Chemical compounds

Details Chemical compounds Chemical compounds

2001-10-02

2004-12-21

McKane, Joseph K. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

N-c doai

C548S443000

Reexamination Certificate

active

06833387

ABSTRACT:

The present invention relates to chemical compounds, to their production as well as to pharmaceutical compositions containing them as well as 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, WO9312780, EP-483881. Other indoles and their use as inhibitors of leukotriene biosynthesis is described in for example. EP-A-275-667.
The applicants have found a particular substitution on the indole ring produces advantageous results when used therapeutically as inhibitors of MCP-1.
According to the present invention there is provided the use of a compound of formula (I)
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 a group OR
15
, S(O)
q
R
15
, NHCOR
16
, NHSO
2
R
16
, (CH
2
)
5
COOH, (CH
2
)
1
CONR
17
R
18
, NR
17
R
18
, SO
2
NR
17
R
18
or optionally substituted alkenyl, where q is 0, 1 or 2, s is 0 or an integer of from 1 to 4, t is 0 or an integer of from 1 to 4, R
15
is a substituted alkyl or cycloalkyl group or an optionally substituted heteroaryl group, R
16
is optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl and R
17
and R
18
are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl and optionally substituted heteroaryl, with the proviso that at least one of R
17
or R
18
is other than hydrogen, or R
16
and R
17
together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring which optionally contains further heteroatoms; and
R
4
, R
5
, R
6
and R
7
are independently selected from hydrogen, a functional group or an optionally substituted hydrocarbyl groups or optionally substituted heterocyclic groups: for use in the preparation of a medicament for the inhibition of monocyte chemoattractant protein-1 and/or RANTES induced chemotaxis.
Pharmaceutically acceptable salts, esters and amides of compounds of formula (I) may also be used in this way.
In particular in the above formula s is an integer of from 1 to 4.
Suitably R
4
is other than a group OR
18′
, S(O)
m
R
18′
, NR
19
R
20
, C(O)NR
19
R
20
, NHCOR
18
, NHSO
2
R
18
or OCONR
19
R
20
or an alkyl group substituted by OR
18
, S(O)
m
R
18
, NR
19
R
20
where R
18
, R
19
, R
20
and m are as defined hereinafter and R
18′
is a substituted hydrogen-containing alkyl group.
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 preparation of a medicament for 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.
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, benzoxazolyl, 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)
n
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 with the atom to which they are attached, form an optionally substituted heterocyclyl ring as defined above which optionally contains further heteroatoms such as S(O)
n
, oxygen and nitrogen, n is an integer of 1 or 2, m is 0 or 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, h

Affiliated with

Also associated with

Rating

Chemical compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Chemical compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Chemical compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3281797