1-Amino triazoloc4,3-a! quinazoline-5-ones and/or...

Details 1-Amino triazoloc4,3-a! quinazoline-5-ones and/or... 1-Amino triazoloc4,3-a! quinazoline-5-ones and/or...

2001-10-25

2004-12-07

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S228500, C514S232200, C514S254060, C514S267000, C540S603000, C544S061000, C544S132000, C544S251000

Reexamination Certificate

active

06828315

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel triazolo[4,3-a]quinazoline-5-ones and/or −5-thiones useful for drug preparation for treatment by therapy with a phosphodiesterases 4 inhibitor. These drugs are useful in particular as anti-inflammatories, anti-allergics, bronchodilatators, anti-asthmatics, or TNF &agr;. inhibitors.
BACKGROUND OF THE INVENTION
The cyclic adenosine 3′, 5′-monophosphate (AMPc) is an second ubiquitous intracellular messenger, acting as an intermediate between a first messenger (hormone, neurotrasmitter, or autacoid) and the cellular functional responses: the first messenger stimulates enzyme responsible of the AMPc synthesis; AMPc intervenes then, relying of the cells implicated, in very numerous functions: metabolic, contractile, or secretory.
The effects of AMPc terminate when it is broken down by cyclic nucleotide phosphodiesterases, intracellular enzymes that catalyze its hydrolysis into inactive adenosine 5′-monophosphate. In mammals we distinguish at least seven large families of cyclic nucleotide phosphodiesterases (PDE) numbered from 1 to 7 according to their structure, their kinetic behavior, their substrate specificity, or their sensitivity towards effectors (Beavo J. A. et al (1990) Trends Pharmacol. Sci. 11, 150-155. Beavo J. A. et al (1994) Molecular Pharmacol. 46, 399-405). PDE4s are specific to AMPc.
Some phosphodiesterase non-specific inhibitors are known as inhibiting several families of enzymes. This is the case for some methylxanthins like theophyllin. These compounds have a weak therapeutic index, in particular because of their action on some classes of PDE present in cells other than target cells. Additionally, some families of PDE may be selectively inhibited by various pharmacological agents : hydrolysis of cyclic nucleotides slowed down and therefore their concentration increase in only cells the type of PDE sensitive to the inhibitor is found. Of interest are the phosphodiesterases 4 (PDE4), which have been identified in numerous tissues including the central nervous system, heart, vascular endothelium, vascular smooth muscle and the one of air passage muscle, myeloid and lymphoid lines. AMPc increase in cells implicated in inflammation inhibits their activation:inhibition of synthesis and mediator release in mastocytes, monocytes, eosinophil and basophil polynuclears, inhibition of chimiotactism and degranulation of eosinophil and neutrophil polynuclears, inhibition of division and differentiation of lymphocytes.
The cytokins, in particular TNF and interleukins, produced by different leukocyte classes such as T lymphocytes and eosinophil polynuclears, play an important role in the triggering of inflammatory manifestations in particular in response to stimulation by an allergen in respiratory tracts.
Further, AMPc decreases air passage smooth muscular fiber tonicity; PDE4 inhibitors bring about bronchorelaxation.
Chronic obstructive pneumopathy (chronic obstructive pulmonary disease or COPD) is a chronic pathology, of slow evolution, characterized by obstruction of respiratory tracts (associated with inflammation of respiratory tracts and elevated neutrophil count). Pulmonary function alteration is largely irreversible (although improvement is possible after treatment by bronchodilatators).
Clinical presentation of chronic obstructive pneumopathy may fluctuate according to attack severity, going from simple non-invalidating chronic bronchitis to very invalidating conditions like chronic respiratory insufficiencies. The main clinical characteristics of patients suffering from chronic obstructive pneumopathy are chronic bronchitis and/or emphysema (associated with respiratory tract inflammation and/or elevated neutrophil count). Over the last years, some selective inhibitors of second-generation phosphodiesterase 4 have been suggested as potentially efficient agents in treatment of chronic obstructive pneumopathy. See, among others, Doherty,
Chemical Biology
1999, 3:466-473; Mohammed and al,
Anti
-
inflammatory
&
Immunodilatory Investigational Drugs
1999 1(1):1-28 ; Schmidt and al,
Clinical and Experimental Allergy,
29, supplement 2, 99-109.
Ariflo that is a PDE 4 inhibitor active by oral route, has been suggested for chronic obstructive pneumopathy treatment. See, among others : Nieman and al, Am J Respir Crit Care Med 1998, 157:A413; Underwood and al, Eur Respir J 1998, 12:86s; Compton and al, Am J Respir Crit Care Med 1999, 159:A522. See also the oral presentation by Compton during the meeting of the “European Respiratory Society” which was held in Madrid, on 12
th
October 1999, as well as the one by Torphy and Underwood during the 4
th
worldwide congress on inflammation which was held in Paris, from 27
th
to 30
th
June 1999. Ariflo is currently under study, in some phase III clinical trials, for chronic obstructive pneumopathy treatment.
However, we should point out that Ariflo has some drawbacks. Indeed some significant adverse events, of the nausea and vomiting type, have been reported after administering of a dose of 20 mg as a single intake. See Murdoch and al, Am J Respir Crit Care Med 1998, 157:A409. Appearance of adverse effects at such low doses will limit the call for Ariflo and prevent use of daily single dosage pharmaceutical, leading therefore to patient discomfort. Osteoporosis is a disease characterized by bone mass decrease and skeleton architecture loss, leading to bone fracture. A large number of women, at the post-menopausal stage, suffer this disease and patient numbers keeps increasing.
Two types of distinct cells exist in bone : osteoblasts, which participate in bone formation; and osteoclasts, which play a role in bone resorption. More particularly, bone mass results from the sum of bone formation by osteoblasts and bone resorption by osteoclasts. Consequently, molecules inhibiting bone resorption induced by osteoclasts are efficient in osteoporosis treatment. Calcitonin, biphosphonates and possibly estrogens are agents fighting against resorption and they are used in the clinical area Molecules stimulating bone formation by osteoblasts also constitute some promising agents in osteoporosis treatment. See also, Yoshihiro et al Jpn. J. Pharmacolog. 1999, 79, 477-483. For several years, extensive research has been performed to obtain and develop powerful PDE4 inhibitors. This has proved to be difficult due to the fact that lots of potential PDE4 inhibitors have some activity on phosphodiesterases in other families.
To date, the lack of selectivity of PDE4 inhibitors represents then an important problem, given the extent of functions regulated by AMPc. There is now a need for powerful and selective PDE4 inhibitors, thus without effect on PDE belonging to other families.
European patent EP 0076199 disclosed compounds with the following general formula:
in which R and R′, identical or different, represent H, halogen, alkyl C
1-3
, alkoxy or nitro; Y represents alkyl cycloalkyl C
3-8
, alkenyl C
2-4
, aryl ou aralkyl group, and B represents (CH
2
)
n
with n=1, 2, 3 or CH(CH
3
). The use of these compounds is suggested for treatment of asthma, bronchitis and allergic disorders.
Patent DDR158549 disclosed compounds with 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, S-alkyl; R
4
represents H, alkyl, halogenoalkyl, OH, SH, O-alkyl, S-alkyl, SO
2
-alkyl, NH
2
, SCN, aryl, (CH
2
)
n
COOalkyl and n=0 to 2. The use of these compounds is suggested as am diuretics and antianaphylactics.
Ram and al., in J.Prakt.Chem, 1990, 332(5), 629-39 describe compounds with the following general formula:
The use of these compounds is suggested for treatment of high blood pressure.
SUMMARY OF THE INVENTION
The invention related to triazolo[4,3-a]quinazoline-5-ones and/or −5-thiones of formula I or II:
I and II are position isomers of group R on nitrogens 3 or 4, in which:
A
1
is O or S;
X
1
and X
2
, similar or different, represent:
hydrogen, h

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