U.S. patent application number 12/758348 was filed with the patent office on 2010-08-05 for indole-3-sulphur derivatives.
Invention is credited to Roger Bonnert, Mark Dickinson, Rukhsana Rasul, Hitesh Sanganee, Simon Teague.
Application Number | 20100197756 12/758348 |
Document ID | / |
Family ID | 30117585 |
Filed Date | 2010-08-05 |
United States Patent
Application |
20100197756 |
Kind Code |
A1 |
Bonnert; Roger ; et
al. |
August 5, 2010 |
Indole-3-Sulphur Derivatives
Abstract
The present invention relates to substituted indoles useful as
pharmaceutical compounds for treating respiratory disorders. (I)
##STR00001##
Inventors: |
Bonnert; Roger;
(Loughborough, GB) ; Dickinson; Mark;
(Loughborough, GB) ; Rasul; Rukhsana;
(Loughborough, GB) ; Sanganee; Hitesh;
(Loughborough, GB) ; Teague; Simon; (Loughborough,
GB) |
Correspondence
Address: |
FISH & RICHARDSON P.C.
P.O BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Family ID: |
30117585 |
Appl. No.: |
12/758348 |
Filed: |
April 12, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10521325 |
Aug 15, 2005 |
7723373 |
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PCT/SE03/01216 |
Jul 15, 2003 |
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12758348 |
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Current U.S.
Class: |
514/418 ;
548/484 |
Current CPC
Class: |
A61P 1/16 20180101; A61P
25/28 20180101; A61P 11/16 20180101; A61P 9/10 20180101; A61P 43/00
20180101; A61K 31/405 20130101; A61P 25/14 20180101; A61P 31/00
20180101; C07D 209/30 20130101; A61P 11/02 20180101; A61P 13/12
20180101; A61P 11/06 20180101; A61P 29/00 20180101; A61P 37/06
20180101; A61P 1/04 20180101; A61P 3/10 20180101; A61P 11/00
20180101; A61P 11/14 20180101; A61P 9/00 20180101; A61P 17/00
20180101; A61P 17/06 20180101; A61P 25/00 20180101; A61P 25/06
20180101; A61P 11/08 20180101; A61P 31/18 20180101; A61P 19/02
20180101; A61P 37/08 20180101 |
Class at
Publication: |
514/418 ;
548/484 |
International
Class: |
A61K 31/40 20060101
A61K031/40; C07D 209/30 20060101 C07D209/30; A61P 11/00 20060101
A61P011/00; A61P 11/06 20060101 A61P011/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 17, 2002 |
SE |
0202241-6 |
Dec 13, 2002 |
SE |
0203713-3 |
Claims
1. A compound of formula (I) or a pharmaceutically acceptable salt
thereof: ##STR00033## in which: n represents 1 or 2; R.sup.1 is one
or more substituents independently selected from halogen, CN,
nitro, 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,
NR.sup.9SO.sub.2R.sup.4, NR.sup.9CO.sub.2R.sup.4,
NR.sup.9COR.sup.4, aryl, heteroaryl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl or C.sub.1-6alkyl, the latter five groups
being optionally substituted by one or more substituents
independently selected from halogen, OR.sup.7 and NR.sup.8R.sup.9,
NR.sup.8R.sup.9, S(O).sub.xR.sup.7 where x is 0, 1 or 2; R.sup.2 is
hydrogen, halogen, CN, SO.sub.2R.sup.4 or CONR.sup.5R.sup.6,
COR.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 a 5-7 membered aromatic
ring containing one or more heteroatoms selected from N, S and O,
each of which is optionally substituted by one or more substituents
independently selected from halogen, CN, nitro, SO.sub.2R.sup.4,
OH, 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, NR.sup.9SO.sub.2R.sup.4,
NR.sup.9CO.sub.2R.sup.4, NR.sup.9COR.sup.4, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkyl, the latter
three groups being optionally substituted by one or more
substituents independently selected from halogen atoms, OR' and
NR.sup.8R.sup.9, S(O).sub.xR.sup.7 where x is 0, 1 or 2; R.sup.4
represents aryl, heteroaryl, or C.sub.1-C.sub.6 alkyl, all of which
may be optionally substituted by one or more substituents
independently selected from halogen atoms, aryl, heteroaryl,
OR.sup.10 and NR.sup.11R.sup.12S(O).sub.xR.sup.13 (where x=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-C.sub.6 alkyl group, 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.13 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, CN, nitro; 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 the ring itself optionally substituted by
C.sub.1-C.sub.3 alkyl; R.sup.7 and R.sup.13 independently represent
a C.sub.1-C.sub.6 alkyl group, an aryl or 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, aryl or heteraryl groups,
both of which may also be optionally substituted by one or more
fluorine atoms); an aryl or a heteroaryl group, which may be
optionally substituted by one or more halogen atoms; 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 one or more halogen atoms); and R.sup.16 is
hydrogen, C.sub.1-4 alkyl, --C(O)C.sub.1-C.sub.4 alkyl,
C(O)YC.sub.1-C.sub.4alkyl, Y is O or NR.sup.7. or a
pharmaceutically acceptable salt or solvate thereof.
2. A compound according to claim 1 in which n is 2.
3. A compound according to claim 1 in which R.sup.1 is halogen,
nitrile, C.sub.1-6alkyl or SO.sub.2R.sup.4, NO.sub.2,
NR.sup.9COR.sup.4, NR.sup.9SO.sub.2R.sup.4, aryl,
NR.sup.5R.sup.6.
4. A compound according to claim 1 in which the substituent(s)
is/are in the 4- and/or 5-position.
5. A compound according to claim 1 in which R.sup.2 is
C.sub.1-6alkyl.
6. A compound according to claim 4 in which R.sup.3 is phenyl
substituted by halogen.
7. A compound according to claim 1 selected from:
3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;
5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid;
6-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid;
7-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid;
5-chloro-3-[(4-chlorophenyl)sulfonyl]-4-cyano-2-methyl-1H-indole-1-acetic
acid;
5-chloro-3-[(4-chlorophenyl)sulfonyl]-6-cyano-2-methyl-1H-indole-1--
acetic acid;
3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid;
3-[(4-chlorophenyl)sulfonyl]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1-
H-indole-1-acetic acid;
3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic
acid;
3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic
acid;
5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid,
4-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid; 3-[(4-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid; 3-[(3-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid; 3-[(2-Chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid; 3-[(3-Chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid; 3-[(4-Cyanophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic
acid; 3-[(2-methylphenyl)sulfonyl]-2,5-Dimethyl-1H-indol-1-acetic
acid; 3-[(2-ethylphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid;
3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-nitro-1H-indole-1-acetic
acid;
4-(Acetylamino)-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid;
3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-[(methylsulfonyl)amino]-1H--
indole-1-acetic acid;
3-[(4-chlorophenyl)sulfonyl]-4-(ethylamino)-2-methyl-1H-indole-1-acetic
acid;
3-[(2,6-Dichlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic
acid;
3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-phenyl-1H-indole-1-acetic
acid
3-[(4-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-acetic
acid,
3-[(3-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-acetic
acid,
5-fluoro-2-methyl-3-[[4-(trifluoromethyl)phenyl]sulfonyl]-1H-indole-
-1-acetic acid, and pharmaceutically acceptable salts thereof.
8. (canceled)
9. A method of treating a disease mediated by prostaglandin D2,
which comprises administering to a patient a therapeutically
effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt as defined in claim 1.
10. A method according to claim 9 where the disease is asthma or
rhinitis.
11. Use of a compound of a compound of formula (I), or a
pharmaceutically acceptable salt as defined in claim 1, in the
manufacture of a medicament for treating a disease mediated by
prostaglandin D2.
12-13. (canceled)
14. A process for the preparation of a compound of formula (I) of
claim 1 which comprises reaction of a compound of formula (II): (a)
oxidation of a compound of formula (II): ##STR00034## in which
R.sup.17 is hydrogen or alkyl and R.sup.1, R.sup.2 and R.sup.3 are
as defined in claim 1 or are protected derivatives thereof, or (b)
reaction of a compound of formula (III): ##STR00035## in which
R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1 or are
protected derivatives thereof, with a compound of formula (IV):
R.sup.18--O(CO)CH.sub.2-L (IV) where R.sup.18 is an alkyl group and
L is a leaving group in the presence of a base, and optionally
thereafter (a) or (b) in any order: hydrolysing the ester group
R.sup.17 or R.sup.18 to the corresponding acid removing any
protecting group forming a pharmaceutically acceptable salt.
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. GB 1356834
discloses a series of compounds said to possess anti-inflammatory,
to analgesic and antipyretic 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
thereof:
##STR00002##
in which: n represents 1 or 2; R.sup.1 is one or more substituents
independently selected from halogen, CN, nitro, 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, NR.sup.9SO.sub.2R.sup.4,
NR.sup.9CO.sub.2R.sup.4, NR.sup.9COR.sup.4, aryl, heteroaryl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.1-6alkyl,
the latter five groups being optionally substituted by one or more
substituents independently selected from halogen, OR.sup.7 and
NR.sup.8R.sup.9, NR.sup.8R.sup.9, S(O).sub.xR.sup.7 where x is 0, 1
or 2; R.sup.2 is hydrogen, halogen, CN, SO.sub.2R.sup.4 or
CONR.sup.5R.sup.6, COR.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 a 5-7 membered heteroaryl ring containing one or more
heteroatoms selected from N, S and O, each of which is optionally
substituted by one or more substituents independently selected from
halogen, CN, nitro, SO.sub.2R.sup.4, OH, 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, NR.sup.9SO.sub.2R.sup.4, NR.sup.9CO.sub.2R.sup.4,
NR.sup.9COR.sup.4, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkyl, the latter three groups being
optionally substituted by one or more substituents to independently
selected from halogen atoms, OR.sup.7 and NR.sup.8R.sup.9,
S(O).sub.xR.sup.7 where x is 0, 1 or 2; R.sup.4 represents aryl,
heteroaryl, or C.sub.1-C.sub.6 alkyl, all of which may be
optionally substituted by one or more substituents independently
selected from halogen atoms, aryl, heteroaryl, OR.sup.10 and
NR.sup.11R.sup.12S(O).sub.xR.sup.13 (where x=0, 1 or 2),
CONR.sup.14R.sup.15, NR.sup.14COR.sup.15,
SO.sub.2NR.sup.14R.sup.15, is 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-C.sub.6 alkyl group, 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.13 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, CN, nitro; 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 the ring itself optionally substituted by
C.sub.1-C.sub.3 alkyl; R.sup.7 and R.sup.13 independently represent
a C.sub.1-C.sub.6 alkyl group, an aryl or 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, aryl or heteraryl groups,
both of which may also be optionally substituted by one or more
fluorine atoms); an aryl or a heteroaryl group, which may be
optionally substituted by one or more halogen atoms; 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 one or more halogen atoms); and R.sup.16 is
hydrogen, C.sub.1-4 alkyl, --C(O)C.sub.1-C.sub.4 alkyl,
C(O)YC.sub.1-C.sub.4alkyl, 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 is phenyl and naphthyl.
[0006] When R.sup.3 is heteroaryl, examples include pyridine,
pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan,
isoxazole, pyrrole, isothiazole and azulene.
[0007] When R.sup.4 is heteroaryl this includes 5-7 membered
aromatic rings or can be a 6,6- or 6,5-fused bicyclic ring system,
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.
[0008] Heterocyclic rings as defined for R.sup.5 and R.sup.6 means
saturated heterocycles, examples include morpholine,
thiomorpholine, azetidine, imidazolidine, pyrrolidine, piperidine
and piperazine.
[0009] Preferably n is 2.
[0010] Preferably R.sup.1 is halogen, nitrile, C.sub.1-6alkyl or
SO.sub.2R.sup.4, NO.sub.2, NR.sup.9COR.sup.4,
NR.sup.9SO.sub.2R.sup.4, aryl, NR.sup.5R.sup.6. More preferably
R.sup.1 is methyl, nitrile, chloro, SO.sub.2Me, SO.sub.2Et,
NHCOR.sup.4, NHSO.sub.2R.sup.4, phenyl, NH(alkyl).
[0011] The R.sup.1 group(s) 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. Preferably the number of substituents
R.sup.1 other than hydrogen is 1 or 2.
[0012] Preferably R.sup.2 is C.sub.1-6alkyl, more preferably
methyl.
[0013] Preferably R.sup.3 is phenyl optionally substituted by
halogen, alkyl, alkoxy or nitrile. More preferably R.sup.3 is
chloro, methyl, ethyl, cyano or methoxy.
[0014] Substituents can be present on any suitable position of an
R.sup.3 group.
[0015] Preferred compounds of the invention include: [0016]
3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;
[0017]
5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid; [0018]
6-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid; [0019]
7-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid; [0020]
5-chloro-3-[(4-chlorophenyl)sulfonyl]-4-cyano-2-methyl-1H-indole-1-
-acetic acid; [0021]
5-chloro-3-[(4-chlorophenyl)sulfonyl]-6-cyano-2-methyl-1H-indole-1-acetic
acid; [0022]
3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid;
[0023]
3-[(4-chlorophenyl)sulfonyl]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indo-
le-1-acetic acid; [0024]
3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic
acid; [0025]
3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic
acid; [0026]
5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid, sodium salt; [0027]
4-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid; [0028]
3-[(4-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;
[0029] 3-[(3-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid; [0030]
3-[(2-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;
[0031] 3-[(3-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid; [0032]
3-[(4-cyanophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid;
[0033] 3-[(2-methylphenyl)sulfonyl]-2,5-Dimethyl-1H-indol-1-acetic
acid; [0034]
3-[(2-ethylphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid;
[0035]
3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-nitro-1H-indole-1-acetic
acid; [0036]
4-(acetylamino)-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid; [0037]
3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole-
-1-acetic acid; [0038]
3-[(4-chlorophenyl)sulfonyl]-4-(ethylamino)-2-methyl-1H-indole-1-acetic
acid; [0039]
3-[(2,6-Dichlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic
acid; [0040]
3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-phenyl-1H-indole-1-acetic
acid [0041]
3-[(4-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-acetic
acid, [0042]
3-[(3-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-acetic
acid, [0043]
5-fluoro-2-methyl-3-[[4-(trifluoromethyl)phenyl]sulfonyl]-1H-indole-1-ace-
tic acid, and pharmaceutically acceptable salts thereof.
[0044] In a further aspect the invention provides a sub-class of
compounds of formula (IA):
##STR00003##
in which R.sup.1 and R.sup.2 are independently hydrogen, halogen,
CN, amino, nitro, C.sub.1-6alkyl, C.sub.1-6alkoxy,
SO.sub.2C.sub.1-6alkyl or CONR.sup.4R.sup.5 where R.sup.4 and
R.sup.5 independently hydrogen or C.sub.1-6alkyl; and R.sup.3 is
phenyl substituted by halogen, and pharmaceutically acceptable
salts thereof.
[0045] Preferably for compounds (IA) R.sup.1 is hydrogen or
C.sub.1-6alkyl. More preferably R.sup.1 is methyl. The R.sup.1
group can be present at any suitable position on the indole ring,
preferably the R.sup.1 group is at the 5-position.
[0046] Preferably for compounds (IA) R.sup.2 is C.sub.1-6alkyl,
more preferably methyl.
[0047] Preferably for compounds (IA) R.sup.3 is phenyl substituted
by chloro.
[0048] Preferred compounds (IA) include: [0049]
{3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-yl}acetic
acid. and pharmaceutically acceptable salts thereof.
[0050] In a further aspect the invention provides a further
sub-class of compounds of formula (IB):
##STR00004##
in which: n represents 1 or 2; R.sup.1 is halogen, CN, nitro,
SO.sub.2R.sup.4, OR.sup.4, SR.sup.4, SO.sub.2R.sup.4,
SO.sub.2NR.sup.5R.sup.6, CONR.sup.5R.sup.6, NR.sup.5R.sup.6,
NR.sup.7SO.sub.2R.sup.4, NR.sup.7CO.sub.2R.sup.4, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.1-6 alkyl, the latter
three groups being optionally substituted by one or more
substituents independently selected from halogen, --OR.sup.7 and
--NR.sup.8R.sup.9, S(O)xR.sup.7 where x is 0, 1 or 2; p is 0 to 4;
R.sup.2 is hydrogen, halogen, CN, SO.sub.2R.sup.4 or
CONR.sup.5R.sup.6, COR.sup.4 or C.sub.1-7alkyl, the latter three
groups being optionally substituted by one or more substituents
independently selected from halogen atoms, --OR.sup.7 and
--NR.sup.8R.sup.9, S(O)xR.sup.7 where x is 0, 1 or 2: R.sup.3 is
R.sup.3 is phenyl optionally substituted by halogen; R.sup.4
represents hydrogen or C.sub.1-6alkyl which may be optionally
substituted by one or more substituents independently selected from
halogen atoms, aryl, --OR.sup.10 and --NR.sup.11R.sup.12. R.sup.5
and R.sup.6 independently represent a hydrogen atom, a
C.sub.1-6alkyl group, or phenyl group the latter two of which may
be optionally substituted by one or more substituent groups
independently selected from halogen atoms, aryl, --OR.sup.13 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; 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,
NR.sup.16, and itself optionally substituted by C.sub.1-3 alkyl,
halogen; each of R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11,
R.sup.12, R.sup.13, R.sup.12, R.sup.13, R.sup.14, R.sup.15,
independently represents a hydrogen atom, C.sub.1-C.sub.6, alkyl,
or an aryl group; and R.sup.16 is hydrogen, C.sub.1-4 alkyl,
--COC.sub.1-C.sub.4 alkyl, --COYC.sub.1-C.sub.4alkyl, Y.dbd.O or
NR.sup.7.
[0051] Preferably for compounds (IB) R.sup.1 is halogen, nitrile,
C.sub.1-6alkyl or SO.sub.2R.sup.4. More preferably R.sup.1 is
methyl, nitrile, chloro, SO.sub.2Me, SO.sub.2Et. Preferably p is 1
or 2.
[0052] 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.
[0053] Preferably for compounds (IB) R.sup.2 is C.sub.1-6alkyl,
more preferably methyl.
[0054] Preferably for compounds (IB) R.sup.3 is phenyl optionally
substituted by halogen, more preferably chloro.
[0055] Preferred compounds (18) include: [0056]
{3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-yl}acetic
acid, [0057]
5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid, [0058]
6-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid, [0059]
7-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid, [0060]
5-chloro-3-[(4-chlorophenyl)sulfonyl]-4-cyano-2-methyl-1H-indole-1-acetic
acid, [0061]
5-chloro-3-[(4-chlorophenyl)sulfonyl]-6-cyano-2-methyl-1H-indole-1-acetic
acid, [0062]
3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic acid,
[0063]
3-[(4-chlorophenyl)sulfonyl]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indo-
le-1-acetic acid, [0064]
3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic
acid, [0065]
3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic
acid, [0066] Sodium
5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetate,
and pharmaceutically acceptable salts thereof.
[0067] In a still further aspect the invention provides the use of
a compound of formula (IC) or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for the treatment of a
disease where the inhibition of CRTh2 is beneficial:
##STR00005##
in which: n represents 1 or 2; R.sup.1 is one or more substituents
independently selected from halogen, CN, nitro, 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, NR.sup.9SO.sub.2R.sup.4,
NR.sup.9CO.sub.2R.sup.4, NR.sup.9COR.sup.4, aryl, heteroaryl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.1-6alkyl,
the latter five groups being optionally substituted by one or more
substituents independently selected from halogen, OR.sub.7 and
NR.sup.8R.sup.9, NR.sup.8R.sup.9, S(O).sub.xR.sup.7 where x is 0, 1
or 2; R.sup.2 is hydrogen, halogen, CN, SO.sub.2R.sup.4 or
CONR.sup.5R.sup.6, COR.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 a 5-7 membered or 6,6- or 6,5-fused bicyclic aromatic ring
each containing one or more heteroatoms selected from N, S and O,
and each of which is optionally substituted by one or more
substituents independently selected from halogen, CN, nitro,
SO.sub.2R.sup.4, OH, 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,
NR.sup.9SO.sub.2R.sup.4, NR.sup.9CO.sub.2R.sup.4,
NR.sup.9COR.sup.4, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkyl, the latter three groups being
optionally substituted by one or more substituents independently
selected from halogen atoms, OR.sup.7 and NR.sup.8R.sup.9,
S(O).sub.xR.sup.7 where x is 0, 1 or 2; R.sup.4 represents aryl,
heteroaryl, or C.sub.1-C.sub.6 alkyl, all of which may be
optionally substituted by one or more substituents independently
selected from halogen atoms, aryl, heteroaryl, OR.sup.10 and
NR.sup.11R.sup.12S(O).sub.xR.sup.13 (where x=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,
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-C.sub.6 alkyl
group, 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.13 and NR.sup.14R.sup.15,
CONR.sup.14R.sup.15, NR.sup.14SO.sub.2R.sup.15,
SO.sub.2NR.sup.14R.sup.15, NR.sup.14SO.sub.2R.sup.15, CN, nitro; 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 the ring itself optionally
substituted by C.sub.1-C.sub.3 alkyl; R.sup.7 and R.sup.13
independently represent a C.sub.1-C.sub.6 alkyl group, an aryl or
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,
aryl or heteraryl groups, both of which may also be optionally
substituted by one or more fluorine atoms); an aryl or a heteroaryl
group, which may be optionally substituted by one or more halogen
atoms; 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 one or more halogen atoms); and R.sup.16
is hydrogen, C.sub.1-4 alkyl, --C(O)C.sub.1-C.sub.4 alkyl,
C(O)YC.sub.1-C.sub.4alkyl, Y is O or NR.sup.7.
[0068] As used below, the term "compound of formula (I)" referes to
any compound above of formula (I), (IA), (IB) or (IC).
[0069] 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.
[0070] The compound of formula (I) above may be converted to a
pharmaceutically acceptable salt or solvate thereof, preferably a
basic addition salt such as sodium, potassium, calcium, aluminium,
lithium, magnesium, zinc, benzathine, chloroprocaine, choline,
diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine
or procaine, or an acid addition salt such as a hydrochloride,
hydrobromide, phosphate, acetate, fumarate, maleate, tartrate,
citrate, oxalate, methanesulphonate or p-toluenesulphonate.
Preferred salts include sodium salts.
[0071] 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 is
`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).
[0072] Compounds of formula (I) can be prepared by:
(a) oxidation of a compound of formula (II):
##STR00006##
in which R.sup.17 is hydrogen or alkyl and R.sup.1, R.sup.2 and
R.sup.3 are as defined in formula (I) or are protected derivatives
thereof, or (b) reaction of a compound of formula (M):
##STR00007##
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
(IV):
L-C(O)OR.sup.18 (IV)
where R.sup.18 is an alkyl group and L is a leaving group in the
presence of a base, and optionally thereafter (a) or (b) in any
order: [0073] hydrolysing the ester group R.sup.17 or R.sup.18 to
the corresponding acid [0074] removing any protecting group [0075]
forming a pharmaceutically acceptable salt.
[0076] For process (a) suitable oxidising agents include MCPBA,
H.sub.2O.sub.2 or oxone. When R.sup.17 is alkyl, ethyl, methyl or
tertiary-butyl groups are preferred. Where R.sup.17 is hydrogen
compounds of formula (I) are obtained directly by optionally
removing of a protecting group and formation of appropriate
salts.
[0077] Where R.sup.17 is alkyl the corresponding ester can be
hydrolysed. Hydrolysis of the ester group R.sup.17 can be carried
out using routine procedures, for example by stirring with base,
preferably aqueous sodium or lithium hydroxide, or stirring with an
acid such as TFA and optionally removing of protecting groups and
formation of appropriate salts.
[0078] For process (b) 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.18 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 (IV) is ethyl bromoacetate.
[0079] Hydrolysis of the ester group R.sup.18 can be carried out
using routine procedures as described above for R.sup.17.
[0080] Compounds of formula (III) can be prepared by reaction of a
compound of formula (V) using process (a):
##STR00008##
in which R.sup.1, R.sup.2 and R.sup.3 are as defined in formula (I)
or are protected derivatives thereof, with an oxidising agent, and
optionally thereafter removing any protecting group.
[0081] Compounds of formula (V) where R.sup.1, R.sup.2 and R.sup.3
are as defined in formula (I) or are protected derivatives thereof
can be prepared by reacting a compound of formula (VI) with a
compound of formula (VII):
##STR00009##
in which R.sup.1, R.sup.2 and R.sup.3 are as defined in formula
(I), or protected derivatives thereof.
[0082] Preferably the reaction is carried out in acetic acid with
heating.
[0083] Or, compounds of formula (V) where R.sup.1, R.sup.2 and
R.sup.3 are as defined in formula (I) or are protected derivatives
thereof, can be prepared by reacting a compound of formula (VIII)
with a compound of formula (VII):
##STR00010##
[0084] Compounds of formula (VI), ((VII) and (VIII) are
commercially available or can be prepared using standard chemistry
well known in the art. Where R.sup.1, R.sup.2 and R.sup.3 are as
defined in formula (I) or are protected derivatives thereof.
Preferably the reaction is carried out in a suitable solvent, such
as dichloromethane or THF in the presence of a chlorinating agent
such as sulfonyl chloride or tertiary-butyl hypochlorite.
[0085] Alternatively compounds of formula (I) can be prepared by
reacting compounds of formula (IX) with compounds of formula (X).
Where R.sup.1, R.sup.2 and R.sup.3 are as defined in formula (I) or
are protected derivatives thereof.
##STR00011##
[0086] Preferably the reaction is carried out in a suitable solvent
such as ethanol or DMF, in the presence of iodine.
[0087] Compounds of formula (IX) can be prepared by reaction of
compounds of formula (XI) and (IV) as outlined above.
##STR00012##
[0088] Compounds of formula (X) and (XI) are commercially available
or can be prepared using standard chemistry well known in the art.
Where R.sup.1, R.sup.2 and R.sup.3 are as defined in formula (I) or
are protected derivatives thereof.
[0089] Compounds of formula (II) in which R.sup.1 is aryl are
prepared from compounds of formula (II) in which R.sup.1 is
halogen, preferably bromine or iodine using Suzuki coupling
conditions, preferably using tetrakistriphenylphosphine palladium
(0) as a catalyst in a suitable organic solvent, such as toluene,
with heating.
##STR00013##
[0090] Compounds of formula (II) in which R.sup.1 is
NR.sup.9SO.sub.2R.sup.4 are prepared from compounds of formula
(XII) by reacting with a suitable base, preferably sodium
hydroxide.
##STR00014##
[0091] Compounds of formula (XII) are prepared from compounds of
formula (XIII)
##STR00015##
[0092] Compounds of formula (XIII) are hydrogenated in the presence
of a suitable catalyst such as platinum on charcoal, in acidic
conditions. The product of this reaction is then reacted with a
sulfonyl chloride compound in the presence of a base, preferably
triethylamine in an organic solvent, such as acetonitrile.
[0093] Compounds of formula (XIII) are prepared from compounds of
formula (II) in which R.sup.1 is NO.sub.2, by reaction with a
suitable oxidising agent (process A).
[0094] Compounds of formula (I) in which R.sup.1 is NRCOR are
prepared by hydrogenation of a to compound of formula (II) in which
R.sup.1 is nitro, as outlined for compounds of formula (XII) above.
The reduced product is then treated with an acyl chloride
[ClC(O)R.sup.4] in the presence of base to give a compound of
formula (II), this is subsequently hydrolysed and oxidised
(processes a and b) to give a compound of formula (I) as outlined
previously.
[0095] The compounds of formula (I) have activity as
pharmaceuticals, in particular as modulators of CRTh2 receptor
activity, and may be used in the treatment (therapeutic or
prophylactic) of conditions/diseases in human and non-human animals
which are exacerbated or caused by excessive or unregulated
production of PGD.sub.2 and its metabolites. Examples of such
conditions/diseases include: [0096] (1) (the respiratory tract)
obstructive airways diseases including: asthma (such as bronchial,
allergic, intrinsic, extrinsic and dust asthma particularly chronic
or inveterate asthma (e.g. late asthma and airways
hyper-responsiveness)); chronic obstructive pulmonary disease
(COPD)(such as irreversible COPD); bronchitis (including
eosinophilic bronchitis); acute; allergic, atrophic rhinitis or
chronic rhinitis (such as rhinitis caseosa, hypertrophic rhinitis,
rhinitis purulenta, rhinitis sicca), rhinitis medicamentosa,
membranous rhinitis (including croupous, fibrinous and
pseudomembranous rhinitis), scrofoulous rhinitis, perennial
allergic rhinitis, easonal rhinitis (including rhinitis nervosa
(hay fever) and vasomotor rhinitis); nasal polyposis; sarcoidosis;
farmer's lung and related diseases; fibroid lung; idiopathic
interstitial pneumonia; cystic fibrosis; antitussive activity;
treatment of chronic cough associated with inflammation or
iatrogenic induced; [0097] (2) (bone and joints) arthrides
including rheumatic, infectious, autoimmune, seronegative,
spondyloarthropathies (such as ankylosing spondylitis, psoriatic
arthritis and Reiter's disease), Behcet's disease, Sjogren's
syndrome and systemic sclerosis; [0098] (3) (skin and eyes)
psoriasis, atopical dermatitis, contact dermatitis, other eczmatous
dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus,
bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas,
vasculitides, erythemas, cutaneous eosinophilias, chronic skin
ulcers, uveitis, Alopecia greatacorneal ulcer and vernal
conjunctivitis; [0099] (4) (gastrointestinal tract) Coeliac
disease, proctitis, eosinopilic gastro-enteritis, mastocytosis,
Crohn's disease, ulcerative colitis, irritable bowel disease;
food-related allergies which have effects remote from the gut,
(such as migraine, rhinitis and eczema); [0100] (5) (central and
peripheral nervous system) Neurodegenerative diseases and dementia
disorders (such as Alzheimer's disease, amyotrophic lateral
sclerosis and other motor neuron diseases, Creutzfeldt-Jacob's
disease and other prion diseases, HIV encephalopathy (AIDS dementia
complex), Huntington's disease, frontotemporal dementia, Lewy body
dementia and vascular dementia), polyneuropathies (such as
Guillain-Barre syndrome, chronic inflammatory demyelinating
polyradiculoneuropathy, multifocal motor neuropathy), plexopathies,
CNS demyelination (such as multiple sclerosis, acute
disseminated/haemorrhagic encephalomyelitis, and subacute
sclerosing panencephalitis), neuromuscular disorders (such as
myasthenia gravis and Lambert-Eaton syndrome), spinal diorders
(such as tropical spastic paraparesis, and stiff-man syndrome),
paraneoplastic syndromes (such as cerebellar degeneration and
encephalomyelitis), CNS trauma, migraine and stroke. [0101] (6)
(other tissues and systemic disease) atherosclerosis, Acquired
Immunodeficiency Syndrome (AIDS), lupus erythematosus; systemic
lupus, erythematosus; Hashimoto's thyroiditis, type I diabetes,
nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome,
lepromatous leprosy, idiopathic thrombocytopenia pupura;
post-operative adhesions, sepsis and ischemic/reperfusion injury in
the heart, brain, peripheral limbs hepatitis (alcoholic,
steatohepatitis and chronic viral), glomerulonephritis, renal
impairment, chronic renal failure and other organs [0102] (7)
(allograft rejection) acute and chronic following, for example,
transplantation of kidney, heart, liver, lung, bone marrow, skin
and cornea; and chronic graft versus host disease; [0103] (8)
Diseases associated with raised levels of PGD.sub.2 or its
metabolites.
[0104] 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.
[0105] Preferably the compounds of the invention are used to treat
diseases in which the chemokine receptor belongs to the CRTh2
receptor subfamily.
[0106] 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.
[0107] 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 to manufacture
of a medicament for use in therapy.
[0108] In a further aspect, the present invention provides the use
of a compound or formula (I), or a pharmaceutically acceptable salt
or solvate thereof, as hereinbefore defined in the manufacture of a
medicament for use in therapy in combination with drugs used to
treat asthma and rhinitis (such as inhaled and oral steroids,
inhaled O.sub.2-receptor agonists and oral leukotriene receptor
antagonists).
[0109] In a still further aspect, the present invention provides
the use of a compound of formula (I), or a pharmaceutically
acceptable salt or solvate thereof; as hereinbefore defined in the
manufacture of a medicament for the treatment of human diseases or
conditions in which modulation of CRTh2 receptor activity is
beneficial.
[0110] In the context of the present specification, the term
"therapy" also includes "prophylaxis" unless there are specific
indications to the contrary. The terms "therapeutic" and
"therapeutically" should be construed accordingly.
[0111] The invention still further provides a method of treating
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.
[0112] 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, solvate or
prodrug thereof, as hereinbefore defined.
[0113] For the above-mentioned therapeutic uses the dosage
administered will, of course, vary with the compound employed, the
mode of administration, the treatment desired and the disorder
indicated.
[0114] The compound of formula (I) and pharmaceutically acceptable
salts and solvates thereof may be used on their own but will
generally be administered in the form of a pharmaceutical
composition in which the formula (I) compound/salt/solvate (active
ingredient) is in association with a pharmaceutically acceptable
adjuvant, diluent or carrier. Depending on the mode of
administration, the pharmaceutical composition will preferably
comprise from 0.05 to 99% w (percent by weight), more preferably
from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and
even more preferably from 0.10 to 50% w, of active ingredient, all
percentages by weight being based on total composition.
[0115] The present invention also provides a pharmaceutical
composition comprising a compound 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.
[0116] The pharmaceutical compositions may be administered
topically (e.g. to the lung and/or airways or to the skin) in the
form of solutions, suspensions, heptafluoroalkane aerosols and dry
powder formulations; or systemically, e.g. by oral administration
in the form of tablets, capsules, syrups, powders or granules, or
by parenteral administration in the form of solutions or
suspensions, or by subcutaneous administration or by rectal
administration in the form of suppositories or transdermally.
Preferably the compound of the invention is administered
orally.
[0117] 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 to (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:
[0118] EtOAc Ethylacetate [0119] DMF N,N-Dimethyl formamide [0120]
NMP N-methylpyrrolidine [0121] THF tetrahydrofuran [0122] RT room
temperature [0123] trifluoroacetic acid [0124] MCPBA
meta-chloroperbenzoic acid
EXAMPLE 1
3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid
[0125] (a) 3-[(4-chlorophenyl)thio]-2,5-dimethyl-1H-indole
[0126] To a solution of methylphenylhydrazine (7 g) in acetonitrile
(100 ml) was added 1-[(4-chlorophenyl)thio]acetone (8.84 g) and
water (10 ml). The mixture was stirred at room temperature
overnight. The reaction mixture was concentrated in vacuo and the
residue dissolved in dichloromethane. The solution was washed with
sodium hydrogen carbonate, brine, dried (MgSO.sub.4) and
concentrated in vacuo. The residue was recrystallised (methanol) to
give the sub-title compound (6 g).
[0127] MS: APCI+ [M+H] 288
(b) 3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole
[0128] The product of example 1 step (a) (1.85 g) was dissolved in
dichloromethane (20 ml) at 0.degree. C., to this solution MCPBA
(2.85 g) was added and stirred for 2 hours. The reaction mixture
was then washed with sodium carbonate solution, the organic
extracts were dried with MgSO.sub.4. Purification by Flash column
chromatography (35% EtOAc/hexane as eluent) gave of the sub-title
compound (1.27 g).
[0129] MS: ES+ [M+H] 320
(c) 3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid, ethyl ester
[0130] The product of step (b) (1.27 g) was dissolved in THF (20
ml) at .degree. C. and NaH (0.115 g, 60% dispersion in oil) was
added and stirred for 30 min. Ethylbromoacetate (0.66 ml) was then
added and stirred for 1 h at room temperature. Ethanol was added to
quench the reaction, the solvent was removed and the product washed
with water and extracted with EtOAc. Purification by Flash column
chromatography (30% EtOAc/hexane as eluent) gave the sub-title
compound (0.716 g).
[0131] MS: ES+[M+H] 406
(d) 3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid
[0132] The product of step (c) was dissolved in ethanol (10 ml) and
10% NaOH (aq) (10 ml) was added and stirred for 1 h. The reaction
mixture was then acidified with HCl (aq), and extracted with EtOAc.
Purification by solid phase extraction using NH.sub.2 sorbent (2
g), eluting with acetonitrile followed by 10% acetic
acid/acetonitrile, gave the title compound (0.301 g).
[0133] MS: ES- [M-H] 376
[0134] .sup.1H NMR (DMSO) .delta. 2.42 (3H, s), 2.62 (3H, s), 4.68
(2H, s), 7.01 (1H, dd), 7.29-7.33 (1H, m), 7.58-7.62 (2H, m),
7.65-7.69 (1H, m), 7.87-7.93 (2H, m).
EXAMPLE 2
5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid
a) 5-chloro-3-[4(-chlorophenyl)sulfonyl]-2-methyl-1H-indole
[0135] To a suspension of (4-chlorophenyl)-hydrazine hydrochloride
(2 g) in acetic acid (30 ml) was added
1-[(4-chlorophenyl)thio]-acetone (2.24 g), acetonitrile (20 ml) and
water (10 ml). The mixture was strirred at room temperature
overnight. The reaction mixture was concentrated in vacuo and the
residue suspended in EtOAc, washed with sodium hydrogen carbonate
solution, brine, dried (MgSO.sub.4) and concentrated in vacuo. The
residue was dissolved in acetic acid (20 ml) and heated to
80.degree. C. overnight. The reaction mixture was poured into
water, basified using NaOH and the organics extracted into EtOAc.
The EtOAc was washed with brine, dried (MgSO.sub.4) and
concentrated in vacuo. Purification by Flash column chromatography
(20% EtOAc/hexane as eluent) gave the sub-title compound (2.2
g).
[0136] .sup.1H NMR (CDCl.sub.3) .delta. 8.31 (1H, s), 7.48 (1H, d),
7.26 (2H, m), 7.13 (3H, m), 6.93 (2H, m), 2.51 (3H, s).
b) 5-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid, methyl ester
[0137] To a solution of the product of step (a) (0.2 g) in THF (5
ml) was added 1M sodium bis(trimethylsilyl)amide solution in THF
(0.65 ml). The mixture was stirred for 30 min before bromo-acetic
acid, methyl ester (62 .mu.l) was added, the reaction was stirred
at room temperature overnight. A further 0.3 ml of 1.0M sodium
bis(trimethylsilyl)amide solution in THF and 30 .mu.l of methyl
bromoacetate was added to the mixture and was stirred for a further
3 h. The mixture was then adsorbed onto silica and purified by
Flash column chromatography (14% EtOAc/hexane as eluent) to give
sub-title compound (0.21 g).
[0138] .sup.1H NMR (CDCl.sub.3) d 7.52 (1H, d), 7.27 (1H, d),
7.20-7.10 (3H, m), 6.97-6.89 (2H, m), 4.80 (2H, d), 3.79 (3H, d),
2.47 (3H, d).
c)
5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid, methyl ester
[0139] To a solution of the product of step (b) (0.1 g) in
dichloromethane (5 ml) was added MCPBA (121 mg). The mixture was
stirred at room temperature overnight. The reaction was diluted
with dichloromethane (10 ml), washed with sodium hydrogen carbonate
solution, brine, dried (MgSO.sub.4) and concentrated in vacuo to
give sub-title compound (0.1 g). Used in step (d) without further
purification and characterisation.
d)
5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid
[0140] To a solution of the product from step (c) (0.09 g) in THF
(5 ml) was added a 1.25 M solution of NaOH(aq) (0.25 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 was isolated by
filtration, dried under vacuum at 40.degree. C. to give the title
compound.
[0141] MS: APCI-[M-H] 398
[0142] .sup.1H NMR (DMSO) .delta. 7.94 (2H, m), 7.89 (1H, d),
7.67-7.62 (3H, m), 7.29 (1H, m), 5.12 (2H, s), 2.63 (3H, s).
EXAMPLE 3
6-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid
a) 6-chloro-3-[4(-chlorophenyl)thio]-2-methyl-1H-indole
[0143] The subtitle compound was prepared by the method of example
2 part (a) using (3-chlorophenyl)-hydtazine hydrochloride. Product
purified using Flash column chromatography (10% EtOAc/hexane as
eluent).
[0144] .sup.1H NMR (CDCl.sub.3) .delta. 8.27 (1H, s) 7.39 (1H, d)
7.34 (1H, d), 7.10 (3H, m), 6.92 (2H, m), 2.50 (3H, s).
b) 6-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid, methyl ester
[0145] The sub-title compound was prepared by the method of example
2 part (b) using the product from part (a). .sup.1H NMR
(CDCl.sub.3) .delta. 7.43 (1H, d), 7.27-7.25 (1H, m), 7.14-7.09
(3H, m), 6.92 (2H, dd), 4.85 (2H, s), 3.80 (3H, d), 2.46 (3H,
d).
c)
6-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid, methyl ester
[0146] The sub-title compound was prepared by the method of example
2 part (c) using the product from part (b). Used in step (d)
without further purification or characterisation.
d)
6-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid
[0147] The title compound was prepared by the method of example 2
part (d) using the product from part (c).
[0148] MS: ES- [M-H] 398
[0149] .sup.1H NMR (DMSO) .delta. 7.94-7.89 (3H, m), 7.80 (1H, d)
7.64 (2H, m), 7.27 (1H, m), 5.13 (2H, s), 2.63 (3H, s).
EXAMPLE 4
7-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid
a) 7-chloro-3-[4(-chlorophenyl)thio]-2-methyl-1H-indole
[0150] The subtitle compound was prepared by the method of example
2 part (a) using (2-chlorophenyl)-hydrazine hydrochloride. .sup.1H
NMR (CDCl.sub.3) .delta. 8.48 (1H, s) 7.40 (1H, d), 7.19 (1H, m)
7.13-7.11 (2H, m), 7.06 (1H, t), 6.96-6.92 (2H, m), 2.55 (3H,
s).
b) 7-chloro-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid, methyl ester
[0151] The sub-title compound was prepared by the method of example
2 part (b) using the product from step (a).
[0152] .sup.1H NMR (CDCl.sub.3) .delta. 7.44 (1H, d), 7.18-7.09
(3H, m), 7.03 (1H, td), 6.92 (2H, dd), 5.37 (2H, d), 3.81 (3H, d),
2.46 (3H, d).
c)
7-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid, methyl ester
[0153] The sub-title compound was prepared by the method of example
2 part (c) using the product from step (b). Used in step (d)
without further purification or characterisation.
d)
7-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid
[0154] The title compound was prepared by the method of example 2
part (d) using the product from part (c).
[0155] MS: ES- [M-H] 398
[0156] .sup.1H NMR (DMSO) .delta. 7.96-7.93 (3H, m), 7.65 (2H, m),
7.30 (1H, m), 7.22 (1H, t) 5.32 (2H, s), 2.70 (3H, s).
EXAMPLE 5
5-chloro-3-[(4-chlorophenyl)sulfonyl]-4-cyano-2-methyl-4H-indole-1-acetic
acid
a)
3-[(4-chlorophenyl)thio]-2,5-dimethyl-1H-indole-4-carbonitrile
[0157] A stirred solution of 1-[(4-chlorophenyl)thio]-acetone (6.14
g) in dry dichloromethane (150 ml) at -78.degree. C. was treated
with sulphuryl chloride (2.25 ml). After 30 min a prepared solution
of N,N,N',N'-tetramethyl-1,8-naphthalenediamine (6.01 g) and
5-amino-2-chloro-benzonitrile (3.89 g) in dry dicholoromethane (80
ml) was added dropwise over 30 min. The mixture was stirred for a
further 2 h, after which triethylamine (4.26 ml) was added and the
reaction allowed to reach room temperature. The reaction mixture
was diluted with dichloromethane (200 ml), washed with water, 1N
HCl and brine. The organic phase was dried (MgSO.sub.4), evaporated
in vacuo, and the residue purified by flash column chromatography
eluting with iso-hexane and ethyl acetate (1:1) to give the
sub-title compound (1 g), and the regioisomer (600 mg) used in
example 6 below.
[0158] .sup.1H NMR CDCl.sub.3: .delta. 12.52 (s, 1H), 7.74 (d, 1H),
7.38 (dd, 1H), 7.29 (m, 2H), 6.97 (m, 2H), 3.29 (s, 3H).
b) 3-[(4-chlorophenyl)thio]-4-cyano-2,5-dimethyl-1H-indole-1-acetic
acid, methyl ester
[0159] The sub-title compound was prepared by the method of example
1 part (c) using the product of part (a).
[0160] .sup.1H NMR CDCl.sub.3: .delta. 7.37 (1H, d), 7.30 (1H, d),
7.18-7.13 (2H, m), 7.00-6.96 (2H, m), 4.92 (2H, m), 3.80 (3H, m),
2.55 (3H, s).
c)
5-chloro-3-[(4-chlorophenyl)sulfonyl]-4-cyano-2-methyl-1H-indole-1-acet-
ic acid, methyl ester
[0161] The sub-title compound was prepared by the method if example
1 part (b) from the product of part (b).
(d)
5-Chloro-3-[(4-chlorophenyl)sulfonyl]-4-cyano-2-methyl-1H-indole-1-ace-
tic acid
[0162] The title compound was prepared by the method of example 1
part (d) using the product of part (c).
[0163] .sup.1H NMR DMSO: .delta. 2.81 (3H, s), 5.29 (2H, s), 7.62
(1H, s), 7.7 (2H, m), 7.98 (2H, m) and 8.08 (1H, d).
[0164] MS: APCI+ [M+H] 422
EXAMPLE 6
5-chloro-3-[(4-chlorophenyl)sulfonyl]-6-cyano-2-methyl-1H-indole-1-acetic
acid
a)
5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-6-carbonitrile
[0165] Obtained from example 5 part (a)
[0166] .sup.1H NMR CDCl.sub.3: .delta. 8.68 (1H, s), 7.69 (1H, s),
7.61 (1H, s), 7.15 (2H, dt), 6.91 (2H, dt), 2.57 (3H, s).
b)
5-chloro-3-[(4-chlorophenyl)sulfonyl]-6-cyano-2-methyl-1H-indole-1-acet-
ic acid
[0167] Prepared by the method of example 2 part (d) to give the
title compound as a white solid.
[0168] .sup.1H NMR DMSO: .delta. 8.42 (1H, s), 7.59 (1H, s), 7.3
(2H, dt), 6.99 (2H, dt), 5.24 (2H, s), 2.46 (3H, s).
[0169] M.pt 256-258.degree. C.
[0170] MS: APCI [M-H] 389
EXAMPLE 7
3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic
acid
a) 3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic
acid, ethyl ester
[0171] MCPBA (1.07 g) was added to a solution of example 1 part a)
(1.79 g) in dichloromethane (20 ml) at 0.degree. C. The reaction
mixture was stirred for 1 h, after which further mCPBA (53 mg) was
added and stirred for a further 30 min. The reaction mixture was
allowed to reach room temperature and the sub-title compound was
obtained as a white solid after filtration (0.68 g). Used directly
in the next step without further purification.
b) 3-[(4-chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic
acid
[0172] NaH (0.13 g, 60% dispersion in mineral oil) was added to the
product from part (a) (0.685 g) in THF at 0.degree. C. The reaction
mixture was stirred for 30 min and then ethyl bromoacetate (0.26
ml) was added and the mixture stirred for 1 h. Ethanol was added
and then concentrated in vacuo. The product was extracted with
EtOAc, dried (MgSO.sub.4) and concentrated in vacuo to give a white
solid (761 mg). The solid was dissolved in ethanol (15 ml), NaOH
(10% solution, 5 ml) and then the solution stirred overnight. The
reaction mixture was acidified (dilute HCl) and extracted with
EtOAC. The organic phase was dried (MgSO.sub.4) and concentrated in
vacuo. The product was purified with amine resin, eluting with MeCN
and then 5% acetic acid in MeCN to give the title compound (60
mg).
[0173] .sup.1H NMR DMSO: .delta. 7.61 (4H, s), 7.2-7.25 (1H, m),
6.88-6.91 (1H, m), 6.88-6.86 (1H, m), 4.43 (2H, s), 2.57 (3H, s)
and 2.21 (3H, s).
EXAMPLE 8
3-[(4-chlorophenyl)sulfonyl]-4-(ethylsulfonyl)-7-methoxy-2-methyl-4H-indol-
e-1-acetic acid
a)
3-[(4-chlorophenyl)thio]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole
[0174] Prepared by the method of example 5 part (a) from
5-(ethylsulfonyl)-2-methoxy-benzenamine.
[0175] .sup.1H NMR CDCl.sub.3: .delta. 9.00 (1H, s), 7.91 (1H, d),
7.12 (2H, dd), 6.86 (2H, m), 6.73 (1H, d), 4.05 (3H, s), 3.46 (2H,
q), 2.46 (3H, s) and 1.16 (3H, t).
b)
3-[(4-chlorophenyl)thio]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-indole-
-1-acetic acid, methyl ester
[0176] Prepared by the method of example 5 part (b), using the
product of sterp (a.)
[0177] .sup.1H NMR CDCl.sub.3: .delta. 7.92 (1H, d), 7.13 (2H, dt),
6.85 (2H, dt), 6.73 (1H, d), 5.27 (2H, s), 3.98 (3H, s), 3.79 (3H,
s), 3.48 (2H, q), 2.38 (3H, s) and 1.18 (3H, t).
c)
3-[(4-chlorophenyl)sulfonyl]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-in-
dole-1-acetic acid, methyl ester
[0178] Prepared by the method of example 5 part (c) using the
product of step (b).
[0179] MS: ES+ [M+H] 435
d)
3-[(4-chlorophenyl)sulfonyl]-4-(ethylsulfonyl)-7-methoxy-2-methyl-1H-in-
dole-1-acetic acid
[0180] Prepared by the method of example 5 part (d) using the
product of step (c).
[0181] .sup.1H NMR DMSO: .delta. 7.79 (1H, d), 7.73 (2H, d), 7.58
(2H, d), 7.04 (1H, d), 5.07 (2H, s), 3.95 (3H, s), 3.58 (2H, q),
2.66 (3H, s) and 1.23 (3H, t).
EXAMPLE 9
3-[(4-chlorophenyl)sulfinyl]-5-cyano-2-methyl-1H-indole-1-acetic
acid
a) 3-[(4-chlorophenyl)thio]-5-cyano-2-methyl-1H-indole
[0182] To a stirred solution of 4-aminobenzonitrile (5 g) in
dichloromethane (150 ml) cooled to -70.degree. C. was added t-butyl
hypochlorite (4.6 g) dropwise over 5 mins. The reaction was stirred
for 10 mins before 1-[4-chlorophenyl)thio]-2-propanone (8.49 g) was
added as a solution in dichloromethane (20 ml). After 1 h
triethylamine (5.9 ml) was added and the reaction allowed to warm
to room temperature. The reaction was diluted with dichloromethane,
washed with HCl (aq), brine, dried over MgSO.sub.4, and
concentrated in vacuo to give a brown solid. Purification by
recystallisation from Methanol gave the subtitle compound (7.5
g).
[0183] .sup.1H NMR (CDCl.sub.3) .delta. 8.61 (s, 1H), 7.84 (s, 1H),
7.44 (dd, 1H), 7.41 (d, 1H), 7.19-7.08 (m, 2H), 6.93 (dd, 2H), 2.56
(s, 3H).
b) 3-[(4-chlorophenyl)thio]-5-cyano-2-methyl-1H-indole-acetic acid,
ethyl ester
[0184] The subtitle compound was prepared by the method of example
5 part (b) using the product from part (a) and ethyl bromoacetate.
The product was used without further characterisation in part
(c).
c) 3-[(4-chlorophenyl)sulfinyl]-5-cyano-2-methyl-1H-indole-1-acetic
acid, methyl ester
[0185] mCPBA (128 mg) was added to the product of part (b) (200 mg)
in dichloromethane (10 ml), and stirred overnight. The solution was
washed (NaHCO.sub.3), brine, then dried (MgSO.sub.4) and
concentrated in vacuo to give the subtitle compound as a white
solid (170 mg).
d) 3-[(4-chlorophenyl)sulfinyl]-5-cyano-2-methyl-1H-indole-1-acetic
acid
[0186] The title compound was prepared by the method of example 5
part (d) using the product of step (c).
[0187] .sup.1H NMR (DMSO) .delta. 7.69-7.57 (m, 6H), 7.51 (dd, 1H),
4.85 (dd, 2H) and 2.63 (s, 3H)
EXAMPLE 10
3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic
acid
a) 1H-indole-1-acetic acid,
3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic
acid, methyl ester
[0188] The sub-title compound was prepared by the method of example
5 part (c) using the product of example 9 part (b).
[0189] .sup.1H NMR (DMSO) .delta. 8.35 (d, 1H), 8.03 (dt, 2H), 7.82
(d, 1H), 7.71-7.62 (m, 3H), 5.32 (s, 2H), 4.15 (q, 2H), 2.67 (s,
3H) and 1.18 (td, 3H)
b) 1H-indole-1-acetic acid,
3-[(4-chlorophenyl)sulfonyl]-5-cyano-2-methyl-1H-indole-1-acetic
acid
[0190] The title compound was prepared by the method of example 5
part (d) using the product of step (a)
[0191] .sup.1H NMR (DMSO) .delta. 8.35 (d, 1H), 8.05-8.01 (m, 2H),
7.82 (d, 1H), 7.69-7.63 (m, 3H), 5.20 (s, 2H) and 2.67 (s, 3H).
EXAMPLE 11
Sodium
5-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetate
[0192] Sodium hydroxide (1M, 4.3 ml) was added to a solution of the
product of example 1 part (c) (1.75 g) in THF (60 ml). The reaction
mixture was stirred overnight and then concentrated in vacuo. The
residue was recrystallised from water to give the title compound as
a white solid.
[0193] .sup.1H NMR (DMSO) .delta. 7.89 (dd, 2H), 7.66 (d, 1H), 7.61
(m, 2H), 7.26 (d, 1H.), 6.99 (1H, dd), 4.39 (s, 2H), 2.59 (s, 3H)
and 2.4 (s, 3H).
EXAMPLE 12
4-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid
##STR00016##
[0194] a) 4-chloro-3-[4(-chlorophenyl)thio]-2-methyl-1H-indole
[0195] The subtitle compound was prepared by the method of example
2 part (a) using (3-chlorophenyl)-hydrazine hydrochloride. Product
purified using Flash column chromatography (10% EtOAc/hexane as
eluent).
[0196] .sup.1H NMR (CDCl.sub.3) .delta. 8.38 (1H, s), 7.27-7.24
(2H, m), 7.15-7.11 (2H, m), 7.09-7.08 (1H, m), 6.96 (2H, dt), 2.52
(3H, s)
b) 4-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole
[0197] The subtitle compound was prepared by the method of example
1 part (b) using the product from part (a). Product was purified
using Flash column chromatography (33% EtOAc/hexane as eluent).
.sup.1H NMR (DMSO) .delta. 12.57 (1H, s), 7.83 (2H, dt), 7.60 (2H,
dt), 7.41 (1H, dd), 7.18-7.08 (2H, m), 2.80 (3H, s)
c)
4-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid, ethyl ester
[0198] The subtitle compound was prepared by the method of example
1 part (c) using the product from part (b). Product was purified
using Flash column chromatography (33% EtOAc/hexane as eluent).
[0199] .sup.1H NMR (DMSO) .delta. 7.80 (2H, dt), 7.63 (3H, m),
7.25-7.16 (2H, m), 5.36 (2H, s), 4.20, (2H, q), 2.81 (3H, s), 1.23
(3H, t).
d)
4-chloro-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid
[0200] The title compound was prepared by the method of example 2
part (d) using the product from part (c). Product was purified
using reverse phase preparative HPLC (eluent
MeCN/NH.sub.3(aq)).
[0201] .sup.1H NMR (DMSO) .delta. 7.79 (2H, dt), 7.62 (2H, dt),
7.52 (1H, dd), 7.19-7.11 (2H, m), 4.84 (2H, s), 2.78 (3H, s).
[0202] APCI- (M-H) 395.
EXAMPLE 13
3-[(4-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid
##STR00017##
[0203] a) 2,5-dimethyl-1H-indol-1-acetic acid
[0204] 60% sodium hydride/oil (0.64 g) was added to a solution of
2,5-dimethyl-1H-indole (2.0 g) in DMF (15 ml). After 15 min ethyl
bromoacetate (2.7 ml) was added quickly and the reaction stirred
for 20 min. The mixture was quenched with 1% aqueous acetic acid
(100 ml), extracted with ethyl acetate (2.times.100 ml) and washed
with water (2.times.50 ml) and brine (20 ml). The extracts were
dried (MgSO.sub.4), filtered and evaporated in vacuo to yield a
brown solid. The solid was dissolved in EtOH (20 ml) and aqueous
sodium hydroxide (1M, 10 ml) added. After 1 h the solution was
adjusted to pH6 with aqueous hydrochloric acid (1M, .about.10 ml),
and then evaporated in vacuo. The residue was purified by flash
column chromatography (gradient 1-10% methanol in dichloromethane).
The sub-title compound was obtained as a red/brown solid (1.3
g).
[0205] MS: APCI+ [M+H] 204
[0206] .sup.1H NMR .delta..sub.(DMSO) 7.22-7.17 (2H, m), 6.85 (1H,
d), 6.11 (1H, s), 4.87 (2H, s), 2.34 (3H, s), 2.30 (3H, s)
b) 3-[(4-methoxyphenyl)thio]-2,5-dimethyl-1H-indol-1-acetic acid,
ammonium salt
[0207] Iodine (0.51 g) was added to a solution of
4-methoxylbenzenethiol (0.25 g) and the product from example 13
step a) (0.2 g) in DMF (5 ml). After 1 h the solution was purified
by reverse phase HPLC. The solvent was evaporated in vacuo and the
oily residue treated with ether to give a solid. Filtered off and
dried to yield the title compound as a white solid (0.27 g).
[0208] MS (APCI-) 340 [(M-NH.sub.4)--H].sup.-
[0209] .sup.1H NMR .delta..sub.(DMSO) 7.24 (1H, d), 7.15 (1H, s),
6.95 (2H, d), 6.90 (1H, d), 6.78 (2H, d), 4.60 (2H, s), 3.66 (3H,
s), 2.38 (3H, s), 2.33 (3H, s)
c) 3-[(4-methoxyphenyl)sulfonyl]-2,5-Dimethyl-1H-indol-1-acetic
acid
[0210] 3-Chlorobenzenecarboperoxoic acid (0.44 g) was added to a
solution of the product from example 13 step ii) (0.2 g) in
acetonitrile (4 ml). The reaction was stirred for 1 h, 1M aqueous
sodium thiosulphate (2 ml) added and stirred for a further 15 min.
The mixture was filtered, purified by reverse phase HPLC and
evaporated in vacuo to yield the title compound as a white solid
(98 mg).
[0211] MS: APCI- [M-H] 372
[0212] .sup.1H NMR .delta..sub.(DMSO) 7.83 (2H, d), 7.69 (1H, s),
7.33 (1H, d), 7.09-6.98 (1H, m), 7.06 (2H, d), 4.79 (3H, s), 3.78
(3H, s), 2.59 (3H, s), 2.40 (3H, s)
EXAMPLE 14
3-[(3-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid
##STR00018##
[0213] a) 3-[(3-methoxyphenyl)thio]-2,5-dimethyl-1H-indol-1-acetic
acid
[0214] Iodine (0.51 g) was added to a solution of
3-methoxylbenzenethiol (0.25 g) and the product from example 13
step i) (0.2 g) in DMF (5 ml). After 1 h the solution was purified
by reverse phase HPLC. The solvent was evaporated in vacuo and the
oily residue treated with ether to give a solid. Filtered off and
dried to yield the title compound as a white solid (0.22 g).
[0215] MS: APCI- [M-H] 340
[0216] .sup.1H NMR .delta..sub.(DMSO) 7.40 (1H, d), 7.16 (1H, s),
7.11 (1H, t), 6.98 (1H, d), 6.63 (1H, d), 6.55 (1H, d), 6.45 (1H,
s), 5.08 (2H, s), 3.61 (3H, s), 2.39 (3H, s), 2.34 (3H, s)
b) 3-[(3-methoxyphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid
[0217] 3-Chlorobenzenecarboperoxoic acid (0.4 g) was added to a
solution of the product from example 14 step i) (0.18 g) in
acetonitrile (4 ml). The reaction was stirred for 1 h, 1M aqueous
sodium thiosulphate (2 ml) added and stirred for a further 15 min.
The mixture was filtered, purified by reverse phase HPLC and
evaporated in vacuo to yield the title compound as a white solid
(70 mg).
[0218] MS: APCI- [M-H] 372
[0219] .sup.1H NMR .delta..sub.(DMSO) 7.69 (1H, s), 7.48-7.43 (2H,
m), 7.36-7.32 (1H, m), 7.31 (1H, d), 7.18-7.11 (1H, m), 7.01 (1H,
d), 4.66 (2H, s), 3.78 (3H, s), 2.61 (3H, s), 2.40 (3H, s)
EXAMPLE 15
3-[(2-Chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid
##STR00019##
[0220] a) 3-[(2-Chlorophenyl)thio]-2,5-dimethyl-1H-indol-1-acetic
acid, sodium salt
[0221] Iodine (0.22 g) was added to a solution of
2-chlorobenzenethiol (0.13 g) and the product from example 13 step
a) (015 g) in EtOH (5 ml). After 1 h the solution was purified by
reverse phase HPLC. The solvent was evaporated in vacuo to yield
the product as a colourless oil. The oil was then dissolved in MeOH
(10 ml) treated with aqueous sodium hydroxide (1M, 0.52 ml) and
evaporated in vacuo to yield the sodium salt as a white solid (0.13
g).
[0222] MS: APCI- [M-Na] 344
[0223] .sup.1H NMR .delta..sub.(DMSO) 7.28-7.15 (2H, m), 7.13-7.06
(2H, m), 6.97-6.88 (3H, m), 4.42 (2H, s), 2.36 (3H, s), 2.33 (3H,
s)
b) 3-[(2-Chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid
[0224] 3-Chlorobenzenecarboperoxoic acid (0.14 g) was added to a
solution of the product from example 15 step a) (0.07 g) in
acetonitrile (2 ml) and water (0.5 ml). The reaction was stirred
for 1 h, 1M aqueous sodium thiosulphate (2 ml) added and stirred
for a further 15 min. The mixture was filtered, purified by reverse
phase HPLC and evaporated in vacuo to yield the title compound as a
white solid (11 mg).
[0225] MS APCI- [M-H] 376
[0226] .sup.1H NMR .delta..sub.(DMSO) 8.32-8.25 (1H, m), 7.64-7.52
(3H, m), 7.39 (1H, s), 7.34 (1H, d), 6.99 (1H, d), 4.73 (2H, s),
2.59 (3H, s), 2.32 (3H, s)
EXAMPLE 16
3-[(3-Chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid
##STR00020##
[0227] a) 3-[(3-Chlorophenyl)thio]-2,5-dimethyl-1H-indol-1-acetic
acid, sodium salt
[0228] Iodine (0.29 g) was added to a solution of
3-chlorobenzenethiol (0.175 g) and the product from example 13 step
a) (0.2 g) in EtOH (5 ml). After 1 h the solution was purified by
reverse phase HPLC. The solvent was evaporated in vacuo to yield
the product as a colourless oil. The oil was then dissolved in MeOH
(10 ml) treated with aqueous sodium hydroxide (1M, 0.52 ml) and
evaporated in vacuo to yield the sodium salt as a white solid (0.19
g).
[0229] MS (APCI-) 344 [(M-Na)-H].sup.-
[0230] .sup.1H NMR .delta..sup.(DMSO) 7.28-7.15 (2H, m), 7.13-7.06
(2H, m), 6.97-6.88 (3H, m), 4.42 (2H, s), 2.36 (3H, s), 2.33 (3H,
s)
b) 3-[(3-Chlorophenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid
[0231] 3-Chlorobenzenecarboperoxoic acid (0.32 g) was added to a
solution of the product from is example 16 step a) (0.16 g) in
acetonitrile (4 ml) and water (1 ml). The reaction was stirred for
1 h, 1M aqueous sodium thiosulphate (2 ml) added and stirred for a
further 15 min. The mixture was filtered, purified by reverse phase
HPLC and evaporated in vacuo to yield the title compound as a white
solid (65 mg).
[0232] MS APCI-[M-H].sup.- 376
[0233] .sup.1H NMR .delta..sub.(DMSO) 7.87 (2H, d), 7.68 (2H, d),
7.63-7.56 (1H, m), 7.36 (1H, d), 7.04 (1H, d), 4.79 (2H, s), 2.62
(3H, s), 2.41 (3H, s)
EXAMPLE 17
3-[(4-Cyanophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic
acid
##STR00021##
[0235] a) 3-[(4-Cyanophenyl)thio]-2,5-dimethyl-1H-indol-1-acetic
acid, ammonium salt
[0236] Iodine (0.51 g) was added to a solution of
4-cyanobenzenethiol (0.27 g) and the product from example 13 step
a) (0.2 g) in DMF (5 ml). After 1 h the solution was purified by
reverse phase HPLC. The solvent was evaporated in vacuo and the
oily residue treated with ether to give a solid. Filtered off and
dried to yield the title compound as a white solid (0.25 g).
[0237] MS APCI-[(M-NH.sub.4)-H].sup.- 334
[0238] .sup.1H NMR .delta..sub.(DMSO) 7.62 (2H, d), 7.35 (1H, d),
7.10 (1H, s), 7.08 (2H, d), 6.97 (1H, d), 4.80 (2H, s), 2.36 (3H,
s), 2.32 (3H, s)
b) 3-[(4-Cyanophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic
acid
[0239] 3-Chlorobenzenecarboperoxoic acid (0.44 g) was added to a
solution of the product from example 17 step a) (0.21 g) in
acetonitrile (4 ml). The reaction was stirred for 1 h, 1M aqueous
sodium thiosulphate (2 ml) added and stirred for a further 15 min.
The mixture was filtered, purified by reverse phase HPLC and
evaporated in vacuo to yield the title compound as a white solid
(58 mg).
[0240] MS (APCI-) [M-H].sup.- 367
[0241] .sup.1H NMR .delta..sub.(DMSO) 8.04 (4H, dd), 7.69 (1H, s),
7.36 (1H, d), 7.04 (1H, d), 4.76 (2H, s), 2.61 (3H, s), 2.41 (3H,
s)
EXAMPLE 18
3-[(2-methylphenyl)sulfonyl]-2,5-Dimethyl-1H-indol-1-acetic
acid
##STR00022##
[0243] a) 3-[(2-methylphenyl)thio]-2,5-dimethyl-1H-indol-1-acetic
acid, ammonium salt
[0244] Iodine (0.29 g) was added to a solution of
2-methylbenzenethiol (0.16 g) and the product from example 13 step
a) (0.2 g) in DMF (5 ml). After 1 h the solution was purified by
reverse phase HPLC. The solvent was evaporated in vacuo and the
oily residue treated with ether to give a solid. Filtered off and
dried to yield the title compound as a white solid (0.19 g).
[0245] MS APCI- [(M--NH.sub.4)--H].sup.- 324
[0246] .sup.1H NMR .delta..sub.(DMSO) 7.24 (1H, d), 7.15 (1H, d),
7.07 (1H, s), 6.97-6.86 (3H, m), 6.47 (1H, d), 4.49 (2H, s), 2.42
(3H, s), 2.33 (3H, s), 2.31 (3H, s)
b) 3-[(2-methylphenyl)sulfonyl]-2,5-Dimethyl-1H-indol-1-acetic
acid
[0247] 3-Chlorobenzenecarboperoxoic acid (0.32 g) was added to a
solution of the product from example 18 step a) (0.14 g) in
acetonitrile (4 ml). The reaction was stirred for 1 h, 1M aqueous
sodium thiosulphate (2 ml) added and stirred for a further 15 min.
The mixture was filtered, purified by reverse phase HPLC and
evaporated in vacuo to yield the title compound as a white solid
(65 mg).
[0248] MS APCI- [M-H]- 356
[0249] .sup.1H NMR .delta..sub.(DMSO) 8.05 (1H, d), 7.54-7.40 (2H,
m), 7.44 (1H, s), 7.40 (1H, d), 7.31 (1H, d), 7.01 (1H, d), 4.94
(2H, s), 2.54 (3H, s), 2.38 (3H, s), 2.33 (3H, s)
EXAMPLE 19
3-[(2-ethylphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic acid
##STR00023##
[0250] a) 3-[(2-ethylphenyl)thio]-2,5-dimethyl-1H-indol-1-acetic
acid, ammonium salt
[0251] Iodine (0.44 g) was added to a solution of
2-ethylbenzenethiol (0.32 g) and the product from example 13 step
a) (0.2 g) in DMF (5 ml). After 1 h the solution was purified by
reverse phase HPLC. The solvent was evaporated in vacuo and the
oily residue treated with ether to give a solid. Filtered off and
dried to yield the title compound as a white solid (0.18 g).
[0252] MS (APCI-) 338 [(M--NH.sub.4)--H].sup.-
[0253] .sup.1H NMR .delta..sub.(DMSO) 7.26 (1H, d), 7.16 (1H, d),
7.08 (1H, s), 7.01-6.85 (3H, m), 6.48 (1H, d), to 4.57 (2H, s),
2.83 (2H, q), 2.34 (3H, s), 2.31 (3H, s), 1.31 (3H, t)
b) 3-[(2-ethylphenyl)sulfonyl]-2,5-dimethyl-1H-indol-1-acetic
acid
[0254] 3-Chlorobenzenecarboperoxoic acid (0.32 g) was added to a
solution of the product from example 19 step a) (0.14 g) in
acetonitrile (4 ml). The reaction was stirred for 1 h, 1M aqueous
sodium thiosulphate (2 ml) added and stirred for a further 15 min.
The mixture was filtered, purified by reverse phase HPLC and
evaporated in vacuo to yield the title compound as a white solid
(45 mg).
[0255] MS APCI- [M-H]- 370
[0256] .sup.1H NMR .delta..sub.(DMSO) 7.95 (1H, d), 7.58-7.50 (1H,
m), 7.47 (1H, s), 7.44-7.34 (3H, m), 7.00 (1H, d), 4.81 (2H, s),
2.87 (2H, q), 2.51 (3H, s), 2.33 (3H, s), 0.94 (3H, t)
EXAMPLE 20
3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-nitro-1H-indole-1-acetic
acid
##STR00024##
[0257] a) 3-[(4-chlorophenyl)thio]-2-methyl-4-nitro-1H-indole
[0258] To a stirred solution of 3-nitroaniline (8 g) in THF (700
ml) cooled to -78.degree. C. was added t-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 tetrahydrofuran (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
subtitle compound (5.8 g).
[0259] .sup.1H NMR (DMSO) 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)
b) 3-[(4-chlorophenyl)thio]-2-methyl-4-nitro-1H-indole-acetic acid,
ethyl ester
[0260] 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 (a) (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 boiling ethanol gave the subtitle
compound (5 g).
[0261] .sup.1H NMR (DMSO) 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).
c) 3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-nitro-1H-indole-acetic
acid, ethyl ester
[0262] To a solution of the product from part (b) (0.2 g) in
dichloromethane (10 ml) was added MCPBA (0.245 g). After string
overnight a further 20 ml of dichloromethane was added to the
reaction before the mixture was washed with sodium hydrogen
carbonate solution, brine, dried (MgSO.sub.4) and concentrated in
vacuo. The residue was used without further characterisation in
step (d).
d) 3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-nitro-1H-indole-acetic
acid
[0263] The title compound was prepared by the method of example 2
part (d) using the product from part (c). Product was purified
using reverse phase preparative HPLC (eluent
MeCN/NH.sub.3(aq)).
[0264] .sup.1H NMR (DMSO) 7.97 (1H, dd), 7.85 (2H, dt), 7.68 (2H,
m), 7.65 (1H, d), 7.40 (1H, t), 5.10 (2H, s), 2.77 (3H, s). APCI-
(M-H) 407
EXAMPLE 21
4-(Acetylamino)-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid
##STR00025##
[0265] a)
4-amino-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic acid,
ethyl ester
[0266] A suspension of the product from example 20 part (b) (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) gave the subtitle compound (1.4 g).
[0267] .sup.1H NMR (DMSO) .delta. 7.30 (dd, 2H), 7.0 (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).
[0268]
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).
[0269] .sup.1H NMR (DMSO) .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).
b)
4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-acetic
acid, ethyl ester
[0270] To a solution of the product from part (a) (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 flash column chromatography (33%
EtOAc/hexane as eluent) to give the subtitle compound (0.52 g).
[0271] .sup.1H NMR (DMSO) .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).
c)
4-(acetylamino)-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceti-
c acid, ethyl ester
[0272] The subtitle compound was prepared by the method of example
20 part (c) using the product from part (b). Used without further
characterisation in part (d).
d)
4-(acetylamino)-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-aceti-
c acid
[0273] The title compound was prepared by the method of example 2
part (d) using the product from part (c). Product was purified
using reverse phase preparative HPLC (eluent
MeCN/NH.sub.3(aq)).
[0274] .sup.1H NMR (DMSO) .delta. 10.34 (1H, s), 8.01 (1H, d), 7.77
(2H, dt), 7.67 (2H, m), 7.29 (1H, d), 7.19 (1H, t), 4.82 (2H, s),
2.66 (3H, s), 2.06 (3H, s).
[0275] APCI- (M-H) 419
EXAMPLE 22
3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-[(methylsulfonyl)amino]-1H-indole--
1-acetic acid
##STR00026##
[0277] a)
4-amino-3-[(4-chlorophenyl)sulfonyl]-2-methyl-1H-indole-1-acetic
acid, ethyl ester
[0278] A suspension of the product from example 20 part (c) (1 g)
in glacial acetic acid (50 ml) was stirred in the presence of 5%
Pt/C (0.5 g) under 3 bar pressure of H.sub.2 for 24 hours. The
catalyst was removed by filtration and the filtrates concentrated
in vacuo. Purification by flash column chromatography (20%
EtOAc/hexane as eluent) gave the subtitle compound (0.45 g).
[0279] .sup.1H NMR (DMSO) .delta. 7.89 (2H, dt), 7.66 (2H, dt),
6.96 (1H, t), 6.72 (1H, d), 6.45 (1H, d), 5.96 (2H, s), 5.13 (2H,
s), 4.14 (2H, q), 2.63 (3H, s), 1.18 (3H, t)
[0280]
3-[(4-chlorophenyl)sulfonyl]-4-(ethylamino)-2-methyl-1H-indole-1-ac-
etic acid, ethyl ester was isolated as a by product from the
reaction.
[0281] .sup.1H NMR (DMSO) .delta. 7.83 (2H, dd), 7.67 (2H, dt),
7.06 (1H, t), 6.78 (1H, d), 6.72 (1H, t), 6.31 (1H, d), 5.16 (2H,
s), 4.15 (2H, q), 3.12 (2H, dt), 2.65 (3H, s), 1.28-1.16 (6H,
m)
b)
3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-[(methylsulfonyl)amino]-1H-indo-
le-1-acetic acid, ethyl ester
[0282] To a solution of the product from part (a) (0.2 g) in
acetonitrile (10 ml) was added triethylamine (72 ul) and methane
sulfonylchloride (41 ul), the reaction was heated to reflux
overnight. The mixture was then adsorbed onto silica gel and
purified by flash column chromatography (33% EtOAc/hexane as
eluent) to give the subtitle compound (0.18 g)
[0283] .sup.1H NMR (DMSO) .delta. 9.83 (1H, s), 7.84 (2H, d), 7.71
(2H, d), 7.40 (1H, d), 7.33-7.27 (2H, m), 5.31 (2H, s), 4.17 (2H,
q), 2.99 (3H, s), 2.68 (3H, s), 1.20 (3H, t)
c)
3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-[(methylsulfonyl)amino]-1H-indo-
le-1-acetic acid
[0284] The title compound was prepared by the method of example 2
part (d) using the product of part (b). The product was
recystallised from boiling aqueous ethanol.
[0285] .sup.1H NMR (DMSO) .delta. 9.84 (1H, s), 7.84 (2H, dt), 7.71
(2H, dt), 7.40 (1H, dd), 7.33-7.27 (2H, m), 5.15 (2H, s), 2.98 (3H,
s), 2.68 (3H, s)
[0286] MS: APCI- [M-H] 455
[0287] m.p. dec>237.degree. C.
EXAMPLE 23
3-[(4-chlorophenyl)sulfonyl]-4-(ethylamino)-2-methyl-1H-indole-1-acetic
acid
##STR00027##
[0288] a)
3-[(4-chlorophenyl)sulfonyl]-4-(ethylamino)-2-methyl-1H-indole-1-
-acetic acid
[0289] The title compound was prepared by the method of example 2
part (d) using the by product from example 22 part (a). Product was
purified using reverse phase preparative HPLC.
[0290] NMR (DMSO) .delta. 7.83 (2H, dt), 7.65 (2H, dt), 7.02 (1H,
t), 6.73-6.69 (2H, m), 6.27 (1H, d), 4.68 (2H, s), 3.12 (2H, dt),
2.62 (3H, s), 1.25 (3H, t)
[0291] MS: APCI- [M-H] 405
EXAMPLE 24
3-[(2,6-Dichlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic
acid
##STR00028##
[0292] a)
3-[(2,6-Dichlorophenyl)thio]-2,5-dimethyl-1H-indole-1-acetic
acid
[0293] Iodine (0.51 g) was added to a solution of
2,6-dichlorobenzenethiol (0.36 g) and the product from example 13
step a) (0.2 g) in DMF (5 ml). After 1 h the solution was purified
by reverse phase HPLC. The solvent was evaporated in vacuo and the
oily residue treated with ether to give a solid. Filtered off and
dried to yield the title compound as a white solid (0.22 g).
[0294] MS: APCI- [M-H].sup.- 378
[0295] .sup.1H NMR .delta..sub.(DMSO) 7.49 (2H, d), 7.29 (1H, m),
7.24 (1H, d), 7.13 (1H, s), 6.88 (1H, d), 4.81 (2H, s), 2.44 (3H,
s), 2.29 (3H, s)
b) 3-[(2,6-Dichlorophenyl)sulfonyl]-2,5-dimethyl-1H-indole-1-acetic
acid
[0296] 3-Chlorobenzenecarboperoxoic acid (0.34 g) was added to a
solution of the product from example 24 step a) (0.18 g) in
acetonitrile (5 ml) and water (0.5 ml). The reaction was stirred
for 1 h, 1M aqueous sodium thiosulphate (2 ml) added and stirred
for a further 15 min. The mixture was filtered, purified by reverse
phase HPLC and evaporated in vacuo to yield the title compound as a
white solid (40 mg).
[0297] MS: APCI- 410 [M-H].sup.-
[0298] .sup.1H NMR .delta..sub.(DMSO) 7.64-7.60 (2H, m), 7.57-7.51
(1H, m), 7.45 (1H, s), 7.42 (1H, d), 7.03 (1H, d), 5.01 (2H, s),
2.60 (3H, s), 2.33 (3H, s)
EXAMPLE 25
3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-phenyl-1H-indole-1-acetic
acid
##STR00029##
[0299] a) 4-bromo-3-[4(-chlorophenyl)thio]-2-methyl-1H-indole
[0300] The subtitle compound was prepared by the method of example
2 part (a) using (3-bromophenyl)-hydrazine hydrochloride. Product
purified using Flash column chromatography (10% EtOAc/hexane as
eluent).
[0301] .sup.1H NMR (CDCl.sub.3) .delta. 7.31 (1H, s), 7.30 (2H, d),
7.13 (2H, dt), 7.02 (1H, t), 6.94 (2H, dt), 2.52 (3H, s).
b) 4-bromo-3-[(4-chlorophenyl)thio]-2-methyl-1H-indole-1-acetic
acid, 1,1-dimethylethyl ester
[0302] The subtitle compound was prepared by the method of example
20 part (b) using the product of part (a) and t-butylbromoacetate.
Product was purified using Flash column chromatography (10%
EtOAc/hexane as eluent).
[0303] .sup.1H NMR (CDCl.sub.3) d 7.31 (1H, dd), 7.21 (1H, dd),
7.14-7.10 (2H, m), 7.05 (1H, t), 6.94-6.91 (2H, m), 4.77 (2H, s),
2.49 (3H, s), 1.43 (9H, s).
c) 3-[(4-chlorophenyl)thio]-2-methyl-4-phenyl-1H-indole-1-acetic
acid, 1,1-dimethylethyl ester
[0304] To a solution of the product of part (b) (0.5 g) in ethanol
(0.8 ml) and toluene (3 ml) was added 2 M sodium carbonate solution
in water (1.4 ml), phenylboronic acid (0.131 g) and
tetrakis(triphenylphosphine)palladium(0) (1.2 g). The reaction was
heated to reflux for 2 hours, cooled and concentrated in vacuo. The
residue was purified by flash column chromatography to give the
subtitle compound (0.4 g).
[0305] .sup.1H NMR (DMSO) d 7.53 (1H, d), 7.25-7.18 (2H, m),
7.15-7.09 (6H, m), 6.87 (1H, d), 6.54 (2H, m), 5.17 (2H, s), 2.39
(3H, s), 1.43 (9H, s).
d)
3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-phenyl-1H-indole-1-acetic
acid, 1,1-dimethylethyl ester
[0306] The subtitle compound was prepared by the method for example
20 part (c) using the product from part (c). The product was used
without further characterisation in part (e).
e)
3-[(4-chlorophenyl)sulfonyl]-2-methyl-4-phenyl-1H-indole-1-acetic
acid
[0307] The title compound was prepared by the method of example 2
part (d) with the addition that the reaction mixture was heated to
reflux for 20 minutes. Product was purified using reverse phase
preparative HPLC (eluent MeCN/NH.sub.3(aq)).
[0308] .sup.1H NMR (DMSO) .delta. 7.51-7.41 (3H, m), 7.24-7.12 (4H,
m), 7.06 (2H, t), 6.82 (2H, d,), 6.75 (1H, d), 4.68 (2H, s), 2.73
(3H, s)
[0309] MS: APCI- [M-H] 438
EXAMPLE 26
3-[(4-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-4H-indole-1-acetic
acid, ammonium salt
##STR00030##
[0310] a) 5-fluoro-2-methyl-1H-indole-1-acetic acid methyl
ester
[0311] A mixture of 5-fluoro-2-methylindole (2.4 g), cesium
carbonate (16.6 g) and methyl bromoacetate (5.4 ml) in acetone 240
ml was stirred and heated under reflux for 16 h. The solvent was
removed, water and ethyl acetate were added and the organic phase
separated.
[0312] The aqueous phase was re-extraced with ethyl acetate and the
combined organic solution dried and concentrated to a solid.
Purification by flash chromaography using
dichloromethane:ethylacetate gave the subtitle compound as a solid
(2.9 g)
[0313] MS: APCI+ [M+H] 222
b) 5-fluoro-2-methyl-1H-indole-1-acetic acid
[0314] The product from step a) was dissolved in THF (30 ml) and a
solution of LiOH.H20 (0.91 g) in H.sub.2O (10 ml) was added. After
24 h the solvent was removed, 10% (aq) HCl and ethyl acetate were
added and the organic phase separated. The aqueous phase was
re-extraced with ethyl acetate and the combined organic solution
washed with brine, dried and concentrated to an oil. Purification
by flash chromaography using dichloromethane:ethylacetate gave the
subtitle compound as a yellow powder (1.2 g).
[0315] MS: APCI [M-H].sup.- 206
c) 3-[(4-chlorophenyl)thio]-5-fluoro-2-methyl-1H-indole-1-acetic
acid
[0316] Iodine (0.98 g) was added to a solution of
4-chlorolbenzenethiol (0.55 g) and the product from step b) (0.4 g)
in NMP (5 ml). The solution was stirred for 24 h and the crude
product purified by reverse phase chromatography to give the
subtitle compound as a solid (0.29 g)
[0317] MS: APCI [M-H].sup.- 348/50
[0318] .sup.1H NMR (DMSO) .delta. 7.4 (1H, m), 7.25 (2H, d),
7.0-6.9 (4H, m), 4.59 (2H, s), 2.37 (3H, s).
d)
3-[(4-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-acetic
acid, ammonium salt
[0319] 3-Chlorobenzenecarboperoxoic acid (0.4 g) was added to a
solution of the product from step c) (0.19 g) in acetonitrile (4
ml). The reaction was stirred for 3 h, 1M aqueous sodium
thiosulphate (5 ml) was added and stirred for a further 15 min, 10%
aqu HCl and ethyl acetate were added and the organic phase
separated. The aqueous phase was re-extracted with ethyl acetate
and the combined organic solution washed with brine, dried and
concentrated to a solid which was purified by reverse phase
chromatography to give the title compound as a solid (0.12 g)
[0320] MS: APCI [M-H].sup.- 380/82
[0321] .sup.1H NMR (DMSO) .delta. 7.94 (2H, m), 7.62 (2H, m),
7.6-7.55 (2H, m), 7.4-6.8 (1H bs), 7.05 (1H, dt), 4.8 (2H, s), 2.61
(3H, s).
EXAMPLE 27
3-[(3-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-acetic
acid, ammonium salt
##STR00031##
[0322] a)
3-[(3-chlorophenyl)thio]-5-fluoro-2-methyl-1H-indole-1-acetic
acid
[0323] Prepared by the method of example 26 step c) using the
product of example 26 step b) (0.55 g), iodine (0.98 g) and
3-chlorolbenzenethiol to give the subtitle compound as a solid
(0.25 g)
[0324] MS: APCI [M-H].sup.- 348/50 .sup.1H NMR (DMSO) .delta. 7.4
(1H, m), 7.2 (1H, m), 7.16 (1H, m), 7.0-6.95 (4H, m), 4.57 (2H, s),
2.28 (3H, s)
b)
3-[(3-chlorophenyl)sulfonyl]-5-fluoro-2-methyl-1H-indole-1-acetic
acid, ammonium salt
[0325] Prepared by the of example 26 step d) using the product of
example 27 step a) (0.15 g) and 3-chlorobenzenecarboperoxoic acid
(0.32 g) to give the title compound as a solid (0.09 g).
[0326] MS: APCI [M-H].sup.- 380/82
[0327] .sup.1H NMR (DMSO) .delta. 7.94 (2H, m), 7.7 (1H, m), 7.6
(2H, m), 7.55 (1H, m), 7.2-7.0 (1H bs), 7.05 (1H, dt), 4.79 (2H,
s), 2.63 (3H, s).
EXAMPLE 28
5-fluoro-2-methyl-3-[[4-(trifluoromethyl)phenyl]sulfonyl]-1H-indole-1-acet-
ic acid, ammonium salt
##STR00032##
[0328] a)
5-fluoro-2-methyl-3-[[4-(trifluoromethyl)phenyl]thio]-1H-indole--
1-acetic acid
[0329] Prepared by the method of example 26 step c) using the
product of example 26 step b) (0.55 g), iodine (0.98 g) and
4-trifluoromethylbenzenethiol (0.67 g) to give the subtitle
compound as a solid (0.25 g).
[0330] MS: APCI [M-H].sup.- N382
[0331] .sup.1H NMR (DMSO) .delta. 7.57 (3H, m), 7.05 (2H, m), 7.02
(2H, m), 5.0 (2H, s), 2.4 (3H, s)
b)
5-fluoro-2-methyl-3-[[4-(trifluoromethyl)phenyl]sulfonyl]-1H-indole-1-a-
cetic acid, ammonium salt
[0332] Prepared by the method of example 26 step d) using the
product of example 28 step a) (0.17 g) and
3-chlorobenzenecarboperoxoic acid (0.33 g) to give the title
compound as a solid (0.11 g).
[0333] MS: APCI [M-H].sup.- 414
[0334] .sup.1H NMR (DMSO) .delta. 8.18 (2H, d), 7.95 (2H, d),
7.65-58 (2H, m), 7.2-6.9 (1H, bs), 7.14-7.09 (1H, m), 5.02 (2H, s),
2.67 (3H, s).
Pharmacological Data
Ligand Binding Assay
[0335] [.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.
[0336] HEK cells expressing rhCRTh2/G.alpha.16 were routinely
maintained in DMEM containing 10% Foetal Bovine Serum (HyClone), 1
mg/ml geneticin, 2 mM L-glutamine and 1% non-essential amino acids.
For the preparation of membranes, the adherent transfected HEKcells
were grown to confluence in two layer tissue culture factories
(Fisher, catalogue number TKT-170-070E). Maximal levels of receptor
expression were induced by addition of 500 mM sodium butyrate for
the last 18 hours of culture. The adherent cells were washed once
with phosphate buffered saline (PBS, 50 ml per cell factory) and
detached by the addition of 50 ml per cell factory of ice-cold
membrane homogenisation buffer [20 mM HEPES (pH 7.4), 0.1 mM
dithiothreitol, 1 mM EDTA, 0.1 mM phenyl methyl sulphonyl fluoride
and 100 .mu.g/mlbacitracin]. 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.
[0337] 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.
[0338] 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 to 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).
[0339] Compounds of formula (I) have an IC.sub.50 value of less
than (<) 10 .mu.M. Specifically example 2 has a pIC.sub.50=8.1
example 6 has a pIC.sub.50=7 and example 7 has a pIC.sub.50=6.6
* * * * *