Benzazine derivatives as phosphodiesterase 4 inhibitors

Details Benzazine derivatives as phosphodiesterase 4 inhibitors Benzazine derivatives as phosphodiesterase 4 inhibitors

2001-04-13

2002-03-19

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S139000, C546S152000, C514S314000

Reexamination Certificate

active

06358973

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to benzazine derivatives, to the pharmaceutical compositions containing them and to their use as phosphodiesterase 4 inhibitors.
2. Description of Related Art
Phosphodiesterases are a family of isoenzymes which constitute the basis of the main mechanism of cAMP (cyclic adenosine-3′,5′-monophosphate) hydrolytic inactivation. cAMP has been shown to be the second messenger mediating the biologic response to many of hormones, neurotransmitters and drugs (
Krebs Endocrinology Proceedings of the
4
th International Congress Excerpta Medica,
17-29, 1973). When the suitable agonist binds to the cell surface, the adenylated cyclase activates and turns Mg
2+
-ATP into cAMP. cAMP modulates the activity of the majority, if not of all the cells contributing to the pathophysiology of various respiratory diseases, both of allergic origin and not. It follows that an increase of the cAMP concentration yields beneficial effects such as airway smooth muscle relaxation, inhibition of the mast cell mediator release (basophil granulose cells), suppression of the neutrophil and basophil degranulation, inhibition of the monocyte and macrophage activation. Thus, compounds able of activating adenylate cyclase or of inhibiting phosphodiesterases could suppress the undesired activation of the airway smooth muscle and of a great number of inflammatory cells.
In the phosphodiesterase family there is a distinct group of isoenzymes, phosphodiesterases 4 (hereinafter PDE 4) specific for the hydrolysis cAMP in the airway smooth muscle and inflammatory cells (Torphy, “
Phosphodiesterase Isoenzymes: Potential Targets for Novel Anti
-
asthmatic Agents”
in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd, 1989). Studies carried out on this enzyme show that its inhibition yields not only the airway smooth muscle relaxation, but also the suppression of mastocyte, basophil and neutrophil degranulation, so as the inhibition of the monocyte and neutrophil activation. In addition, the action of PDE 4 inhibitors is markedly strengthened when the adenylate cyclase activity of the target cells is increased by endogenous hormones, as it happens in vivo. Thus PDE 4 inhibitors are effective in the therapy of asthma. Such compounds offer a unique approach to the therapy of various respiratory diseases, both of allergic origin and not, and possess significant therapeutic advantages over the current therapy.
The excessive or irregular production of tumour necrosis factor (hereinafter TNF
&agr;
), a cytokine with pro-inflammatory activity produced by various kinds of cells, affects the mediation or the exacerbation of many pathologies such as, for example, the adult respiratory distress syndrome (ARDS) and the chronic pulmonary inflammatory disease. Therefore compounds able to control the negative effects of TNF
&agr;
, i.e. the inhibitors of this cytokine, are to be considered as useful against many pathologies.
The patent application EP 0 490 823 (Sandoz) illustrates isoquinolines of formula
wherein
R
1
-R
4
are lower alkoxy groups, as inhibitors of phosphodiesterase III, IV and V.
The patent application EP 0 491 441 (Shell Internationale Research) describes, inter alia, isoquinolines of formula
wherein R
1
-R
4
are hydrogen, alkyl or alkoxy; R
5
and R
6
are hydrogen or together form a bond; R
7
is hydrogen, alkyl or alkoxy; R
8
and R
9
are hydrogen or together form a bond; and A is an optionally substituted phenyl. These compounds have fungicide activity in agricultural field.
The patent GB 1,199,768 (Pfizer) describes, inter alia, compounds of formula
wherein A and B are independently hydrogen or (C
1-5
)alkoxy; R
1
is hydrogen, an optionally substituted alkyl, benzyl, phenyl or phenethyl group, D
1
and D
2
are alternatively —N═ or —CH═; and Y is —NR
6
R
7
wherein R
6
and R
7
are independently hydrogen or an aryl up to 10 carbon atoms optionally substituted by 1-3 halogen atoms. These compounds are bronchodilators and anti-hypertensives.
The U.S. Pat. No. 5,556,862 (Nippon Zoki Pharmaceutical) claims pharmaceutical compositions containing isoquinolines of formula
wherein R is hydrogen or alkoxy, useful as PDE 4 inhibitors.
The patent application WO 97/04779 (Chirosciente) claims, inter alia, quinolinones of formula
wherein R
1
is (C
1-6
)alkyl or (C
1-6
)alkyl-heterocycle optionally substituted by halogen atoms; R
3
is phenyl or pyridyl, furyl, etc.: R
4
-R
7
are hydrogen or (C
1-6
)alkoxy, and n is 0-3. These compounds are PDE 4 and TNF
&agr;
inhibitors.
The patent application EP 0 569 592 (Otsuka) describes quinolinones of formula
wherein R represents several kinds of chains ending with an amino group; A is lower alkylene and W is O or S. These compounds are phosphodiesterase inhibitors in general with particular reference to an inhibiting activity of piastrinic aggregation.
The patent application WO 97/38977 (Astra) claims isoquinolines of formula
wherein R can be alkyl or a cyclic substituent, R
1
can be hydrogen or phenylalkyl, R
2
can be hydrogen, alkyl or phenyl-alkynyl and R
3
is hydrogen or a halogen atom. These compounds have anti-inflammatory activity.
The patent application EP 0 848 000 (Tanabe Seiyaku) describes compounds of formula
wherein A is one of the rings
wherein R
1
and R
2
are hydrogen or an optionally protected hydroxy group; R
31
, R
41
, and R
42
are optionally protected hydroxymethyl; R
32
is hydrogen, lower alkyl or optionally protected hydroxymethyl; and R
5
and R
6
are hydrogen, amino or can form a heterocycle. These compounds are PDE 4 inhibitors.
It has been now surprisingly found a new class of benzazine derivatives able to selectively inhibit PDE 4 and further to inhibit TNF
&agr;
.


REFERENCES:
patent: 5455252 (1995-10-01), Wilhelm et al.
patent: 5556862 (1996-09-01), Imai et al.
patent: 0 490 823 (1992-06-01), None
patent: 0 722 936 (1996-07-01), None
patent: 0 848 000 (1998-06-01), None
patent: 1199768 (1970-07-01), None
patent: WO 88/07041 (1988-09-01), None
patent: WO 97/04779 (1997-02-01), None
patent: WO 97/38977 (1997-10-01), None
patent: WO 88/07041 (1998-09-01), None
patent: WO 99/32449 (1999-07-01), None
Knabe et al, Chemical Abstracts, vol. 83, No. 21, Abstract 178765e, p. 548, Nov. 1975.*
Knabe et al, Chemical Abstracts, vol. 82, No. 24, Abstract 170629x, p. 512, Jun. 1975.

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