ii) and thiophene-2-boronic
acid. Used without further characterisation.
ii)
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(2-thiophenyl)-1H-indole-
-1-acetic acid
[0393] The title compound was prepared by the method of Example 1
part (v) using the product from part (ii). The basic solution was
adjusted to pH 5 with 0.5 M hydrochloric acid and the resulting
precipitate filtered off and dried, then recrystallised from
acetonitrile to give the title compound.
[0394] .sup.1H NMR (DMSO-d6) 7.72 (d, 2H), 7.63 (d, 1H), 7.53 (m,
2H), 7.42 (d, 1H), 7.39 (t, 1H), 7.18 (d, 2H), 7.08 (m, 1H), 5.15
(s, 2H), 3.13 (s, 3H) 2.42 (s, 3H)
[0395] APCI- [M+H] 458
EXAMPLE 34
##STR00043##
[0396]
5-(3,5-Dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl-
]thio]-1H-indole-1-acetic acid
i)
5-(3,5-dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]thi-
o]-1H-indole-1-acetic acid, ethyl ester
[0397] The sub-title compound was prepared by the method of Example
3 part (iii) using the product of part (ii) and
3,5-dimethylisoxazolyl-4-boronic acid. Used in the next step
without characterisation.
ii)
5-(3,5-dimethyl-4-isoxazolyl)-2-methyl-3-[[4-(methylsulfonyl)phenyl]th-
io]-1H-indole-1-acetic acid
[0398] The title compound was prepared by the method of Example 1
part (v) using the product from part (ii). The basic solution was
adjusted to pH5 with 0.5M hydrochloric acid and the resulting
precipitate filtered, dried and recrystallised from
cyclohexane/ethanol to give the title compound.
[0399] .sup.1H NMR (DMSO-d6) 7.73 (d, 2H), 7.66 (d, 1H), 7.24 (d,
1H), 7.19 (m, 3H), 5.19 (s, 2H), 3.13 (s, 3H) 2.44 (s, 3H), 2.31
(s, 3H), 2.13 (s, 3H)
[0400] APCI+ [M+H] 471
EXAMPLE 35
##STR00044##
[0401]
2-Methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-pyridinyl)-1H-indo-
le-1-acetic acid
i)
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-pyridinyl)-1H-indole-1-
-acetic acid, ethyl ester
[0402] The sub-title compound was prepared by the method of Example
3 part (iii) using the product of part (ii) and pyridine-3-boronic
acid.
[0403] .sup.1H NMR (CDCl.sub.3) .delta. 8.85 (s, 1H), 8.54 (s, 1H),
7.87 (m, 1H), 7.73-7.69 (m, 3H), 7.49 (d, 1H), 7.39 (d, 1H), 7.33
(t, 1H), 7.14 (d, 2H), 4.95 (s, 2H), 4.26 (q, 2H), 2.98 (s, 3H),
2.51 (s, 3H), 1.29 (t, 3H).
ii)
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(3-pyridinyl)-1H-indole--
1-acetic acid
[0404] The title compound was prepared by the method of Example 1
part (v) using the product from part (ii). The basic solution was
adjusted to pH5 with 0.5M hydrochloric acid and the resulting
precipitate filtered off and dried to give the title compound (20
mg).
[0405] .sup.1H NMR (DMSO-d6) 8.84 (d, 1H), 8.5 (dd, 1H), 8.1 (m,
1H), 7.73-7.69 (d, 3H), 7.63 (d, 1H), 7.53 (dd, 1H), 7.43 (dd, 1H),
7.18 (d, 2H), 5.22 (s, 2H), 3.12 (s, 3H) 2.44 (s, 3H)
[0406] APCI+ [M+H] 453
EXAMPLE 36
##STR00045##
[0407]
2-Methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(1H-pyrazol-4-yl)-1H--
indole-1-acetic acid
i)
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(1H-pyrazol-4-yl)-1H-indo-
le-1-acetic acid, ethyl ester
[0408] The sub-title compound was prepared by the method of Example
3 part (iii) using the product of part (ii) and
(1H-pyrazol-4-yl)-boronic acid and used in the next step without
characterisation.
ii)
2-methyl-3-[[4-(methylsulfonyl)phenyl]thio]-5-(1H-pyrazol-4-yl)-1H-ind-
ole-1-acetic acid
[0409] The title compound was prepared by the method of Example 1
part (v) using the product from part (ii). The basic solution was
adjusted to pH5 with 0.5M hydrochloric acid and the resulting
precipitate filtered off and dried to give the title compound.
[0410] .sup.1H NMR (DMSO-d6) .delta. 7.97 (s, 2H), 7.71 (d, 2H),
7.56 (d, 1H), 7.53 (s, 1H), 7.45 (dd, 1H), 7.16 (d, 2H), 5.14 (s,
2H), 3.12 (s, 3H) 2.4 (s, 3H)
[0411] APCI+ [M+H] 442
EXAMPLE 37
##STR00046##
[0412]
4-(Acetylamino)-3-[(4-cyanophenyl)thio]-2-methyl-1H-indole-1-acetic
acid
i)
4-(acetylamino)-3-[(4-cyanophenyl)thio]-2-methyl-1H-indole-1-acetic
acid, ethyl ester
[0413] The sub-title compound was prepared by the method of Example
5 part (iv) using the product from Example 13 part (i) (330 mg) and
4-mercaptobenzonitrile (330 mg). Purified using column
chromatography (3% EtOAc/dichloromethane as eluent) to give the
sub-title compound (300 mg).
[0414] .sup.1H NMR (DMSO-d6) .delta. 9.33 (s, 1H), 8.07 (d, 1H),
7.47 (d, 2H), 7.23 (t, 1H), 7.09 (d, 2H), 7.02 (d, 1H), 4.88 (s,
2H), 4.23 (q, 2H), 2.44 (s, 3H), 1.93 (s, 3H), 1.28 (t, 3H)
[0415] APCI+ [M+H] 408
[0416] M.p. 263-5.degree. C.
ii)
4-(acetylamino)-3-[(4-cyanophenyl)thio]-2-methyl-1H-indole-1-acetic
acid
[0417] The title compound was prepared by the method of Example 1
part (v) using the product from part (ii). The basic solution was
adjusted to pH5 with 0.5M hydrochloric acid and the resulting
precipitate filtered, dried to give the title compound.
[0418] .sup.1H NMR (DMSO-d6) 7.63 (d, 2H), 7.37 (d, 1H), 7.27 (d,
1H), 7.13 (t, 1H), 7.07 (d, 2H), 5.13 (s, 2H), 2.37 (s, 3H) 1.79
(s, 3H)
[0419] APCI+ [M+H] 380
Pharmacological Data
Ligand Binding Assay
[0420] [.sup.3H]PGD.sub.2 was purchased from Perkin Elmer Life
Sciences with a specific activity of 100-210 Ci/mmol. All other
chemicals were of analytical grade.
[0421] 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 FPTA, 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.
[0422] 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.
[0423] 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 10
.mu.l 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).
[0424] Compounds of formula (I) have an IC.sub.50 value of less
than (<) 10 .mu.M. Specifically, example 14 has a
pIC.sub.50=6.65, example 26 has a pIC.sub.50=8.35, and example 34
has a pIC.sub.50=9.4.
* * * * *