Phenyl peptides, method for preparing same, and pharmaceutical c

Details Phenyl peptides, method for preparing same, and pharmaceutical c Phenyl peptides, method for preparing same, and pharmaceutical c

1997-02-26

1998-12-01

Tsang, Cecilia J.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

8 to 10 amino acid residues in defined sequence

514 2, 514 15, A61K 3800, A61K 3806, A61K 3808, C07K 702

Patent

active

058440780

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the field of organic chemistry and more particularly to that of therapeutic chemistry.
A more particular subject of the invention is new peptides containing phenylalanine (Phe) in which the methylene group has been replaced by an isostere: sulphur, oxygen, amino or sulphoxide.
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, SEQ ID NO: 1 the methylene group of which carried by the phenylalanine molecule (Phe) has been replaced by an isostere, that is to say that the change in structure according to the invention can be written in the following way: ##STR2## in which formula X and Y are protected or unprotected amino acid residues, or peptides alkyl amino, alkoxy, trifluoromethyl, trifluoromethoxy, carboxamido or cyano 2 or 3
The Patent WO-A-91 10679 describes renin-inhibiting peptides having an amino acid with a heteroatom in a position at position P.sub.3 of the peptide of general formula: P.sub.2 and, W and U positions P.sub.1 and P'.sub.1.
The preferred compounds which are described in this patent are those for which: --NHCH(SCH(CH.sub.3).sub.2)CO--, --NHCH(SO.sub.2 CH (CH.sub.3).sub.2)CO--, NHCH(NPhCH.sub.3)CO--, heptanoic acid)
These peptides are renin inhibitors and are used to treat hypertension phenomena, heart failure, glaucoma, hyperaldosteronism.
Renin, just like the HIV protease, is an aspartyl protease and the compounds of Patent WO-A-91 10679 are also used to treat illnesses caused by retroviruses including HTLV -I, -II, -III.
The U.S. Pat. No. 4,454,065 describes pro-drugs having an oligopeptide chain substituted in a position by a chemotherapeutic residue W.
These pro-drugs have the following general formula: ##STR3## P and Q in particular being able to be amino acids
The glycyl unit 1 is the unit which carries the chemotherapeutic residue W.
One of the preferred compounds of the invention is L-alanyl-L-(.alpha.-phenylthio)glycine.
These pro-drugs are used to increase penetration into the infected cells, against which the transported chemotherapeutic residues (W) are active. These chemotherapeutic residues (for example thiophenol) are anti-microbial or anti-parasitic agents.
The reference J. MED. CHEM. (1992), 35(6), 1032-42, describes renin-inhibiting peptides, containing an amino acid with a heteroatom in a position at position P.sub.2.
The inhibition of renin can provide an effective treatment for hypertension.
The derivatives described are in particular: heptanoic acid H.sub.5 their alkylated analogues.
The reference INT. J. PEPT. PROTEIN RES. (1986), 27(6), 659-665, describes the synthesis of .alpha.-thiophenylglycine peptides and more particularly the dipeptide and the two tripeptides which follow:
These .alpha.-substituted glycine peptides are used for transporting the medicament into the microbial cell.
Thus, due to a cleavage produced by peptidase, they deliver the .alpha. substituent, that is to say the thiophenol, to the microbial cell.
The compounds according to the invention of formula I can be written more accurately in the following simplified way: ##STR4## in which Ar is a non-substituted or substituted phenyl radical. Z is an isostere as defined previously.
In a preferred manner, in this general formula I, Z is sulphur. The compounds of formula I are inhibitors of HIV replication by acting as an inhibitor of a small aspartyl protease dimer which specifically cleaves the precursors of a polyprotein coding for the structural proteins and the constitutive enzymes of the virus (Martin S. A, Recent Advances in the Design of HIV proteinase inhibitors, Antiviral Res. 17 (1992) 265-278).
The compounds of general formula I are prepared using a synthon: ##STR5## in which Y is a phenyl radical, non-substituted or substituted by one, two or three R" substituents introduce the basic unit on which the present invention rests.
Sheet 1, attached hereto, explains the different stages of the synthesis of synthon II, for which Z is sulphur.
This synthon II is prepar

REFERENCES:
patent: 4454065 (1984-06-01), Gilvarg et al.
patent: 5221667 (1993-06-01), Kaltenbronn et al.
Kingsbury-William et al. Int. J. Pept. Protein Res. 27(6), 659-665, Jun. 1986.
Kraus et al. Eur. J. Med. Chem. 27(1), 19-26, Jan. 1992.

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