Indole derivatives and their use as MCP-1 antagonist

Details Indole derivatives and their use as MCP-1 antagonist Indole derivatives and their use as MCP-1 antagonist

2001-10-19

2004-05-18

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S414000, C546S276400, C546S278400, C548S484000, C548S490000

Reexamination Certificate

active

06737435

ABSTRACT:

The present invention relates to anti-inflammatory compounds that act via antagonism of the CCR2 receptor, (also known as the MCP-1 receptor), leading inter alia to inhibition of Monocyte Chemoattractant Protein-1 (MCP-1). These compounds contain an indole moiety. The invention further relates to pharmaceutical compositions containing them, processes for their preparation, intermediates useful in their preparation and to their use as therapeutic agents.
MCP-1 is a member of the chemokine family of pro-inflammatory proteins 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, glormerular 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 CCR2 receptor. MCP-2 and MCP-3 may also act, at least in part, through this 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 CCR2 receptor.
The applicants have found a class of compounds containing an indole moiety which have useful inhibitory activity against MCP-1. Co-pending application UK 9716657.3 discloses a class of indoles with MCP-1 inhibitory activity. This application is based on the surprising discovery that particular substituted 5-hydroxy indoles are MCP-1 inhibitors which possess unexpected and beneficial properties with respect to potency and/or blood levels and/or bioavailability and/or solubility.
Accordingly, the present invention provides a compound of the formula (I):
wherein:
R
1
is hydrogen, halo or methoxy;
R
2
is hydrogen, halo, methyl, ethyl or methoxy;
R
3
is carboxy, tetrazolyl or —CONHSO
2
R
4
where R
4
is methyl, ethyl, phenyl, 2,5-dimethylisoxazolyl or trifluoromethyl;
T is —CH
2
— or —SO
2
—; and
ring A is 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl or 2,3-dichloropyrid-5-yl; or a pharmaceutically acceptable salt or prodrug thereof.
In this specification the term “alkyl” includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” are specific for the straight chain version only. The term “halo” refers to fluoro, chloro, bromo and iodo.
Particular novel compounds of the invention include, for example, compounds of the formula (I), or pharmaceutically-acceptable salts or prodrugs thereof, wherein, unless otherwise stated:
a) R
1
has any of the values defined in i)-iii) hereinafter or a combination of two of these values;
b) R
2
has any of the values defined in iv)-viii) hereinafter or a combination of two of these values;
c) R
3
has any of the values defined in ix)-xi) hereinafter or a combination of two of these values;
e) T has any of the values defined in xii)-xiii) hereinafter;
f) ring A has any of the values defined in xiv)-xxi) hereinafter or a combination of two or more of these values;
i) R
1
is hydrogen;
ii) R
1
is halo;
iii) R
1
is methoxy;
iv) R
2
is hydrogen;
v) R
2
is halo;
vi) R
2
is methyl;
vii) R
2
is ethyl;
viii) R
2
is methoxy;
ix) R
3
is carboxy;
x) R
3
is tetrazolyl;
xi) R
3
is —CONHSO
2
R
4
where R
4
is methyl, ethyl, phenyl, 2,5-dimethylisoxazolyl or trifluoromethyl;
xii) T is —CH
2
—;
xiii) T is —SO
2
—;
xiv) Ring A is 3-chlorophenyl;
xv) Ring A is 4-chlorophenyl;
xvi) Ring A is 3-trifluoromethylphenyl;
xvii) Ring A is 3,4-dichlorophenyl;
xviii) Ring A is 3,4-difluorophenyl;
xix) Ring A is 3-fluoro-4-chlorophenyl;
xx) Ring A is 3-chloro-4-fluorophenyl; and
xxi) Ring A is 2,3-dichloropyrid-5-yl.
Preferably R
1
is hydrogen.
Preferably R
2
is hydrogen.
Preferably R
3
is carboxy.
Preferably T is —CH
2
—.
Preferably Ring A is 3-chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-fluoro-4-chlorophenyl or 3-chloro-4-fluorophenyl.
More preferably Ring A is 3,4-dichlorophenyl, 3-fluoro-4-chlorophenyl or 3-chloro-4-fluorophenyl.
For example, Ring A is 3,4-dichlorophenyl or 3-chloro-4-fluorophenyl.
In another aspect of the invention preferably Ring A is 3,4-dichlorophenyl, 2,3-dichloropyrid-5-yl or 3-chloro-4-fluorophenyl.
Therefore, in a preferred aspect of the invention there is provided a compound of formula (I) as depicted above wherein:
R
1
is hydrogen;
R
2
is hydrogen;
R
3
is carboxy;
T is —CH
2
—; and
Ring A is 3,4-dichlorophenyl, 3-fluoro-4-chlorophenyl or 3-chloro-4-fluorophenyl, in particular 3,4-dichlorophenyl or 3-chloro-4-fluorophenyl; or a pharmaceutically acceptable salt or prodrug thereof.
Preferred compounds of the invention include any one of the Examples. More preferred compounds of the invention are Examples 1, 3 and 4, for instance, Example 1 and 3.
The invention further relates to all tautomeric forms of the compounds of formula (I).
It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.
Compounds of formula (I) are inhibitors of monocyte chemoattractant protein-1. In addition, they appear to inhibit RANTES induced chemotaxis. RANTES (Regulated upon Activation, Normal T-cell Expressed and Secreted) 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.
Suitable pharmaceutically acceptable salts of compounds of formula (I) include base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium; an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine. In another aspect, where the compound is sufficiently basic, suitable salts include acid addition salts such as methanesulphonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically acceptable salt is a sodium salt.
Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);
b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and
e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).
Examples of such prodrugs are in vivo cleavable esters of a compound of the invention. An in vivo cleavable ester of a compound of the invention contai

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