EP0787143A2 - Phenylpeptide, herstellungsmethode und diese peptide enthaltende arznei - Google Patents

Phenylpeptide, herstellungsmethode und diese peptide enthaltende arznei

Info

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Withdrawn
Application number
EP96924035A
Other languages
English (en)
French (fr)
Inventor
Valérie Niddam
Michel Camplo
Jean-Louis Kraus
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratoire Laphal
Original Assignee
Laboratoire Laphal
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Laboratoire Laphal filed Critical Laboratoire Laphal
Publication of EP0787143A2 publication Critical patent/EP0787143A2/de
Withdrawn legal-status Critical Current

Links

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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Virology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Communicable Diseases (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Immunology (AREA)
  • AIDS & HIV (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
EP96924035A 1995-06-29 1996-06-28 Phenylpeptide, herstellungsmethode und diese peptide enthaltende arznei Withdrawn EP0787143A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9507817 1995-06-29
FR9507817A FR2736055B1 (fr) 1995-06-29 1995-06-29 Nouveaux thiophenoxy peptides, leur procede de preparation et les compositions pharmaceutiques en renfermant
PCT/FR1996/001008 WO1997001576A2 (fr) 1995-06-29 1996-06-28 Peptides phenyles, leur procede de preparation et les compositions pharmaceutiques qui en renferment

Publications (1)

Publication Number Publication Date
EP0787143A2 true EP0787143A2 (de) 1997-08-06

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP96924035A Withdrawn EP0787143A2 (de) 1995-06-29 1996-06-28 Phenylpeptide, herstellungsmethode und diese peptide enthaltende arznei

Country Status (17)

Country Link
US (1) US5844078A (de)
EP (1) EP0787143A2 (de)
JP (1) JPH10505613A (de)
KR (1) KR970705576A (de)
CN (1) CN1165521A (de)
AP (1) AP683A (de)
AU (1) AU706799B2 (de)
BR (1) BR9606455A (de)
CA (1) CA2197861A1 (de)
FR (1) FR2736055B1 (de)
HU (1) HUP9701940A3 (de)
IL (1) IL120341A (de)
NO (1) NO970895D0 (de)
NZ (1) NZ312726A (de)
OA (1) OA10403A (de)
PL (1) PL318880A1 (de)
WO (1) WO1997001576A2 (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1292438B1 (it) * 1997-06-30 1999-02-08 Zambon Spa Derivati peptidomimetici inibitori suicidi della proliferazione del hiv
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)

* Cited by examiner, † Cited by third party
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
AU563196B2 (en) * 1982-05-18 1987-07-02 Smithkline Beckman Corporation Peptide prodrug transport system
US4454065A (en) * 1982-05-18 1984-06-12 Smithkline Beckman Corporation 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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9701576A2 *

Also Published As

Publication number Publication date
WO1997001576A2 (fr) 1997-01-16
NZ312726A (en) 1998-07-28
BR9606455A (pt) 1998-07-14
AP683A (en) 1998-09-30
CN1165521A (zh) 1997-11-19
AU706799B2 (en) 1999-06-24
HUP9701940A3 (en) 2001-07-30
CA2197861A1 (fr) 1997-01-16
JPH10505613A (ja) 1998-06-02
IL120341A (en) 2001-01-28
IL120341A0 (en) 1997-06-10
NO970895L (no) 1997-02-27
FR2736055A1 (fr) 1997-01-03
AP9700964A0 (en) 1997-04-30
NO970895D0 (no) 1997-02-27
FR2736055B1 (fr) 1997-09-12
US5844078A (en) 1998-12-01
KR970705576A (ko) 1997-10-09
HUP9701940A2 (hu) 1998-03-02
OA10403A (fr) 2001-12-05
AU6462496A (en) 1997-01-30
PL318880A1 (en) 1997-07-07
WO1997001576A3 (fr) 1997-05-15

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