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WO2002000688A1 - Compose peptidique, compositions pharmaceutiques et medicaments contenant ceux-ci comme principe actif - Google Patents

Compose peptidique, compositions pharmaceutiques et medicaments contenant ceux-ci comme principe actif Download PDF

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Publication number
WO2002000688A1
WO2002000688A1 PCT/JP2001/005461 JP0105461W WO0200688A1 WO 2002000688 A1 WO2002000688 A1 WO 2002000688A1 JP 0105461 W JP0105461 W JP 0105461W WO 0200688 A1 WO0200688 A1 WO 0200688A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmacologically acceptable
active ingredient
acceptable salt
compound according
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/JP2001/005461
Other languages
English (en)
Japanese (ja)
Inventor
Takashi Inoue
Akihiro Nakanishi
Seiji Kamiya
Norio Ohno
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.)
Daicel Corp
Tanabe Pharma Corp
Original Assignee
Mitsubishi Tokyo Pharmaceuticals Inc
Daicel Chemical Industries Ltd
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 Mitsubishi Tokyo Pharmaceuticals Inc, Daicel Chemical Industries Ltd filed Critical Mitsubishi Tokyo Pharmaceuticals Inc
Priority to AU66331/01A priority Critical patent/AU6633101A/en
Publication of WO2002000688A1 publication Critical patent/WO2002000688A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
    • 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 peptide compounds. More specifically, the present invention relates to a peptide compound having a selective oxytocin receptor antagonistic activity or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same as an active ingredient, and a drug.
  • the peptide compound provided by the present invention or a pharmacologically acceptable salt thereof is particularly useful for preventing or treating imminent preterm birth.
  • Imminent premature birth is a major cause of prenatal morbidity and mortality, but methods to prevent existing premature birth are not successful and can have significant side effects.
  • oxytocin One of the major causes of this imminent preterm birth is the uterine contractile effect of oxytocin. Since the action of oxytocin is thought to be mediated by the oxytocin receptor on the cell membrane, a substance that antagonizes the binding of oxytocin to its receptor is useful as an agent for preventing or treating imminent premature birth.
  • oxotocin receptor antagonists often also antagonize the receptor for vasopressin, an antidiuretic hormone with a similar structure to oxytocin. Therefore, selective antagonism of the oxytocin receptor is an essential condition as a preventive or therapeutic agent for imminent premature birth with less side effects such as lowering of blood pressure.
  • Japanese Patent Application Laid-Open No. H10-077995 reports a compound represented by the following chemical formula ( ⁇ ) having an oxytocin receptor antagonistic activity equivalent to that of compound (I). It has glycinamide at the C-terminus and has a different structure from compound (I).
  • the present inventors have conducted intensive studies to provide compounds having potent and selective antagonism against oxytocin receptors, and as a result, have found that certain peptide compounds or their pharmacologically acceptable They found a salt and completed the present invention.
  • a first aspect of the present invention provides a peptide compound represented by the following chemical formula (I) or a pharmacologically acceptable salt thereof.
  • a second aspect of the present invention provides an oxytocin receptor antagonist comprising, as an active ingredient, the compound according to the first aspect of the present invention or a pharmacologically acceptable salt thereof.
  • a third aspect of the present invention provides a pharmaceutical composition for preventing or treating impending premature birth, comprising the compound according to the first aspect of the present invention or a pharmacologically acceptable salt thereof as an active ingredient.
  • a fourth aspect of the present invention provides a prophylactic or therapeutic agent for imminent premature birth, comprising the compound according to the first aspect of the present invention or a pharmacologically acceptable salt thereof as an active ingredient.
  • a fifth aspect of the present invention provides an oxytocin receptor antagonist which becomes a compound according to the first aspect of the present invention or a pharmacologically acceptable salt thereof in a living body.
  • a sixth aspect of the present invention is to provide a pharmaceutical composition for preventing or treating imminent premature birth, comprising, as an active ingredient, the compound according to the first or a pharmacologically acceptable salt thereof in vivo. provide.
  • a seventh aspect of the present invention provides a preventive or therapeutic agent for imminent premature birth, comprising the compound according to the first or a pharmacologically acceptable salt thereof as an active ingredient in a living body.
  • Arg arginine
  • Asn asparagine
  • G1n glumin
  • G1y glycine
  • Pro proline
  • Trp tryptophan
  • Pen penicillamine
  • HOB t 1-hydroxybenzotriazole
  • DCC dicyclohexyl carbodiimide
  • DIEA diisopropylethylamine
  • DCM dichloromethane
  • TFA trifluoroacetic acid
  • DMF N, N-dimethylformamide
  • Compound (I) can be synthesized by a solid phase method or a liquid phase method which is a general peptide synthesis method. There are no general rules for selecting the solid phase method or the liquid phase method, and the synthesis method is selected based on the physical properties and required amount of the target peptide.
  • the “pharmacologically acceptable salt” of the compound (I) includes conventional non-toxic salts, that is, acid addition salts and salts with various bases. More specifically, inorganic acid salts such as hydrochloric acid, nitric acid, and sulfuric acid; organic acid salts such as acetic acid, citric acid, fumaric acid, and tartaric acid; sulfonic acid salts such as methanesulfonic acid and p-toluenesulfonic acid; and alanine and leucine Inorganic base salts such as glutamic acid and the like, alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, magnesium salt, calcium salt, etc.) and triethylamine salts, pyridine salts, Organic amine salts such as picolin salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N, dibenzylethylenediamine salt and the
  • compound (I) Since compound (I) has a strong antagonistic effect on oxytocin receptor, it can be used as an agent for preventing or treating imminent premature birth.
  • Compound (I) may be administered parenterally by injection, nasal drop, eye drop, poultice, ointment, cream or suppository, or tablet, capsule, granule, powder, inhalant or the like. Oral administration using a syrup or the like can be mentioned. In preparing these formulations, they can be manufactured by a conventional method using a pharmaceutically acceptable carrier.
  • the dose of compound (I) as a drug is appropriately determined in consideration of the degree of symptoms, general condition of the patient, age, body weight, administration route, dosage form, and the like.
  • parenteral administration it is usually 2 g to 20 mg / kg, preferably 20 g to 2 mg / kg per day in terms of the amount of (I).
  • oral administration it is usually 10 zg to 100 mg per day. And preferably from 100 g to 10 mg / kg.
  • the dose is usually 5 ⁇ g to 50mgZkg, preferably 50 / _ig to 5mg / kg.
  • a peptide chain was constructed on a resin by a solid phase method using a Boc amino acid using a peptide synthesizer (430A type manufactured by ABI).
  • the reverse phase HP LC analysis conditions at that time are shown below.
  • the carrier resin, protected amino acids and reagents used in the synthesis are shown below.
  • the protected amino acid to be introduced, HOBt and DCC were all 2 mmol, and the condensation reaction time was set to 120 minutes.
  • TBTU method The protected amino acid to be introduced, HOBt and TBTU were all used at 2 mmol, DI EA was used at 4 mmol, and the condensation reaction time was set at 120 minutes. Furthermore, the completeness of the reaction when each amino acid was introduced was confirmed by the Kaiser test (Isatin test when Pen (MBz1) residue was introduced).
  • Boc-A rg (Mt s) — OCH 2 — PAM resin (0.5 mmo 1) was added to the reaction vessel of the synthesizer, washed three times with 10 ml of DCM, left overnight in DCM, The resin was sufficiently swollen. After filtration, 10 ml of a 50% TFA_ / DCM solution was added to the above resin, and the mixture was stirred for about 2 minutes. After filtration, 10 ml of a 50% TFA / DCM solution was further added, and the mixture was stirred for 30 minutes to perform a Boc removal reaction. After completion of the reaction, the TFA solution was filtered, washed three times with 10 ml each of DCM, and filtered.
  • TFA was removed by neutralizing twice with 10 ml each of a 10% DI EAZDMF solution to release amino groups. Further, washing and filtration were repeated 6 times with 10 ml each of DMF, and the remaining DIEA was removed.
  • Boc-Pro-OH was activated in parallel with the above operations. That is, Boc—Pro—OH (431 mg, 2 mmol) and HOB t (306 mg, 2 mmol) were dissolved in 4 ml of DMF, added to another reaction tank, and 4 ml of 0.5 M DCC / DCM solution was added. The mixture was added and stirred under a nitrogen stream for about 40 minutes to lead to an activated ester.
  • the obtained activation solution was added to the reaction vessel containing the resin and stirred to start the condensation reaction.
  • the reaction time was 120 minutes.
  • the resultant was washed three times with 10 ml each of DMF and further six times with 10 ml each of DCM, followed by filtration. After washing and filtration, a part of the resin was subjected to a Kaiser test. With the introduction of one amino acid, the condensation reaction was repeated until the Kaiser test (or Isatin test) became negative.
  • the obtained protected peptide resin was sufficiently washed with an appropriate amount of DCM, dried under reduced pressure (yield: 127 Omg), and subjected to HF treatment.
  • Liquid HF treatment Add 127 Omg of the protected peptide resin obtained in [1] and a Teflon-coated magnet to an HF reaction vessel, add 1.3 ml of anisol and 3 ml of EMI. Leave for 30 minutes at room temperature under reduced pressure. did.
  • the reaction vessel was cooled with a refrigerant, 13 ml of double distilled HF was added, and the mixture was stirred at 120 ° C. for 120 minutes.
  • HF was distilled off under reduced pressure (1 hour with an aspirator, 2 hours with a vacuum pump), and 30 ml of getyl ether was added to the residue, followed by stirring until smooth. After suction filtration, it was washed three times with 30 ml each of getyl ether and dried under reduced pressure. .
  • the peptide-resin mixture obtained in [2] was sufficiently added to 30 ml of 1M acetic acid which had been sufficiently degassed and cooled, and stirred to dissolve the peptide component. After suction filtration, the filtrate was quickly poured into 150 Oml of pure water. The filtered material on the glassfill was further washed three times with 30 ml each of cold 1 M acetic acid, and quickly added to the pure water. To this diluted aqueous solution, 13 ml of 28% aqueous ammonia was dropped to obtain ⁇ 9.47. The mixture was stirred at 24.5 for about 24 hours to carry out a C C-C reaction.
  • Estradiol lmg / kg was subcutaneously administered to SD female rats. Twenty-four hours later, the uterine horn was removed, a small section was prepared, and immediately suspended on a Magnus apparatus. Organ '
  • Compound (I) inhibited oxytocin-induced uterine contractile response in a dose-dependent manner, with IC 5 .
  • Value (a value representing the concentration of antagonist that inhibits 50% of the reaction by ⁇ Gore two strike alone) was 3. 18 X 10_ S M.
  • VIa receptor vasopressin VIa receptor
  • Compound (I) or a control compound was cumulatively administered to a final concentration of 1 0 one 9 ⁇ 10_ 5 M, respectively. With respect to the vasoconstriction response by AVP, the relaxation response by each drug was measured. Table 2 shows the results of compound (I) and compound (II). Compound (I) dose-dependently inhibited AVP-stimulated vasoconstriction, with IC 5 . The value was 8. 70X10 one 7 M. Table 2
  • Compound (I) has a selective antagonism of oxytocin receptor over vasopressin receptor as compared with conventional compounds. Can be provided.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Endocrinology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Biochemistry (AREA)
  • Diabetes (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)
  • Reproductive Health (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un composé peptidique (I) ou des sel de ce composé répondant aux normes pharmacologiques, qui présente un antagonisme sélectif plus dirigé contre le récepteur d'oxytocine que contre le récepteur de vasopressine, et qui est efficace dans la prévention ou le traitement des menaces de naissance prématurée.
PCT/JP2001/005461 2000-06-28 2001-06-26 Compose peptidique, compositions pharmaceutiques et medicaments contenant ceux-ci comme principe actif Ceased WO2002000688A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU66331/01A AU6633101A (en) 2000-06-28 2001-06-26 Peptide compound and pharmaceutical compositions and medicines containing the same as the active ingredient

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000-195332 2000-06-28
JP2000195332A JP2003335797A (ja) 2000-06-28 2000-06-28 ペプチド化合物及びそれを有効成分とする医薬組成物

Publications (1)

Publication Number Publication Date
WO2002000688A1 true WO2002000688A1 (fr) 2002-01-03

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2001/005461 Ceased WO2002000688A1 (fr) 2000-06-28 2001-06-26 Compose peptidique, compositions pharmaceutiques et medicaments contenant ceux-ci comme principe actif

Country Status (3)

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JP (1) JP2003335797A (fr)
AU (1) AU6633101A (fr)
WO (1) WO2002000688A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006045328A (ja) * 2004-08-04 2006-02-16 Asahi Kasei Chemicals Corp ポリオレフィン製微多孔膜の製造方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2526318A1 (fr) * 1982-05-10 1983-11-10 Ceskoslovenska Akademie Ved Analogues d'hormones neurohypophysaires ayant des proprietes inhibitrices
EP0206730A2 (fr) * 1985-06-18 1986-12-30 Smithkline Beckman Corporation Antagonistes de vasopressine
EP0225109A2 (fr) * 1985-11-19 1987-06-10 Smithkline Beckman Corporation Antagonistes de la vasopressine
WO1994025485A1 (fr) * 1993-04-26 1994-11-10 Northwestern University Antagoniste de l'oxytocine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2526318A1 (fr) * 1982-05-10 1983-11-10 Ceskoslovenska Akademie Ved Analogues d'hormones neurohypophysaires ayant des proprietes inhibitrices
EP0206730A2 (fr) * 1985-06-18 1986-12-30 Smithkline Beckman Corporation Antagonistes de vasopressine
EP0225109A2 (fr) * 1985-11-19 1987-06-10 Smithkline Beckman Corporation Antagonistes de la vasopressine
WO1994025485A1 (fr) * 1993-04-26 1994-11-10 Northwestern University Antagoniste de l'oxytocine

Also Published As

Publication number Publication date
JP2003335797A (ja) 2003-11-28
AU6633101A (en) 2002-01-08

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