Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-10
2001-05-29
Kifle, Bruck (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S496000
Reexamination Certificate
active
06239130
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new [1,4]diazepino[6,7,1-hi]indol-4-ones which are useful for the preparation of medicaments that enable complaints which are amenable to therapy by a phosphodiesterase 4 inhibitor to be treated. These medicaments are useful, in particular, as anti-inflammatories, anti-allergics, bronchodilators or anti-asthmatics and are bereft of digestive or cardiac side-effects. Conditions also amenable to treatment with a compound according to the invention include inflammatory bowel diseases like ulcerative colitis and Crohn's disease, disorders characterized by a significant increase of TNF-&agr;, such as pulmonary hypertension (primary or secondary), liver failure in particular following immunologic or inflammatory hepatic injury, bone loss (osteoporosis or osteomalacia), septic shock, and multiple sclerosis.
TECHNOLOGICAL BACKGROUND OF THE INVENTION
Cyclic adenosine 3′,5′-monophosphate (cAMP) is a ubiquitous intracellular second messenger, intermediate between a first messenger (hormone, neurotransmitter or autacoid) and the cellular functional responses: the first messenger stimulates the enzyme responsible for cAMP synthesis; cAMP then participates, depending on the cells in question, in a very large number of functions: metabolic, contractile or secretory.
The effects of cAMP come to an end when it is degraded by the cyclic nucleotide phosphodiesterases, intracellular enzymes which catalyze its hydrolysis to inactive adenosine 5′-monophosphate.
In mammals, at least seven types of cyclic nucleotide phosphodiesterases (PDE) are distinguished, numbered from 1 to 7 according to their structure, their kinetic behavior, their substrate specificity or their sensitivity to effectors (Beavo J. A. et al. (1990) Trends Pharmacol. Sci. 11, 150-155. Beavo J. A. et al. (1994) Molecular Pharmacol. 46, 399-405). The distribution of these different types varies according to the tissues.
Accordingly, a specific inhibitor of one type of PDE isoenzyme should bring about an increase in the cAMP only in the cells in which this type of enzyme is to be found.
An increase in the cAMP in the leukocytes involved in inflammation inhibits their activation: inhibition of the synthesis and release of mediators in the mast cells, monocytes, eosinophilic and basophilic polynuclear leukocytes, inhibition of neutrophilic and eosinophilic polynuclear leukocyte chemotaxis and degranulation, inhibition of lymphocyte division and differentiation. Among these mediators, the cytokines, in particular (tumor necrosis factor)TNF-&agr; and interleukins, produced by the T lymphocytes and eosinophilic polynuclear leukocytes play an important part in the triggering of inflammatory manifestations, especially in response to stimulation by an allergen in the airways. Furthermore, cAMP decreases the tonus of the smooth muscle fibers of the airways.
In these cells and these tissues, the PDE4 enzymes play an important part in the hydrolysis of cAMP. Selective PDE4 inhibitors can hence be expected to possess therapeutic activity as anti-inflamnnatory, antiallergic and bronchodilatory medicaments, and in the treatment of asthma where an infiltration of the airways by inflammatory cells and bronchoconstriction are observed. Asthma is a frequent and often severe condition. While mortality trends for other medical conditions amenable to treatment have declined in recent decades, asthma has become more prevalent, more severe and more deadly, despite the availability of improved pharmacotherapy to treat it (Lang D. M., Ann. Allergy Asthma Immunol ,1997; 78: 333-7.) Prevalence is especially high in children, which makes the availability of an oral treatment highly desirable.
For some years, extensive research has been carried out in order to obtain and develop potent PDE4 inhibitors. This proves difficult on account of the fact that many potential PDE4 inhibitors are not without activity with respect to the phosphodiesterases of the other families.
The level of activity and of selectivity of PDE4 inhibitors represents a considerable problem in view of the range of flnctions which are regulated by cAMP. There hence exists a need for potent and selective PDE4 inhibitors, that is to say ones that have no action with respect to the PDEs belonging to other families. The international Patent Application published under No. WO 96 11690 describes the application of diazepinoindolone derivatives of formula
in which R is hydrogen, lower alkyl or lower alkoxy and A is an optionally substituted aromatic ring system, for the preparation of medicaments intended for the treatment of complaints which are amenable to a phosphodiesterase 4 inhibitor. International Application WO 97/36905 describes diazepinoindoles of formula
in which A is aryl or nitrogenous heteroaryl, optionally substituted; B is a hydroxyl or amino radical which is itself optionally substituted. These products are useful for treating complaints which are amenable to therapy by the inhibition of PDE4.
The search for potent and selective PDE4 inhibitors remains a major objective for the treatment of pathologies in which the PDE4 enzymes are involved.
SUMMARY OF THE INVENTION
The present invention provides new [1,4]diazepino[6,7,1-hi]indol-4-one derivatives, which are very potent PDE4 inhibitors, at concentrations at which they have no action on the other PDE families.The invention relates to the diazepinoindolones (I) of formula
in which:
A is hydrogen, C
1
-C
4
alkyl, OR
1
, hydroxy, nitro, cyano, —NH
2
, —NHR
1
, or —NR
1
R
2
;
R
1
and R
2
independently are C
1
-C
4
alkyl, cyclopropyl, cyclopropylmethyl, or NR
1
R
2
taken together with the nitrogen to which they are bound complete a ring having 4 or 5 carbon atoms;
B is hydrogen, C
1
-C
4
alkyl, —CH
2
OM, —CH
2
OC(═O)(CH
2
)
a
(CO)
b
Y
1
-Y
2
, or
—(CH
2
)
c
C(═O)OM;
Y
1
is —(VCH
2
CH
2
)
c
—, with V═—NH— or —O—; or Y
1
is —NHCHR
A
—C(═O)—;
Y
2
is hydrogen, hydroxy, —OCH
3
, or 4-morpholinyl;
M is hydrogen or C
1
-C
4
alkyl;
a=1 or 2; b=0 or 1; c=0, 1, or 2;
Z is CH, then Z
1
and Z
2
both are CH or N; or
Z is N, then Z, and Z
2
are CH;
X
1
and X
2
independently are hydrogen, C
1
-C
4
alkyl, —(CH
2
)
n
—OR , halogen, cyano,
—O—C
1
-C
6
alkyl, —C(═O)R
3
, C(═O)OR
3
,—C(═O)NR
4
R
3
, or
R
3
is hydrogen, C
1
-C
6
alkyl, benzyl, phenethyl, or —Q
1
-Q
2
;
R
4
is hydrogen, or C
1
-C
4
alkyl;
R
5
is hydrogen, C
1
-C
4
alkyl, —CHR
A
—C(═O)OM
1
, or —Q
3
-Q
4
,
R
6
is hydrogen, C
1
-C
4
alkyl, or —Q
3
-Q
5
;
R
A
is a residue of a natural &agr;-amino-acid, the carbon atom to which it is linked having either a S configuration, or a R configuration;
Q
1
is —(CH
2
)
n
—(CHOH)
m
—(CH
2
)
p
—;
Q
2
is hydroxy, —O—C
1
-C
6
alkyl, —OC(═O)—C
1
-C
6
alkyl, or 4-morpholinyl;
Q
3
is —(CH
2
)
n
—;
Q
4
is —NHM
1
, —NM
1
M
2
, or 4-morpholinyl;
Q
5
is —M
1
or —OM
1
;
M
1
and M
2
are independently hydrogen or C
1
-C
4
alkyl;
n is 1,2, or 3; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3, provided that if mis not 0, then p is not 0;
their racemic forms and each of their isomers, in particular those whose configuration is determined by carbon 3 of the [1,4]diazepino[6,7,1-hi]-indol-4-one ring system,
and the pharmaceutically acceptable salts, solvates, esters, amides, and prodrugs thereof.
The invention also relates to a process for preparing them and to their application for obtaining medicaments intended for treating complaints which are amenable to therapy by the inhibition of PDE4.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to the diazepinoindolones (I) of formula xi
in which:
A is hydrogen, C
1
-C
4
alkyl, OR
1
, hydroxy, nitro, cyano, —NH
2
, —NHR
1
, or —NR
1
R
2
;
R
1
and R
2
independently are C
1
-C
4
alkyl, cyclopropyl, cyclopropylmethyl, or NR
1
R
2
taken together with the nitrogen to which they are bound complete a ring having 4 or 5 carbon atoms;
B is hydrogen, C
1
-C
4
alkyl, —CH
2
OM, —CH
2
OC(═O)(CH
2
Burnouf Catherine
Calvet Alain
Dahl Svein
Gaudilliere Bernard
Jacobelli Henry
Ashbrook Charles W.
Kifle Bruck
Warner-Lambert & Company
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