Substituted azabicyclic compounds

Details Substituted azabicyclic compounds Substituted azabicyclic compounds

1998-12-18

2001-10-16

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S339000, C514S338000, C546S273400, C546S272100, C546S269100, C546S277400, C546S278100, C546S269400, C544S124000

Reexamination Certificate

active

06303600

ABSTRACT:

This invention is directed to substituted azabicyclic compounds, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states associated with proteins that mediate cellular activity.
Tumour necrosis factor (TNF) is an important pro-inflammatory cytokine which causes hemorrhagic necrosis of tumors and possesses other important biological activities. TNF is released by activated macrophages, activated T-lymphocytes, natural killer cells, mast cells and basophils, fibroblasts, endothelial cells and brain astrocytes among other cells.
The principal in vivo actions of TNF can be broadly classified as inflammatory and catabolic. It has been implicated as a mediator of endotoxic shock, inflammation of joints and of the airways, immune deficiency states, allograft rejection, and in the cachexia associated with malignant disease and some parasitic infections. In view of the association of high serum levels of TNF with poor prognosis in sepsis, graft versus host disease and adult respiratory distress syndrome, and its role in many other immunologic processes, this factor is regarded as an important mediator of general inflammation.
TNF primes or activates neutrophils, eosinophils, fibroblasts and endothelial cells to release tissue damaging mediators. TNF also activates monocytes, macrophages and T-lymphocytes to cause the production of colony stimulating factors and other pro-inflammatory cytokines such IL
1
, IL
6
, IL
8
and GM-CSF, which in some case mediate the end effects of TNF. The ability of TNF to activate T-lymphocytes, monocytes, macrophages and related cells has been implicated in the progression of Human Immunodeficiency Virus (HIV) infection. In order for these cells to become infected with HIV and for HIV replication to take place the cells must be maintained in an activated state. Cytokines such as TNF have been shown to activate HIV replication in monocytes and macrophages. Features of endotoxic shock such as fever, metabolic acidosis, hypotension and intravascular coagulation are thought to be mediated through the actions of TNF on the hypothalamus and in reducing the anti-coagulant activity of vascular endothelial cells. The cachexia associated with certain disease states is mediated through indirect effects on protein catabolism. TNF also promotes bone resorption and acute phase protein synthesis.
The discussion herein relates to disease states associated with TNF including those disease states related to the production of TNF itself, and disease states associated with other cytokines, such as but not limited to IL-1, or IL-6, that are modulated by associated with TNF. For example, a IL-1 associated disease state, where IL-1 production or action is exacerbated or secreted in response to TNF, would therefore be considered a disease state associated with TNF. TNF-alpha and TNF-beta are also herein referred to collectively as “TNF” unless specifically delineated otherwise, since there is a close structural homology between TNF-alpha (cachectin) and TNF-beta (lymphotoxin) and each of them has a capacity to induce similar biological responses and bind to the same cellular receptor.
Cyclic AMP phosphodiesterases are important enzymes which regulate cyclic AMP levels and in turn thereby regulate other important biological reactions. The ability to regulate cyclic AMP phosphodiesterases therefore, has been implicated as being capable of treating assorted biological conditions. In particular, inhibitors of type IV cyclic AMP phosphodiesterase have been implicated as being bronchodilators agents, prophylactic agents useful against asthma and as agents for inhibiting eosinophil accumulation and of the function of eosinophils, and for treating other diseases and conditions characterised by, or having an etiology involving, morbid eosinophil accumulation. Inhibitors of cyclic AMP phosphodiesterase are also implicated in treating inflammatory diseases, proliferative skin diseases and conditions associated with cerebral metabolic inhibition.
It has already been reported that certain substituted monocyclic aromatic compounds have valuable pharmaceutical properties, in particular the ability to regulate proteins that mediate cellular activity, for example, type IV cyclic AMP phosphodiesterase and/or TNF, as described, for example, in the specification of International Patent Application Publication No. WO 95/04045.
Certain substituted bicyclic aromatic compounds, for example amino-substituted benzofurans and benzothiophenes, are reported in European Patent Application EP-A-0685475, to have the ability to regulate elevated cellular cyclic AMP levels probably due to inhibition of type IV cyclic AMP phosphodiesterase.
Further examples of substituted bicyclic aromatic compounds with type IV cyclic AMP phosphodiesterase and/or TNF inhibitory activity include dihydrobenzofurans reported in WO 96/36625 and WO 96/36626.
We have now found a novel group of azabicyclic compounds which have valuable pharmaceutical properties, in particular the ability to regulate proteins that mediate cellular activity, for example, cyclic AMP phosphodiesterases (in particular type IV) and/or TNF.
Thus, in one aspect, the present invention is directed to compounds of general formula (I):
wherein
represents a bicyclic ring system, of about 10 to about 13 ring members, in which the ring
is an azaheterocycle, and the ring
represents an azaheteroaryl ring, or an optionally halo substituted benzene ring;
R
1
represents hydrogen or a straight- or branched-chain alkyl group of 1 to about 4 carbon atoms, optionally substituted by hydroxy or one or more halogen atoms, or when Z
1
represents a direct bond R
1
may also represent a lower alkenyl or lower alkynyl group, or a formyl group;
R
2
represents hydrogen, alkenyl, alkoxy, alkyl, alkylsulphinyl, alkylsulphonyl, alkylthio, aryl, arylalkyloxy, arylalkylsulphinyl, arylalkylsulphonyl, arylalkylthio, aryloxy, arylsulphinyl, arylsulphonyl, arylthio, cyano, cycloalkenyl, cycloalkenyloxy, cycloalkyl, cycloalkyloxy, heteroaryl, heteroarylalkyloxy, heteroaryloxy, hydroxy, —SO
2
NR
4
R
5
, —NR
4
SO
2
R
5
, —NR
4
R
5
, —C(═O)R
5
, —C(═O)C(═O)R
5
, —C(═O)NR
4
R
5
, —C(═O)OR
5
, —O(C═O)NR
4
R
5
, or —NR
4
C(═O)R
5
(where R
4
and R
5
, which may be the same or different, each represent a hydrogen atom, or an alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heteroarylalkyl group);
R
3
represents a group selected from:
(i) —C(═Z)—N(R
7
)R
6
(ii) —C(═Z)—CHR
12
R
6
(iii) —C(═Z)—R
6
(iv) —CR
8
═C(R
9
)(CH
2
)
p
—R
6
(v) —C(R
10
)═C(R
11
)R
12
(vi) —C(R
13
)(R
10
)C(R
11
)(R
14
)R
12
(vii) —C(R
8
)(R
15
)CH(R
9
)(CH
2
)
p
—R
6
(viii) —R
6
(ix) —N(R
16
)C(═Z)R
6
(x) —C(R
17
)═N—OC(═O)R
18
(xi) —C(═O)—N(R
19
)OR
20
(xii) —C≡C—R
6
(xiii) —CH
2
—C(═Z)—R
6
(xiv) —C(═Z)—C(═Z)R
6
(xv) —CH
2
—NHR
6
(xvi) —CH
2
—ZR
6
(xvii) —CH
2
—SOR
6
(xviii) —CH
2
—SO
2
R
6
(xix) —CF
2
—OR
6
(xx) —NH—CH
2
R
6
(xxi) —Z—CH
2
R
6
(xxii) —SO—CH
2
R
6
(xxiv) —SO
2
—CH
2
R
6
(xxv) —O—CF
2
R
6
(xxiii) —O—C(═Z)R
6
(xxvi) —N═N—R
6
(xxvii) —NH—SO
2
R
6
(xxviii) —SO
2
—NR
21
R
22
(xxix) —CZ—CZ—NHR
6
(xxx) —NH—CO—OR
6
(xxxi) —O—CO—NHR
6
(xxxii) —NH—CO—NHR
6
(xxxiii) —R
23
(xxxiv) —CX
1
═CX
2
R
6
(xxxv) —C(═NOR
24
)—(CH
2
)
q
R
6
(xxxvi) —CH
2
—CO—NH(CH
2
)
q
R
6
(xxxvii) —CH
2
—NH—CO(CH
2
)
q
R
6
(xxxviii) —CH
2
—CO—CH
2
R
6
(xxxix) —C(═NR
25
)—NH(CH
2
)
q
R
6
(xxxx) —C(X
3
)═N—(CH
2
)
q
R
6
(xxxxi) —CH(X
4
)—CH
2
R
6
[where:
R
6
is aryl or heteroaryl;
R
7
is a hydrogen atom or an alkyl or amino group;
R
8
and R
9
, which may be the same or different, is each a hydrogen atom or alkyl, —CO
2
R
5
, —C(═Z)NR
26
R
27
(where R
26
and R
27
may be the same or different and each is as described for R
5
), —CN or —CH
2
CN;
R
10
and R
11
, which may be the same or different, is each a group —(CH
2
)
p
R
6
;
R
12
is a hydrogen atom or an alkyl group;
R
13

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