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WO1993004080A1 - Pseudopentapeptides presentant une acivite d'immunomodulation - Google Patents

Pseudopentapeptides presentant une acivite d'immunomodulation Download PDF

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Publication number
WO1993004080A1
WO1993004080A1 PCT/JP1992/001046 JP9201046W WO9304080A1 WO 1993004080 A1 WO1993004080 A1 WO 1993004080A1 JP 9201046 W JP9201046 W JP 9201046W WO 9304080 A1 WO9304080 A1 WO 9304080A1
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WO
WIPO (PCT)
Prior art keywords
asp
val
arg
phe
mmol
Prior art date
Application number
PCT/JP1992/001046
Other languages
English (en)
Inventor
Joseph I. Degraw
Ronald Almquist
Charles Hiebert
R. Lane Smith
Itsuo Uchida
Original Assignee
Japan Tobacco Inc.
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 Japan Tobacco Inc. filed Critical Japan Tobacco Inc.
Priority to KR1019930701259A priority Critical patent/KR930702383A/ko
Publication of WO1993004080A1 publication Critical patent/WO1993004080A1/fr

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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
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/66—Thymopoietins
    • C07K14/662—Thymopoietins at least 1 amino acid in D-form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link

Definitions

  • the invention relates to synthetic
  • pseudopentapeptides having immunomodulating activity to pharmaceutical compositions and to their use in the treatment of immune diseases such as arthritis. More particularly, it concerns improved pseudopentapeptides which are designed to exhibit enhanced stability in serum.
  • thymopoietin The isolation of a 49 amino acid peptide from thymus tissue which was named "thymopoietin" was reported in
  • Thymopentin as a generic drug is often referred to as "thypentin.” The terms are used interchangeably herein.
  • thymopoietin enhances differentiation of prothymocytes to thymocytes, as well as late stage B-cell differentiation, induction of complement receptor, and lymphoid cell transcription. Its effects in vivo include induction of prothymocytes, T-cell dependent antibody response enhancement, and delays in the onset of autoimmune hemolytic anemia in mice.
  • thysplenin a 49 amino acid peptide similar to thymopoietin (differing only in position 34 by replacement of the aspartic acid residue with glutamic acid), was isolated from bovine spleen.
  • Val at position 4 could be replaced by its D-isomer, Ala or sarcosine.
  • the Tyr residue at position 5 could not be deleted, or replaced by Ala, but analogs with varying activities were obtained when it was
  • thysplenin which substitutes Ala for the Glu of bovine thysplenin in the 34-position of the full-length peptide (3-position of the pentapeptide)
  • Human "splenopentin" splenin having the sequence Ac-Arg-Lys-Ala-Val-Tyr-NH 2 was inactive with respect to the receptors on CEM cells but active with respect to MOLT-4 cells. This pattern was retained when the corresponding tetrapeptide missing the C-terminal Tyr or its Pro 2 analog was used.
  • thymopentin reversed the pattern activity.
  • Japanese application 80/46990 based on U.S. priorities of 12 April 1979 and 13 March 1980, discloses and claims a large genus of pentapeptides notably including Arg-D-Ala- Asp-Val-Tyr-NH 2 .
  • Japanese application J61/050998-A laid open 7 August 1989, to Sloan-Kettering, discloses and claims derivatized forms of the pentapeptide wherein the side-chains of the various residues are modified.
  • European application publication No. 282891 published 21 September 1988, discloses and claims "retroinverso" analogs of the pentapeptide and a tripeptide fragment. In these
  • thymopentin activity which have acceptable half-lives in plasma and which retain the nontoxicity and effectiveness of the drug.
  • the present invention is directed to such analogs wherein one or more of the peptide linkages of thymopentin or an active analog thereof is replaced by an isosteric nonpeptide linkage.
  • the invention provides protease-resistant pseudo- peptides which are effective in modulating the immune system and in treating immune diseases such as arthritis. They are useful in the treatment and control of diseases such as autoimmune and infectious diseases.
  • the invention is a
  • AA 1 is an L- or D-form of an arginyl residue
  • AA 2 is an L- or D-form of a basic amino acid residue, a neutral/nonaromatic amino acid residue or proline residue, or is an N-alkylated (1-6C) form thereof;
  • AA 3 is an L- or D-form of an aspartic acid or
  • glutamic acid residue wherein the remaining carboxyl group may optionally be esterified with an alkyl group (1-6C), or an alanine residue;
  • AA 4 is an L- or D-form of a neutral/nonaromatic amino acid residue
  • AA 5 is an L- or D-form of a neutral/aromatic amino acid residue wherein one or more hydrogens of its
  • aromatic portion can be substituted by NO 2 or halogen or is an L- or D-form of a neutral/nonpolar/large/
  • nonaromatic amino acid residue or is the N-alkylated (1-6C) form of the above;
  • R is acyl (1-6C), arylsulfonyl, alkylsulfonyl, arylalkylsulfonyl or alkoxycarbonyl group;
  • R. is -OH, -NR 2 R 3 or -OR 4 wherein each of R 2 and R 3 is independently hydrogen or an alkyl group (1-6C) and R 4 is alkyl group (1-6C);
  • linkages numbered I-IV is a modified peptide linkage selected from the group consisting of -COCH 2 -, -CH(OH)CH 2 - and -CH 2 NH-, and the remaining linkages are -CONH- or -CON(CH 3 )-,
  • the invention is directed to pseudopeptides of the formula:
  • AA 1 is an L- or D-form of an arginyl
  • AA 2 is an L- or D-form of a basic amino acid
  • AA 3 is an L- or D-form of an aspartic acid residue wherein the remaining carboxyl group may optionally be esterified with an alkyl group (1-6C);
  • AA 4 is an L- or D-form of a neutral/nonaromatic amino acid residue
  • AA 5 is an L- or D-form of a neutral/aromatic amino acid residue wherein one or more hydrogens of its
  • aromatic portion can be substituted by NO 2 or halogen or is an L- or D-form of a valine residue, or is an
  • R is acyl (1-6C), arylsulfonyl, alkylsulfonyl, arylalkylsulfonyl or alkoxycarbonyl group;
  • R 1 is -OH, -NR 2 R 3 or -OR 4 wherein each of R 2 and R 3 is independently hydrogen or an alkyl group (1-6C) and R 4 is alkyl group (1-6C);
  • linkages numbered I-IV is a modified peptide linkage selected from the group consisting of -COCH 2 -, -CH(OH)CH 2 - and -CH 2 NH-, and the remaining linkages are -CONH- or -CON(CH-)-,
  • the invention is directed to pseudopeptides of the formula:
  • AA 1 is an L- or D-form of an arginyl residue
  • AA 2 is an L- or D-form of a basic amino acid
  • AA 3 is an L- or D-form of an aspartic acid residue wherein the remaining carboxyl group may optionally be esterified with an alkyl group (1-6C);
  • AA 4 is an L- or D-form of an alanine or valine residue
  • AA 5 is an L- or D-form of a neutral/aromatic amino acid residue wherein one or more hydrogens of its
  • aromatic portion can be substituted by NO 2 or halogen or is an L- or D-form of a valine residue, or is an
  • R is acyl (1-6C), arylsulfonyl, alkylsulfonyl, arylalkylsulfonyl or alkoxycarbonyl group;
  • R 1 is -OH, -NR 2 R 3 or -OR 4 wherein each of R 2 and R 3 is independently hydrogen or an alkyl group (1-6C) and R 4 is alkyl group (1-6C);
  • linkages numbered I-IV is a modified peptide linkage selected from the group consisting of -COCH 2 -, -CH(OH)CH 2 - and -CH 2 NH-, and the remaining linkages are -CONH- or -CON(CH 3 )-;
  • the invention is directed to pseudopeptides of the formula:
  • AA 2 is an L- or D-form of a basic amino acid
  • AA 3 is an L- or D-form of an aspartic acid residue wherein the remaining carboxyl group may optionally be esterified with an alkyl group (1-6C);
  • AA 4 is an L- or D-form of an alanine or valine residue
  • AA 5 is an L- or D-form of a phenylalanine or
  • tyrosine residue wherein one or more hydrogens of its aromatic portion can be substituted by NO 2 or halogen or is an L- or D-form of a valine residue, or is an
  • R is acyl (1-6C), arylsulfonyl, alkylsulfonyl, arylalkylsulfonyl or alkoxycarbonyl group;
  • R 1 is -OH, -NR 2 R 3 or -OR 4 wherein each of R 2 and R 3 is independently hydrogen or an alkyl group (1-6C) and R 4 is alkyl group (1-6C);
  • linkages numbered I-IV is a modified peptide linkage selected from the group consisting of -COCH 2 -, -CH(OH)CH 2 - and -CH 2 NH-,
  • the invention is directed to pseudopeptides of the formula:
  • AA 1 is an L- or D-form of an arginyl residue
  • AA 2 is an L- or D-form of a lysine, alanine, ⁇ -aminoisobutyric acid, leucine, norleucine or proline residue, or is an N-alkylated (1-6C) form thereof;
  • AA 3 is an L- or D-form of an aspartic acid residue wherein the remaining carboxyl group may optionally be esterified with an alkyl group (1-6C);
  • AA 4 is an L- or D-form of an alanine or valine residue
  • AA 5 is an L- or D-form of a phenylalanine or
  • tyrosine residue wherein one or more hydrogens of its aromatic portion can be substituted by NO 2 or halogen or is an L- or D-form of a valine residue, or is an
  • R is acyl (1-6C), arylsulfonyl, alkylsulfonyl, arylalkylsulfonyl or alkoxycarbonyl group;
  • R 1 is -OH, -NR 2 R 3 or -OR 4 wherein each of R 2 and R 3 is independently hydrogen or an alkyl group (1-6C) and R 4 is alkyl group (1-6C);
  • linkages numbered I-IV is a modified peptide linkage selected from the group consisting of -COCH 2 -, -CH(OH)CH 2 - and -CH 2 NH-, and the remaining linkages are -CONH- or -CON(CH 3 )-, and the pharmaceutically acceptable salts thereof.
  • the invention is directed to pseudopeptides of the formula: I II III
  • AA 1 is an L- or D-form of an arginyl
  • AA 2 is an L- or D-form of a lysine, alanine,
  • ⁇ -aminoisobutyric acid leucine, norleucine or proline residue, or is an N-alkylated (1-6C) form thereof;
  • AA 3 is an L- or D-form of an aspartic acid residue wherein the remaining carboxyl group may optionally be esterified with alkyl group (1-6C);
  • AA 4 is an L- or D-form of an alanine or valine residue
  • R is an acyl group (1-6C) or an arylsulfonyl group, alkylsulfonyl group, arylalkylsulfonyl group or
  • R 5 is selected from the group consisting of a benzyl optionally substituted by NO 2 or halogen, 4-hydroxy-benzyl optionally substituted by NO 2 or halogen and isopropyl group, or is an N-alkylated (1-6C) form thereof;
  • the invention is also directed to pharmaceutical compositions containing the compound of the present invention as active ingredient; these compositions are useful for effecting immunomodulation or for the
  • the invention is directed to methods to effect immunomodulation in a subject or to treat immune diseases such as arthritis using the compounds and compositions of the invention.
  • Figure 1 schematically outlines the classification of amino acids.
  • the invention compounds are pseudopeptides containing five amino acid residues wherein at least one peptide bond linking these residues is substituted for by an isosteric linkage selected from the group set forth above. That is, in place of the CONH linkage ordinarily coupling the amino acid residues of the compound of the present invention, these functionalities (derived from the amino acid residues) are modified so as to obtain the isosteres.
  • the resulting compounds have enhanced
  • R-AA 1 - AA 2 - AA 3 - AA 4 - AA 5 -R 1 (1) are defined in terms of specifying amino acid residues AA 1 -AA 5 .
  • AA 2 is defined as a basic amino acid, a neutral/nonaromatic amino acid, or proline residue;
  • AA 4 is a neutral/nonaromatic amino acid residue, and
  • AA 5 is a neutral/aromatic amino acid or a
  • Amino acid residues can be generally subclassified into four major subclasses as follows:
  • Acidic The residue has a negative charge due to loss of H ion at physiological pH and the residue is attracted by aqueous solution so as to seek the surface positions in the conformation of a peptide in which it is contained when the peptide is in aqueous medium at physiological pH.
  • the residue has a positive charge due to association with H ion at physiological pH and the residue is attracted by aqueous solution so as to seek the surface positions in the conformation of a peptide in which it is contained when the peptide is in aqueous medium at physiological pH.
  • Neutral/nonpolar The residues are not charged at physiological pH and the residue is repelled by aqueous solution so as to seek the inner positions in the
  • nonpolar is arbitrary and, therefore, amino acids
  • Amino acid residues can be further subclassified as cyclic or noncyclic, and aromatic or nonaromatic,
  • residue is considered small if it contains a total of 4 carbon atoms or less, inclusive of the
  • Acidic Aspartic acid and Glutamic acid
  • Neutral/polar/small Glycine, Serine, Cysteine
  • Neutral/polar/large/nonaromatic Threonine
  • Neutral/nonpolar/large/aromatic Phenylalanine, and Tryptophan.
  • the gene-encoded amino acid proline although technically within the group neutral/nonpolar/large/ cyclic and nonaromatic, is a special case due to its known effects on the secondary conformation of peptide chains, and is not, therefore, included in this defined group.
  • amino acids which are not encoded by the genetic code, include, for example, beta-alanine (beta-Ala), or other omega-amino acids, such as 3-aminopropionic, 4-aminobutyric and so forth,
  • alpha-aminoisobutyric acid (Aib), sarcosine (Sar), ornithine (Orn), citrulline (Cit), t-butylalanine (t-BuA), t-butylglycine (t-BuG), N-methylisoleucine (N-Melle), phenylglycine (Phg), and cyclohexylalanine (Cha), norleucine (Nle), cysteic acid (Cya) and
  • MSO methionine sulfoxide
  • Sar, beta-Ala and Aib are neutral/nonpolar/small;
  • t-BuA, t-BuG, N-Melle, Nle and Cha are neutral/ nonpolar/large/nonaromatic;
  • Orn is basic/noncyclic
  • Phg is neutral/nonpolar/large/aromatic.
  • omega-amino acids are classified according to size as neutral/nonpolar/small (beta-ala, i.e., 3-aminopropionic, 4-aminobutyric) or large (all others).
  • amino acid substitutions of those encoded in the gene can also be included in peptide compounds within the scope of the invention and can be classified within this general scheme.
  • Preferred embodiments for AA 2 include the lysyl residue of the known thymopentin, and also residues of proline, norleucine, leucine, alanine, ⁇ -aminoisobutyric acid and N-alkylated form thereof.
  • a preferred embodiment of AA 3 is an aspartyl residue wherein the remaining carboxyl group may optionally be esterified with an alkyl group (1-6C).
  • Preferred embodiments of AA 4 include the valyl residue of thymopentin, as well as the residues of alanine, isoleucine and leucine.
  • Preferred embodiments of AA 5 include the residue of phenylalanine and tyrosine (which occurs in thymopentin) wherein hydrogen atoms of their aromatic part can be substituted by NO 2 group or halogen, and valine and
  • the ⁇ -amino group at the N-terminus of the compounds of formula (1) can also be acylated, arylsulfonylated, alkylsulfonylated, arylalkylsulfonylated or alkoxy carbonylated.
  • the acylating groups are corresponding
  • 1-6C acyl moieties including formyl, acetyl, pentanyl, isobutyryl, and the like.
  • the arylsulfonylating groups are benzensulfonyl, o-toluene-sulfonyl, m-toluene- sulfonyl, p-toluene-sulfonyl, xylenesulfonyl
  • alkylsulfonylating groups are methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl,
  • arylalkylsulfonylating groups are benzylsulfonyl, phenylethylsulfonyl, phenylpropylsulfonyl,
  • carbonylating groups are ethoxy carbonyl, butoxy
  • the carboxyl group may be in the underviatized form or may be amidated or esterified; in the underivatized form the carboxyl may be as a free acid or a salt, preferably a pharmaceutically acceptable salt.
  • the nitrogen atom of the amido group, covalently bound to the carbonyl carbon at the C-terminus, will be NH 2 , -NHR, or NRR', wherein R and R' are straight or branched chain alkyl of 1-6C, such alkyls are 1-6C straight- or branched-chain saturated hydrocarbon
  • residues such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, isopentyl, and the like.
  • amido groups are: -NH-, -NHCH-, -N(CH 3 ) 2 , -NHCH 2 CH 3 , -NHCH-CH(CH 3 ) 2 , and
  • esterified forms are methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, and the like.
  • the substituted-for peptide linkage of the invention is selected from the group consisting of -COCH 2 - ,
  • preferred embodiments of the compounds of the invention are those wherein only two such linkages are substituted, and most preferably one peptide linkage is substituted, and in all of the cases the remaining linkages except for the modified linkages are -CONH- or -CON(CH 3 )-.
  • the efficacy of the various pseudopeptides of the invention can be determined experimentally using a number of in vitro model systems. Competition for T-cell receptors with labeled thymopentin or thymopoietin is one convenient way to ascertain the ability of the
  • pseudopeptide to bind to target cells.
  • the ability of the pseudopeptides to stimulate cyclic GMP production in targeted T-cells can also be determined. Both of these determinations can be made according to the methods of Heavner, G.A., et al., Arch Biochem Biophys (1985) 242:248-255, cited above.
  • CEM cells are obtained from the
  • Typical competitive thymopentin binding assays employ tritiated thymopentin with a specific activity of 37 Ci/mmole. CEM cells are adjusted to a final
  • thymopentin or thymopentin analogs are added to the cells over a concentration range of 10 -6 to 10 -3 M.
  • the radiolabeled 3 H-thymopentin is then added
  • Corroborative results are obtainable in alternate assays testing the ability of a sample compound to enrich a population of prethymocytes for the presence of the Thy + -1 thymocyte marker. To conduct this assay,
  • prethymocytes are prepared from isolated spleens of nude mice.
  • spleen cell preparation whole spleens are collected from Balb/C, nu/nu mice, minced and pooled in RPMI-1640. The thymocytes are collected by centrifuga- tion in Ficoll-Hypaque and then resuspended at 1 x 10 6 cells/mL in RPMI-1640.
  • the spleen cells are incubated with test compound at various concentrations for 4.5 hours at 37°C, washed in PBS containing 0.1% azide, and then treated with
  • FITC-labelled antibody at 4°C for 30 minutes. The cells are then washed by centrifugation through heat- inactivated fetal bovine serum and then fixed for
  • the humoral response is measured by ELISA.
  • the ELISA is conducted by assay coating Iramulon II microtiter wells at 4°C overnight using 100 ⁇ l of a 10 yg/mL
  • N-terminal amino group is assumed to be to the left and the carboxy group to the right of each amino acid in the peptide.
  • the amino- and carboxy-terminal groups although often not specifically shown, will be understood to be in the form they would assume at physiological pH values, unless otherwise specified.
  • amino acids not encoded genetically are N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the L-form of any amino acid residue having an optical isomer is intended unless otherwise expressly indicated by a D or a dagger superscript ( ⁇ ). While the residues of the invention peptides are normally in the natural L optical isomer form, one or two, preferably one, amino acid may be replaced with the optical isomer D-form.
  • Free functional groups on the side chains of the amino acid residues can also be modified by amidation, acylation or other substitution, which can, for example, change the solubility of the compounds without affecting their activity.
  • thymopentin which is abbreviated THP.
  • Thymopentin in humans is a pentapeptide of the formula Arg-Lys- Asp-Val-Tyr, in positions 1-5.
  • the pseudopentapeptides are designated by modifications of this
  • P 2 -THP denotes the
  • D ⁇ 3 -THP represents a form in which the Asp at position 3 is replaced by its
  • Acylation at the N-terminus is noted as a prefix to the formula.
  • Ac-P 2 -THP represents acetylated thymopentin where the amino acid at position 2 is proline;
  • CH 3 CH 2 CO-F 5 -THP refers to propionyl
  • a 4 -THP-NHCH 3 refers to an analog wherein the amino acid at position 4 is alanine and the tyrosine at position 5 is amidated with methylamine.
  • THP refers to an analog wherein the amino acid at
  • D 3 (OMe)F 5 (OMe)-THP refers to an analog wherein the aspartic acid at position 3 is esterified with a methyl group and the amino acid at position 5 is phenylalanine which is also esterified with a methyl group.
  • pseudopeptides of the invention contain at least one bond which is a substitute for the ordinary peptide linkage; this is indicated by a Roman numeral before the name.
  • a Roman numeral in parentheses indicates the position of the substituted bond.
  • -COCH 2 - is a preferred embodiment of the substitution, if nothing else is indicated, this is the substituted bond at the indicated location. However, if a different embodiment of the substitution is intended, this is placed in parentheses after the designation, as indicated in compound 6 in Table 2 below.
  • the peptide-linked portions of the pseudopepetides of the present invention can be synthesized chemically by means well known in the art such as, e.g., solid- phase peptide synthesis.
  • the synthesis is commenced from the carboxy-terminal end of the peptide using an ⁇ -amino protected amino acid.
  • protective groups can be used for all amino groups even though other protective groups are suitable.
  • Boc-Asp-OH, Boc-Val-OH, Boc-Phe-OH, Boc-Arg-OH, Boc-Nle-OH or Boc-Tyr-OH can be esterified to chloro- methylated polystyrene resin supports.
  • the polystyrene resin support is preferably a copolymer of styrene with about 0.5 to 2% divinyl benzene as a cross-linking agent which causes the polystyrene polymer to be completely insoluble in certain organic solvents. See Stewart, et al., Solid-Phase Peptide Synthesis (1969), W.H.
  • the analog compounds can be synthesized directly, for example, by using Boc-AA -pMBHA-Resin or
  • AA x is the selected carboxy- terminal amino acid of the N-terminal compound as
  • At least one amide linkage (-CONH-) within the pentapeptide must be replaced with another linkage which is an
  • isostere such as -CH 2 NH-, -COCH 2 - and -CH(OH)CH 2 -, by methods known in the art.
  • the following references describe preparation of peptide analogs which include these alternative-linking moieties: Spatola, A.F., Vega Data (March 1983), Vol. 1, Issue 3, "Peptide Backbone Modifications" (general review); Spatola, A.F., in
  • immunomodulators and are helpful in treating immune diseases such as arthritis in the intact mammal.
  • compositions containing them can find use as therapeutic agents in the treatment of various immune-system conditions such as congenital immunodeficiency (e.g., Digeorge Syndrome); acquired immunodeficiency (e.g., postburn, postsurgery or
  • arthritis e.g., arthritis ; allergic diseases (e . g . , atopic dermatitis); inflammation; acute, chronic or recurrent infections by fungal, mycoplasma or virus (e.g., herpes, leprosy);
  • compositions containing an effective amount of compounds of the present invention including the nontoxic addition salts, amides and esters thereof, which may, alone, serve to provide the above-recited therapeutic benefits.
  • Such compositions can also be provided together with physiologically tolerable liquid, gel or solid diluents, adjuvants and excipients.
  • compositions can be administered to mammals for veterinary use, such as with domestic animals, and clinical use in humans in a manner similar to other therapeutic agents.
  • dosage required for therapeutic efficacy will range from about 0.01 to 50,000 ⁇ g/kg, more usually 0.1 to 10,000 yg/kg of the host body weight.
  • dosages within these ranges can be administered by constant infusion over an extended period of time until the desired
  • compositions are prepared as
  • injectables either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection may also be prepared.
  • the preparation may also be emulsified.
  • compositions are often mixed with diluents or excipients which are physiologically tolerable and compatible with the active ingredient.
  • diluents and excipients are, for example, water, saline, dextrose, glycerol, or the like, and combinations thereof.
  • the compositions may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, stabilizing or pH-buffering agents, and the like.
  • compositions are conventionally administered parenterally, by injection, for example, either
  • Additional formulations which are suitable for other modes of administration include suppositories, intranasal aerosols, and, in some cases, oral formulations.
  • suppositories traditional binders and excipients may include, for example,
  • polyalkylene glycols or triglycerides such suppositories may be formed from mixtures containing the active
  • Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained-release formulations, or powders, and contain 1% to 95% of active ingredient, preferably 1% to 10%.
  • the peptide compounds may be formulated into the compositions as neutral or salt forms.
  • Pharmaceutically acceptable nontoxic salts include the acid addition salts (formed with the free amino groups) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or organic acids such as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups may be derived from
  • inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • the compounds of the invention also can be any organic compound having the same properties.
  • the compounds of the invention also can be any organic compound having the same properties.
  • polypeptides of the present invention can also be used for preparing antisera for use in immunoassays employing labeled reagents, usually antibodies.
  • labeled reagents usually antibodies.
  • the polypeptides can be conjugated to an antigenicity- conferring carrier, if necessary, by means of
  • chromophores such as, e.g., fluorescein or rhodamine
  • radioisotopes such as 125 I, 35 S, 14 C, or 3 H, or
  • labeled compounds and reagents can find use as, e.g., diagnostic reagents.
  • Samples derived from biological specimens can be assayed for the presence or amount of substances having a common antigenic determinant with compounds of the present invention.
  • monoclonal antibodies can be prepared by methods known in the art, which antibodies can find therapeutic use, e.g., to neutralize overproduction of immunologically related compounds in vivo.
  • Examples 1 to 3, 5 to 13, and 15 to 21 represents the synthesis of a compound of Formula (1) which has a -COCH 2 - linkage at peptide bond IV, I or III.
  • Example 4 represents the synthesis of a compound of formula (1) which has a -CHOHCH 2 -linkage at peptide bond IV.
  • Example 22 represents the synthesis of a compound of formula (1) which has a -CH 2 NH- linkage at peptide bond I. In general, these syntheses can be seen in Reaction Schemes 1 to 13 and 15 to 22.
  • Example 14 represents the synthesis of a compound of Formula (1) which has a -COCH 2 - linkage at peptide bond IV by solution-phase peptide synthesis protocols.
  • Example 23 and 24 represent the synthesis of a compound of Formula (1) which has a -COCH 2 - linkage at peptide bond III by solution-phase peptide synthesis protocols. These approaches are seen in Reaction Schemes 14, 23 and 24, respectively.
  • the mixture was extracted with ether (3x500 mL).
  • the organic extracts were combined, dried on sodium sulfate and concentrated.
  • the white foam (27.3 g) was dissolved in 300 mL ethyl acetate and treated with 8.5 g (76.4 mmol) 2-mercaptopyridine.
  • the solution was cooled to 0°C and treated with 15.75 g (76.4 mmol) dicyclohexyl- carbodiimide.
  • the solution was stirred at 0°C for 3 hours then at room temperature for 16 hours.
  • the mixture was filtered and the filtrate concentrated.
  • Isomer A of the ketomethylene subunit 1-7 (0.500 g, 1.38 mmol) was dissolved in a mixture of MeOH and water (50 mL, 9:1). Solid cesium bicarbonate (0.268 g, 1.38 mmol) was added to the mixture and the solution stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the resulting residue was evaporated from toluene three times (50 mL each) to remove residual water, then placed under high vacuum overnight. The ketomethylene cesium salt was dissolved in DMF (50 mL) and Merrifield chloromethyl resin (2.01 g, 0.75 meq/g resin) was added to the solution. The
  • succinimydyl ester was dissolved in THF (10 mL) and added to the aspartic acid solution. The pH was adjusted to 8 using N-methylmorpholine and the reaction was allowed to stir overnight. The THF was removed under reduced pressure and the crude material partitioned between diethyl ether (200 mL) and 5% sodium bicarbonate (200 mL). The bicarbonate layer was acidified carefully to pH 3 and extracted with three portions of ethyl acetate (100 mL each). The combined organic layers were dried over sodium sulfate, filtered, and evaporated to a solid foam.
  • Boc-Lys (ClZ)Asp (cHex) (1-9) (1.22 g, 2.0 mmoles) and HOBt hydrate (0.310 g, 2.03 mmol) were dissolved in DMF (5 mL) diluted with methylene chloride (5 mL) and cooled to 0°C in an ice bath.
  • DCC (0.446 g, 2.16 mmol) in methylene chloride (10 mL) was added dropwise over 5 minutes. The reaction was stirred in methylene chloride for 15 minutes followed by treatment with 40% TFA/10% anisole/50% CH 2 Cl 2 for 30 minutes to remove the Boc group.
  • the activated dipeptide solution (prepared from 1-9 above) was
  • the activated ester was added to the resin along with diisopropylethylamine (0.350 mL, 2.0 mmol) and the reaction vessel was shaken overnight. The reaction was checked for completion (negative Kaiser test), and the peptide-resin was successively washed with methylene chloride (3x), isopropanol (2x), methylene chloride (2x), and methanol (2x). The peptide-resin was placed under vacuum overnight to give 3.04 g of dry peptide-resin. The Boc group was removed as described above and the resin washed successively with methylene chloride (3x),
  • the peptide-resin was washed and reacted 2.5 hours with the HOBt ester of N ⁇ -Boc-N g -tosyl arginine, prepared by reacting the amino acid derivative (0.857 g, 2.0 mmol) with HOBt hydrate (0.316 g, 2.06 mmol) and DCC (0.448 g, 2.17 mmol) in the presence of diisopropylethylamine
  • the Grignard reagent II-5 was prepared as described previously (l-3, Example 1) using halide II-4 (2.2 g,
  • the mixture was filtered through a pad of Celite and the pad washed with acetone (2x30 mL). The acetone was removed under vacuum and the resulting aqueous solution diluted with water (80 mL) and saturated with NaCl. The aqueous material was extracted with CH 2 Cl 2 (3x100 mL), the extracts dried over Na 2 SO 4 , and the resulting material evaporated to a brown gum.
  • Impure fractions were lyophilized and stored for further purification.
  • HPLC analysis indicated that the material existed in a 19:1 ratio of open hydroxy acid to lactone.
  • Nle 2 F 5 -THP (CHOH) (10.5 mg, 12.0 ⁇ mol) prepared similarly in a test reaction, and the combined materials were purified on HPLC using a 15-26% gradient of acetonitrile in water containing 0.1% TFA. Under the acidic
  • N ⁇ -Boc-Ng-Tosyl-L-arginine (1.90 g, 3.0 mmol), DCC (670 mg, 3.25 mmol), and HOBt (462 mg, 3.0 mmol) were combined and the resulting activated ester was added along with diisopropylethylamine (0.53 mL, 3.0 mmol) to the resin. After shaking overnight, the coupling was incomplete (positive Kaiser test).
  • N ⁇ -Boc-Ng-Tosyl-L-arginine (1.86 g, 3.0 mmol), DCC (670 mg , 3.25 mmol), and HOBt (465 mg, 3.0 mmol) were combined and the resulting material again coupled with the resin overnight. Coupling was judged complete after the second treatment. The Boc group was removed and the resin was washed and dried to yield
  • N ⁇ -(N ⁇ -Boc-L-alanyl)-L-aspartic acid ⁇ -benzyl ester VII-2 N ⁇ -Boc-L-alanine (5.67 g; 30 mmol) and N- hydroxysuccinimide (3.62 g; 31.5 mmol) were dissolved in THF (15 mL) and the resulting solution cooled to 0°C (ice bath). DCC (6.80 g; 33.0 mmol) in THF (10 mL) was added dropwise with vigorous stirring. The reaction was stirred at 0°C for 2 hours, then at room temperature overnight. The precipitated DCU was filtered off, and the filtrate was evaporated to give an oily gum.
  • succinimide ester The succinimide ester (6.06 g; 20.0 mmol) was added to a solution of L-aspartic acid ⁇ -benzyl ester (4.46 g; 20.0 mmol) and triethylamine (2.80 mL;
  • N ⁇ -Boc-N g -Tosyl-L-arginine (429 mg, 1.0 mmol), DCC (227 mg, 1.1 mmol), and HOBt (153 mg, 1.0 mmol) were combined and the resulting activated ester was added along with diisopropylethylamine (0.18 mL, 1.0 mmol) to the resin.
  • the diazoketone (9.85 g, 16.4 mmol) was dissolved in 80% aq. AcOH (250 mL) containing anhydrous LiCl (35 g, 0.83 mol) at 0°C. The mixture was allowed to warm to ambient temperature overnight.
  • the reaction was transferred via cannula to a flask containing NaH, 50% in mineral oil (150 mg, 3.13 mmol).
  • 1-iodobutane (3.45 g, 18.8 mmol) was added to the mixture.
  • TLC indicated that the reaction was complete.
  • the reaction was quenched with a few drops of AcOH and the DME was removed in vacuo.
  • the crude material was dissolved in CH 2 Cl 2 (100 mL), washed with 0.1 N HCl (2x50 mL) and saturated NaCl (250 mL), dried over MgSO 4 , and evaporated.
  • the oily residue was flash-chromatographed (40x300 mm), eluting the hexanes (500 mL), EtOAc-hexanes (1:9, 1000 mL), and EtOAc-hexanes (1:3, 1000 mL).
  • Boc-L-Asp (OBzl)-L-Val-L-Phe resin (0.80 g of 0.52 meq/g [theoretical], 0.42 mmol), prepared by standard solid-phase peptide synthesis.
  • the reaction was stirred in methylene chloride for 15 minutes followed by treatment with 40% TFA/10% anisole/50% CH 2 Cl 2 for 30 minutes to remove the Boc group.
  • the resin was washed numerous times with methylene chloride and isopropyl alcohol, neutralized with 10% DIEA and washed with methylene chloride.
  • the activated ester of isomer A of VIII-3 was filtered into the resin reaction vessel and the vessel was shaken overnight.
  • the peptide was cleaved from the resin by stirring with 10% anisole in anhydrous HF at 0-5°C for 90 minutes. After evaporation of HF, the resin was washed with anhydrous diethyl ether (250 mL) and the peptide was extracted with 20% acetronitrile in water containing 0.5% TFA (8x25 mL). The extracts
  • Boc-L-Agp(OBzl)-L-Val-L-Phe resin (0.90 g of 0.52 meq/g [theoretical], 0.47 mmol), prepared by standard solid-phase peptide synthesis, by treatment with 40% TFA/10% anisole in methylene chloride for 5 minutes, then 30 minutes.
  • the resin was washed numerous times with methylene chloride and isopropyl alcohol, neutralized with 10% DIEA and washed with methylene chloride.
  • the activated ester of isomer B of VIII-3 was filtered into the resin reaction vessel and the vessel was shaken overnight.
  • the peptide was cleaved from the resin by stirring with 10% anisole in anhydrous HF at 0-5°C for 90 minutes. After evaporation of HF, the resin was washed with anhydrous diethyl ether (250 mL) and the peptide was extracted with 20% acetronitrile in water containing 0.5% TFA (8x25 mL). The extracts containing peptide were combined and lyophilized to give 212 mg of crude material. The crude material was purified using a 90-minute linear preparative gradient of 10-40%
  • HOBt (164.0 mg, 1.07 mmol), BOP (473 mg, 1.07 mmol), and N-methyl-morpholine (175 ⁇ l, 1.59 mmol) were mixed in DMF (15 mL) at room temperature for 30 minutes.
  • Trityl chloride (21.0 g, 75 mmol) in CH 2 Cl 2 was added and the reaction was stirred for 3 hours.
  • MeOH (50 mL) was added to the reaction and the material was stirred at room temperature for 30 minutes.
  • the reaction was concentrated under a vacuum to a viscous yellow oil, which was dissolved in Et 2 O and extracted with 1 N NaOH (4x250 mL). The combined aqueous layers were cooled to 0°C and neutralized with solid citric acid.
  • the Grignard reagent was prepared by activating a suspension of Mg turnings (4.83 g, 0.2 mol) in Et 2 O (30 mL) with a dropwise addition of 1,2-dibromoethane (11.8 g, 63 mmol) in Et 2 O (30 mL). The addition was kept at a rate to maintain a steady reflux.
  • N ⁇ -Carbobenzyloxy-L-lysine (5.60 g, 20 mmol) was suspended in a mixture of 1,4-dioxane (25 mL) and isobutylene (50 mL). Concentrated H 2 SO 4 (2 mL) was added carefully to the reaction, and the reaction allowed to proceed at room temperature while employing a Dewar condenser (dry ice/acetone) to keep isobutylene from evaporating. After 4 hours, the Dewar condenser was removed and the excess isobutylene allowed to evaporate. The reaction was poured into ice-cold 1 N NaOH (200 mL) and extracted with diethyl ether (3x100 mL).
  • N ⁇ , N ⁇ , N ⁇ -Tricarbobenzyloxy-L-argine (5.76 g, 10 mmol) was dissolved in THF (40 mL) and cooled to -10°C with an ice-methanol bath.
  • N-Methyl-morpholine (1.05 mL, 11 mmol)
  • isobutylchloroformate (1.55 mL, 12 mmol) were added successively.
  • a solution of XI' -2 (3.72 g, 11 mmol) in THF (10 mL) was added to the reaction. The reaction was stirred an additional 2 hours, and then it was poured into a 50% saturated brine solution (200 mL) and a solid gum precipitated.
  • the aqueous material was decanted, and the gum was dissolved in methylene
  • N-Boc-L-phenylalanine resin (373 mg of 0.67 meq/g resin, 0.25 mmol) was treated with 40% TFA/10% anisole in methylene chloride for 5 minutes and then 30 minutes to remove the N-terminal Boc group.
  • ketomethylene subunit XI-8 312 mg, 0.75 mmol
  • BOP 333 mg, 0.75 mmol
  • HOBt 115 mg, 0.75 mmol
  • N-methylmorpholine (1.40 mL, 1.50 mmol). After allowing the activated ketomethylene dipeptide to react with the resin overnight, a Kaiser test suggested that coupling was still incomplete. The resin was therefore treated with acetic anhydride (1 mL) and pyridine (0.1 mL) in methylene chloride for 30 minutes. Next, the Boc group was removed with 40% TFA/10% anisole in methylene chloride.
  • N ⁇ , N ⁇ , N ⁇ -Tricarbobenzyloxy-L-arginyl- N ⁇ -carbobenzyloxy-L-lyslne XI' -4 (840 mg, 1.0 mmol) and HOBt (153.3 mg, 1.0 mmol) were dissolved in DMF (2 mL) in a separate flask and cooled to 0°C.
  • Dicyclohexyl- carbodiimide (228.2 mg, 1.1 mmol) in methylene chloride (5 mL) was added and the reaction stirred at 0°C for 15 minutes, then at room temperature for 30 minutes.
  • the peptide-resin was washed alternately with methylene chloride and isopropyl alcohol to remove residual TFA.
  • the activated dipeptide prepared in the separate flask was added to the peptide-resin, followed by addition of diisopropylethylamine (175 ⁇ l, 1.0 mmol).
  • the reaction vessel was then shaken overnight.
  • the coupling was checked for completion (negative Kaiser test) and the peptide-resin washed with methylene chloride.
  • the peptide was cleaved from the resin by stirring with 10% anisole in anhydrous HF at 0-5°C for 1 hour. After evaporation of the HF, the resin was washed with diethyl ether and chloroform, and then the peptide was eluted with 20% acetonitrile in water with 0.5% TFA present.
  • the extract was frozen and lyophilized to give 128 mg of crude (III) F 5 -THP.
  • the isomers were separated by HPLC using a preparative gradient of 0-30% acetonitrile in water with 0.1% TFA. The separated isomers were further purified: isomer A was chromatographed under isocratic conditions using 18% acetonitrile in water with 0.1% TFA; isomer B was chromatographed under isocratic
  • Tribenzyloxycarbonyl arginine (2.88 g, 5.0 mmol) in THF (40 mL) was cooled to -10°C (ice-methanol) and N-methylmorpholine (0.53 mL, 5.5 mmol) and isobutyl- chloroformate (0.78 mL, 6.0 mmol) were added successively.
  • a solution of proline t-butyl ester (2.31 g) in THF (10 mL) was added to the reaction followed by N-methylmorpholine (0.52 mL, 5.5 mmol). After stirring at room temperature for 2 hours, the reaction was evaporated to an oil.
  • the succinimide was dissolved in CH 2 Cl 2 (10 mL) and added to the resin along with a catalytic amount of HOBt (5 mg). The reaction was allowed to proceed 7 days with periodic monitoring using the Kaiser test. The resin was then capped using acetic anhydride (1 mL) and pyridine (0.2 mL) in CH 2 Cl 2 (10 mL). The Boc was removed as usual, leaving the resin as the TFA salt. Meanwhile, Z 3 -L-Arg-L-Pro (XII'-4, 1.05 g , 1.56 mmol) and HOBt (250 mg, 1.64 mmol) were dissolved in CH 2 Cl 2 and cooled to 0°C, after which DCC (350 mg, 1.70 mmol) was added. The resin was
  • Boc group was removed from Boc-L-Tyr(Z)-O-Resin (2.59 g, 1.50 mmol @ 0.58 meq/g) in the usual manner, and the resin was washed with CH 2 Cl 2 (3x), neutralized with 10% DIEA in CH 2 Cl 2 (2x), and washed with CH 2 Cl 2 (3x).
  • the activated ketomethylene was added to the resin and shaken for 7 days. Because there were excess
  • XIV-3 was prepared in good yield by standard methods. This dipeptide was then condensed using N-hydroxysuccin- imide and DCC with the benzhydryl ester of aspartic acid (XIV-4) (prepared as shown) to give XIV-5 in 84% yield. Benzhydryl ester XIV-5 was then cleaved using
  • N ⁇ , N ⁇ , N ⁇ -Tribenzyloxycarbonyl-L-arginine (2.88 g; 5.0 mmol) in methylene chloride (50 mL) was cooled to -10°C, and triethylamine (0.68 mL; 5.0 mmol) and
  • Aspartic acid- ⁇ -cyclohexyl- ⁇ -tert-butyl ester (XV-5) (433 mg; 1.60 mmol) in methylene chloride (10 mL) was added to the reaction, along with N-methylmorpholine (0.18 mL; 1.60 mmol), and stirred overnight.
  • the reaction was evaporated to an oil and subjected to flash chromatography using a step gradient of 10, 20, and 30% ethyl acetate in hexane (500 mL each). Product fractions were pooled and evaporated to give 1.04 g (85%) of XV-6.
  • Example 1 the Boc group was removed from the Boc- Val (k)Phe-Resin (0.50 g; 0.25 meq) by treatment with a cocktail containing 40% TFA and 10% anisole in methylene chloride for 5 min, followed by a second treatment with fresh cocktail for 30 min. After removal of the Boc group, the resin was washed four times alternately with methylene chloride and isopropanol, then finally with methylene chloride (3x). Meanwhile, tripeptide XV-7 (675 mg; 0.75 mmol) and HOBt (122 mg; 0.80 mmol) were dissolved in DMF (1 mL), diluted with methylene chloride (10 mL), and cooled to 0°C (ice bath). DCC (186 mg;
  • XVI-2 was transferred via cannula to a cooled (0°C) solution of XVI-3 (3.18 g; 7.5 mmol) in THF (30 mL) .
  • the reaction was allowed to proceed at room temperature overnight.
  • the material was partitioned between diethyl ether (300 mL) and saturated NH 4 Cl (300 mL) .
  • the Boc group was removed from the resin XVI-7 (1.0 g; 0.33 meq) by treatment with a cocktail containing 40% TFA and 10% anisole in methylene chloride for 5 min, followed by a second treatment with fresh cocktail for 30 min. After removal of the Boc group, the resin was washed three times alternately with methylene chloride and isopropanol, then finally with methylene chloride (3 times).
  • tripeptide XVI-8 (XV-7 in Example 15) (333 mg; 0.37 ramol) and HOBt (57 mg; 0.37 mmol) were dissolved in DMF (2 mL), diluted with methylene chloride (4 mL), and cooled to 0°C (ice bath).
  • DCC (84 mg; 0.41 mmol) in methylene chloride (2 mL) was added, and the resulting mixture stirred at 0°C for 10 min, then at room temperature for 20 min.
  • the solution was added to the resin along with diisopropylethylamine (65 ⁇ l; 0.37 mmol), and the resulting reaction was shaken overnight.
  • Tripeptide XVI-8 (110 mg; 0.12 mmol), HOBt (19 mg; 0.12 mmol) and DCC (28 mg; 0.14 mmol) were combined to form additional activated XVI-9.
  • the solution was added to the resin and the reaction was shaken for 2 days.
  • the peptide-resin was washed with methylene chloride (2 times), isopropanol (2 times) and finally methylene chloride (2 times), to give 1.317 g.
  • the peptide was cleaved from the resin with concomitant removal of side-chain protecting groups by treating the peptide-resin with 10% anisole in HF (12 mL) at 0°C for 1 hour, followed by vacuum removal of the HF/anisole mixture.
  • the resin was washed with ether and the peptide extracted with 50% acetic acid (50 mL) .

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Abstract

Pseudopeptides répondant à la formule (α) dans laquelle AA1 représente un reste arginyle; AA2 représente un reste acide aminé fondamental, un reste acide aminé neutre/non aromatique ou un reste proline, ou bien représente une forme N-alkylée (1-6 C) d'un tel reste; AA3 représente un acide aspartique ou un acide glutamique dans lequel le groupe carboxyle restant peut être estérifié par alkyle (1-6 C), ou un reste alanine; AA4 représente un reste acide aminé neutre/non aromatique; AA5 représente un reste acide aminé neutre/aromatique dans lequel un ou plusieurs atomes d'hydrogène de sa partie aromatique peuvent être substitués par NO2 ou halogène, ou représente un reste acide aminé neutre/non polaire/grand/non aromatique, ou bien la forme N-alkylée (1-6 C) d'un tel reste; R représente un reste acyle (1-6 C), arylsulfonyle, alkylsulfonyle, arylalkylsulfonyle, ou alcoxycarbonyle; et R1 représente -OH, -NR2R3 ou -OR4, R2 et R3 représentant chacun un hydrogène ou un groupe alkyle (1-6 C), et R4 représentant un groupe alkyle (1-6 C). Dans ladite formule au moins une des liaisons I-IV est une liaison peptidique modifiée -COCH2-, -CH(OH)CH2- ou bien -CH2NH-, et les liaisons restantes sont -CONH- ou bien -CON(CH3)-.
PCT/JP1992/001046 1991-08-26 1992-08-19 Pseudopentapeptides presentant une acivite d'immunomodulation WO1993004080A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2763071A1 (fr) * 1997-05-07 1998-11-13 Centre Nat Rech Scient Analogues peptidiques, et leurs utilisations notamment dans des compositions pharmaceutiques et pour le diagnostic
EP1138673A3 (fr) * 1994-03-25 2001-10-17 Vertex Pharmaceuticals Incorporated Nouveaux carbamates et urées utilisés pour modifier la résistance multi-medicamenteuse
US8362068B2 (en) 2009-12-18 2013-01-29 Idenix Pharmaceuticals, Inc. 5,5-fused arylene or heteroarylene hepatitis C virus inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0342962A2 (fr) * 1988-05-19 1989-11-23 Immunobiology Research Institute, Inc. Peptides à activité de cellule T helper
EP0393786A1 (fr) * 1989-04-21 1990-10-24 SCLAVO S.p.A. Rétro-inverso peptides, analogues de la thymopentine ayant une ou plusieurs liaisons, procédés pour les préparer et leur utilisation pour confectionner un médicament

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0342962A2 (fr) * 1988-05-19 1989-11-23 Immunobiology Research Institute, Inc. Peptides à activité de cellule T helper
EP0393786A1 (fr) * 1989-04-21 1990-10-24 SCLAVO S.p.A. Rétro-inverso peptides, analogues de la thymopentine ayant une ou plusieurs liaisons, procédés pour les préparer et leur utilisation pour confectionner un médicament

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1138673A3 (fr) * 1994-03-25 2001-10-17 Vertex Pharmaceuticals Incorporated Nouveaux carbamates et urées utilisés pour modifier la résistance multi-medicamenteuse
FR2763071A1 (fr) * 1997-05-07 1998-11-13 Centre Nat Rech Scient Analogues peptidiques, et leurs utilisations notamment dans des compositions pharmaceutiques et pour le diagnostic
WO1998050423A3 (fr) * 1997-05-07 1999-08-19 Centre Nat Rech Scient Analogues peptidiques et leurs utilisations notamment dans des compositions pharmaceutiques et pour le diagnostic
US8362068B2 (en) 2009-12-18 2013-01-29 Idenix Pharmaceuticals, Inc. 5,5-fused arylene or heteroarylene hepatitis C virus inhibitors
US9187496B2 (en) 2009-12-18 2015-11-17 Idenix Pharmaceuticals Llc 5,5-fused arylene or heteroarylene hepatitis C virus inhibitors

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CA2094822A1 (fr) 1993-02-27
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JPH06501961A (ja) 1994-03-03

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