Process for the preparation of a pharmacologically active...

Details Process for the preparation of a pharmacologically active... Process for the preparation of a pharmacologically active...

1997-05-16

2002-04-09

Qazi, Sabiha (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S043000

Reexamination Certificate

active

06369260

ABSTRACT:

This invention refers to a process for the preparation of a pharmaceutically active chemical combination constituted by the association, through chemical bonds, of two units equal to one another, having pharmacological activity.
The invention also relates to said pharmacologically active chemical combination obtained through said process, and its utilization for the preparation of pharmaceutical compositions having pharmacological activity.
The invention furtherly relates to pharmaceutical compositions comprising said chemical combination as active principle.
PRIOR ART
The researchers of the whole world have been engaged for many years in the study and development of pharmacologically active compounds, in order to obtain new drugs. Parallelly to this line of research, great importance is given also the research aiming at finding systems allowing to improve the therapeutical performances of large consumption drugs that are already marketed. Many medicines known and commonly utilized in therapy, while being provided with a good pharmacological activity, have often some drawbacks; some of these problems are due, for instance, to the fact that, often because of unsuitable hydrophilic or hydrophobic, characteristics, the drug may have a far from optimum bioavailability, which may constitute an obstacle to reach the action site, with ensuing reduction in the therapeutical activity. Furthermore, once the molecule constituting the active principle has entered the circle, it may be subjected to the activity of aspecific enzymes, which may cause adverse reactions of different nature; furthermore, the administration system of the drug may sometimes involve problems, due for instance to the chemical-physical instability of the molecule that constitute the active principle, with ensuing inactivation risks and also marked inconveniences for the patient.
As known, the systems suitable to improve the tharapeutical performances of drugs require, for instance, the use of appropriate delivery systems, based on appropriate pharmaceutical formulations which, while keeping the activity of the drug inalterated, improve its absorption, the bioavalability and make its administration easier. Other systems used for this purpose involve the preparation of prodrugs, precursor compounds, mostly pharmacologically inert, of the real drug, which are transformed into the pharmacologically active product through one or more chemical and/or enzymatic reactions. Different examples in this sense are reported in the literature, some of which have had a remarkable success from both therapeutical and commercial points of view.
A particular interpretation of the “prodrug” concept is represented, as is reported in the literature by some known products used in the inflammatory pathologies of the intestine, such as for ice Olsalazine and Sulfasalazine, whose molecular structure is derived from two phamacologically active units, either equal to or different from one another, directly bound to one another by transformation of the aninic groups of the two molecules in to an azoic type bond. Generally, the aforementioned therapeutical approaches have the drawback of supplying often non constant and non foreseeable responses during the therapy being carried on, with ensuing difficulty in the choice of the adequate therapy and possible inconveniences for the patients subjected to such therapies.
A very much felt problem in the field of pharmacological therapy is that associated to the duration of the effect reached through the administration of the drug. Usually, in fact, once administered, the drug employs a variable time, which depends on the whole of all the factors already considered (for instance, bioavailability, absorption level, stability, administration method) to reach the target; once the target has been reached, the drug exerts its activity, whose effect generally depends on the administered dose, after which it undergoes several chemical-physical changes, and is metabolized and eliminated in variable times. Because of this mechanism of activity, most drugs cannot achieve a long-lasting effect; in most cases; such effect disappears as soon as die metabolization process starts. This causes considerable inconveniences since, to obtain a longer effect, it is almost always necessary to administer drug doses at shorter intervals, with a risk of accumulation and ensuing increase in side effects.
OBJECTS OF THE INVENTION
Object of this invention is therefore to realize a process for the preparation of a pharmacologically active chemical combination allowing the controlled release of the constituent active principles once the target site has been reached.
A further object of this invention is to realize a process for the realization of a pharmacologically active chemical combination with good characteristics of bioavailability, well tolerated (often even more than he individual constituent active principle) and of easy administration
Still a further object of this invention is to realize a process for the preparation of a pharmacologically active chemical combination allowing to obtain a long-lasting therapeutical effect, without recourse to a proportional increase in the frequency of the doses used.
Still another object of this invention is to provide a pharmacologically active chemical combination, realized by means of said process, as well as pharmaceutical compositions comprising as active principle said chemical combination.
DESCRIPTION OF THE INVENTION
These and still other objects and related advantages, which will be more clearly apparent from the following description, are reached by a process for the preparation of a pharmacologically active chemical combination, which, according to this invention, consists in chemically combining a first and a second unit (or radical) of molecular structures corresponding to pharmacologically active compounds, through a system having a “bidentate” structure, so as to realize a chemical combination having the following general formula:
M—A—X—B—M  (I)
where
M indicates said first and second units (or radicals) of molecular structures corresponding to pharmacologically active compounds, said units (or radicals) being related down to said molecular structures by saturation of the free valences with atoms or groups of atoms such as hydrogen, OH group, OEt group;
X indicates a “bidentate” structure, suitable to interconnect said M according to the general formula (I);
A and B are equal to or different from one another and indicate functional groups which allow said interconnection between said M and said X.
More particularly, always according to this invention, said M, equal to one another, are chosen among the following groups:
According to this invention, said X having a “bidentate” molecular structure, suitable to interconnect said M according to the general formula (I) is chosen among:
saturated, unsaturated, linear, branched or cyclic, substituted or unsubstituted alkyl chain;
substituded or unsubstituted arylidenic benzenoid, naphthalenic, heteroaromatic pyridinic, pyrimidinic, pyrazolic, pyrazinic, imidazolic, benzimidazolic system;
arylaliphatic system in which the first of said functional groups A and B is on the aromatic portion and the second of said functional groups A and B is on the aliphatic portion, said aromatic portion being constituted by a substituted or unsubstituted benzenoid or heteroaromatic system and said aliphatic portion being constituted by a saturated or unsaturated, linear or branched, substituted or unsubstituted alkylidenic group;
 —(CH
2
)
m
—Z—(CH
2
)
n
—  (CXLI)
 where
m,n=1-3, with m=n or m≠n
Z=O, substituted or unsubstituted benzenoidic or heteroaromatic ring
X=O,S
Y(CH
2
CH
2
)
2
  (XCVI)
Y=S, S—S, (OCH
2
CH
2
O)
n
n=1-5,
R—N where R is chosen among: substituted or unsubstituted, linear, branched alkyl, substituted or unsubstituted aryl
Said functional groups indicated by A and B which allow said interconnection between said M and said X are chosen, always ac

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