EP0000919B1 - Somatostatin ähnliche Verbindungen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel. - Google Patents

Somatostatin ähnliche Verbindungen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel. Download PDF

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Publication number
EP0000919B1
EP0000919B1 EP78100673A EP78100673A EP0000919B1 EP 0000919 B1 EP0000919 B1 EP 0000919B1 EP 78100673 A EP78100673 A EP 78100673A EP 78100673 A EP78100673 A EP 78100673A EP 0000919 B1 EP0000919 B1 EP 0000919B1
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Prior art keywords
phe
pro
thr
lys
bzl
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French (fr)
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EP0000919A1 (de
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Daniel Frank Veber
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Merck and Co Inc
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Merck and Co Inc
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    • 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
    • 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

  • the present invention concerns novel somatostatin analogs having a more potent biological activity and a longer duration of action than naturally occurring somatostatin.
  • Somatostatin is a tetradecapeptide having the structure:
  • Somatostatin has the properties of inhibiting the release of growth hormone, inhibiting the release of insulin and glucagon and reducing gastric secretion.
  • 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. Once dissolved, however, the derivatives are no more stable to inactivation by aminopeptidases and carboxypeptidases than somatostatin itself.
  • cyclic undecapeptides having a bridging group comprising 1 to 5 -CH 2 -groups.
  • Said cyclic peptides differ from the inventive somatostatin analogs in that they have the conventional 5-Asn and 13-Ser groups.
  • the present invention provides somatostatin analogs having higher biological activities and a longer duration of action than somatostatin and a novel method for preparing said analogs.
  • This invention is concerned with novel somatostatin analogs having a more potent biological activity and a longer duration of action than naturally occurring somatostatin having the structural formula: wherein
  • Still further preferred somatostatin analogs are those having the structural formulas: and 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 acid addition salts can be conveniently prepared by dissolving the above novel compounds in water, adding two equivalents of appropriate acid and freeze drying.
  • the somatostatin analogs of the present invention differ from somatostatin by virtue of the fact that at least one of positions 5 and 13 is substituted with Pro.
  • Peptidases are believed to preferentially cleave peptide amide bonds wherein the amide is formed from a primary amino acid, i.e., only one substituent on the a-nitrogen atom such as Phe and Ser.
  • Peptide amide bonds wherein the amide is formed from a secondary amino acid, i.e., proline are. resistant to cleavage by peptidases. Accordingly, the present invention provides novel active somatostatin analogs which have prolonged activity and increased potency believed to be due to resistance to peptidases.
  • the present novel somatostatin analogs lack an N-terminal amino group thus eliminating the group involved in enzymic cleavage of the molecule by aminopeptidases. Furthermore, the deletion of the adjacent heteroatoms of the disulfide bridge of somatostatin increases the stability of the analogs in vivo by slowing down enzymatic degradation by reductive cleavage. Therefore, the analogs of the present invention are more resistant 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 Cys 3 to Cys 14 forms a dodecapeptide of the following structure: The peptide backbone and the disulfide bridge form a 38 atom ring.
  • the present invention includes somatostatin analogs wherein the Ala 1- Gly 2 and the amino group of Cys 3 are deleted. Furthermore, the disulfide atoms of the cystine, -S-S-, have been replaced by the dicarba group, -CH 2 -CH 2 -. Whereas, in somatostatin positions 3 and 14 are bridged by cystine, the present invention provides somatostatin analogs wherein positions 3 and 14 are bridged by 7-aminoheptanoic acid or D- or L- ⁇ -aminosuberic acid.
  • the somatostatin analogs of the present invention include those wherein Asn 5 is deleted or replaced by a-aminobutyric acid, Pro or Ala; Phe 7 is replaced by Tyr; Trp 8 is replaced by D-Trp and Thr 10 and 12 are independently replaced by Val; and Ser 13 is replaced by Pro, Ala or Gly.
  • the novel somatostatin analogs are prepared by cyclizing corresponding linear peptides.
  • the linear peptides are prepared by using the solid phase sequential 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 alalog: 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 divinyl-benzene.
  • 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-divinyl-benzene 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 and Ser 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-CI-CBZ) group.
  • the E -amino group with 2-CI-CBZ group it is preferred to protect the E -amino group with 2-CI-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 or catalytic hydrogenation. 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 undecapeptide.
  • the resulting ester may be converted to the hydrazide which may then be cyclized, via- the azide, to the desired cyclic peptide.
  • the preferred method for cleaving the peptide from the resin 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 soiid phase resin. More specifically, in the process for preparing cyclo(Aha-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro), the caboxyl 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 linear peptide cyclizes to form cyclo[Aha-( ⁇ -2-Cl-CBZ)Lys-Asn-Phe-Phe-D-Trp-( E -2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe-(O-Bzl)Thr-Prol.
  • 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 moistened narrow range pH paper.
  • Step a) Preparation of BOC-D-Trp-( ⁇ 2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe-(O-Bzl)Thr-Pro-Aha-( ⁇ -2-Cl-CBZ)Lys-Asn-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. After removal of the solvent, the resin was washed using the stirred column with:
  • BOC-Phe-O-CH 2 - ⁇ -resin (2.13 g.; 2.0 mmole) was carried through the procedures in Tables III and IV using 2 d'eblockings (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-undecapeptide-O-CH 2 - ⁇ -resin was obtained.
  • DCCI was used as the sole coupling agent in every remaining step except the coupling of BOC-Pro to Aha-( ⁇ -2-Cl-CBZ)Lys-Asn-Phe-Phe-O-CH 2 - ⁇ -resin in which case the coupling was carried out in the presence of DCCI and 1-hydroxybenzotriasole monohydrate (HBT.H Z O).
  • 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-CI-CBZ.
  • Step bj Preparation of D-Trp-( ⁇ -2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe-(O-Bzl)Thr-Pro-Aha-( ⁇ -2-Cl-CBZ)Lys-Asn-Phe-Phe-NH-NH 2
  • the semi-solid residue was triturated with 60 ml. ether to obtain a solid.
  • the solid was collected by filtration, slurried with ether 3 x 20 ml. and dried in vacuo for 20 min. to yield 3.89 g. crude product.
  • the solid was slurried with 4 x 30 ml. water to remove all traces of formylhydrazide and dried in vacuo overnight to give 3.02 g. of product.
  • Step c) Preparation of D-Trp-( ⁇ -2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe-(O-Bzl)Thr-Pra-Aha-( ⁇ -2-Cl-CBZ)Lys-Asn-Phe-Phe-N 3
  • Step d) Preparation of Cyclo[Aha;( ⁇ -2-Cl-CBZ)Lys-Asn-Phe-Phe-D-Trp-( ⁇ -2-Cl-CBZ)Lys-(O-Bzl)-Thr-Phe-(O-Bzl)Thr-Pro]
  • Step f) Purification of Cyc/o(Aha-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro)
  • Step a) Preparation of D-Trp-( ⁇ -2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe-(O-Bzl)Thr-(O-Bzl)Ser-Aha-( ⁇ -2-Cl-CBZ)Lys-Pro-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. After removal of the solvent, the resin was washed using the stirred column with:
  • BOC-Phe-O-CH 2 - ⁇ -resin (2.31 g.; 2.0 mmoles) was carried through the procedures in Tables III of Example 1 and Table VI 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- undecapeptide-O-CH 2 - ⁇ -resin was obtained.
  • DCCI was used as the coupling agent in every step. The coupling of each amino acid proceeded smoothly. Best yields were obtained when the coupling was repeated in each step. When the coupling was repeated, the initial two chloroform washes, the deblocking step and the succeeding three chloroform washes were all omitted and replaced by a single chloroform wash.
  • the coupling reactions were carried out in methylene chloride, or a mixture of freshly degassed DMF and methylene chloride.
  • the N-terminal amino group was blocked with a BOC group in each case; the hydroxy group of Thr and Ser was blocked with Bzl and the E -amino group of Lys with 2-CI-CBZ.
  • An acid hydrolysate showed the following amino acid composition:
  • Step b) Preparation of D-Trp-( ⁇ -2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe(O-Bzl)Thr-(O-Bzl)Ser-Aha-( ⁇ -2-CBZ)Lys-Pro-Phe-Phe-NH-NH,
  • Step c) Preparation of D-Trp-( ⁇ -2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe(O-Bzl)Thr-(O-Bzl)Ser-Aha-( ⁇ -2-Cl-CBZ)Lys-Pro-Phe-Phe-N 3
  • Step d) Preparation of Cyclo[(O-Bzl)Thr-(O-Bzl)Ser-Aha-( ⁇ -2-Cl-CBZ)Lys-Pro-Phe-Phe-D-Trp-( ⁇ -2-Cl-CBZ)Lys-(O-Bzl)Thr-Phe]
  • An acid hydrolysate showed the following amino acid composition:
  • Step e) Preparation of Cyc/o(Aha-Lys-Pro-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser)
  • Step fl Purification of Cyclo(Aha-Lys-Pro-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser)
  • 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. They are useful for inhibiting the release of glucagon and alone or in conjunction with insulin, for lowering blood glucose as in the treatment of diabetes. They inhibit the release of gastric secretions and are useful as in the treatment of gastric ulcers.
  • 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.

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Claims (4)

1. Verbindungen mit der Formel:
Figure imgb0029
worin
R H, COOH ist
A (Asn)n, a-Abu, Pro, Ala, worin n = 0 oder 1, ist
B Phe, Tyr ist
C und D unabhängig Thr, Val sind,
E Ser, Pro, Ala, Gly ist,

worin mindestens eines von A und E Pro ist und der Ring, der durch das Peptidgerüst gebildet wird, 35 oder 38 Atome enthält, und pharmazeutisch brauchbare nicht-toxische Säureadditionssalze davon.
2. Verbindung nach Anspruch 1, worin
R H ist,
A Asn, Pro ist,
B Phe ist,
C und D Thr sind,
E Ser, Pro ist,

worin mindestens eines von A und E Pro ist.
3. Verfahren zur Herstellung der Peptide mit der Formel:
Figure imgb0030
worin
R H, COOH ist,
A (Asn)n, α-Abu, Ala, worin n = 0 oder 1, ist,
B Phe, Tyr ist,
C und D unabhängig Thr, Val sind,
E Ser, Pro, Ala, Gly ist,

worin mindestens eines von A und E Pro ist und der Ring, der durch das Gerüst gebildet wird, 35 oder 38 Atome enthält, und pharmazeutisch brauchbarer nicht-toxischer Säureadditionssalze davon, das darin besteht:
a) ein entsprechendes blockiertes, lineares Peptid, das an ein festphasiges Harz gebunden ist, herzustellen, worin die -OH-Gruppe von Thr und Ser durch Bzl blockiert ist; die E-Aminogruppe von Lys durch 2-CI-CBZ blockiert ist; die N-endständige Aminogruppe durch BOC blockiert ist und für den Fall, daß R COOH ist, die C-endständige Carbonsäuregruppe durch t-Butyl blockiert ist;
b) die BOC-Gruppe von der N-endständigen Aminogruppe selektiv zu entfernen und für den Fall, daß R COOH ist, die t-Butylgruppe zu entfernen;
c) das an das Harz gebundene lineare Peptid mit Hydrazin zu behandeln, zur Entfernung des Peptids von dem Harz, unter Erzielung des linearen Peptidhydrazids mit entblockierter N-endständiger Gruppe;
d) das lineare Peptid mit Isoamylnitrit bei saurem pH-Wert zu behandeln unter Erzielung des entsprechenden Azids; die Azidlösung zur verdünnen und zu neutralisieren unter Erzielung des entsprechenden cyclischen Peptids und;
e) das cyclische Peptid mit HF zu behandeln zur gleichzeitigen Entfernung der Bzl- und 2-CI-CBZ-Blockierungsgruppen.
4. Zusammensetzung enthaltend eine therapeutisch wirksame Menge von einem oder mehreren Peptiden mit der Struktur:
Figure imgb0031
worin
R H, COOH ist,
A (Asn)., a-Abu, Pro, Ala, worin n = 0 oder 1, ist,
B Phe, Tyr ist,
C und D unabhängig Thr, Val sind,
E Ser, Pro, Ala, Gly ist,

worin mindestens eines von A und E Pro ist und der Ring, der durch das Peptidgerüst gebildet wird, 35 oder 38 Atome enthält, und pharmazeutisch brauchbare, nicht-toxische Säureädditionssalze davon in einem pharmazeutisch brauchbaren Excipienten.
EP78100673A 1977-08-29 1978-08-16 Somatostatin ähnliche Verbindungen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel. Expired EP0000919B1 (de)

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US828791 1977-08-29
US05/828,791 US4115554A (en) 1977-08-29 1977-08-29 Somatostatin analogs

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EP0000919B1 true EP0000919B1 (de) 1982-01-13

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US (1) US4115554A (de)
EP (1) EP0000919B1 (de)
DE (1) DE2861530D1 (de)
DK (1) DK378178A (de)
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IT (1) IT1106138B (de)

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US4211693A (en) * 1977-09-20 1980-07-08 The Salk Institute For Biological Studies Peptides with para-substituted phenylalanine
LU78191A1 (de) * 1977-09-28 1979-05-25 Ciba Geigy Ag Verfahren zur herstellung von neuen cyclopeptiden
JPS5819669B2 (ja) * 1978-10-28 1983-04-19 白井松新薬株式会社 新規生理活性ペプチド化合物及びその製造法
US4191754A (en) * 1979-02-28 1980-03-04 Merck & Co., Inc. Bicyclic somatostatin analogs
US4316890A (en) * 1979-03-16 1982-02-23 Ciba-Geigy Corporation Peptides and processes for the manufacture thereof
US4244947A (en) * 1979-08-13 1981-01-13 Ayerst Mckenna And Harrison Inc. Carba decapeptide derivatives of [TYR6 ]-somatostatin
US4369179A (en) * 1979-12-14 1983-01-18 Ciba-Geigy Corporation Acylpeptides
ES2703499T3 (es) 2010-12-22 2019-03-11 Salk Inst Biological Studies Péptidos antagonistas de CRF cíclicos
KR101773437B1 (ko) * 2017-02-13 2017-08-31 (주)원하이테크 흡착제가 복합 충진된 산소발생기용 흡착탑

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DE2460469A1 (de) * 1974-12-20 1976-07-01 Hoechst Ag Neue peptide mit biologischer wirkung und verfahren zu ihrer herstellung
US4011182A (en) * 1975-03-21 1977-03-08 American Home Products Corporation Cyclic undecapeptide analogs of somatostatin and intermediates
NL7607987A (nl) * 1975-08-08 1977-02-10 Merck & Co Inc Werkwijze voor het bereiden van peptiden.
US4133805A (en) * 1975-12-16 1979-01-09 American Home Products Corporation Cyclic undecapeptides related to somatostatin and intermediates therefor
CA1083143A (en) * 1976-01-02 1980-08-05 Nedumparambil A. Abraham Carba derivatives of somatostatin and process therefor

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DK378178A (da) 1979-03-01
IT1106138B (it) 1985-11-11
IT7850877A0 (it) 1978-08-28
EP0000919A1 (de) 1979-03-07
IE781724L (en) 1979-02-28
IE47320B1 (en) 1984-02-22
DE2861530D1 (en) 1982-02-25

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