EP0000252A1 - Peptides, compositions pharmaceutiques les contenant et procédé de préparation de ces peptides - Google Patents

Peptides, compositions pharmaceutiques les contenant et procédé de préparation de ces peptides Download PDF

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Publication number
EP0000252A1
EP0000252A1 EP78300046A EP78300046A EP0000252A1 EP 0000252 A1 EP0000252 A1 EP 0000252A1 EP 78300046 A EP78300046 A EP 78300046A EP 78300046 A EP78300046 A EP 78300046A EP 0000252 A1 EP0000252 A1 EP 0000252A1
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EP
European Patent Office
Prior art keywords
amino acid
peptide
lys
product
boc
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Granted
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EP78300046A
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German (de)
English (en)
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EP0000252B1 (fr
Inventor
Peter Roy
Brian George Overell
Denis Raymond Stanworth
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Beecham Group PLC
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Beecham Group PLC
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Publication of EP0000252A1 publication Critical patent/EP0000252A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 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
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
    • C07K16/065—Purification, fragmentation
    • 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
    • C07K5/06052—Val-amino acid
    • 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
    • C07K5/06069—Ser-amino acid
    • 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
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • 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
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • 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
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S930/00—Peptide or protein sequence
    • Y10S930/01—Peptide or protein sequence
    • Y10S930/32—Modification to prevent enzymatic degradation

Definitions

  • This invention relates to certain peptides useful for desensitisation therapy, and to desensitisation compositions containing them.
  • non-selective and selective release of histamine can be distinguished respectively by the presence or absence either of simultaneously released intracellular enzymes, or of radioactive chromium previously absorbed by that substances capable of causing selective release of histamine may be used in lasensitisation therapy of allergic humans.
  • An object of this invention is to provide a novel class of peptides having this property, and desensitisation compositions, particularly vaccines containing such peptides.
  • the present invention provides a peptide of formula (I): and salts thereof, consisting of 6 to 12 naturally occurring amino acid residues, wherein R is an optionally present group, capable of confering on a peptide resistance to enzyme breakdown; R l represents a residue of a basic amino acid, optionally linked to one or more residues of neutral non-hydrophobic amino acids and/or basic amino acids; R 2 represents a residue of a neutral non- hydrophobic amino acid, optionally linked to one or more durtner residues of neutral non-hydrophobic amino acids; R 3 represents a residue of a hydrophobic amino acid, tionally linked to one or more residues of neutral non- drophobic amino acids and/or hydrophobic amino acids; is hydrogen, or a N . - protecting group; and Y is hydroxyl, C - terminal protecting group.
  • amino acids referred to --eafter are in the L- configuration.
  • R When R is present, it is a group capable of confering a peptide resistance to enzyme breakdown. Examples of groups R are given in J-. Rudinger,"The Design of reptide Hormone Analogues",Chapter 9 in Drug Design, volume (II) edited by E. J. Ariens, Academic Press, New ark and London, 1971.
  • R when present, include hydroxyprolyl, the D- form of a common amino acid or an amino acid residue with omission of the amino group.
  • Particularly suitable examples of R 1 include Lys-Thr-Lys, Arg-Lys-Thr-Lys and the like.
  • R 1 will consist of 1 to 5 amino acid residues, suitably 3 to 5 residues.
  • R 1 will often contain at least two basic amino acid residues and at least one neutral non- hydrophobic amino acid residue.
  • R 2 examples include glycyl, alanyl, seryl and threonyl and combinations of such residues.
  • a particularly suitable example of R 2 is Gly-Ser-Gly.
  • R 2 consists of 1 to 5 amino acid residues, for example 3 amino acid residues.
  • Suitable examples of hydrophobic amino acids R 3 include residues of amino acids notionally derived from alanine ⁇ -substituted by an aromatic or aliphatic hydrophobic group, such as phenylalanyl, valyl and leucyl; and combinations of such residues.
  • Particularly suitable examples of R 3 include Phe-Phe and Phe-Phe-Val-Phe.
  • Preferably R 3 consists-of 1 to 4 amino acid residues, for example 2 or 4 residues.
  • N-protecting groups X are hydrogen or a N-protecting group.
  • Suitable examples of N-protecting groups X include those conventionally known for this use in peptide chemistry. Examples of such groups include carboxylic acid groups such as acetyl, chloroacetyl, trifluoroacetyl, butyryl, benzoyl, phenylacetyl, pyridine-carbonyl; or an acid group derived from carbonic acid such as ethoxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl, biphenylisopropoxycarbonyl, p-methoxy-benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-phenylazobenzyloxycarbonyl, p-(p'-methoxyphenylazo)-benzyloxycarbonyl, t-amyloxycarbonyl; or an acid group derived
  • protecting groups Y include ester residues of C 1-6 alkyl esters such as methoxy, ethoxy and t-butoxy; benzyloxy, p-nitrobenzyloxy,
  • the peptides of the invention have 6 to 12 amino acid esidues. Preferably they have 8 to 10 amino acid residues ...
  • One particularly suitable.group of peptides is of formula (II): wherein X, Y and R are as defined; c and e are lysyl, arginyl or ornithyl; d is threonyl or seryl; b is an optionally present arginyl, lysyl or ornithyl; f and h are glycyl or alanyl; g is seryl or threonyl; i and j are phenylalanyl, valyl or leucyl; and k and 1 are optionally present phenylalanyl, valyl or leucyl; and salts thereof.
  • X is hydrogen and Y is hydroxyl,-NH 2 or C 1 _ 4 alkoxy such as methoxy, and,when R is present, it is prolyl or hydroxyprolyl.
  • Y is hydroxyl, NH 2 or methoxy.
  • the peptides of this invention may be prepared by methods known in the art of peptide synthesis comprising dupling the amino acids from which the peptide is derived ally to build up the desired peptide.
  • amide linkage is usually prepared by condensing an amino acid, or peptide, having a protected a-amino group and a free or activated terminal carboxyl group, with an amino acid or peptide with a protected carboxyl group and a free a-amino group.
  • Activation of the carboxyl group can be effected, for example, by converting the carboxyl group into an acid halide, an azide, anhydride or imidazolide, or into an activated ester such as the cyanomethyl ester, p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester, benztriazole ester.
  • the removal of the protecting group(s) present in the resultant peptide may be effected by an appropriate procedure depending upon the kind(s) of the protective group(s).
  • Some typical procedures are as follows: hydrogenation in the presence of palladium catalyst (e.g. palladium carbon, palladium black) for benzyloxycarbonyl, p-hitrobenzyloxycarbonyl, p-bromo-benzyloxycarbonyl, p-phenylazobenzyloxycarbonyl, p-(p'-methoxyphenylazo)-benzyloxycarbonyl and trityl groups protecting the amino end; treatment.with hydrogen bromide in glacial acetic acid
  • mucosa as a liquid spray or as snuff.
  • the present invention includes a pharmaceutical composition adapted for use in desensitisation therapy, comprising a peptide or pharmaceutically acceptable salt of formula (I) together with a pharmaceutically acceptable carrier suitable for parenteral, intra-nasal or buccal administration.
  • a preferred composition of the invention is a desensitisation vaccine.
  • compositions of the invention may be administered in conventional manner for desensitisation therapy.
  • Peptides were synthesised by classical methods of peptide synthesis described in the literature of peptide chemistry, for example by means of classical solution synthesis or solid phase peptide synthesis (SPPS), or by use of a combination of these methods.
  • SPPS solution synthesis or solid phase peptide synthesis
  • Partially protected octapeptide (IV) (O.lOg) was hydrogenated in 85% AcOH (70ml) with 10% Pd/C catalyst (0.20g) over a steady stream of hydrogen for 20 hours. The mixture was filtered, evaporated in vacuo and residue filtered on Sephadex LH20 eluting with water to give the desired octapeptide methyl ester (V) (0.03g, 46% yield). TLC examination showed 1 spot at Rf 0.2 in 5:2:2 BAW (t-BuOCl/KI-starch stain) and Rf 0.5 in 5:2:3 BAW (Ninhydrin stain).
  • This nonapeptide was prepared by coupling of (IV) above with Z .Arg (Z ) 2 ,, .OSu, followed by hydrogenolysis of the resultant fully protected nonapeptide.
  • decapeptide free acid was synthesised by a 4+2+4 fragment condensaiton strategy as follows:-
  • ZLys(Z)OTcp (1.80g, 0.003M) was coupled to compound (iv) (1.72g, 0.003M) in dioxan (45ml) at R.T. for 4 hours in the presence of Et 3 N (1 equivalent). The product was filtered off, washed with water and dried in vacuo (1.36g, 50% yield). M.P. 185-188°. T.L.C. 9:1 CHCl 3 : MeOH (1 2 stain showed one spot at Rf 0.76.
  • Peptide (XIV) 0.40 g, 0.0033M) was coupled to compound (VIII) (0.20g, 0.0034M) in DMF (5ml) in the presence of Et 3 N (1 equivalent), DCCI (0.07g, 0.0035M) and hydroxybenzotriazole (0.044g, 0.0035M) at 5° for 1 hour then at R.T. for 1 hour.
  • the precipitated urea was filtered off and the required product (0.50g) isolated by pouring the reaction mixture into iced water and isolating by .filtration in 88% yield.
  • T.L.C. 9:1 CHCl 3 :MeOH (I 2 stain) showed one spot at Rf 0.52.
  • the NMR was consistent with structure.
  • the octapeptide free acid was synthesised by a 4+4 fragment condensation strategy as follows:-
  • BOCPheOH (11.88g, 0.045M) was coupled to PheOBz.pTsa-19.4g, O.o45M) in MDC (200 ml) at 0° for 1 hour then at R.T. overnight in the presence of Et 3 N (1 equivalent) and DCCI (1 equivalent).
  • the reaction mixture was filtered and the product (14.92g) isolated in 64% yield upon evaporation in vacuo and recrystallisation from EtOAc/80-100° petrol (14.92g).
  • the purified cells were washed twice in Dulbecco's complete (i.e. free from mineral salts) buffer and then resuspended in Dulbecco's medium to the required volume. a typical experiment, sufficient cells were available duplicate challenges, i.e. 60 samples and in this resuspension volume employed was 6.1 mls. 0.1 ml were taken for estimating the cell
  • One third of the cell suspension was employed. 0.9 ml duplicate aliquots of challenge solution, in complete Dulbecco's medium and prewarmed to 37°C, was added 0.1 ml of cell suspension. The solutions were then shaken gently, and allowed to incubate for 5 minutes at 37°C. The reaction tubes were then quickly removed from the incubator and placed in an ice bath. Supernatants were then separated from the cell population following centrifugation for 3 minutes at 1000 r.p.m. The cell residues were then treated with 2 mls of 0.4N perchloric acid and allowed to stand for approximately 30 minutes at ambient temperature. The precipitated protein was removed by centrifugation and the supernatant solutions set aside for histamine analysis.
  • the original supernatant solutions were treated with 1.0 ml of 0.8N perchlorate and then treated in a similar manner to the cell residues. Histamine was measured by the method according to Evans, Lewis and Thompson (Life Sciences, 12, 327, 1973) using a Technicon Auto-analyser. Histamine release was calculat as a percentage of total histamine available in each challenge solution.
  • One third of the cell.suspension was employed. To approximately 2.0 ml of cell suspension in Dulbecco's medium was added 0.1 ml of a solution of Cr 51 labelled sodium chromate. Approximately 50-1OO ⁇ Ci Cr 51 was employed (specific activity: 300-500 ⁇ Ci/mg Cr). The cells were allowed to stand for 30 minutes at ambient temperature and then excess chromium was removed by washing the cells thee times in Dulbecco's buffer. The cell pellet was finally resuspended in the same buffer and 0.1 ml of cell suspension was then added to 0.9 ml of each challenge Tracer Laboratory Spectromatic ⁇ counter. The percentage of Cr 51 released was assessed in relation to the values obtained for the positive and negative control solutions.
  • Peptide in aqueous sodium or saline control were injected or 0.10 ml volumes. Skin reactions were read 20 minutes after intradernal challenge.
  • Brown Norway rats were immunised intraperitoneally with lOO ⁇ g of ovalbumen (XOA) in 1mg 'alum'.
  • XOA ovalbumen
  • peritoneal mast cells were removed, bulked and washed. Aliquots of cells were desensitised by the addition of 4 x 5 minute incubations with various XOA or peptide concentrations or buffer alone. The cells were then submitted to an optimal histamine releasing challenge of peptide, XOA, or challenged with buffer alone.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
EP78300046A 1977-06-29 1978-06-15 Peptides, compositions pharmaceutiques les contenant et procédé de préparation de ces peptides Expired EP0000252B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB2714077 1977-06-29
GB2714077 1977-06-29

Publications (2)

Publication Number Publication Date
EP0000252A1 true EP0000252A1 (fr) 1979-01-10
EP0000252B1 EP0000252B1 (fr) 1982-02-03

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EP78300046A Expired EP0000252B1 (fr) 1977-06-29 1978-06-15 Peptides, compositions pharmaceutiques les contenant et procédé de préparation de ces peptides

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US (1) US4223016A (fr)
EP (1) EP0000252B1 (fr)
JP (1) JPS5416402A (fr)
AU (1) AU522641B2 (fr)
CA (1) CA1105006A (fr)
DE (1) DE2861593D1 (fr)
DK (1) DK292778A (fr)
ES (1) ES471243A1 (fr)
IE (1) IE47105B1 (fr)
IL (1) IL54967A (fr)
IT (1) IT7850095A0 (fr)
NZ (1) NZ187638A (fr)
ZA (1) ZA783699B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986001211A1 (fr) * 1984-08-10 1986-02-27 MERCK Patent Gesellschaft mit beschränkter Haftung Agents polypeptides immunotherapeutiques
US4752601A (en) * 1983-08-12 1988-06-21 Immunetech Pharmaceuticals Method of blocking immune complex binding to immunoglobulin FC receptors
WO1996014333A1 (fr) * 1994-11-04 1996-05-17 Peptide Therapeutics Limited Peptides utilises dans les traitements anti-allergies
WO2007123467A1 (fr) 2006-04-25 2007-11-01 Livsafe Inc. Systeme de suspension de volant de direction
WO2008107506A1 (fr) 2007-03-08 2008-09-12 Universidad De Sevilla Nouveaux caramels à teneur élevée en oligosaccharides prébiotiques, procédé de préparation et utilisation

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56119178U (fr) * 1980-02-13 1981-09-11
US4683292A (en) * 1983-08-12 1987-07-28 Immunetech, Inc. Immunotherapeutic polypeptide agents which bind to lymphocyte immunoglobulin FC receptors
GB8913737D0 (en) * 1989-06-15 1989-08-02 Univ Birmingham A novel anti-allergy treatment
US5955076A (en) * 1989-06-15 1999-09-21 Peptide Therapeutics Limited Immunoactive peptides and antibodies and their use in anti-allergy treatment
JP2000505077A (ja) 1996-01-16 2000-04-25 レンセレール ポリテクニック インスティチュート 骨芽細胞の接着を改良するためのペプチド
US6610297B1 (en) 1996-03-01 2003-08-26 Novartis Ag Peptide immunogens for vaccination against and treatment of allergy
US6573372B2 (en) 1999-01-07 2003-06-03 Heska Corporation Feline immunoglobulin E molecules and compositions there of
RU2309144C2 (ru) 2005-03-25 2007-10-27 Общество С Ограниченной Ответственностью "Фарминтерпрайсез" Фенилсодержащие n-ацильные производные аминов, способ их получения, фармацевтическая композиция и их применение в качестве противовоспалительных и анальгетических средств

Citations (2)

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Publication number Priority date Publication date Assignee Title
JPS4876817A (fr) * 1972-01-17 1973-10-16
FR2257304A1 (fr) * 1974-01-10 1975-08-08 Becton Dickinson Co

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NL6501206A (fr) * 1964-02-12 1965-08-13
NL6509727A (fr) * 1965-07-28 1967-01-30
US3832337A (en) * 1970-07-28 1974-08-27 Squibb & Sons Inc Peptide enzyme inhibitors
US3864481A (en) * 1972-12-14 1975-02-04 St Lukes Hospital Anti disease producing synthetic material for the prevention suppression and diagnosis of multiple sclerosis and method of treatment therefor
US4113858A (en) * 1975-01-20 1978-09-12 St. Luke's Hospital Novel compounds, compositions and methods of their use
FR2329293A1 (fr) * 1975-10-29 1977-05-27 Parke Davis & Co Nouveaux nonapeptides et procedes pour leur production
SE436645C (sv) * 1976-04-29 1996-07-22 Bonnierfoeretagen Ab Antigeniskt aktiv polypeptid, som kan användas vid cancerdiagnosticering och vid framställning av antikroppar
US4059693A (en) * 1976-06-11 1977-11-22 University Patents, Inc. Analgesic action of substance P
US4087419A (en) * 1976-11-05 1978-05-02 Parke, Davis & Company Heptapeptides and methods for their production

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
JPS4876817A (fr) * 1972-01-17 1973-10-16
FR2257304A1 (fr) * 1974-01-10 1975-08-08 Becton Dickinson Co

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS vol. 72, nr. 67261r (1970) & Vest Mosk Univ Khim, 1969, 24 (6), 113 *
CHEMICAL ABSTRACTS, vol. 77, nr. 20028h (1972) & HU-A-3841 (Gyogyszerkutato Int.) *
CHEMICAL ABSTRACTS, vol. 80, nr. 48404p (1974) & JP-A-48 076 817 (Kurihara) *
CHEMICAL ABSTRACTS, vol. 82, nr. 112240c (1975) & Endocrinol. Gut 1973 103-6 *
CHEMICAL ABSTRACTS, vol. 83, nr. 43727y (1975) & J. Biol. Chem. 1975 250 (5), 1912-18 *
PETTIT "Synthetic peptides", 1971, Edit. Reinhold CO., Vol. 2, New York. Page 102. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4752601A (en) * 1983-08-12 1988-06-21 Immunetech Pharmaceuticals Method of blocking immune complex binding to immunoglobulin FC receptors
WO1986001211A1 (fr) * 1984-08-10 1986-02-27 MERCK Patent Gesellschaft mit beschränkter Haftung Agents polypeptides immunotherapeutiques
WO1996014333A1 (fr) * 1994-11-04 1996-05-17 Peptide Therapeutics Limited Peptides utilises dans les traitements anti-allergies
US5945104A (en) * 1994-11-04 1999-08-31 Peptide Therapeutics Limited Peptides for anti-allergy treatment
WO2007123467A1 (fr) 2006-04-25 2007-11-01 Livsafe Inc. Systeme de suspension de volant de direction
WO2008107506A1 (fr) 2007-03-08 2008-09-12 Universidad De Sevilla Nouveaux caramels à teneur élevée en oligosaccharides prébiotiques, procédé de préparation et utilisation

Also Published As

Publication number Publication date
DE2861593D1 (en) 1982-03-11
IE47105B1 (en) 1983-12-28
IT7850095A0 (it) 1978-06-29
JPS5416402A (en) 1979-02-07
IL54967A0 (en) 1978-08-31
IL54967A (en) 1982-03-31
DK292778A (da) 1978-12-30
IE781290L (en) 1978-12-29
ES471243A1 (es) 1979-10-01
CA1105006A (fr) 1981-07-14
ZA783699B (en) 1979-06-27
AU3762878A (en) 1980-01-03
AU522641B2 (en) 1982-06-17
NZ187638A (en) 1981-07-13
US4223016A (en) 1980-09-16
EP0000252B1 (fr) 1982-02-03

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