Inflammatory cell inhibitors

Details Inflammatory cell inhibitors Inflammatory cell inhibitors

1999-07-21

2001-06-26

Reamer, James H. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S547000, C514S430000, C514S431000, C514S432000, C514S315000, C514S401000

Reexamination Certificate

active

06251940

ABSTRACT:

This application is a 371 of PTC/GB99/00663, Mar. 5, 1999.
The present invention relates to the use of certain esters and thioesters for the treatment of diseases responsive to inhibition of monocyte and/or macrophage and/or lymphocyte activation and of lymphocyte proliferation.
BACKGROUND TO THE INVENTION
Inflammatory diseases represent a large and increasing health burden throughout the world. Chronic inflammatory conditions include autoimmune disorders (rheumatoid arthritis, multiple sclerosis, psoriasis), allergies, periodontists and gastrointestinal inflammatory diseases. These diseases are characterised by an influx of inflammatory cells into the extravascular connective tissue of target organs. In these sites, aberrant activation of circulating and/or resident lymphocytes becomes self-perpetuating and this leads to chronic tissue destruction. The main cells responsible for this destruction are lymphocytes and monocyte/macrophages. This type of inflammation may also be generated by persistent infection (e.g., tuberculosis), in chronic rejection of solid organ transplants and in chronic graft-versus-host disease following bone marrow transplantation.
The recruitment and accumulation of these cells into the target site is regulated by the release of soluble chemokines and by specific adhesion molecules expressed on the extravascular tissues and on the migrating lymphoid/myeloid cells. Activation of macrophages and the proliferation of lymphocytes, particularly T lymphocytes, within these sites leads to the production of pro-inflammatory molecules; chemokines, cytokines, enzymes, reactive oxygen species (ROS), leukotrienes and prostaglandins.
Chemokines such as RANTES, MIP-1alpha/beta, MIP-3alpha/beta, MCP-1 to MCP-4, TARC, PARC, lymphotactin and fractalkine are released at inflammatory sites and recruit monocytes and T cells. Cytokines such as TNF, INFgamma, IL-1beta, IL-2, IL-12 and IL-18 are released which drive cell proliferation. Multiple enzymes are activated in these inflammatory cells and these include LTA4 hydrolase, 5-LO, COX-2 and PLA-2. Tissue-degrading enzymes such as metalloproteases and cysteine proteases are also released. Gene expression of many of these molecules is regulated by the ubiquitous transcription factor NFkB. The anti-inflammatory activity of steroids is largely through inhibition of activated NFkB but they also affect other pathways which results in toxic side effects. There are various modes of treatment for chronic inflammatory conditions but they largely consist of using a non-steroidal anti-inflammatory agent initially followed up by steroids, cyclosporin/FK506 or, in severe conditions, nucleoside synthesis inhibitors and alkylating agents.
In addition to chronic inflammatory diseases, there are several clinically-important conditions associated with acute inflammation. These include acute respiratory distress syndrome (ARDS), pancreatitis and the allergic conditions of rhinitis and urticaria. Acute transplant rejection and graft-versus-host disease are also a result of rapid inflammatory responses. Lymphocytes are important in priming many acute inflammatory responses due to antibody production (IgE, complement fixing IgG or IgM) and cytokine production but granulocytes and mast cells tend to play a more direct role in the pathogenesis. Monocyte products also drive acute inflammation.
Agents which can inhibit monocyte/macrophage and lymphocyte activation and subsequent lymphocyte proliferation would be useful in treating inflammatory disorders. Such agents would reduce the number of cells in the inflammatory site and the levels of pro-inflammatory mediators.
BRIEF DESCRIPTION OF THE INVENTION
This invention is based on the finding that certain esters and thioesters have these properties, and are therefore of use for the treatment of chronic and acute inflammatory conditions responsive to such inhibiton. Chronic and acute inflammatory conditions include autoimmune disorders (eg rheumatoid arthritis, multiple sclerosis, psoriasis), allergies, periodontists, gastrointestinal inflammatory diseases, acute respiratory distress syndrome (ARDS), pancreatitis, the allergic conditions of rhinitis and urticaria, transplant rejection and graft-versus-host disease.
In our earlier international patent application PCT/GB97/02398 (WO 98/11063), there is disclosed the use of the same class of esters and thioesters as inhibitors of the proliferation of rapidly dividing cells, and thus as agents for the treatment, inter alia, of cancer. However, the present utility as inhibitors of monocyte and/or macrophage and/or lymphocyte activation and of lymphocyte proliferation is unrelated to and not predictable from the teaching of that application.
A few patent publications (WO 92/09563, U.S. Pat. 5,183,900, U.S. Pat. 5,270,326, EP-A-0489577, EP-A-0489579, WO 93/09097, WO 93/24449, WO 94/25434, WO 94/25435, WO 95/04033, WO 95/19965, and WO 95/22966) include within their generic disclosure carboxylate ester compounds having matrix metalloproteinase inhibitory activity. In accordance with the present invention, such compounds are now recognised to have activity as inhibitors of monocyte and/or macrophage and/or lymphocyte activation and of lymphocyte proliferation, but that activity is not suggested by, or predictable from, those publications.
WO 95/04033 discloses N
4
-hydroxy-N′-(1-(S)-methoxycarbonyl-2,2-dimethylpropyl)-2-(R)-(4-chlorophenylpropyl)succinamide as an intermediate for the preparation of the corresponding methylamide MMP inhibitor. In addition,
Int. J. Pept. Protein Res
. (1996), 48(2), 148-155 discloses the compound
Ph-CH
2
CH(CO-Ile-OtBu)CH
2
CONHOH
as an intermediate in the preparation of compounds which are inhibitors of neurotensin-degrading enzymes. However, those two appear to be the only specific known carboxylate ester compounds of the kind with which this invention is concerned.
DETAILED DESCRIPTION OF THE INVENTION
In its broadest aspect, the present invention provides a method for treatment of mammals suffering diseases responsive to inhibition of monocyte and/or macrophage and/or lymphocyte activation and of lymphocyte proliferation, comprising administering to the mammal suffering such disease an amount of a compound of general formula (I) or a pharmaceutically acceptable salt hydrate or solvate thereof sufficient to inhibit such activity:
wherein
R is hydrogen or (C
1
-C
6
)alkyl;
R
1
is hydrogen;
(C
1
-C
6
)alkyl;
(C
2
-C
6
)alkenyl;
phenyl or substituted phenyl;
phenyl (C
1
-C
6
)alkyl or substituted phenyl(C
1
-C
6
)alkyl;
phenyl (C
2
-C
6
)alkenyl or substituted phenyl(C
2
-C
6
)alkenyl
heterocyclyl or substituted heterocyclyl;
heterocyclyl(C
1
-C
6
)alkyl or substituted heterocyclyl(C
1
-C
6
)alkyl;
a group BSO
n
A- wherein n is 0, 1 or 2 and B is hydrogen or a (C
1
-C
6
) alkyl,
phenyl, substituted phenyl, heterocyclyl substituted heterocyclyl, (C
1
-C
6
)acyl, phenacyl or substituted phenacyl group, and A represents (C
1
-C
6
)alkylene;
hydroxy or (C
1
-C
6
)alkoxy;
amino, protected amino, acylamino, (C
1
-C
6
)alkylamino or di-(C
1
-C
6
)alkylamino;
mercapto or (C
1
-C
6
)alkylthio;
amino(C
1
-C
6
)alkyl, (C
1
-C
6
)alkylamino(C
1
-C6)alkyl, di(C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, mercapto(C
1
-C
6
)alkyl or carboxy(C
1
-C
6
) alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl-group amidated;
lower alkyl substituted by carbamoyl, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, di(lower alkyl)amino, or carboxy-lower alkanoylamino; or
a cycloalkyl, cycloalkenyl or non-aromatic heterocyclic ring containing up to 3 heteroatoms, any of which may be (i) substituted by one or more substituents selected from C
1
-C
6
alkyl, C
2
-C
6
alkenyl, halo, cyano (—CN), —CO
2
H, —CO
2
R, —CONH
2
, —CONHR, —CON(R)
2
, —OH, —OR, oxo-, —SH, —SR, —NHCOR, and —NHCO
2
R wherein R is C
1
-C
6
alkyl or benzyl and/or (ii) fused to a cycloalkyl or heterocyclic ring;
R
2
is a C
1
-C
12
alkyl,
C
2
-C
12
alkenyl,
C
2
-C
12
alkynyl,
phenyl(C
1
-C
6
alkyl)-,

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