FR2646354A1 - Use of peptides that inhibit acid proteases for the preparation of medicaments which are useful for the treatment of viral diseases - Google Patents

Abstract

The invention relates to the use of peptides that inhibit acid proteases for the preparation of medicaments which are useful for the treatment of viral diseases, and more especially for the treatment of human immunodeficiency also known by the name of AIDS.

Description

Use of acid protease inhibitor peptides for the preparation of rutile drugs for the treatment of viral diseases.

 The subject of the present invention is the use of acid protease inhibitor peptides for the preparation of medicaments useful for the treatment of viral diseases and more particularly for the treatment of human immunodeficiency, also known under the name of AIDS.

AIDS or acquired immunodeficiency syndrome is the terminated phase of a disease, currently experiencing an epidemic expansion, the responsible agent of which is one of the retroviruses of human immunodeficiency or HIV virus (HIV 1 or
HIV 2).

 The HIV viruses, transmitted in particular by asexual route or during a blood transfusion with contaminated blood, have for their targets the cells having on their surface an antigenic receptor known under the name of surface molecule CD4 or CD4 receptor. The T4 lymphocytes which play an essential role in the immune system possess this CD4 receptor and are therefore target cells of the HIV viruses.

 Infection with HIV viruses therefore begins with the attachment of viral particles, and more particularly of the gp 120 protein of the viral envelope, to the CD4 receptors of T4 lymphocytes. IT continues with the fusion of the viral envelope and the cell membrane; The ART of the viral genome is then transcribed using a specific enzyme, reverse transcriptase or reverse transcriptase (which does not exist in normal cells) in double stranded and integrated DNA or cell genome.

 A cell thus infected then synthesizes viral proteins and in particular the gp 120 protein, which is housed on the cell membrane. Due to the great affinity of the gp 120 protein for CD4 receptors, this infected cell can fix healthy T4 lymphocytes and form a syncytium incapable of surviving. A single infected cell can therefore kill many healthy T4 cells.

 On the other hand, isolated gp 120 viral proteins sometimes circulate in the blood and the lymph and bind to the CD4 receptors of healthy T4 lymphocytes, which then become target cells for the immune system.

HIV viruses also replicate in Monocytes, Macrophages and related cells and probably disrupt
Their functioning. Infection with an HIV virus can in some way modify the quantity or structure of the cytokines produced by activated macrophages and activated lymphocytes, these cytokines then being toxic for T4 helper lymphocytes.

 Any of the above mechanisms results in the destruction of T4 Lymphocytes and simultaneously the collapse of the immune system.

 Different means of action on HIV viruses have already been envisaged, in particular at the level of virus replication.

For this purpose, we can refer in particular to the work of F. BARRE-SINOUSSI et al. titled "AIDS IN QUESTION", Collection
Témoins d'Aujourd'hui, edited by PLON (1987) and an article by R.

YARCHOAN and aL. entitled "TREATMENTS OF AIDS", in the journal "Pour la Science" December 1988, p. 94-104.

 The reverse transcriptase inhibitors currently used in the treatment of AIDS are dideoxynucleosides, which are analogues of nucleosides, and in particular azidothymidine (AZT).

 One of the problems posed by these inhibitors is that they are never completely specific and that at certain doses they can prevent the division of uninfected cells, thus leading to significant toxicities, necessitating the interruption of treatment.

 The use of oligonucleosides has also been proposed, complementary to part of the viral messenger RNAs.

 It has now been found that it is possible to use, for the treatment of viral diseases, in particular those caused by retroviruses and more particularly for the treatment of AIDS, peptides inhibiting acid proteases.

 Thus, the subject of the present invention is the use for the preparation of such medicaments of the acid protease inhibitor peptides corresponding to formulas I, I ′, II and III below.

These peptides have been described in Patent applications
EP 192,554, 193,445, 211,744 and Patent FR 2,577,931.

The abbreviations used in this description are in agreement with those indicated by the
Nomenclature of the IUPAC-IUB, biochemistry section, as well as with those reported in Eur. J. Biochem., 1984, 138, 5-7 and 9-37.

 More particularly, Abu represents 2-amino butyric acid, Cpg represents cycLopentyLglycine and Phg PhenyLglycine.

dans laquelle : R1 représente un groupe acyle choisi parmi Les groupes alkyl
carbonyle, aLcoxycarbonyle, aryLcarbonyLe, aryLaLkyLcarbonyLe,
ary La Icoxycarbonyle, heterocycLyLcarbonyLe, heterocycLyLaLkyLcar-
bonyle dans lequel Le groupe aLkyLe est éventueLLement substitué
par un groupe hydroxy, hétérocyclylcarbonylalkylcarbonyle, hété
rocyclylaLcénylcarbonyle, cycloalkylcarbonyle, ou un groupe
(alkyle inférieur) sutfonyle non substitué ou substitué sur
L'aLkyLe par un groupe amino Libre ou portant un groupe protec
teur ou par un phényle ou un groupe phényLsuLfonyle non substitué
ou substitué sur Le noyau phényLe par un alkyle inférieur ;
R2 représente un groupe aLkyle inférieur non substitué ou
substitué par un phényle, naphtyle, cyclohexyLe, ou pyridyle ou
R2 représente un radical phényLe, naphtyle, cyclohexyle ou
pyridyle ; R3 représente L'hydrogène, un alcényle inférieur, un phényle,- un
naphtyle, un cycLoalkyle contenant 3 à 6 atomes de carbone, un
groupe hétérocyclique monocycLique à 5 ou 6 chainons non substi
tué ou substitué par un alkyle inférieur ou trifluorométhyle ; ou
bien un alkyle inférieur substitué par un groupe di(alkyle infé
rieur)amino, par un carboxyle estérifié par un alkyLe inférieur
ou un benzyle, par un carbamoyle libre ou substitué par un ou deux
alkyles inferie:s ou par un phényle, par un groupe alcoxy infé
rieur ou benzyloxy, par un groupe pyridylméthyloxy, par un groupe
Caîkyle inférieur) sulfinyle ou (alkyle inférieur) sulfonyle,
par un cycloalkyle contenant 3 à 6 atomes'de carbone ou par un
groupe hétérocyclique monocyclique à 5 ou 6 chaînons non substi
tué ou substitué avec un alkyle inférieur ou un trifluorométhyle,
à la condition que R3 ne soit pas le groupe (imidazolyl-4)
méthyle ; R4 représente un hydroxyle, un alcoxy inférieur, un benzyloxy ou
un groupe amino libre ou substitué par 1 ou 2 alkyles infé
rieurs ; ; Z1 représente l'isopropyle, le phényle ou le cyclohexyle formant
respectivement avec le radical

The peptides of formula (I) described in European patent application 0 192 554 correspond to the following general formula:

in which: R1 represents an acyl group chosen from alkyl groups
carbonyl, aLcoxycarbonyle, aryLcarbonyLe, aryLaLkyLcarbonyLe,
ary La Icoxycarbonyle, heterocycLyLcarbonyLe, heterocycLyLaLkyLcar-
bonyle in which the alkyl group is optionally substituted
hydroxy, heterocyclylcarbonylalkylcarbonyl, hetero
rocyclylaLcénylcarbonyle, cycloalkylcarbonyle, or a group
(lower alkyl) unsubstituted or substituted sutfonyl on
The alkyl by a free amino group or carrying a protected group
or by a phenyl or an unsubstituted phenylSulfonyl group
or substituted on the phenyl nucleus with lower alkyl;
R2 represents an unsubstituted lower alkyl group or
substituted by phenyl, naphthyl, cyclohexyLe, or pyridyle or
R2 represents a phenyl, naphthyl, cyclohexyl or
pyridyle; R3 represents hydrogen, lower alkenyl, phenyl, - a
naphthyl, a cycLoalkyl containing 3 to 6 carbon atoms, a
monocyclic heterocyclic group with 5 or 6 links, not substi
killed or substituted by lower alkyl or trifluoromethyl; or
although lower alkyl substituted with a di group (lower alkyl
laughing) amino, by a carboxyl esterified by a lower alkyl
or a benzyl, by a free carbamoyl or substituted by one or two
lower alkyls: s or phenyl, lower alkoxy group
laughing or benzyloxy, by a pyridylmethyloxy group, by a group
Lower caikyl) sulfinyl or (lower alkyl) sulfonyl,
by a cycloalkyl containing 3 to 6 carbon atoms or by a
5- or 6-membered monocyclic heterocyclic group, non-substi
killed or substituted with lower alkyl or trifluoromethyl,
provided that R3 is not the group (imidazolyl-4)
methyl; R4 represents a hydroxyl, a lower alkoxy, a benzyloxy or
an amino group which is free or substituted by 1 or 2 lower alkyls
laughing; ; Z1 represents isopropyl, phenyl or cyclohexyl forming
respectively with the radical

the residue of the amino acid statin (Sta), namely, the acid (3S,
4S) 4-amino-3-hydroxy-6-methyl heptanoic or Acid (3S,
4S) 4-amino-3-hydroxy-5-phenyl pentanoic acid (AHPPA) or Acid
(3S, 4S) 4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA); - XY is a dipeptide chosen from ALa-Sta, Ala-Leu, Leu-Phe,
Val-Sta, Abu-Sta, Ite-Ser, Phg-Sta.

dans laquelle
R1 représente un groupe acyle choisi parmi les groupes hétérocyclyLcarbonyle, hétérocyclylalkylcarbonyle, dans lequel le groupe alkyle est éventuellement substitué par un groupe hydroxy, hétérocyclylcarbonylalkylcarbonyle, hétérocyclyalcénylcarbonyle ou un groupe (alkyle inférieur) sulfonyle non substitué ou substitué sur l'alkyle par un groupe amino Libre ou portant un groupe protecteur ou par un groupe phényle ou un groupe phénytsulfonyle non substitué ou substitué sur le noyau phényle par un alkyle inférieur ;;
R2 représente un groupe alkyle inférieur non substitué ou substitué par un phényle, naphtyle, cyclohexyle, ou pyridyle ou
R2 représente un radical phényle, naphtyle, cyclohexyle ou pyridyle ;
R3 représente un alkyle inférieur non substitué ou substitué par un groupe amino libre ou portant un groupe protecteur, par un carboxyle Libre, par un groupe hydroxy, par un groupe alkylthio inférieur, par un phényle, par un naphtyle ou par un imidazolyl-4 ; R4 représente un hydroxyLe, un alcoxy inférieur, un benzyloxy ou un groupe amino Libre ou substitué par 1 ou 2 aLkyles inférieurs ;;
Z1 représente t'isopropyle, le phényle ou le cyclohexyle formant respectivement avec le radical,

le résidu de L'aminoacide statine, à savoir L'acide (35, 4S) amino-4 hydroxy-3 méthyle6 heptanoique ou de L'acide (3S, 4S) amino-4 hydroxy-3 phényle pentanoique (AHPPA) ou de L'acide (3S, 4S) amino-4 cyclohexyl-5 hydroxy-3 pentanoique (ACHPA) ;
X - Y est un dipeptide choisi parmi Ala-Sta, Ala-Leu, Leu-Phe,
Val-Sta, Abu-Sta, ILe-Ser, Phg-Sta.The peptides of formula (I ′) described in patent application EP 193 445 correspond to the following general formula

in which
R1 represents an acyl group chosen from heterocyclyLcarbonyl, heterocyclylalkylcarbonyl, in which the alkyl group is optionally substituted by a hydroxy group, heterocyclylcarbonylalkylcarbonyl, heterocyclyalkenylcarbonyl or a (lower alkyl) sulfonyl group unsubstituted or substituted by amino or bearing a protective group or by a phenyl group or a phenytsulfonyl group which is unsubstituted or substituted on the phenyl ring by lower alkyl;
R2 represents a lower alkyl group which is unsubstituted or substituted by phenyl, naphthyl, cyclohexyl, or pyridyl or
R2 represents a phenyl, naphthyl, cyclohexyl or pyridyl radical;
R3 represents a lower alkyl unsubstituted or substituted by a free amino group or carrying a protective group, by a free carboxyl, by a hydroxy group, by a lower alkylthio group, by a phenyl, by a naphthyl or by a 4-imidazolyl; R4 represents a hydroxyLe, a lower alkoxy, a benzyloxy or an amino group Free or substituted by 1 or 2 lower alkyls;
Z1 represents isopropyl, phenyl or cyclohexyl respectively forming with the radical,

the residue of the amino acid statin, namely 4-amino-3-hydroxy-3-methyl6 heptanoic acid or (3S, 4S) 4-amino-3-hydroxyphenyl pentanoic acid (AHPPA) or L (3S, 4S) 4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA);
X - Y is a dipeptide chosen from Ala-Sta, Ala-Leu, Leu-Phe,
Val-Sta, Abu-Sta, ILe-Ser, Phg-Sta.

dans laquelle
R1 représente un groupe acyle ou un groupe (alkyle inférieur)
sulfonyle non substitué ou substitué sur L'alkyle par un groupe
amino libre ou portant un groupe protecteur, ou par un phényle ;
ou un groupe phenylsuLfonyle non substitué ou substitué sur le
noyau phényle par un alkyle inférieur ; R2 représente un groupe alkyle inférieur non substitué ou
substitué par un phényle, naphtyle, cyclohexyte, ou pyridyle ;; R3 représente l'hydrogène, un alkényle inférieur, un phényle, un
naphtyle, un cycloaikyle contenant 3 à 6 atomes de carbone, un
groupe héterocyclique monocyclique à 5 ou 6 chainons non
substitué ou substitué avec un alkyle inférieur ou
trîfluorométhyle, ou bien un alkyle inférieur non substitué ou
substitué par -un groupe amino Libre ou portant un groupe
protecteur, par un groupe di(alkyle inférieur)amino, par un
carboxyle libre ou estérifié avec un alkyle inférieur ou un
benzyle, par un carbamoyle libre ou substitué avec un ou deux
alkyles inférieurs ou avec un phényle, par un groupe hydroxy,
alcoxy inférieur ou benzyloxy, par un groupe pyridylmethyloxy,
par un groupe alkylthio inférieur, (alkyle inférieur)sulfinyLe
ou (alkyle inférieur > sutfonyle, par un phényle, par un naphtyle,
par un cycloalkyle contenant de 3 à 6 atomes de carbone ou par
un groupe hétérocycLique monocyclique à 5 ou 6 chaînons non
subsitué ou substitué avec un alkyle inférieur ou un
trifluorométhyle ; Z1 représente l'isopropyle, le phényle ou le cyclohexyle formant
respectivement avec le radical

The compounds (II) described in French patent 2,577,931 correspond to the following general formula:

in which
R1 represents an acyl group or a group (lower alkyl)
sulfonyl unsubstituted or substituted on alkyl by a group
amino free or carrying a protective group, or by a phenyl;
or an unsubstituted or substituted phenylsuLfonyl group on the
phenyl ring by lower alkyl; R2 represents an unsubstituted lower alkyl group or
substituted with phenyl, naphthyl, cyclohexyte, or pyridyl ;; R3 represents hydrogen, lower alkenyl, phenyl,
naphthyle, a cycloaikyle containing 3 to 6 carbon atoms, a
5- or 6-link monocyclic heterocyclic group no
substituted or substituted with lower alkyl or
trifluoromethyl, or an unsubstituted lower alkyl or
substituted by -a free amino group or carrying a group
protective, by a di (lower alkyl) amino group, by a
free or esterified carboxyl with lower alkyl or
benzyl, with a free carbamoyl or substituted with one or two
lower alkyls or with a phenyl, by a hydroxy group,
lower alkoxy or benzyloxy, by a pyridylmethyloxy group,
by a lower alkylthio group, (lower alkyl) sulfinyLe
or (lower alkyl> sutfonyl, by phenyl, by naphthyl,
by a cycloalkyl containing from 3 to 6 carbon atoms or by
a 5- or 6-membered monocyclic heterocyclic group not
substituted or substituted with lower alkyl or
trifluoromethyl; Z1 represents isopropyl, phenyl or cyclohexyl forming
respectively with the radical

the residue of the amino acid Sta, or AHPPA, or ACHPA; - X is either a direct bond or the residue of an amino acid
such as Ala, Nva, Val, Leu, Nle, Ile ;; R4 represents hydrogen or unsubstituted lower alkyl or
substituted by an indolyl, pyridyl, imidazolyl or
phenyl; - Alk represents a methyl group, ethylene, a group
unsubstituted or substituted lower alkylidene in omega position
by a free amino group or carrying a protective group, a
benzylidene or a 2-cyclohexylethylidene group or a group
phenylethylidene unsubstituted or substituted on the phenyl ring
by a hydroxyl; Alk cannot be other than methylene or
ethylene when R4 is other than Hydrogen
and - m is O or 1.

dans laquelLe : - R1 représente un groupe acyle choisi parmi les groupes
alkyLcarbonyle, alcoxycarbonyle, arylcarbonyle, arylalkyl
carbonyle, aryLalcoxycarbonyle, héterocycLylcarbonyle, hétéro
cyclyalkylcarbonyLe dans Lequel le groupe alyte est éventueL
Lement substitué par un groupe hydroxy ; hétérocyclyLcarbonyl-
alkylcarbonyle, hétérocyclylalcénylcarbonyle, cycloatkylcarbonyle
ou un groupe (aLkyLe infèrieur)-suLfonyle non substitué ou
substitué sur l'alkyle par un groupe amino Libre ou portant un
groupe protecteur ou par un phényle ; ou un groupe phénylsulfo
nyle non substitué ou substitué sur le noyau phényle par un
alkyle inférieur ; R2 représente un groupe aLkyle inférieur non substitué ou
substitué par un phényle, naphtyle, cyclohexyle, ou pyridyle ou
R2 représente un radical phényle, naphtyle, cyclohexyle ou
pyridyle ;; R3 représente l'hydrogène, un alcényle inférieur, un phényle, un
naphtyle, un cycloalkyle contenant 3 à 6 atomes de carbone, un
groupe hétérocyclique monocyclique à 5 ou 6 chainons non
substitue ou substitué avec un alkyle inférieur ou trifluoro
méthyle, ou bien un alkyle inférieur non substitué ou substitué
par un groupe amino libre ou portant un groupe protecteur, par un
groupe di(alkyle inférieur)amino, par un carboxyle libre ou
estérifié avec un alkyle inférieur ou un benzyle, par un
carbamoyle Libre ou substitué avec un ou deux alkyles inférieurs
ou avec un phényle, par un groupe hydroxy, alcoxy inférieur ou
benzyloxy, par un groupe pyridylméthyloxy, par un groupe
alkylthio inférieur, Caîkyle inférieur)sulfinyle ou (alkyle
inférieur)sutfonyle, par un phényle non substitue ou substitué
par un hydroxyle, par un naphtyle, par un cycloalkyle contenant
de 3 à 6 atomes de carbone, par un groupe hétérocyclique
monocyclique à 5 ou 6 chaînons non substitué ou substitué avec un
alkyLe inférieur ou un trifluorométhyle ou par un groupe
hétérocyclique bicyclique non substitué ou substitué avec un
alkyle inferieur ou un trifLuorométhyle ; - Q représente l'isopropyle, le phényle ou le cyclohexyle formant
respectivement avec le radical : :

The compounds (III) described in European patent application 211 744 correspond to the following general formula

in which: - R1 represents an acyl group chosen from the groups
alkyLcarbonyle, alkoxycarbonyle, arylcarbonyle, arylalkyl
carbonyl, aryLalkoxycarbonyl, heterocycLylcarbonyl, hetero
cyclyalkylcarbonyLe in which the alyte group is included
Lely substituted by a hydroxy group; heterocyclyLcarbonyl-
alkylcarbonyl, heterocyclylalkenylcarbonyl, cycloatkylcarbonyl
or an unsubstituted (lower alkyl) -suLfonyl group or
substituted on the alkyl with a free amino group or carrying a
protecting group or by phenyl; or a phenylsulfo group
unsubstituted or substituted nyl on the phenyl ring with a
lower alkyl; R2 represents an unsubstituted lower alkyl group or
substituted with phenyl, naphthyl, cyclohexyl, or pyridyl or
R2 represents a phenyl, naphthyl, cyclohexyl or
pyridyle ;; R3 represents hydrogen, lower alkenyl, phenyl,
naphthyl, a cycloalkyl containing 3 to 6 carbon atoms, a
5- or 6-link monocyclic heterocyclic group no
substitutes or substituted with lower alkyl or trifluoro
methyl, or unsubstituted or substituted lower alkyl
by a free amino group or carrying a protective group, by a
di (lower alkyl) amino group, by a free carboxyl or
esterified with lower alkyl or benzyl, by a
carbamoyl Free or substituted with one or two lower alkyls
or with phenyl, by a hydroxy group, lower alkoxy or
benzyloxy, by a pyridylmethyloxy group, by a group
lower alkylthio, lower Caikyl) sulfinyl or (alkyl
lower) sutfonyl, with unsubstituted or substituted phenyl
by a hydroxyl, by a naphthyl, by a cycloalkyl containing
from 3 to 6 carbon atoms, by a heterocyclic group
5- or 6-membered monocyclic unsubstituted or substituted with a
lower alkyl or trifluoromethyl or by a group
bicyclic heterocyclic unsubstituted or substituted with a
lower alkyl or trifluoromethyl; - Q represents isopropyl, phenyl or cyclohexyl forming
respectively with the radical::

the residue of the amino acid Sta, or AHPPA or ACHPA; - X is either a direct bond or the residue of an amino acid
such as Ala, Nva, Val, Leu, Nle, Île, Phg, Abu, Cpg; - R4 represents hydrogen or an unsubstituted lower alkyl or
substituted by an indolyte, pyridyl, imidazolyl or
phenyl; - R5 represents an aliphatic or cyclic hydrocarbon group of 3
with 20 carbon atoms unsubstituted or substituted by a group
phenyl, hydroxyphenyl or amino, said hydrocarbon group
containing at least one hydroxyl group and at least
a carbon atom having no CH bond.

 The term "alkyl" denotes saturated or unsaturated aliphatic hydrocarbon radicals containing 1 to 10 carbon atoms. Preferred "alkyl" groups for the purposes of the invention are lower alkyl groups as defined below.

 The terms "lower alkyl", "lower alkenyl" and "lower alkylidene ', as used herein, refer to radicals of saturated or unsaturated aliphatic hydrocarbons containing up to 6 carbon atoms.

 The expressions "lower alkoxy" and "lower alkylthio" represent the hydroxyl and thiol groups substituted by a lower alkyl group as defined above.

 The term 5- or 6-membered monocyclic heterocycle "includes your pyrrolidine, imidazole, thiazole, thiophene, furan, pyrrole, triazole, oxazole, isoxazole, pyridine, thiadiazoles.

 The term "bicyclic heterocycle" includes benzimidazole, benzothiazole, benzoxazole, indole or their hydrogenated counterparts.

 By "protective group" is meant a protective group normally used in the chemistry of peptides, for example Boc, Z or iVa.

The expression "acyl group" is used for the definition of
R1 includes residues of aliphatic, alicyctic, aromatic or heterocyclic carboxylic acids. Preferred acyl groups are the residue of esterified carbonic acid, in particular the Boc and Z groups, the residue of alkanoic acids containing from 2 to 6 carbon atoms, in particular the iVa group, the residue of cyctohexylcarboxylic acid, residue of phenylali phatic acids, in particular the phenylacetic groups, 3-phenylpropionyl, dibenzylacetyl, the residue of arylcarboxylic acids, such as
Naphthoic, biphenyl carboxylic acid and Unsubstituted or substituted benzoic acid on the phenyl ring, in particular the benzoyl group, the residue of a carboxylic acid, the carboxyl of which is linked to a 5- to 6-membered monocyclic heterocycle, in particular the picolinoyl, nicotinoyl and isonicotinoyl groups and the residue of alkanoic or alenoic acids, such as acetic acid, propionic acid, butyric acid, valeric acid and their omega-2-hyzroxy or omega-2 derivatives oxo, substituted in the omega position by a 5- to 6-link monocyclic heterocycle as exemplified above.

 The invention also relates to the use of the acceptable pharmaceutical salts, when they exist, of the peptides of formulas (I), (I '), (II) and CIII) above.

 These peptides can be prepared according to the usual methods in peptide synthesis.

In particular, they can be prepared by a step-by-step process called "stepwise process from the end
C-terminal as indicated in the previously mentioned patent applications
The evaluation of the antiviral effect of the peptides used according to the invention was carried out according to the following protocol.

 The evaluation is based on the study of the cytopathogenic effect of the HIV1 virus on the MT4 cell line, after infection with the HIV1 virus.

The stock solutions of the compounds tested are at a concentration of 1D 3M in a volume-to-volume mixture of solutions A and B (solution A: 1 ml pure acetic acid + 19 ml methanol, solution B: 10 ml 1N NaOH + 20 ml methanol ). Successive dilutions are made in mid-place RPMI-1640 (Roswell
Park Memorial Institute, RPMI-1640) containing 10X FCS (Fetal Penknife
Serum) + 1X PSN (Penicillin Streptomycin Neomycin) + 1X
Glutamine.

Example: Evaluation by the MT4 test (myeloblastoid tumor)
The MT4 cells on day 2 after the last subculturing are pre-incubated for 1 h at 370C with dilutions of the various compounds to be studied at the rate of 3.105 cells per 100 μl of final volume (96-well microplate).

 The infection is carried out in microwells by adding 100 l of an appropriate dilution of the HIV1 virus (the dilution of virus has been determined to induce the formation of syncytia in 4 or 5 days).

 After an incubation of 1 h at 370C, the infected MT4 cells are washed 5 times before being cultured at a concentration of 3.105 cells per ml in a 24-well microplate, in the presence of the various compounds at the chosen dilutions.

 Every 3 or 4 days, the cells are diluted 3 or 4 times with RPMI-164 medium at 10% FCS + 1X PSN + 1Z Glutamine, always in the presence of the various compounds studied.

 Every 2 days, the appearance of syncytia is observed in your cultures.

 With the various compounds studied, the formation of syncytia is delayed or even entirely suppressed.

 In the absence of treatment, your syncytia formation is observed 4 to 6 days after infection, followed by cell death.

 Compounds (I), (I '), (II) and (III) can therefore be used as medicaments for the treatment of viral diseases and in particular for the treatment of acquired immunodeficiency syndrome.

 The present application also relates to pharmaceutical compositions containing at least one of the compounds of formula (I), (I '), (II) or (III) or one of their salts as active ingredient intended for the treatment of viral diseases.

 The pharmaceutical compositions according to the present invention are preferably administered by injectable route in the form of injectable solution or suspensions.

 The amount of active ingredient varies depending on the nature and severity of the infection to be treated. In humans, the dosage is most often between 1 and 500 mg per day.

Claims (2)

 1. Use, for the preparation of a medicament intended for the treatment of viral diseases, of an acid protease inhibitor peptide, chosen from the compounds of formula (I), CI '), (II) or (III) ci- below:

 in which : R1 represents an acyl group chosen from alkylcar groups  bonyle, alkoxycarbonyle, arylcarbonyle, arylalkylcarbonyLe, aryl  alkoxycarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbo-  nyle in which the alkyl group is optionally substituted  hydroxy, heterocycLylcarbonylalkylcarbonyl, hetero  rocyclylalcénylcarbonyle, cycloalkylcarbonyle, or a group  (lower alkyl) sulfonyl unsubstituted or substituted on  alkyl by a free amino group or carrying a protec group  or by a phenyl or an unsubstituted phenylsulfonyl group  killed or substituted on the phenyl ring with lower alkyl; R2 represents an unsubstituted or substituted lower alkyl group  killed by phenyl, naphthyl, cyclohexyl, or pyridyl or R2  represents a phenyl, naphthyl, cyclohexyl or pyri radical  dyle; R3 represents hydrogen, lower alkenyl, phenyl,  naphthyl, a cycloalkyl containing 3 to 6 carbon atoms, a  5- or 6-membered monocyclic heterocyclic group, non-substi  killed or substituted by lower alkyl or trifluoromethyl ;;  or a lower alkyl substituted by a di (alkyl) group  lower) amino, by a carboxyl esterified by lower alkyl  laughing or benzyl, by a free carbamoyl or substituted by a  or two lower alkyls or by phenyl, by a group  lower alkoxy or benzyloxy, with a pyridylmethyloxy group,  by a group (lower alkyl) sulfinyl or lower Caikyle) -  sulfonyl, by a cyctoalkyle containing 3 to 6 carbon atoms  or by an unsubstituted 5 or 6-membered heterocyclic group  or substituted with lower alkyl or trifluoromethyl, to  The condition that R3 is not the group (imidazolyl-4)  methyl; R4 represents a hydroxyl, a lower alkoxy, a benzyloxy or  an amino group which is free or substituted by 1 or 2 lower alkyls  laughing; Z1 represents isopropyl, phenyl or cyclohexyl forming  respectively with te radical:

Z1 represents isopropyl, phenyl or cyclohexyl forming respectively with the radical, R4 represents a hydroxyLe, a lower alkoxy, a benzyloxy or an amino group Free or substituted by 1 or 2 lower alkyls; R3 represents a lower alkyl unsubstituted or substituted by a free amino group or carrying a protective group, by a free carboxyl, by a hydroxy group, by a lower alkylthio group, by a phenyl, by a naphthyl or by a 4-imidazolyl; R2 represents a lower alkyl group unsubstituted or substituted by phenyl, naphthyl, cyclohexyl, or pyridyl or R2 represents a phenyl, naphthyl, cyclohexyl or pyridyl radical; Alkyl with a free amino group or one bearing a protective group or with a phenyl group or a phenylsulfonyl group which is unsubstituted or substituted on the phenyl ring by lower alkyl;  in which R1 represents an acyl group chosen from heterocy ctylcarbonyl, heterocyclylalkylcarbonyl groups, in which the alkyl group is optionally substituted by a hydroxy group, hetero cyclylcarbonytaLkylcarbonyl, heterocyclylalkenylcarbonyl or a group (lower alkyl) substituted or unsubstituted substituted or lower substituted

 Sta, Abu-Sta, ILe-Ser, Phg-Sta ;;  4S) 4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA); - X-Y is a dipeptide chosen from Ala-Sta, Ala-Leu, Leu-Phe, Val  4-amino-3-hydroxy-5-phenyl pentanoic acid (AHPPA) or acid (3S,  4-amino-3 hydroxy6 methyl heptanoic or Acid (3S, 4S)  The residue of the amino acid statin, namely the acid (3S, 4S)

 respectively with the radical  lower alkyl or trifluoromethyl; Z1 represents isopropyl, phenyl or cyclohexyl forming  monocyclic with 5 or 6 knuckles unsubstituted or substituted with  from 3 to 6 carbon atoms or by a heterocyclic group  nyle, by phenyl, by naphthyl, by cycloalkyl tale  laughing, (lower alkyl) sulfinyl or (lower alkyl) sulfo  by a pyridylmethyLoxy group, by an inferior atkylthio group  phenyl, by a hydroxy, lower alkoxy or benzyloxy group,  or substituted with one or two lower alkyls or with a  with lower alkyl or benzyl, with free carbamoyl  di (lower alkyl) amino, by a free or esterified carboxyl  amino group free or carrying a protective group, by a group  or a lower alkyl which is unsubstituted or substituted by a  killed or substituted with lower alkyl or trifluoromethyl,  5- or 6-membered monocyclic heterocyclic group, non-substi  naphthyl, a cycloalkyl containing 3 to 6 carbon atoms, a R3 represents hydrogen, lower alkenyl, phenyl,  killed by phenyl, naphthyl, cyclohexyl, or pyridyl;  phenyl ring by lower alkyl; R2 represents an unsubstituted or substituted lower alkyl group  or an unsubstituted or substituted phenylsutfonyl group on the  amino free or carrying a protective group, or by a phenyl;  sulfonyl unsubstituted or substituted on alkyl by a group  in which: R1 represents an acyl group or a (lower alkyl) group

Sta, Abu-Sta, ILe-Ser, phg-Sta; X-Y is a dipeptide chosen from Ala-Sta, Ala-Leu, Leu-Phe, Val The residue of the amino acid statin, namely (3S, 4S) 4-amino-3-hydroxy-6-methyl heptanoic or (3S, 4S) -4-amino-3-hydroxy-5-phenyl pentanoic acid (AHPPA ) or (3S, 4S) 4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA);

 respectively with The radical ::  trifluoromethyl; - Q represents isopropyl, te phenyl or cyclohexyl forming  bicyclic unsubstituted or substituted with lower alkyl or  or a trifluoromethyl or by a heterocyclic group  5 or 6-membered unsubstituted or substituted with lower alkyl  6 carbon atoms, by a monocyclic heterocyclic group with  hydroxyl, by a naphthyl, by a cycloalkyl containing from 3 to  nyle, by a phenyl which is unsubstituted or substituted by a  laughing, (lower alkyl) sylfinyl or lower caikyl) sulfo  by a pyridylmethyloxy group, by a lower alkylthio group  phenyl, by a hydroxy, lower alkoxy or benzyloxy group,  or substituted with one or two lower alkyls or with a  with lower alkyl or benzyl, with free carbamoyl  di (lower alkyl) amino, by a free or esterified carboxyl  amino Free or carrying a protective group, by a group  well lower alkyl unsubstituted or substituted by a group  killed or substituted with lower alkyl or trifluoromethyl, or  5 or 6-link monocyclic heterocyclic group, non-substi  naphthyl, a cycloalkyl containing 3 to 6 carbon atoms, a R3 represents hydrogen, a lower alkenyte, a phenyl, a  dyle ;;  represents a phenyl, naphthyl, cyclohexyl or pyri radical  killed by phenyl, naphthyl, cyclohexyl, or pyridyl or R2 R2 represents an unsubstituted or substituted lower alkyl group  on the phenyl ring by lower alkyl;  phenyl; or an unsubstituted or substituted phenylsulfonyl group  a free amino group or carrying a protective group or by a  lower) -sulfonyte unsubstituted or substituted on the alkyl with  rocyclyalcénylcarDonyle, cycloalkylcarbonyle or a group (alkyl  hydroxy, heterocyclylcarbonylalkylcarbonyl, hetero  nyle in which the alkyl group is optionally substituted  alkoxycarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbo-  bonyle, alkoxycarbonyle, arylcarbonyle, arylalkylcarbonyle, aryl R1 represents an acyl group chosen from alkylcar groups  in which :

 and - m is O or 1;  lene when R4 is other than hydrogen  hydroxyl; Alk not being able, inter alia, to methylene or ethyl  ethylidene unsubstituted or substituted on the phenyl ring with a  lidene or a 2-cyclohexylethylidene group or a phenyl group  a free amino group or one bearing a protective group, a benzy  lower bare unsubstituted or substituted in omega position by  phenyl; ; - ALk represents a methylene group, methylene, an alkyli group  substituted by an indolyl, pyridyl, imidazolyl or  such as Ata, Nva, Val, Leu, NLe, Ile; R4 represents hydrogen or an unsubstituted lower alkyl or  The residue of the amino acid Sta, or AHPPA or ACHPA; - X is either a direct bond or the residue of an amino acid  pharmaceutically acceptable salts.  a carbon atom not having Liai its C-H and their  simultaneously containing at least one hydroxyl group and at least  phenyl, hydroxyphenyl or amino, Said hydrocarbon group  with 20 carbon atoms unsubstituted or substituted by a group  phenyl; - R5 represents an aliphatic or cyclic hydrocarbon group of 3  substituted by an indolyl, pyridyl, imidazolyl or  such as Ala, Nva, Val, Leu, Nle, Ile, Phg, Abu, Cpg; - R4 represents hydrogen or an unsubstituted lower alkyl or  the residue of the amino acid Sta, or AHPPA or ACHPA; - X is either a direct bond or the residue of an amino acid  2. Use of a compound according to claim 1, in Which viral disease is caused by the human immunodeficiency retrovirus or HIV virus in particular HIV1 and HIV2.