Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-25
2003-02-25
Davis, Zinna Nothington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S336000
Reexamination Certificate
active
06525078
ABSTRACT:
FIELD OF THE INVENTION
This application is based on European Patent Application No. 01830413.9 filed on Jun. 21, 2001, the content of which is incorporated hereinto by reference.
The present invention relates to 4-methoxy-N
1
-(4-trans-nitrooxycyclohexyl)-N
3
-(3-pyridinylmethyl)-1,3-benzenedicarboxamide (formula 1 in
FIG. 1
) as a pharmacologically active compound in the treatment of vascular diseases.
More particularly, this invention relates to 4-methoxy-N
1
-(4-trans-nitrooxycyclohexyl)-N
3
-(3-pyridinylmethyl)-1,3-benzenedicarboxamide as well as the acid addition salts thereof with pharmaceutically acceptable organic or inorganic acids as pharmacologically active compounds in the treatment of atherosclerotic-thrombotic pathological conditions and other pathological conditions which can benefit from the inhibition of thromboxane A
2
and from a pharmacological supply of nitric oxide (NO).
The invention also relates to processes for the preparation of 4-methoxy-N
1
-(4-trans-nitrooxycyclohexyl)-N
3
-(3-pyridinylmethyl)-1,3-benzenedicarboxamide and the acid addition salts thereof with pharmaceutically acceptable organic or inorganic acids.
Furthermore, the invention relates to a pharmaceutical composition comprising 4-methoxy-N
1
-(4-trans-nitrooxycyclohexyl)-N
3
-(3-pyridinylmethyl)-1,3-benzenedicarboxamide or an acid addition salt thereof with pharmaceutically acceptable organic or inorganic acids, as an active ingredient, together with at least a pharmaceutically acceptable ingredient.
The invention also relates to a method of use of both said compound and said pharmaceutical composition in the treatment of said conditions.
BACKGROUND OF THE INVENTION
Evidence is growing for a dynamic interplay between the processes of thrombosis and atherosclerosis in the vascular system, starting from the initial development of vascular diseases and continuing in the dramatic events that are the cause of death and disability in a large section of the population. Diabetes, hypertension, tobacco smoke and unhealthy dietary habits are among the leading causes of these diseases.
Blood and vascular wall exert mutual influences in their physiological functions, which are mediated by the contact of blood cells (including platelets, which differ from other cells by lacking the cellular nucleus) with the vascular endothelial and smooth muscular cells, via mechanisms of adhesion and infiltration, and by the exchange of a number of biochemical mediators.
Most of these interactions are also involved in pathological processes, such as the development of acute vasospastic conditions, the formation of occlusive thrombi and the development of atherosclerotic plaques.
The role played by activated platelets has special relevance, since the present advancement of knowledge indicates that the pro-thrombotic and pro-atherogenic role of platelet activation is not limited to the initiation of the formation of thrombi starting from platelet aggregates, but it involves adhesion and the mutual interchange of biochemical mediators with the vascular wall, especially when the latter is pathologically altered, as in the case of endothelial lesions and of atherosclerotic plaques (R Ross, NE J Med 340 (1999) 115-126; B Osterud, Thromb Res 85 (1997) 1-22).
Platelet-released mediators have a role in vasospasms, a critical mechanism of various ischemic conditions, and in the proliferation of vascular smooth muscle, an essential step of the atherosclerotic process (AA Weber, K Schror, Thromb Haemost 80 (1998) 207-208; T Grosser et al, Eur J Pharmacol 319 (1997) 327-332; R Pakala et al, Circulation 96 (1997) 2280-2286; A Sachinidis et al, Hypertension 26 (1995) 771-780), which in turn, by the alteration of the vascular surface and the rupture of plaques contributes to platelet activation and has an immediate causative role in acute thrombotic and ischemic events.
Among the mediators released by platelets, thromboxane A
2
, serotonin, and growth factors, such as PDGF and TGF-&bgr;1 are the most pathologically relevant.
On the other hand, the endothelial lining of the vascular wall, when not pathologically altered, opposes the actions of activated platelets by the release of mediators (DA Jones et at, Mol Pharmacol 48 (1995) 890-896; PM Vanhoutte, JV Mombouli, Progress in Cardiovascular Diseases 39 (1996) 229-238) such as EDRF (the endothelial derived relaxing factor, identified as NO, nitric oxide), and as prostacyclin. Both induce relaxation and reduce proliferation of the arterial wall, and counteract platelet aggregation and adhesion (U Forstermann et al, Circulation Res 63 (1988) 306-312; MW Radomski et al, Br J Pharmacol 92 (1987) 639-646).
Cellular interactions of platelets, blood cells, and vascular cells have special relevance in the synthesis of a cascade of metabolites of arachidonic acid, the eicosanoids (J Macloufet al, Thromb Haemost. 79 (1998) 691-705). Arachidonic acid is converted by the enzymatic action of the cyclooxygenases, into the endoperoxides PGG
2
and PGH
2
. These metabolites are further converted into thromboxane A
2
and into prostacyclin PGI
2
, as wells as into PGE
2
, PGD
2
and other prostaglandins, by the enzymatic action of specific synthetases.
Owing to the different cellular locations of these enzymes, the transcellular exchange of the precursor arachidonic acid (which is also carried by fragmented platelets) and, most importantly, of the endoperoxides PGG
2
and PGH
2
exerts significant influence in the generation of the biologically active eicosanoids, and among them thromboxane A
2
and prostacyclin. Important amount of endoperoxides are formed in platelet and in endothelial cells under the influence of cyclooxygenase-1. These amount predominate in normal conditions, over those produced in other cells, such as lymphocytes (including the monocyte-macrophage type) and vascular smooth muscle cells.
The synthesis of endoperoxides can however be amplified, in pathological situations, by the induction, in all the above cells, but not in platelets, of the formation of large amounts of cyclooxygenase-2. The induction is mediated by pro-inflammatory stimuli, and is marked in atherosclerosis-damaged tissues (JA Rimarachin et al, Arterioscler Thromb 14 (1994) 1021-1031; D Bishop-Bailey et al, ibid, 18 (1998) 1655-1661). It has to be noted that eicosanoids generation, via cyclooxygenase-1 and/or cyclooxygenase-2 has important physiological and pathological roles, in addition to those elicited within the circulatory system, in various body organs.
According to their respective physiological role, platelets are abundantly endowed with thromboxane synthetase, as endothelial cells are with prostacyclin synthetase.
Thromboxane A
2
, acting as an inducer of irreversible platelet aggregation and also representing an amplifying signal of platelet activation, has a key role in platelet-vascular wall interactions not only because of its direct action, but also for the stimulation of the release of the other vasospastic and proliferative mediators generated by platelets and for the progression of the fissuring of atherosclerotic plaques, leading to occlusive vascular events.
The efforts of developing clinical applications of drugs acting by inhibition of thromboxane A
2
have been enacted by different approaches. The first therapeutic approach directed to the inhibition of the synthesis of thromboxane A
2
has been based on the use of acetylsalicylic acid, which is now known to be able to inhibit cyclooxygenase-1 selectively and irreversibly; the therapeutic usefulness has been clinically demonstrated, but the blockade of the first, common step of the synthesis of the eicosanoids brings together the inhibition the synthesis of physiologically beneficial prostaglandins in the circulatory system, in particular prostacyclin, and also of prostaglandins performing a protective role in gastric and renal tissues by maintaining perfusion and cytoprotection.
The benefit of this pharmacological approach is thus limited by undesirable effects. Furthermore, acetylsalicylic acid proved to be unable to inhibit the ind
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