Benzazine derivatives phosphodiesterase 4 inhibitors

Details Benzazine derivatives phosphodiesterase 4 inhibitors Benzazine derivatives phosphodiesterase 4 inhibitors

2000-07-13

2001-10-02

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S309000, C514S310000, C546S141000, C546S143000, C546S144000, C546S146000, C546S148000, C546S150000

Reexamination Certificate

active

06297257

ABSTRACT:

This is a 371 of International Application Serial No. PCT/EP98/08292, filed Dec. 17, 1998.
The present invention relates to benzanine derivatives, the pharmaceutical compositions comprising them and their use as phosphodiesterase 4 inhibitors.
Phosphodiesterases are a family of isoenzymes which constitutes 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 4th International Congress Excerpta Medica, 17-29, 1973]. When the suitable agonist binds 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 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 isoenzyines, phosphodiesterases 4 (hereinafter PDE 4) specific for the hydrolysis of the airway smooth muscle and inflammatory cells cAMP (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 mastocyte suppression, basophil and neutrophil degranulation, so as the monocyte inhibition and neutrophil activation. Furthermore the PDE 4 inhibitors activity is markedly improved when the adenylated cyclase activity of the target cells is enhanced by endogenous hormones, as the case in vivo. Thus PDE 4 inhibitors should be effective in the therapy of asthma Such compounds would 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 the tumor necrosis factor (hereinafter TNF
&agr;
), a cytokine with pro-inflammatory activity produced by various kind of cells, affects the mediation or the exacerbation of many pathologies such as, for example, the adult respiratory disease 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 (in the name of Sandoz) describes isoquinolines of formula
wherein R
1
-R
4
are lower alkoxy groups, as PDE 3, 4 and 5 inhibitors.
The patent application EP-0 491 441 (in the name of Shell Internationale Research) claims, inter alia, isoquinoline derivatives of formula
wherein R
1
-R
4
are 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 optionally substituted phenyl. These compounds have a fungicide activity in the agricultural field.
The patent GB 1,199,768 (in the name of Pfizer) illustrates, inter alia, compounds of formula
wherein A and B independently are (C
1-5
)alkoxy groups; R
1
is hydrogen or an alkyl group; D
1
and D
2
alternatively are —N═ or —H═; and Y is —NR
6
R
7
wherein R
6
and R
7
independently are hydrogen or an aryl up to 10 carbon atoms optionally substituted by 1-3 halogen atom(s). Said compounds are disclosed to be bronchodilators and anti-hypertensive agents.
The patent U.S. Pat. No. 5,556,862 (in the name of Nippon Zoki Pharmaceutical) claims pharmaceutical compositions containing isoquinolines of formula
wherein Rs are hydrogen or alkoxy, useful as PDE 4 inhibitors.
The patent application WO 97/04779 (in the name of Chiroscience) claims, inter alia, quinolinones of formula
wherein R
1
is (C
1-6
)alkyl or (C
1-6
)alkylheterocycle optionally substituted, for example, by halogen atoms; R
3
is phenyl, pyridyl, furyl, etc.; R
4
-R
7
are hydrogen or (C
1-4
)-alkoxy; and n is 0-3.
These compounds PDE 4 and TNF
&agr;
inhibitors.
The patent U.S. Pat. No. 5,656,643 (in the name of Rhone Poulenc Rorer) discloses compound of
wherein X is methyl, ethyl or branched alkyl optionally interrupted by O, NH, S, SO or SO
2
; R may be alkoxy, aralkoxy, acyloxy, halogen, alkyl, acylamino, amino, amido. These compounds are tirosin-kinase inhibitors also useful as antinflammatory drugs.
The patent application WO97/32837 (in the name of Sumitomo) claims, inter alia, compounds of formula
wherein R
0
may be a protecting group; R
1
may be an optionally protected hydroxy group; R
2
may be optionally substitued CH
2
-aryl; R
4
is H or C
1-6
alkyl, A may be CH
2
and E may be NH or, respectively, the corresponding dehydrogenated groups when ═ is a double bond; R
10
and R
12
are H, (C
1-6
)alkyl or (C
1-6
)haloalkyl; Z may be COOH or CONH
2
. These compounds are oestrogenic or anti-oestrogenic agents.
The patent application EP-0 811 613 (in the name of Pfizer) describes, inter alia, compounds of formula
wherein R
1
is H, lower alkyl, phenyl optionally substituted by, for example, 1-3 halogen atom(s); R
2
is alkyl, alkenyl, alkynyl optionally substituted by phenyl, phenyl, naphthyl, furyl, pyridyl; R
3
is lower alkyl, phenyl, benzyl all being optionally substituted; R
4
, R
5
, R
6
and R
7
are independently H, lower alkyl, alkoxy; X, Y and Z are independently C or N. These compounds are active as antibiotics.
It has been now surprisingly found a new class of benzazine derivatives able to selectively inhibit PDE 4 and furthermore to inhibit TNF
&agr;
.
The patent application WO97/48697 (in the name of Rhone Poulenc Rorer), published on Dec. 24, 1997, discloses, inter alia, compounds of formula
wherin A is an azaheterocycle and B an azaheteroaryl ring or an optionally halo-substituted benzene ring, Z
1
is a bond or an oxygen atom, R
1
is H or lower alkyl optionally substituted by halogen atom(s); A
1
is a bond or a C
1-6
alkylene optionally substituted by aryl, cycloalkyl or heteroaryl; R
2
may be H, aryl, heteroaryl; R
3
may be aryl, heteroaryl, aryl-methoxy, heteroaryl-methoxy; n and m are alternatively 0 or 1. The aryl and heteroaryl moieties may be substituted by halogen atoms. These compounds are PDE 4 and TNF inhibitors.
Therefore the present invention relates to compounds of formula I
wherein A is an orthocondensed heterocycle selected from the group consisting of
wherein R is hydrogen or a (C
1-4
)alkyl group, and being A optionally substituted by (C
1-4
)alkyl, (C
1-4
)alkoxy or —COOR′, wherein R′ is hydrogen or a (C
1-4
)alkyl group, and necessarily substituted by a group —B—Cy wherein B is methylene, ethylene, amino, CONH or a bond; and Cy is a 5- or 6-membered heterocycle containing from 1 to 3 nitrogen atom(s) optionally substituted by one or more halogen(s);
R
1
is a (C
1-6
)alkyl or polyfluoro(C
1-6
)alkyl group,
R
2
is aryl, aryl-(C
1-10
)alkyl or a (C
4-7
)cycloalkyl optionally containing an oxygen atom and optionally substituted by a polar substituent,;
and the N→O derivatives and pharmaceutically acceptable salts thereof:
with the proviso that when R is H, R
2
is not aryl-methyl.
The compounds of formula I may have an asymmetric centre and thus be in form of stereoisomers. Object of the present invention are compounds of formula I in form of stereoisomeric mixture so as single stercoisomers.
The compounds of formula I are active as selective PDE 4 and TNF
&agr;
inhibitors, and thus are used a

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