Pyrrolopyrrolone derivatives

Details Pyrrolopyrrolone derivatives Pyrrolopyrrolone derivatives

2000-05-05

2001-01-23

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S137000, C544S144000, C546S199000, C548S248000, C548S453000

Reexamination Certificate

active

06177425

ABSTRACT:

The present invention relates to therapeutically active bicyclic compounds, processes for their manufacture, pharmaceutical formulations containing them and their use in chemotherapy. In particular, we have found a group of novel bicyclic compounds which are effective in treating inflammatory diseases.
Inflammation is a primary response to tissue injury or microbial invasion and is characterised by circulating leukocytes binding to and extravasation through vascular endothelium. Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes and lymphocytes. Different forms of inflammation involve different types of infiltrating leukocytes.
The inflammatory process can be triggered in a number of ways, including by infection, tissue damage and autoimmune reactions. As part of the inflammatory process, neutrophils move from the bloodstream into the tissue at the site of tissue lesion. The neutrophils contain large numbers of different intracellular granules and when activated at the site of inflammation the contents of these granules are secreted into the tissue. The different granules contain a variety of enzymes and other proteins, many of which have antibacterial properties.
One of the enzymes found in the azurophilic granules is neutrophil elastase. Neutrophil elastase has a wide spectrum of activities in the body. For example, within the lung the enzyme increases mucus production and changes the cellular composition of the epithelium. The enzyme also causes vascular permeability changes within the microcirculation of many tissues and it is a potent destructive agent against a number of connective tissue components.
Although there are within the body endogenous inhibitors of elastase, including the anti-trypsin and the leukocyte protease inhibitor, elastase activity has been implicated in the pathogenesis of a number of disease states including inflammatory diseases of the airways, the joints and the skin. The enzyme is also responsible for some or most of the symptoms of acute respiratory distress syndrome (ARDS) and other acute inflammatory states brought about by trauma and/or sepsis.
We have now found a group of novel compounds which inhibit neutrophil elastase. These compounds are therefore of potential therapeutic benefit in the treatment and amelioration of symptoms of diseases where elastase activity is implicated.
Thus, according to one aspect of this invention, we provide a compound of the formula (I)
(relative stereochemistry indicated)
wherein:
R
1
represents C
1-6
alkyl;
R
2
represents C
2-4
alkyl or C
2-4
alkenyl;
X represents CO or SO
2
;
R
3
represents:
(a) C
2-8
alkenyl NR
4
R
5
;
(b) phenyl substituted by (CH
2
)
a
Q(CH
2
)
b
NR
4
R
5
;
(c) a 5 or 6 membered heterocyclic aromatic ring containing 1 or 2 heteroatoms selected from N, S and O substituted by (CH
2
)
a
Q(CH
2
)
b
NR
4
R
5
;
(d) phenyl substituted by NHCOC
1-8
alkyl;
(e) a group as defined in (b), (c), or (d) further substituted on the phenyl or heterocyclic ring by one or more groups selected from C
1-4
alkyl, C
1-4
alkoxy, halogen and nitro; or
(f) C
1-8
alkylNR
4
R
5
;
R
4
and R
5
independently represent hydrogen, C
1-8
alkyl, —(CH
2
)
1-4
CONR
6
R
7
, COC
1-4
alkyl or (CH
2
)
0-2
Ph where Ph represents phenyl optionally substituted by one or more C
1-4
alkyl or halogen groups or NR
4
R
5
together represents azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, piperazinyl or N—C
1-6
alkyl-piperazinyl or such a heterocyclic ring optionally substituted by one or more C
1-4
alkyl, CONR
6
R
7
or COOR
6
groups;
Q represents a bond, S, O or NR
8
;
a represents 0 to 4 and b represents 2 to 4 save that a+b lies in the range 2 to 6 except when Q represents a bond in which case b may also represent 0 or 1 and a+b may lie in the range 0 to 6;
R
6
, R
7
and R
8
independently represent hydrogen or C
1-4
alkyl; and salts and solvates thereof (hereinafter “compounds of the invention”).
Formula (I) shows the relative stereochemistry of the chiral centres. The invention embraces compounds of the invention in racemic form as well as in a form in which one enantiomer predominates or is present exclusively. Generally, we prefer to provide a compound of formula (I) in enantiomerically pure form, most particularly the enantiomer having absolute stereochemistry as illustrated in formula (I).
The present invention also covers the physiologically acceptable salts of the compounds of formula (I). Suitable inorganic and organic acid salts include the hydrochloride and tartrate.
When used herein “alkyl” includes branched as well as straight chain alkyl and may also include cycloalkyl when 3 or more carbon atoms are present.
When R
3
represents C
2-8
alkenylNR
4
R
5
, examples include CH═CHCH
2
NR
4
R
5
.
When R
3
represents phenyl substituted by NHCOC
1-8
alkyl, examples include phenyl substituted by NHCOMe.
When R
3
represents C
1-8
alkylNR
4
R
5
, examples include (CH
2
)
3
NR
4
R
5
.
When R
3
represents a substituted 5 or 6 membered heterocyclic aromatic ring, examples of heterocycles include furan, pyrrole, thiophene, imidazole, thiazole, isoxazole, pyrazole, pyrazine and pyridine.
When R
4
and R
5
independently represent C
1-8
alkyl, examples include methyl and cyclopropyl.
When R
4
and R
5
independently represent (CH
2
)
1-4
CONR
6
R
7
examples include CH
2
CONMe
2
.
When R
4
and R
5
independently represent COC
1-4
alkyl, examples include COMe.
Suitable R
1
alkyl groups include methyl, ethyl and propyl.
We prefer R
1
to represent methyl or ethyl, especially methyl.
We prefer R
2
to represent isopropyl or propyl, especially isopropyl.
We prefer X to represent CO.
We prefer R
3
to represent
(a) C
2-8
alkenyl NR
4
R
5
;
(b) phenyl substituted by (CH
2
)
a
Q(CH
2
)
b
NR
4
R
5
;
(c) a 5 or 6 membered heterocyclic aromatic ring containing 1 or 2 heteroatoms selected from N, S and O substituted by (CH
2
)
a
Q(CH
2
)
b
NR
4
R
5
;
(d) phenyl substituted by NHCOC
1-8
alkyl; or
(e) a group as defined in (b), (c), or (d) further substituted on the phenyl or heterocyclic ring by one or more groups selected from C
1-4
alkyl, C
1-4
alkoxy, halogen and nitro.
We particularly prefer R
3
to represent:
(a) C
2-8
alkenyl NR
4
R
5
;
(b) phenyl substituted by (CH
2
)
a
Q(CH
2
)
b
NR
4
R
5
;
(c) a 5 or 6 membered heterocyclic aromatic ring containing 1 or 2 heteroatoms selected from N, S and O substituted by (CH
2
)
a
Q(CH
2
)
b
NR
4
R
5
; or
(d) a group as defined in (b) or (c) further substituted on the phenyl or heterocyclic ring by one or more groups selected from C
1-4
alkyl, C
1-4
alkoxy, halogen and nitro.
We prefer R
4
and R
5
independently to represent hydrogen or C
1-8
alkyl or for NR
4
R
5
to represent pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl optionally N-substituted by C
1-8
alkyl or phenyl (optionally substituted by halogen or C
1-4
alkyl).
We prefer Q to represent a bond and for a+b to represent 1 or 2.
The potential for compounds of the invention to inhibit neutrophil elastase activity may be demonstrated, for example, using the following in vitro and in vivo assays:
In vitro Assays of Human Neutrophil Elastase
Assay contents:
50 mM Tris/HCl (pH 8.6)
150 mM NaCl
11.8 nM purified human neutrophil elastase
Suitable concentrations of compound under test diluted with water from a 10 mM stock solution in dimethylsulphoxide. Values above are final concentrations after the addition of substrate solution (see below).
The mixture above is incubated for fifteen minutes at 30° C. at which time the remaining elastase activity is measured for 10 minutes in a BioTek 340i plate-reader, after the addition of 0.6 mM MeO-succinyl-alanyl-alanyl-prolyl-valyl-p-nitroanilide. The rate of increase in absorbance at 405 nm is proportional to elastase activity. Enzyme activity is plotted against concentration of inhibitor and an IC
50
determined using curve fitting software.
In vivo Activity of Inhibitors of Human Neutrophil Elastase: An Oral in vivo Model Using IL-8 Induced Lung Infiltrates for the Assessment of Intracellular Elastase Inhibition
Adult hamster

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