Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-10-20
1999-10-26
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540496, C07D48706, C07D51900, A61K 3155
Patent
active
059729279
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel [1,4]diazepino[6,7,1-hi]indoles which are useful for the preparation of medicinal products which make it possible to treat complaints that fall within the scope of a therapy by a phosphodiesterase 4 inhibitor. These medicinal products are useful in particular as antiinflammatory agents, antiallergic agents, bronchodilators or antiasthmatic agents, and are devoid of secondary effects on the heart or digestive system.
TECHNICAL BACKGROUND OF THE INVENTION
In contrast to the properties disclosed by the present invention, the prior art is based on is [1,4]diazepino[6,7,1-hi]indoles for which antagonist properties with respect to cholecystokinin (CCK) and/or gastrin are described, and which are proposed for complaints of the digestive tract: stomach, intestine, pancreas and gall bladder, and in particular eating disorders.
Thus, European patent application No. 340,064 describes compounds of formula: ##STR2## in which R.sub.1 and R.sub.2 are hydrogen or halogen, Ar is indolyl or phenyl and n is 2 or 3. These compounds are peripheral cholecystokinin antagonists (CCK.sub.A).
European patent application no. 360,079 describes peripheral and/or central CCK-antagonist compounds of formula: ##STR3## in which R.sup.1 is optionally substituted aryl, X is oxygen or methylene optionally substituted with a lower alkyl radical, A is a bond or lower alkylene which may have one or more lower alkyl groups, and R.sup.2 is hydrogen or acyl. Unpublished French patent application No. FR 94/12282 describes the application of diazepinoindole derivatives of formula ##STR4## in which R is hydrogen, lower alkyl or lower alkoxy, and A is an optionally substituted aromatic ring, some of which derivatives are novel, for the preparation of medicinal products intended for the treatment of complaints that fall within the scope of a phosphodiesterase 4 inhibitor.
As regards the inhibition of phosphodiesterases, it is recalled that adenosine 3', 5'-cyclic monophosphate (cAMP) is a ubiquitous intracellular second messenger, which is intermediate between a first messenger (hormone, neurotransmitter or autacoid) and the functional responses of the cell: the first messenger stimulates the enzyme responsible for the synthesis of cAMP; depending on the cells under consideration, the cAMP then becomes involved in a great many functions: metabolic, contractile or secretory.
The effects of cAMP come to an end when it is degraded by cyclic nucleotide phosphodiesterases, intracellular enzymes which catalyze its hydrolysis into inactive adenosine 5'-monophosphate.
In mammals, it is possible to distinguish at least five major classes of cyclic nucleotide phosphodiesterase (PDE) numbered from 1 to 5 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 PDEs 4 are specific for cAMP.
Nonspecific phosphodiesterase inhibitor compounds are known, these inhibiting several classes of enzymes. This is the case for certain methylxanthines 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. In contrast, certain classes of PDE can be selectively inhibited by various pharmacological agents: hydrolysis of the cyclic nucleotides is slowed down and thus their concentration increases only in those cells containing the type of PDE which is sensitive to the inhibitor.
Particular interest is evident for phosphodiesterases 4 (PDEs 4), which have been identified in many tissues including the central nervous system, the heart, vascular endothelium, vascular smooth muscle and that of the airways and the myeloid and lymphoid lines.
An increase in cAMP in the cells involved in inflammation inhibits their activation: inhibition of the synthesis and of the release of mediators at the level of mastocytes, monocytes, e
REFERENCES:
patent: 5082937 (1992-01-01), Calvet et al.
patent: 5852190 (1998-12-01), Pascal et al.
Calvet Alain
Dahl Svein G.
Jacobelli Henry
Pascal Yves
Payne Adrian
Crissey Todd M.
Jouveinal
Kifle Bruck
Shah Mukund J.
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