WO1995002609A1 - Peptides exhibiting oxytocin antagonistic activity - Google Patents
Peptides exhibiting oxytocin antagonistic activity Download PDFInfo
- Publication number
- WO1995002609A1 WO1995002609A1 PCT/SE1994/000674 SE9400674W WO9502609A1 WO 1995002609 A1 WO1995002609 A1 WO 1995002609A1 SE 9400674 W SE9400674 W SE 9400674W WO 9502609 A1 WO9502609 A1 WO 9502609A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- peptide
- pharmaceutical composition
- composition according
- asn
- nαmeorn
- Prior art date
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 new peptides exhibiting oxytocin antagonistic activity.
- the peptides are built up of 7 amino acid residues and comprises an intramolecular ring structure. They can be used as active ingredients in pharmaceutical compositions for the inhibition of excessive uterus muscle contractions. These constitute the background for painful menstruations and premature labour.
- vasotocin analogues do not have any side effects, but they have a limited biological half-life and thus give a rather short effect duration.
- the enzymatic stability of the molecule, and thus the duration of the effect, is of major clinical importance at a single administration. Since the effect duration of these vasotocin analogues is comparatively short and the therapeutic dose is rather high, they have hitherto been administered intravenously in hospitals only.
- the present invention comprises a new peptide of the formula:
- Mpa is 3-mercaptopropionic acid residue (-S-CH 2 -CH 2 -CO-)
- X is D-tryptophan (D-Trp) or ⁇ - (2-Naphtyl) -D-alanine (D-Nal) lie is isoleucine
- Y is alloisoleucine (allolle) or
- CH 2 I and N ⁇ MeOrn is N ⁇ -methyl-ornithine.
- One aspect of the invention is directed to a peptide according to the invention for use as an active ingredient in a medicament.
- compositions which comprise at least one of the peptides according to the invention as active ingredient (s) in combination with pharmaceutically acceptable additives and/or diluents, and optionally enhancers.
- pharmaceutically acceptable diluent preferably isotonic saline solution may be used.
- additives such can be found in the literature, e.g. the US Pharmacopoeia, and these additives shall be chosen in conformity with the specific form of the composition for a specific administration route.
- Enhancers which may be used are any enhancers known to facilitate absorption of a drug through a mucous membrane. Examples of absorption enhancers in nasal drug delivery has been disclosed by Merkus, F.W.H.
- a composition according to the invention can be in a form which is suitable for intravenous, intranasal or oral administration.
- a form which is suitable for oral administration may be a tablet which is taken orally and which preferably is coated with a layer which is dissolved mainly in the intestines so that the active ingredient can be absorbed through the intestinal mucous membrane.
- An embodiment of this aspect of the invention is directed to a pharmaceutical composition according to the invention for use in therapeutic treatment of excessive uterus muscle contractions.
- Yet another aspect of the invention is directed to a method of counteracting excessive uterus muscle contractions, whereby a pharmaceutical composition according to the invention is administered in a therapeutically effectiv amount to a woman who is in need of such a treatment.
- the peptides according to the present invention have a specific effect on the uterus muscle and totally lack agonistic effect as well as antidiuretic effect and blood-pressure effect, resulting in high specificity, which means that possible clinical side effects are minimized.
- the peptides according to the invention can be prepared in 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 liquid phase, e.g. as described by Law, H.B. & Du Vigneaud, V. in Journal of the American Chemical Society 32, (1960) 4579-4581, Zhuze, A.L. , Jost, K. , Kasafirek, E. S_ Rudinger, J. in Collection of Czechoslovak Chemical Communications 22., (1964), 2648-2662, and modified by Larsson, L.-E., B Lindeberg, G., Melin, P. / Pliska, V. in the Journal of Medicinal Chemistry 21, (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 use of a solid phase (usually a resin) as starting material, 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.
- the ring closure is performed as the last step of synthesis after or before the release of the complete peptide from the solid phase.
- this so-called solid phase technique has been utilized in accordance with the disclosure according to Merrifield, R.B., J. Am. Chem. Soc. (1963), 35., 2149, Merrifield, R.B. Biochemistry (1964), 2, 1385 and K ⁇ nig, W. , Geiger, R., Chem. Ber. (1970), 103. 788.
- 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 ⁇ or 5 ⁇ , 100 A, C 18 or C 8 (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 was freeze-dried from water.
- the purity and structure of the peptides were determined by HPLC, amino acid analysis and FAB-MS.
- Fmoc-homoCys(CH 2 CH 2 COOt-Bu) -OH was synthesized according to a publication of E. Prochazka et al, Collect. Czech. Chem. Commun. 1992, 52, 1335.
- Fmoc-N ⁇ MeOrn(Pht) -OH was synthesized in the same way as the corresponding lysine derivative according to a publication of R. M. Freidinger et al, J. Org. Chem. 1983, 4£, 77.
- TBTU 2- (1-H-benzotriazol-l-yl) -1,1,3,3-tetramethyl-uronium- tetrafluoroborate
- MBHA 4-methyl-benzhydrylamine
- Boc t-buthyloxycarbonyl
- NMP N-methylpyrrolidone
- HOBt 1-hydroxybenzotriazole
- DBU l , 8 -diazabicyclo [5 .4 . 0] undec-7-ene
- DMF Dimethylformamide
- DIPEA Diisopropylethylamine
- the peptide was synthesized according to a mixed Boc/Fmoc methodology on solid phase. Activation of the amino acids was made with TBTU/HOBt. The resin was of MBHA-type with the loading of 0.65 mmole/g, and 0.33 g was used for each synthesis. The first amino acid was N ⁇ Boc protected. The Boc group was removed with 50 % trifluoroacetic acid in dichloromethane. The rest of the synthesis followed the Fmoc strategy, i.e. N ⁇ -Fmoc protected amino acids were coupled to the free amino group of the previously coupled amino acid. The N ⁇ -Fmoc group was removed with 20 % piperidine in NMP.
- the resin was treated with 20 % piperidine in NMP, followed by 50 % TFA in dichloromethane.
- the peptide chain was thereafter cyclized while it was still attached to the resin, from D-Trp 2 to homoCys(CH 2 CH 2 COOH) 6 by activating with TBTU/HOBt, i.e. between positions 1 and 2.
- the peptide was cleaved from the resin with liquid hydrogen fluoride-thiocresol- cresol-dimethylsulfide in the ratio of 8-0.25-0.75-1 at 0°C.
- the resin was suspended in diethyl eter, filtrated and washed with additional diethyl eter.
- the precipitated peptide was recovered from the resin by dissolving in acetic acid.
- the acetic acid was evaporated and the residue freez-dried from water.
- the freez- dried product was dissolved in ethanol, whereupon hydrazine hydrate was added in a molar excess.
- the solution was stirred over night at room temperature, whereupon it was acidified with H 3 0 + and evaporated, and freez-dried from water.
- the peptide was synthesized according to Fmoc methodology on solid phase. Activation of the amino acids was made with DIC/HOBt.
- the resin was of TentaGel-S-type with RAM-linker (Rapp Polymere S 30023) .
- the N ⁇ -Fmoc-groups were removed by 2% DBU in DMF.
- the peptide was cleaved from the resin and deprotected with TFA/ethanedithiol/anisole in the ratio of 95:2.5:2.5.
- the reaction mixture was filtered and the filtrate was concentrated.
- the peptide was precipitated with diethyl ether.
- the peptide was cyclized between the positions 1 and 2 by activation with TBTU/HOBt/DIPEA in DMF.
- N ⁇ MeOrn(Pht) was deprotected by the addition of hydrazine hydrate. Following stirring overnight at room temperature, the solution was neutralized and evaporated.
- the product was purified as disclosed above.
- the peptide was synthesized according to the same methodology as in Example 2. At the purification performed as above the analogues with the R and S isomers of Ala( ⁇ -Et 2 ), respectively, were separated. The S isomer (Peptide 5) was eluated after the R isomer.
- the enantiomeric forms of the respective peptide analogue was determined by first hydrolyzing and then derivatizing the amino acids, and analyzing the mixture on a chiral column by a gas chro athographic method.
- Sprague Dawley rats 250 g in natural estrous were anaesthesized with Inactin (0.5 mg/lOO g body weight i.p.) .
- the activity of the myometrium was measured with the aid of a catheter which had been fixed in the uterus cavity and which had been filled with modified Locke's solution.
- the catheter was connected to a Statham P23d force transducer and the contractions were registered on a Grass polygraph (model 7D) .
- 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 which gives an effect corresponding to an intraluminar contraction pressure of 10-30 mg Hg and which lies on the linear part of the dose-effect curve.
- the effects are measured as the net values of the integrated curve measured during 15 minutes after the injection.
- the effect (eff x) of the agonist is calculated for its half dose (x) .
- at least two doses of antagonist (Peptide 1-4) are injected in combination with the agonist dose (2 x) .
- the antagonist dose corresponding to the effect (eff x) of the agonist dose (x) i.e. the I.D. dose, is obtained.
- Table I The results are shown in Table I.
- Antagonist tests effect duration.
- a dose of the agonist is selected (5.10 "4 - 5.10 "3 ⁇ mole/kg) which gives an effect (the effect is measured during a 15 minutes period after agonist and antagonist administration, respectively, the contraction curve being integrated) corresponding to approximately 50 % of the maximum effect (ED 50 ) .
- I ⁇ BLEJ Pharmacological data for oxytocin antagonists
- Test substance ID nmol/kg Duration, min 0.75
- Peptide 5 (inv.) 2.7 ⁇ 0.1 226 ⁇ 41
- WO 92/00996 has the longest duration, having the formula
- Peptide 3 (inv.) The peptide according to the invention having the formula
- Peptide 4 (inv.) The peptide according to the invention having the formula
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU72406/94A AU676071B2 (en) | 1993-07-13 | 1994-07-07 | Peptides exhibiting oxytocin antagonistic activity |
JP7504493A JPH09502427A (ja) | 1993-07-13 | 1994-07-07 | オキシトシン拮抗薬活性を示すペプチド |
EP94921875A EP0791012A1 (en) | 1993-07-13 | 1994-07-07 | Peptides exhibiting oxytocin antagonistic activity |
KR1019950705294A KR960702848A (ko) | 1993-07-13 | 1995-11-27 | 옥시토신 길항적 활성을 나타내는 펩티드 |
NO955059A NO955059L (no) | 1993-07-13 | 1995-12-13 | Peptider som utviser oksytocin antagonistisk aktivitet |
FI960119A FI960119A (fi) | 1993-07-13 | 1996-01-10 | Peptidit, joilla on oksitosiinin vastaista aktiivisuutta |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9302414A SE501678C2 (sv) | 1993-07-13 | 1993-07-13 | Peptid med oxytocinantagonistaktivitet samt farmaceutisk komposition innehållande nämnda peptid |
SE9302414-9 | 1993-07-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995002609A1 true WO1995002609A1 (en) | 1995-01-26 |
Family
ID=20390606
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE1994/000674 WO1995002609A1 (en) | 1993-07-13 | 1994-07-07 | Peptides exhibiting oxytocin antagonistic activity |
Country Status (16)
Country | Link |
---|---|
EP (1) | EP0791012A1 (fi) |
JP (1) | JPH09502427A (fi) |
KR (1) | KR960702848A (fi) |
CN (1) | CN1126999A (fi) |
AU (1) | AU676071B2 (fi) |
CA (1) | CA2163114A1 (fi) |
CZ (1) | CZ9896A3 (fi) |
FI (1) | FI960119A (fi) |
HU (1) | HUT74874A (fi) |
IL (1) | IL110267A0 (fi) |
NO (1) | NO955059L (fi) |
PL (1) | PL312568A1 (fi) |
SE (1) | SE501678C2 (fi) |
TW (1) | TW268009B (fi) |
WO (1) | WO1995002609A1 (fi) |
ZA (1) | ZA945090B (fi) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998023636A1 (en) * | 1996-11-26 | 1998-06-04 | Ferring B.V. | Heptapeptide oxytocin analogues |
US7091314B2 (en) | 2002-02-27 | 2006-08-15 | Ferring Bv | Intermediates and methods for making heptapeptide oxytocin analogues |
WO2017060339A1 (en) | 2015-10-06 | 2017-04-13 | Ferring B.V. | New methods for making barusiban and its intermediates |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992000996A1 (en) * | 1990-07-09 | 1992-01-23 | Ferring Ab | Derivatives of pituitary posterior lobe hormones |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5373089A (en) * | 1988-09-02 | 1994-12-13 | Northwestern University | Oxytocin antagonist |
SE501677C2 (sv) * | 1993-06-18 | 1995-04-10 | Ferring Bv | Biologiskt aktiva vasopressinanaloger, farmaceutiska preparat innehållande dem samt deras användning för framställning av läkemedel |
-
1993
- 1993-07-13 SE SE9302414A patent/SE501678C2/sv not_active IP Right Cessation
-
1994
- 1994-07-07 CA CA002163114A patent/CA2163114A1/en not_active Abandoned
- 1994-07-07 HU HU9503768A patent/HUT74874A/hu unknown
- 1994-07-07 WO PCT/SE1994/000674 patent/WO1995002609A1/en not_active Application Discontinuation
- 1994-07-07 JP JP7504493A patent/JPH09502427A/ja active Pending
- 1994-07-07 AU AU72406/94A patent/AU676071B2/en not_active Ceased
- 1994-07-07 CN CN94192763A patent/CN1126999A/zh active Pending
- 1994-07-07 CZ CZ9698A patent/CZ9896A3/cs unknown
- 1994-07-07 EP EP94921875A patent/EP0791012A1/en not_active Withdrawn
- 1994-07-07 PL PL94312568A patent/PL312568A1/xx unknown
- 1994-07-11 IL IL11026794A patent/IL110267A0/xx unknown
- 1994-07-13 ZA ZA945090A patent/ZA945090B/xx unknown
- 1994-08-05 TW TW083107195A patent/TW268009B/zh active
-
1995
- 1995-11-27 KR KR1019950705294A patent/KR960702848A/ko not_active Application Discontinuation
- 1995-12-13 NO NO955059A patent/NO955059L/no unknown
-
1996
- 1996-01-10 FI FI960119A patent/FI960119A/fi not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992000996A1 (en) * | 1990-07-09 | 1992-01-23 | Ferring Ab | Derivatives of pituitary posterior lobe hormones |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998023636A1 (en) * | 1996-11-26 | 1998-06-04 | Ferring B.V. | Heptapeptide oxytocin analogues |
LT4650B (lt) | 1996-11-26 | 2000-04-25 | Ferring B. V. | Heptapeptidiniai oksitocino analogai |
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 |
WO2017060339A1 (en) | 2015-10-06 | 2017-04-13 | Ferring B.V. | New methods for making barusiban and its intermediates |
RU2726414C2 (ru) * | 2015-10-06 | 2020-07-14 | Ферринг Б.В. | Новые способы получения барусибана и его промежуточных соединений |
Also Published As
Publication number | Publication date |
---|---|
SE501678C2 (sv) | 1995-04-10 |
EP0791012A1 (en) | 1997-08-27 |
CN1126999A (zh) | 1996-07-17 |
CA2163114A1 (en) | 1995-01-26 |
KR960702848A (ko) | 1996-05-23 |
ZA945090B (en) | 1995-02-22 |
TW268009B (fi) | 1996-01-11 |
FI960119A0 (fi) | 1996-01-10 |
SE9302414L (sv) | 1995-01-14 |
AU7240694A (en) | 1995-02-13 |
JPH09502427A (ja) | 1997-03-11 |
NO955059D0 (no) | 1995-12-13 |
CZ9896A3 (en) | 1996-06-12 |
HU9503768D0 (en) | 1996-02-28 |
AU676071B2 (en) | 1997-02-27 |
SE9302414D0 (sv) | 1993-07-13 |
HUT74874A (en) | 1997-02-28 |
FI960119A (fi) | 1996-01-10 |
IL110267A0 (en) | 1994-10-21 |
NO955059L (no) | 1995-12-13 |
PL312568A1 (en) | 1996-04-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6143722A (en) | Heptapeptide oxytocin analogues | |
FI92326C (fi) | LHRH:n nonapeptidi- ja dekapeptidianalogeja, jotka ovat käyttökelpoisia LHRH:n antagonisteina | |
HU224345B1 (hu) | Növekedési hormont felszabadító tulajdonságú peptidek, ezeket hatóanyagként tartalmazó gyógyszerkészítmények és alkalmazásuk | |
JP2001523232A (ja) | GnRH拮抗物質 | |
US5106834A (en) | Linear free-sulfhydryl-containing oligopeptide derivatives as antihypertensive agents | |
JPH0219397A (ja) | アルギニンバソプレシン拮抗剤の新規線形誘導体類 | |
JPS63154699A (ja) | バソプレシン拮抗剤 | |
WO2018128828A1 (en) | Novel hepcidin mimetics and uses thereof | |
JPS61191698A (ja) | 新規な環状ヘキサペプチドlhrh拮抗剤 | |
SE501677C2 (sv) | Biologiskt aktiva vasopressinanaloger, farmaceutiska preparat innehållande dem samt deras användning för framställning av läkemedel | |
CA2405704C (en) | Bombesin analogs for treatment of cancer | |
AU676071B2 (en) | Peptides exhibiting oxytocin antagonistic activity | |
KR0171614B1 (ko) | 혈관활성 바소토신 유도체 | |
EP1198478B1 (en) | Somatostatin analogs and their use for the treatment of cancer | |
IE912378A1 (en) | Derivatives of pituitary posterior lobe hormones | |
US6989371B1 (en) | Bombesin analogs for treatment of cancer | |
JPS63303999A (ja) | バソプレシン拮抗剤 | |
WO2002000688A1 (fr) | Compose peptidique, compositions pharmaceutiques et medicaments contenant ceux-ci comme principe actif |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 94192763.6 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU BG BY CA CN CZ FI HU JP KR LT LV MD NO NZ PL RO RU SI SK UA US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2163114 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1994921875 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 960119 Country of ref document: FI |
|
ENP | Entry into the national phase |
Ref document number: 1996 569140 Country of ref document: US Date of ref document: 19960111 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: PV1996-98 Country of ref document: CZ |
|
WWP | Wipo information: published in national office |
Ref document number: PV1996-98 Country of ref document: CZ |
|
WWP | Wipo information: published in national office |
Ref document number: 1994921875 Country of ref document: EP |
|
WWR | Wipo information: refused in national office |
Ref document number: PV1996-98 Country of ref document: CZ |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1994921875 Country of ref document: EP |