EP0000053B1 - Analogues de la somatostatine, procédé pour leur préparation et des compositions pharmaceutiques les contenant - Google Patents

Analogues de la somatostatine, procédé pour leur préparation et des compositions pharmaceutiques les contenant Download PDF

Info

Publication number
EP0000053B1
EP0000053B1 EP78100095A EP78100095A EP0000053B1 EP 0000053 B1 EP0000053 B1 EP 0000053B1 EP 78100095 A EP78100095 A EP 78100095A EP 78100095 A EP78100095 A EP 78100095A EP 0000053 B1 EP0000053 B1 EP 0000053B1
Authority
EP
European Patent Office
Prior art keywords
phe
tyr
thr
peptide
resin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP78100095A
Other languages
German (de)
English (en)
Other versions
EP0000053A1 (fr
Inventor
Daniel Frank Veber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co 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 Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0000053A1 publication Critical patent/EP0000053A1/fr
Application granted granted Critical
Publication of EP0000053B1 publication Critical patent/EP0000053B1/fr
Expired legal-status Critical Current

Links

Classifications

    • 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
    • C07K14/655—Somatostatins
    • C07K14/6555—Somatostatins at least 1 amino acid in D-form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • 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
    • Y10S930/16—Somatostatin; related peptides

Definitions

  • Somatostatin is a tetradecapeptide having the structure: and has the properties of inhibiting the release of growth hormone, inhibiting the release of insulin and glucagon and reducing gastric secretion. This lack of specificity of the biological activity of somatostatin has led to an intensive search for analogs which exhibit a more specific biological activity. Somatostatin itself has a short duration of action because it is inactivated, inter alia, by aminopeptidases and carboxypeptidases present in vivo. This problem of the short duration of action has been partially solved in the prior art by preparing derivatives of somatostatin which have low solubility, thus attaining a slow release on subcutaneous injection.
  • the derivatives are no more stable to inactivation by aminopeptidases and carboxypeptidases than somatostatin itself.
  • the present invention provides somatostatin analogs having no material affect on gastric secretion and a longer duration of action and a novel method for preparing said analogs.
  • the present invention further provides somatostatin analogs which are easier to prepare because they contain only 26 atoms in the peptide backbone.
  • This invention is concerned with novel somatostatin analogs having a more specific biological activity and duration of activity than naturally occurring somatostatin and which are easier to prepare because of the smaller ring size and having the structural formula: wherein
  • the preferred somatostatin analogs of the present invention are illustrated by the following structural formula: and the pharmaceutically acceptable non-toxic acid addition salts thereof.
  • acid addition salts are hydrochloride, hydrobromide, sulfate, phosphate, maleate, acetate, citrate, benzoate, succinate, malate, ascorbate and the like.
  • the somatostatin analogs of the present invention differ from somatostatin by virtue of the fact that they lack an N-terminal amino group and a C-terminal carboxyl group thus eliminating the groups involved in enzymic cleavage of the molecule by aminopeptidases and carboxypeptidases. Furthermore, the deletion of the adjacent heteroatoms of the disulfide bridge of somatostatin increases the stability of the analogs in vivo by preventing enzymatic degradation by reductive cleavage. Therefore, the analogs of the present invention are more resistent to cleavage in vivo than somatostatin and thus have a prolonged duration of action.
  • Somatostatin is a tetradecapeptide having the structure: The portion of somatostatin extending from amino acid Cys 3 to Cys' 4 forms a dodecapeptide of the following structure: The peptide backbone and the disulfide bridge consist of a continuous 38 atom ring.
  • the present invention provides somatostatin analogs wherein the Ala'-Gly 2 , Lys 4 -Asn 5 , Thr 12- Ser 13 and the amino groups of Cys 3 and carboxyl group of Cys 14 are deleted.
  • the disulfide atoms of the cystine, -S-S- have been replaced by the dicarba group, ⁇ CH 2 ⁇ CH 2 .
  • the present invention provides somatostatin analogs wherein amino acids 6 and 11 are bridged by 7-aminoheptanoic acid.
  • the resulting ring contains 26 atoms.
  • the somatostatin analogs of the present invention include those wherein Phe 6 is replaced by Tyr or O-Me-Tyr; Phe 7 is replaced by Tyr; Trp 8 is replaced by D-Trp and Thr'° is replaced by Val.
  • the novel somatostatin analogs are prepared by cyclizing corresponding linear peptides.
  • the linear peptides are prepared by using the solid phase sequencial synthesis technique.
  • the process for preparing the somatostatin analogs of the present invention comprises a) preparing a corresponding blocked linear peptide attached to a solid phase resin; b) selectively deblocking the N-terminal amine group;.c) removing the linear peptide from the resin; d) treating the linear peptide with a cyclizing agent to obtain the cyclic peptide; and e) removing the remaining blocking groups.
  • linear peptide When the linear peptide is prepared on the resin, it is not critical which amino acid is selected to be at the C-terminal position provided only that the sequence of amino acids in the linear peptide corresponds to that in the desired somatostatin analog. Once a linear peptide has been cyclized one can no longer determine which amino acid was at the C-terminus of the linear peptide. As an example to illustrate this, either of the two following linear peptides, when cyclized, will give the identical somatostatin analog: or
  • the synthesis of the linear peptides by the solid phase technique is conducted in a stepwise manner on chloromethylated resin.
  • the resin is composed of fine beads (20-70 microns in diameter) of a synthetic resin prepared by copolymerization of styrene with 1 to 2 percent divinylbenzene.
  • the benzene rings in the resin are chloromethylated in a Friedel-Crafts reaction with chloromethyl methyl ether and stannic chloride. The Friedel-Crafts reaction is continued until the resin contains 0.5 to 5 mmoles of chlorine per gram of resin.
  • the amino acid selected to be the C-terminal amino acid of the linear peptide is converted to its amino protected derivative.
  • the carboxyl group of the selected C-terminal amino acid is bound covalently to the insoluble polymeric resin support, as for example, as the carboxylic ester of the resin-bonded benzyl chloride present in chloromethyl-substituted polystyrene-divinylbenzene resin.
  • the amino protected derivative of the next amino acid in the sequence is added along with a coupling agent, such as dicyclohexylcarbodiimide.
  • the amino acid reactant may be employed in the form of a carboxyl-activated amino acid such as the ONp ester, an amino acid azide, and the like. Deprotection and addition of successive amino acids is performed until the desired linear peptide is formed.
  • protecting groups are, in part, dictated by particular coupling conditions, in part by the amino acid and peptide components involved in the reaction.
  • Amino-protecting groups ordinarily employed include those which are well known in the art, for example, urethane protecting substituents such as benzyloxycarbonyl (carbobenzoxy), p-methoxy- carbobenzoxy, p-nitrocarbobenzoxy, t-butyloxycarbonyl, and the like. It is preferred to utilize t-butyloxycarbonyl (BOC) for protecting the a-amino group in the amino acids undergoing reaction at the carboxyl end of said amino acid.
  • BOC t-butyloxycarbonyl
  • the BOC protecting group is readily removed following such coupling reaction and prior to the subsequent step by the relatively mild action of acids (i.e., trifluoro acetic acid, or hydrogen chloride in ethyl acetate).
  • the -OH group of Thr can be protected by the Bzl group and the E -amino group of Lys can be protected by the INOC group or the 2-chlorobenzyloxycarbonyl (2-Cl-CBZ) group.
  • the E -amino group with 2-Cl-CBZ group it is preferred to protect the E -amino group with 2-Cl-CBZ group as this group is removed simultaneously with the Bzl groups by treatment with HF after the linear peptide has been cyclized.
  • the INOC group is not removed by HF and requires an additional treatment with Zn. Neither group is affected by TFA, used for removing BOC protecting groups.
  • the linear peptide may be removed from the resin by a variety of methods which are well known in the art.
  • the peptide may be cleaved from the resin with hydrazine and thus directly form the peptide hydrazide which may be subsequently cyclized via the azide to the desired cyclic peptide.
  • the hydrazide is converted to the corresponding azide by reaction with a reagent which furnishes nitrous acid in situ.
  • Suitable reagents for this purpose include a lower alkyl nitrite (e.g.
  • t-butyl nitrite, isoamyl nitrite) or an alkali metal nitrite salt e.g., sodium nitrite, potassium nitrite
  • a strong acid such as hydrochloric, phosphoric, sulfonic, etc.
  • This reaction is carried out in the presence of either water and/or a non-aqueous solvent such as dimethylformamide, tetrahydrofuran, dioxane, chloroform, methylene chloride, etc., at a temperature between about -40°C and +20°C.
  • the peptide may be removed from the resin by treatment with a lower alcohol such as methanol in the presence of an organic base such as triethylamine, thus resulting in the formation of the corresponding lower alcohol ester of the linear hexapeptide.
  • a lower alcohol such as methanol
  • an organic base such as triethylamine
  • the resulting compound may be converted to the azide via the hydrazide which may then be cyclized to the desired cyclic peptide.
  • the preferred method in the present invention is the use of hydrazine.
  • one preferred overall procedure for preparing the desired cyclic peptides of the present invention involves the stepwise synthesis of the linear peptide on a solid phase resin. More specifically, in the process for preparing cyc/o(Aha-Phe-Phe-D-Trp-Lys-Thr-Phe), the carboxyl end of the N-blocked amino acid phenylalanine is bound covalently to an insoluble polymeric resin support as the carboxylic acid ester of the resin-bonded benzyl chloride. The amino group of Phe is protected by the BOC group. After the attachment of the Phe is completed on the resin, the protecting group BOC is removed by treatment with TFA in CH 2 CL 2 .
  • the subsequent amino acids are attached, in the form of BOC-amino acid, using DCCI as the condensing agent or an active ester such as ONp.
  • DCCI condensing agent
  • an active ester such as ONp.
  • the N-terminal amino group is selectively deblocked and the peptide is removed from the resin by treatment with hydrazine.
  • the resulting linear peptide hydrazide with the N-terminal amino group deblocked having the amino acid sequence: D-Trp-( ⁇ -2-CI-CBZ)Lys-(O-Bzl)Thr-Phe-Aha-Phe-Phe-NH ⁇ NH 2 is treated with isoamyl nitrite in acid pH to form the corresponding azide.
  • the azide solution is diluted with solvent and neutralized with an organic base.
  • the linear peptide cyclizes to form cyclo[Aha-Phe-Phe-D-Trp-( ⁇ -2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe].
  • the "pH” is checked and maintained at neutral by the addition of organic base.
  • the "pH” in organic solvent is determined by the application of an aliquot of the solution to narrow range pH paper.
  • Step a) Preparation of D-Trp-( ⁇ -2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe Aha-Phe-Phe-O-CH 2 - ⁇ -Resin
  • Chloromethyl resin (2% cross-linked Merrifield resin), 862.0 g. (2.37 moles), having 2.75 meq. chlorine/g., and 607.0 g. (2.37 moles, 1 equivalent) of BOC-Phe were added to 4320 ml. of peroxide- free tetrahydrofuran. The mixture was stirred in an oil bath at 80°C. bath temperature for 45 minutes. Triethylamine, 310.0 ml., was added and the reaction mixture stirred at 80°C. bath temperature for 70 hours, cooled to 25°C. and transferred to a stirred solid phase reaction column with 2000 ml. of tetrahydrofuran.
  • BOC-Phe-O-CH 2 - ⁇ -resin (2.84 g.; 2.0 mmole) was carried through the procedures in Tables III and IV using 2 deblockings (2 minutes and 25 minutes) with 25% TFA in methylene chloride, and 2.5 equivalents of BOC-amino acid in the required sequence until the desired BOC-octapeptide-O-CH2- ⁇ - resin was obtained.
  • DCCI was used as the coupling agent in every step except the coupling of BOC-Phe-to Aha-Phe-Phe-O-CH 2 - ⁇ -resin in which case the coupling was carried out in the presence of DCCI and 1-hydroxybenzotriazole monohydrate (HBT. H 2 0).
  • the coupling reactions were carried out in methylene chloride, freshly degassed DMF or a mixture of these two solvents.
  • the N-terminal amino group was blocked with a BOC group in each case; the hydroxy group of Thr was blocked with Bzl and the e-amino group of Lys with 2-Cl-CBZ.
  • Step b) ⁇ Preparation of D-Trp-( ⁇ -2-Cl ⁇ CBZ)-Lys-(O-Bz)Thr-Phe Aha-Phe-Phe-NH-NH 2
  • Step cJ Preparation of D-Trp-( ⁇ -2-Cl-CBZ-)Lys-(O-Bzl)Thr-Phe-Aha-Phe-Phe-N 3
  • Step d) Preparation of Cyclo[Aha-Phe-Phe-D-Trp-( ⁇ -2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe)
  • Step f) Purification of Cyclo(Aha-Phe-Phe-D-Trp-Lys-Thr-Phe)
  • the somatostatin analogs of the present invention and the non-toxic pharmaceutically acceptable salts thereof are useful in humans and animals for inhibiting growth hormone release as in the treatment of acromegaly, inhibiting the release of glucagon and alone or in conjunction with insulin, for lowering blood glucose as in the treatment of diabetes with reduced gastrointestinal side effects.
  • the number and size of daily doses and the time of administration are determined by an individual study of each subject. The method of determining these factors is known to those skilled in the art.
  • the somatostatin analogs described herein may be administered to warm blooded animals, including humans, either intravenously, subcutaneously, intramuscularly or orally.
  • the contemplated dose range for oral administration in tablet or capsule form to large mammals is about 0.001 mg. to about 7 mg./kg. of body weight per day.
  • These somatostatin analogs are preferably administered by injection.
  • a therapeutically effective amount of an analog is ordinarily supplied at a dosage level of from about 0.001 mg. to about 2 mg./kg. of body weight.
  • the range is from about 0.00142 mg. to about 0.428 mg./kg. of body weight administered by intravenous infusion or by subcutaneous injection.
  • the required dosage will vary with the particular condition being treated, the severity of the condition and the duration of treatment.
  • the tablet may contain: a binder such as gum tragacanth, corn starch, gelatin, an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, and alginic acid; a lubricant such as magnesium stearate; and a sweetening and/or flavoring agent such as sucrose, lactose and wintergreen.
  • a binder such as gum tragacanth, corn starch, gelatin, an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, and alginic acid
  • a lubricant such as magnesium stearate
  • a sweetening and/or flavoring agent such as sucrose, lactose and wintergreen.
  • suitable liquid carriers for intravenous administration include sterile water, isotonic saline and phosphate buffer solutions or other pharmaceutically acceptable injectable carriers.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biophysics (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Toxicology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nutrition Science (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (4)

1. Composés de formule:
Figure imgb0023
dans laquelle
A représente Phe, Tyr, O-Me-Tyr
B représente Phe, Tyr
C représente Thr, Val,

le cycle formé par le squelette de peptide contenant 26 atomes, et leurs sels formés par addition avec des acides non toxiques acceptables pour l'usage pharmaceutique.
2. Le composé selon la revendication 1, répondant à la formule:
Figure imgb0024
3. Le procédé de préparation des peptides répondant à la formule:
Figure imgb0025
dans laquelle
A représente Phe, Tyr, O-Me-Tyr
B représente Phe, Tyr
C représente Thr, Val

qui comprend:
a) la préparation d'un peptide linéaire correspondant bloqué fixé sur une résine en phase solide dans lequel, lorsque C représente Thr, le groupe -OH de Thr est bloqué par Bzl; le groupe epsilon- amino de Lys est bloqué par 2-CI-CBZ et le groupe amino sur l'azote terminal est bloqué par BOC;
b) l'élimination sélective du groupe BOC du groupe amino sur l'azote terminal;
c) le traitement du peptide linéaire par le nitrile d'isoamyle à pH acide, conduisant à l'azide correspondant; la dilution et la neutralisation de la solution de l'azide donnant le peptide cyclique correspondant, et
e) le traitement du peptide cyclique par HF en vue d'éliminer simultanément les groupes bloquant Bzl et 2-CI-CBZ.
4. Une composition comprenant une quantité thérapeutique efficace des peptides possédant la structure:
Figure imgb0026
dans laquelle
A représente Phe, Tyr, O-Me-Tyr,
B représente Phe, Tyr,
C représente Thr, Val,

dans lequel le cycle formé par le squelette de peptide contient 26 atomes, et des sels de ces composés formés par addition avec des acides non toxiques acceptables pour l'usage pharmaceutique dans un excipient acceptable pour l'usage pharmaceutique.
EP78100095A 1977-06-08 1978-06-06 Analogues de la somatostatine, procédé pour leur préparation et des compositions pharmaceutiques les contenant Expired EP0000053B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US80467877A 1977-06-08 1977-06-08
US804678 1977-06-08

Publications (2)

Publication Number Publication Date
EP0000053A1 EP0000053A1 (fr) 1978-12-20
EP0000053B1 true EP0000053B1 (fr) 1981-05-27

Family

ID=25189555

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100095A Expired EP0000053B1 (fr) 1977-06-08 1978-06-06 Analogues de la somatostatine, procédé pour leur préparation et des compositions pharmaceutiques les contenant

Country Status (7)

Country Link
US (1) US4146612A (fr)
EP (1) EP0000053B1 (fr)
JP (1) JPS543085A (fr)
DE (1) DE2860734D1 (fr)
DK (1) DK252778A (fr)
IE (1) IE47421B1 (fr)
IT (1) IT1105131B (fr)

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LU78191A1 (de) * 1977-09-28 1979-05-25 Ciba Geigy Ag Verfahren zur herstellung von neuen cyclopeptiden
US4190648A (en) * 1979-03-13 1980-02-26 Merck & Co., Inc. Peptides having somatostatin activity
NZ195303A (en) * 1979-10-31 1984-10-19 Merck & Co Inc Cyclic hexapeptide somatostatin analogues,and pharmaceutical compositions
EP0031303A3 (fr) * 1979-12-21 1981-11-04 Ciba-Geigy Ag Cyclooctapeptides et leurs préparations pharmaceutiques, procédé pour leur préparation et leur application
US4508711A (en) * 1983-04-18 1985-04-02 American Cyanamid Company Cyclic pentapeptide displaying somatostatin antagonism and method of treatment of mammals therewith
DE3845000C2 (de) * 1987-07-10 1998-11-19 Novartis Ag Anwendung von Octreotid zur Behandlung von Brustkrebs
ZW11290A1 (en) * 1989-07-14 1990-10-31 Smithkline Beecham Corp Hemoregulatory peptides
DE69020722T2 (de) * 1989-11-08 1996-01-18 Daicel Chem Peptide und verfahren zur herstellung von zyklischen peptiden.
US6001960A (en) * 1992-09-01 1999-12-14 The Trustees Of The University Of Pennsylvania Synthetic somatostatin mimics
US5700905A (en) * 1992-09-01 1997-12-23 The Trustees Of The University Of Pennsylvania Synthetic somatostatin mimics
US5965694A (en) * 1992-09-01 1999-10-12 The Trustees Of The University Of Pennsylvania Somatostatin mimics and synthetic methods therefor
US5504069A (en) * 1993-02-11 1996-04-02 Biomeasure, Inc. Inhibition of trauma-induced tumor growth
DE4342907A1 (de) * 1993-12-16 1995-06-22 Bayer Ag Neue cyclische Depsipeptide mit 18 Ringatomen und ihre Verwendung zur Bekämpfung von Endoparasiten
US6506174B1 (en) * 1994-11-03 2003-01-14 The Saunders Group, Inc. Portable traction device
US5597894A (en) * 1995-06-05 1997-01-28 The Louisiana State University Medical Center Foundation Multi-tyrosinated somatostatin analogs
ES2216290T3 (es) * 1997-05-13 2004-10-16 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. Somatostatina y agonistas de la somatostatina para el tratamiento de insensibilidad a la insulina y de sindrome x.
US6004928A (en) * 1997-05-13 1999-12-21 Biomeasure, Incorporated Method of treating hyperlipidemia
AU7655098A (en) * 1997-05-13 1998-12-08 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Somatostatin and somatostatin agonists for decreasing body weight
US7026289B2 (en) * 1997-05-13 2006-04-11 Societe De Conseils De Recherches Et D'applications Scientifiques, Sas Method and compositions for treating hyperlipidemia and other conditions
US5968903A (en) * 1998-05-07 1999-10-19 Biomeasure, Incorporated Inhibition of H. pylori proliferation
US6171273B1 (en) 1999-08-06 2001-01-09 The Saunders Group, Inc. Self-seating occiput wedge system for applying a therapeutic traction force
JP3996897B2 (ja) 2001-06-08 2007-10-24 ソシエテ・ドゥ・コンセイユ・ドゥ・ルシェルシュ・エ・ダプリカーション・シャンティフィック・エス・ア・エス ソマトスタチン−ドーパミンキメラ類似体
US7189214B1 (en) 2002-01-22 2007-03-13 The Saunders Group, Inc. Multi-axis cervical and lumbar traction table
US20040145462A1 (en) * 2003-01-29 2004-07-29 Honda Giken Kogyo Kabushiki Kaisha Variable electronic display apparatus for a vehicle, and method of using same
NZ564694A (en) 2003-04-22 2009-11-27 Sod Conseils Rech Applic Peptide vectors
JP5799397B2 (ja) 2008-06-12 2015-10-28 イプセン・バイオイノベーション・リミテッドＩｐｓｅｎ Ｂｉｏｉｎｎｏｖａｔｉｏｎ Ｌｉｍｉｔｅｄ 癌の抑制
CA2727082C (fr) 2008-06-12 2019-02-26 Syntaxin Limited Proteines de fusion destinees a la suppression de l'acromegalie
GB0820970D0 (en) 2008-11-17 2008-12-24 Syntaxin Ltd Suppression of cancer

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US781610A (en) * 1904-01-11 1905-01-31 Winfield S Livengood Wagon-brake.
US3904594A (en) * 1973-07-02 1975-09-09 Salk Inst For Biological Studi Somatostatin and acylated des-(ala' 1', gly' 2') derivatives thereof
US3882098A (en) * 1974-01-03 1975-05-06 American Home Prod Synthesis of des-Ala{hu 1{b , Gly{hu 2{b , Asn{hu 5{b -SRIF and intermediates
DE2460469A1 (de) * 1974-12-20 1976-07-01 Hoechst Ag Neue peptide mit biologischer wirkung und verfahren zu ihrer herstellung
US3933784A (en) * 1975-01-27 1976-01-20 American Home Products Corporation Des-(ser13)-srif and intermediates
US4011182A (en) * 1975-03-21 1977-03-08 American Home Products Corporation Cyclic undecapeptide analogs of somatostatin and intermediates
CA1083143A (fr) * 1976-01-02 1980-08-05 Nedumparambil A. Abraham Derives carba de la somatostatine et procede de preparation

Also Published As

Publication number Publication date
IT7849736A0 (it) 1978-06-06
IE781151L (en) 1978-12-08
US4146612A (en) 1979-03-27
JPS543085A (en) 1979-01-11
IT1105131B (it) 1985-10-28
IE47421B1 (en) 1984-03-07
EP0000053A1 (fr) 1978-12-20
DK252778A (da) 1978-12-09
DE2860734D1 (en) 1981-09-03

Similar Documents

Publication Publication Date Title
EP0000053B1 (fr) Analogues de la somatostatine, procédé pour leur préparation et des compositions pharmaceutiques les contenant
US4191754A (en) Bicyclic somatostatin analogs
Cai et al. Synthesis and biological activity of highly potent octapeptide analogs of somatostatin.
US4310518A (en) Cyclic hexapeptide somatostatin analogs
EP0017746B1 (fr) Peptides à activité analogue à la somatostatine, compositions les contenant et procédé pour la fabrication des peptides
US4235886A (en) Cyclic hexapeptide somatostatin analogs
EP0143307B1 (fr) Hexapeptides cycliques analogues au somatostatin, procédé de leur préparation et compositions pharmaceutiques les contenant
US4238481A (en) Novel cyclopeptides
EP0063308B1 (fr) D-rétro hexapeptides cycliques modifiés, analogues de somatostatine, leur procédé de préparation et compositions thérapeutiques les contenant
EP0000919B1 (fr) Analogues de somatostatine, leur procédé de préparation et leur utilisation comme produits pharmaceutiques.
EP0002264B1 (fr) Analogues de la somatostatine, leur procédé de préparation et leur composition pharmaceutique
US4486415A (en) Cyclic hexapeptide somatostatin analogs
KR100629013B1 (ko) Ｉｇｆ-ⅰ 및 -ⅱ를 억제하는 ｇｈ-ｒｈ의 길항 유사체
US4703034A (en) Novel cyclic tetrapeptide
US4162248A (en) Somatostatin analogs
EP0206118B1 (fr) Analogues des hexapeptides cycliques de somatostatine, leur procédé de préparation et compositions pharmaceutiques les contenant
EP0029310B1 (fr) Hexapeptides cycliques analogues à la somatostatine, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0002262B1 (fr) Analogues de la somatostatine et leur procédé de préparation
EP0104348A2 (fr) Héxapeptides cycliques fluorés analogues de somatostatine, leur procédé de préparation, les intermédiaires servant à leur préparation et les compositions pharmaceutiques les contenant
EP0113029B1 (fr) Hexapeptides dicycliques, leur procédé de préparation et leurs compositions pharmaceutiques
US4159263A (en) (D-Ala5)-somatostatin and analogues thereof
IE46462B1 (en) Somatostatin peptide analogues
JPS636560B2 (fr)
IE47454B1 (en) Somatostatin analogs

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): BE CH DE FR GB LU NL SE

17P Request for examination filed
GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): BE CH DE FR GB LU NL SE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19810630

REF Corresponds to:

Ref document number: 2860734

Country of ref document: DE

Date of ref document: 19810903

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19820322

Year of fee payment: 5

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 19820331

Year of fee payment: 5

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 19820525

Year of fee payment: 5

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19820630

Year of fee payment: 5

Ref country code: NL

Payment date: 19820630

Year of fee payment: 5

Ref country code: DE

Payment date: 19820630

Year of fee payment: 5

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19830301

Year of fee payment: 6

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Effective date: 19830606

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19830607

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19840101

GBPC Gb: european patent ceased through non-payment of renewal fee
NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19840229

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19840301

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Effective date: 19840630

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19881117

EUG Se: european patent has lapsed

Ref document number: 78100095.5

Effective date: 19850610

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT