Pyrrolopyrrolone derivatives as inhibitors of neutrophil...

Details Pyrrolopyrrolone derivatives as inhibitors of neutrophil... Pyrrolopyrrolone derivatives as inhibitors of neutrophil...

2000-03-03

2001-04-10

Stockton, Laura L. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S531000, C548S543000

Reexamination Certificate

active

06215002

ABSTRACT:

The present invention relates to therapeutically active bicyclic compounds, processes for the manufacture of said compounds, pharmaceutical formulations containing said compounds and the use of said compounds in chemotherapy. In particular, we have found a novel group of 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 novel group of compounds which inhibit neutrophil elastase. The 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 general formula (I)
wherein:
R
1
represents C
1-6
alkyl; C
2-6
alkenyl; aryl, aryl-C
1-4
alkyl, aryl-C
2-4
alkenyl, heteroaryl, heteroaryl-C
1-4
alkyl, or heteroaryl-C
2-4
alkenyl, or such a group in which the aryl or heteroaryl moiety is substituted by one or more C
1-4
alkyl, halo, tetrazolyl, trifluoromethyl-sulphonamide, NR
9
CO—C
1-8
alkyl, —(CH
2
)
m
—NR
4
R
5
, —CN, —COOR
9
, —CONR
9
R
10
, —NO
2
, —SO
2
—C
1-6
alkyl, —CF
3
or C
1-6
alkoxy groups; —(CH
2
)
n
—NR
4
R
5
; C
2-8
alkenyl-NR
4
R
5
; —(CH
2
)
n
CONR
4
R
5
; —(CH
2
)
n
NR
9
CO—C
1-6
alkyl; C
2-8
alkenyl-COOR
9
; (CH
2
)
n
COOR
9
; and C
2-8
alkenyl CONR
4
R
5
;
X, represents
(where carbonyl is bound to the ring nitrogen);
R
2
represents C
2-4
alkyl, C
2-4
alkenyl, C
1-3
alkoxy or C
1-3
alkylthio;
R
3
represents C
1-6
alkyl; —CH
2
(CF
2
)
0-4
CF
3
; aryl or heteroaryl, which aryl or heteroaryl are mono-ring, or have two fused rings one of which may be saturated, and which aryl and heteroaryl groups may be substituted by one or more C
1-4
alkyl, halo, —NR
7
R
8
, —SO
2
NR
7
R
8
, —CONR
7
R
8
, —C
1-6
alkyl ester, —CN, —CH
2
OH, —O—C
1-6
alkyl, —CF
3
, or nitro groups; aryl-C
1-4
alkyl, aryl-C
1-4
alkyl-NH— or aryl-C
2-4
alkenyl, or such groups wherein aryl is substituted by one or more C
1-4
alkyl or halo groups;
R
4
and R
5
independently represent hydrogen, C
1-4
alkyl, C
1-4
alkoxy, —(CH
2
)
1-4
CONR
11
R
12
, —CO—C
1-4
alkyl or phenyl optionally substituted by one or more C
1-4
alkyl or halogen groups or R
4
and R
5
may be joined such that NR
4
R
5
represents a mono, bi- or tri-cyclic ring system containing −15 ring carbon atoms, wherein one or more rings may be optionally interrupted by one or more heteroatoms selected from O, N and S and wherein one or more ring carbon atoms may have carbonyl functionality;
or —(CH
2
)
n
—NR
4
R
5
may represent a group of formula 1a:
wherein
R
6
is hydrogen or a carboxy C
1-6
alkyl ester, n
1
is 0-6 and a and b independently represent an integer 0-3 provided a+b is in the range 3-5;
R
7
, R
8
, R
9
, R
10
, R
11
, R
12
independently represent hydrogen or C
1-4
alkyl;
m represents an integer 0 to 8; n represents an integer 1 to 9;
and salts and solvates thereof.
Formula (I) shows the relative stereochemistry of the chiral centres. The invention embaces compounds of formula (I) 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.
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
4
and R
5
are joined such that —NR
4
R
5
represents a mono- bi- or tri-cyclic ring system, one or more rings may be unsaturated or aromatic. Examples of ring systems which —NR
4
R
5
may represent include unsaturated monocycles such as azetidine, pyrrolidine, piperidine, azepine, piperazine, morpholine; bicycles such as dihydrosoquinoline, tetrahydrosoquinoline, octahydroisoquinoline, desmethyl tropane; and tricycles such as hexahydrobenzoisoindole. Carbonyl containing ring systems include pyrrolone (e.g. pyrrol-2-one) and oxopyridine (e.g. 2-oxo-2H-pyridine and 4-oxo-4H-pyridine). Ring carbon atoms may be substituted by C
1-4
alkyl, CONR′R″, COOR′ (R′, R″ independently represent hydrogen or C
1-4
alkyl) or halogen groups and ring nitrogen atoms may be substituted by C
1-4
alkyl or —CO—C
1-4
alkyl groups. Particularly suitable carbon substituents include methyl (for example as in 2,5-dimethyl pyrrolidine and 2,6-dimethyl piperidine), —CONH
2
(for example as in 4-(H
2
NCO)-piperidine) and —COOMe (for example as in 2-(MeOCO)-pyrrolidine). Suitable nitrogen substituents include methyl (for example as in 4-methyl-piperazine), and —COMe (for example as in 4-(MeCO)-piperazine).
Suitable R
4
, R
5
alkyl groups include methyl, ethyl, n-propyl, isopropyl and cyclopropyl.
Suitable R
4
,R
5
alkoxy groups include methoxy.
Suitable R
4,
R
5
—(CH
2
)
1-4
CONR
11
R
12
groups include —CH
2
CONH
2
.
Suitable R
4
,R
5
—CO—C
1-4
alkyl groups include —COMe.
Suitable R
1
alkyl groups include methyl, ethyl and propyl.
Suitable R
1
C
2-6
alkenyl groups include CH═CH—CH
3
.
Suitable R
1
aryl groups have up to two rings. They suitably include phenyl and naphthyl, most suitably phenyl.
Suitable R
1
arylalkyl groups include phenylmethyl and phenylethyl.
Suitable R
1
arylalkenyl groups include styryl.
Especially suitable R
1
aryl substituents include C
1-4
alkyl, such as methyl or ethyl; C
1-6
alkoxy, such as methoxy, ethoxy and n-butyloxy; halo such as chloro, bromo or iodo; —SO
2
C
1-6
alkyl, such as —SO
2
Me; tetrazolyl bonded through carbon; —CF
3
; —NO
2
; —CN; —(CH
2
)
m
—NR
4
R
5
such as —NH
2
, —CH
2
NH
2
, —CH
2
NH(cyclopropyl), —CH
2
N(Me)(nPr), —CH
2
(4-Me-piperazin-1-yl) and 2-oxopyrrolidin-1-yl; and —NR
9
COC
1-8
alkyl such as —NHCOMe. Often there will be 1, 2 or 3 such substituents.
Suitable R
1
heteroaryl groups include those containing sulphur, nitrogen or oxygen heteroatoms. Suitable R
1
heteroaryl groups will have up to two rings. Examples include imidazolyl, optionally N-substituted by C
1-4
alkyl; pyridyl; furanyl; pyrrolyl and thienyl.
Suitable R
1
heteroaryl alkyl and alkenyl groups include pyridylmethyl, pyridylethyl and pyridylethenyl.
Suitable R
1
heteroaryl substituents include those as described above in regard to aryl substituents.
Suitable —(CH
2
)
n
—NR
4
R
5
groups for R
1
also include those of the above formula (Ia

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