EP0787143A2 - Phenyl peptides, method for preparing same, and pharmaceutical compositions containing said peptides - Google Patents
Phenyl peptides, method for preparing same, and pharmaceutical compositions containing said peptidesInfo
- Publication number
- EP0787143A2 EP0787143A2 EP96924035A EP96924035A EP0787143A2 EP 0787143 A2 EP0787143 A2 EP 0787143A2 EP 96924035 A EP96924035 A EP 96924035A EP 96924035 A EP96924035 A EP 96924035A EP 0787143 A2 EP0787143 A2 EP 0787143A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- ile
- amino
- leu
- sulfur
- peptides
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- 150000002978 peroxides Chemical class 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- UVIZKKLXYCUTJB-UHFFFAOYSA-N prop-2-enyl 2-hydroxyacetate Chemical compound OCC(=O)OCC=C UVIZKKLXYCUTJB-UHFFFAOYSA-N 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000002976 reverse transcriptase assay Methods 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 238000012882 sequential analysis Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003463 sulfur Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 230000006490 viral transcription Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
- C07K14/08—RNA viruses
- C07K14/15—Retroviridae, e.g. bovine leukaemia virus, feline leukaemia virus human T-cell leukaemia-lymphoma virus
- C07K14/155—Lentiviridae, e.g. human immunodeficiency virus [HIV], visna-maedi virus or equine infectious anaemia virus
- C07K14/16—HIV-1 ; HIV-2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06043—Leu-amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16211—Human Immunodeficiency Virus, HIV concerning HIV gagpol
- C12N2740/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Definitions
- the present invention relates to the field of organic chemistry and more particularly to that of therapeutic chemistry.
- the invention relates to a synthetic peptide containing at least nine amino acids of formula: Ile-Arg-Lys-Ile-Phe-Leu-Asp-Gly-Ile, including the methylene group carried by the phenylalanine molecule ( Phe) has been replaced by an isostere, that is to say that the change in structure according to the invention can be written as follows:
- R is an alkyl radical, linear or branched
- R '' is an alkyl, phenyl, halogen, nitro, amino, alkyl amino, alkoxy, trifluoromethyl, trifluoromethoxy, carboxamido or cyano radical
- Z is sulfur, oxygen, amino or sulfoxide and n is 0, 1 , 2 or 3.
- Patent WO-A-91 10679 describes renin inhibitor peptides, having an amino acid with an ⁇ heteroatom at the P 3 position of the peptide of general formula:
- A represents the position P 4
- X the position P 3 / Y the position P 2 and, W and U the positions P x and P ' 3.
- A is IVA (isovaleryl) or BOC (ter-butyloxycarbonyl)
- X is -NHCH (SPh) CO-, -NHCH (OPh) CO-, -NHCH (NHPh) CO-,
- Y is HIS (L-histidine) or LEU (L-leucine)
- W is CAD (peptidylaminodiols) or STA (4 (S) -amino-3 (S) - hydroxy-6-methyl heptanoic acid)
- U is MBA (1-hydroxymethyl-2-methyl-butylamine) with the restriction that if W is CAD, U is absent
- Renin like the HIV protease, is an aspartyl protease and the compounds of patent WO-A-91 10679 are also used to treat diseases caused by retroviruses including HTLV -I, -II, -III.
- P and Q can in particular be amino acids
- the glycyl unit i is the unit carrying the chemotherapeutic residue W.
- One of the preferred compounds of the invention is L-alanyl-L- ( ⁇ -phenylthio) glycine.
- These prodrugs are used to increase penetration into infected cells, against which the transported chemotherapy residues (W) are active.
- chemotherapeutic residues for example thiophenol
- chemotherapeutic residues are antimicrobial or antiparasitic agents.
- Inhibition of renin can provide effective treatment for hypertension.
- BNMA (position P 3 ) represents acetic acid bis (1- naphthylmethyl)
- STA (position P x ) represents heptanoic acid 4 (S) -amino- 3 (S) -hydroxy-6-methyl
- MBA (position P ' x ) represents the 2 (S) -methylbutylamine X can for example be: SC 6 H 5 , 0-C 6 H 5 , NC ⁇ H 5
- the S-, O- and N-aryl derivatives are generally less active than their alkylated analogs.
- Ala represents alanine
- TPG represents thiophenylglycine (-NHCH (SPh) CO-)
- ⁇ -substituted glycine peptides are used to transport the drug into the microbial cell.
- Ar is an unsubstituted or substituted phenyl radical.
- Z is an isostere as defined above.
- Ile is the amino acid isoleucine
- Arg is the amino acid arginine
- Lys is the amino acid lysine
- Leu is the amino acid leucine
- Gly is the amino acid glycine
- Z is sulfur
- the compounds of formula I are inhibitors of HIV replication by acting as an inhibitor of a small dimeric aspartyl protease which specifically cleaves the precursors of a polyprotein encoding the structural proteins and enzymes constituting the virus (Martin SA, Recent Advances in the Design of HIV proteinase inhibitors, Antiviral Res. 17 (1992) 265-278).
- Y is a phenyl radical, unsubstituted or substituted by one, two or three substituents R ''
- Z is a sulfur, oxygen, amino and sulfur isoster
- This synthon II is prepared by the following method: Boc-Leucinamide (3) [(Boc Leu) amino] »+ allyl glyoxylate (4) allyl hydroxyacetate (5)
- Boc-Leucinamide (3) was condensed with allyl glyoxalate hydrate (4) to provide the corresponding ⁇ -hydroxylated derivative, therefore the allyl ester of Boc-Leu-Gly (5).
- the resulting ester (6) was displaced by a nucleophilic agent such as a thiophenol to obtain the compound (7).
- a nucleophilic agent such as a thiophenol
- the same type of synthesis can be used to introduce an -O- or -NH- isostere.
- the sulfur oxide compound is prepared by oxidation using a peroxide of the corresponding sulfur derivative.
- the various amino acids which constitute the chain of this peptide containing at least nine amino acids.
- Leu- (S) Phe can be represented as follows: O
- compositions intended in particular for the treatment of viral infections due to the HIV virus, which contain, as active principle, at least one compound of general formula I:
- R is a linear or branched alkyl radical
- R '' is an alkyl, phenyl, halogen, nitro, amino, alkyl amino, alkoxy, trifluoromethyl, trifluoromethoxy, carboxamido or cyano radical
- Z is sulfur, oxygen, amino or sulfoxide and n is 0, 1, 2 or 3
- compositions in particular intended for the treatment of viral infections due to the HIV virus, which contain, as active principle, at least one compound of simplified formula (I):
- Z is sulfur, oxygen, amino or sulfur oxide
- Ar is a phenyl radical, unsubstituted or substituted
- Ar preferably used as active ingredient, that for which Ar is a phenyl radical. It is also possible to use compounds for which Ar is a phenyl substituted by one, two or three radicals chosen from the group formed by a lower alkyl, a lower alkoxy, a trifluoromethyl, a trifluoromethoxy, a nitro, a carboxamido, a cyano, the halogens and phenyl.
- the AIDS virus produces a dimeric aspartyl protease which specifically cuts off the polyprotein precursors which code for the structural proteins and enzymes that make up the virus.
- proteolytic activity is necessary for the production of mature infectious virions and is, therefore, an interesting objective for a therapeutic intervention.
- Chemists in therapeutic chemistry have tried to design and synthesize inhibitors of this enzyme aspartyl protease which plays a decisive role.
- transition state analog This concept consists in synthesizing the shortest possible peptide substrate, in which the amide bond, normally cleaved, is replaced by a non-hydrolysable function mimicking a motif of the tetrahedral transition state.
- HIV1 protease inhibitors have also been designed taking into account the tertiary structure of the enzyme. These compounds can be classified as symmetric inhibitors or as dimerization inhibitors. In an effort to increase the generality and the approach of the anti-HIV peptide, the applicants made their study focus on a new concept of HIV-2 inhibitor based on the following experimental observations:
- Synthon (II) was used in the form of the mixture of diastereoisomers. Taking into account the unexpected anti-HIV results, it is advantageous to perform the separation by reverse phase HPLC of the mixture of (2) and / or the enantiomeric synthesis of the corresponding peptide in a second research step.
- the model peptides listed in Table 1 were incubated with the partially purified HIV-1 protease using a standard procedure (Billich, J. Biol. Chem. 1988, 263, 17905-17908) and the cleavage products were analyzed by reverse phase HPLC. Only the peptide 1 model was cleaved. Surprisingly, the sulfur-containing peptides (2,7,8,9,10 and 11) were resistant to any proteolytic cleavage under the conditions of the test. In addition, the sulfur-containing peptides were added to a test using peptide I as a substrate model. It was found that they were not inhibitors at concentrations of molarity equal to the substrates (approximately 2 mM).
- the evaluation of the antiviral effect is based on the study of the cytopathogenic effect of the HIV 1 virus on the MT4 cell line.
- the MT4 line originates from T cells isolated from a patient, transformed by the HTLV 1 virus. This line is mycoplasmated. Mycoplasmas are ubiquitous infectious agents, bacteria living on the surface of MT4 as natural hosts. This bacterium, of the order of 300 to 700 nm, is responsible for the great cytopathogenic effect of HIV by the formation of giant cells (fusion by gp 120) called SYNCITIA. This HIV infection is observed 4 to 5 days after infection and followed by cell death.
- This cytopathogenic effect is directly correlated with infection of cells by the virus, its intracellular replication and the expression of viral antigens by cells. An inhibition of this effect therefore corresponds to an inhibition of the multiplication of the HIV 1 virus.
- This lymphoblastoid line infected with HIV 1 can be used for viral production.
- the antiviral perspectives mainly concern the protease inhibitors which control the maturation of proteins and therefore the production of infectious particles, as well as the inhibitors of the TAT protein which participates in the awakening and dissemination of the positive regulatory virus of viral transcription. and finally on reverse transcriptase inhibitors which transform viral RNA into double stranded DNA, containing the viral message and which integrates as a provirus in the DNA of the host cell.
- Successive dilutions are made in 10% medium in order to be able to culture the MT4 for 8 days and to be able to read the formation of syncitia.
- the MT4 cells are washed 3 times with RPMI 1640 and cultured at the rate of 3.10 5 cells for 1 ml of each of the concentrations of the compounds to be tested in plates 24 wells. The day of cultivation is considered OJ.
- the MT4 cells are diluted 1/3, again in the different concentrations of the antiviral. Each day, the appearance of syncitia is observed under the microscope to see if there is a delay compared to the HIV-1 control.
- the reverse transcriptase assay is carried out. If the cells are not infected, then there has been protection by the antiviral tested. The dose IC 50 , concentration of the antiviral which inhibits by 50% the value of the reverse transcriptase of the HIV 1 control, has been determined.
- TI therapeutic index concentration required for 50% of MT4 cells to be uninfected (ID 50 ) compared to the concentration required to inhibit syncitia formation by 50% (IC 50 )
- the foreseeable dosage of the compounds of general formula I will be between 0.1 and 100 mg per unit dose.
- Their administration will be by digestive or parenteral route. Their use may be envisaged in the treatment of diseases linked to HIV viruses in the form of injectable compositions or else in the form of capsules or tablets.
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Abstract
A synthetic peptide for use in organic chemistry and particularly in therapeutical chemistry. The peptide contains at least nine amino acids of formula (I), wherein X and Y are protected or unprotected amino acid residues or peptides, R is a straight or branched alkyl radical, R'' is an alkyl radical, phenyl, halogen, nitro, amino, alkylamino, alkoxy, trifluoromethyl, trifluoromethoxy, carboxamido or cyano, Z is sulphur, oxygen, amino or sulphoxide, and n is 0, 1, 2 or 3. The compounds of formula (I) are HIV replication inhibitors in that they inhibit a small aspartyl-protease dimer that specifically cleaves precursors of a polyprotein coding for HIV enzymes and structural proteins.
Description
NOUVEAUX PEPTIDES PHENYLES, NEW PHENYL PEPTIDES,
LEUR PROCEDE DE PREPARATIONTHEIR PREPARATION PROCESS
ET LES COMPOSITIONS PHARMACEUTIQUES QUI EN RENFERMENTAND THE PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT
La présente invention se rapporte au domaine de la chimie organique et plus particulièrement à celui de la chimie thérapeutique.The present invention relates to the field of organic chemistry and more particularly to that of therapeutic chemistry.
Elle a plus particulièrement pour objet de nouveaux peptides contenant de la phenylalanine (Phe) dans lequel le groupe méthylène a été remplacé par un isostère : soufre, oxygène, amino ou suifoxyde.It relates more particularly to new peptides containing phenylalanine (Phe) in which the methylene group has been replaced by an isostere: sulfur, oxygen, amino or sulfoxide.
Spécifiquement, l'invention se rapporte à un peptide synthétique contenant au moins neuf amino-acides de formule : Ile-Arg-Lys-Ile-Phe-Leu-Asp-Gly-Ile, dont le groupe méthylène porté par la molécule de phenylalanine (Phe) a été remplacé par un isostère, c'est-à-dire que le changement de structure selon l'invention peut s'écrire de la façon suivante :Specifically, the invention relates to a synthetic peptide containing at least nine amino acids of formula: Ile-Arg-Lys-Ile-Phe-Leu-Asp-Gly-Ile, including the methylene group carried by the phenylalanine molecule ( Phe) has been replaced by an isostere, that is to say that the change in structure according to the invention can be written as follows:
X -C - NH -CH C - NH CHX -C - NH -CH C - NH CH
O CH, O RO CH, O R
X - C - NH - CH - C - NH - CH - YX - C - NH - CH - C - NH - CH - Y
O Z O R (I)O Z O R (I)
(R">„
formule dans laquelle X et Y sont des résidus d'acides aminés, protégés ou non, ou des peptides ( R ">„ formula in which X and Y are amino acid residues, protected or not, or peptides
R est un radical alcoyle, linéaire ou ramifiéR is an alkyl radical, linear or branched
R' ' est un radical alcoyle, phényle, halogène, nitro, amino, alcoyl amino, alcoxy, trifluorométhyle, trifluorométhoxy, carboxamido ou un cyano Z est un soufre, un oxygène, un amino ou un sulfoxide et n est égal à 0, 1, 2 ou 3.R '' is an alkyl, phenyl, halogen, nitro, amino, alkyl amino, alkoxy, trifluoromethyl, trifluoromethoxy, carboxamido or cyano radical Z is sulfur, oxygen, amino or sulfoxide and n is 0, 1 , 2 or 3.
• Le brevet WO-A-91 10679 décrit des peptides inhibiteurs de rénine, ayant un acide aminé avec un hétéroatome en α à la position P3 du peptide de formule générale :Patent WO-A-91 10679 describes renin inhibitor peptides, having an amino acid with an α heteroatom at the P 3 position of the peptide of general formula:
A - X - Y - W - UA - X - Y - W - U
dans laquelle A représente la position P4 , X la position P3/ Y la position P2 et, W et U les positions Px et P'3..in which A represents the position P 4 , X the position P 3 / Y the position P 2 and, W and U the positions P x and P ' 3..
Les composés qui y sont décrits, préférés, sont ceux pour lesquels : A est IVA (isovaléryl) ou BOC (ter-butyloxycarbonyl)The preferred compounds described therein are those for which: A is IVA (isovaleryl) or BOC (ter-butyloxycarbonyl)
X est -NHCH(SPh)CO- , -NHCH(OPh) CO- , -NHCH(NHPh) CO- ,X is -NHCH (SPh) CO-, -NHCH (OPh) CO-, -NHCH (NHPh) CO-,
- NHCH(SCH(CH3)2)CO-, -NHCH(S02CH(CH3)2) CO- , -NHCH(NPhCH3)CO-,- NHCH (SCH (CH 3 ) 2 ) CO-, -NHCH (S0 2 CH (CH 3 ) 2 ) CO-, -NHCH (NPhCH 3 ) CO-,
Y est HIS (L-histidine) ou LEU (L-leucine)Y is HIS (L-histidine) or LEU (L-leucine)
W est CAD (peptidylaminodiols) ou STA (l'acide 4 (S) -amino-3 (S) - hydroxy-6-methyl heptanoïque)W is CAD (peptidylaminodiols) or STA (4 (S) -amino-3 (S) - hydroxy-6-methyl heptanoic acid)
U est MBA (1-hydroxyméthyl-2-methyl-butylamine) avec la restriction que si W est CAD, U est absentU is MBA (1-hydroxymethyl-2-methyl-butylamine) with the restriction that if W is CAD, U is absent
Ces peptides sont des inhibiteurs de rénine et sont utilisés pour traiter les phénomènes d'hypertension, les défaillances cardiaques, le glaucome, l'hyperaldostéronisme. La rénine, tout comme la protease HIV, est une aspartyl protease et les composés du brevet WO-A-91 10679 sont également
utilisés pour traiter les maladies causées par les rétrovirus incluant HTLV -I, -II, -III.These peptides are renin inhibitors and are used to treat hypertension, heart failure, glaucoma, hyperaldosteronism. Renin, like the HIV protease, is an aspartyl protease and the compounds of patent WO-A-91 10679 are also used to treat diseases caused by retroviruses including HTLV -I, -II, -III.
• Le brevet US-A-4 454 065 décrit des prodrogues ayant une chaîne oligopeptide substituée à la position α par un résidu chimiothérapique W.• US-A-4,454,065 describes prodrugs having an oligopeptide chain substituted at the α position by a chemotherapeutic residue W.
Ces prodrogues ont pour formule générale :These prodrugs have the general formula:
P-NHCH(RJCO-NHCH(W) CO-Q 2 XP-NHCH (RJCO-NHCH (W) CO-Q 2 X
P et Q pouvant notamment être des acides aminésP and Q can in particular be amino acids
L'unité glycyl i est l'unité porteuse du résidu chimiothérapique W. Un des composés préférés de l'invention est la L-alanyl-L- (α- phénylthio)glycine.The glycyl unit i is the unit carrying the chemotherapeutic residue W. One of the preferred compounds of the invention is L-alanyl-L- (α-phenylthio) glycine.
Ces prodrogues sont utilisés pour augmenter la pénétration dans les cellules infectées, contre lesquelles les résidus chimiotherapiques transportés (W) sont actifs. Ces résidus chimiotherapiques (par exemple le thiophenol) sont des agents antimicrobiens ou antiparasitaires.These prodrugs are used to increase penetration into infected cells, against which the transported chemotherapy residues (W) are active. These chemotherapeutic residues (for example thiophenol) are antimicrobial or antiparasitic agents.
• La référence J. MED. CHEM. (1992) , 35(6) , 1032-42, décrit des peptides inhibiteurs de rénine, contenant un acide aminé avec un hétéroatome en α à la position P2 .• The J. MED reference. CHEM. (1992), 35 (6), 1032-42, describes renin inhibitor peptides, containing an amino acid with an α heteroatom at the P 2 position.
L'inhibition de la rénine peut fournir un traitement effectif pour l'hypertension.Inhibition of renin can provide effective treatment for hypertension.
Les dérivés décrits sont notamment :The derivatives described are in particular:
BNMA - NHCH(X)CO - STA - MBABNMA - NHCH (X) CO - STA - MBA
BNMA (position P3) représente l'acide acétique bis (1- naphtylméthyl)BNMA (position P 3 ) represents acetic acid bis (1- naphthylmethyl)
STA (position Px) représente l'acide heptanoique 4(S) -amino- 3 (S) -hydroxy-6-methylSTA (position P x ) represents heptanoic acid 4 (S) -amino- 3 (S) -hydroxy-6-methyl
MBA (position P'x) représente la 2 (S) -méthylbutylamine X peut par exemple être : S-C6H5 , 0-C6H5 , N-CβH5
Cependant, les dérivés S-, O- et N-aryl sont en général moins actifs que leurs analogues alcoylés.MBA (position P ' x ) represents the 2 (S) -methylbutylamine X can for example be: SC 6 H 5 , 0-C 6 H 5 , NC β H 5 However, the S-, O- and N-aryl derivatives are generally less active than their alkylated analogs.
• La référence INT. J. PEPT. PROTEIN RES. (1986) , 27(6), 659- 665, décrit la synthèse de peptides α-thiophénylglycine et plus particulièrement le dipeptide et les deux tripeptides suivants :• The INT reference. J. PEPT. PROTEIN RES. (1986), 27 (6), 659-665, describes the synthesis of α-thiophenylglycine peptides and more particularly the following dipeptide and the following two tripeptides:
Ala - α -TPG Ala - α -TPG - AlaAla - α -TPG Ala - α -TPG - Ala
Ala - Ala - α -TPGAla - Ala - α -TPG
Ala représente l'alanineAla represents alanine
TPG représente la thiophénylglycine (-NHCH(SPh) CO-)TPG represents thiophenylglycine (-NHCH (SPh) CO-)
Ces peptides de glycine α-substitués sont utilisés pour le transport du médicament dans la cellule microbienne.These α-substituted glycine peptides are used to transport the drug into the microbial cell.
Ainsi, grâce à une coupure produite par la peptidase, ils délivrent le substituent α, c'est à dire le thiophenol, dans la cellule microbienne.Thus, thanks to a cut produced by the peptidase, they deliver the substitute α, ie thiophenol, in the microbial cell.
Les composés selon l'invention de formule I peuvent s'écrire plus précisément de la manière simplifiée suivante :The compounds according to the invention of formula I can be written more precisely in the following simplified manner:
Ile - Arg - Lys - Ile - NH - CH - CONH - Leu - Asp - Gly - IleIle - Arg - Lys - Ile - NH - CH - CONH - Leu - Asp - Gly - Ile
II
Z (I)Z (I)
ArAr
dans laquelle Ar est un radical phényle non substitué ou substitué.wherein Ar is an unsubstituted or substituted phenyl radical.
Z est un isostère tel que défini précédemment.Z is an isostere as defined above.
Ile est l'acide aminé isoleucineIle is the amino acid isoleucine
Arg est l'acide aminé arginine Lys est l'acide aminé lysineArg is the amino acid arginine Lys is the amino acid lysine
Leu est l'acide aminé leucineLeu is the amino acid leucine
Asp est l'acide aminé acide aspartiqueAsp is the amino acid aspartic acid
Gly est l'acide aminé glycine
D'une manière préférée, dans cette formule générale I, Z est du soufre.Gly is the amino acid glycine Preferably, in this general formula I, Z is sulfur.
Les composés de formule I sont des inhibiteurs de réplication du HIV en agissant comme inhibiteur d'une petite aspartyl protease dimère qui clive spécifiquement les précurseurs d'une polyprotéine codant pour les protéines de structure et les enzymes constitutives du virus (Martin S.A, Récent Advances in the Design of HIV proteinase inhibitors, Antiviral Res. 17 (1992) 265-278) .The compounds of formula I are inhibitors of HIV replication by acting as an inhibitor of a small dimeric aspartyl protease which specifically cleaves the precursors of a polyprotein encoding the structural proteins and enzymes constituting the virus (Martin SA, Recent Advances in the Design of HIV proteinase inhibitors, Antiviral Res. 17 (1992) 265-278).
Les composés de formule générale I sont préparés en utilisant un synthon : l'acide [ (Boc-Leu) - amino] phenyl Z acétique de formule II :The compounds of general formula I are prepared using a synthon: [(Boc-Leu) - amino] phenyl Z acetic acid of formula II:
Boc NH - CH - CONH - CH - C>^Boc NH - CH - CONH - CH - C> ^
\\
OH Z (II)OH Z (II)
Boc = t.butoxycarbonylBoc = t.butoxycarbonyl
dans laquelle Y est un radical phényle, non substitué ou substitué par un, deux ou trois substituants R' 'in which Y is a phenyl radical, unsubstituted or substituted by one, two or three substituents R ''
Z est un isostère soufre, oxygène, amino et suifoxydeZ is a sulfur, oxygen, amino and sulfur isoster
qui est employé au cours de la synthèse peptidique sur matrice pour introduire le motif fondamental sur lequel repose la présente invention.which is used during peptide matrix synthesis to introduce the fundamental motif on which the present invention is based.
La planche 1, jointe en annexe, explicite les différentes étapes de la synthèse du synthon II, pour lequel Z est du soufre .Plate 1, attached in the appendix, explains the different stages of the synthesis of synthon II, for which Z is sulfur.
Ce synthon II est préparé par la méthode suivante :
Boc-Leucinamide (3) [ (Boc Leu)amino] » + glyoxylate d'allyle (4) hydroxyacetate d'allyle (5)This synthon II is prepared by the following method: Boc-Leucinamide (3) [(Boc Leu) amino] »+ allyl glyoxylate (4) allyl hydroxyacetate (5)
t (Boc Leu) amino]acétoxy acétate d'allyle (6) i [(Boc Leu) amino]phenyl sulfanyl acétate d'allyle (7) i Acide [ (Boc Leu) amino] phénylsulfanylacétique (II)t (Boc Leu) amino] acetoxy allyl acetate (6) i [(Boc Leu) amino] phenyl sulfanyl allyl acetate (7) i Acid [(Boc Leu) amino] phenylsulfanylacetic (II)
Boc-Leucinamide (3) a été condensé avec l'hydrate de glyoxalate d'allyle (4) pour fournir le dérivé α-hydroxylé correspondant, donc l'ester allylique de Boc-Leu-Gly (5) . Après acétylation de la fonction hydroxylée, l'ester résultant (6) a été déplacé par un agent nucleophile comme un thiophenol pour obtenir le composé (7) . L'élimination du groupe ester allylique en utilisant le complexe (bis palladium triphénylphosphine) en présence de triphénylphosphine conduit au. synthon désiré (II) sous la forme d'un mélange de diastereoisomeres. On doit noter que l'emploi d'autres esters d'acide glyoxylique a été trouvé moins approprié pour la condensation sur le Boc- Leucinamide. Vraisemblablement, les conditions de déprotection finale de la fonction ester conduisent au clivage de la liaison peptidique. En outre, la condensation directe entre l'acide glyoxylique et l'acide Boc-Leucine s'est avérée être inopérante dans les conditions expérimentales de l'essai, car la synthèse en phase solide (décrite ci-après) des peptides (énumérés au Tableau 1 ci-joint) , exige des grammes de synthon (II) .Boc-Leucinamide (3) was condensed with allyl glyoxalate hydrate (4) to provide the corresponding α-hydroxylated derivative, therefore the allyl ester of Boc-Leu-Gly (5). After acetylation of the hydroxylated function, the resulting ester (6) was displaced by a nucleophilic agent such as a thiophenol to obtain the compound (7). The elimination of the allyl ester group using the complex (bis palladium triphenylphosphine) in the presence of triphenylphosphine leads to. desired synthon (II) in the form of a mixture of diastereoisomers. It should be noted that the use of other glyoxylic acid esters has been found less suitable for condensation on Boc-Leucinamide. Presumably, the conditions of final deprotection of the ester function lead to the cleavage of the peptide bond. In addition, direct condensation between glyoxylic acid and Boc-Leucine acid was found to be ineffective under the experimental conditions of the test, since the solid phase synthesis (described below) of the peptides (listed in Table 1 attached), requires grams of synthon (II).
Le même type de synthèse peut être utilisé pour introduire un isostère -O- ou -NH- . Le composé suifoxydique est préparé par oxydation au moyen d'un peroxyde du dérivé soufré correspondant.
En utilisant la méthode de synthèse peptidique en phase solide, suivant le mode opératoire décrit par Nguyen et al (J.Chem.Soc, Perkin Transact . 1 (1987) 1915-1919) , on accroche au départ de ce synthon les différents aminoacides qui constituent la chaîne de ce peptide contenant au moins neuf amino-acides. On part d'une résine MBHA (p.methyl benzhydrylamine) ou d'une résine CM (résine chlorométhylée réticulée à 1%) contenant 0,40 mmol d'Ile par gramme. Le couplage a été effectué en utilisant deux équivalents de Boc amino-acide et deux équivalents d'hexafluoro phosphate de [benzotriazolyloxy tris-dimethyl aminophosphonium] (BOP) (Novabiochem) . Après couplage, on effectue la déprotection avec 50 % de l'acide trifluoroacétique (TFA)à 50% dans le chlorure de méthylène (DCM) . On peut également réaliser en une seule étape la déprotection de la chaîne et le clivage de la résine, en employant de l'acide fluorhydrique en présence d'anisole. Le peptide résultant de la condensation est purifié dans une solution aqueuse d'acétonitrile. Les peptides suivants (représentés avec leur numéro) ont été préparés successivement :The same type of synthesis can be used to introduce an -O- or -NH- isostere. The sulfur oxide compound is prepared by oxidation using a peroxide of the corresponding sulfur derivative. Using the solid phase peptide synthesis method, according to the procedure described by Nguyen et al (J. Chem. Soc, Perkin Transact. 1 (1987) 1915-1919), the various amino acids which constitute the chain of this peptide containing at least nine amino acids. We start with an MBHA resin (p.methyl benzhydrylamine) or a CM resin (1% cross-linked chloromethylated resin) containing 0.40 mmol of Ile per gram. The coupling was carried out using two equivalents of Boc amino acid and two equivalents of hexafluoro phosphate of [benzotriazolyloxy tris-dimethyl aminophosphonium] (BOP) (Novabiochem). After coupling, deprotection is carried out with 50% of trifluoroacetic acid (TFA) at 50% in methylene chloride (DCM). It is also possible in one step to deprotect the chain and cleave the resin, using hydrofluoric acid in the presence of anisole. The peptide resulting from the condensation is purified in an aqueous acetonitrile solution. The following peptides (represented with their number) were prepared successively:
(1) Ile-Arg-Lys-Ile-Leu-Phe-Leu-Asp-Gly-Ile-OH(1) Ile-Arg-Lys-Ile-Leu-Phe-Leu-Asp-Gly-Ile-OH
(8) Fmoc-Ile-Arg-Lys-Ile-Leu- (S) Phe-Leu-Asp-Gly-NH2 (8) Fmoc-Ile-Arg-Lys-Ile-Leu- (S) Phe-Leu-Asp-Gly-NH 2
(9) Ile-Arg-Lys-Ile-Leu- (S) Phe-Leu-Asp-Gly-NH2 (10) Fmoc-Ile-Arg-Lys-Ile-Leu- (S) Phe-Leu-Asp-Gly-Ile-OH (11) Ile-Arg-Lys-Ile-Leu- (S) Phe-Leu-Asp-Gly-Ile-OH(9) Ile-Arg-Lys-Ile-Leu- (S) Phe-Leu-Asp-Gly-NH 2 (10) Fmoc-Ile-Arg-Lys-Ile-Leu- (S) Phe-Leu-Asp- Gly-Ile-OH (11) Ile-Arg-Lys-Ile-Leu- (S) Phe-Leu-Asp-Gly-Ile-OH
(2) BocNH-Leu- (S) PheOH(2) BocNH-Leu- (S) PheOH
(7) BocNH-Leu- (S) PheOCH2-CH=CH2 (7) BocNH-Leu- (S) PheOCH 2 -CH = CH 2
dans cet énoncé et dans ce qui suit, le symbole Fmoc signifie : 9-fluorenylmethoxycarbonylin this statement and in the following, the symbol Fmoc means: 9-fluorenylmethoxycarbonyl
L'enchaînement préféré, Leu- (S) Phe, peut être représenté comme suit :
OThe preferred sequence, Leu- (S) Phe, can be represented as follows: O
-NH-CH -C- NH-CH -C--NH-CH -C- NH-CH -C-
CH,CH,
L'activité anti HIV-1 de ces peptides est représentée dans le tableau 1 ci-après.The anti HIV-1 activity of these peptides is shown in Table 1 below.
L'invention a encore pour objet les compositions pharmaceutiques, destinées notamment au traitement des infections virales dues au virus HIV, qui contiennent, à titre de principe actif, au moins un composé de formule générale I :Another subject of the invention is pharmaceutical compositions, intended in particular for the treatment of viral infections due to the HIV virus, which contain, as active principle, at least one compound of general formula I:
X - C - NH - CH - C - NH - CH - YX - C - NH - CH - C - NH - CH - Y
II I II I d) II I II I d )
O Z O RO Z O R
dans lequel X et Y sont des résidus d'acides aminés, protégés ou non, ou des peptidesin which X and Y are amino acid residues, protected or not, or peptides
R est un radical alcoyle linéaire ou ramifié R' ' est un radical alcoyle, phényle, halogène, nitro, amino, alcoyl amino, alcoxy, trifluorométhyle, trifluorométhoxy, carboxamido ou cyanoR is a linear or branched alkyl radical R '' is an alkyl, phenyl, halogen, nitro, amino, alkyl amino, alkoxy, trifluoromethyl, trifluoromethoxy, carboxamido or cyano radical
Z est un soufre, un oxygène, un amino ou un sulfoxide et n est égal à 0, 1, 2 ou 3Z is sulfur, oxygen, amino or sulfoxide and n is 0, 1, 2 or 3
en association ou en mélange avec un excipient ou un véhicule inerte, non toxique, pharmaceutiquement acceptable.
L'invention concerne encore les compositions pharmaceutiques, notamment destinées au traitement des infections virales dues au virus HIV, qui contiennent, à titre de principe actif, au moins un composé de formule simplifiée (I) :in combination or in mixture with an inert, non-toxic, pharmaceutically acceptable excipient or vehicle. The invention also relates to pharmaceutical compositions, in particular intended for the treatment of viral infections due to the HIV virus, which contain, as active principle, at least one compound of simplified formula (I):
Ile - Arg - Lys - Ile - NH - CH - CONH - Leu - Asp - Gly - IleIle - Arg - Lys - Ile - NH - CH - CONH - Leu - Asp - Gly - Ile
II
Z (I)Z (I)
I ArI Ar
dans laquelle Z est du soufre, un oxygène, un amino ou un suifoxydein which Z is sulfur, oxygen, amino or sulfur oxide
Ar est un radical phényle, non substitué ou substituéAr is a phenyl radical, unsubstituted or substituted
en association ou en mélange avec un excipient ou un véhicule inerte, non toxique, pharmaceutiquement acceptable.in combination or in mixture with an inert, non-toxic, pharmaceutically acceptable excipient or vehicle.
Parmi les composés de formule générale I, on utilisera de préférence comme principe actif, celui pour lequel Ar est un radical phényle. On pourra également utiliser des composés pour lesquels Ar est un phényle substitué par un, deux ou trois radicaux choisis dans le groupe formé par un alcoyle inférieur, un alcoxy inférieur, un trifluorométhyle, un trifluorométhoxy, un nitro, un carboxamido, un cyano, les halogènes et un phényle.Among the compounds of general formula I, preferably used as active ingredient, that for which Ar is a phenyl radical. It is also possible to use compounds for which Ar is a phenyl substituted by one, two or three radicals chosen from the group formed by a lower alkyl, a lower alkoxy, a trifluoromethyl, a trifluoromethoxy, a nitro, a carboxamido, a cyano, the halogens and phenyl.
Le virus du SIDA produit une aspartyl-protéase dimère qui coupe spécifiquement les précurseurs de polyprotéine qui code pour les protéines structurelles et les enzymes constitutifs du virus.The AIDS virus produces a dimeric aspartyl protease which specifically cuts off the polyprotein precursors which code for the structural proteins and enzymes that make up the virus.
Cette activité protéolytique est nécessaire pour la production de virions infectieux matures et est, par conséquent, un objectif intéressant pour une intervention sur le plan thérapeutique.
Les chimistes de chimie thérapeutique ont essayé de concevoir et de synthétiser des inhibiteurs de cet enzyme aspartyl protease qui joue un rôle décisif.This proteolytic activity is necessary for the production of mature infectious virions and is, therefore, an interesting objective for a therapeutic intervention. Chemists in therapeutic chemistry have tried to design and synthesize inhibitors of this enzyme aspartyl protease which plays a decisive role.
La plupart des laboratoires ont employé le concept d'analogue d'état de transition. Ce concept consiste à synthétiser le substrat de peptide le plus court possible, dans lequel la liaison amide, normalement clivée, est remplacée par une fonction non hydrolysable mimant un motif de l'état de transition tétrahédrique.Most laboratories have used the concept of transition state analog. This concept consists in synthesizing the shortest possible peptide substrate, in which the amide bond, normally cleaved, is replaced by a non-hydrolysable function mimicking a motif of the tetrahedral transition state.
Jusqu'à présent, un grand nombre de motifs mimant l'état de transition tétrahédrique de différents états ont été mis en présence de la protease de HIVl. Il s'agit d'isostères aminoéthyléniques (RICH D.H et al. J.Med.Chem. 3! (1990) 1285- 1288), d'analogues de statine (HUY K.Y et al. FASEB J. 5 (1991) 2606-2610 - VENAUD S et al. Res. Virol. 141 (1992) 311-319), d'isostères d'acide phosphinique (Grobeiny D et al. Biochem.Biophys.Res.Commun. 169 (1990) 1111-1116), de difluorocétones (SHAM H.L et al. Biochem.Biophys.Res.Commun. 175 (1991) 914-919), d'isostères dihydroxyéthylène et hydroxyéthylamine (THAISRIVONGS S et al. J.Med.Chem. 3_4 (1991) 2344-2356 - RICH D.H et al. J.Med.Chem. 34 (1991) 1222-1225).Up to now, a large number of motifs mimicking the tetrahedral transition state of different states have been brought into contact with the HIV1 protease. These are aminoethyl isosteres (RICH DH et al. J. Med. Chem. 3! (1990) 1285-1288), statin analogues (HUY KY et al. FASEB J. 5 (1991) 2606- 2610 - VENAUD S et al. Res. Virol. 141 (1992) 311-319), isosteres of phosphinic acid (Grobeiny D et al. Biochem.Biophys.Res.Commun. 169 (1990) 1111-1116), difluoroketones (SHAM HL et al. Biochem.Biophys.Res.Commun. 175 (1991) 914-919), dihydroxyethylene and hydroxyethylamine isosteres (THAISRIVONGS S et al. J.Med.Chem. 3_4 (1991) 2344-2356 - RICH DH et al. J. Med. Chem. 34 (1991) 1222-1225).
Les inhibiteurs de protease de HIVl ont été également conçus en tenant compte de la structure tertiaire de l'enzyme. Ces composés peuvent être classifiés comme inhibiteurs symétriques ou comme inhibiteurs de dimérisation. Dans un souci d'augmenter la portée générale et l'approche du peptide anti-HIV, les demandeurs ont fait porter leur étude sur un nouveau concept d'inhibiteur de HIV-2 basé sur les observations expérimentales suivantes :HIV1 protease inhibitors have also been designed taking into account the tertiary structure of the enzyme. These compounds can be classified as symmetric inhibitors or as dimerization inhibitors. In an effort to increase the generality and the approach of the anti-HIV peptide, the applicants made their study focus on a new concept of HIV-2 inhibitor based on the following experimental observations:
1. Si après analyse séquentielle des séquences de protéines structurales et des enzymes des virions matures infectieux on ne peut pas mettre en évidence un substrat spécifique de la protease HIV, on remarque cependant certaines
spécificités dans les sites de clivage effectués par ces virions infectieux.1. If after sequential analysis of the structural protein sequences and of the enzymes of the infectious mature virions it is not possible to demonstrate a specific substrate for the HIV protease, we nevertheless note certain specificities in the cleavage sites carried out by these infectious virions.
2. Beaucoup de peptides qui représentent des modèles connus de site de traitement protéolytique à l'intérieur des polyprotéines de HIV-l ont été considérés comme étant clivés avec précision par une protease synthétique ou recombinante de HIV-l.2. Many peptides which represent known patterns of proteolytic processing site within the HIV-1 polyproteins have been considered to be precisely cleaved by a synthetic or recombinant HIV-1 protease.
3. Des peptides ont été conçus par déduction du séquençage des fonctions amine ou carboxyle terminale des protéines de HIV- 1 matures. Parmi celles-ci, le peptide synthétique Ile-Arg- Lys-Ile-Leu-Phe-Leu-Asp-Gly-Leu a été trouvé comme étant clivé entre le résidu Leu-Phe, cette coupure correspondant au site de clivage 727/728 pol normal (Darke, P.L., Biochem. Biophys. Res. Commun. 1988, 156, 297) . En supposant que le remplacement du groupe méthylène du résidu phenylalanine (Phe) dans le peptide I par un hétéroatome tel que le soufre, l'oxygène, un amino, un sulfoxide, ne va pas changer le site de clivage entre Leu et Phe, il est possible de mentionner la synthèse et les propriétés inhibitrices surprenante vis-à-vis de HIV-l, de nouveaux isostères du peptide I . Ces nouveaux peptides contiennent une glycine substituée en α par un Z-phényl dans lequel Z représente le soufre, l'oxygène, un amino, un sulfoxide. D'une manière habituelle, une glycine α-substituée dans laquelle le carbone en α est relié à un atome d'azote, d'oxygène ou de soufre est instable. Cependant, différentes glycines α- substituées N-acétylées de ce type, ont été décrites dans la littérature. L'acylation du groupe amino mène à la stabilisation de la molécule en délocalisant les électrons de l'azote sur la liaison peptidique. Au lieu d'utiliser une simple N-acylation pour fournir la stabilité chimique de telles glycines α-substituées, les demandeurs ont utilisé la liaison peptidique Leu-Phe de façon à mimer le peptide I.
On a synthétisé les peptides énumérés dans le Tableau 1 par la technique de la synthèse en phase solide. Cette synthèse nécessite l'emploi d'un synthon clé (II) .3. Peptides were designed by deduction of the sequencing of the terminal amine or carboxyl functions of mature HIV-1 proteins. Among these, the synthetic peptide Ile-Arg-Lys-Ile-Leu-Phe-Leu-Asp-Gly-Leu was found to be cleaved between the Leu-Phe residue, this cut corresponding to the cleavage site 727/728 normal pol (Darke, PL, Biochem. Biophys. Res. Commun. 1988, 156, 297). Assuming that replacing the methylene group in the phenylalanine (Phe) residue in peptide I with a heteroatom such as sulfur, oxygen, amino, sulfoxide, will not change the cleavage site between Leu and Phe, it is possible to mention the surprising synthesis and inhibitory properties vis-à-vis HIV-1, new isosteres of peptide I. These new peptides contain a glycine substituted in α by a Z-phenyl in which Z represents sulfur, oxygen, an amino, a sulfoxide. In the usual way, an α-substituted glycine in which the carbon at α is linked to a nitrogen, oxygen or sulfur atom is unstable. However, various N-acetylated α-substituted glycines of this type have been described in the literature. The acylation of the amino group leads to the stabilization of the molecule by delocalizing the electrons from the nitrogen on the peptide bond. Instead of using a simple N-acylation to provide the chemical stability of such α-substituted glycines, the applicants have used the peptide bond Leu-Phe so as to mimic peptide I. The peptides listed in Table 1 were synthesized by the solid phase synthesis technique. This synthesis requires the use of a key synthon (II).
Les synthons (2) et (7) ont été synthétisés selon la Planche 1Synthons (2) and (7) were synthesized according to Plate 1
Le synthon (II) a été employé sous la forme du mélange de diastereoisomeres. Compte tenu des résultats anti-HIV inattendus, il est avantageux d'effectuer la séparation par HPLC en phase inverse du mélange de (2) et/ou la synthèse énantiomérique du peptide correspondant dans une deuxième étape de recherche.Synthon (II) was used in the form of the mixture of diastereoisomers. Taking into account the unexpected anti-HIV results, it is advantageous to perform the separation by reverse phase HPLC of the mixture of (2) and / or the enantiomeric synthesis of the corresponding peptide in a second research step.
TEST D'ACTIVITE DE LA PROTEASE HIVlHIVl PROTEASE ACTIVITY TEST
Les peptides modèles énumérés au Tableau 1 ont été mis en incubation avec la protease de HIV-l partiellement purifiée en employant une procédure standard (Billich, J. Biol. Chem. 1988, 263, 17905-17908) et les produits de clivage ont été analysés par HPLC en phase inverse. Seul le modèle de peptide 1 a été clivé. D'une manière surprenante, les peptides contenant du soufre (2,7,8,9,10 et 11) ont été résistants à tout clivage protéolytique dans les conditions de l'essai. De plus, les peptides contenant du soufre ont été ajoutés à un essai utilisant le peptide I comme modèle de substrat. On a constaté qu'ils n'étaient pas des inhibiteurs à des concentrations de molarité égale aux substrats (environ 2mM) .The model peptides listed in Table 1 were incubated with the partially purified HIV-1 protease using a standard procedure (Billich, J. Biol. Chem. 1988, 263, 17905-17908) and the cleavage products were analyzed by reverse phase HPLC. Only the peptide 1 model was cleaved. Surprisingly, the sulfur-containing peptides (2,7,8,9,10 and 11) were resistant to any proteolytic cleavage under the conditions of the test. In addition, the sulfur-containing peptides were added to a test using peptide I as a substrate model. It was found that they were not inhibitors at concentrations of molarity equal to the substrates (approximately 2 mM).
ACTIVITE ANTI-VIRALEANTI-VIRAL ACTIVITY
Les composés représentatifs énumérés au Tableau 1 ont été également testés pour leur aptitude à inhiber l' infection par HIVl en culture de cellules. L'effet fusogenique de HIVl dans la lignée cellulaire MT4 a été déterminé comme décrit par REY et coll. (J. Virol. Methods 1987, 16, 239-249) ainsi qu'il est montré dans le Tableau 1. Certains des nouveaux phénylpeptides de l'invention ont été trouvés actifs comme inhibiteurs de la réplication de HIV.The representative compounds listed in Table 1 were also tested for their ability to inhibit HIV1 infection in cell culture. The fusogenic effect of HIV1 in the MT4 cell line was determined as described by REY et al. (J. Virol. Methods 1987, 16, 239-249) as shown in Table 1. Some of the new phenylpeptides of the invention have been found active as inhibitors of HIV replication.
Les composés les plus actifs ont été (9) et (11) . Ces résultats montrent que la protection du groupement N-terminal par un groupe FMOC dans les composés (8) ou (10) a entraîné une perte
importante de l'aptitude à l'inhibition de la réplication virale comparativement aux congénères dont le groupement N- terminal est libre (9) et (11) . En outre, les résultats antérieurs, publiés par BILLICH et al (J. Biol. Chem. 263 (1988) 17905-17908) , ont montré que des peptides synthétiques contenant de 7 à 18 amino acides de long, peuvent être employés comme substrats modèles inhibiteurs, pour l'investigation de la protease. On a trouvé maintenant que la longueur minimale pour les peptides contenant de la glycine substituée par un Z- phényle en α, était de 9 ou 10 amino acides. Dans cette perspective, les deux dipeptides (2) et (7) qui contiennent enchaînement -Leu- (S) Phe- , se sont avérés n'être pas actifs en tant qu'inhibiteur de la réplication virale. En ce qui concerne le résidu terminal carboné, ce résultat préliminaire semble indiquer que le groupe carboxyle (11) ou le groupe carboxamide (9) peuvent être appropriés en tant qu'inhibiteurs de la réplication du virus HIV.The most active compounds were (9) and (11). These results show that the protection of the N-terminal group by a FMOC group in compounds (8) or (10) resulted in a loss important in the ability to inhibit viral replication compared to congeners whose N-terminal group is free (9) and (11). In addition, previous results, published by BILLICH et al (J. Biol. Chem. 263 (1988) 17905-17908), have shown that synthetic peptides containing 7 to 18 amino acids long can be used as model substrates inhibitors, for the investigation of the protease. It has now been found that the minimum length for peptides containing glycine substituted by a Z-phenyl at α, is 9 or 10 amino acids. In this perspective, the two dipeptides (2) and (7) which contain chain -Leu- (S) Phe-, have been found not to be active as an inhibitor of viral replication. With regard to the carbonaceous terminal residue, this preliminary result seems to indicate that the carboxyl group (11) or the carboxamide group (9) may be suitable as inhibitors of the replication of the HIV virus.
Cette étude a montré que des inhibiteurs modérément puissants de la réplication de HIV-l, incorporant un isostère de phenylalanine pourraient être identifiés. A la connaissance des demandeurs, c'est la première fois que des peptides synthétiques qui ne sont pas des substrats ou des inhibiteurs de protease de HIV-l peuvent être actifs sur l'infection par HIV-l dans les cultures de cellule MT4. Cette nouvelle classe de peptides synthétiques de la protease de HIV qui est basée sur le remplacement isostérique d'un groupe méthylène par un atome isostère Z dans un résidu phenylalanine positionné sur le site de clivage d'un substrat peptidique synthétique de protease de HIV, présente un grand intérêt.This study showed that moderately potent inhibitors of HIV-1 replication, incorporating an isostere of phenylalanine, could be identified. To the applicants' knowledge, this is the first time that synthetic peptides which are not substrates or inhibitors of HIV-1 protease can be active on HIV-1 infection in MT4 cell cultures. This new class of synthetic peptides of the HIV protease which is based on the isosteric replacement of a methylene group by an isosteric atom Z in a phenylalanine residue positioned on the cleavage site of a synthetic peptide substrate of HIV protease, presents A big interest.
La question du mécanisme d'action pour cette nouvelle classe de composés semble être cruciale. Les essais destinés à identifier la cible dans le cycle de replication de HIV déclanchée par cette nouvelle classe de composés, devront être poursuivis. Cependant, en analysant les essais effectués pour déterminer le mécanisme par lequel ces composés interfèrent avec le cycle de replication virale à l'intérieur de la cellule, les résultats
rapportés ici laissent supposer que certains peptides qui incorporent un motif Z-phenyl ne sont pas cependant actifs au niveau de l'inhibition du virus HIV. Ce manque d'activité peut être associé à une faible perméabilité membranaire des composés vis-à-vis de cellules MT4, pour ces nouveaux peptides synthétiques. En effet, pour autant que les composés comme (9) et (11) qui ont une fonction ester terminale libre, ont montré le plus grand effet anti-HIV, les peptides (8) et (10) ont été trouvés inactifs dans des cultures infectées. Il apparait donc qu'à l'intérieur de cette nouvelle classe de peptides synthétiques qui incorpore la fraction Z-phényl, les composés qui entrent dans la cellule infectée, avec la plus grande efficacité constituent de bons candidats pour des études de mécanisme d'action.The question of the mechanism of action for this new class of compounds seems to be crucial. The tests intended to identify the target in the replication cycle of HIV triggered by this new class of compounds should be continued. However, by analyzing the tests performed to determine the mechanism by which these compounds interfere with the viral replication cycle inside the cell, the results reported here suggest that certain peptides which incorporate a Z-phenyl motif are not, however, active in the inhibition of the HIV virus. This lack of activity can be associated with a low membrane permeability of the compounds with respect to MT4 cells, for these new synthetic peptides. Indeed, insofar as the compounds like (9) and (11) which have a free terminal ester function, have shown the greatest anti-HIV effect, the peptides (8) and (10) have been found inactive in cultures. infected. It therefore appears that within this new class of synthetic peptides which incorporates the Z-phenyl fraction, the compounds which enter the infected cell with the greatest efficiency are good candidates for studies of the mechanism of action. .
En résumé, une nouvelle série d'inhibiteurs de la replication du virus HIV en culture cellulaire qui favorise le remplacement dans le résidu phenylalanine d'un atome Z (Z étant défini comme précédemment) a été développée. Si le mécanisme d'action de ces nouveaux composés synthétiques demeure peu connu, ils représentent une nouvelle approche dans la recherche de nouveaux médicaments anti-HIV.In summary, a new series of inhibitors of the replication of the HIV virus in cell culture which promotes the replacement in the phenylalanine residue of a Z atom (Z being defined as above) has been developed. If the mechanism of action of these new synthetic compounds remains little known, they represent a new approach in the search for new anti-HIV drugs.
MODE OPERATOIRE POUR L'EVALUATION DES PROPRIETES ANTIRETROVIRALES DE NOUVEAUX ANALOGUES PEPTIDIQUES INCLUANT UN RESIDU GLYCINE α-SUBSTITUEPROCEDURE FOR THE ASSESSMENT OF THE ANTIRETROVIRAL PROPERTIES OF NEW PEPTIDE ANALOGS INCLUDING A GLYCIN-SUBSTITUTED RESIDUE
METHODEMETHOD
L'évaluation de l'effet antiviral est basée sur l'étude de l'effet cytopathogène du virus HIV 1 sur la lignée cellulaire MT4.The evaluation of the antiviral effect is based on the study of the cytopathogenic effect of the HIV 1 virus on the MT4 cell line.
La lignée MT4 a pour origine des cellules T isolées d'un patient, transformées par le virus HTLV 1. Cette lignée est mycoplasmée. Les mycoplasmes sont des agents infectieux ubiquitaires, bactéries vivant à la surface des MT4 en tant qu'hôtes naturels. Cette bactérie, de l'ordre de 300 à 700 nm, est responsable du grand effet cytopathogène du HIV par la
formation de cellules géantes (fusion par la gp 120) dénommées SYNCITIA. Cette infection par HIV est observée 4 à 5 jours après l'infection et suivie par la mort des cellules.The MT4 line originates from T cells isolated from a patient, transformed by the HTLV 1 virus. This line is mycoplasmated. Mycoplasmas are ubiquitous infectious agents, bacteria living on the surface of MT4 as natural hosts. This bacterium, of the order of 300 to 700 nm, is responsible for the great cytopathogenic effect of HIV by the formation of giant cells (fusion by gp 120) called SYNCITIA. This HIV infection is observed 4 to 5 days after infection and followed by cell death.
Cet effet cytopathogène est directement corrélé à l'infection des cellules par le virus, à sa réplication intracellulaire et à l'expression des antigènes viraux par les cellules. Une inhibition de cet effet correspond donc à une inhibition de la multiplication du virus HIV 1. Cette lignée lymphoblastoide infectée par HIV 1 peut être utilisée pour la production virale.This cytopathogenic effect is directly correlated with infection of cells by the virus, its intracellular replication and the expression of viral antigens by cells. An inhibition of this effect therefore corresponds to an inhibition of the multiplication of the HIV 1 virus. This lymphoblastoid line infected with HIV 1 can be used for viral production.
L'action du traitement par des agents infectieux est permanent. En effet, il est présent avant, pendant et après l'infection virale.The action of treatment with infectious agents is permanent. Indeed, it is present before, during and after the viral infection.
Les perspectives antivirales portent essentiellement sur les inhibiteurs de la protease qui contrôle la maturation des protéines et donc la production de particules infectieuses, ainsi que sur les inhibiteurs de la protéine TAT qui participe au réveil et à la dissémination du virus régulateur positif de la transcription virale et enfin sur les inhibiteurs de la transcriptase inverse (reverse transcriptase) qui transforme l'ARN viral en ADN double brin, renfermant le message viral et qui s'intègre à l'état de provirus dans l'ADN de la cellule hôte.The antiviral perspectives mainly concern the protease inhibitors which control the maturation of proteins and therefore the production of infectious particles, as well as the inhibitors of the TAT protein which participates in the awakening and dissemination of the positive regulatory virus of viral transcription. and finally on reverse transcriptase inhibitors which transform viral RNA into double stranded DNA, containing the viral message and which integrates as a provirus in the DNA of the host cell.
METHODES BIOLOGIQUESBIOLOGICAL METHODS
INHIBITION IN VITRO DE LA REPLICATION DU VIRUS HIV-l SUR LA LIGNEE CELLULAIRE MT4IN VITRO INHIBITION OF HIV-1 VIRUS REPLICATION ON THE MT4 CELL LINE
Des dilutions successives sont effectuées dans du milieu à 10% afin de pouvoir cultiver les MT4 pendant 8 jours et de pouvoir lire la formation des syncitia.Successive dilutions are made in 10% medium in order to be able to culture the MT4 for 8 days and to be able to read the formation of syncitia.
TEST MT4 :
- avant infectionTEST MT4: - before infection
3.105 cellules MT4/100 μl sont distribuées dans une microplaque à 96 puits, centrifugées 3 fois à 2000 tpm et le culot est préincubé avec 100 μl de concentrations successives de l'antiviral à tester, 1 heure à 37° sous C02.3.10 5 MT4 cells / 100 μl are distributed in a 96-well microplate, centrifuged 3 times at 2000 rpm and the pellet is preincubated with 100 μl of successive concentrations of the antiviral to be tested, 1 hour at 37 ° C. under CO 2 .
- infection- infection
Elle est réalisée en micropuits en ajoutant une dilution IO"3 de virus HIV (cette dilution du virus HIV 1 est déterminée pour induire la formation de syncitia en 4 à 5 jours) . L'antiviral est toujours présent lors de l'infection, la concentration finale du virus est alors de 5.10"4.It is carried out in microwells by adding an IO 3 dilution of HIV virus (this dilution of HIV 1 virus is determined to induce the formation of syncitia in 4 to 5 days). The antiviral is always present during infection, the final concentration of the virus is then 5.10 "4 .
- après infection Après une incubation de 1 heure à 37° sous C02, les cellules MT4 sont lavées 3 fois avec du RPMI 1640 et mises en culture à raison de 3.105 cellules pour 1 ml de chacune des concentrations des composés à tester en plaques 24 puits. Le jour de mise en culture est considéré comme JO.- after infection After an incubation of 1 hour at 37 ° C under CO 2 , the MT4 cells are washed 3 times with RPMI 1640 and cultured at the rate of 3.10 5 cells for 1 ml of each of the concentrations of the compounds to be tested in plates 24 wells. The day of cultivation is considered OJ.
A J3 ou J4, les cellules MT4 sont diluées au 1/3, de nouveau dans les différentes concentrations de l'antiviral. Chaque jour, l'apparition de syncitia est observée au microscope pour voir s'il y a un retard par rapport au témoin HIV-l.On D3 or D4, the MT4 cells are diluted 1/3, again in the different concentrations of the antiviral. Each day, the appearance of syncitia is observed under the microscope to see if there is a delay compared to the HIV-1 control.
A J8, le dosage de la transcriptase inverse est effectué. Si les cellules ne sont pas infectées, c'est donc qu'il y a eu une protection par l'antiviral testé. La dose IC50, concentration de l'antiviral qui inhibe de 50% la valeur de la transcriptase inverse du témoin HIV 1, a été déterminée.On D8, the reverse transcriptase assay is carried out. If the cells are not infected, then there has been protection by the antiviral tested. The dose IC 50 , concentration of the antiviral which inhibits by 50% the value of the reverse transcriptase of the HIV 1 control, has been determined.
Tableau 1 -.Activité anti HIV-l des peptides contenant l'enchaînement : -Leu- (S)Phe-
TABLE 1 Anti-HIV-1 activity of the peptides containing the sequence: -Leu- (S) Phe-
IC 50 concentration requise pour inhiber la formation de syncitia de 50% par rapport à l'essai témoinIC 50 concentration required to inhibit syncitia formation by 50% compared to the control test
TI index thérapeutique : concentration requise pour que 50% de cellules MT4 soient non infectées (ID50) par rapport à la concentration requise pour inhiber la formation de syncitia de 50% (IC50)TI therapeutic index: concentration required for 50% of MT4 cells to be uninfected (ID 50 ) compared to the concentration required to inhibit syncitia formation by 50% (IC 50 )
Essais effectués sur cellules MT4. Souche virale HIV-l BruTests carried out on MT4 cells. HIV-l Bru virus strain
La posologie prévisible des composés de formule générale I sera comprise entre 0,1 et 100 mg par prise unitaire.The foreseeable dosage of the compounds of general formula I will be between 0.1 and 100 mg per unit dose.
Leur administration se fera par voie digestive ou parentérale. On pourra envisager leur utilisation dans le traitement des maladies liées aux virus HIV sous forme de compositions injectables ou bien sous forme de gélules ou de comprimés.
Their administration will be by digestive or parenteral route. Their use may be envisaged in the treatment of diseases linked to HIV viruses in the form of injectable compositions or else in the form of capsules or tablets.
Claims
R E V E N D I C A T I O N SR E V E N D I C A T I O N S
l. Un peptide synthétique contenant au moins neuf amino-acides dont la structure s'écrit :l. A synthetic peptide containing at least nine amino acids whose structure is written:
X C - NH CH NH - CH - YX C - NH CH NH - CH - Y
O OO O
dans laquelle X et Y sont des résidus d'acides aminés, protégés ou non, ou des peptidesin which X and Y are amino acid residues, protected or not, or peptides
R est un radical alcoyle linéaire ou ramifié R' ' est un radical alcoyle, phényle, halogène, nitro, amino, alcoyl amino, alcoxy, trifluorométhyle, trifluorométhoxy, carboxamido ou cyano Z est un soufre, un oxygène, un amino ou un suifoxyde et n est égal à O, 1, 2 ou 3R is a linear or branched alkyl radical R '' is an alkyl, phenyl, halogen, nitro, amino, alkyl amino, alkoxy, trifluoromethyl, trifluoromethoxy, carboxamido or cyano Z radical is a sulfur, an oxygen, an amino or a sulfur oxide and n is equal to O, 1, 2 or 3
2. Un peptide synthétique selon la revendication 1 dont la structure s'écrit :2. A synthetic peptide according to claim 1, the structure of which is written:
X - C - NH - CH - C - NH - CH - Y ι l ιι lX - C - NH - CH - C - NH - CH - Y ι l ιι l
O S O RO S O R
dans laquelle X, Y, R, R' ' et n sont tels que défini à la revendication 1 in which X, Y, R, R '' and n are as defined in claim 1
3. Un peptide selon la revendication 1, dont la formule simplifiée est : Ile-Arg-Lys - Ile -NH-CH- CONH-Leu-Asp-Gly- Ile3. A peptide according to claim 1, the simplified formula of which is: Ile-Arg-Lys - Ile -NH-CH- CONH-Leu-Asp-Gly- Ile
ArAr
dans laquelle Ar est un radical phényle, non substitué ou substitué.in which Ar is a phenyl radical, unsubstituted or substituted.
Z est un soufre, un oxygène, un amino ou un suifoxydeZ is sulfur, oxygen, amino or sulfur
4. Un peptide selon la revendication 3, dont la formule simplifiée est :4. A peptide according to claim 3, the simplified formula of which is:
Ile-Arg-Lys-Ile-NH-CH-CONH-Leu-Asp-Gly-IleIle-Arg-Lys-Ile-NH-CH-CONH-Leu-Asp-Gly-Ile
ArAr
dans laquelle Ar est tel que défini à la revendication 3wherein Ar is as defined in claim 3
5. Un peptide selon l'une des revendications 1 ou 2, à savoir5. A peptide according to one of claims 1 or 2, namely
Ile-Arg-Lys-Ile-Leu- (S) Phe-Leu-Asp-Gly-NH2 Ile-Arg-Lys-Ile-Leu- (S) Phe-Leu-Asp-Gly-NH 2
6. Un peptide selon l'une des revendications 1 ou 2, à savoir6. A peptide according to one of claims 1 or 2, namely
Ile-Arg-Lys-Ile-Leu- (S) Phe-Leu-Asp-Gly-Ile-OHIle-Arg-Lys-Ile-Leu- (S) Phe-Leu-Asp-Gly-Ile-OH
7. Un procédé d'obtention des peptides selon l'une des revendications 1 à 6, dans lequel on utilise comme synthon l'acide [(Boc Leu) -amino] phenyl Z acétique de formule II : 7. A process for obtaining peptides according to one of claims 1 to 6, in which the [(Boc Leu) -amino] phenyl Z acetic acid of formula II is used as synthon:
OHOH
CH, ( II )CH, (II)
CHCH
CH, \ CH,CH, \ CH,
dans laquelle Y est un radical phényle, non substitué ou substitué par un, deux ou trois substituants R ' 'in which Y is a phenyl radical, unsubstituted or substituted by one, two or three substituents R ''
Z est un soufre, un oxygène, un amino ou un suifoxydeZ is sulfur, oxygen, amino or sulfur
auquel on accroche les différents amino acides qui constituent la chaîne de ce nonapeptide par la technique des résines en phase solide.to which the various amino acids which constitute the chain of this nonapeptide are attached by the technique of solid phase resins.
puis on déprotège la fonction amine terminale par l'acide trifluoroacétique ou bien on réalise la déprotection de la chaîne et le clivage de la résine à l'aide d'acide fluorhydrique en présence d'anisole.then the terminal amine function is deprotected with trifluoroacetic acid or else the chain is deprotected and the resin is cleaved using hydrofluoric acid in the presence of anisole.
8. Les compositions pharmaceutiques qui contiennent à titre de principe actif au moins un composé de formule générale I8. Pharmaceutical compositions which contain, as active principle, at least one compound of general formula I
X - C - NH - CH - C - NH - CH - YX - C - NH - CH - C - NH - CH - Y
0 ι Z ι O g R ι (I)0 ι Z ι O g R ι (I)
dans laquelle X et Y sont des résidus d'acides aminés, protégés ou non, ou des peptides R est un radical alcoyle linéaire ou ramifié R' ' est un radical alcoyle, phényle, halogène, un nitro, amino, alcoyl amino, alcoxy, trifluorométhyle, trifluorométhoxy, carboxamido ou cyano Z est un soufre, oxygène, amino, sulfoxide et n est égal à O, 1, 2 ou 3in which X and Y are amino acid residues, protected or not, or peptides R is a linear or branched alkyl radical R '' is an alkyl, phenyl, halogen radical, a nitro, amino, alkyl amino, alkoxy, trifluoromethyl, trifluoromethoxy, carboxamido or cyano Z is a sulfur, oxygen, amino, sulfoxide and n is equal to O, 1, 2 or 3
en association ou en mélange avec un excipient ou un véhicule inerte, non toxique, pharmaceutiquement acceptable.in combination or in mixture with an inert, non-toxic, pharmaceutically acceptable excipient or vehicle.
9. Les compositions pharmaceutiques qui contiennent à titre de principe actif au moins un composé de formule générale I :9. Pharmaceutical compositions which contain, as active principle, at least one compound of general formula I:
Ile -Arg- Lys - Ile - NH - CH - CONH - Leu - Asp - Gly - IleIle -Arg- Lys - Ile - NH - CH - CONH - Leu - Asp - Gly - Ile
II
Z - Ar (I)Z - Ar (I)
dans laquelle Z est du soufre, de l'oxygène, un amino, un sulfoxide et Ar est un radical phényle, non substitué ou substituéwherein Z is sulfur, oxygen, amino, sulfoxide and Ar is phenyl, unsubstituted or substituted
en association ou en mélange avec un excipient ou un véhicule inerte, non toxique, pharmaceutiquement-acceptable.in combination or in mixture with an inert, non-toxic, pharmaceutically acceptable excipient or vehicle.
10.A titre d'intermédiaire pour la synthèse des composés de formule I10.As an intermediary for the synthesis of the compounds of formula I
Fmoc-Ile-Arg-Lys-Ile-Leu- (S)Phe-Leu-Asp-Gly-NH 2Fmoc-Ile-Arg-Lys-Ile-Leu- (S) Phe-Leu-Asp-Gly-NH 2
11.A titre d'intermédiaire pour la synthèse des composés de formule I11.As an intermediary for the synthesis of the compounds of formula I
Fmoc-Ile-Arg-Lys-Ile-Leu- (S)Phe-Leu-Asp-Gly-Ile-OH Fmoc-Ile-Arg-Lys-Ile-Leu- (S) Phe-Leu-Asp-Gly-Ile-OH
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9507817 | 1995-06-29 | ||
| FR9507817A FR2736055B1 (en) | 1995-06-29 | 1995-06-29 | NOVEL THIOPHENOXY PEPTIDES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| PCT/FR1996/001008 WO1997001576A2 (en) | 1995-06-29 | 1996-06-28 | Phenyl peptides, method for preparing same, and pharmaceutical compositions containing said peptides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0787143A2 true EP0787143A2 (en) | 1997-08-06 |
Family
ID=9480502
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP96924035A Withdrawn EP0787143A2 (en) | 1995-06-29 | 1996-06-28 | Phenyl peptides, method for preparing same, and pharmaceutical compositions containing said peptides |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US5844078A (en) |
| EP (1) | EP0787143A2 (en) |
| JP (1) | JPH10505613A (en) |
| KR (1) | KR970705576A (en) |
| CN (1) | CN1165521A (en) |
| AP (1) | AP683A (en) |
| AU (1) | AU706799B2 (en) |
| BR (1) | BR9606455A (en) |
| CA (1) | CA2197861A1 (en) |
| FR (1) | FR2736055B1 (en) |
| HU (1) | HUP9701940A3 (en) |
| IL (1) | IL120341A (en) |
| NO (1) | NO970895L (en) |
| NZ (1) | NZ312726A (en) |
| OA (1) | OA10403A (en) |
| PL (1) | PL318880A1 (en) |
| WO (1) | WO1997001576A2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1292438B1 (en) * | 1997-06-30 | 1999-02-08 | Zambon Spa | PEPTIDOMIMETIC DERIVATIVES SUICIDE INHIBITORS OF HIV PROLIFERATION |
| US6118226A (en) | 1998-07-31 | 2000-09-12 | Federal-Mogul World Wide, Inc. | Electrodeless neon light module for vehicle lighting systems |
| US8886480B2 (en) | 2011-06-27 | 2014-11-11 | Synaptics Incorporated | System and method for signaling in gradient sensor devices |
| US9188675B2 (en) | 2012-03-23 | 2015-11-17 | Synaptics Incorporated | System and method for sensing multiple input objects with gradient sensor devices |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1193598A (en) * | 1982-05-06 | 1985-09-17 | Rafael Foguet | 2-amino-benzoic acid derivatives and processes for their production |
| US4454065A (en) * | 1982-05-18 | 1984-06-12 | Smithkline Beckman Corporation | Oligopeptide prodrugs |
| ZA832844B (en) * | 1982-05-18 | 1984-03-28 | Smithkline Beckman Corp | Oligopeptide prodrugs |
| US5036054A (en) * | 1988-02-11 | 1991-07-30 | Warner-Lambert Company | Renin inhibitors containing alpha-heteroatom amino acids |
| US5221667A (en) * | 1990-01-22 | 1993-06-22 | Warner-Lambert Company | Renin inhibiting peptides having an α-heteroatom amino acid at the P3 position |
-
1995
- 1995-06-29 FR FR9507817A patent/FR2736055B1/en not_active Expired - Lifetime
-
1996
- 1996-06-28 BR BR9606455A patent/BR9606455A/en not_active Application Discontinuation
- 1996-06-28 CA CA002197861A patent/CA2197861A1/en not_active Abandoned
- 1996-06-28 EP EP96924035A patent/EP0787143A2/en not_active Withdrawn
- 1996-06-28 IL IL12034196A patent/IL120341A/en active IP Right Grant
- 1996-06-28 US US08/793,647 patent/US5844078A/en not_active Expired - Fee Related
- 1996-06-28 HU HU9701940A patent/HUP9701940A3/en unknown
- 1996-06-28 PL PL96318880A patent/PL318880A1/en unknown
- 1996-06-28 WO PCT/FR1996/001008 patent/WO1997001576A2/en not_active Application Discontinuation
- 1996-06-28 AU AU64624/96A patent/AU706799B2/en not_active Ceased
- 1996-06-28 KR KR1019970701333A patent/KR970705576A/en not_active Application Discontinuation
- 1996-06-28 AP APAP/P/1997/000964A patent/AP683A/en active
- 1996-06-28 NZ NZ312726A patent/NZ312726A/en unknown
- 1996-06-28 JP JP9504212A patent/JPH10505613A/en active Pending
- 1996-06-28 CN CN96190943A patent/CN1165521A/en active Pending
-
1997
- 1997-02-27 NO NO970895A patent/NO970895L/en not_active Application Discontinuation
- 1997-02-28 OA OA60971A patent/OA10403A/en unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9701576A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| NO970895D0 (en) | 1997-02-27 |
| FR2736055A1 (en) | 1997-01-03 |
| AU6462496A (en) | 1997-01-30 |
| IL120341A0 (en) | 1997-06-10 |
| IL120341A (en) | 2001-01-28 |
| WO1997001576A3 (en) | 1997-05-15 |
| BR9606455A (en) | 1998-07-14 |
| NZ312726A (en) | 1998-07-28 |
| US5844078A (en) | 1998-12-01 |
| HUP9701940A3 (en) | 2001-07-30 |
| FR2736055B1 (en) | 1997-09-12 |
| AP683A (en) | 1998-09-30 |
| CA2197861A1 (en) | 1997-01-16 |
| JPH10505613A (en) | 1998-06-02 |
| CN1165521A (en) | 1997-11-19 |
| NO970895L (en) | 1997-02-27 |
| AP9700964A0 (en) | 1997-04-30 |
| PL318880A1 (en) | 1997-07-07 |
| AU706799B2 (en) | 1999-06-24 |
| WO1997001576A2 (en) | 1997-01-16 |
| OA10403A (en) | 2001-12-05 |
| KR970705576A (en) | 1997-10-09 |
| HUP9701940A2 (en) | 1998-03-02 |
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