Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-22
2002-01-22
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S237000
Reexamination Certificate
active
06340684
ABSTRACT:
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 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. 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-0 017 411 (in the name of Pfizer) illustrates phthalazines of formula:
wherein
R
1
is a lower alkyl; and Y is —(CH
2
)
m
—Z wherein m is 1 or 2 and Z is carbamoyloxy, carbonylamino, sulphamoyl, ureido, amino-sulphamoyl, carboxyamino substituted in the terminal position by a (C
3-7
)cycloalkyl. These compounds are said to be inhibitors of the phosphodiesterases with stimulant function on the cardiac muscle, therefore their activity does not relate to PDE 4.
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 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 heteroarylalkyl group, 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 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 hypotensive activity, with no mention of the mechanism of action.
The patent 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 5 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-, 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.
The patent application NL 8005411 (in the name of Mitsubishi Yuka) describes phthalazines of formula:
wherein X is oxygen 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. These compounds are used as inhibitors of the piastrinic aggregation.
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.
It has now been 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;
B is NH, methylene, a C
2-6
alkylene chain optionally branched and/or unsaturated and/or interrupted by a C
5-7
cycloalkyl residue;
A is phenyl or heterocycle optionally substituted by one or more substituent(s) or a COR
4
group wherein R
4
is hydroxy, C
1-4
alkyl, amino optionally mono- or di-substituted by a C
1-6
-alkyl group or monohydroxylated;
R represents two hydrogen atoms or a C═O group when
is a single bond or, when
is a double bond, is hydrogen, optionally substituted aryl or heterocycle, (C
1-8
)-alkyl, (C
2-8
)-alkenyl or (C
2-8
)-alkynyl optionally substituted by aryl or heterocycle; aryloxy, heterocyclyloxy, aryl-C
1-4
-alkoxy, heterocyclyl-C
1-4
-alkoxy, amino substituted by one or two C
1-4
-alkyl group(s), aryl-amino, heterocyclyl-amino, aryl-C
1-4
-alkyl-amino, heterocyclyl-C
1-4
-alkylamino;
R
1
is a C
1-6
-alkyl, aryl, aryl-C
1-10
-alkyl, C
4-7
-cycloalkyl group optionally containing an oxygen atom and/or substituted by a polar substituent;
R
2
is a C
1-6
-alkyl, polyfluoroC
1-6
-alkyl group;
R
3
is absent when
is a double bond, or, when
is a single bond, is hydrogen;
C
1-6
-alkyl optionally substituted by aryl, by heterocycle or by a COR
5
group wherein R
5
is hydroxy, C
1-4
-alkoxy or hydroxyamino;
—COR
6
wherein R
6
is hydrogen, aryl, aryl-C
1-6
-alkyl, amino optionally alkylated or monohydroxylated, hydroxy, C
1-4
-alkoxy, carboxy, C
1-4
-alkoxycarbonyl,
or C
1-4
-alkyl optionally substituted by heterocycle;
d) C
1-4
-alkyl-sulfonyl;
the N→O derivatives of the compounds of formula I and the pharmaceutically acceptable salts thereof;
provided that when
is a double bond, A is phenyl or nitrogen heterocycle, and R
1
is an aryl, aryl-C
1-10
-alkyl, C
4-7
-cycloalkyl optionally containing an oxygen atom and/or substituted by a polar substituent; then R is different from hydrogen, phenyl or (C
1-4
)alkyl optionally substituted by aryl.
The proviso present in the meanings of formula I has the aim of excluding the compounds described in the Italian patent application no. MI97A002806 in the name of the same Applicant.
Preferred compounds of formula I are those wherein
is a single or double bond;
B is methylen
Grancini Giancarlo
Morazzoni Gabriele
Napoletano Mauro
Norcini Gabriele
Pellacini Franco
Bernhardt Emily
Zambon Group S.p.A.
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