WO1983002271A1 - Utilisation de peptides comme medicament - Google Patents

Utilisation de peptides comme medicament Download PDF

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Publication number
WO1983002271A1
WO1983002271A1 PCT/DK1981/000119 DK8100119W WO8302271A1 WO 1983002271 A1 WO1983002271 A1 WO 1983002271A1 DK 8100119 W DK8100119 W DK 8100119W WO 8302271 A1 WO8302271 A1 WO 8302271A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
glucagon
gln
thr
Prior art date
Application number
PCT/DK1981/000119
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English (en)
Inventor
Industri A/S Novo
Behrend Friedrich Lundt
Karin Damm JORGENSEN
Niels Langeland Johansen
Frederik Christian Gronvald
Erik Kai Frandsen
Alister James Moody
Jan Markussen
Original Assignee
Novo Industri As
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 Novo Industri As filed Critical Novo Industri As
Priority to GB08322272A priority Critical patent/GB2123836A/en
Priority to PCT/DK1981/000119 priority patent/WO1983002271A1/fr
Publication of WO1983002271A1 publication Critical patent/WO1983002271A1/fr

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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
    • C07K14/605—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the use of peptides of the general formula I
  • R represents OH, the peptide chain -Phe-Val-Gln-Trp-Leu or -Met-Asn-Thr or a corresponding peptide chain which is identical with the two last-men ⁇ tioned peptide chains with the proviso that one or more of the amino ac ⁇ d(s) has/have been omitted, or salts thereof.
  • Compounds of formula I show interesting and surprising pharmacological properties.
  • Glucagon a polypeptide hormone consisting of 29 amino acids, is known to possess several pharmacological effects.
  • the use of glucagon for the treatment of hypoglycemia is based upon its metabolic effects.
  • glucagon exerts a spasmolytic effect on smooth muscle and an inhibitory effect on gastric acid secretion.
  • compounds of formula I as to quantity possess a similar spasmolytic effect and a similar inhibi ⁇ tory effect on gastric acid secretion as that of glucagon, although compounds of formula I show no or minor, negligible metabolic effect under normoglycaemic conditions.
  • compounds of formula I are considered superior to glucagon when only a spasmolytic effect or an inhibition of gastric acid secretion is desired.
  • Glucagon.. _ 21 , glucagon., _ ⁇ - and des(22-26)glucagon have for instance been found to have almost the same potency as glucagon as regards inhibitory effect on the amplitude of the contractions of
  • glucagon-. - has almost the same potency as glucagon with respect to reducing effect on intestinal motility in rabbits ]n_ vivo. 100 to 200 ⁇ g glucagon and 77 to 154 ⁇ g glucagon ⁇ _ ⁇ administered intravenously as a bolus to anaesthetised rabbits of 2.5 to 3.0 kg body weight caused an inhibition of intestinal motility be ⁇ ginning 1 minute after the administration and lasting for about 10 minutes .
  • CMPI free fat cells ⁇ __ vitro and their effect on the activation of the aden- ylate cyclase ini vitro, are negligible compared with the metabolic ef ⁇ fects of glucagon . No metabolic effects have been found after admini ⁇ stration to normally fasted and fed rats hn vivo.
  • glucagon.. _ ?1 has no such effect when it is infused to the same concentration as glucagon , provided the buffer glucose concentration is 0.6 mg/ml glucose. Furthermore, glucagon., 21 - contrary to glucagon - does not cause hyperglycem ⁇ a
  • glucagon., 21 has been found to possess about 85% of glucagon's I Rl ( ⁇ mmunoreact ⁇ ve insulin) releasing effect in the per ⁇ fused rat pancreas model , when the buffer glucose concentration is 2.0 mg/ml and about 60% of glucagon's I Rl releasing effect when the
  • buffer glucose is 1 .5 mg/ml glucose.
  • Preliminary studies in glucose primed pigs have shown that 100 ⁇ g/kg/h glucagon., folk-. infused intravenously improves the glucose tolerance.
  • the drug may be used in the treatment of diabetics with remaining ⁇ -cell function .
  • the drug should be especially safe as no hypoglycem ⁇ as will occur du.r ⁇ ng the treatment because of the lack of I RI-releas ⁇ ng effect in the presence of hypoglycem ⁇ a and normoglycemia.
  • gluca ⁇ gon., pfi and des(22-26)glucagon possesses an insulin releasing effect in the perfused rat pancreas model when the buffer glucose concen ⁇ tration is 2.0 mg/ml glucose.
  • glucagon- _ 21 as well as glucagon inhibits pentagastrin stimulated
  • GIucagon 1 _ ?1 and glucagon are almost equ ⁇ potent as re ⁇ gards relaxing effect on a submaximally contracted rabbit gall bladder preparation hi vitro, and both compounds cause an increase in gall flow in rats hi vivo.
  • a gall bladder strip was contracted with -6 0.1 ⁇ g/ml cholecystochinin octapeptide 10 IVI glucagon caused 39% relaxation and 10 M glucagon.. _.. caused 41% relaxation .
  • compounds of formula I may have a potential utility in the treatment of biliary tract and - because of their general spasmolytic properties - possibly urinary calculi patients. As regards this utility, the fact that com ⁇ pounds of formula I have no or minor, negligible metabolic effect under normoglycaemic conditions must be a considerable advantage. Hence, a compound of formula I or a salt thereof may be used as a therapeut ⁇ cu or a diagnosticum.
  • the indication areas for use of the compounds of formula I and salts thereof in therapy will be, for example, biliary tract and urinary tract calculi, spasms in the digestive system and gastro-duodenal ulcers, besides the treat ⁇ ment of diabetics with remaining ⁇ -cell function .
  • the indication areas for use of the compounds of formula I and salts thereof for diagno ⁇ stic purposes will be ⁇ nvestigational techniques such as radiology " (X-ray examination), endoscopy (direct observation of the gastro ⁇ intestinal tract) and hysterosalpingographia .
  • Compounds of formula 1 and salts thereof can, as diagno ⁇ sticum, be used in analogy with the use of glucagon for the same purpose.
  • Compounds of formula I and salts thereof can be adm ⁇ ni- stered ⁇ ntraveneously, intramuscularly or subcutaneously at dosages in the range of from about 1 to 1000 ⁇ g/kg body weight, preferably from about 10 to 100 ⁇ g/kg body weight, although a lower or higher dosage may be administered .
  • the required dosage will depend on the severity of the condition of the patient and the duration of treat- ment.
  • a higher dosage may be used for biliary tract and urinary tract calculi patients and gastro-duodenal ulcer patients besides diabetic patents and, in these cases, multiple dosages of the com ⁇ pounds may be administered, for example, parenterally (for example as a continuous infusion) or by the nasal or rectal route.
  • Compounds of formula I may possibly be administered oral ⁇ ly, e. g . by the use of special additives.
  • compounds of formula I are dissolved in distilled water and the pH-value is adjust ⁇ ed to about 6 to 8.
  • lactose could be added to the solution.
  • the solution is sterile filtered and filled in vials. Thereafter, the so ⁇ lutions are lyophilized and the vials are sealed under aseptic condi ⁇ tions.
  • Other pharmaceutical methods can be employed to control the duration and even the side of action.
  • Retarded preparations can be achieved by the use of polymers to complex or absorb compounds of formula I .
  • the controlled delivery is excerc ⁇ sed by selecting appropriate macromolecules (e.g.
  • glucagon- _ 21 in ethylene v ⁇ nylacetate copolymer or in a biode- gradable polymer matrix, e.g. poly(lat ⁇ c acid).
  • a biode- gradable polymer matrix e.g. poly(lat ⁇ c acid).
  • entrap compounds of formula I in m ⁇ crocapsufes prepared by conservation techniques or by ⁇ nterfacial polymerisation, e.g. hydroxyethylcellu- lose or gelatine microcapsules and poly(methylmethacryiate) microcap- sufes respectively, or in colloidal drug delivery systems, e.g. lipo- somes, albumin microspheres, nanoparticles and nanocapsules or in macroemuls ⁇ ons.
  • Another mechanism to achieve retarded preparations is through the use of biological acceptable oil solutions (e.g. viscoleo and arachn ⁇ s oil) where the release of drug is controlled by parti- t ⁇ on ⁇ ng of drug out of the oil into the surrounding aqueous milieu.
  • biological acceptable oil solutions e.g. viscoleo and arachn ⁇ s oil
  • an oil suspension which combines the principles involved in aqueous suspensions and oil solutions.
  • a solution in a nasal spraying device or nebulisator is used.
  • the compounds of for- mula I are dissolved in distilled water, the pH-value is adjusted to about 6 to 8 by adding sodium phosphate and citric acid as buffer.
  • Sodium chloride, sorbitol and giycerol are used to obtain an isotonic solution with a suitable viscosity.
  • the solution is administered by the use of a suitable nebulisator or plastic spray.
  • the solution may be preserved by the use of known preservatives and a know,- sur ⁇ factant may be added .
  • the peptides are mixed with suitable constituents and a mixture of halogencarbons, i .e. monofluorotrichloromethane, difluo- rodichloromethane and tetrafiuorodichloroethane, in order to obtain a mixture with a vapour pressure producing a well defined single dose when the mixture is administered by the use of a dose aerosol spray.
  • halogencarbons i .e. monofluorotrichloromethane, difluo- rodichloromethane and tetrafiuorodichloroethane
  • the compounds of formula I are preferably used by nasal administration in a dosage range between about 0.1 and 100 ⁇ g/kg body weight, preferably between 1 and 10 ⁇ g/kg body weight, per single dose. This dose could be administered several times per day.
  • suppositories are produced by admixing compounds of formula I , with an inactive con ⁇ stituent such as cocoa butter or with a base such as Polysorbate 85, - propylene glycol monostearate and white bee's wax.
  • compounds of formula I and salts thereof can be prepared by methods which are generally known in peptide synthesis. Briefly, compounds of formula I can be built up from a protected glucagon fragment, e.g. protected glucagon- 15 , and a protected peptide con ⁇ taining the remaining amino acids of the desired compound of formula I .
  • the preparation of protected glucagon- -_ is described in Res. Disci . 1979, 247.
  • Peptides containing more than amino acids Nos . 16 - 21 in glucagon can be built up from a protected glucagon frag ⁇ ment, e. g . protected glucagon- - -- , and a protected peptide contain ⁇ ing the remaining amino acids.
  • suitable protecting groups and activations during the peptide synthesis is known to the skilled art worker. It is desired to use protecting groups which can easily be removed .
  • glucagon- _ 2 - , glucagon- 2 g and des(22-26)-glucagon can be prepared by coupling the protected glucagon fragment: Adoc-His(Adoc)-Ser(Bu t )-Gln-Gly-Tbr(Bu t )-Phe- -Thr(Bu t )-Ser(Bu t ) ⁇ Asp(OBu t )-Tyr(Bu t )-Ser(Bu t )- ys- (Boc)-Tyr(Bu t )-Leu-Asp(OBu t )-OH ( II) with the protected glucagon fragments:
  • the fully protected peptides so obtained can be deprotected under acid conditions, e. g . by treatment with trifluoroacetic acid containing 10% 1 ,2-ethaned ⁇ th ⁇ ol .
  • the crude peptides can be purified by ion-exchange chromatography, e.g . QAE-Sephadex A-25, followed by a desalting procedure, e. g. gelf ⁇ ltration on Sephadex G-25.
  • the purified peptides can be isolated by lyophilization .
  • the intermediate protected glucagon fragments IV and V can be prepared by coupling, using the mixed anhydride procedure, the protected gluca ⁇ gon fragment: Bpoc-Ser(Bu t )-Arg(HBr)-Arg(HBr)-Ala-Gln-Asp(OBu t )-
  • H-Phe-Val-GIn-Tro-Leu-OBu* VI I
  • H-Met-Asn-Th Bu -OBu 1 VI 11
  • the N-term ⁇ nal Bpoc group can be removed selectively under mild acid conditions, e.g. by treatment with HCI (0.2N) in methanol/N, N-dimethylformam ⁇ de.
  • the protected peptide fragments I I I , VI , VI I and VI I I were synthesized by stepw ⁇ se chain elongation applying conventional procedure such as the active ester or mixed anhydride methods for coupling .
  • Peptides of formula I wherein R represents the peptide chain -Phe-Val-Gln-Trp-Leu or -Met-Asn-Thr in which one or more amino ac ⁇ d(s) has/have been omitted, can be prepared in a similar manner as described above with the exception that one or more of the amino ac ⁇ d(s) in question has/have been omitted in the protected peptide fragments VI I and VI I I .
  • a preferred subclass of compounds of formula I is com ⁇ pounds wherein the amino acid sequence is identical with a continuous part of the amino acid sequence of glucagon .
  • compounds of formula I within this class of compounds, compounds of formula I ,
  • a preferred compound of formula I is glucagon- -- , be ⁇ cause it shows superior pharmacological properties and because it can easily be obtained, e.g. from natural glucagon.
  • the present invention relates to novel com ⁇ pounds of the general formula I '
  • R is as defined above, and R' has the same meaning as
  • compounds of formula I 1 may be prepared by treat ⁇ ing a compound of the general formula
  • salts of compounds of formula I for examp ⁇ le sodium, potassium, magnesium, calcium and zink salts and acid addition salts with organic or inorganic acids such as formic acid , methansulfonic acid, hydrochloric acid and sulphuric acid can be mentioned .
  • Preferred salts of compounds of formula I are phys ⁇ ologi- cally and pharmaceutically acceptable salts .
  • the present invention also relates to a pharmaceutical com ⁇ position comprising a compound of formula I or a salt thereof and one or more pharmaceutically acceptable carrier(s) , diluent(s) prefer ⁇ ably water, and/or exc ⁇ p ⁇ ent(s) .
  • pharmaceutically acceptable carrier(s) e. g. methyl or propyl p-hydroxybenzoate, and sodium chloride can be mentioned .
  • glucagon-(1-21 )-heneicosapept ⁇ de herein has been designated glucagon- _ 21
  • glucagon-(1-26)-hexacosapept ⁇ de has been designated glucagon- _ 2g
  • des-pentapeptide-(22-26)-glucagon has been designated des(22-26)gIucagon.
  • Bpoc represents 1-(biphenyl-4-
  • Adoc represents 1-adamantyloxycarbon- yi
  • Bu represents tertiary butyl
  • Boc represents tert-butyloxy- carbonyl .
  • Example 1 des(22-26)glucagon .
  • a preparation for parenteral administration containing 1 mg of glucagon- _ 2 - per m] may be prepared as follows:
  • Example 3 A preparation for parenteral administration containing 10 mg of glucagon- _ 2 - per ml may be prepared as follows:
  • Rectal suppositories are prepared by admixing 1 mg of glu ⁇ cagon- _ 21 with 4 g of cocoa butter.
  • Example 5 A nasal plastic spray may be prepared as follows:
  • glucagon- 2 - 0.5 g of glucagon- 2 - is dissolved in about 95 ml of 0.01 M phosphate buffer (pH-value: 7.4) which is made isotonic by the addition of giycerol .
  • the solution is preserved by the addition of 0.01% benzalkonium chloride and 0.05% EDTA whereafter 0.5% poly- oxysorbate is added.
  • An isotonic phosphate buffer is added in order to give a resulting volume of 100 ml and the solution is sterile filter ⁇ ed. 15 ml of said solution is filled in a plastic spray giving 0.5 mg of glucagon- 2 - , when activated .
  • Experiment A Spasmolytic Effect.
  • One male rabbit weighing 2.56 kg was anaesthetized with nembutal after an overnight fast.
  • the position of the balloon used for measurement of intestinal motility was 1 meter from pylorus in the jejunum.
  • the motility was registered before and after intraven- eous administration of 77 ⁇ g glucagon- _ ? - in 1 ml 0.9% saline contain- ing 0.1% human serum albumin.
  • the effect obtained was nearly complete atonia of the intestine.
  • the onset of effect was 1 minute after the administration and the duration of effect was 11 minutes.
  • Experiment B Spasmolytic Effect.
  • 308 ⁇ g glucagon- 2 - in 1 ml of the above solution had a distinct spasmolytic effect causing nearly complete atonia.
  • the onset of the effect was 2 minute and the duration of the effect was 6 minutes.
  • glucagon was administered to the same rab ⁇ bit.
  • 200 ⁇ g glucagon intravenously had no detectable effect, however, 400 ⁇ g gave a distinct effect comparable to the effect caused by 308 ⁇ g glucagon 1 21 .
  • Experiment C Gastric Acid Inhibitory Effect.
  • pentagastrin Peptavlon
  • 1 ml placebo (0.9% saline with 0.1% human serum albumin) was administered subcutaneously through another cannula in the neck at the same time as the administration of pentagastrin.
  • 9 ⁇ g of glucagon- _ 2 - in 1 ml of the above solution was administered simultaneously with the administration of pentagastrin.
  • One rex rabbit weighing 2.0 kg was equipped with a catheter In the bile duct during nembutal anaesthesia on the day before the experiment. On the day of the experiment the bile was collected for periods of 15 minutes.
  • the group which received glucagon-tician- had a significantly lower blood glucose level compared to the other group after the addi ⁇ tion of glucagon- _ p - to the infusion fluid.
  • Glucagon 1 mg/kg, and an equ ⁇ molar dos ⁇ s of gluca- gon- p - , i.e. 0.77 mg/kg, were injected intravenously at the time 0 minutes to normal fed male W ⁇ star rats weighing 150 ⁇ 5 g. Blood samples were taken from the orbital plexus at the times: -5, 2, 5, 10, 15, 30 and 60 minutes. Blood glucose was assayed according to the method stated in Experiment E and plasma insulin was assayed by RIA. Glucagon had a significantly increasing effect on blood glucose and plasma IR! (immunoreact ⁇ ve insulin). Contrary to gluca ⁇ gon, glucagon- _ 2 - had no effect on these parameters.
  • Glucagon.. _ 21 0.77 mg/kg 32 30 33 35 43 38 30 experimental

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Gastroenterology & Hepatology (AREA)
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  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
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  • Endocrinology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Peptides du type à glucagon ayant la formule générale R1-R2, dans laquelle R1 représente$(6,)$ou une chaîne de peptides correspondante qui est identique aux deux chaînes de peptides mentionnées en dernier à condition qu'un ou plusieurs des acides aminés ait été omis, ou leurs sels utilisés en tant que médicaments ou diagnosticum. Par exemple, on peut l'utiliser comme spasmolyticum, comme un agent d'abaissement de la sécrétion d'acide gastrique ou comme un agent de libération d'insuline. L'invention concerne également des compositions pharmaceutiques contenant les peptides ainsi que la préparation des peptides et des compositions pharmaceutiques contenant les peptides.
PCT/DK1981/000119 1981-12-28 1981-12-28 Utilisation de peptides comme medicament WO1983002271A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
GB08322272A GB2123836A (en) 1981-12-28 1981-12-28 Use of peptides as a medicament
PCT/DK1981/000119 WO1983002271A1 (fr) 1981-12-28 1981-12-28 Utilisation de peptides comme medicament

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/DK1981/000119 WO1983002271A1 (fr) 1981-12-28 1981-12-28 Utilisation de peptides comme medicament

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WO1983002271A1 true WO1983002271A1 (fr) 1983-07-07

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE356294B (fr) * 1967-08-19 1973-05-21 Hoechst Ag
EP0044168A1 (fr) * 1980-07-01 1982-01-20 Novo Nordisk A/S Peptides en tant que médicaments, et certains peptides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE356294B (fr) * 1967-08-19 1973-05-21 Hoechst Ag
EP0044168A1 (fr) * 1980-07-01 1982-01-20 Novo Nordisk A/S Peptides en tant que médicaments, et certains peptides

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, Vol. 70 (1969), abstract No. 20330f; & Chem. Ber. 1968, 101(11), 3659-63 *
Chemical Abstracts, Vol. 71 (1969), abstract No. 120077t; & Endocrinology 1969, 85(4), 638-43 *
Chemical Abstracts, Vol. 75 (1971), abstract No. 59193s; & Proc. Nat. Acad. Sci. U.S. 1971, 68(5), 909-13 *
Chemical Abstracts, Vol. 77 (1972), abstract No. 162866d; & Diabetes 1972, 21(8), 843-55 *
Chemical Abstracts, Vol. 79 (1973), abstract No. 1672p; & Can. J. Physiol. Pharmacol. 1973, 5u(4), 243-8 *
Chemical Abstracts, Vol. 79 (1973), abstract No. 521b; & Horm. Metab. Res. 1973, 5(1), 60 *
Chemical Abstracts, Vol. 85 (1976), abstract No. 617m; & Biochem. Pharmacol. 1976, 25(2), 210-11 *
Chemical Abstracts, Vol. 88 (1978), abstract No. 1887y; & Biochemistry 1977, 16(25), 5398-5402 *
Chemical Abstracts, Vol. 89 (1978), abstract No. 191435r; & J. Biol. Chem. 1978, 253(18), 6338-40 *
Chemical Abstracts, Vol. 91 (1979), abstract No. 193614p; & Photochem. Photobiol. 1979, 29(5), 905-4 *
Journal of the American Chemical Society, Vol. 100, No. 6, 15 March 1978, D.A. Deranleau et al: "Conformations of Polypeptide Hormones by Optically Detected Magnetic Resonance and a Zimm-Bragg Analysis of Helical Folding in Glucagon", p. 1913-1917 *
The Journal of Biological Chemistry, Vol.247, No.4, 25 February 1972, I.D. Goldfine et al: "Glucagon Receptors in beta-Cells", p. 1211-1218 *

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GB8322272D0 (en) 1983-09-21
GB2123836A (en) 1984-02-08

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