Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-22
2004-09-07
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S217060, C540S600000, C544S251000
Reexamination Certificate
active
06787554
ABSTRACT:
The present invention relates to triazolo[4,3-a]pyrido[2,3-d]pyrimidine-5-one derivatives of general formula (I):
in which R1, R2, X and R have the meanings indicated below, their regioisomers, their salts and their solvates if they exist, their preparation, compositions containing them and their use.
Cyclic adenosine 3′,5′-monophosphate (cAMP) is an omnipresent second intracellular messenger. More recently, cAMP is an intermediate between the first messenger (hormone, neurotransmitter or autacoid) and functional cell responses. The first messenger stimulates the enzyme responsible for the synthesis of cAMP which then becomes involved, depending on the relevant cells, in a large number of functions (metabolic, contractile or secretory functions for example). The effects of cAMP stop when it is degraded by cyclic nucleotide phosphodiesterases (PDE), which are intracellular enzymes which catalyse the hydrolysis of cAMPs to inactive adenosine 5′-monophosphate.
At least 11 large families of phosphodiesterases (PDE) have been identified in mammals. These families are 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., 1990, Trends Pharmacol. Sci., 11, 150-5; Beavo J. A. et al., 1994, Molecular Pharmacol., 46, 399-405).
Nonspecific PDE inhibiting compounds, that is to say which inhibit several families of enzymes, are known. That is the case, for example, for certain methylated xanthines such as theophylline. These compounds have a low therapeutic index, in particular because of their action on types of PDE present in cells other than the target cells. Conversely, some families of PDE may be selectively inhibited by various pharmacological agents. The hydrolysis of cyclic nucleotides is then slowed and their concentration increases as a result, but only in the cells containing the type of PDE sensitive to the inhibition.
One particular advantage of the PDE4 enzymes has been shown. Indeed, these enzymes are widely represented in the inflammatory and immunocompetent cells, and induce a reduction in the level of cAMP. The inhibition of these enzymes by PDE4-specific inhibitors thus leads to an intracellular increase in cAMP and to a consequent decrease in the functions of the inflammatory cells. In addition, cAMP reduces the tonicity of the smooth muscle fibres of the airways. Thus, PDE4 inhibitors also cause bronchorelaxation. Various experiments in models of pulmonary inflammation such as that described in asthma have, for example, shown that PDE4 inhibitors induce a drastic reduction in the influx of the inflammatory cells and a considerable decrease in bronchial hyperreactivity. Recently, the use of PDE4 inhibitors has also been recommended in the treatment of chronic obstructive pulmonary disease and rheumatoid arthritis. Moreover, as PDE4 inhibitors have been described as potential blockers of the production of TNF&agr;, these compounds ought to be beneficial in the context of the treatment of a pathology involving this proinflammatory cytokine.
Thus, numerous research studies have been carried out in order to identify selective PDE4 inhibitors having a therapeutic activity as anti-inflammatory and anti-allergic medicaments, and in the treatment of various respiratory diseases such as asthma, emphysema and chronic bronchitis. These research studies are long and difficult since a number of potential PDE4 inhibitors are not free of activity on the phosphodiesterases of the other families. To date, the lack of selectivity of the PDE4 inhibitors therefore represents a major problem, given the large number of functions regulated by cAMP. Adding to this problem is the fact that the PDE4 inhibitors proposed up until now quite often induce undesirable effects, in particular nausea and vomiting. In parallel, the PDE4 inhibitors proposed up until now sometimes exhibit poor overall bioavailability.
Patent application WO 00/66584 proposes selective PDE4 inhibitors of formula:
Other publications also describe triazoloquinazolinone derivatives having a structural unit similar to the structure indicated above and which carry various substituents, for the treatment of asthma, bronchitis and allergic disorders (EP 0 076 199), as diuretic and antianaphylactic agents (DDR 158 549), or as antihypertensives (Ram et al., J. Prakt. Chem., 1990, 332 (5), 629-39).
Application WO 92/08719 describes compounds of formula:
which are useful as herbicides.
On the basis of the same structural unit, but carrying other substituents, there have finally been described:
1) the compounds of formula:
as antihypertensives (DE 3601731) or as analgesics (EP 0 316 668),
2) the compounds of formula:
for treating bronchial asthma (EP 0 994 113) or for treating dermatitis when the substituent is a benzyl (EP 1 145 716),
3) the compounds of formula:
as antiallergics (EP 0 243 311).
It has now been found that the triazolo[4,3-a]pyrido[2,3-d]pyrimidin-5-one derivatives of general formula (I) in which:
X represents a radical chosen from:
hydrogen,
hydroxyl, halogen, amino, nitro, mercapto, cyano or carboxyl radicals,
alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl radicals optionally substituted with 1, 2 or 3 halogen atoms,
the radicals —NR3R4 with R3 and R4, which are identical or different, chosen from the following radicals:
hydrogen,
alkyl optionally substituted with 1, 2 or 3 groups chosen from halogen, hydroxyl, cyano and alkoxy,
—C(O)R5 with R5 chosen from hydrogen or alkyls optionally substituted with a hydroxyl, alkoxy, mercapto or alkylthio radical,
—(CH2)x-cycloalkyl optionally substituted with a hydroxyl, alkoxy, mercapto, alkylthio, amino, alkylamino, N-alkyl, N-alkylamino or alkyl radical comprising 1, 2, 3 or 4 carbon atoms in the form of a linear or branched chain, x being an integer chosen from 0, 1, 2, 3 and 4,
the radicals of formula:
in which:
n is an integer chosen from 0 and 1,
when n=1, then A represents either a hydrogen atom or a substituent CO—Q1—Q2—Q3,
Q1 represents a radical oxy(—O—), —NH—,
p and p′ being integers chosen, independently of each other, from 0, 1, 2 and 3 and Z representing a —CH—, —N— or alternatively oxy group,
Q2 represents either a group —(CH2)q—, q being an integer chosen from 0, 1, 2, 3 and 4, or a group —(CH2—CH2—O)r—, r being an integer chosen from 2, 3 and 4, and
Q3 represents a hydrogen atom or a radical chosen from hydroxyl, methoxy, —O—CO—X1, —NHX2 and —N(X1)X2, X1 and X2, which are identical or different, representing an alkyl radical or X1 and X2 being linked such that they form, together with the nitrogen atom to which they are attached, an azacycloalkyl radical comprising 3, 4, 5, 6, 7, 8, 9 or 10 members and being capable, in addition, of comprising 1, 2 or 3 heteroatoms chosen from oxygen, sulphur and/or nitrogen,
it being possible for the substituents —CO—Q1—Q2—Q3 to be identical or different within the same unit of formula [N(A)]n—CO—Q1—Q2—Q3, and
the radicals of formula:
in which the ring formed with the nitrogen atom comprises 3, 4, 5, 6, 7, 8, 9 or 10 members and may, in addition, comprise 1, 2 or 3 heteroatoms chosen from oxygen, sulphur and/or nitrogen, it being possible for the said ring to also be bridged by an alkyl, to be gem dialkylated or substituted with 1, 2 or 3 groups chosen from hydroxyl, oxo, alkyl and/or alkoxy radicals or with a group —CO—Q1—Q2—Q3 as defined above,
R represents a radical chosen from:
alkyl, alkenyl, alkynyl, 2-, 3- or 4-pyridylalkyl radicals, it being possible for the said pyridyls to be optionally substituted once, twice or three times with alkyl, alkoxy, hydroxyl, halogen and/or amino radicals,
the radicals of the following formulae:
in which:
s is an integer chosen from 1, 2, 3 and 4,
Ar represents a 5- or 6-membered aryl radical which may comprise, in addition, 1, 2, 3 or 4 heteroatoms chosen from oxygen, sulphur and/or nitrogen,
Y1, Y2 and Y3, which are identical or different, are radicals chosen from:
hydrogen, h
Raymond Richard L.
Ronau Robert T.
Warner-Lambert LLC
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