WO2011147254A1 - Dérivés de phénylbutyryl curcumine et leurs utilisations dans la préparation de médicaments anti-tumoraux - Google Patents

Dérivés de phénylbutyryl curcumine et leurs utilisations dans la préparation de médicaments anti-tumoraux Download PDF

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Publication number
WO2011147254A1
WO2011147254A1 PCT/CN2011/073844 CN2011073844W WO2011147254A1 WO 2011147254 A1 WO2011147254 A1 WO 2011147254A1 CN 2011073844 W CN2011073844 W CN 2011073844W WO 2011147254 A1 WO2011147254 A1 WO 2011147254A1
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Prior art keywords
compound
curcumin
group
pharmaceutically acceptable
cancer
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PCT/CN2011/073844
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English (en)
Chinese (zh)
Inventor
许建华
刘洋
吴丽贤
林燕芳
吴枝娟
郭晓丹
吴敏
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福建医科大学
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Priority to GB1223251.8A priority Critical patent/GB2494595B/en
Publication of WO2011147254A1 publication Critical patent/WO2011147254A1/fr

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    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters

Definitions

  • the invention belongs to the field of pharmacy, and in particular relates to a phenylbutyryl curcumin derivative and a preparation method thereof, and the use thereof in preparing an antitumor drug.
  • Curcumin (Cur) is an active ingredient extracted from the rhizome of the turmeric, turmeric, turmeric, and turmeric of the genus Zingiberaceae. It has anti-tumor, anti-inflammatory, anti-human immunodeficiency virus, anti-cholesterol, anti-oxidation and so on. A pharmacological effect has a good clinical application potential.
  • Cur is unstable, rapid metabolism in the body, low bioavailability, and it is difficult to achieve an effective concentration in the body, which seriously restricts the development of curcumin into an effective anticancer drug.
  • Curcumin derivatives synthesized through structural transformation, improve bioavailability, prolonged biological t 1/2 elimination half-life is important.
  • One of the objects of the present invention is to provide 4-[bis(2-chloroethyl:)amino]phenylbutanoyl curcumin and 4,4'-[bis(2-chloroethyl:)amino]bisphenylbutanoyl turmeric And its pharmaceutically acceptable salt.
  • a second object of the present invention is to provide 4-[bis(2-chloroethyl:)amino]phenylbutanoyl curcumin and 4,4'-[bis(2-chloroethyl:)amino]bisphenylbutanoyl turmeric And a method for preparing the pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salts include alkali metal salts, alkaline earth metal salts, organic base-containing salts, and organic base-containing salts.
  • the acceptable salts include calcium salts, magnesium salts, ammonium salts, triethylamine salts, and ethanolamine salts.
  • the preparation method of the curcumin derivative and the salt of the present invention is specifically as follows: The curcumin is dissolved in the dried dichloromethane, and the catalytic amount of DMAP ( ⁇ , ⁇ -4-dimethylaminopyridine) is added. Then, 4-[bis(2-chloroethyl:)amino] phenylbutyric acid which has been dissolved in methylene chloride is added for esterification, and then the product is separated and purified by column chromatography.
  • a dehydrating agent DCC (dicyclohexylcarbodiimide) or EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) may be added first.
  • DCC diclohexylcarbodiimide
  • EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • the curcumin derivatives of the compound 1 and the compound 2 synthesized by the present invention are all obtained by nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), ultraviolet spectroscopy (UV), and liquid chromatography-mass spectrometry (HPLC-Mass). After the identification of Compound 1 and Compound 2, a suitable pharmaceutically acceptable dosage form is prepared as needed.
  • the present invention is a pharmaceutical composition or preparation comprising a medicament for protecting Compound 1 or Compound 2 or a pharmaceutically acceptable salt thereof, or a medicament containing Compound 1 or Compound 2 or a pharmaceutically acceptable salt thereof.
  • the carrier is a conventional pharmaceutical carrier in the pharmaceutical field, such as a diluent, an excipient, a filler, a binder, a disintegrant, a surfactant, a lubricant, etc.;
  • Various dosage forms for oral administration and other modes of administration such as oral liquids, suspensions, capsules, tablets, pills, granules, powder injections, etc.; prepared by conventional production methods in the pharmaceutical field, which are selected to contain weight percentages It is 0.1% to 99.5% active ingredient of Compound 1 or Compound 2.
  • Pharmaceutical compositions which may also contain from 0.1% to 99.5% of Compound 1 or Compound 2; are those which can be practiced by one of ordinary skill in the art.
  • the dosage of the present invention may be changed according to the route of administration, the age and weight of the patient, the type and severity of the disease to be treated, and the dose may be 0.001 - 10 g / k g body weight, which may be given one or more times. medicine.
  • the third object of the present invention is to 4-[bis(2-chloroethyl:)amino]phenylbutanoyl curcumin and 4,4'-[bis(2-chloroethyl)amino]bisphenylbutanoyl curcumin, For the preparation of anti-tumor drugs.
  • Curcumin derivatives can be used, but are not limited to, to prepare drugs for the treatment of leukemia, skin cancer, gastric cancer, colon cancer, liver cancer, breast cancer or prostate cancer.
  • Leukemia is preferably human chronic myeloid leukemia.
  • the compound 1 curcumin 4- [bis(2-chloroethyl)amino] phenylbutyrate of the present invention is significantly inhibited in various animal tumor cell transplantation models in vivo, especially
  • the inhibitory effect on human chronic myeloid leukemia K562 cells in nude mice can be as high as 60%, and the weight of nude mice in the drug-administered group did not decrease significantly, and no animal died.
  • FIG. 1 is a graph showing the inhibitory effect of intravenous administration of Compound 1 on mouse liver cancer H22 xenografts.
  • Figure 2 is a graph showing the inhibitory effect of oral administration of compound 1 on liver cancer H22 xenografts in mice.
  • Figure 3 is a graph showing the growth curve of compound 1 in human chronic myeloid leukemia K562 cells transplanted in nude mice.
  • Figure 4 is a diagram showing the effect of Compound 1 on human chronic myeloid leukemia K562 cells transplanted in nude mice.
  • Figure 5 and Figure 6 are the gross anatomy of mouse 1 in mouse model of human chronic myeloid leukemia and the mouse bone marrow bcr-abl gene. Expression map
  • Figure 7 and Figure 8 are the peripheral blood images of NS group and compound 1 administered to human chronic myeloid leukemia model mice.
  • Figure 9 is a graph showing the inhibitory effect of Compound 2 on mouse liver cancer H22 xenografts
  • H22 mouse xenografts were established, and the physiological saline (control group) of the mice was intravenously administered, Compound 1 : 50, 70 mg/kg (administration group).
  • the tumor inhibition rate is as high as 60%.
  • H22 mouse xenografts were established and administered orally to mice with physiological saline (control group).
  • Compound 1 50, 75, 100 mg/kg (administration group), curcumin 50 mg/kg (curcumin) Control group).
  • the tumor inhibition rates of the drug-administered group were 41.21%, 52.93%, and 75.06%, respectively.
  • the anti-tumor rate of the curcumin control group (equal to the compound lOOmg/kg) was only 16.58%, and the anti-tumor effect of the compound was significantly stronger than that of curcumin.
  • a nude mouse xenograft model of human chronic myeloid leukemia K562 cells was established and administered orally to nude mice (control group), compound 1: 40, 60 mg/kg (administration group).
  • control group nude mice
  • compound 1 40, 60 mg/kg
  • the length, width and height of the mouse tumor were measured with vernier calipers.
  • Calculated tumor volume length> ⁇ width X height xl/2
  • percentage of growth (%) (average tumor volume of the experimental group)
  • the mean tumor volume of the control group was ⁇ 100%.
  • the growth of tumors in the drug-administered group was significantly inhibited.
  • a nude mouse xenograft model of ⁇ 562 cells was established and orally administered to nude mice (control group), compound 1: 40, 60 mg/kg (administration group).
  • the tumor inhibition rates were 66.6% and 56.7%, respectively.
  • a human chronic myeloid leukemia model was constructed using NOD-SCID mice.
  • the control group was grossly dissected, and a large amount of bloody ascites was seen in the abdominal cavity, and solid tumors appeared.
  • the characteristic gene bcr-abl of human chronic myeloid leukemia was detected by RT-PCR, indicating that human chronic myeloid leukemia cell K562 homing to the bone marrow of NOD-SCID mice.
  • NOD-SCID mouse human chronic myeloid leukemia model was orally administered to normal saline (control group), compound 1: 60 mg/kg (administered group), peripheral blood group of the drug-administered group.
  • the naive cells were also significantly less than the control group.
  • the physiological saline (control group) of the mice was orally administered, Compound 2: 35, 50, 75, 115 mg/kg (administration group), curcumin 50 mg/kg (curcumin control group).
  • the tumor inhibition rates of the drug-administered group were 27.43%, 32.25%, 62.60%, and 58.39%, respectively.
  • Curcumin group (compound 100m g / kg equimolar) inhibition rate was 13.42%, visible inhibitory effect of Compound 2 significantly stronger than curcumin.
  • EDCI 1 92g (10mmol) was dissolved in anhydrous dichloromethane 200ml, stirred in an ice bath and added with curcumin 7.36g (20mmol), DMAP 0. 244g (2mmol), then slowly added to dissolve 4- [Bis(2-chloroethyl)amino] phenylbutyric acid 3. 04 g (10 mmol) of dichloromethane (200 ml), and the reaction was further stirred at room temperature for 6 hours. After washing with distilled water, the organic phase was dried over anhydrous magnesium sulfate, and then filtered and evaporated to give a crude product.
  • EDCI 1 92g (10mmol) was dissolved in 100ml of anhydrous dichloromethane, stirred in an ice bath and added with curcumin 1.84g (5mmol), DMAP 0. 122g (lmmol), then slowly added to dissolve 4- [Bis(2-chloroethyl)amino] phenylbutyric acid 3. 04 g (10 mmol) of dichloromethane (200 ml), and the reaction was further stirred at room temperature for 6 hours. After washing with distilled water, the organic phase was dried over anhydrous magnesium sulfate, and then filtered and evaporated to give a crude product.
  • mice 8 ⁇ 12 weeks old Kunming healthy mice, female, weighing (20 ⁇ 2) g; mice were provided by Experimental Animal Center of Fujian Medical University (certificate No. SCXK ( ⁇ :) 200420002). Mouse liver cancer cell line H22.
  • H22 tumor cells were passed for more than two generations. The number of cells was adjusted to 10 7 /ml, 0.2 mL/only inoculated into the right forelimb of mice, and 2 inoculated. After about two weeks, the tumor was stripped, homogenized, and inoculated again.
  • a total of 3 groups The mice after 24 h inoculation of tumors were randomly divided into 3 groups: Group I was a saline control group, and Compound 1 was prepared by the method of the above examples. The same group II was compound 1 low. The dose group (Compound 1 50 mg/kg), Group III was Compound 1 high dose group (70 mg/kg), and the administration method was tail vein injection, 0.1 ml/10 g.
  • mice A total of 5 groups: 24 hours after inoculation of tumors, the mice were randomly divided into 5 groups: group I was saline group (ie, tumor control group), group II was compound 1 low dose group (dose was 50 mg/kg) , III group compound 1 dose (a dose of 75mg / kg), IV group compound high dose groups (dose 100m g / k g), V group Cur group (at a dose of 50mg / kg, with a high dose Group IV equimolar), the method of administration is gavage,
  • the tumor inhibition rate (%) the average tumor quality of the control group - the average tumor mass of the experimental group / the average tumor mass of the control group ⁇ %.
  • Compound 1 has a significant inhibitory effect on the transplant rate of mouse liver cancer H22 (see Table 1, Figure 1 of the accompanying drawings).
  • Table 1 Compound 1 intravenous administration to mouse liver cancer H22 xenograft inhibition agent number of rats tumor weight (g) tumor inhibition rate group other mg/kg > ⁇ day before / after (%)
  • the antitumor effect of oral administration for 6 days was observed. It can be seen that the tumor inhibition rate increases with the increase of dose, showing a good dose-effect relationship.
  • the anti-tumor rate of the drug-administered group (100m g /k g ) was significantly higher than that of the equimolar control drug curcumin (50 mg/kg), and no mice died in the large dose. Compound 1 was safer. (See Table 2 and Figure 2 of the drawing) Instruction manual
  • K562 cells were passed for more than two generations, and the number of cells was adjusted to 5 ⁇ 10 7 /ml, 0.2 mL/only inoculated into the right forelimb of nude mice, and 30 cells were inoculated.
  • mice After 6 days of inoculation of tumors, the mice were randomly divided into 3 groups according to the tumor size of the mice: Group I was the saline control group, and Group II was the compound 1 low dose group. 40 mg/kg), group III was compound 1 high dose group (60 mg/kg), and the administration method was intragastric administration, 0.1 ml/10 g.
  • the tumor inhibition rate (%) (the average tumor mass of the control group - the average tumor mass of the experimental group) / the average tumor mass of the control group X 1 oo %.
  • Fig. 3 of the accompanying drawings The dynamic changes of tumor growth in each group of tumor-bearing mice are shown in Fig. 3 of the accompanying drawings, and it can be seen that the tumor growth rate of the drug-administered group is significantly lower than that of the NS control group.
  • mice Both female and male, 4 to 6 weeks old, weighing 18 to 22 g, provided by the Laboratory Animal Research Institute of the Chinese Academy of Medical Sciences, license number: SCXK (Beijing) 2005-0013.
  • SCXK Beijing 2005-0013.
  • NOD-SCID mice were housed in a SPF laboratory laminar box with a cover mouse (in accordance with SPF standards:). Standard pellet feed, drinking water, litter and all contact with the mouse are sterilized.
  • NOD-SCID mice received whole body irradiation with 2.0 Gy X-rays, and K562 cells in logarithmic growth phase were used for transplantation the next day, and l xlO 7 cell/mouse was injected once in the tail vein.
  • mice After transplanting K562 cells into NOD-SCID mice, they were randomly divided into normal saline control group and drug-treated group, with four groups in each group.
  • the blank control group was given 0.2 ml/supply of normal saline, and the treatment group was administered with compound 1 60 mg/kg, and the administration was started two weeks after the transplantation, and the administration was continued for 5 days, and the treatment group was stopped for 5 days. Continuous medication for 8 days.
  • the general condition, body weight and food intake of the mice were closely observed during the administration, and the toxicity of the drug and the tolerance of the animal to the drug were evaluated to adjust the administration schedule.
  • the survival time of the mice in each experimental group was recorded for three months. The survival of K562 cells after transplantation for more than two months was long-term survival.
  • mice in each experimental group were counted before the inoculation and 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks after the inoculation, and the total number of white blood cells was counted in the tail vein blood, and blood smears were prepared. , stained by Wright-Gimsa, sorted and counted under oil mirror.
  • mice in the saline control group were 32.5 ⁇ 9.0 days after transplantation of human chronic myeloid leukemia cell K562.
  • Peripheral blood leukocytes increased significantly in the three weeks after transplantation, which was 2-10 times before transplantation, and a large number of immature cells were seen in peripheral blood smears.
  • the dead mice were grossly dissected, and a large amount of bloody ascites was seen in the abdominal cavity, and solid tumors appeared, and the splenomegaly was not obvious (see Figure 5 of the specification).
  • the saline-controlled group of NOD-SCID mouse bone marrow cells detected the human bcr-abl gene by RT-PCR (see Figure 6 of the specification), indicating that human chronic myeloid leukemia cell K562 homing to the bone marrow of NOD-SCID mice.
  • the human chronic granulocyte white blood model was successfully constructed.
  • Compound 2 was prepared by the method of the above examples, and the test method of this example was the same as Compound 1.
  • Compound 2 was formulated to the desired concentration prior to use.
  • the mice with good tumor growth were sacrificed by cervical dislocation, the tumor pieces were removed under aseptic conditions, and the tumor tissues with good growth state were taken, and the single cell suspension was prepared by homogenization filtration, and the number of cells was adjusted to 1.
  • OX IOVml each inoculation 0. 2ml was placed in the right axilla of the mouse to establish a H22 mouse xenograft model.
  • mice were randomized by body weight, 9 mice per group, and the pre-dose weight was recorded.
  • Tumor inhibition rate (%) [analytical tumor mass of the control group - mean tumor mass of the experimental group] / average tumor mass of the control group X 100%.
  • the present invention can also be verified in the same manner as the above examples, including Compound 1 or Compound 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing Compound 1 or Compound 2 or a pharmaceutically acceptable salt form thereof having similar properties.
  • the pharmaceutically acceptable salt include an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, a salt containing an organic base such as an ammonium salt, or a salt of an organic base such as triethylamine.

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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

L'invention concerne des dérivés de phénylbutyryl curcumine, leurs procédés de préparation, des compositions pharmaceutiques contenant lesdits dérivés et leurs utilisations pour préparer des médicaments anti-tumoraux. De façon spécifique, lesdits dérivés de curcumine sont la 4-[bis(2-chloroéthyl)amino]phénylbutyryl curcumine et la 4,4'-bis[bis(2-chloroéthyl)amino]phénylbutyryl curcumine, et leurs sels pharmaceutiquement acceptables. Les dérivés de curcumine sont efficaces pour inhiber divers modèles de transplantation de cellules tumorales animales in vivo, et n'ont pas de toxicité sérieuse dans la souris.
PCT/CN2011/073844 2010-05-26 2011-05-09 Dérivés de phénylbutyryl curcumine et leurs utilisations dans la préparation de médicaments anti-tumoraux WO2011147254A1 (fr)

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GB1223251.8A GB2494595B (en) 2010-05-26 2011-05-09 Phenylbutyryl curcumin derivatives and use thereof in manufacturing medicaments for preventing tumors

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CN2010101835096A CN101830819B (zh) 2010-05-26 2010-05-26 苯丁酰基姜黄素衍生物及其在制备抗肿瘤药物中的应用

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CN101830819B (zh) * 2010-05-26 2013-08-28 福建医科大学 苯丁酰基姜黄素衍生物及其在制备抗肿瘤药物中的应用
CN102552224A (zh) * 2011-12-16 2012-07-11 西安交通大学 姜黄素衍生物c2在抗结肠癌药物中的应用

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WO2004031122A1 (fr) * 2002-10-01 2004-04-15 Dr. André Rieks - Labor Für Enzymtechnologie Gmbh Nouveaux derives de curcumine/tetrahydrocurcumine destines a etre utilises dans des produits cosmetiques et pharmaceutiques ainsi que dans l'alimentation
WO2008045534A2 (fr) * 2006-10-12 2008-04-17 Research Foundation Of The City University Of New York Nouveaux dérivés de curcumine et de tétrahydrocurcumine
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CN101830819A (zh) * 2010-05-26 2010-09-15 福建医科大学 苯丁酰基姜黄素衍生物及其在制备抗肿瘤药物中的应用

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US7355081B2 (en) * 2002-04-17 2008-04-08 The University Of North Carolina At Chapel Hill Curcumin analogues and uses thereof
CN101003470B (zh) * 2007-01-22 2011-11-02 温州医学院生物与天然药物开发中心有限公司 姜黄素单羰基结构类似物及其用途
CN101255119B (zh) * 2008-01-07 2014-05-21 沈阳药科大学 四氢姜黄素衍生物及盐类
CN101434524B (zh) * 2008-06-05 2012-07-25 福建医科大学 4-(4-羟基-3-甲氧基苯亚甲基)姜黄素及其制备方法和在制备抗癌药物的应用
CN101524546B (zh) * 2008-11-07 2012-06-06 浙江中医药大学 聚乙二醇和姜黄素衍生物缀合的缀合物

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Publication number Priority date Publication date Assignee Title
WO2004031122A1 (fr) * 2002-10-01 2004-04-15 Dr. André Rieks - Labor Für Enzymtechnologie Gmbh Nouveaux derives de curcumine/tetrahydrocurcumine destines a etre utilises dans des produits cosmetiques et pharmaceutiques ainsi que dans l'alimentation
WO2008045534A2 (fr) * 2006-10-12 2008-04-17 Research Foundation Of The City University Of New York Nouveaux dérivés de curcumine et de tétrahydrocurcumine
CN101669931A (zh) * 2008-09-08 2010-03-17 北京鼎国昌盛生物技术有限责任公司 长效姜黄素衍生物在制备抗肿瘤症药物中的应用
CN101830819A (zh) * 2010-05-26 2010-09-15 福建医科大学 苯丁酰基姜黄素衍生物及其在制备抗肿瘤药物中的应用

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GB201223251D0 (en) 2013-02-06
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CN101830819A (zh) 2010-09-15
GB2494595B (en) 2018-03-21

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