[go: up one dir, main page]

WO1992000996A1 - Derives d'hormones du lobe pituitaire posterieur - Google Patents

Derives d'hormones du lobe pituitaire posterieur Download PDF

Info

Publication number
WO1992000996A1
WO1992000996A1 PCT/SE1991/000477 SE9100477W WO9200996A1 WO 1992000996 A1 WO1992000996 A1 WO 1992000996A1 SE 9100477 W SE9100477 W SE 9100477W WO 9200996 A1 WO9200996 A1 WO 9200996A1
Authority
WO
WIPO (PCT)
Prior art keywords
peptide
thr
tyr
mpa
derivatives
Prior art date
Application number
PCT/SE1991/000477
Other languages
English (en)
Inventor
Jerzy Trojnar
Michal Lebl
Per Melin
Original Assignee
Ferring Ab
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 Ferring Ab filed Critical Ferring Ab
Priority to MC91@@D priority Critical patent/MC2291A1/fr
Priority to JP91512399A priority patent/JPH05508849A/ja
Publication of WO1992000996A1 publication Critical patent/WO1992000996A1/fr
Priority to FI930013A priority patent/FI930013A0/fi
Priority to CZ939A priority patent/CZ993A3/cs
Priority to NO93930016A priority patent/NO930016L/no

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/16—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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 derivatives of pituitary posterior lobe hormones, more precisely to new vasotocin derivatives which are competitive oxytocin receptor antagonists and inhibit excessive uterus contractions.
  • the new vasotocin derivatives are modified in relation to the vasotocin molecule by having shortened and optionally even modified C-terminal along with alterations in the positions 1, 2 , 4 and optionally 6.
  • Oxytocin is a pituitary posterior lobe hormone, and receptors specific for said hormone are found in the body of mammals including humans. The sites of the receptors are hitherto found in the uterus, the lactation ducts and the ovaries. Oxytocin receptor antagonists may thus be used as competitive receptor blockers in case of increased endogenous oxytocin secretion or increased receptor density.
  • EP-A-0 182 627 discloses a large number of structurally similar vasopressin analogues, which are said to be basic Vi-Vasopressin antagonists and may be useful in the treatment of hypertension and cardiac ischaemic diseases.
  • the compounds of the invention are represented by a general structural formula which has been restricted by a provisio, to delimit the compounds from the compounds of the EP-A-0 182 627.
  • the present invention provides new derivatives of pituitary posterior lobe hormones which are vasotocin derivatives having enhanced potency and longer effect duration than our prior vasotocin derivatives disclosed in EP-A-0 112 809.
  • Vasotocin derivatives of the invention are comprised by the following formula:
  • A Mpa (3-mercaptopropionyl residue; -S-CH2-CH2-CO-) or Hmp (2-hydroxy-3-mercaptopropionyl residue;
  • F a L- or D-residue of the fomula NH-(CH2) m -CH-L
  • the present invention also comprises pharmaceutical composi ⁇ tions, which include at least one vasotocin derivative according to the invention as an active ingredient in combination with pharmaceutically acceptable additives and/or diluents.
  • pharmaceutically acceptable diluent preferably isotonic saline solution may be used.
  • other pharmaceutically acceptable additives such can be found in the literature, e.g. the US Pharmacopoeia, and these additives can be chosen in conformity with the specific form of the composition for a specific administration rout.
  • a composition of the invention can be in a form which is suitable for intravenous, intranasal or intraintestinal administration.
  • a form which is suitable for intraintestinal administration may be a tablet which is taken orally and which preferably is coated with a layer which is at least not completely dissolved in the stomach but primarily in the intestines so that the active ingredient can be resorbed through the intestinal mucous membrane.
  • vasotocin derivatives according to the present invention totally lack agonistic effect as well as antidiuretic effect and blood-pressure effect, resulting in that possible clinical side effects are minimized.
  • Figure 1 presents antagonistic effect on rat uterus in vivo, following intranasal administration of a reference substance (Peptide 1) and a vasotocin derivative according to the invention (Peptide 2).
  • Figure 2 presents antagonistic effect on rat uterus in vivo, following intraintestinal administration of the same peptides as in Figure 1.
  • Figure 3 presents antagonistic effect on rat uterus in vivo, following intravenous administration of the same peptides as in Figure 1.
  • Figure 4 presents antagonistic effect on rat uterus in vivo, following intravenous administration of a reference substance (Peptide 1) in a dose of 10 -8 mole/kg and a vasotocin derivative according to the invention (Peptide 3) in a dose of 2 x 10 ⁇ 9 mole/kg (i.e. one fifth of the dose of the reference) .
  • a reference substance Peptide 1
  • a vasotocin derivative according to the invention Peptide 3
  • Figure 5 presents antagonistic effect on rat uterus in vivo, following intraintestinal administration of a dose of 8 x 10 ⁇ 6 mole/kg of the same peptides as in Figure 4.
  • vasotocin derivatives according to the invention can be prepared —l analogy with processes well known in the peptide field.
  • the compounds according to the invention may be prepared in conventional manner by incremental coupling of amino acids to one another in the liquid phase, for instance in accordance with the technique reported by Law, H.B. & Du Vigneaud, V. in the Journal of the American Chemical Society 12 (1960) 4579-4581, Zhuze, A.L., Jost, K., Kasafirek, E. & Rudinger, J. in the Collection of Czechoslovak Chemical Communications 2£, (1964), 2648-2662, and modified by Larsson, L.-E., Lindeberg, G., Melin, P. / Pliska, V. in the Journal of Medicinal Chemistry ___, (1978), 352-356.
  • the coupling of the amino acids to one another, whereby so-called peptide bonds are formed may also be carried out by starting with a solid phase (usually a resin) to which the C-terminal of the first amino acid is coupled, whereupon the C-terminal of the next amino acid is coupled to the N-terminal of the first amino acid etc. Finally, the built-up peptide is released from the solid phase.
  • a solid phase usually a resin
  • the built-up peptide is released from the solid phase.
  • peptides disclosed in the following examples were synthesized using the solid phase technique (J. M. Stewart, J.D. Young. Solid Phase Peptide Synthesis, Pierce Chemical Company) .
  • the peptides were purified by liquid chromatography (reversed phase).
  • the stationary phase was composed of Kromasil®, 13 u, 100 A, C 18 (EKA Nobel, Sweden) and the mobile phase was acetonitrile/water having 0.1 % trifluoroacetic acid. Those fractions containing pure product (HPLC analysis) were pooled, evaporated and the product freeze-dried from water.
  • Boc t-butyloxycarbonyl
  • FmocONSu 9-fluorenylmethoxycarbonyl-N-hydroxy- succinimide
  • D-Phe(p-Et) p-ethyl-D-phenylalanyl
  • HOBt hydroxybenzotriazole
  • NS-benzyloxycarbonyl ornithine (5.3 g, 20 mole) was suspended in a mixture of water (50 ml) and acetonitrile (100 ml). Diisopropylethylamine (3.4 ml) and Fmoc-ONSu (7.4 g 22 mmole) were added. Following agitation for 2 hours at room temperature, the acetonitrile was distilled off. The residue was acidified with 1 M hydrochloric acid and the product was extracted into ethyl acetate. The ethyl acetate phase was washed with water, dried with sodium sulphate, filtered and evaporated.
  • N -tert-butyloxycarbonyl-D,L-p-ethylphenylalanine (A.L. Zhuse, K. Jost, E. Ka ⁇ afirek, J. Rudinger. Collection Czechoslov Chem Commun. Vol 2£, 2648 (1964) (0.88 g, 3 mmole), pentafluorophenol (0.61 g, 3.3 mmole) and dicyclo- hexyl carbodiimide (0.68 g, 3.3 mmole) were dissolved in 6 ml ethyl acetate.
  • Homocystine (8.06 g, 30 mmole) was reduced with sodium in liquid ammonia (300 ml). The excess sodium was destroyed with ammonium chloride (the solution was decolourized) and the ammonia was evaporated. The residue was dissolved in water
  • the dicyclohexylammonium salt of the derivative II (3.4 g, 5 mmole) was suspended in ethyl acetate and shaken with 0.5 M H2SO4. The phases were separated and the organic phase was washed with water, dried with sodium sulphate, filtered and evaporated. The residue was dissolved in ethyl acetate (10 ml). Pentafluorophenol (1.02 g, 5.5 mmole) and dicyclohexyl carbodiimide (1.13 g, 5.5 mmole) were added. Following agitation at room temperature for 1 hour, the reaction mixture was cooled with ice for 2 hours, whereupon the dicyclohexyl urea was filtered off. The filtrate was concentrated, diluted with hexane and cooled. The product (III) was filtered off and washed with hexane. Yield 2.3 g (70 %). Mp: 58-59°C.
  • the peptide was synthesized according to the general description of synthesis by the use of Boc/benzyl methodol ⁇ ogy.
  • the tiol groups in cysteine and mercaptopropionic acid were blocked with p-methoxy-benzyl groups.
  • Activation of the amino acids was effectuated with DDC/HOBt and the group N ⁇ - Boc was removed with 50 % trifluoroacetic acid in methylene chloride.
  • the resin was of methylbenzhydryl type with the loading of 0.7 mmole/g. Resin in an amount of 0.7 g was used in every synthesis.
  • the peptide was deblocked and cleaved from the resin with liquid hydrogen fluoride/anisole/ethylmethyl-sulphide in the ratio of 90:5:5. Following the evaporation of the hydrogen fluoride, the resin was suspended in ethyl acetate, filtered and washed with additional ethyl acetate. The resin was triturated with acetic acid in order to yield the peptide. The resin was filtered off and the filtrate diluted with 20 % acetic acid in methanol, so that the peptide concentration became approximately 0.5 mmole/1. This solution was treated with 0.1 M iodine solution in methanol until a faint yellowish brown colour persisted.
  • the peptide was synthesized and purified in accordance with the methods used for the peptide in Example 1. Yield: 25 mg. Purity (HPLC): ⁇ 99%.
  • the peptide was synthesized in accordance with the general description of synthesis by using Fmoc/t-butyl methodology.
  • the resin was of polyamide kiselguhr type (PepSyn KB, loading 0.09 mmole/g) and 2.2 g was used in every synthesis.
  • Fmoc- -0rn(Cbz)-0H was coupled to the resin as a symmetric an ⁇ hydride.
  • the other amino acid derivatives were coupled as active esters (4 eqv) .
  • the following derivatives were used:
  • Fmoc-Pro-OPfp derivative III, Fmoc-A ⁇ n-OPfp, Fmoc-Thr(t-Bu)- -ODhbt, Fmoc-Ile-OPfp and Boc-D-Tyr(Et)-OPfp.
  • the peptide resin IV was treated with trifluoroacetic acid/methylene chloride/anisole in the ratio of 45:45:10; (2x15 min.) Then, the peptide resin was washed with methylene chloride, 5 % diisopropylethylamine in methylene chloride and methylene chloride. The peptide was then cleaved from the resin with ammonia (100 ml) in methanol (50 ml). The resin was filtered off and the methanol solution was evaporated. The residue was dissolved in a small volume of methanol. The peptide (V) was precipitated with ether. Yield 130 mg.
  • the peptide V (100 mg) was cyclized with diphenyl-phosphoryl azide (DPPA, 50 ⁇ l) and K HP0 4 (110 mg) in dimethylformamide (25 ml) at 0°C for 24 hours.
  • DPPA diphenyl-phosphoryl azide
  • K HP0 4 110 mg
  • the protective group of ornithine in the peptide VI was removed with liquid hydrogene fluoride/anisole in the ratio of 10:1.
  • the hydrogene fluoride was distributed in ethyl acetate and water.
  • the aqueous phase, which contained the peptide 3 was freeze-dried.
  • the peptide was purified according to the above method. Yield 38 mg. Purity (HPLC): ⁇ 99%.
  • Example 3 For the synthesis, the same method as disclosed in Example 3 was used, with the exception that a racemate was used at the coupling of the amino acid in the position 2 (Boc-D,L-Phe- (p-Et)-OPfp) . Only 1.1 equivalents of Boc-D,L-Phe(p-Et)-OPfp was used in the first coupling, so that neither of the enantiomers would be favoured in the coupling. The period of coupling was increased to 4 hours compared to ordinarily 45 minutes. In the second coupling, 0.8 equivalents of Boc-D,L- Phe(p-Et)-OPfp was used.
  • the peptide was synthesized and purified in accordance with the methods used for the peptide in the Example 1, with the exception of D-Tyr(Et) which was replaces by D-Trp in position 2. Yield: 26 mg. Purity (HPLC): ⁇ 99%.
  • the peptide was synthesized and purified in accordance with the methods used for the peptide in the Example 2, with the exception of D-Tyr(Et) which was replaced by D-Trp in position
  • the peptide was synthesized and purified in accordance with the methods used for the peptide in Example 3, with the exception of D-Tyr(Et) which was replaced by D-Trp in position 2. Yield: 45 mg. Purity: ⁇ 99%.
  • the peptide was synthesized and purified in accordance with the methods used for the peptide in Example 1, with the exception of Thr which was replaced by Val in position 4. Yield: 28 mg. Purity (HPLC): ⁇ 99%.
  • the compounds according to the invention were investigated with regard to uterotonic potency on isolated rat uterus and myometric tissue from woman, using oxytocin (OT) as agonist.
  • OT oxytocin
  • the antagonistic properties of the compounds were also evaluated with the aid of this preparation.
  • rat uterus in vivo tests using oxytocin as the agonist were carried out, the results being compared to those obtained with a reference substance, Peptide 1; a compound according to EP-A-0 112 809).
  • Tissue from the myometrium was obtained at Caesarean sections (from the University Clinic of Lund, Sweden). Tissue pieces from pregnant women were excised from the isthmus part of the uterus. Isometric contractions were measured on isolated tissue (2x2x20 mm), and the recording of the contractions were performed with the aid of a Grass force transduser (F03) and polygraph (P 08) at a resting tension of 10 mN. Krebs-Ringer (1.5 mmole/1) buffer was used as buffer at 37°C. A dose of the agonist (oxytocin) was given to concentration (0.1 j ⁇ mol/1) either alone or 2 minutes after a dose of reference substance the Peptide 1 or the Peptides 2-4 according to the invention.
  • F03 Grass force transduser
  • P 08 polygraph
  • each of the reference and test preparations were administered to the same tissue preparation in a randomized manner, and 4 tissue preparations were tested in parallel.
  • the effects on the myometrium was measured by integrating the registration curves during 10 minutes after the addition of the agonist. Inhibition was expressed as per cent of the average effect following administration of agonist only at the beginning and the end of the experiment.
  • the per cent inhibition of each inhibitor (the Peptides 2-4) was compared with the reference substance (the Peptide 1) according to a so-called 4-point test (St ⁇ rmer 1968). The results are given in Table 1, Column a.
  • Sprague Dawley rats (body weight approximately 250 g) in natural estrous were selected by vaginal smears.
  • An ap ⁇ proximately 20 mm long segment was cut from the middle of a uterine horn and mounted in an organ bath containing 10 ml of a modified Locke's solution of the following composition (mM: NaCl 153, KC1 5.63, CaCl 2 0.541, NaHC0 3 5.95 and glucose 2.78).
  • the solution was ga ⁇ ed with 5% C0 2 in oxygen at 30°C.
  • the uterine contractions were allowed to stabilize for 30 minutes. The contractions were recorded isometrically at a loading of 1.5 g with the aid of a Grass force transduser (Ft.03).
  • the antagonistic potency of the analogues were calculated as their pA 2 -values (Rudinger, J. & Krejci, I. Experientia 18, (1962), 585-588).
  • pA 2 is a measure of the inhibitory property of the peptide and was defined by Schild (Schild, H.O. British Journal of Pharmacology, 2, (1947), 189-206) as the negative logarithm of the molar concentration of an antagonist which reduces the effect of a dose of agonist to that of half the dose.
  • the possible agonistic effects of the antagonists were investigated by adding to the bath containing the uterus preparation a varying amount of peptide, cr -esponding at most to a concentration of 4 nmole/ml. No agonistic effect was observed in any of the cases. The results are shown in Table I, Column b.
  • Oxytocin was infused intra ⁇ venously (0.05 ⁇ g/min/100 g body weight).
  • the antagonist 0.8-8.0 Hg/100 9 body weight
  • the recorded curve was integrated over a 15 minutes period immediately before and after injection of the antagonist.
  • the inhibition of the increase in the magnitude of the uterus contractions caused by oxytocin infusion was compared with the inhibition caused by the reference Peptide 1, which was given the value 100.
  • Table 1 Column A.
  • the dose-effect curve for oxytocin (2*10 ⁇ 4 - 5'10 ⁇ 3 ⁇ mole/kg) was carried out.
  • Such an oxytocin dose (2 x) is selected that gives an effect corresponding to an intraluminar contraction pressure of 10-30 mg Hg and that lies on the linear part of the dose-effect curve.
  • the effects are measured as the net values of the integrated curve recorded over 15 minutes after injection.
  • the effect (eff x) of the agonist for its half dose (x) is calculated. Thereafter at least two doses of antagonist (Peptide 1-4) are injected in combination with the agonist dose (2 x). By interpolating the dose-effect curve for the inhibition, the antagonist dose corresponding to the effect (eff x) of the agonist dose (x), i.e. the I.D. dose, is obtained.
  • the results are shown in Table I, Column B.
  • Such a dose of the agonist is selected (5*10 ⁇ 4 - 5*10 ⁇ 3 ⁇ mole/kg) that gives an effect (the effect was measured over a 15 minutes period after agonist and antagonist administration, respectively, the contraction curve being integrated) corresponding to approximately 50 % of the maximum effect (ED50).
  • a measure of the bioavailability of the peptide is obtained if the inhibitory effect of the intranasal ad ⁇ ministration is compared to the effect after intravenous administratio .
  • Oxytocin (OT) is infused intravenously (0.5 ⁇ g/ in/kg) to elicit an agonist effect.
  • the antagonist 0.01-0.1 ⁇ g/kg
  • the effects of two different doses were investigated. When the effects had ceased the peptide was administered, after a period of 15 minutes, intranasaly in a single dose (0.1-1.0 ⁇ g/kg).
  • the peptide was administered in a volume of 10 ⁇ l in isotonic saline solution via a fine tube, the tip of which being 10 mm inside the nasal cavity of the rat. Rinsing of this was performed by perfusion with saline solution (20 ml/h) over 10 minutes via an additional tube, which had been introduced into the esophagus. The results are shown in Figure 1.
  • the peptide was administered via a catheter into an approxi- raately 20 cm long segment of the small intestine, which had been ligated from the rest of the intestine by ligatures at both ends of the section of the intestine, and a tube had been fixed to each of these ends for rinsing and peptide administration.
  • the rinsing liquid was driven out by air prior to the administration of the peptide, which was effectuated via the distal intestinal tube in 1 ml volume of saline solution per 10 cm intensine. The results are shown in Figures 2 and 5.
  • the potency increase up to five times with the Peptides 2-4, 7, 8 and 10, i.e. they can be injected in doses correspondingly lower compared to the corresponding known peptides of full length.
  • the duration of the inhibitory effect is unchanged with the Peptide 5, increases at least two times with the Peptides 2 and 7, three times with the Peptide 3 and four times or more with the Peptides 4 and 8.
  • the Peptides 3 and 4 which both are ⁇ -Abu 6 derivatives, give, in analogy with what has been previously known from pituitary posterior lobe agonists, a further prolonged effect duration. It is remarkable that the Peptides 3 and 7 additionally give a substantially enhanced inhibitory effect in regard to isolated human myometrium, which indicates an enhanced receptor affinity.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Reproductive Health (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Saccharide Compounds (AREA)
  • Steroid Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention décrit des dérivés d'hormones du lobe pituitaire postérieur, plus précisément, de nouveaux dérivés de vasotocine. Les nouveaux dérivés de vasotocine correspondent à la formule (I), dans laquelle A = Mpa ou Hmp, B = D-Tyr, D-Tyr(Et), D-Phe, D-Phe(p-Et) ou D-Trp, C = Thr, Val ou Hgn, D = Cys ou α-Abu, E = Pro ou une liaison de peptide, F = (a), dans laquelle m = 0-6, n = 0-6, L = H, COOH, CO-NH2 ou CH2-OH, K = H, (b) ou un résidu d'acide aminé dans la mesure ou L n'est pas H quand A est Mpa, C est Thr ou Val et D est Cys. De plus, l'invention décrit, des compositions pharmaceutiques comprenant les nouveaux dérivés de vasotocine, de préférence sous forme appropriée à l'administration intraveineuse, intranasale ou intraintestinale. Les compositions sont particulièrement destinées au traitement thérapeutique des contractions excessives du muscle utérin.
PCT/SE1991/000477 1990-07-09 1991-07-04 Derives d'hormones du lobe pituitaire posterieur WO1992000996A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
MC91@@D MC2291A1 (fr) 1990-07-09 1991-07-04 Derives d'hormones du lobe posterieur de l'hypophyse
JP91512399A JPH05508849A (ja) 1990-07-09 1991-07-04 下垂体後葉ホルモン誘導体
FI930013A FI930013A0 (fi) 1990-07-09 1993-01-04 Hormonderivat av bakre hypofysloben
CZ939A CZ993A3 (en) 1990-07-09 1993-01-05 derivatives of neurohypophysis lobe hormones
NO93930016A NO930016L (no) 1990-07-09 1993-01-05 Derivater av hypofysens baklapphormoner

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9002384A SE9002384D0 (sv) 1990-07-09 1990-07-09 Derivat av baklobshormoner
SE9002384-7 1990-07-09

Publications (1)

Publication Number Publication Date
WO1992000996A1 true WO1992000996A1 (fr) 1992-01-23

Family

ID=20379963

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1991/000477 WO1992000996A1 (fr) 1990-07-09 1991-07-04 Derives d'hormones du lobe pituitaire posterieur

Country Status (11)

Country Link
EP (1) EP0538367A1 (fr)
JP (1) JPH05508849A (fr)
AU (1) AU8225191A (fr)
CA (1) CA2085603A1 (fr)
FI (1) FI930013A0 (fr)
IE (1) IE912378A1 (fr)
IL (1) IL98737A0 (fr)
MC (1) MC2291A1 (fr)
PL (1) PL297600A1 (fr)
SE (1) SE9002384D0 (fr)
WO (1) WO1992000996A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001368A1 (fr) * 1993-06-29 1995-01-12 Ferring B.V. Synthese amelioree de peptides cycliques
WO1995002609A1 (fr) * 1993-07-13 1995-01-26 Ferring B.V. Peptides presentant une activite antagoniste de l'oxytocine
WO1998023636A1 (fr) * 1996-11-26 1998-06-04 Ferring B.V. Analogues d'heptapeptide oxytocine
US7091314B2 (en) 2002-02-27 2006-08-15 Ferring Bv Intermediates and methods for making heptapeptide oxytocin analogues

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0112809A1 (fr) * 1982-12-21 1984-07-04 Ferring AB Dérivés de vasotocine
US4483794A (en) * 1983-05-10 1984-11-20 Ceskoslovenska Akademie Ved Analogs of neurohypophysial hormones
EP0182627A2 (fr) * 1984-11-21 1986-05-28 Smithkline Beckman Corporation Antagonistes V1-vasopressine basiques
EP0182626A2 (fr) * 1984-11-21 1986-05-28 Smithkline Beckman Corporation Antagonistes V1-vasopressine
WO1987002676A1 (fr) * 1985-10-25 1987-05-07 Gibson-Stephens Neuropharmaceuticals, Inc. Antagonistes de l'oxytocine a conformation limitee presentant des activites biologiques prolongees

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0112809A1 (fr) * 1982-12-21 1984-07-04 Ferring AB Dérivés de vasotocine
US4483794A (en) * 1983-05-10 1984-11-20 Ceskoslovenska Akademie Ved Analogs of neurohypophysial hormones
EP0182627A2 (fr) * 1984-11-21 1986-05-28 Smithkline Beckman Corporation Antagonistes V1-vasopressine basiques
EP0182626A2 (fr) * 1984-11-21 1986-05-28 Smithkline Beckman Corporation Antagonistes V1-vasopressine
WO1987002676A1 (fr) * 1985-10-25 1987-05-07 Gibson-Stephens Neuropharmaceuticals, Inc. Antagonistes de l'oxytocine a conformation limitee presentant des activites biologiques prolongees

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001368A1 (fr) * 1993-06-29 1995-01-12 Ferring B.V. Synthese amelioree de peptides cycliques
US5596078A (en) * 1993-06-29 1997-01-21 Ferring Ab Synthesis of cyclic peptides
US5726287A (en) * 1993-06-29 1998-03-10 Ferring Ab Synthesis of cyclic peptides
WO1995002609A1 (fr) * 1993-07-13 1995-01-26 Ferring B.V. Peptides presentant une activite antagoniste de l'oxytocine
AU676071B2 (en) * 1993-07-13 1997-02-27 Ferring B.V. Peptides exhibiting oxytocin antagonistic activity
WO1998023636A1 (fr) * 1996-11-26 1998-06-04 Ferring B.V. Analogues d'heptapeptide oxytocine
US6143722A (en) * 1996-11-26 2000-11-07 Ferring, B.V. Heptapeptide oxytocin analogues
CZ299532B6 (cs) * 1996-11-26 2008-08-27 Ferring B.V. Heptapeptidový analog, farmaceutická kompozice obsahující tento analog, zpusob prípravy heptapeptidového analogu a jeho použití a zpusob prípravy farmaceutické kompozice obsahující tento analog
US7091314B2 (en) 2002-02-27 2006-08-15 Ferring Bv Intermediates and methods for making heptapeptide oxytocin analogues
US7304181B2 (en) 2002-02-27 2007-12-04 Ferring Bv Methods for making intermediates and oxytocin analogues
US7816489B2 (en) 2002-02-27 2010-10-19 Ferring B.V. Methods for making intermediates and oxytocin analogues

Also Published As

Publication number Publication date
EP0538367A1 (fr) 1993-04-28
IL98737A0 (en) 1992-07-15
FI930013A7 (fi) 1993-01-04
CA2085603A1 (fr) 1992-01-10
AU8225191A (en) 1992-02-04
PL297600A1 (fr) 1992-07-13
IE912378A1 (en) 1992-01-15
JPH05508849A (ja) 1993-12-09
SE9002384D0 (sv) 1990-07-09
FI930013A0 (fi) 1993-01-04
MC2291A1 (fr) 1993-07-14

Similar Documents

Publication Publication Date Title
US6143722A (en) Heptapeptide oxytocin analogues
EP0112809B1 (fr) Dérivés de vasotocine
US4490364A (en) CCK Agonists II
US4604378A (en) Basic V1 -vasopressin antagonists
EP0269299A2 (fr) Peptides atriaux
CA2022740C (fr) Antagonistes cycliques de la neurokinine a
WO1992000996A1 (fr) Derives d'hormones du lobe pituitaire posterieur
US4684621A (en) Methods of producing vasodilation or antioxytocic activity
US4658015A (en) Polypeptide intermediates
JPS62209096A (ja) バソプレシン化合物
CA2163114A1 (fr) Peptides presentant une activite antagoniste pour l'oxytocine
CZ993A3 (en) derivatives of neurohypophysis lobe hormones
JPS63303999A (ja) バソプレシン拮抗剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR CA CS FI HU JP KP KR LK MC MG MW NO PL RO SD SU US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE BF BJ CF CG CH CI CM DE DK ES FR GA GB GN GR IT LU ML MR NL SE SN TD TG

WWE Wipo information: entry into national phase

Ref document number: 2085603

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1991913318

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 930013

Country of ref document: FI

WWE Wipo information: entry into national phase

Ref document number: PV1993-9

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1991913318

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: PV1993-9

Country of ref document: CZ

WWW Wipo information: withdrawn in national office

Ref document number: 1991913318

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: PV1993-9

Country of ref document: CZ