WO2002102833A1 - Nouveaux derives d'endomorphine - Google Patents

Nouveaux derives d'endomorphine Download PDF

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Publication number
WO2002102833A1
WO2002102833A1 PCT/JP2002/005953 JP0205953W WO02102833A1 WO 2002102833 A1 WO2002102833 A1 WO 2002102833A1 JP 0205953 W JP0205953 W JP 0205953W WO 02102833 A1 WO02102833 A1 WO 02102833A1
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WIPO (PCT)
Prior art keywords
phe
dmp
tyr
mmol
yield
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Application number
PCT/JP2002/005953
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English (en)
Japanese (ja)
Inventor
Takashi Yamada
Original Assignee
Senju Pharmaceutical Co., Ltd.
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Application filed by Senju Pharmaceutical Co., Ltd. filed Critical Senju Pharmaceutical Co., Ltd.
Priority to JP2003506305A priority Critical patent/JPWO2002102833A1/ja
Publication of WO2002102833A1 publication Critical patent/WO2002102833A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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 a novel endomorphine derivative having physiological activities such as analgesia, anti-anxiety and tension relief, a physiologically acceptable salt thereof, and a pharmaceutical comprising the derivative and a physiologically acceptable salt thereof.
  • Opioid receptors are mainly classified into ⁇ , ⁇ , and ⁇ subtypes. 8 The receptor has been identified as an endogenous agonist by enkephalin and the kappa receptor by dynorphin.
  • Morphine is the strongest agonist for ⁇ receptors, but its endogenous A gonist was discovered in human brain by Zadina et al. In 1997, and Endomonolein-1 (Tyr-Pro-Trp-Phe-N) and Endmorphin-1 (Tyr-Pro-Phe-Phe-NH) 2 ) [JE Zadina, L. hackler, LJ Ge and AJ Kastin, Nature, 386, 499 (1997)].
  • endmorphin-11 for ⁇ receptor is more than 150,000 times higher than that of ⁇ receptor, and that of endmorphin-12 is more than 1300 times higher than that of ⁇ receptor.
  • the analgesic effect in Escherichia coli is also reported to be strong and long-lasting [E. Za dina, L. hackler, LJ Ge and AJ Kastin, Nature, 386, 499 (1997)] Have been.
  • Endomorphin-1 and endmorphin-2 have similar analgesic activity and reduce arterial blood pressure (HC Champion, JE Zadina, AJ Kastin, L. hackler, LJ Ge, PJ Kadowitz. Biochem. Biophys. Res. Commun., 235, 567 (1997); YR Yang, TH Chiu, CL Chen, Eur. J. Pharmacol., 372, 229 (1999)].
  • Ki 6.59 ⁇ 0.06 ⁇ ⁇
  • Ki ( ⁇ ) / Ki ( ⁇ ) 844
  • a higher value of 507 ⁇ . Takahashi, A. Fukumizu, Y. Shimizu, Y. Tsuda, T. Yokoi, SD Bryant, LH Lazarus and Y. Okada, Peptide Science 1999, 437 (2000).
  • the present inventor has been studying the synthesis of ⁇ , -disubstituted glycine and peptides containing the same, and their effects on the stereochemistry and bioactivity of the peptide.
  • end morphine-2 a mono-substituted glycine After the introduction of the peptide, the conformation, resistance to proteolytic enzymes, strength of bioactivity, affinity for each subtype of opioid receptor, selectivity, etc., are carefully examined. I explored the possibility I 1 production as a medicament.
  • the Pro is a 2-position amino acid of E-end mono-les-fin 1 ⁇ Pi Endomorufin one 2 ⁇ 3 ⁇ 4, and ⁇ - two which is a kind of 1-amino-cyclopropane force carboxylic acid-substituted glycine (AC3C 2). It has been found that the novel peptide substituted with (1) has strong physiological activity, high affinity and selectivity for ⁇ receptor, and has strong resistance to proteolytic enzymes. The present invention has been completed based on these findings.
  • Y is Trp, or the endomorphine derivative or a physiologically acceptable salt thereof according to (1),
  • Y is D / L-2, 6′-dimethylphenylalanine, or the endmorphin derivative or a physiologically acceptable salt thereof according to (1),
  • a pharmaceutical composition comprising the endomorphine derivative according to any one of the above (1) to (4) or a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the compound of the present invention can be produced according to a known peptide synthesis method.
  • it can be produced by an N-edge extension method using a liquid phase method according to the following general reaction formula.
  • EDC 1-Ethyl-3- (3-dimethylaminopropyl) -carposimid
  • EDC 'HCl 1-Ethyl-3- (3-dimethylaminopropyl) monocarposimido hydrochloride
  • EDC-HOBt method can be used for coupling, and HBrZAcOH or catalytic hydrogenolysis method can be used for deprotection.
  • the novel endomorphine derivative of the present invention can be used as it is or as a physiologically acceptable salt.
  • physiologically acceptable salt include salts of mineral acids such as hydrochloric acid, sulfuric acid, and carbonic acid, and salts of organic acids such as acetic acid and citric acid.
  • novel endmorphin derivatives and physiologically acceptable salts of the present invention are agonists of opioid receptors and are therefore used in all pharmaceutical applications where morphine is used, such as analgesia, anti-anxiety, and detonation. Is possible.
  • the medicament containing the endmorphin derivative of the present invention and a physiologically acceptable salt can be administered systemically or locally. In addition to systemic administration, it can be administered by parenteral methods such as intravenous injection, subcutaneous injection, and intramuscular injection. It is topically administered intranasally and intraocularly.
  • compositions containing the endmorphin derivative of the present invention and a physiologically acceptable salt include solid forms such as powders, granules, tablets, capsules, suppositories, syrups, injections, And liquid preparations such as eye drops and nasal drops.
  • Preparations for oral administration to humans include, for example, powders, granules, tablets, capsules Preparations, syrup preparations and liquid preparations.
  • any pharmaceutical carrier suitable for preparing a solid preparation such as excipients (starch, corn starch, glucose, fructose, sucrose, etc.), lubricants
  • the coating may be made with an enteric coating agent (eg, cellulose acetate phthalate, methacrylic acid copolymer, hydroxypropylcellulose phthalate, carboxymethylethylcellulose, etc.).
  • enteric coating agent eg, cellulose acetate phthalate, methacrylic acid copolymer, hydroxypropylcellulose phthalate, carboxymethylethylcellulose, etc.
  • a coating agent for a sustained-release preparation for example, hydroxypropylmethylcellulose, ethylcellulose, hydroxymethinoresenolerose, hydroxypropinoresenolerose, polyoxyethylene glycol, Tween 80, pull mouth Yuk F68, cellulose acetate phthalate, hydroxypropinolemethinoresenolerose phthalate, hydroxymethylinoresenolerose acetate succinate, Eudragit (Rohm, Germany, methacrylic acid / acrylic acid copolymerization) are used.
  • suitable excipients such as magnesium stearate, calcium stearate, talc, and light caffeic anhydride for improving fluidity and lubricity, and pressurized fluidity
  • suitable excipients such as magnesium stearate, calcium stearate, talc, and light caffeic anhydride for improving fluidity and lubricity, and pressurized fluidity
  • those to which the above-mentioned disintegrants etc. are appropriately added are evenly mixed or granulated or granulated and coated with a coating agent suitable for the above-mentioned coating agent.
  • glycerin or sorbitol to a suitable capsule base (such as gelatin) and then encapsulate it with a plastic base that has increased plasticity.
  • Capsules can be enteric coated capsules, gastric resistant capsules, or controlled release capsules in addition to ordinary capsules.
  • enteric capsules granules coated with an enteric coating agent are filled into a normal capsule, or capsules themselves are coated with an enteric coating agent, or molded using an enteric polymer as a base. be able to.
  • the formulation is syrup or liquid
  • a stabilizer eg, sodium edetate
  • a suspending agent eg, gum arabic, carmellose
  • a flavoring agent eg, simple syrup, pudose
  • a fragrance eg, simple syrup, pudose
  • Parenteral preparations include injections, eye drops, nasal drops, suppositories and the like.
  • solvents such as distilled water for injection
  • stabilizers such as sodium edetate
  • tonicity agents such as sodium chloride, glycerin, and mannitol
  • pH regulators Hydrochloric acid, citric acid, sodium hydroxide, etc.
  • suspending agents methylcellulose, sodium carboxymethylcellulose, etc.
  • Topical preparations include, for example, eye drops, nasal drops and eye ointments.
  • solvents physiological saline, purified water, etc.
  • buffers borax, sodium acetate, citrate buffer, phosphate buffer, etc.
  • Isotonic agents sodium chloride, glycerin, mannitol, etc.
  • stabilizing agents sodium edetate, citric acid, etc.
  • preservatives quaternary ammonium salts such as benzalkonidum chloride, parabens, chlorobutanol, sorbic acid
  • PH adjuster hydroochloric acid, sodium hydroxide, etc.
  • suspending agent hydroxypropyl methinoresenolerose, hydroxymethinoresenolerose, canolepox methinoresenolerose sodium, methylcellulose, etc.
  • surfactant Polysorbate 80, polyoxyethylene hydrogenated castor oil, etc.
  • emulsifier polybutyl
  • the medicament containing the novel endmorphin derivative of the present invention and a physiologically acceptable salt is low toxic, and uses morphine from animals, particularly mammals (eg, human, dog, rabbit, rat, mouse, etc.). It is advantageously used for the prevention or treatment of all the diseases mentioned.
  • Dosage for humans depends on age, weight, general health, gender, diet, time of administration, mode of administration, rate of excretion, combination of drugs, and the extent of the condition being treated by the patient at the time. The decision is made in consideration of these and other factors. For example, when the compound of the present invention is administered orally or intravenously to an adult (body weight 50 Kg) as an analgesic, 0.1 to 20 mg, preferably 1 to: LO mg is expressed once. Once or three times, for oral sustained-release preparations, the dose is about 1-2 mg / day.
  • Trp Tryptophan
  • Xaa 1-aminocyclopropanecarboxylic acid or D / L-2 ', 6'-dimethylpheninolealanine
  • sequence numbers in the sequence listing in the present specification indicate the following sequences.
  • DEVEL0SIL 100-5 C is (4.6 mm ⁇ 150 mm)
  • Dmp contained in the diastereomer A dip B of the obtained dipeptide will be referred to as Dmp (A) and Dmp (B), respectively.
  • DEVEL0SIL 100-5 C is ( ⁇ 4.6 mm l50 mm)
  • the above components are mixed and dissolved by a conventional method to prepare an injection. Dispense this into 2 mL glass ampules and seal.
  • [Acsc 2 ] 1-end morphine 1 and lactose corn starch are added and mixed well to obtain granules for tableting according to the wet tablet preparation method. Tablets are added with magnesium stearate to make 400 tablets. Tablets are coated with an enteric coating (methacrylic acid copolymer).
  • the above components are mixed by a conventional method to prepare eye drops.
  • the peptide was dissolved in 50 mM Tris-HCl (pH 7.4) buffer to a final concentration of 1 mM.
  • Carboxypeptidase Y was dissolved in 50 mM Tris-HCl (pH 7.4) buffer in each case.
  • Half-life was determined as a first-order response.
  • End morphin-2 has a half-life of 8 times that of end morphine 1-2 and [Ac 3 c 2 ] —End mono ref 1 is 3 times that of end mono ref 1 , And both showed significantly higher enzymatic degradation resistance to endmorphin-12 and endmonorefin-1.
  • End mono reflex in one 1 end mono reflex in _ 2
  • radioactive ligand receptor binding assay A receptor binding test was performed.
  • Rat brains were homogenized in cold 10 mM Tris-HCl buffer and centrifuged at 40,000 g I min at 4 ° C for 15 minutes. The supernatant was discarded. The resulting pellet is The cells were resuspended in the same amount of Tris-HCl buffer as at the beginning, homogenized, and centrifuged. This washing process was repeated twice.
  • the resulting pellet was finally suspended in Tris-HCl buffer (24 mL) and this 500 mL membrane preparation was used for binding studies in a final volume of 2 mL.
  • Tyr-D-Ala-Gly-MePhe-Gly-ol ([3 ⁇ 4] DAG0) (1.80 TBq I ramol; New England Nuclear, Boston, Mass. USA), Tyr-D-Ala-Phe-Glu-Va Val_Gly-NH 2 ([ 3 H] DEL) (1.85-3.18 TBq I ramol; Amershara Pharmacia Biotech) as a selective tracer for ⁇ and ⁇ Obioid receptors at a final concentration of 0.25 ⁇ Using. The culture was performed at 25 ° C. for 60 minutes in a 50 mM Tris-HCl buffer (pH 7.5) containing 0.1% bovine serum albumin. Bacitracin (100 mg / mL) was added as an enzyme inhibitor.
  • the released ligand was separated from the bound radioligand membrane by filtration through a Whatmann GF / B glass fiber filter. The filters were washed twice with 4 mL of Tris-HCl buffer.
  • Dose-response curves were generated for 7 to 10 doses, and the results were compiled using computer programs (A. De Lean, PJ Munson and D. Rodbar d, Am. J. Physiol., 235). , E97 (1978)].
  • Data were subjected to least squares processing of a logistic curve linking the binding of labeled ligand [ 3 H] DAG0 to [] DEL with unlabeled ligand concentration.
  • Endomo / finfin-1 and endmorphin-12 showed about 3-fold and about 6-fold stronger activity, respectively, on the body.
  • the [Ac 3 c 2 ] -endomorphin-1 and [Ac so 2 ] endmorphin-12 had about 1,400-fold and about 700-fold selectivity of the ⁇ receptor for the ⁇ receptor, respectively.
  • the very high activity and high selectivity of the analog were obtained by substituting only one residue of a, a-disubstituted glycine. The fact that the conformation immobilization by AC3C It is thought that the conformation suitable for the binding was taken.
  • Endmorphin-2 [Ac 3 c 2 , Dmp (A) 3 ] —endomo / refin-1 2 shows almost the same activity as ⁇ -monorefinin 1-2 on ⁇ receptor, and [Ac 3 c 2 , Dmp (B) 3 ] —Endomorphin-12 showed 1/3 of the activity of endmorphin-12 on the receptor.
  • novel endomorphic derivative of the present invention has strong affinity and selectivity especially for ⁇ receptors among opioid receptors, and therefore has physiological activities such as analgesia, anxiety, and relaxation of tension.
  • a conformational fixation factor, 1-aminocyclopropanecarboxylic acid is introduced at the 2-position, so that the peptide can adopt a desirable conformation, exhibit resistance to degradation by proteolytic enzymes, and Demonstrate strong bioactivity.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
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Abstract

L'invention concerne de nouveaux dérivés d'endomorphine, obtenus par substitution d'un acide aminé Pro en position 2 d'une endomorphine-1 et d'une endomorphine-2 par un acide 1-aminocyclopropanecarboxylique. Ces nouveaux dérivés d'endomorphine possèdent chacun une grande affinité et une grande sélectivité pour les récepteurs opioïdes, et font preuve d'activités physiologiques telles que sédation, anti-anxiété, détente, etc. et de résistance aux enzymes de décomposition de protéine.
PCT/JP2002/005953 2001-06-15 2002-06-13 Nouveaux derives d'endomorphine WO2002102833A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2003506305A JPWO2002102833A1 (ja) 2001-06-15 2002-06-13 新規エンドモルフィン誘導体

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2001182292 2001-06-15
JP2001-182292 2001-06-15
JP2002-073224 2002-03-15
JP2002073224 2002-03-15

Publications (1)

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WO2002102833A1 true WO2002102833A1 (fr) 2002-12-27

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PCT/JP2002/005953 WO2002102833A1 (fr) 2001-06-15 2002-06-13 Nouveaux derives d'endomorphine

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011026346A (ja) * 2003-02-04 2011-02-10 Cornell Research Foundation Inc ミトコンドリア透過性転移の阻止方法
JP2011508727A (ja) * 2007-12-13 2011-03-17 サイトジェル ファーマ リミテッド ライアビリティ カンパニー μ−オピエート受容体ペプチドの有利な塩
CN101139383B (zh) * 2004-09-30 2011-09-07 兰州大学 C末端修饰的内吗啡肽2
US10975121B2 (en) 2017-06-24 2021-04-13 Cytogel Pharma, Llc Analgesic mu-opioid receptor binding peptide pharmaceutical formulations and uses thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
SASAKI Y. ET AL.: "Biological properties of opioid peptides replacing Tyr at position 1 by 2,6-dimethyl-Tyr", CHEM. PHARM. BULL., vol. 47, no. 10, 1999, TOKYO, pages 1506 - 1509, XP002956388 *
STEWART H.C. ET AL.: "Peptide synthesis with 1-aminocyclopropane-1-carboxylic acid", AUST. J. CHEM., vol. 34, 1981, pages 2431 - 2438, XP002956387 *
ZADINA J.E. ET AL.: "A potent and selective endogenous agonist for the mu-opiate receptor", NATURE, vol. 386, no. 6624, 1997, pages 499 - 502, XP002117509 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011026346A (ja) * 2003-02-04 2011-02-10 Cornell Research Foundation Inc ミトコンドリア透過性転移の阻止方法
JP2013249313A (ja) * 2003-02-04 2013-12-12 Cornell Research Foundation Inc ミトコンドリア透過性転移の阻止方法
CN101139383B (zh) * 2004-09-30 2011-09-07 兰州大学 C末端修饰的内吗啡肽2
JP2011508727A (ja) * 2007-12-13 2011-03-17 サイトジェル ファーマ リミテッド ライアビリティ カンパニー μ−オピエート受容体ペプチドの有利な塩
US8940704B2 (en) 2007-12-13 2015-01-27 Cytogel Pharma, Llc Advantageous salts of μ-opiate receptor peptides
US10975121B2 (en) 2017-06-24 2021-04-13 Cytogel Pharma, Llc Analgesic mu-opioid receptor binding peptide pharmaceutical formulations and uses thereof
US11603385B2 (en) 2017-06-24 2023-03-14 Cytogel Pharma, Llc Analgesic mu-opioid receptor binding peptide pharmaceutical formulations and uses thereof

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