WO1987002676A1 - Antagonistes de l'oxytocine a conformation limitee presentant des activites biologiques prolongees - Google Patents

Antagonistes de l'oxytocine a conformation limitee presentant des activites biologiques prolongees Download PDF

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Publication number
WO1987002676A1
WO1987002676A1 PCT/US1985/002104 US8502104W WO8702676A1 WO 1987002676 A1 WO1987002676 A1 WO 1987002676A1 US 8502104 W US8502104 W US 8502104W WO 8702676 A1 WO8702676 A1 WO 8702676A1
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phe
tyr
thr
orn
asn
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PCT/US1985/002104
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English (en)
Inventor
Victor J. Hruby
Todd W. Rockway
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Gibson-Stephens Neuropharmaceuticals, Inc.
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Priority to PCT/US1985/002104 priority Critical patent/WO1987002676A1/fr
Priority to EP19850905687 priority patent/EP0247033A1/fr
Publication of WO1987002676A1 publication Critical patent/WO1987002676A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • polypeptides which are analogs of the hormone oxytocin.
  • the polypeptides are biologi ⁇ cally long-acting, oxytocin antagonists which inhibit oxytocin induced uterine contractions.
  • Oxytocin has the following formula:
  • a receptor is that entity, on a cell, which recognizes and binds a chemical substance. Once a chemical substance, such as a drug, binds to the receptor, it may act to initiate or block various biochemical an physiological se ⁇ quences. Such initiation or blockage is known as transduction.
  • com ⁇ petitive antagonists are molecules that bind to the receptor but do not transduce the biological system to pro ⁇ quiz a response.
  • antagonists block the action of the native hormone. It is, therefore, critical in drug design to develop a drug which has a structure and conformation specific to a particular receptor and specific for either binding or transduction.
  • a hormone antagonist must have a structure and conformation which enables it to bind to the corre ⁇ sponding hormone receptor and at the same time not transduce.
  • Oxytocin antagonists have been developed and studied. See generally, Hruby, V.J., “Topics in Molecular Pharmacology", Burgen, A.S.V. and Roberts, G.C.K., eds. , Elsevier/North Holland Biomedical Press, Amsterdam, pp. 99-126 (1981); Hruby, V.J. and Mosberg, H.I. in "Hormone Antagonists," Agarwal, M.K., ed., Walter de Gruyter and Co., Berlin, pp. 433-474 (1982); Manning, M. and Sawyer, W.H. in "Conference on the Neurohypophysis, " Moses, A., ed., S.
  • Examples of previously synthesized oxytocin antagonists include [dPen , Tyr(OMe) , Thr ] oxytocin, and [dPen , Phe , Asn 4, Orn8] oxytocin which are disclosed by Sawyer, W.H., Holdar,
  • Peptides are identi ⁇ fied by a ino acid sequence using established abbreviations.
  • Gly stands for glycine
  • Leu stands for leucine
  • '-'Tyr stands for tyrosine
  • Pen stands for penicillamine
  • dPen stands for 1-deaminopenicillamine
  • Cys stands for cysteine
  • Phe stands for phenylalanine
  • Phe(4-Me) stands for 4-methyl phenylalanine
  • Thr stands for threonine
  • Gin stands for glutamine
  • Ser stands for serine
  • Val stands for valine
  • Asn stands for asparagine
  • Orn stands for ornithine
  • lie stands for isoleucine
  • Pro stands for proline.
  • Polypeptide derivatives in which one or more of the amino acids have been replaced by another amino acid are often described by reference to the basic compound and the position and nature of the substitution.
  • the position of substitution is usu ⁇ ally identified by reference to the number of the amino acid in the sequence starting with the amino acid at the amino terminus of the peptide chain.
  • F ] oxytocin stands for H-dP -Gly- NH memo.
  • amino acids may exist as stereoisomers in both L and D configurations.
  • oxytocin antagonists One problem associated with the development of oxytocin antagonists is that such compounds have exhibited only short du ⁇ rations of biological acitivity or have not exhibited sufficient biological activity in vivo.
  • the present invention provides novel polypeptide com ⁇ pounds which are long acting antagonists of oxytocin and which exhibit prolonged in vitro and in vivo biological activity.
  • the compounds are a series of cyclic, conformationally constrained analogs of the natural hormone, oxytocin, which are especially effective in inhibiting oxytocin induced uterine contractions in mammals.
  • X is hydrogen or -NHject ;
  • Y and Z are independently sulfur or -CH ;
  • R and R which may be the same or different, are hy ⁇ drogen, methyl, cyclopentamethylene or lower alkyl having 1 to 5 carbon atoms;
  • R is Phe, D-Phe, Tyr, D-Tyr, Tyr(OMe), D-Tyr(OMe),
  • D-Phe(4-Et) ; 4 R is Gin, Thr, Ser, Asn, or Val;
  • R is Orn, Arg, Lys, Leu, or lie; provided, however, that when X is hydrogen and R is Phe and R is Asn, R 5 may not be Orn.
  • Particularly preferred compounds include:
  • the present invention relates to poly ⁇ peptides of the formula:
  • X is hydrogen or -NH_
  • Y and Z are sulfur or CHschreib
  • R 1 and R2 which may be the same or different, are hy ⁇ drogen, methyl, cyclopentamethylene or lower alkyl having 1 to 5 carbon atoms;
  • R is Phe, D-Phe, Tyr, D-Tyr, Tyr(OMe), D-Tyr(OMe * ), Tyr(OEt), D-Tyr(OEt), Phe(4-Me), D-Phe(4-Me), Phe(4-Et), or
  • R is Gin, Thr, Ser, Asn, or Val
  • R 5 i.s Orn, Arg, Lys, Leu, or lie; provided, however, that when X is hydrogen and R is
  • Tyr(OMe) R may not be Thr or when X is hydrogen, R is Phe, and R 4 i.s Asn, R5 may not be Orn. All amino acid residues which have chiral centers are of the L configuration except for those in position 2 which can be either the L or D configuration.
  • R 1 and R2 are both methyl groups the ammo acid residue in the 1 position is penicillamine, "Pen”.
  • an alkyl group is in one or both of these positions the molecule is fur ⁇ ther restrained which accounts in part for the prolonged biologi ⁇ cal activity of the compounds.
  • Particularly preferred compounds include:
  • polypeptides of the present invention are potent antagonists of oxytocin which exhibit prolonged bio ⁇ logical activity both din vivo and in vitro. It is believed that the polypeptides are potent antagonists which exhibit prolonged biological activity due in part to the O-alkyl or 4-alkyl substi ⁇ tuted amino acid in position 2.
  • the prolonged bio ⁇ logical activity is believed to be primarily attributable to the presence of a penicillamine amino acid derivative or a modified penicillamine amino acid derivative in position 1, a 4-sub- stituted alkyl or aryl L or D amino acid derivative at position 2, a carboxa ide or hydroxy-containing amino acid at position 4 and a basic amino acid at position 8. It is believed that the combination of the above factors accounts for the prolonged bio ⁇ logical activities of the compounds of the present invention.
  • [Pen , D-Phe(4-Me) , Thr , Orn ] oxytocin is a potent antagonist having an antagonist potency (pA 2 ) greater than 7.3.
  • pA « values represent the negative log to the base 10 of the average molar concentration of an antagonist which will reduce the response of the uterine horn of 2X units of pharmacologically active compound to X units of the agonist, in this case oxytocin.
  • the pA campground values in Table I represent only the lower limit of antagonist activity and, thus, the actual antago ⁇ nist activity may be considerably higher due to the prolonged activity of the compound.
  • An effective dosage of the compounds of the present invention can be determined by one of ordinary skill in the art without undue experimentation.
  • the t 1/2 values for several compounds of the invention are summarized in Table I.
  • the t 1/2 value represents the abil ⁇ ity of an antagonist to stop the contraction of the uterine mus ⁇ cle over time.
  • the t 1/2 value was 2 hours and 28 minutes.
  • the t 1/2 value of the aforementioned compound should be contrasted with the t 1/2 value for oxytocin and previously known antagonists wherein complete reversal is normally observed in vitro in sever ⁇ al minutes.
  • the prolonged biological activity coupled with the potent antagonist.activity of the compounds of the present inven ⁇ tion render them useful in the prevention of premature birth in mammals.
  • the compounds of the claimed invention are also useful in blocking the release of prostaglandin and may also be useful in affecting the release of aldosterone. Additionally, it is be ⁇ lieved that the compounds of the present invention can be effec ⁇ tive in regulating the effects of oxytocin in the mammary glands and the central nervous system.
  • Example I Preparation of compounds within the scope of the pres ⁇ ent invention appear in the following examples.
  • Example I Preparation of N' 1 -benzyloxycarbonyl-S-benzyl-L- penicillaminyl-0-methyl-L-tyrosyl-L-isoleucyl-O-benzyl-L- threonylasparaginyl-S-benzy1-L-cysteinyl-L-prolyl-N -tosyl- I-ornithinylglycinamide.
  • Chloromethylated (1.02 mmol/g resin) polystyrene resin (1% crosslinked with divinylbenzene) was used for solid phase synthesis.
  • the carboxyl terminal amino acid (N -Boc-Gly) was attached to the resin as an ester linkage to a substitution level of about' 0.45 mmols of the protected amino acid/g resin using the method of Gisen, B., Helv. Chim Acta, 56, 1476-1482 (1973) which is specifically incorporated by reference herein.
  • the synthetic resin of the title compound was prepared, and the synthesis was carried out on approximately a 1.0 mmol scale (about 2.2-2.3 g of resin).
  • Boc-Gly-resin was placed into a solid phase peptide synthesis vessel and Boc-Orn(N -Tos), Boc-Pro, Boc-Cys (S-Bzl), Boc-Asn-ONp, Boc-Thr(O-Bzl) , Boc-Ile, Boc-Tyr(OMe) , and Z-Pen(S-Bzl) were then incorporated onto the growing peptide chain according to the protocol of Agenda A (set forth in the end of the example) and for Boc-Asn-ONp-the protocol of Agenda B (set forth in the end of the example) was followed to yield the resin compound Z-Pen(S-Bzl)-Tyr(OMe)-Ile-Thr(O-Bzl)-Asn-Cys-(S-Bzl)- Pro-0rn(N -To s)-Gly-0-Resin.
  • the peptide resin was removed from the reaction vessel by washing the resin four times with 30 ml of N,N-dimethylformamide (DMF) into a sintered glass funnel, followed by washing the resin with four 30 ml portions of CH 2 Cl 2 .
  • the resin was dried in vacuo for 3 hours and then weighed.
  • a portion of the peptide was hydrolyzed in a sealed ampoule con ⁇ taining 2 ml of a 1:1 mixture of 12N HC1 and propionic acid for 22 hr. at 110°C. The sample was then cooled and the solvents evaporated off in vacuo.
  • the protected peptide resin was placed in a 250 ml round bottom flask contain ⁇ ing a mixture of 150 ml of freshly distilled anhydrous methanol (from Mg(OMe) 2 ) and anhydrous ammonia (freshly distilled from Na) at -5°C to saturation of the ammonia in methanol.
  • the volume in the flask increased about 20 ml with the addition of the ammonia to the methanol.
  • the flask was wired shut and stirred in a dessicator containing KOH pellets for 4 days at 25°C.
  • the solvents were removed, first, by aspiration, then by rotary evaporation in vacuo to give a dry solid mixture.
  • the carboxamide terminal peptide was extracted from the resin by the addition of 125 ml of DMF and heating the resulting mixture at 62°C for 8 hours. The mixture was cooled, the resin filtered, and a fresh 125 ml portion of DMF added to the resin and the mix ⁇ ture heated at 85°C for 2 hours. The resin mixture was cooled, the resin filtered off, and the combined DMF solution evaporated down to 15 ml by rotary evaporatin in vacuo. Then, 125 ml of deionized water was slowly added and a white precipitate formed.
  • a sample of 250 mg of the protected nonapeptide from Example I was dissolved in 200 ml of anhydrous ammonia (freshly distilled from sodium). The solution was warmed to the boiling point and treated with a sodium stick until a blue color persisted for 60 seconds. If the blue color persisted for longer than 60 sec, the addition of a few mg of NH.C1 crystals rapidly dissipated the color and prevented cleavage at the proline resi ⁇ due. The ammonia was evaporated off under nitrogen and the last 20 ml was evaporated by l.yophilization. The white powder was dissolved in 650 ml of deaerated 0.1% aqueous acetic acid under a nitrogen atmosphere.
  • the pH of the solution was adjusted to 8.5 with 3N ammonium hydroxide.
  • the solution was then oxidized with an excess of 0.01 N K_Fe(CN),.
  • the resultant yellow solution was stirred for 30 min. while maintaining the pH at 8.5.
  • the excess ferro- and ferri-cyanide ions were removed from the solution by first adjusting the pH to 5 with 20% acetic acid and then adding 5 ml of the anion exchange resin, Rexyn 203 (Cl cycle) or the anion exchange resin BioRad AG3X4A (Cl cycle). The mixture was stirred for 20 minutes. The resin was then filtered off and washed with 20% aqueous acetic acid 3 times using 20 ml portions.
  • the combined aqueous solution was evaporated down to about 100 ml by rotary evaporation in vacuo at 20-30°C.
  • the compound was then purified by partition chromatography and gel filtration after lyophilization of the 100 ml of solution to a dry powder, as sum ⁇ marized below.
  • the analytic HPLC determinations were performed using a VYDAC 218 TP 4.6 15-16 CIS reverse phase col ⁇ umn 0.46 cm i.d. by 25 c ⁇ r. length (Separations Group, Inc., Hesperia, CA) .
  • Semipreparative HPLC purifications were performed on a Waters C18 reverse phase column 0.8 cm i.d. by 10 cm length contained in a Radial Compression Module (RCM) .
  • Flow rates were generally 1 ml/min in the analytical runs and 2-4 ml/min in the semipreparative runs.
  • Boc-Orn(N ⁇ -Tos) Boc-Pro
  • Boc-Cys(S-Bzl) Boc-Asn-ONp
  • the peptide was cleaved from the resin as its carboxamide terminal peptide after removal first of the N ⁇ -Boc group followed by neutralization (first 6 steps of Agenda A).
  • Example II The scheme outlined in Example II was used with a sam ⁇ ple of 250 mg of the peptide from Example III to obtain the title compound.
  • purification was achieved using the solvent system 1-butanol-water (containing 3.5% acetic acid and 1.5% pyridine).
  • Example V Preparation of L-penicillaminyl-D-phenylalanyl(4- methyl)-L-isoleucyl-L-threonyl-L-asparaginyl-L-cysteinyl- L-prolyl-L-ornithinylglycinamide cyclic disulfide.
  • Example IV The scheme outlined in Example IV was used since the title compound was present simultaneously with Examiner IV. On partition chromatography it eluted at Rf 0.37 and hence was read ⁇ ily separated from compound IV. Following gel filtration on
  • Example I The scheme outlined in Example I was followed except that N ⁇ -Boc-D,L-4-ethylphenylalanine was used for coupling this amino acid to the two (2) position in the peptide resin.
  • the synthesis involved coupling the following amino acids to the Boc- glycine-resi r Boc-Orn(N ⁇ -Tos) , Boc-Pro, Boc-Cys(S-Bzl) , Boc- Asn-ONp, Boc-Thr(O-Bzl) , Boc-Ile, Boc-D,L-Phe(4-Et) , and Boc- Pen(S-Bzl) to give the peptide resin Pen(S-Bzl)-D,L-Phe(4-Et) -Ile-Thr(O-Bzl)-Asn-Cys(S-Bzl)-Pro-Orn(N ⁇ -Tos)Gly-Resin.
  • Example VII Preparation of L-penicillaminyl-D-phenylalanyl(4- ethyl)-L-isoleucyl-L-threonyl-L-asparaginyl-L-cysteinyl- L-prolyl-L-ornithinylglycinamide cyclic disulfide.
  • Antioxytocic potencies were determined in the in vitro assay system using the pA2 method described by Schild, H.O., Brit J. Pharmacol. r 2_ 189-206 (1947) which is specifically incorpo ⁇ rated by reference herein.

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Abstract

Polypeptides de formule (I) où X est hydrogène ou -NH2; Y et Z sont indépendamment soufre ou CH2, R1 et R2 sont hydrogène, méthyle, cyclopentaméthylène ou un groupe alkyle possédant de 1 à 5 atomes de carbone; R3 est Phe, D-Phe, Tyr, D-Tyr, Tyr(OMe), D-Tyr(OMe), Tyr(OEt), D-Tyr(OEt), Phe(4-Me), D-Phe(4-Me), Phe(4-Et) or D-Phe(4-Et); R4 est Gln, Thr, Ser, Asn, ou Val; et R5 est Orn, Arg, Lys, Leu, ou Ile; à condition toutefois que lorsque X est hydrogène et R3 est Tyr(OMe), R4 ne puisse pas être Thr ou lorsque X est hydrogène, R3 est Phe et R4 est Asn, R5 ne puisse pas être Orn. Ces polypeptides sont des antagonistes de l'oxytocine et sont utiles en tant qu'inhibiteurs des contractions induites par l'oxytocine chez les mammifères.
PCT/US1985/002104 1985-10-25 1985-10-25 Antagonistes de l'oxytocine a conformation limitee presentant des activites biologiques prolongees WO1987002676A1 (fr)

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PCT/US1985/002104 WO1987002676A1 (fr) 1985-10-25 1985-10-25 Antagonistes de l'oxytocine a conformation limitee presentant des activites biologiques prolongees
EP19850905687 EP0247033A1 (fr) 1985-10-25 1985-10-25 Antagonistes de l'oxytocine a conformation limitee presentant des activites biologiques prolongees

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992000996A1 (fr) * 1990-07-09 1992-01-23 Ferring Ab Derives d'hormones du lobe pituitaire posterieur
US5225528A (en) * 1990-02-27 1993-07-06 Merck & Co., Inc. Cyclic hexapeptide oxytocin antagonists
US8338565B2 (en) 2008-08-20 2012-12-25 Ensemble Therapeutics Corporation Macrocyclic compounds for inhibition of tumor necrosis factor alpha

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4237119A (en) * 1976-07-16 1980-12-02 Ceskoslovenska Akademie Ved Long-acting oxytocin analogs for use in inducing and accelerating labor in mammals, particularly farm animals
EP0037516A1 (fr) * 1980-03-24 1981-10-14 Vega Laboratories, Inc. Dérivés N-omega substituées des analogues de 1-Desamino-vasopressin
EP0061356A2 (fr) * 1981-03-24 1982-09-29 Medical College of Ohio Antagonistes de l'activité antidiurétique et/ou vasopresseuse de vassopressine arginine
FR2528036A1 (fr) * 1982-06-03 1983-12-09 Ceskoslovenska Akademie Ved Analogues des hormones neurohypophysaires ayant des effets inhibiteurs
US4483794A (en) * 1983-05-10 1984-11-20 Ceskoslovenska Akademie Ved Analogs of neurohypophysial hormones
EP0125469A1 (fr) * 1983-05-16 1984-11-21 Gibson-Stephens Institute Analogues cycliques d'encéphaline à conformation forcée ayant une activité spécifique sur les récepteurs delta

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4237119A (en) * 1976-07-16 1980-12-02 Ceskoslovenska Akademie Ved Long-acting oxytocin analogs for use in inducing and accelerating labor in mammals, particularly farm animals
EP0037516A1 (fr) * 1980-03-24 1981-10-14 Vega Laboratories, Inc. Dérivés N-omega substituées des analogues de 1-Desamino-vasopressin
EP0061356A2 (fr) * 1981-03-24 1982-09-29 Medical College of Ohio Antagonistes de l'activité antidiurétique et/ou vasopresseuse de vassopressine arginine
FR2528036A1 (fr) * 1982-06-03 1983-12-09 Ceskoslovenska Akademie Ved Analogues des hormones neurohypophysaires ayant des effets inhibiteurs
US4483794A (en) * 1983-05-10 1984-11-20 Ceskoslovenska Akademie Ved Analogs of neurohypophysial hormones
EP0125469A1 (fr) * 1983-05-16 1984-11-21 Gibson-Stephens Institute Analogues cycliques d'encéphaline à conformation forcée ayant une activité spécifique sur les récepteurs delta

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Title
CHEMICAL ABSTRACTS, Volume 101, No. 17, October 1984, Columbus, Ohio, (US) M. LEBL et al.: "Synthesis of Cyclic Peptides by Solid-Phase Methodology", see page 763, Abstract No. 152319c & Thetrahedron Lett. 1984, 25 (20), 2067-8 *
CHEMICAL ABSTRACTS, Volume 101, No. 5, July 1984, Columbus, Ohio, (US) M. LEBL. et al.: "Synthesis and some Activities of (1-Penicillaminedeamino-6-Carbaoxytocin", see page 546, Abstract No. 38807k & Pept. Struct. Funct.,Proc. Am. Pept. Symp. 8th 1983, 357-60 *
CHEMICAL ABSTRACTS, Volume 69, 1986, Columbus, Ohio, (US) T. BRAUN et al.: "Insulin-Like Action of an Oxytocin Analog Lacking a Disulfide Group, and of a Cystathionine Peptide Related to a Sequence of Insulin, on Rat Epididymal Adipose Tissue in Vitro." see page 9681, Abstract No. 103470g & Experientia 1968, 24 (10), 1060-1 *
Collection of Czechoslovak Chemical Communications, Volume 50, No. 1, 1985, Academia Nakladatelstvi Ceskoslovenske Akademie Ved 1985 MICHAL LEBI et al.: "Oxytocin Analogues with Inhibitory Properties, Containing in Position 2 A Hydrophobic Amino Acid of d-Configuration", pages 132-145 *
Helvetica Chimica Acta, Volume XLV, No. 296, 1962, Soc. Chim. Suisse St. Guttmann: "Synthese de la Ser4-1le8-Oxytocine, une Eventuelle Hormone Hypophysaire de Certains Poissons (Isotocine)", see the whole document *
Journal of Medicinal Chemistry, Volume 15, No. 2, 1972, American Chemical Society R.J. VAVREK et al.: "Synthesis of Three Oxytocin Analogs Related to (1-Deamino-Penicillamine) Oxytocin Possessing Antioxytocic Activity", see the whole article *
Journal of Medicinal Chemistry, Volume 22, No. 5, 1979, American Chemical Society J. LOWBRIDGE et al.: "Synthetic Antagonists of in Vivo Responses by the Rat Uterus to Oxytocin1", pages 565-569 *
Journal of Medicinal Chemistry, Volume 9, No. 5, 1966, American Chemical Society H. SCHULZ et al.: "Synthesis of 1-6-Penicillamine-Oxytocin, 1-L-Penicillamine-Oxytocin, 1-D-Penicillamine-Oxytocin, Potent Inhibitors of the Oxytocic Response of Oxytocin1", see the whole article *
Unlisted Drugs, Volume 2m, No. 8, 1975, Spec. Libr. Assoc. "Y 4266", page 123 & Japan J Pharmacol 25:15, January 1975 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5225528A (en) * 1990-02-27 1993-07-06 Merck & Co., Inc. Cyclic hexapeptide oxytocin antagonists
WO1992000996A1 (fr) * 1990-07-09 1992-01-23 Ferring Ab Derives d'hormones du lobe pituitaire posterieur
US8338565B2 (en) 2008-08-20 2012-12-25 Ensemble Therapeutics Corporation Macrocyclic compounds for inhibition of tumor necrosis factor alpha

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