EP1001969A1 - Peptidomimetic derivatives suicidal inhibitors of the hiv proliferation - Google Patents

Peptidomimetic derivatives suicidal inhibitors of the hiv proliferation

Info

Publication number
EP1001969A1
EP1001969A1 EP98939556A EP98939556A EP1001969A1 EP 1001969 A1 EP1001969 A1 EP 1001969A1 EP 98939556 A EP98939556 A EP 98939556A EP 98939556 A EP98939556 A EP 98939556A EP 1001969 A1 EP1001969 A1 EP 1001969A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
group
hiv
phenyl
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Withdrawn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
EP98939556A
Other languages
German (de)
English (en)
French (fr)
Inventor
Domenico Ungheri
Franco Pellacini
Stefano Romagnano
Jean-Louis Kraus
Jean-Claude Chermann
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.)
Institut National de la Sante et de la Recherche Medicale INSERM
Zambon Group SpA
Zambon SpA
Original Assignee
Institut National de la Sante et de la Recherche Medicale INSERM
Zambon Group SpA
Zambon SpA
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 Institut National de la Sante et de la Recherche Medicale INSERM, Zambon Group SpA, Zambon SpA filed Critical Institut National de la Sante et de la Recherche Medicale INSERM
Publication of EP1001969A1 publication Critical patent/EP1001969A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • Peptidomimetic derivatives suicidal inhibitors of the HIV proliferation.
  • the present invention refers to peptidomimetic derivatives and the therapeutical use thereof.
  • EP-0 094 815 (in the name of SmithKline Beecham) describes ohgopeptides containing an ⁇ -substituted glycine residue, for example phenylthiogly- cine, useful as pro-drugs for antitumoral and antimicrobial agents in view of their ability of crossing the cell membrane and releasing the active principle therein following an enzymatic degradation.
  • These ohgopeptides must not bear protecting groups on the terminal positions or such groups must be in vivo detachable, and the ⁇ -substituted glycine must be of the L-serie, otherwise the ohgopeptides cannot get into the cell.
  • thiophenol is said to be particularly useful for studying the protease/peptidase activity in biological systems.
  • the patent application WO 91/10679 (in the name of Warner-Lambert) teaches renin- inhibitor peptide derivatives having the -NH-CH(S-phenyl)-CO- group useful, inter alia, in the treatment of diseases caused by retrovirus such as HTLV-I, -II and -III.
  • the HIV-aspartyl-protease is said to act on natural substrates made by at least 9 ami- noacids only. For example, Niddam V. et al., Bioorg. & Med. Che .
  • the compounds of the invention have a small dimension (two aminoacid residues versus the at least 9 showed by WO 97/01576 and Niddam V et al supra) and are substituted on the N- and C-terminal positions (contrary to what taught in EP-0 094 815 supra) Nevertheless they show specificity for the HIV-protease and hence for the cells infected by this virus They are deacylated by the above said enzyme in this site only, and become sufficiently unstable to release the cytocidal agent, I e thiophenol
  • suicidal inhibitor is known in pharmacology since a long time Contrary to the classic inhibitors, these molecules interact with the target structure just to be destroyed and thus release a portion thereof which kills the host cell It is clear that such substances can show their activity only with a target well defined and peculiar for the pathology to combat As for our knowledge, until now no suicidal inhibitor for the HIV virus was found and this is an important feature of the present invention Therefore the present
  • X is an oxygen atom or a SO 2 group
  • R is hydrogen or a protecting group of the hydroxy moiety
  • the compounds of formula I have asymmetric centres, thus can be in form of stereoi- somers
  • Object of the present invention are the compounds of formula I m form of both stereoisomeric mixtures and single stereoisomers.
  • the compounds of formula I are suicidal inhibitors of the HIV proliferation. They are able to release thiophenol, the cytocidal agent, inside the infected cell after having been selectively deacylated by the HIV-aspartyl-protease, and this ensures an activity selective for the HIV infected cells and, consequently, a negligible toxicity.
  • thiophenol the cytocidal agent
  • the preferred configuration of the compounds of formula I is 1 S,2R for the 2-hy- droxy-indan-1-yl residue and 3S for the tetrahydro-3-furanyl residue.
  • one of the isomer of the compounds of formula I has shown a higher affinity for the enzyme and a greater ability of releasing the thiophenol moiety, but this is not preferred with respect nor to the other isomer neither to the racemate.
  • the compounds of formula I may be obtained starting from L-phenyl-alanine
  • acylating agent such as, for example, di-t-butyldicar- bonate, benzylchloroformate, t-butyldimethylsilyloxy-chloroformate, optionally in the presence of an organic base, to yield a compound of formula III
  • Rj is a lower alkyl group or a -CH 2 CC1 3 group, in the presence of a condensing agent such as, for example, 1 -hydroxybenzotriazole, N-hydroxysuccinimide, and dicyclohexylcarbodiimide.
  • a condensing agent such as, for example, 1 -hydroxybenzotriazole, N-hydroxysuccinimide, and dicyclohexylcarbodiimide.
  • Pg and Rj are as defined above, which is hydrolysed in the presence of a strong base such as sodium, potassium or tetrabutylamrnoniurn hydroxide, and gives a compound of formula VI
  • Pg is as defined above, which is hydrolysed in the presence of a strong acid, for example hydrochloric, hydrobromic or trifluoroacetic acid, and gives a compound of formula VIII
  • the compounds of formula I are suicidal inhibitors of the HIV as shown by the HIV- aspartyl-protease enzyme affinity test and by the thiophenol release test (example 13 and 14)
  • a structurally analogous compound comprised by the general formula of the patent application EP-0 094 815 discussed above was em- ployed This has shown a good affinity for the enzyme, whereas did not provide the release of thiophenol thus demonstrating not to be endowed with the features of the suicidal inhibitors of formula I of the invention
  • the compounds of formula I may be administered both parenterally and orally
  • the therapeutical doses are generally comprised between 1 and 40 mg a day via par- enteral route, and between 20 and 200 mg for single administration via oral route
  • a further object of the present invention are the pharmaceutical compositions contain- ing a therapeutically effective amount of the compounds of formula I or of the pharmaceutically acceptable salts thereof in admixture with a suitable carrier
  • the pharmaceutical compositions object of the invention may be liquid, suitable for the enteral or parenteral administration, and, preferably, solid, such as tablets, capsules, granulates, suitable for the oral administration
  • Example 8 Separation of the isomers of (3S)-tetrahvdro-3-furanyl ri-(lS)- ⁇
  • Example 13 Test for the evaluation of the affinity for the HIV-1 aspartyl protease enzyme The incubation mixture was made of 0.5 ⁇ g/sample of HIV- 1 aspartyl protease (Ba- chem AG, Switzerland, in 0 1M sodium acetate buffer, pH 5 5 + 10% (v/v) glycerol + 5% (v/v) ethylenglycole), lO ⁇ g/sample of HIV protease III substrate (H-His-Lys-Ala- Arg-Val-Leu-p-nitro-Phe-Glu-Ala-Nle-Ser-NH2 by Bachem).
  • reaction buffer 50mM sodium acetate pH 4,9 + 200mM NaCl + 5mM dithiotreitol + glycerol 10% v/v
  • the hydrolysis of the substrate was evaluated by reversed phase HPLC using a C 18 column for proteins and peptides (Vydac, cat 218TP54) The products were eluted with a linear gradient of 10-60%) of acetonitrile+0 1% of trifluoroacetic acid in water, at a flow of 1 ml/min for 15 minutes The wavelength used was 220 nm.
  • the hydrolysis of substrate III occurs between the Leu and p-nitro-Phe residues, yielding two peaks eluting before the substrate
  • the affinity of the compounds of the invention is expressed as the concentration able to inhibit at 50% the hydrolysis of the substrate (IC 5 n) The results are set forth in the following table.
  • the reaction mixture was made of HIV-1 aspartyl protease (0.5 ⁇ g/sample), a compound of the invention (at the 50 ⁇ M standard concentration) and a reaction buffer to a final volume of 125 ⁇ l.
  • the reaction was effected in hermetically sealed tubes for 120 minutes at 37°C and quenched by adding 85 ⁇ l of acetonitrile.
  • the thiophenol release was evaluated by HPLC using a Nucleosil C18 column (Macherey Nahel) and eluting with phosphoric acid 0.2% w/v acetonitrile 40:60 at a flow of 1.2 ml/min.
  • the wavelength for the evaluation of thiophenol was 238 nm. The results are set forth in the following table 2.
  • Example 15 Test for the evalutation of the cytotoxicitv
  • the CEM ATCC cells (lymphoblastoid line) infected by the HIV-1 BRU virus (CEM ATCC/BRU) are particular as they produce the virus while multiplying This system put into evidence the cytotoxicity due to the compound tested and not due to the virus Such a toxicity is more evident for the treated infected cells then for the untreated ones used as a control In the same way such a toxicity is weaker for the uninfected CEM ATCC cells
  • the CEM ATCC and CEM ATCC/BRU cells were at a concentration of 5xl0 5 cells/ lOO ⁇ l They were treated for 1 hour with 100 ⁇ l of a solution containing the compound to be tested at various concentrations At the day 4 a count with Trypan blue was carried out and the numer of cells was adjusted to 5xl0 5 cells/1 OO ⁇ l, then moved to a 24-well plate in 1 ml of the same compound From day 5 to day 7 the cells were counted each day with Trypan blue for evaluating the ratio between infected and uninfected control

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
EP98939556A 1997-06-30 1998-06-29 Peptidomimetic derivatives suicidal inhibitors of the hiv proliferation Withdrawn EP1001969A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IT97MI001545A IT1292438B1 (it) 1997-06-30 1997-06-30 Derivati peptidomimetici inibitori suicidi della proliferazione del hiv
ITMI971545 1997-06-30
PCT/EP1998/003970 WO1999001470A2 (en) 1997-06-30 1998-06-29 Peptidomimetic derivatives suicidal inhibitors of the hiv proliferation

Publications (1)

Publication Number Publication Date
EP1001969A1 true EP1001969A1 (en) 2000-05-24

Family

ID=11377465

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98939556A Withdrawn EP1001969A1 (en) 1997-06-30 1998-06-29 Peptidomimetic derivatives suicidal inhibitors of the hiv proliferation

Country Status (4)

Country Link
EP (1) EP1001969A1 (enrdf_load_stackoverflow)
AU (1) AU8802598A (enrdf_load_stackoverflow)
IT (1) IT1292438B1 (enrdf_load_stackoverflow)
WO (1) WO1999001470A2 (enrdf_load_stackoverflow)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU563196B2 (en) * 1982-05-18 1987-07-02 Smithkline Beckman Corporation Peptide prodrug transport system
US5221667A (en) * 1990-01-22 1993-06-22 Warner-Lambert Company Renin inhibiting peptides having an α-heteroatom amino acid at the P3 position
FR2736055B1 (fr) * 1995-06-29 1997-09-12 Laphal Sa Lab Nouveaux thiophenoxy peptides, leur procede de preparation et les compositions pharmaceutiques en renfermant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9901470A3 *

Also Published As

Publication number Publication date
AU8802598A (en) 1999-01-25
WO1999001470A2 (en) 1999-01-14
WO1999001470A3 (en) 1999-03-25
ITMI971545A1 (it) 1998-12-30
ITMI971545A0 (enrdf_load_stackoverflow) 1997-06-30
IT1292438B1 (it) 1999-02-08

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