WO2008019594A1 - Dihydrate de sulfate d'agmatine, et son utilisation médicale - Google Patents

Dihydrate de sulfate d'agmatine, et son utilisation médicale Download PDF

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Publication number
WO2008019594A1
WO2008019594A1 PCT/CN2007/002379 CN2007002379W WO2008019594A1 WO 2008019594 A1 WO2008019594 A1 WO 2008019594A1 CN 2007002379 W CN2007002379 W CN 2007002379W WO 2008019594 A1 WO2008019594 A1 WO 2008019594A1
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WO
WIPO (PCT)
Prior art keywords
agmatine
sulfate dihydrate
dihydrate
agmatine sulfate
crystalline form
Prior art date
Application number
PCT/CN2007/002379
Other languages
English (en)
Chinese (zh)
Inventor
Song Li
Yunde Xie
Zhibing Zheng
Hongxia He
Jin Li
Original Assignee
Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
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 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China filed Critical Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China
Publication of WO2008019594A1 publication Critical patent/WO2008019594A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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

Definitions

  • the present invention relates to agmatine sulfate dihydrate or a crystalline form, a process for the preparation thereof, a pharmaceutical composition thereof and agmatine sulfate salt hydrate or a crystal form thereof for use in detoxification, anti-inflammatory, hypoglycemic and prophylactic and/or therapeutic treatments Use of disorders caused by abnormal metabolism of butanamine. Background technique
  • Agmatine is a product of L-arginine decarboxylase catalyzed decarboxylation of arginine (Science. 1994, 263 (5149): 966-969), a neurotransmitter widely present in neurons of the central nervous system, and Focus on the bubble (Life Science. 1995, 56 (26): 2319-2330).
  • Agmatine has many biological effects, such as: Increasing the plasma adrenaline content in rats with essential hypertension ( Ann NY Acad Sci. 1995, 763: 573-579 ), stimulating hypothalamic luteinizing hormone-hormone Luteinizing hormone axis, directly or indirectly stimulates the synthesis of luteinizing hormone releasing hormone (LHRH) and regulates its release (Neurosci Lett.
  • agmatine sulfate II Hydrate, which has high stability in air and is not easy to deliquesce. Due to its high stability, the final preparation (pharmaceutical composition) of the pharmaceutically active ingredient (API) is more suitable, and the storage is more convenient and the storage period is more convenient. long. Furthermore, the preparation of agmatine sulfate dihydrate is simple and more suitable for industrial production. It was further confirmed by single crystal X-ray diffraction experiments that agmatine sulfate dihydrate was present in a stable form of a dihydrate (see Fig. 1). This dihydrate also has a characteristic powder X-ray diffraction pattern (see Figure 2 and Table 1). The present invention has been completed based on the above findings. Table 1. X-ray diffraction characteristic peaks of agmatine sulfate dihydrate powder
  • the invention therefore relates to agmatine sulfate dihydrate of formula I,
  • the invention further relates to a crystalline form of the agmatine sulfate dihydrate of formula I having the X-ray diffraction data of Table 1.
  • a further aspect of the invention relates to a pharmaceutical composition comprising agmatine sulfate dihydrate or a crystalline form thereof and a pharmaceutically acceptable carrier or excipient.
  • the present invention also relates to a process for the preparation of agmatine sulfate dihydrate comprising reacting methylisothiourea with 1,4-butanediamine and then adjusting the pH ⁇ 7 with an aqueous solution of sulfuric acid.
  • the invention further relates to the use of agmatine dihydrate or a crystalline form thereof for the manufacture of a medicament for use in detoxification, anti-inflammatory, hypoglycemic and prophylactic and/or therapeutic treatment of agmatine metabolism of an acid.
  • the method for preparing agmatine sulfate dihydrate of the present invention comprises: reacting with an appropriate concentration of methyl isothiourea and an aqueous solution of 1,4-diaminediamine, filtering out the insoluble solid, and carefully adjusting with an aqueous solution of sulfuric acid After pH ⁇ 7, concentrated under reduced pressure to a certain volume, the crystal is cooled and cooled in the temperature range of 5-15 Torr.
  • the most suitable condition is 10 CC standing crystallization, and the corresponding crystal of agmatine sulfate dihydrate is obtained.
  • the reaction synthesis route is as follows:
  • the pharmaceutical compositions of the present invention comprise an effective amount of agmatine sulfate hydrate and one or more suitable pharmaceutically acceptable carriers, including but not limited to: ion exchangers, oxidizing agents.
  • suitable pharmaceutically acceptable carriers including but not limited to: ion exchangers, oxidizing agents.
  • the pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, Intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or input, or with the aid of an external
  • the medicated reservoir is used.
  • oral administration, intraperitoneal or intravenous administration is preferred.
  • Figure 1 is a stable form of agmatine sulfate dihydrate.
  • Figure 2 X-ray diffraction pattern of agmatine sulfate dihydrate.
  • the melting point of the compound was determined by a RY-1 type melting point apparatus, and the thermometer was not corrected.
  • ⁇ NMR was measured by an ARX-400 NMR instrument. Mass spectra were determined by a VG-ZabSpec MS instrument. All reactions were pretreated with a solvent that was not indicated.
  • Single crystal culture method reference (SHELXS-97, SHELXL-97. Program for Crystal Structure Refinement, University of Gettingen, Germany 1997).
  • the morphine 10 mg/kg was administered subcutaneously three times a day for 7 days, and a mouse dependence model was established. On the 8th day, 5 mg/kg of naloxone was administered intraperitoneally 5-6 hours after the last administration. The number of withdrawals, the percentage of jumps, the percentage of writhing, and the change in body weight 1 hour before and after naloxone were recorded within 15 minutes after recording naloxone.
  • Subcutaneous injection of the agmatine sulfate dihydrate of Example 1 under subcutaneous injection of morphine has a significant preventive effect on naloxone-induced morphine-dependent mouse withdrawal syndrome. The results are shown in Table 2. Table 2. Prevention of naloxone-induced morphine-dependent mouse withdrawal syndrome by subcutaneous administration of Example 1 agmatine hydrate
  • a mouse-dependent model was established by subcutaneous administration of morphine.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Addiction (AREA)
  • Rheumatology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne le composé dihydrate de sulfate d'agmatine représenté par la formule (I), sa forme cristalline, une composition pharmaceutique le comprenant, et son utilisation pour traiter les toxicomanies, les troubles inflammatoires, abaisser la glycémie, ainsi que pour prévenir et/ou traiter des maladies provoquées par une anomalie du métabolisme de l'agmatine.
PCT/CN2007/002379 2006-08-09 2007-08-08 Dihydrate de sulfate d'agmatine, et son utilisation médicale WO2008019594A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200610109605.X 2006-08-09
CN200610109605XA CN101121677B (zh) 2006-08-09 2006-08-09 胍丁胺硫酸盐二水合物及其医药用途

Publications (1)

Publication Number Publication Date
WO2008019594A1 true WO2008019594A1 (fr) 2008-02-21

Family

ID=39081938

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2007/002379 WO2008019594A1 (fr) 2006-08-09 2007-08-08 Dihydrate de sulfate d'agmatine, et son utilisation médicale

Country Status (2)

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CN (1) CN101121677B (fr)
WO (1) WO2008019594A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021048871A1 (fr) 2019-09-15 2021-03-18 Celagenex Research (India) Pvt. Ltd. Compositions bioactives synergiques pour traiter des troubles neurologiques

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101062906B (zh) * 2006-04-26 2012-02-08 中国人民解放军军事医学科学院毒物药物研究所 胍丁胺硫酸盐水合物及其用于戒毒,抗炎,降血糖以及胍丁胺代谢异常所致疾病的用途
CN103755598A (zh) * 2014-01-23 2014-04-30 上海旭新化工科技有限公司 胍丁胺硫酸盐的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1444930A (zh) * 2002-03-19 2003-10-01 中国人民解放军军事医学科学院毒物药物研究所 胍丁胺的新用途
CN1729172A (zh) * 2002-12-17 2006-02-01 希格马托制药工业公司 胍的不同取代的衍生物及其作为具有抗糖尿病和/或抗肥胖活性的药物的用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1444930A (zh) * 2002-03-19 2003-10-01 中国人民解放军军事医学科学院毒物药物研究所 胍丁胺的新用途
CN1729172A (zh) * 2002-12-17 2006-02-01 希格马托制药工业公司 胍的不同取代的衍生物及其作为具有抗糖尿病和/或抗肥胖活性的药物的用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHANDRASEKHAR K. ET AL.: "Structure of agmatine sulfate dihydrate: an extensive amine-sulfate-water hydrogen-bond network", ACTA CRYSTALLOGR., SECT. B, vol. B38, no. 9, pages 2538 - 2540 *
SU RENBIN: "Agmatine and its prime biological activity", GUOWAI YIXUE YAOXUE FENCE (FOREIGN MEDICAL SCIENCES SECTION ON PHARMACY), vol. 28, no. 2, April 2001 (2001-04-01), pages 65 - 69 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021048871A1 (fr) 2019-09-15 2021-03-18 Celagenex Research (India) Pvt. Ltd. Compositions bioactives synergiques pour traiter des troubles neurologiques

Also Published As

Publication number Publication date
CN101121677B (zh) 2011-05-11
CN101121677A (zh) 2008-02-13

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