Phthalazine derivatives as phosphodiesterase 4 inhibitors

Details Phthalazine derivatives as phosphodiesterase 4 inhibitors Phthalazine derivatives as phosphodiesterase 4 inhibitors

2000-08-10

2003-07-08

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S241000, C544S180000, C544S237000

Reexamination Certificate

active

06589951

ABSTRACT:

This is a 371 of International Application Serial No. PCT/EP98/08291, filed Dec. 17, 1998.
The present invention relates to phthalazine derivatives, to pharmaceutical compositions comprising them and to 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 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, of 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 capable 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 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 airway smooth muscle relaxation, but also mastocyte suppression, basophil and neutrophil degranulation, thus inhibiting monocyte activation 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 useful against many pathologies.
The patent application EP-0 722 936 (in the name of Eisai) claims, inter alia, compounds of formula
wherein n=0-4; R
1
, is an optionally substituted lower alkoxy or cycloalkyl, or a —OR
9
group wherein R
9
is an optionally substituted arylalkyl group; Y is —CB═ wherein B is an optionally substituted heteroarylalkyl group or —NR
7
R
8
wherein one of R
7
, and R
8
may be H and the other an optionally substituted heteroarylalkyl group; A is hydrogen or a halogen atom, optionally mono- or bi-substituted amino group, optionally substituted aryl, heteroaryl or heteroarylalkyl group. Among the groups optionally substituting the above mentioned residues halogen atoms are listed. Such compounds are said to be active as cGMP-PDE inhibitors, i.e. PDE 5, a phosphodiesterase acting by a cGMP-dependent mechanism and whose field of action is markedly cardiovascular (Schudt C. et al., Phosphodiesterase Inhibitors, Academic Press).
The patent application EP0 498 723 (in the name of Roussel Uclaf) discloses, inter alia, compounds of formula
wherein R
2
b and R
3
b are hydrogen, hydroxy, alkyl, cycloalkyl, acyloxy, at least one but no more then two of A
1
b, A
2
b, A
3
b and A
4
b are a nitrogen atom and at least one of them is a methyne radical substituted by the —R
5
—Y
B
group wherein R
5
is a divalent alkylene radical, and Y
B
represents the radical —Y
1B
—B—Y
2B
wherein Y
1B
is a monocyclic aryl optionally containing nitrogen, B is a single bond and Y
2B
is hydrogen or halogen. These compounds are said to be effective for the treatment of arterial hypertension, heart and renal failure and for the prevention of restenosis after angioplasty.
The patent application EP-0 017 411 (in the name of Pfizer) claims phthalazines of formula
wherein R
1
is lower alkyl; Y is —(CH
2
)
m
—Z wherein m is 1 or 2, and Z is carbamoyloxy, carbonylamino, sulfamoyl, ureido, amino-sulfamoyl, carboxamino substituted on the terminal portion by a (C
3-7
)cycloalkyl. These compounds are said to be phosphodiesterase inhibitors and to have a cardiac muscle stimulating activity, thus their action does not relate to PDE 4. The U.S. Pat. No. 3,274,185 (in the name of Messengill) describes, inter alia, phthalazines of formula
wherein Y and Y
1
are lower alkoxy; Z is phenyl optionally substituted by halogen or benzyl; and R is hydrogen. These phthalazines are endowed with sedative and hypertensive activity, without an explicit mechanism of action.
The U.S. Pat. No. 3,813,384 (in the name of Asta-Werke) illustrates, inter alia, benzylphthalazinones of formula
wherein R
1
and R
2
are 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 a C
3-8
mono-, bi- or tricyclic residue containing one or two nitrogen atom(s). Such compounds have a hystaminolytic action and are useful, for example, in the treatment of asthma.
The patent application NL 8005411 (in the name of Mitsubishi Yuka) describes phthalazines of formula
wherein X is O or NH, R
1
, R
2
and R
3
are, inter alia, (C
1-5
)alkyl, (C
1-5
)alkoxy, halogen or CF
3
; n, m and p are 0-3. The use of these compounds is as platelet aggregation inhibitors.
The patent application JP-56061365 (in the name of Showa Denko) describes phthalazinones of formula
wherein, inter alia, R is halogen and n is 1-3, as vasodilators and anti-ulcer agents.
The patent application WO 97/40020 (in the name of Schering AG) illustrates, inter alia, compounds of formula
wherein R
1
and R
2
are H, nitro, halogen, amino, lower alkoxy or —CF
3
; R
4
is H or lower alkyl; R
5
is lower alkyl. These compounds are uncompetitive antagonists of excitatory aminoacids. The patent application WO097/48697 (in the name of Rhone Poulenc Rorer), published on Dec. 24, 1997, disloses, inter alia, compounds of formula
wherein 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 B is methylene, ethylene, amino, CONH or a bond;
Cy is phenyl or a 5- or 6-membered heterocycle containing from 1 to 3 nitrogen atom(s), being both the residues optionally substituted by one or more substituent(s);
R is H, phenyl or a (C
1-4
)alkyl group optionally substituted by an aromatic or hydrogenated ring containing from 5 to 7 members;
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 group optionally containing an oxygen atom and optionally substituted by a polar substituent;
and the N→O derivatives and pharmaceutically acceptable salts thereof;
with

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