Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-08
2001-04-17
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S409000, C514S412000, C514S423000, C548S409000, C548S322500, C548S492000, C548S533000
Reexamination Certificate
active
06218417
ABSTRACT:
The present invention relates to products having an antihypertensive activity combined with a platelet-antiaggregating activity, and pharmaceutical compositions thereof.
In particular, it relates to products having an improved antihypertensive activity and fewer side effecs, in particular in the bronchi, compared to the products currently being marketed as antihypertensive agents. The antihypertensive activity is combined with a platelet-antiaggregating activity.
Antihypertensive agents are known in the art. Particularly known are ACE inhibitors, which represent a first-choice pharmacological measure in the treatment of cardiovascular diseases such as hypertension, angina, myocardial ischaemia, congestive heart failure, and others. ACE inhibitors act on the renin-angiotensin system which releases angiotensin II, one of the most effective hypertensive agents known. More precisely, these drugs inhibit the activity of the angiotensin converting enzyme, a carboxypeptidase which is mostly present in lungs, kidneys, and vessels. The action of this enzyme is not specific. It inactivates plasma bradykinin, which possesses a vasodilatatory activity, and also helps diuresis and, in particular, natriuresis. In other terms, plasma bradykinin possesses opposite effects compared to those of angiotensin II. Therefore, ACE inhibitors prevent formation of angiotensine II and, at the same time, degradation of bradykinin. Hence, ACE inhibitors certainly represent one of the most significant pharmacological innovation of the past few decades.
However, the administration of ACE inhibitors is often (about 20 to 30% of the cases) accompanied by side effects in the respiratory system, such as cough, dyspnea, broncho-constriction. Furthermore, these drugs show a rather limited therapeutic profile, for example they have no platelet-antiaggregating activity, so that, in the above cardiovascular treatments, they are often associated with other drugs having an antiaggregating activity. For example, in the treatment of myocardial infarction and prevention of relapses, it is essential to use a multiple cardiovascular therapy including, among others, the association of an antihypertensive with an antiaggregating agent.
It was felt the need for drugs with a better therapeutic profile and fewer side effects, in particular, at the respiratory system, for example the bronchi.
The Applicant has unexpectedly and surprisingly found a specific class of ACE-inhibitor salts characterised by the fact that they possess, compared to other salts of the same compounds, a better antihypertensive activity and have fewer side effects in the bronchi.
An object of the present invention is, therefore, the nitric salts of ACE inhibitors having the following formulas:
in formula
or N—CH
3
;
Y=CH
3
, phenyl;
R
III
=H,
R
III
together with R
IV
forms the following ring in the carbon at position 4
R
III
together with R
V
(carbons at positions 4 and 5) forms the cyclohexane or cyclopentane rings
R
IV
=H, or R
IV
forms with R
III
ring (IVa);
R
V
=H, or a free valence, or R
V
forms with R
III
rings (IIIa) or (IIIb);
R
VI
=H, or a single bond —O when R
V
is a free valence so as to form a ketone group with the carbon atom at position 5.
The preferred nitrate salts of formula (I) include:
when X=C (R
III
) (R
IV
) as above defined, Y=phenyl, R
III
=R
IV
=R
V
=R
VI
=H, the residue of Enalapril;
as in Enalapril but with R
III
which, together with R
IV
, forms ring (IVa), the residue of Spirapril;
as in Enalapril but with R
III
which, together with R
V
, forms ring (IIIb), the residue of Ramipril;
as in Enalapril but with Y=CH
3
and R
III
which, together with R
V
, forms ring (IIIa), the residue of Perindopril;
as in Enalapril, but with X=N—CH
3
, R
V
is a free valence and R
VI
=—O so as to form with carbon atom C
5
a ketone group, the residue of Imidapril.
The compounds of the classes of the invention, which are the precursors of the salts, are used as optically-active single isomers or as mixtures thereof or in the form of racemates.
The precursor of class II is known as Lisinopril, that of class III is known as Alacepril. The precursors are prepared according to the methods described in “The Mercx Index, Ed. 12”, herein incorporated by reference.
The salts of the present invention are prepared according to the following method. The substance to be salified is dissolved in an organic solvent, not containing in the molecule free hydroxyl groups, and then a stoichiometric amount of concentrated nitric acid is added. The salt is recovered by filtration and washed several times with a solvent, for example that used in the reaction. Polar organic solvents are preferred, such as , for example, acetonitrile, ethyl acetate, and others.
It has surprisingly been found that the compounds of the present invention improve, compared to the same substances and ACE salts generally, the pharmacological profile of the above ACE inhibitors and, additionally, exhibit a more favourable general and regional tolerability.
The compounds of the present invention can be used as cardiovascular drugs, in particular in the treatnent of hypertension, angina, myocardial ischaemia, congestive heart failure.
The salts of the present invention are formulated in the correspomding pharmaceutical compositions according to the methods well known to those skilled in the art, which are, for example, described in Remington's Pharmaceutical Sciences, Ed. 15.
REFERENCES:
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Laubie et al., “Inhibition of Angiotensin I-Converting Enzyme with S 9490: Biochemical Effects, Interspecies Differences, and Role of Sodium Diet in Hemodynamic Effects”,Journal of Cardiovascular Pharmacology, pp. 1076-1081, (1984), vol. 6, No. 6.
Subissi et al., “Angiotensin converting enzyme inhibitors potentiate the bronchoconstriction induced by substance P in the guinea-pig”.Br. J. Pharmacol, (1990), 100, pp. 502-506.
J.F. Pinon, “In Vivo Study of Platelet Aggregation in Rats”Journal of Pharmacmacological Methods12, pp. 79-84 (1984).
Konzett, Arch. Exp. Pathol. Pharmacol, 195, 71, (1984).
Arent Fox Kintner Plotkin & Kahn
Nicox S.A.
Stockton Laura L.
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