WO2015070713A1 - Dérivés d'éther d'oxime de limonine, procédé de préparation et usage médicinal associés - Google Patents

Dérivés d'éther d'oxime de limonine, procédé de préparation et usage médicinal associés Download PDF

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Publication number
WO2015070713A1
WO2015070713A1 PCT/CN2014/090148 CN2014090148W WO2015070713A1 WO 2015070713 A1 WO2015070713 A1 WO 2015070713A1 CN 2014090148 W CN2014090148 W CN 2014090148W WO 2015070713 A1 WO2015070713 A1 WO 2015070713A1
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compound
acid
preparation
group
pharmaceutically acceptable
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PCT/CN2014/090148
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English (en)
Chinese (zh)
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徐云根
何广卫
朱启华
杨芸
龚国清
储昭兴
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中国药科大学
合肥医工医药有限公司
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Publication of WO2015070713A1 publication Critical patent/WO2015070713A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/008—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by two hetero atoms
    • 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]

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to a kind of water-soluble limonin and deoxy limonoid oxime ether derivatives, a preparation method thereof, and an analgesic, anti-inflammatory and therapeutic effect on rheumatoid arthritis.
  • RA Rheumatoid arthritis
  • RA Rheumatoid arthritis
  • non-steroidal anti-inflammatory drugs are more commonly used to relieve symptoms, but the efficacy is weak, and the gastrointestinal side effects are large; the immunosuppressive agents such as methotrexate have clear effects.
  • the immunosuppressive agents such as methotrexate have clear effects.
  • it is currently the gold standard for the treatment of rheumatoid arthritis, but its slow onset, high toxicity, many adverse reactions and difficult to tolerate, long-term blood concentration monitoring; biological agents such as adalimumab have clear efficacy, but It is expensive and difficult to popularize; small molecule-targeted drugs such as tofacitini have been approved for marketing in 2012.
  • Limonoid analogues are highly oxidized tetracyclic triterpenoids of the family Rutaceae and Polygonaceae, which are widely found in citrus plants. To date, more than 300 limonoid analogs have been isolated, and limonin is representative of such compounds. Limonin is easily soluble in fat-soluble organic solvents, and has a high solubility in methanol and ethanol, but it is almost insoluble in water, and its oral bioavailability is extremely low, which limits its clinical application.
  • the invention discloses a compound of the general formula I and II.
  • the pharmacological experiments show that the compound of the invention has good analgesic, anti-inflammatory activity and obvious curative effect of rheumatoid arthritis.
  • the compounds of the formula I, II according to the invention are clinically useful for relieving pain and have an anti-inflammatory effect, in particular for the treatment of rheumatoid arthritis.
  • R 1 , R 2 represents: CH 3 , C 2 H 5 , C 3 H 7 , CH(CH 3 ) 2 or C 4 H 9
  • n 1 or 2.
  • the compound of the formula I of the present invention can be produced by the following method:
  • the process for preparing compound IV by deuteration of compound III the reactant is hydroxylamine hydrochloride; the catalyst is pyridine, triethylamine or potassium carbonate; the solvent is ethanol or isopropanol.
  • the process for preparing compound I from compound IV the base used is sodium hydride, potassium t-butoxide, sodium methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide; the catalyst is tetrabutylammonium bromide (TBAB) or benzyl tri Ethyl ammonium chloride (TEBA); the activator is sodium iodide or potassium iodide; the solvent is N, N-dimethylformamide, tetrahydrofuran or a mixed solvent of the two.
  • TBAB tetrabutylammonium bromide
  • TEBA benzyl tri Ethyl ammonium chloride
  • the activator is sodium iodide or potassium iodide
  • the solvent is N, N-dimethylformamide, tetrahydrofuran or a mixed solvent of the two.
  • the reactant is a saturated hydrogen chloride solution in diethyl ether, a saturated hydrogen chloride solution in ethanol, a saturated hydrogen chloride solution in methanol or a saturated aqueous solution of hydrogen chloride in ethyl acetate;
  • the solvent is methanol, ethanol, and Methyl chloride or ethyl acetate.
  • the compound of the formula II of the present invention can be produced by the following method:
  • reaction reagent is hydroiodic acid
  • reaction solvent is acetic acid
  • the reactant is hydroxylamine hydrochloride
  • the catalyst is pyridine, triethylamine or potassium carbonate
  • the solvent is ethanol, acetonitrile or a mixed solvent of the two.
  • the process for preparing compound II from compound VII the base used is sodium hydride, potassium t-butoxide, sodium methoxide, sodium ethoxide, sodium hydroxide or potassium hydroxide; the catalyst is tetrabutylammonium bromide or benzyltriethyl chloride. Ammonium; the activator is sodium iodide or potassium iodide; the solvent is N, N-dimethylformamide, tetrahydrofuran or a mixed solvent of the two.
  • the reactant is a saturated hydrogen chloride solution in diethyl ether, a saturated hydrogen chloride solution in ethanol, a saturated hydrogen chloride solution in methanol or a saturated aqueous solution of hydrogen chloride in ethyl acetate;
  • the solvent is methanol, ethanol, and Methyl chloride or ethyl acetate.
  • the pharmaceutically acceptable salt of the compound of the present invention has the same activity as the compound, wherein the pharmaceutically acceptable salt is an acid addition salt of the compound of the formula (I) or (II) with the following acid: hydrochloric acid, hydrobromic acid, Sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
  • the pharmaceutically acceptable salt is an acid addition salt of the compound of the formula (I) or (II) with the following acid: hydrochloric acid, hydrobromic acid, Sulfuric acid, carbonic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesul
  • the compound code I series (e.g., I-1) represents a derivative of the compound of formula I
  • the II series (e.g., II-1) represents a derivative of the compound of formula II.
  • mice 1. Compound acetic acid writhing test test of mice:
  • mice male and female, 18-22 g, were randomly divided into control group, aspirin group, limonin group, and compound group of the present invention, with 8 rats in each group. After 1 hour of intragastric administration, the mice were intraperitoneally injected with 0.7% acetic acid 0.1 ml/10 g. Immediately observe and record the number of writhing in each group of animals within 15 min, and then calculate the inhibition rate of the mouse writhing according to the following formula. See the result Table 1.
  • Inhibition rate (average number of writhing in negative control group - average number of writhing in experimental group) ⁇ average writhing number in negative control group ⁇ 100
  • mice acetic acid writhing test showed that intraperitoneal injection of 0.7% acetic acid 0.1ml/10g can cause abdominal pain in mice, and a writhing reaction occurs.
  • the compound of the present invention has obvious inhibitory effect on the writhing reaction of mice.
  • ICR male mice, 18-22 g were randomly divided into control group, aspirin group, limonin group, and compound group of the present invention, with 8 rats in each group.
  • 3 cm of the tip of the mouse tail was immersed in a constant temperature water bath at 48 ° C, and the tip of the mouse tail was immersed in a constant temperature water bath at 48 ° C, and twice before the administration (interval of 5 minutes), and the average value was taken.
  • the changes of the tail-end latency of the mice were measured 30 minutes, 60 minutes, 90 minutes, and 120 minutes after the intragastric administration.
  • the response was not more than 25 seconds, and the pain threshold was 25 seconds.
  • the cut-off time here is defined as 25 seconds to protect the mouse's tail skin from damage.
  • mice tail-squeezing experiment showed that the compounds of the present invention can greatly enhance the pain threshold in the tail-finishing reaction of mice, and exhibit strong analgesic activity.
  • ICR male mice 18-22 g were randomly divided into control group, ibuprofen group, limonin group, and compound group of the present invention, with 8 rats in each group.
  • each group was randomly divided into a model group and each test group, with 8 rats in each group.
  • 25 ul of xylene was applied to the right ear of the mice to cause inflammation.
  • the neck was sacrificed.
  • the ears were punched with an 8 mm punch and the ears were weighed to calculate the swelling rate (%). And swelling inhibition rate (%).
  • the results are shown in Table 2.
  • pKa ionization constant
  • log D 7.4 oil-water partition coefficient at pH 7.4
  • solid solubility was determined using a Gemini Profiler instrument (pION).
  • the instrument is based on Avdeef and Tsinman's 'goldstandard' Av-deef-Bucher potentiometric titration, which is in compliance with the US Food and Drug Administration (FDA) requirements for solubility and pKa.
  • FDA US Food and Drug Administration
  • the experimental results of the adjuvant arthritis model showed that the compound I-3 hydrochloride of the present invention has a significant inhibitory effect on CFA-induced adjuvant arthritis, and each dose group can reduce the swelling degree of the model joint and the swelling of the secondary joint. Improve the arthritis index score and inhibit the weight loss caused by arthritis.
  • the swelling degree, body mass index and arthritis index of I-3 hydrochloride 40mg/kg and 20mg/kg groups were significantly better than limonin 40mg/kg group, and 10mg/kg low dose group was more than limonin 40mg/kg.
  • the superiority of the group mainly occurred after 15 days of administration.
  • Figure 1 is the effect of limonoid derivative I-1 ⁇ 5 hydrochloride on tail contraction in mice
  • Figure 2 is the effect of limonoid derivative II-1 ⁇ 5 hydrochloride on tail contraction in mice
  • the residue was added to 100 ml of water, the pH was made acidic with 5% diluted hydrochloric acid, and the aqueous layer was extracted three times with 70 ml of dichloromethane, and the mixture was combined and washed three times with saturated brine and dried over anhydrous sodium sulfate. Filter and distill off the solvent under reduced pressure.
  • the compound I-2 was used as a starting material, and the preparation method of the same I-1 ⁇ HCl was carried out to obtain 0.15 g of a white solid of I-2 ⁇ HCl, yield 71%, and 200° C. (decomposition).
  • the compound I-5 was used as a starting material, and the preparation method of the same I-1 ⁇ HCl was carried out to obtain 0.18 g of a white solid of I-5 ⁇ HCl, yield 84%, and 98° C. (shrinkage).
  • the compound VII and 1-(2-chloroethyl)morpholine hydrochloride were used as the starting materials, and the same method as I-1 was carried out, and the crude product was subjected to column chromatography using dichloromethane:methanol (70:1) to obtain II-2 white.
  • the solid was 0.28 g, and the yield was 45%. 210 ° C (carbonization).
  • the compound VII and 2-chloroethyl dimethylamine hydrochloride were used as the starting materials, and the same method as that of I-1 was carried out.
  • the crude product was chromatographed with dichloromethane:methanol (25:1) to give a white solid. The yield was 26%. 210 ° C (carbonization).
  • Example 2 0.5 g of the compound obtained in Example 2, 2 g of starch, and 1 g of dextrin were mixed, and an appropriate amount of 30% ethanol was used as a wetting agent, granulated, and tableted.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne le domaine de la chimie des médicaments, en particulier les dérivés d'éther d'oxime de limonine (I) et (II), ainsi que leur procédé de préparation et leur usage médicinal. Les expériences pharmacologiques montrent que les composés de la présente invention ont des effets analgésiques et anti-inflammatoires et peuvent être cliniquement utiles pour soulager la douleur et les maladies inflammatoires.
PCT/CN2014/090148 2013-11-14 2014-11-03 Dérivés d'éther d'oxime de limonine, procédé de préparation et usage médicinal associés WO2015070713A1 (fr)

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CN201310567630.2 2013-11-14
CN201310567630.2A CN103588854B (zh) 2013-11-14 2013-11-14 柠檬苦素肟醚衍生物、其制法以及医药用途

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CN103588854B (zh) * 2013-11-14 2015-10-28 中国药科大学 柠檬苦素肟醚衍生物、其制法以及医药用途
CN104744558B (zh) * 2015-03-23 2017-03-22 中国药科大学 柠檬苦素‑7‑氨基衍生物、其制法以及医药用途
CN106928311B (zh) * 2017-03-24 2019-06-04 中国药科大学 柠檬苦素衍生物、其制备方法及医药用途
CN111518111B (zh) * 2020-05-26 2021-06-01 中国药科大学 脱氧柠檬苦素a环开环胺化衍生物或其药学上可接受的盐、制备方法及用途
CN111574533B (zh) * 2020-05-26 2021-06-01 中国药科大学 柠檬苦素a环开环胺化衍生物或其药学上可接受的盐、制备方法及用途
CN113234089B (zh) * 2021-05-08 2022-07-15 南京医科大学 柠檬苦素类化合物、制备方法及其作为治疗棘球蚴包虫病药物的应用

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CN103588854A (zh) * 2013-11-14 2014-02-19 中国药科大学 柠檬苦素肟醚衍生物、其制法以及医药用途

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US8952033B2 (en) * 2011-12-30 2015-02-10 Kaohsiung Medical University 4-anilinofuro[2,3-b]quinoline derivatives, their preparation processes, and pharmaceutical compositions comprising the same
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RUBERTO, G. ET AL.: "Citrus Limonoids and their Semisynthetic Derivatives as Antifeedant Agents against Spodopterafrugiperda Larvae. A Structure-activity Relationship Study", JOURNAL OF AGRICULTURE AND FOOD CHEMISTRY, vol. 50, no. 23, 9 October 2002 (2002-10-09), pages 6766 - 6774 *

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