[go: up one dir, main page]

WO1983002271A1 - Use of peptides as a medicament - Google Patents

Use of peptides as a medicament Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
glucagon
gln
thr
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.)
Ceased
Application number
PCT/DK1981/000119
Other languages
French (fr)
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
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.)
Novo Nordisk AS
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 PCT/DK1981/000119 priority Critical patent/WO1983002271A1/en
Priority to GB08322272A priority patent/GB2123836A/en
Publication of WO1983002271A1 publication Critical patent/WO1983002271A1/en
Anticipated expiration legal-status Critical
Ceased 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
    • C07K14/605—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

Landscapes

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

Abstract

Peptides of the glucagon type having the general formula R?1-R?2 wherein R?1 represents$(6,)$or a corresponding peptide chain which is identical with the two last-mentioned peptide chains with the proviso that one or more of the amino acid(s) has/have been omitted, or salts thereof for the use as a medicament or diagnosticum. For instance the use may be as a spasmolyticum, as a gastric acid secretion depressing agent or as an insulin releasing agent. The invention also has regard to pharmaceutical compositions containing the peptides as well as to the preparation of the peptides and pharmaceutical compositions containing the peptides.

Description

Use of peptides as a medicament
The present invention relates to the use of peptides of the general formula I
R1 --*2 ( I ) ι wherein R represents His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tvr-
Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gin-Asp-, and 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 acϊd(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. Furthermore, glucagon exerts a spasmolytic effect on smooth muscle and an inhibitory effect on gastric acid secretion. It has now, surprisingly, been found that 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. Hence, 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
-5 the electrically stimulated guinea pig ileum ]n vitro. 10 glucagon caused 83 ± 4% (X ± sd, N = 3) inhibition compared to 78 ± 5% for glucagon1_2r The effects of 10"6M was 50 ± 3% and 52 ± 5%, respect- ively, and of 10"7M: 27 ± 3% for either peptide.
Furthermore, glucagon-. -, has almost the same potency as glucagon with respect to reducing effect on intestinal motility in rabbits ]n_ vivo. 100 to 200 μg glucagon and 77 to 154 μg 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 .
The metabolic effects of glucagoni 2- , glucagon-j^g an<^ des(22-26)glucagon, as exemplified by their lipolytic effect on rat
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.
5 It has been shown that glucagon releases insulin from the isolated perfused rat pancreas but 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 hyperglycemϊa
10 or release insulin jn vivo in normally fasted and fed rats. However, surprisingly, glucagon., 21 has been found to possess about 85% of glucagon's I Rl (ϊmmunoreactϊve 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
15. buffer glucose is 1 .5 mg/ml glucose. Preliminary studies in glucose primed pigs have shown that 100 μg/kg/h glucagon., „-. infused intravenously improves the glucose tolerance. As glucagon.. _?1 pos¬ sesses glucagon's I R l releasing effect in the presence of hypergly¬ cemϊa at the same time as the drug is devoid of glucagon's glyco-
20 genolytϊc and gluconeogenetϊc effects, the drug may be used in the treatment of diabetics with remaining β-cell function . The drug should be especially safe as no hypoglycemϊas will occur du.rϊng the treatment because of the lack of I RI-releasϊng effect in the presence of hypoglycemϊa and normoglycemia.
25 Furthermore, it has surprisingly been found that 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. In cats with chronic gastric fistulas glucagon- _21 as well as glucagon inhibits pentagastrin stimulated
30 gastric acid secretion . 1 μg/kg pentagastrin subcutaneously admini¬ stered to gastric fistula cats caused an increase in gastric acid secretion of 856 ± 71 μEq (Eq designates equivalent) acid (X ± S. E.M. , N = 18) . When 2 μg/kg glucagon- _21 was administered subcutaneously at the same time as 1 μg/ kg pentagastrin the increa-
35 se in acid output was only 417 ± 104 μEq acid (N = 6).
GIucagon1 _?1 and glucagon are almost equϊpotent 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. When a gall bladder strip was contracted with -6 0.1 μg/ml cholecystochinin octapeptide 10 IVI glucagon caused 39% relaxation and 10 M glucagon.. _.. caused 41% relaxation . The ED
-6 value was for both peptides 2.7 x 10 . Therefore, 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 therapeutϊcu 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 β-cell function . The indication areas for use of the compounds of formula I and salts thereof for diagno¬ stic purposes will be ϊnvestigational techniques such as radiology " (X-ray examination), endoscopy (direct observation of the gastro¬ intestinal tract) and hysterosalpingographia .
Compounds of formula I are converted into pharmaceutical preparations and administered, preferably to humans, in analogy with known methods.
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 admϊni- stered ϊntraveneously, intramuscularly or subcutaneously at dosages in the range of from about 1 to 1000 μg/kg body weight, preferably from about 10 to 100 μg/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.
For the purpose of parenteral administration, compounds of formula I are dissolved in distilled water and the pH-value is adjust¬ ed to about 6 to 8. In order to facilitate the lyophilϊzation process resulting in a suitable product 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 excercϊsed by selecting appropriate macromolecules (e.g. polyvϊnylpyrrolidone, methylcellu- lose, carboxymethylcellulose, and protamϊne sulphate) and the con¬ centration of macromolecules in order to control the drug-macromole- cule association. Besides it is possible to obtain a longer duration of action by parenteral administration of a suspension of the compounds than by an aqueous solution because the compounds are continuously dissolving, a process which can be controlled by well known factors (e.g. crystal form and surface area) . Another possible method to control the duration of action by retarded preparations is to incorp¬ orate compounds of formula 1 into particles of a polymeric material, e.g. glucagon- _21 in ethylene vϊnylacetate copolymer or in a biode- gradable polymer matrix, e.g. poly(latϊc acid). Instead of incorporat¬ ing the compounds in polymeric particles it is possible to entrap compounds of formula I in mϊcrocapsufes prepared by conservation techniques or by ϊnterfacial 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 macroemulsϊons. Another mechanism to achieve retarded preparations is through the use of biological acceptable oil solutions (e.g. viscoleo and arachnϊs oil) where the release of drug is controlled by parti- tϊonϊng of drug out of the oil into the surrounding aqueous milieu. Besides it is possible to use an oil suspension which combines the principles involved in aqueous suspensions and oil solutions.
For the purpose of nasal administration 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 .
For the purpose of nasal administration by the use of dose aerosol spray 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. The compounds of formula I are preferably used by nasal administration in a dosage range between about 0.1 and 100 μg/kg body weight, preferably between 1 and 10 μg/kg body weight, per single dose. This dose could be administered several times per day. For the purpose of rectal administration 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. The use of 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 .
Thus, glucagon- _2- , glucagon- 2g and des(22-26)-glucagon can be prepared by coupling the protected glucagon fragment: Adoc-His(Adoc)-Ser(But)-Gln-Gly-Tbr(But)-Phe- -Thr(But)-Ser(But)~Asp(OBut)-Tyr(But)-Ser(But)- ys- (Boc)-Tyr(But)-Leu-Asp(OBut)-OH ( II) with the protected glucagon fragments:
H-Ser(But)-Arg(HCI)-Arg(HCl)-Ala-Gln-Asp(OBut)-
-OBu* 20 ' ( I I I )
Figure imgf000007_0001
H-Ser(Bu )-Arg(HBr)-Arg(HBr)-Ala- n-Asp(OBu )- t 20 , -*
-Phe-Val-Gln-Tςp-Leu-OBu ' ( IV) or H-Ser(But)-Arg(HBr)-Arg(HBr)rAla-Gln-Asp(OBut)- t t 20
- et-Asn-Thr(Bu )-OBu (V) respectively, by the mixed anhydride method using isobutyl chioro- formate. The fully protected peptides so obtained can be deprotected under acid conditions, e. g . by treatment with trifluoroacetic acid containing 10% 1 ,2-ethanedϊthϊol . The crude peptides can be purified by ion-exchange chromatography, e.g . QAE-Sephadex A-25, followed by a desalting procedure, e. g. gelfϊltration 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(But)-Arg(HBr)-Arg(HBr)-Ala-Gln-Asp(OBut)-
-OH 2° (VI )
- with the protected glucagon fragments:
H-Phe-Val-GIn-Tro-Leu-OBu* (VI I ) or H-Met-Asn-Th Bu -OBu1 (VI 11 ) respectively, whereupon the N-termϊnal Bpoc group can be removed selectively under mild acid conditions, e.g. by treatment with HCI (0.2N) in methanol/N, N-dimethylformamϊde.
The protected peptide fragments I I I , VI , VI I and VI I I were synthesized by stepwϊse chain elongation applying conventional procedure such as the active ester or mixed anhydride methods for coupling .
2 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 acϊd(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 acϊd(s) in question has/have been omitted in the protected peptide fragments VI I and VI I I .
A process for preparing glucagon- 2- has been described in J.Biol .Chem. 247, 2133, by digesting porcine, bovine or sheep glucagon with carboxypeptidase A. Glucagon -i pe 's known from Me¬ tabolism 25, Suppl . 1 , 1315.
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 . As examples of specific compounds, within this class of compounds, compounds of formula I ,
2 wherein R is Phe, Val, Gin, Trp, Leu, Met, Asn or Thr, can be mentioned . 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.
Furthermore, the present invention relates to novel com¬ pounds of the general formula I '
1 2 R -R' (I')
1 2 wherein R is as defined above, and R' has the same meaning as
2 2 R , provided that R' does not represent -Phe-Val-Gln-Trp-Leu or
25 OH, or a salt thereof.
Briefly, compounds of formula I 1 may be prepared by treat¬ ing a compound of the general formula
Figure imgf000009_0001
one or more of the amino acid(s) has/have been omitted, the peptide moiety -Met-Asn-Thr(Bu )- or corresponding peptide moieties which are identical with said moiety with the proviso that one or more of the amino acid(s) has/have been omitted, and X represents chlorine or bromine, with an acid such as trϊfluoroacetic acid . As examples of 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 physϊologi- 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 excϊpϊent(s) . As examples of such carriers con- ventional preservatives, e. g. methyl or propyl p-hydroxybenzoate, and sodium chloride can be mentioned .
Any novel feature or combination of features described herein is considered essential .
The nomenclature used herein complies with that stated in J . Biol . Chem. 247, 977, and Biochem.J . 104, 17. However, for the sake of brevity, glucagon-(1-21 )-heneicosapeptϊde herein has been designated glucagon- _21 , glucagon-(1-26)-hexacosapeptϊde has been designated glucagon- _2g, and des-pentapeptide-(22-26)-glucagon has been designated des(22-26)gIucagon. Bpoc represents 1-(biphenyl-4-
-yl)-1-methylethoxy-carbonyl, Adoc represents 1-adamantyloxycarbon- yi , Bu represents tertiary butyl , and Boc represents tert-butyloxy- carbonyl .
The following examples which, however, are not considered to be limiting are presented to illustrate the Invention.
Example 1 des(22-26)glucagon .
1 g of Adoc-Hϊs(Adoc)-Ser(But)-Gln-Gly-Thr(But)-Phe-
-Thr(But)-Ser(But)-Asp(OBut)-Tyr(But)-Ser(But)- ys(Boc)- -Tyr(Bu -Leu-As (OBu -Ser(Bu )-Arg(HBr)-Arg(HBr)-Ala-Gln- + 15 t t
-Asp(OBu )-Met-Asn-Thr(Bu )-OBu is dissolved in 25 ml of trϊflu- oroacetic acid containing 10% 1 ,2-ethanedithϊoi and the reaction mix¬ ture Is left at 15°C for 3 hours. Thereafter, 200 ml of tetrahydrofu- ran Is added slowly and the precipitate is isolated, washed with te- trahydrofuran and dried in_ vacuo. The resulting product may be pu¬ rified by Ion-exchange chromatography on QAE Sephadex A-25 and desalted by gel -filtration on Sephadex G-25. Example 2
A preparation for parenteral administration containing 1 mg of glucagon- _2- per m] may be prepared as follows:
1 g of glucagon- 2- and 99 g of lactose are dissolved in 1 litre of distilled water and the pH-value Is adjusted to 7.0. The so¬ lution is thereafter sterile filtered . The sterile solution Is filled in 10 ml vials In such a way that each vial contains 1 .0 ml of the solution. Thereafter, the solutions are lyophilized and the vials are sealed under aseptic conditions.
The preparation in any of the vials is to be dissolved in 1 .0 ml of sterile, Isotonic water before administration. Example 3 A preparation for parenteral administration containing 10 mg of glucagon- _2- per ml may be prepared as follows:
10 g of glucagon- _2- and 90 g of lactose are dissolved in 1 litre of distilled water and the solution is prepared analogously to the method described in Example 2. - — — — ,_ - cι.:?ι Example 4
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:
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 μg 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.
A male rabbit weighing 2.32 kg was treated as described in Experiment A with the following dosages:
77 μg glucagon- 2- in 1 ml of the solution stated in Expe¬ riment A intravenously caused no detectable spasmolytic effect.
154 μg glucagon- _?- in 1 ml of the solution in Experiment
A intravenously had a questionable effect. 308 μg 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.
For comparison glucagon was administered to the same rab¬ bit. 200 μg glucagon intravenously had no detectable effect, however, 400 μg gave a distinct effect comparable to the effect caused by 308 μg glucagon1 21.
Experiment C : Gastric Acid Inhibitory Effect. In a male cat weighing approx. 4.5 kg equipped with a cronic gastric fistula the gastric acid secretion was stimulated with 4.5 μg pentagastrin (Peptavlon ) in a volume of 1 ml 0.9% saline con¬ taining 0.1% human serum albumin subcutaneously in the neck. In 8 experiments 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. In 2 experiments 9 μg of glucagon- _2- in 1 ml of the above solution was administered simultaneously with the administration of pentagastrin. Gastric acid secretion was collected over periods of 15 minutes and titrated with 0.01N NaOH . The increase in acid secretion after the administration of pentagastrin was calculated as μEq acid excreted over ϊ_ hrs. after the administration subtracting the basal acid secretion before administration of pentagastrin. After administration of 4.5 μg pentagastrin plus placebo the increase in gastric acid secretion was 729 ± 89 μEq acid (X ± S. E.M. , N = 8). 4.5 μg penta- gastrin + 9 μg glucagon- ~- caused an increase In acid secretion of 238 μEq in one experiment and 231 μEq in another experiment. Experiment D: Effect on Bile Flow.
In rabbits with catheters in the bile duct the administration of glucagon and glucagon-_2- caused a decrease in gall flow immedia- tely after the administration, probably reflecting a decrease in the tonus of the gall bladder. This decrease in flow was followed by an increase in bile flow to quantities higher than before the administra¬ tion reflecting an increase in production of bile.
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 results obtained appear from Table I .
o:,*?ι
Figure imgf000012_0001
" Table I
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0003
After 45 minutes 200 μg glucagon was administered subcu¬ taneously in 1 ml of 0.9% saline containing 0.1% human serum albu¬ min . After 120 minutes 154 μg glucagon- _?- was administered subcu¬ taneously in 1 ml of the above solution . After 195 minutes the place¬ bo (vide Experiment C) was administered .
Experiment E:
Ten male Wϊstar rats weighing 150 ± 5 g were anesthetized with nembutal and a polyethylene catheter was inserted into a jugular vein for infusions . Another catheter was inserted into a carotid ar¬ tery for blood sampling . One group of five rats received an infusion of glucose, i .e. 2 mg/min . , over 60 minutes. Another group of five rats received an infusion of glucose, i .e. 2 mg/min . , from 0 to 20 minutes and from 20 to 60 minutes infusion was made of glucose, i .e. 2 mg/min . , plus glucagon- _2- , i .e. 100 μg/mϊn . Plasma glucose ana¬ lysis were made according to the hexokinase method on the autoana- lyzer using GLUCOQUANT . The mean plasma glucose values (N = 5) are stated in Table 11 .
O PI - Table I I Plasma glucose, mg/100 ml
Figure imgf000014_0001
The group which received glucagon- „- had a significantly lower blood glucose level compared to the other group after the addi¬ tion of glucagon- _p- to the infusion fluid.
Experiment F:
Glucagon, 1 mg/kg, and an equϊmolar dosϊs of gluca- gon- p- , i.e. 0.77 mg/kg, were injected intravenously at the time 0 minutes to normal fed male Wϊstar 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! (immunoreactϊve insulin). Contrary to gluca¬ gon, glucagon- _2- had no effect on these parameters. Mean blood glucose values (N = 10) are stated in Table I I I and mean plasma IRl values (N = 10) are stated in Table IV.
Figure imgf000015_0002
Table I V
-
Plas ma I Rl μU/ml
Time (min) -5 2 5 10 15 30 60
Glucagon 1 mg/kg 19 95 98 82 67 53 17 experimental
Placebo 17 25 28 23 20 22 25 day 1
Glucagon.. _21 0.77 mg/kg 32 30 33 35 43 38 30 experimental
Placebo 13 20 20 22 24 22 16 day 2
Experiment G: Acute Toxicity Study.
10 mg glucagon- _p- administered intravenously as a bolus to NMRI mice weighing 20 g (i . e. a dose of 500 mg/kg body weight) had no adverse effects. No deaths occurred .
Figure imgf000015_0001

Claims

C l a i m s
1. A compound having the general formula I
R1-R2 (I)
1 wherein R represents His-Ser-Gln-GIy-Thr-Phe-Thr-Ser-Asp-Tyr- -Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-, and 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 acid(s) has/have been omitted, or salts thereof for the use as a medicament or diagnosticum.
2. A compound according to claim 1, c h a r a c t e r ¬ i e d in that it is used as a spasmoiyticum, as a gastric acid se¬ cretion depressing agent or as an insulin releasing agent.
3. A compound according to claim 1, c h a r a c t e r - i z e d in that it is used for treatment of spasms in the digestive system, for treatment of biliary tract and urinary tract calculi, for treatment of gastro-duodenal ulcers or for treatment of diabetics.
4. A compound according to any of the preceeding claims,
2 wherein R represents a peptide chain containing amino acids in exactly the same sequence as the one present in the continuous part of glucagon.
5. A compound according to any of the claims 1 to 3,
2 wherein R represents Phe, Val, Gin, Trp, Leu, Met, Asn or Thr.
6. A compound according to any of the claims 1 to 3, 2 wherein R represents OH, -Phe-Val-Gln-Trp-Leu or -Met-Asn-Th .
7. A compound according to any of the claims 1 to 4 and
2 6, wherein R represents OH.
8. A pharmaceutical composition which comprises an effect¬ ive amount of a compound of formula I , according to claim 1 , or a salt thereof in association with a suitable physiologically acceptable carrier, diluent and/or excipient.
9. A pharmaceutical composition, according to claim 8, c h a r a c t e r i z e d in that it comprises between 7.5 and 75,000 μg, preferably between 75 and 7500 μg, of a compound of formula I or salt thereof per dosage unit.
10. A pharmaceutical composition, according to claim 8 or
9, c h a r a c t e r i z e d in that it contains a compound of
2 formula I , wherein R represents a peptide chain containing amino acids in exactly the same sequence as is present in a continuous part of glucagon.
11. A pharmaceutical composition, according to claim 8 or
9, c h a r a c t e r i z e d in that it contains a compound of
2 formula I, wherein R represents Phe, Val, Gin, Trp, Leu, Met, Asn or Thr.
12. A pharmaceutical composition, according to claim 8 or
9, c h a r a c t e r i z e d in that it contains a compound of
2 formula I, wherein R represents OH, -Phe-Val-Gln-Trp-Leu or
25 -Met-Asn-Thr.
13. A pharmaceutical composition, according to claim 8 or
9, c h a r a c t e r i z e d in that it contains a compound of
2 formula I, wherein R is OH.
14. Novel compounds of the general formula I'
R^R'2 (I')
1 2 wherein R is as defined above, and R' has the same meaning as
2 2
R , provided that R' does not represent -Phe-Val-Gln-Trp-Leu or
25 OH, or a salt thereof.
15. A process for the preparation of compounds of formula I1 or salts thereof, c h a r a c t e r i z e d in that they are pre- pared from the parent L-amino acids by the use of methods which are generally known in peptide synthesis whereafter a compound of formula 1', if desired, is converted into a salt thereof analogously to known methods.
16. A process for the preparation of compounds of formula I' or salts thereof, c h a r a c t e r i z e d in that a compound of the general formula
R3-R4-OBut (IX)
3 t t wherein R represents Adoc-His(Adoc)-Ser(Bu )-Gln-Gly-Thr(Bu )-
-Phe-Thr(But)~Ser(But)-Asp(OBut)-Tyr(But)-Ser(But)-Lys(Boc)- -Tyr(But)-Leu-Asp(OBut)-Ser(But)"Arg(HX)-Arg(HX)-Ala-Gln-
* -~ tN 15 20
-Asp(OBu )-,
4 R represents the peptide moiety -Phe-Val-Gln-Trp-Leu- from which one or more of the amino acid(s) has/have been omitted, the peptide moiety -Met-Asn-Thr(Bu )- or corresponding peptide moieties which are identical with said moiety with the proviso that one or more of the amino acϊd(s) has/have been omitted, and X represents chlorine or bromine, is treated with an acid such as trϊfluoroacetϊc acid, whe¬ reafter the resulting compound, if desired, is converted into a salt thereof.
17. The use of' compounds of formula I as stated in claim 1 or any of the preferred subclasses of compounds stated in any of the claims 4 to 7 or a salt thereof for the preparation of a spasmoly- tϊcum, a gastric acid secretion depressing agent or an insulin releas- ing agent.
18. A compound of formula I as stated in claim 1 or any of the preferred subclasses of compounds stated in any of the claims 4 to 7. for use as a spasmolyticum, a gastric acid secretion depressing agent or an insulin releasing agent.
19. A spasmolyticum, a gastric acid secretion depressing agent or an insulin releasing agent, c h a r a c t e r i z e d in that it comprises a compound of formula I as stated in claim 1 or any of the preferred subclasses of compounds stated in any of the claims 4 to 7.
20. Any novel feature or combination of features described herein .
PCT/DK1981/000119 1981-12-28 1981-12-28 Use of peptides as a medicament Ceased WO1983002271A1 (en)

Priority Applications (2)

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

Applications Claiming Priority (1)

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

Publications (1)

Publication Number Publication Date
WO1983002271A1 true WO1983002271A1 (en) 1983-07-07

Family

ID=8152931

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1981/000119 Ceased WO1983002271A1 (en) 1981-12-28 1981-12-28 Use of peptides as a medicament

Country Status (2)

Country Link
GB (1) GB2123836A (en)
WO (1) WO1983002271A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE356294B (en) * 1967-08-19 1973-05-21 Hoechst Ag
EP0044168A1 (en) * 1980-07-01 1982-01-20 Novo Nordisk A/S The use of peptides as medicaments and certain novel peptides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE356294B (en) * 1967-08-19 1973-05-21 Hoechst Ag
EP0044168A1 (en) * 1980-07-01 1982-01-20 Novo Nordisk A/S The use of peptides as medicaments and certain novel 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 *

Also Published As

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

Similar Documents

Publication Publication Date Title
NZ202757A (en) Peptides and medicaments
EP0894095B1 (en) Insulin derivatives and their use
CA1340985C (en) Peptide derivatives
EP0708179B1 (en) Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
EP0044168B1 (en) The use of peptides as medicaments and certain novel peptides
KR19980703038A (en) Lipophilic peptide hormone derivative
JPH0357119B2 (en)
JP2511159B2 (en) Pharmaceutical formulations for the treatment of immune deficiency conditions
NZ316822A (en) Cyclic peptide analogs of somatostatin
US5863900A (en) Lhrh antagonists
EP1571155B1 (en) Peptides and medicinal compositions containing the same
EP3882263A1 (en) Glucagon-derived peptide and use thereof
EP0269299A2 (en) Atrial peptides
US6316414B1 (en) Somatostatin analogs for the treatment of cancer
WO1983002271A1 (en) Use of peptides as a medicament
JPS61172898A (en) Novel derivative of alginine basopressine antagonistic drug
EP0428266B1 (en) Anticancer agent
CA2385910A1 (en) Somatostatin analogs for the treatment of cancer
US5071836A (en) Competitive gonadoliberin antagonists
IE52233B1 (en) The use of peptides as medicaments and certain novel peptides
US6949513B2 (en) Polypeptides of covalently linked synthetic bioactive peptide analog(s) for treatment of cancer
AU706979B2 (en) LHRH antagonists
AU673147B2 (en) Amylin agonist peptides and uses therefor
GB2233652A (en) Synthesis of peptide alcohols
HK1079222A (en) Peptides and medicinal compositions containing the same

Legal Events

Date Code Title Description
AK Designated states

Designated state(s): CH GB