1-alkyl or...

Details 1-alkyl or... 1-alkyl or...

2002-08-02

2004-06-08

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S251000

Reexamination Certificate

active

06747035

ABSTRACT:

This application is filed claiming priority from co-pending European Patent Application Number 01402168.1, filed Aug. 13, 2001.
FIELD OF THE INVENTION
The present invention relates to novel 1-alkyl or 1-cycloalkyltriazolo[4,3-a]quinazolin-5-ones which are useful for the preparation of medicinal products for treating complaints that fall within the domain of a treatment with a phosphodiesterase-4 (PDE4) inhibitor. These medicinal products are useful in particular as anti-inflammatory agents, antiallergic agents, bronchodilators, anti-asthmatic agents or TNF&agr; inhibitors.
TECHNOLOGICAL BACKGROUND OF THE INVENTION
Cyclic adenosine 3′, 5′-monophosphate (cAMP) is a ubiquitous intracellular second messenger, which is intermediate between a first messenger (hormone, neurotransmitter or autacoid) and the cellular functional responses: the first messenger stimulates the enzyme responsible for the synthesis of cAMP; depending on the cells concerned, the cAMP then intervenes in a great number of functions: metabolic, contractile or secretory.
The effects of cAMP end when it is degraded by cyclic nucleotide phosphodiesterases, which are intracellular enzymes that catalyze its hydrolysis into inactive adenosine 5′-monophosphate.
At least eleven major families of cyclic nucleotide phosphodiesterases (PDE) have been distinguished in mammals, numbered from 1 to 11 according to their structure, their kinetic behaviour, their substrate specificity or their sensitivity to effectors (Beavo J. A. et al. Trends Pharmacol. Sci. (1990) 11, 150-155. Beavo J. A. et al. Molecular Pharmacol. (1994) 46, 399-405). The PDE4 enzymes are specific for cAMP.
Non-specific phosphodiesterase inhibitory compounds are known, which inhibit several families of enzymes. This is the case for certain methyl xanthines such as theophylline. These compounds have a low therapeutic index, in particular on account of their action on types of PDE present in cells other than the target cells. Conversely, certain families of PDE can be selectively inhibited by various pharmacological agents: the hydrolysis of cyclic nucleotides is slowed down and their concentration thus increases in only the cells in which the type of PDE that is sensitive to the inhibitor is found.
A specific advantage is shown for the phosphodiesterases 4 (PDE4), which have been identified in many tissues including the central nervous system, the heart, vascular endothelium, vascular smooth muscle and that of the aerial pathways, myeloid lines and lymphoid lines.
An increase in cAMP in the cells involved in inflammation inhibits their activation: inhibition of the synthesis and release of mediators in mastocytes, monocytes, polymorphonuclear eosinophils and basophils, inhibition of chemotaxis and degranulation of polymorphonuclear neutrophils and eosinophils, inhibition of the proliferation and differentiation of lymphocytes.
Cytokines, in particular TNF and interleukins, produced by various types of leukocytes such as the T lymphocytes and polymorphonuclear eosinophils, play an important role in triggering inflammatory manifestations, in particular in response to stimulation by an allergen in the respiratory pathways.
Moreover, cAMP reduces the tonus of the smooth muscle fibres in the aerial pathways; PDE4 inhibitors bring about bronchorelaxation.
Chronic obstructive pulmonary disease (COPD) is a chronic pathology, of slow evolution, which is characterized by obstruction of the respiratory pathways (associated with an inflammation of the respiratory pathways and an elevated neutrophil count). The impairment in pulmonary function is for the most part irreversible (although improvements are possible by treatment with bronchodilators).
The clinical presentation of chronic obstructive pulmonary disease can vary according to the seriousness of the attack, ranging from a simple, non-incapacitating chronic bronchitis to a highly incapacitating condition of the type with chronic respiratory insufficiency. The main clinical characteristics of patients suffering from chronic obstructive pulmonary disease are chronic bronchitis and/or emphysema (associated with an inflammation of the respiratory pathways and/or an elevated neutrophil count).
In the course of recent years, selective second-generation phosphodiesterase-4 inhibitors have been proposed as agents that are potentially effective in the treatment of chronic obstructive pulmonary disease (see, inter alia, Doherty,
Current opinion in Chemical Biology
1999, 3:466-473; Mohammed et al.,
Anti
-
inflammatory
&
Immunodilatory Investigational Drugs
1999 1(1):21-28; Schmidt et al.,
Clinical and Experimental Allergy,
29, supplement 2, 99-109).
Ariflo, a PDE4 inhibitor which is active via the oral route, has been proposed for the treatment of chronic obstructive pulmonary disease (see, inter alia: Nieman et al., Am J Respir Crit Care Med 1998, 157:A413; Underwood et al., Eur Respir J 1998, 12 :86s; Compton et al., Am J Respir Crit Care Med 1999, 159:A522. See also the oral account by Compton given at the meeting of the “European Respiratory Society” held in Madrid on Oct. 12, 1999, as well as that by Torphy and Underwood at the 4
th
world conference on inflammation, held in Paris from Jun. 27 to 30, 1999. Ariflo is currently under study, in phase III clinical trials, for the treatment of chronic obstructive pulmonary disease.
However, it should be pointed out that Ariflo has a number of drawbacks. Specifically, significant undesirable effects, such as nausea and vomiting, have been reported after administration of a dose of 20 mg as a single intake (see Murdoch et al., Am J Respir Crit Care Med 1998, 157:A409). The appearance of undesirable effects at such low doses will limit the use of Ariflo and will prevent the use of daily single-dose pharmaceutical forms, thus leading to discomfort for the patient.
Extensive research has been carried out in recent years to obtain and develop powerful PDE4 inhibitors. This turns out to be difficult due to the fact that many of the potential PDE4 inhibitors are not without activity on the phosphodiesterases of other families.
At the present time, the lack of selectivity of PDE4 inhibitors represents a major problem, given the extent of the functions regulated by cAMP. There is thus a need for powerful and selective PDE4 inhibitors, i.e. inhibitors which have no action with respect to PDEs belonging to other families.
European patent EP 0076199 describes compounds having the following general formula:
These compounds are proposed for use in the treatment of asthma, bronchitis and allergic disorders.
Patent DD 158 549 describes compounds having the following general formula:
in which R
1
represents H, alkyl or aryl; R
2
and R
3
represent H, alkyl, halogen, OH, SH, O-alkyl or S-alkyl; R
4
represents H, alkyl, haloalkyl, OH, SH, O-alkyl, S-alkyl, SO
2
-alkyl, NH
2
, SCN, aryl or (CH
2
)
n
COOalkyl with n=0 to 2. These compounds are proposed for use as diuretics and anti-anaphylactic agents.
In J. Prakt. Chem, 1990, 332(5), 629-39, Ram et al. describe compounds having the following formula:
These compounds are proposed for use in treating hypertension.
Patent application EP 1 067 130 describes compounds having the following formula (VI)
These compounds are disclosed as intermediates for synthesis.
Patent application WO 00/66584 describes compounds having the following formulas (I) and (II):
These compounds are proposed for use as PDE4 inhibitors.
SUMMARY OF THE INVENTION
The invention relates to a compound of formula (I),
in which,
R
1
is selected from:
hydroxyl, halogen, nitro, mercapto, cyano or carboxyl,
lower alkyl or lower alkoxy, these groups being optionally substituted with 1, 2 or 3 halogen atoms,
—NR
4
R
5
in which R
4
and R
5
are the same or different and are selected from:
H,
lower alkyl, optionally substituted with 1, 2 or 3 groups selected from halogen, hydroxyl, cyano and lower alkoxy,
C(═O)R
6
in which R
6
is selected from:
lower alkyl optionally substituted with OR
7
or SR
7
, or,
—X
1
-cycloalkyl optiona

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