Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-02
2003-09-02
Daymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S227800, C514S378000, C514S381000, C514S419000, C514S415000, C514S359000, C544S060000, C544S062000, C548S240000, C548S250000, C548S492000
Reexamination Certificate
active
06613760
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 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 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 C(O)NR
15
R
16
or a group (CH
2
)
t
R
17
;
where R
15
and R
16
are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl provided that R
15
and R
16
are not both hydrogen, or R
15
and R
16
together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring which optionally contains further heteroatoms;
R
17
is selected from NR
18
R
19
, OR
20
or S(O)
s
R
21
where R
18
and R
19
are independently selected from hydrogen, optionally substituted hydrocarbyl or optionally substituted heterocyclyl, or R
18
and R
19
together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring which optionally contains further heteroatoms;
R
20
is substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl,
R
21
is optionally substituted hydrocarbyl or optionally substituted heterocyclyl, s is 0, 1 or 2 and t is an integer of from 1-4;
R
5
, R
6
and R
7
are independently selected from hydrogen, a functional group or an optionally substituted hydrocarbyl groups or optionally substituted heterocyclyl groups.
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.
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” or “heterocyclic” 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. Nitrogen heteroatoms may be substituted for example with hydrogen or hydrocarbyl depending on the available bonds. Sulphur atoms may be in the form of S, S(O) or S(O)
2
.
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
22
, OR
22
, S(O)
m
R
22
, NR
23
R
24
, C(O)NR
23
R
24
, OC(O)NR
23
R
24
, —NR
23
C(O)
n
R
22
, —NR
22
CONR
23
R
24
, —N═CR
22
R
23
, S(O)
m
NR
23
R
24
or —NR
23
S(O)
m
R
22
where R
22
, R
23
and R
24
are independently selected from hydrogen or optionally substituted hydrocarbyl, or R
23
and R
24
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,
Faull Alan W
Kettle Jason
AstraZeneca AB
Daymond Richard L.
Patel Sudhaker B.
Ropes & Gray LLP
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