EP0000252B1 - Peptides, pharmaceutical compositions containing the peptides and a process for the preparation of the peptides - Google Patents

Peptides, pharmaceutical compositions containing the peptides and a process for the preparation of the peptides Download PDF

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Publication number
EP0000252B1
EP0000252B1 EP78300046A EP78300046A EP0000252B1 EP 0000252 B1 EP0000252 B1 EP 0000252B1 EP 78300046 A EP78300046 A EP 78300046A EP 78300046 A EP78300046 A EP 78300046A EP 0000252 B1 EP0000252 B1 EP 0000252B1
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EP
European Patent Office
Prior art keywords
amino acid
peptide
phe
salt
lys
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Expired
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EP78300046A
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German (de)
English (en)
French (fr)
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EP0000252A1 (en
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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    • 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 which may be used in desensitisation therapy, and to pharmaceutical compositions containing them.
  • the present invention provides a peptide or a salt thereof, characterised by containing 6 to 12 naturally occuring amino acid residues in a sequence-[-R 1 -R 2 -R 3 -], wherein, R 1 consists of a residue of a basic amino acid, optionally linked to one or more residue of a neutral non-hydrophobic amino acid and/or to one or more further residue of a basic amino acid; R 2 consists of one or more residue of a neutral non-hydrophobic amino acid; and R 3 consists of a residue of a hydrophobic amino acid, optionally linked to one or more residue of a neutral non-hydrophobic amino acid and/or to one or more further residue of a hydrophobic amino acid; the said basic amino acid residues are selected from arginyl, lysyl and ornithyl; the said neutral non-hydrophobic amino acid residues are selected from glycyl, alanyl, seryl and threonyl; and the said hydropho
  • amino acids referred to hereafter are in the L-configuration.
  • R When R is present, it is a group capable of confering on a peptide resistance to enzyme breakdown. Examples of suitable groups R are given in J. Rudinger, "The Design of Peptide Hormone Analogues", Chapter 9 in Drug Design, Volume (II) edited by E. J. Ari ⁇ ns, Academic Press, New York and London, 1971.
  • R when present, include prolyl, hydroxyprolyl, the D- form of a common amino acid residue or an amino acid residue with omission of the terminal amino group.
  • R 1 particularly suitable examples include Lys-Thr-Lys and Arg-Lys-Thr-Lys.
  • 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 is Gly-Ser-Gly.
  • R 2 consists of 1 to 5 amino acid residues, for example 3 amino acid residues.
  • R 3 include Phe-Phe and Phe-Phe-Val-Phe.
  • 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
  • Suitable C- terminal protecting groups Y include ester residues, for example residues of C 1-6 alkyl esters such as methoxy, ethoxy and t-butoxy, benzyloxy, p-nitrobenzyloxy, p-methoxybenzyloxy; residues of trimethylsilyl esters; and residues of amides, substituted amides (e.g. amides substituted by one or two C 1-6 alkyl groups, or by a C 1-6 acyl group), and hydrazino residues.
  • Preferred groups Y include hydroxyl and methoxy.
  • the peptides of the invention have 6 to 12 amino acid residues in the ⁇ R 1 -R 2 -R 3 ⁇ sequence. Preferably they have 8 to 10 amino acid residues in this sequence.
  • 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 I 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.
  • the peptides of this invention may be prepared by methods known in the art of peptide synthesis comprising the sequential coupling of the amino acids from which the peptide is derived.
  • 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 or benztriazole ester.
  • Any reactive groups in the amino acid or peptide which are not to take part in the condensation reaction should be protected by any of the N-protecting groups or carboxyl protecting groups described above which can be readily removed after the condensation.
  • 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-nitrobenzyloxycarbonyl, p-bromo-benzyloxycarbonyl, p-phenylazobenzyloxycarbonyl, p-(p'-methoxyphenylazo)-benzyloxycarbonyl and trityl groups protecting the amino end; treatment with hydrogen bromide in glacial acetic acid for benzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-phenylazobenzyloxycarbonyl and t-butyloxycarbonyl groups protecting the amino end; treatment with metallic sodium in liquid ammonia for benzyloxycarbonyl, p-bromo
  • Acid addition salts of compounds of formula (I) are included within this invention, for example the salts of pharmaceutically acceptable acids as a hydrohalide, especially the hydrochloride or hydrobromide; or the phosphate, acetate, phenylpropionate, maleate, tartrate and citrate.
  • the peptides and salts of the present invention may be employed as the active agents in desensitisation vaccines.
  • Such vaccines are well known to those skilled in the art and comprise a sterile liquid vehicle in which the active agent is dissolved or suspended. If suspended, the particles of active agent should be small enough not to block the orifice of an injection needle.
  • Certain adjuvants such as tyrosine are often included in such vaccine compositions and are believed to provide a support and prolonged slow release of active material in vivo.
  • a patient receiving treatment with such desensitisation vaccines is administered a number of injections, spread over a period of weeks or days, each injection containing a higher concentration of active agent than the preceding one. In this way the patient is desensitised such that his allergic reaction to allergens is reduced or eliminated.
  • An alternative mode of administration for desensitisation agents is by application to the nasal mucosa as a liquid spray or as a dry powder snuff.
  • the present invention includes a pharmaceutical composition 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.
  • compositions of the invention may be administered in conventional manner for desensitisation therapy.
  • the invention also provides a peptide of the formula (I) as defined, or a salt thereof, for use in the desensitisation therapy of allergies.
  • Peptides were synthesized 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
  • the octapeptide methyl ester was prepared by a 4 + 4 fragment condensation strategy, one fragment (I) being prepared by solid phase peptide synthesis (SPPS) (according to SPPS Manual by J. M. Stewart and J. D. Young Freeman and Company, San Francisco, 1969) and the other fragment (11) by classical solution synthesis. Combination of I and II gave fully protected octapeptide (III) which on deprotection afforded the desired product (V).
  • SPPS solid phase peptide synthesis
  • This intermediate was prepared by SPPS, employing standard DCCI mediated coupling procedures using a 0.47 mM/g glycine substituted Merrifield Resin.
  • the tetrapeptide methyl ester hydrochloride was prepared by solution synthesis in six stages.
  • BOC-Phe-OSu (5.25 g, 0.0145 M) was coupled to Phe.OMe. HCL (3.13 g, 0.0145 M) in DMF (25 ml) in the presence of 1 equivalent of Et 3 N (2.03 ml) at room temperature over 3 days.
  • Partially protected octapeptide (IV) (0.10 g) was hydrogenated in 85% AcOH (70 ml) with 10% Pd/C catalyst (0.20 g) 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) (0.03 g, 46% yield). TLC examination showed 1 spot at Rf 0.2 in 5:2:2 BAW (t-BuOCI/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.
  • the decapeptide methyl ester was synthesised by a 4 + 2 + 4 fragment condensation strategy as follows:-
  • BOC.VaIOSu (15.7 g, 0.050 M) was coupled to PheOBz.pTsa (21.35 g, 0.050 M) in dioxan (200 ml) at R.T. for 41 2 hours in the presence of 1 equivalent of Et 3 N.
  • the reaction mixture was evaporated at reduced pressure and the resulting residue dissolved in EtAc and the solution washed with water, dried and evaporated in vacuo to leave a crystalline solid (21.3 g).
  • ZLys (Z)OTcp (1.80 g, 0.003 M) was coupled to compound (iv) (1.72 g, 0.003 M) in dioxan (45 ml) 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 (1.36 g, 50% yield). M.P. 185-188°.
  • the intermediate above (0.76 g, 0.0003 M) was deprotected by continuous hydrogenation in 85% acetic acid with 1N HCI (1 mM) for 18 hours in the presence of 10% Pd/charcoal (0.80 g).
  • the product was purified on a Biogel P2 column eluting with 1 M ammonium acetate and subsequently on a CM32 cellulose column eluting with 0.1 M ammonium acetate pH5. Final isolation of the product in 23% yield was by lyopholisation.
  • This decapeptide was synthesised by a 1 + 1 + 4 + 4 fragment condensation strategy as follows:- (XII) Lys(Z)Thr(Bzl)Lys(Z)GlyOMe Prepared in two steps from Thr(Bzl)Lys(Z)GlyOMe described in example 4.
  • Peptide (XIV) (0.40 g, 0.0033 M) was coupled to compound (II) (0.20 g, 0.0034 M) in DMF (5 ml) in the presence of Et 3 N (1 equivalent), DCCI (0.07 g, 0.0035 M) and hydroxybenzotriazole (0.044 g, 0.0035 M) at 5° for 1 hour then at R.T. for 1 hour.
  • the precipitated urea was filtered off and the required product (0.50 g) isolated by pouring the reaction mixture into iced water and isolating by filtration in 88% yield.
  • the intermediate above (0.40 g, 0.0022 M) was deprotected by continuous hydrogenation in 85% acetic acid for 18 hours in the presence of 10% Pd/charcoal catalyst (0.40 g).
  • the product was purified on a Biogel P2 column eluting with water and subsequently on an LH20 Sephadex column again with aqueous elution. Final isolation of the product in 34% yield was by lyopholisation.
  • the octapeptide free acid was synthesized by a 4 + 4 fragment condensation strategy as follows:
  • BOCPheOH 11.88 g, 0.045 M was coupled to PheOBz.pTsa 19.4 g, 0.045 M) 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 (14.92 g) isolated in 64% yield upon evaporation in vacuo and recrystallisation from EtOAc/80-100° petrol (14.92 g). M.P. 123.5-124.5°.
  • the peptides were capable of releasing histamine selectively from rat mast cells in vitro, and producing histamine release effects in rat and baboon skin in vivo. In the latter case in particular (primate tissue) activity was unusually high.
  • Table 2 demonstrates cross-desensitisation in rat mast cells in vitro between the peptides of Example 3 and an antigen.
  • the purified cells were washed twice in Dulbecco's incomplete (i.e. free from mineral salts) buffer and then resuspended in Dulbecco's medium to the required volume. In a typical experiment, sufficient cells were available for 30 duplicate challenges, i.e. 60 samples and in this case the resuspension volume employed was 6.1 mls. 0.1 ml of cell suspension were taken for estimating the cell count.
  • One third of the cell suspension was employed. To 0.9 ml duplicate aliquots of challenge solution, prepared in complete Dulbecco's medium and prewarmed to 37°C, was added 0.1 ml of cell suspensions. 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 0.4 N perchloric acid and allowed to stand for approximately 30 minutes at ambient centrifugation and the supernatant solutions set aside for histamine analysis.
  • 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 50-100 ⁇ 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 three 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 solution, prewarmed to 37°C. After 5 minutes' incubation the cell suspensions were removed from the water bath and the supernatants separated by centrifugation. Activity present in the whole recovered supernatants was measured using a Tracer Laboratory Spectromatic y 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 chloride solution (0.9%), or saline control were injected intradermally in 0.05 ml or 0.10 ml volumes. Skin reactions were read 20 minutes after intradermal challenge.
  • Brown Norway rats were immunised intraperitoneally with 100 ⁇ g of ovalbumen (XOA) in 1 mg '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 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)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
EP78300046A 1977-06-29 1978-06-15 Peptides, pharmaceutical compositions containing the peptides and a process for the preparation of the peptides Expired EP0000252B1 (en)

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 EP0000252A1 (en) 1979-01-10
EP0000252B1 true EP0000252B1 (en) 1982-02-03

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EP78300046A Expired EP0000252B1 (en) 1977-06-29 1978-06-15 Peptides, pharmaceutical compositions containing the peptides and a process for the preparation of the peptides

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

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US4752601A (en) * 1983-08-12 1988-06-21 Immunetech Pharmaceuticals Method of blocking immune complex binding to immunoglobulin FC receptors
EP0190127A1 (en) * 1984-08-10 1986-08-13 MERCK PATENT GmbH Immunotherapeutic polypeptide agents
US5955076A (en) * 1989-06-15 1999-09-21 Peptide Therapeutics Limited Immunoactive peptides and antibodies and their use in anti-allergy treatment
GB8913737D0 (en) * 1989-06-15 1989-08-02 Univ Birmingham A novel anti-allergy treatment
GB9422294D0 (en) * 1994-11-04 1994-12-21 Peptide Therapeutics Ltd Peptides for anti-allergy treatment
WO1997025999A1 (en) * 1996-01-16 1997-07-24 Rensselaer Polytechnic Institute Peptides for altering osteoblast adhesion
KR100498198B1 (ko) 1996-03-01 2005-09-09 노파르티스 아게 알레르기에 대한 백신접종 및 치료를 위한 펩티드 임뮤노겐
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
US7425020B2 (en) 2006-04-25 2008-09-16 Mats Lindkvist Steering wheel suspension system
ES2304223B2 (es) 2007-03-08 2009-05-01 Universidad De Sevilla Nuevos caramelos con elevado contenido en oligosacaridos prebioticos, procedimiento de preparacion y utilizacion.

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JPS5257177A (en) * 1975-10-29 1977-05-11 Parke Davis & Co Production of novel nonapeptide
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Publication number Publication date
IE781290L (en) 1978-12-29
IL54967A (en) 1982-03-31
ES471243A1 (es) 1979-10-01
ZA783699B (en) 1979-06-27
IE47105B1 (en) 1983-12-28
CA1105006A (en) 1981-07-14
NZ187638A (en) 1981-07-13
AU522641B2 (en) 1982-06-17
DK292778A (da) 1978-12-30
DE2861593D1 (en) 1982-03-11
US4223016A (en) 1980-09-16
JPS5416402A (en) 1979-02-07
EP0000252A1 (en) 1979-01-10
IL54967A0 (en) 1978-08-31
AU3762878A (en) 1980-01-03
IT7850095A0 (it) 1978-06-29

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