Phthalazine derivatives phosphodiesterase 4 inhibitors

Details Phthalazine derivatives phosphodiesterase 4 inhibitors Phthalazine derivatives phosphodiesterase 4 inhibitors

2001-01-22

2001-12-11

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S248000, C544S116000, C544S119000, C544S237000

Reexamination Certificate

active

06329370

ABSTRACT:

This application is a 371 of PCT/EP99/04904 filed Jul. 13, 1999.
The present invention relates to phthalazine derivatives, to the pharmaceutical compositions containing them and to their use as phosphodiesterase 4 inhibitors.
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 hormones, neurotransmitters and drugs [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the suitable agonist binds to the cell surface, the adenylate 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 of 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. 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 kind 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;
, the inhibitors of this cytokine, are to be considered as useful against many pathologies.
The patent application EP 722 936 (Eisai) claims, inter alia, compound of formula
wherein n=0-4; R
1
is optionally substituted lower alkoxy, optionally substituted cycloalkyl, or a —OR
9
group wherein R
9
represents an optionally substituted arylalkyl group; X is —N═ or —NR
6
— wherein R
6
is hydrogen, a lower alkyl group, or optionally substituted arylalkyl or heteroarylalkyl groups; Y is —CO or —CB═ wherein B is —NR
7
R
8
wherein one of R
7
and R
8
may be H and the other an optionally substituted heteroaryl, arylalkyl or B is hydrogen or an optionally substituted aryl, heteroaryl, arylalkyl or heteroarylalkyl group; A is a hydrogen or halogen atom, or an optionally mono- or disubstituted amino group, an optionally substituted aryl, heteroaryl or heteroarylalkyl group. Among the groups optionally substituting the above mentioned residues, halogen atoms are cited. These compounds are said to be active as inhibitors of cGMP-PDE, i.e. PDE 5, a phosphodiesterase just acting through a cGMP-dependent mechanism and whose field of application is markedly cardiovascular (Schudt C. et al., Phosphodiesterase Inhibitors, Academic Press).
The patent application EP 634 404 (Rhone Poulenc Agriculture) describes, inter alia, phthalazinones of formula
where in R is an arylalkyl group , in particular pyridyl optionally substituted by halogen atoms; R
1
represents an alkyl chain up to 6 carbon atoms or an arylalkyl group, in particular phenyl; R
2
represents a phenoxy or benzyloxy group; and m=0-4. These compounds are useful as pesticides.
The patent U.S. Pat. No. 3,274,185 (Messengill) describes, inter alia, phthalazines of formula
wherein Y and Y
1
are independently hydrogen or lower alkoxy; Z is phenyl optionally substituted by halogen or benzyl optionally substituted by lower alkyl or alkoxy; and R is hydrogen. These phthalazines are endowed with sedative and hypotensive activity, without mentioning the mechanism of action.
The patent U.S. Pat. No. 3,813,384 (Asta-Werke) illustrates, inter alia, benzylphthalazinones of formula
wherein R
1
and R
2
are hydrogen, lower alkoxy or halogen; X is an optionally branched alkylene chain; m and n are 1-3; p is 0 or 1; and the group
is an optionally substituted (C
3
-C
8
) mono-, di- or tricyclic residue containing one or two nitrogen atom(s). Such compounds have hystaminolytic action and are useful, for example, in the treatment of asthma. All of the exemplified compounds show a residue
which is a saturated heterocycle.
The patent application WO 97/40020 (Schering AG) describes compounds of formula
wherein Y is —NR
3
— or —N═, R
1
and R
2
are H, lower alkyl, nitro, halogen, amino, lower alkoxy or —CF
3
, R
3
is H, —CO— substituted by H, lower alkyl substituted by aryl, amino, lower alkoxy, cycloalkyl or cycloalkoxy, or R
3
is lower alkyl or cycloalkyl, R
4
is H or lower alkoxy, R
5
is lower alkyl. These compounds are said to be uncompetitive antagonists of excitatory amino acids.
The patent application WO 97/48697 (Rhone Poulenc Rorer) describes bicyclic compounds with PDE 4 and TNF
&agr;
inhibiting activity represented by a very broad general formula. Phthalazine compounds could be included in the general formula of this patent application, nevertheless none of the exemplified compounds is a phthalazine derivative and this kind of structure is excluded from the claims.
The patent application EP 848 000 (Tanabe Seiyaku) discloses, inter alia, phthalazine derivatives of formula
wherein A is one of
wherein R
1
and R
2
are H, or optionally protected hydroxy; R
33
is lower alkyl; R
5
and R6 are H, amino or may form a heterocycle. These compounds are PDE 4 inhibitors. It has been now surprisingly found a new class of phthalazine derivatives able to inhibit PDE 4 and TNF
&agr;
.
Therefore the present invention relates to compounds of formula I
wherein
is a single or double bond;
Z is NH, methylene, a (C
2
-C
6
)alkylene chain optionally branched and/or unsaturated and/or interrupted by a (C
5
-C
7
)cycloalkyl residue;
A is phenyl or heterocycle optionally substituted by one or more substituent(s) selected among oxo, nitro, carboxy groups and halogen atoms, or a COR
4
group wherein R
4
is hydroxy, (C
1
-C
6
)alkoxy, amino optionally substituted by one or two (C
1
-C
6
)alkyl group(s) or by hydroxy;
R is a (C
1
-C
6
)alkyl or polyfluoro(C
1
-C
6
)alkyl group;
R
1
is absent when
is a double bond or, when
is a single bond, is
a) hydrogen;
b) (C
1
-C
6
)alkyl optionally substituted by aryl, by heterocycle or by a COR
5
group wherein R
5
is hydroxy, (C
1
-C
4
)alkoxy or hydroxyamino;
c) —COR6 wherein R
6
is hydrogen, aryl, aryl-(C
1
-C
6
)alkyl, amino optionally alkylated or monohydroxylated, hydroxy, (C
1
-C
4
)alkoxy, carboxy, (C
1
-C
4
)alkoxycarbonyl, HN═C—NH
2
, or (C
1
-C
4
)alkyl optionally substituted by heterocycle;
d) (C
1
-C
4
)alkylsulfonyl;
R
2
represents two hydrogen atoms or a group ═O when
is a single bond, or, when
is a double bond, R
2
is hydrogen, cyano, (C
1
-C
4
)alkoxycarbonyl, amido, optionally substituted aryl or heterocycle, (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl or (C
2
-C
8
)alkynyl optionally branched and/or substituted by aryl or heterocycle; aryloxy, heterocyclyloxy, aryl-(C
1
-C
4

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