Anti-inflammatory indole derivatives

Details Anti-inflammatory indole derivatives Anti-inflammatory indole derivatives

2001-09-12

2003-05-27

Fan, Jane (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S380000, C514S381000, C514S228200, C548S492000, C548S243000, C548S252000, C548S253000, C548S493000, C548S466000, C544S058100

Reexamination Certificate

active

06569888

ABSTRACT:

This application is a 371 of PCT/GB00/00275 Jan. 31, 2000 now WO 00/46198.
The present invention relates to chemical compounds, to their production as well as to pharmaceutical compositions containing them and to their use in therapy, in particular of inflammatory disease.
MCP-1 is a member of the chemokine family of pro-inflammatory cytokines which mediate leukocyte chemotaxis and activation. MCP-1 is a C—C chemokine which is one of the most potent and selective T-cell and monocyte chemoattractant and activating agents known. MCP-1 has been implicated in the pathophysiology of a large number of inflammatory diseases including rheumatoid arthritis, glomerular nephritides, lung fibrosis, restenosis (International Patent Application WO 94/09128), alveolitis (Jones et al., 1992
, J. Immunol
., 149, 2147) and asthma. Other disease areas where MCP-1 is thought to play a part in their pathology are atherosclerosis (e.g. Koch et al., 1992
, J. Clin. Invest
., 90, 772-779), psoriasis (Deleuran et al., 1996
, J. Dermatological Science
, 13,. 228-236), delayed-type hypersensitivity reactions of the skin, inflammatory bowel disease (Grimm et al., 1996
, J. Leukocyte Biol
., 59,. 804-812), multiple sclerosis and brain trauma (Berman et al, 1996
, J. Immunol
., 156,. 3017-3023). An MCP-1 inhibitor may also be useful to treat stroke, reperfusion injury, ischemia, myocardial infarction and transplant rejection.
MCP-1 acts through the MCP-1 receptor (also known as the CCR2 receptor). MCP-2 and MCP-3 may also act, at least in part, through the MCP-1 receptor. Therefore in this specification, when reference is made to “inhibition or antagonism of MCP-1” or “MCP-1 mediated effects” this includes inhibition or antagonism of MCP-2 and/or MCP-3 mediated effects when MCP-2 and/or MCP-3 are acting through the MCP-1 receptor.
Copending International Patent Application Nos. PCT/GB98/02340 and PCT/GB98/02341 describe and claim groups of compounds based upon the indole ring structure which are inhibitors of MCP-1 and therefore have applications in therapy.
The use of certain indole derivatives as NMDA antagonists is described is U.S. Pat. No. 5,051,442, WO 9312780, EP-483881. Other indoles and their use as inhibitors of leukotriene biosynthesis is described in for example, EP-A-275-667, EP-A-419049 and U.S. Pat. No. 5,190,968.
More recently, WO 99/33800 describes various indole derivatives as inhibitors of factor XA.
The applicants have found a particular substitution at the 4-position on the indole ring produces advantageous results when used therapeutically as inhibitors of MCP-1.
According to the present invention there is provided a compound of formula (I)
where:
X is CH
2
, or SO
2
R
1
is an optionally substituted aryl or heteroaryl ring;
R
2
is carboxy, cyano, —C(O)CH
2
OH, —CONHR
8
, —SO
2
NHR
9
, tetrazol-5-yl, SO
3
H, or a group of formula (VI)
 where R
8
is selected from hydrogen, alkyl, aryl, cyano, hydroxy, —SO
2
R
12
where R
12
is alkyl, aryl, heteroaryl, or haloalkyl, or R
8
is a group-(CHR
13
)
r
—COOH where r is an integer of 1-3 and each R
13
group is independently selected from hydrogen or alkyl; R
9
is hydrogen, alkyl, optionally substituted aryl such as optionally substituted phenyl or optionally subtituted heteroaryl such as 5 or 6 membered heteroaryl groups, or a group COR
14
where R
14
is alkyl, aryl, heteroaryl or haloalkyl; R
10
and R
11
are independently selected from hydrogen or alkyl, particularly C
1-4
alkyl;
R
3
is hydrogen, a functional group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted alkoxy, optionally substituted aralkyl, optionally substituted aralkyloxy, optionally substituted cycloalkyl;
R
4
is a group OR
15
or S(O)
q
R
15
, where q is 0, 1 or 2 and R
15
is a substituted hydrogen-containing alkyl group; and
R
5
, R
6
and R
7
are independently selected from hydrogen, a functional group or an optionally substituted hydrocarbyl group or optionally substituted heterocyclic group.
Suitably, R
4
is other than a OR
15
where R
15
is C
1-4
alkyl substituted a single unsubstituted phenyl, such as benzyloxy.
In addition, the invention provides a pharmaceutically acceptable salt, in vivo hydrolysable ester, or amide of the compound of formula (I).
Compounds of formula (I) are inhibitors of monocyte chemoattractant protein-1. In addition, they appear to inhibit RANTES induced chemotaxis. RANTES is another chemokine from the same family as MCP-1, with a similar biological profile, but acting though the CCR1 receptor. As a result, these compounds can be used to treat disease mediated by these agents, in particular inflammatory disease. Thus the invention further provides a compound of formula (I) for use in the treatment of inflammatory disease.
In this specification the term ‘alkyl’ when used either alone or as a suffix includes straight chained, branched structures. These groups may contain up to 10, preferably up to 6 and more preferably up to 4 carbon atoms. Similarly the terms “alkenyl” and “alkynyl” refer to unsaturated straight or branched structures containing for example from 2 to 10, preferably from 2 to 6 carbon atoms. Cyclic moieties such as cycloalkyl, cycloalkenyl and cycloalkynyl are similar in nature but have at least 3 carbon atoms. Terms such as “alkoxy” comprise alkyl groups as is understood in the art.
When it is stated that the an alkyl group is “hydrogen containing”, it means that at least one hydrogen atom is present, thus excluding perhaloalkyl groups for example.
The term “halo” includes fluoro, chloro, bromo and iodo. References to aryl groups include aromatic carbocylic groups such as phenyl and naphthyl. The term “heterocyclyl” includes aromatic or non-aromatic rings, for example containing from 4 to 20, suitably from 5 to 8 ring atoms, at least one of which is a heteroatom such as oxygen, sulphur or nitrogen. Examples of such groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl benzothiazolyl, bernzoxazolyl, benzothienyl or benzofuryl.
“Heteroaryl” refers to those groups described above which have an aromatic character. The term “aralkyl” refers to aryl substituted alkyl groups such as benzyl.
Other expressions used in the specification include “hydrocarbyl” which refers to any structure comprising carbon and hydrogen atoms. For example, these may be alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl.
The term “functional group” refers to reactive substituents. They may comprise electron-donating or electron-withdrawing. Examples of such groups include halo, cyano, nitro, C(O)
n
R
18
, OR
18
, S(O)
m
R
18
, NR
19
R
20
, C(O)NR
19
R
20
, OC(O)NR
19
R
20
, —NR
19
C(O)
n
R
18
, —NR
18
CONR
19
R
20
, —N═CR
18
R
19
, S(O)
n
NR
19
R
20
or —NR
19
S(O)
m
R
18
where R
18
, R
19
and R
20
are independently selected from hydrogen or optionally substituted hydrocarbyl, or R
19
and R
20
together form an optionally substituted heterocyclic ring as defined above, which optionally contains further heteroatoms such as sulphur, S(O), SO
2
, oxygen and nitrogen, n is an integer of 1 or 2, m is an integer of 1-3.
Suitable optional substituents for hydrocarbyl groups R
18
, R
19
and R
20
include halo, perhaloalkyl such as trifluoromethyl, mercapto, hydroxy, carboxy, alkoxy, heteroaryl, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyalkoxy, aryloxy (where the aryl group may be substituted by halo, nitro, or hydroxy), cyano, nitro, amino, mono- or di-alkyl amino, oximino or S(O)
m′
R
16
where m′ is 1 or 2 and R
16
is alkyl.
Where R
19
and R
20
form a heterocyclic group, this may be optionally substituted by hydrocarbyl such as alkyl as well as those substituents listed above for hydrocarbyl groups.
Suitable substituents for hydrocarbyl or heterocylic groups R

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