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WO2003086411A1 - Composes et techniques de preparation de carboxylate de diosgenine et d'un derive de succinate monoester de diosgenine - Google Patents

Composes et techniques de preparation de carboxylate de diosgenine et d'un derive de succinate monoester de diosgenine Download PDF

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Publication number
WO2003086411A1
WO2003086411A1 PCT/CN2003/000263 CN0300263W WO03086411A1 WO 2003086411 A1 WO2003086411 A1 WO 2003086411A1 CN 0300263 W CN0300263 W CN 0300263W WO 03086411 A1 WO03086411 A1 WO 03086411A1
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WO
WIPO (PCT)
Prior art keywords
diosgenin
acid
formula
derivative according
carboxylic acid
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/CN2003/000263
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English (en)
Chinese (zh)
Inventor
Zhongrong Liu
Xuechao Wang
Zhonglin Ye
Xiaoli Wang
Bogang Li
Liutang Wang
Shiyong Sun
Lingen Deng
Min He
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.)
Chengdu Diao Pharmaceutical Group Co Ltd
Original Assignee
Chengdu Diao Pharmaceutical Group Co 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
Priority claimed from CN 02111346 external-priority patent/CN1187368C/zh
Priority claimed from CN 03117182 external-priority patent/CN1260245C/zh
Application filed by Chengdu Diao Pharmaceutical Group Co Ltd filed Critical Chengdu Diao Pharmaceutical Group Co Ltd
Priority to AU2003231427A priority Critical patent/AU2003231427A1/en
Publication of WO2003086411A1 publication Critical patent/WO2003086411A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a diosgenin derivative having water solubility, in particular to a diosgenin carboxylic acid and a succinic acid monoester derivative.
  • the present invention also relates to a method for preparing a diosgenin carboxylic acid derivative and a succinic acid monoester derivative.
  • the invention also relates to the use of diosgenin carboxylic acid derivatives and succinate monoester derivatives in the preparation and treatment of cardiovascular diseases. Background technique
  • Diosgenin has the effects of enhancing myocardial contractility, slowing heart rate, anti-arteriosclerosis, improving microcirculation, anti-aging and anti-arthritis.
  • its clinical application is greatly limited. So far, only the production method and clinical application of saponin, a diosgenin water-soluble derivative, have been reported, and no other types of water-soluble derivatives have been reported.
  • saponin a diosgenin water-soluble derivative
  • the inventors designed and synthesized a series of new carboxylic acid derivatives and succinate monoester derivatives, and found that they all have physiological activities. Summary of the Invention
  • Another object of the present invention is to provide a water-soluble diosgenin succinate monoester derivative.
  • Another object of the present invention is to provide a method for preparing a diosgenin succinate monoester derivative.
  • Yet another object of the present invention is to provide an application of a diosgenin succinic acid monoester derivative or a pharmaceutically acceptable salt thereof in the preparation of a cardio-cerebral vascular disease.
  • a diosgenin carboxylic acid derivative having the structure of formula (I) is provided:
  • an alkyl group or a substituted alkyl group selected from 1-2 carbon atoms is preferably:
  • a method for preparing a compound of formula (I) uses diosgenin as a raw material, reacts with an organic anhydride under reflux conditions, and then reacts with sodium bicarbonate to obtain diosgenin.
  • Carboxylic acid derivatives See the following reaction formula:
  • M is H or Na.
  • the reaction is preferably performed in an organic solvent under reflux conditions.
  • the preferred organic solvent is pyridine
  • the preferred solvent is ethanol.
  • diosgenin is reacted with succinate to obtain diosgenin succinate monoester, and then reacted with sodium bicarbonate to obtain diosgenin succinate monoester sodium salt, which Good water solubility has a good preventive effect on myocardial infarction in rats.
  • diosgenin ring deterrent and 2,2-dimethyl-dihydrofuran [3,4-d] [l, 3] -m-dioxoladiene- 4,6-dione reaction to obtain diosgenin 2,2 Difluorenyl- [1,3] dioxolane 4,5-dicarboxylic acid monoester, and then react with sodium bicarbonate to obtain diosgenin 2,2difluorenyl- [1,3] dioxolane 4,5-Dicarboxylic acid monoester sodium salt, which has good water solubility, has a good preventive effect on myocardial infarction in rats.
  • the diosgenin 2,2 difluorenyl- [1,3] dioxolane 4,5-dicarboxylic acid monoester prepared above is reacted with concentrated sulfuric acid to obtain diosgenin
  • This tartrate is reacted with sodium bicarbonate to obtain diosgenin tartaric acid ⁇ sodium salt, which has good water solubility and has a good preventive effect on myocardial infarction in rats.
  • the application of the compound of formula (I) of the present invention in the preparation of a medicament for treating or preventing cardiovascular and cerebrovascular diseases is provided by adding the compound of formula (I) of the present invention to a pharmaceutically acceptable carrier or excipient Agent or optional other ingredients to make a pharmaceutical composition suitable for clinical use, and to treat or prevent myocardial ischemia and myocardial infarction by administering to a human or an animal an effective amount of a compound of the formula (I) of the present invention.
  • the diosgenin succinic acid monoester (compound of formula (II)) obtained by the above reaction can be subjected to a condensation reaction with various amino acids, or further prepared into a salt to obtain a compound of formula (III) Diosgenin succinic acid monoester ⁇ : Bio:
  • AA is various amino acids such as glycine, alanine, cystine, glutamic acid, lysine, proline, threonine, tyrosine, leucine, isoleucine Amino acid, phenylalanine, tryptophan, serine, threonine, cysteine, aspartic acid, arginine, histidine, and their corresponding amino or carboxylic acid salts, and other pharmaceutical Acceptable salt.
  • amino acids such as glycine, alanine, cystine, glutamic acid, lysine, proline, threonine, tyrosine, leucine, isoleucine Amino acid, phenylalanine, tryptophan, serine, threonine, cysteine, aspartic acid, arginine, histidine, and their corresponding amino or carboxylic acid salts, and other pharmaceutical Acceptable salt.
  • the amino acid may be a (L) counterpart or a (D) counterpart; a pharmaceutically acceptable salt thereof is selected from a sodium salt, a potassium salt, a calcium salt, and a magnesium salt, or is selected from a hydrochloride salt, an acetate salt, a pyrene Sulfonates and citrates.
  • AA is glycine, or its sodium salt; or, AA is histidine, or its acetate salt; or, AA is glutamic acid, or its sodium salt; or, AA is asparagus Amino acid, or its sodium salt; or, AA is arginine, or its acetate.
  • the water solubility of these compounds is obviously improved, and they have better anti-myocardial anemia, and can be used to prevent cardiac ischemia.
  • a method for preparing a compound of formula (III) includes combining diosgenin succinic acid monoester of formula (II) with N-hydroxysuccinimide, N, N-dicyclohexyl carbon The diimine is then reacted with various amino acids to obtain a compound of formula (III). The reaction is performed in a mixed solvent.
  • the mixed solvent is preferably tetrahydrofuran and water. The reaction steps are as follows:
  • the reaction step may further include a process of reacting with sodium bicarbonate or potassium bicarbonate under reflux conditions.
  • the application of the compound of formula (III) of the present invention in the preparation of a medicament for treating or preventing cardiovascular disease can be provided by adding the compound of formula (III) of the present invention to a pharmaceutically acceptable Carrier or excipient or optional other ingredients to make a pharmaceutical composition suitable for clinical use, by treating or preventing an effective amount of a compound of formula (III) of the present invention .
  • Diosgenin 2,2 dimethyl- [1,3] dioxolane 4,5-dicarboxylic acid monoester 29.3 g (0.05 mol) was dissolved in 500 ml of absolute ethanol, and then anhydrous hydrogen carbonate was added dropwise.
  • Diosgenin succinate monoester was prepared according to the method of Example 1. 30.8 g (60 mmol) of diosgenin succinic acid monoester and 9 g (78 mmol) of N-hydroxysuccinimide were dissolved in THF (350 ml) under stirring in a water-salt bath, and then ⁇ , ⁇ -bicyclohexyl 14.8 g (72 mmol) of carbodiimide. After 1 hour of reaction, remove the ice salt bath and react at room temperature overnight. The insoluble material was filtered off, and most of the THF was distilled off. The residue was poured into water (1000 ml) and stirred to precipitate a solid. The solid was washed with water. Then dissolved in THF (400ml) to prepare solution A.
  • Diosgenin succinate monoester was prepared according to the method of Example 1. 30.8 g (60 mmol) of diosgenin succinic acid monoester and 9 g (78 mmol) of N-hydroxysuccinimide were dissolved in THF (350 ml) under stirring in a water and salt bath, and then N, N-dicyclohexyl 14.8 g (72 mmol) of carbodiimide, reacted for 1 hour and then reacted at room temperature overnight. The insolubles were filtered off and most of the THF was evaporated. The residue was poured into ice water (1000 ml) and stirred to precipitate a solid, and the solid was washed with water. Then dissolved in THF (400ml) to prepare solution A.
  • IR 3500 ⁇ 3100 (br), 2950, 2907, 1731, 1650, 1600.
  • Diosgenin succinate monoester was prepared according to the method of Example 1. 30.8 g (60 mmol) of diosgenin succinic acid monoester and 9 g (78 mmol) of NH-hydroxysuccinimide were dissolved in THF (350 ml) under stirring in a water-salt bath, and then ⁇ , ⁇ -bicyclohexyl 14.8 g (72 mmol) of carbodiimide, reacted for 1 hour and then reacted at room temperature overnight. The insolubles were filtered off and most of the THF was evaporated. The residue was poured into ice water (1000 ml) and stirred to precipitate a solid, and the solid was washed with ice water. Then dissolved in THF (400ml) to prepare solution A.
  • Diosgenin succinate monoester was prepared according to the method of Example 1. 30.8 g (60 mmol) of diosgenin succinic acid monoester and 9 g of N-hydroxysuccinimide under stirring in a water and salt bath (78 mmol) was dissolved in THF (350 ml), and then 14.8 g (72 mmol) of N, N-dicyclohexylcarbodiimide was added, and reacted at room temperature for 1 hour. The insolubles were filtered off and most of the THF was evaporated. The residue was poured into ice water (1000 ml) and stirred to precipitate a solid, and the solid was washed with water. Then dissolved in THF (400ml) to prepare solution A.
  • IR 3500-3100 (br), 2950, 2904, 1731, 1634.
  • IR 3400 ⁇ 3300 (br), 2950, 1731, 1632.
  • Solubility in water was measured according to the regulations in the Pharmacopoeia of the People's Republic of China (2000 Edition). The results are shown in Table 2. Compounds 1 to 8 in Table 2 are the compounds prepared in Examples 4 to 11, respectively.
  • the animals were randomly divided into 7 groups of 5 animals each: model group (M) (saline, 3ml), test drug group (T) 0.125, 0.063g / Kg group (respectively the maximum dose 1/20, 1 / 40), the tested drugs were: 1 diosgenin sodium succinate monoester sodium salt; 2 diosgenin 2,2 difluorenyl- [1,3] dioxolane 4,5-dicarboxylic acid monoester Ester sodium salt; 3 »Diosgenin tartrate monoester sodium salt.
  • the test drugs were dissolved in physiological saline to a desired concentration, and the administration volume was 3 ml / kg, and the administration route was duodenum.
  • the test was terminated 3 hours after the ligation.
  • Five pieces were transected under the heart ligature line and stained with N-BT.
  • the multimedia color pathology analysis system (MPIAS-500) was used to measure the area of normal myocardium and infarcted myocardium at a fixed image distance. Degree; results were statistically processed (t test).
  • Table 1 Effects of diosgenin carboxylic acid derivatives on myocardial infarction caused by myocardial ischemia in rats Normal myocardium infarct myocardial infarction cardiac infarct heart weight accounted for accounting infarction cardiac ventricle mm 2 mm 2 g 0/0 Heart 0 / n 0 doses.
  • Test method Healthy Wistar rats, male and female, weighing 250-300. Randomly grouped according to body weight, 8 animals in each group. Distilled water (sham operation control, model control group), test substance 125, 250 mg / kg '(test drug group), and heartache 10mg / kg
  • Tool Drug Group The administration volume was 10ml / kg, once a day for 3 days. One hour after the last dose, anesthesia was injected intraperitoneally with chloral hydrate (350 mg / kg), and the normal ECG was measured. The left chest was depilated, the intersection of the midline of the clavicle and the fourth rib was taken as the center, and the skin was cut 2 cm along the midline of the clavicle. The muscle layer was separated sacrifice, and the circumlunar / L layer was used for purse suture.
  • 1% Evans Blue 0.3ml / head was injected through the external jugular vein. After 1 min, the heart was taken out and washed several times with normal saline. The heart was sliced along the vertical direction of the long axis of the heart to a thickness of 1.5 mm. After staining in 1% TTC solution for 15 minutes, the heart sections were removed, and the pathological image analysis system was used to determine and calculate the percentage of myocardial infarction area to the left ventricle area.
  • the CK-MB of compound 7 was significantly reduced after administering the compound.
  • the results are shown in Table 4.
  • the tool drug Xintongding significantly reduced the ST segment elevation of the ischemic ECG, narrowed the scope of myocardial infarction, and decreased serum myocardial enzymes (LDH, CK-MB,).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé de carboxylate de diosgénine représenté par la formule (I) et un dérivé de succinate monoester de diosgénine représenté par la formule (III). Dans la formule (I), R est choisi dans un groupe alkyle ou un groupe alkyle substitué possédant 1 à 2 atomes de carbones, M est H ou Na. Dans la formule (III) AA représente une variété d'amino acide. Les composés de cette invention possèdent une bonne solubilité dans l'eau et peuvent être utilisés pour traiter et prévenir des maladies cérébro-vasculaires et cardio-vasculaires.
PCT/CN2003/000263 2002-04-15 2003-04-14 Composes et techniques de preparation de carboxylate de diosgenine et d'un derive de succinate monoester de diosgenine Ceased WO2003086411A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003231427A AU2003231427A1 (en) 2002-04-15 2003-04-14 Compounds and preparation methods of carboxylate and monoester succinate derivative of diosgenin

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN02111346.7 2002-04-15
CN 02111346 CN1187368C (zh) 2002-04-15 2002-04-15 薯蓣皂甙元羧酸衍生物及制备方法
CN03117182.6 2003-01-17
CN 03117182 CN1260245C (zh) 2003-01-17 2003-01-17 薯蓣皂甙元丁二酸单酯衍生物及其制备方法和应用

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WO2003086411A1 true WO2003086411A1 (fr) 2003-10-23

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006107902A3 (fr) * 2005-04-01 2006-11-30 Samaritan Pharmaceuticals Inc Utilisation de spirostenols dans le traitement des troubles mitochondriaux
EP1809298A4 (fr) * 2004-10-14 2008-06-18 Univ Georgetown Compositions pharmaceutiques neuroprotectrices contenant du spirostenol
WO2014148718A1 (fr) * 2013-03-20 2014-09-25 (주) 셀인바이오 Composition morphogénétique osseuse et application de celle-ci
CN110128498A (zh) * 2019-05-29 2019-08-16 中国科学院昆明植物研究所 一种薯蓣皂苷元衍生物及其药物组合物与其制备和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3890438A (en) * 1972-10-06 1975-06-17 American Home Prod Compositions and methods for reducing blood cholesterol
US4602003A (en) * 1982-05-17 1986-07-22 Medical Research Foundation Of Oregon Synthetic compounds to inhibit intestinal absorption of cholesterol in the treatment of hypercholesterolemia

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3890438A (en) * 1972-10-06 1975-06-17 American Home Prod Compositions and methods for reducing blood cholesterol
US4602003A (en) * 1982-05-17 1986-07-22 Medical Research Foundation Of Oregon Synthetic compounds to inhibit intestinal absorption of cholesterol in the treatment of hypercholesterolemia

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1809298A4 (fr) * 2004-10-14 2008-06-18 Univ Georgetown Compositions pharmaceutiques neuroprotectrices contenant du spirostenol
WO2006107902A3 (fr) * 2005-04-01 2006-11-30 Samaritan Pharmaceuticals Inc Utilisation de spirostenols dans le traitement des troubles mitochondriaux
WO2014148718A1 (fr) * 2013-03-20 2014-09-25 (주) 셀인바이오 Composition morphogénétique osseuse et application de celle-ci
KR101480982B1 (ko) 2013-03-20 2015-02-03 (주)셀인바이오 골형성 유도 화합물 및 이의 응용
CN110128498A (zh) * 2019-05-29 2019-08-16 中国科学院昆明植物研究所 一种薯蓣皂苷元衍生物及其药物组合物与其制备和应用
CN110128498B (zh) * 2019-05-29 2021-11-26 中国科学院昆明植物研究所 一种薯蓣皂苷元衍生物及其药物组合物与其制备和应用

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