Piperazine derivatives inhibiting human immunodeficiency...

Details Piperazine derivatives inhibiting human immunodeficiency... Piperazine derivatives inhibiting human immunodeficiency...

2001-03-20

2003-03-11

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S253010, C514S254010, C544S365000, C544S372000, C544S387000, C544S391000

Reexamination Certificate

active

06531476

ABSTRACT:

FIELD AND BACKGROUND OF THE INVENTION
The invention relates to piperazine derivatives for inhibiting the replication of Human Immunodeficiency Virus.
Besides inducing a breakdown of the immune defences, reflected in infected patients by the occurrence of serious opportunist infectious diseases, infection with Human Immunodeficiency Virus (HIV), the major cell targets of which are the CD4+ T lymphocytes and the cells of the macrophage line, is responsible for a chronic inflammatory syndrome, most particularly in the central nervous system, which is manifested by neurological complications which are grouped together under the name HIV encephalopathy or subacute encephalitis. “Platelet Activating Factor” (PAF), which has been identified as an early mediator of inflammation and allergy, appears to play an essential role in this inflammatory syndrome, not only on account of its role as an inflammation mediator, but also by means of its neurotoxicity.
The efficacy of a treatment in HIV infection is measured by the reduction of the viral load in the blood of the infected patients and by the restoration of the level of circulating CD4+ T lymphocytes. With respect to these criteria, two classes of anti-retroviral agents acting at two different steps in viral replication have been found to be effective to date and consequently form the basis of the current treatment of HIV infection. These are:
firstly, reverse transcriptase inhibitors which are directed toward inhibiting the activity of the viral enzyme which ensures the retrotranscription of the viral ribonucleic acid (RNA) into deoxyribonucleic acid (DNA), this being the form in which the virus passes into the nucleus of the infected cell and becomes incorporated into its cell genome. These reverse transcriptase inhibitors are represented by zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T) and nevirapine; and
secondly, protease inhibitors such as indinavir, ritonavir, saquinavir and nelfinavir, which act by inhibiting the activity of a viral enzyme involved in the process of maturation of the viral particles derived from the replication—that is to say in the installation of their various internal proteins and enzymes —, this maturation process preceding the release of these particles toward other cells to be infected.
These anti-retroviral agents are usually used in combination: thus, triple therapy, which consists in combining two reverse transcriptase inhibitors and a protease inhibitor, is nowadays prescribed as the first line treatment, and quadruple-therapy protocols are currently under clinical evaluation.
Despite their value, the anti-retroviral agents currently available do not really solve the problem of HIV infection.
Specifically, firstly, they induce viral mutations which are responsible for the appearance of resistance to the treatment and, in the long term, for a phenomenon of therapeutic evasion resulting in a resumption of the infection. Furthermore, since the resistances induced are usually crossed between the various anti-retroviral agents, especially between the protease inhibitors, the therapeutic substitutions are very limited.
Secondly, some of these anti-retroviral agents are of limited diffusion in tissues. In particular, they are incapable of crossing the blood-brain barrier and consequently of reaching the central nervous system, which however constitutes a preferred target of the viral infection.
These anti-retroviral agents moreover have numerous side effects (anemia, leukopenia, nausea, vomiting, diarrhea, myalgia, headaches, peripheral neuropathy, skin rashes, fever, pancreatitis, liver toxicity, etc.), these effects being all the more pronounced when they are used in combination. Besides the possibility of these side effects resulting in patient non-compliance due to the inconvenience they cause to the patients, they may in certain cases impose stoppage of the treatment on account of the seriousness of their nature.
Finally, these anti-retroviral agents have the drawback of having limited activity on the virus itself and of being incapable of protecting or reestablishing the immune system of the infected patients.
The problem consequently arises, of providing compounds which, while being active on HIV and consequently suitable for effectively treating an infection with this virus, have broad diffusion in tissues and are especially capable of reaching the central nervous system, do not induce resistance and have no crossed resistance with the anti-retroviral agents currently used, make it possible not only to eliminate the virus but also to protect or even restore the immune system, and also have satisfactory tolerance which is compatible with optimal patient compliance.
1,4,-Bis(3′,4′,5′-trimethoxybenzoyl)-2-(N,N-methoxycarbonyl)-piperazine were disclosed in French patent application No. 89 13258 as anti-ischemic and anti-inflammatory agents.
Moreover, it was shown, in French patent applications No. 89 13259 and No. 90 04798 and in European patent application No. 0 368 670, that trisubstituted piperazine derivatives are capable of inhibiting in vitro the effects of PAF on blood platelet aggregation and, in this respect, can be used in the treatment of pathologies in which this mediator appears to be involved, and especially in the treatment of inflammatory syndromes and allergic syndromes (acute inflammations, gastrointestinal ulcerations, asthma, cardiac anaphylaxis, etc.).
The advantage of piperazine derivatives of this type as PAF antagonists was subsequently confirmed by the studies by Lamouri et al. (
J. Med. Chem.,
1993, 36, 8, 990-1000) and Heymans et al. (
J. Lipid Mediators Cell Signalling,
1994, 10, 153-154;
J. Lipid Mediators Cell Signalling,
1996, 15, 161-173) which were directed toward specifying the influence of the chemical structure of these compounds on their biological activity.
Now, continuing their studies on piperazine derivatives, the Inventors have discovered that, surprisingly, in addition to having anti-PAF activity, some of these derivatives are capable of very efficiently inhibiting HIV replication, and are thus suitable as a therapy of choice in the treatment of HIV infection since they make it possible not only to block the multiplication of this virus within the body and its ultimate elimination, but also to restore the immune functions by virtue of their inhibitory activity toward PAF.
SUMMARY OF THE INVENTION
One subject of the present invention is thus the use of a piperazine derivative corresponding to the general formula (I):
in which:
A and B represent, independently of each other, a C═O, C═S or CR
7
R
8
group in which R
7
represents a hydrogen atom or a group chosen from methyl, cyano, cyanomethyl, CO
2
CH
3
and (C═O)CH
3
groups, while R
8
represents a hydrogen atom or a phenyl group;
R
1
, R
2
, R
3
, R
4
, R
5
and R
6
represent, independently of each other, a hydrogen atom, a hydroxyl group or a linear or branched C
1
-C
5
alkoxy group;
X represents:
either a group chosen from C═O, O(C═O), O(C═S), O(SO
2
), NH(C═O), NH(C═S), NH(SO
2
), S(C═O) and S(C═S) groups, in which case Y represents either a group NR
9
R
10
or CR
9
R
10
R
11
in which R
9
, R
10
and R
11
represent, independently of each other, a hydrogen atom, a linear or branched C
1
to C
5
alkyl, C
2
to C
5
alkenyl or C
2
to C
5
alkynyl group, or a nitrogen heterocycle comprising from 5 to 10 atoms and optionally one or more heteroatoms chosen from nitrogen, oxygen and sulfur;
or an oxygen or sulfur atom or a group chosen from O(C═O)O, NH(C═O)O and S(C═O)O groups, in which case Y represents a group CR
9
R
10
R
11
in which R
9
, R
10
and R
11
have the same meaning as above;
or one of the pharmaceutically acceptable salts thereof, for the preparation of a medicinal product for inhibiting the replication of human immunodeficiency virus (HIV).
In the text hereinabove and hereinbelow:
the expression “linear or branched C
1
to C
5
alkyl group” denotes any

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