Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-30
2003-02-25
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S234000
Reexamination Certificate
active
06525055
ABSTRACT:
The present invention relates to tricyclic 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 of 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 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 cAMP hydrolysis 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 EP 0 526 840 (iKyowa Hakko Kogyo) claims compounds of formula
wherein R
1
is hydrogen, (C
1-6
)alkyl, (C
7-15
)arylalkyl or optionally substituted aryl; and R
2
is hydrogen, (C
1-6
)alkyl, thienyl or optionally substituted aryl. These compounds are said to be active, inter alia, as antiinflammatories, immunosuppressives, bronchodilators.
The patent application JP 09227563 (Lederle Japan) describes compounds of formula
wherein R is an optionally substituted amino group, Z is S or O, A and B form a benzene ring or are absent, and n is 0-2. These compounds are useful as bronchodilators, antiasthmatics, antihypertensives and anticholesterolemics.
The patent application WO 97/34893 (Astra) describes compounds of formula
wherein B, D, E and G may form a benzene ring optionally substituted by alkoxy; X is C═O, C═S, C═NR, CR
3
R
6
or NR
4
; R
3
is H or forms a bond with R
2
; R
4
is lower alkyl or forms a bond with R
2
; R
6
may be H, lower alkyl optionally substituted by phenyl, or cycloalkyl, phenyl, etc.; Y is N or CR; R
2
may be H, lower alkyl optionally substituted by phenyl COOR, NR′R″, OR, F, or cycloalkyl or may form a bond with one of R
1
, R
3
and R
4
; R
1
may be OH or lower alkyl or may form a bond with one of R
2
and R
5
; R
5
is a bond with R
1
or R
8
; Z is OR
8
or O; and Ar
1
may be optionally substituted phenyl, pyridyl, pyrimidyl. These compounds have an antiinflammatory activity.
The patent application WO 98/09969 (Astra) describes compounds of formula
wherein A, A
1
, A
2
and A
3
may be CH or CR
4
, X may be CH
2
or O; Y may be a bond, CH
2
, C═O, C substituted by alkyl in turn substituted by a cyclic residue; Z is a bond or CH
2
; R
1
is hydrogen, lower alkyl or alkoxy; R
2
and R
3
are hydrogen or form a bond; and R
4
may be optionally substituted alkoxy. These compounds have an antiinflammatory and antiallergic activity.
The patent application DE 19617862 (Schering AG) describes compounds of formula
wherein, inter alia, R
1
and R
2
are H, alkyl, nitro, halogen, amino, lower alkoxy, CF
3
; R
3
and R
4
are H, alkyl, aryl, heteroaryl or cycloalkyl; X═H; Y is alkoxy or X+Y=—O—(CH
2
)
n
—O—; n=1-3; and A is a 5-member heterocycle having from 1-3 nitrogen atoms. These compounds are inhibitors of glutamate receptor.
The patent application EP 0 548 923 (Takeda Chemical Ind.) describes, inter alia, compounds of formula
wherein R
1
is H or a lower alkyl group or a halogen atom; R
4
and R
5
are H or a lower alkyl group or form a 3-7 membered cycle optionally containing a heteroatom together with the carbon atom to which they are bound; A is an optionally substituted amino group: and m, n=1-4. These compounds are antiallergics, antiinflammatories and anti-PAF (anti-piastrinic activating factor), and are useful as antiasthmatics. In fact, these compounds act through an anti-PAF mechanism which makes them bronchodilators.
Similar compounds are claimed in the patent application EP 0 620 224 (Takeda Chemical Ind.) which illustrates, inter alia, the general formula
wherein R
1
is H or a lower alkyl group or a halogen atom; X is an oxygen or sulphur atom or a —CH
2
— group; Y is a group
wherein R
4
and R
5
are H or a lower alkyl group, or is a 3-7 membered cycle optionally containing a heteroatom; R
6
and R
7
are H, an optionally substituted lower alkyl, cycloalkyl or aryl or together with the nitrogen atom to which they are bound form a heterocycle, and m, n=0-4. These compounds have the same activity claimed in the just above cited patent application.
The patent application WO 98/21208 (Byk Gulden Lomberg) claims PDE3 and PDE4 inhibitors of formula
wherein, inter alia, R
1
is an alkyl group; R
2
and R
3
are hydroxy, optionally fluorinated alkoxy, cycloalkoxy and cycloalkylmethoxy; and R
4
is a phenyl group substituted by carboxy, amido or alkoxycarbonyl and optionally substituted by halogen, alkyl, CF
3
, nitro or hydroxy. These compounds are said to be useful in the treatment of pathologies of the airways and/or of dermatosis.
It has now surprisingly been found a new class of phthalazine derivatives able to inhibit PDE 4 and TNF
&agr;
.
Therefore the present invention relates to compounds of formula
wherein
A is a 5-7 membered heterocycle containing from 1 to 4 nitrogen atoms, optionally partially or totally unsaturated, and optionally substituted by a (C
1-4
)alkyl group in turn optionally substituted;
Z is NH, methylene, a C
2-6
alkylene chain optionally branched and/or unsaturated and/or interrupted by a C
5-7
cycloalkyl residue;
Cy is phenyl or heterocycle optionally substituted by one or more substituents, or a COR
4
group wherein R
4
is hydroxy, alkoxy, amino optionally substituted by one or two (C
1-6
)alkyl groups or by hydroxy;
R is a (C
1-6
)alkyl or polyfluoro(C
1-6
)alkyl group;
R
1
is hydrogen; a (C
1-8
)-alkyl, (C
2-8
)-alkenyl or (C
2-8
)-alkynyl group optionally substituted by hydroxy, oxo, aryl or heterocycle, and optionally interrupted by one or more heteroatoms or heterogroups; a (C
1-4
)alkoxy group or a (C
4-7
)cycloalkoxy group optional
Morazzoni Gabriele
Napoletano Mauro
Norcini Gabriele
Pellacini Franco
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Raymond Richard L.
Zambon Group S.p.A.
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