WO2017101789A1 - Composé ayant un effet anticancéreux, son procédé de préparation et application - Google Patents

Composé ayant un effet anticancéreux, son procédé de préparation et application Download PDF

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Publication number
WO2017101789A1
WO2017101789A1 PCT/CN2016/109950 CN2016109950W WO2017101789A1 WO 2017101789 A1 WO2017101789 A1 WO 2017101789A1 CN 2016109950 W CN2016109950 W CN 2016109950W WO 2017101789 A1 WO2017101789 A1 WO 2017101789A1
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compound
mmol
reaction
acid
preparation
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PCT/CN2016/109950
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English (en)
Chinese (zh)
Inventor
雷海民
王鹏龙
熊磊
龚兆龙
林毅晖
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四川思路迪药业有限公司
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Priority to CN201680053558.3A priority Critical patent/CN108350023B/zh
Publication of WO2017101789A1 publication Critical patent/WO2017101789A1/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
    • A61K31/56—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton

Definitions

  • the invention relates to a compound, a preparation method and application thereof, and particularly to a compound with selective anticancer activity, a preparation method and application thereof.
  • cancer death especially the liver cancer, colon cancer, cervical cancer and other malignant cancers.
  • chemotherapy is one of the main ways of cancer.
  • Chemotherapy drugs often cause serious side effects on normal organisms while killing cancer cells, such as nephrotoxicity, hepatotoxicity, neurotoxicity and the like. It is the goal of pharmacy workers to obtain anti-cancer drugs with high efficiency, low toxicity and strong selectivity. It is gratifying that the latest researches at home and abroad have found that compounds with strong cytotoxicity have good drug-forming properties, which is in line with the development trend of contemporary precision medicine. (Cancer Cell, 2015, 28, 240-252; Int. J. Mol. Sci. 2015, 16(7), 16401-16413).
  • the invention has a bile acid component having antitumor and anti-hepatic biological activities, mainly comprising cholic acid (CA), deoxycholic acid (DCA), ursodeoxycholic acid (UCA), hyodeoxycholic acid (HCA), Goose deoxycholic acid (CDCA), lithocholic acid (LCA) and the natural drug tetramethylpyrazine (TMP) were used as starting materials to chemically combine to synthesize the compounds of the present invention.
  • CA cholic acid
  • DCA deoxycholic acid
  • UUA ursodeoxycholic acid
  • HCA hyodeoxycholic acid
  • CDA goose deoxycholic acid
  • LCA lithocholic acid
  • TMP lithocholic acid
  • the activity evaluation of the compounds mainly focused on anti-tumor (especially liver cancer, intestinal cancer, etc.), and the analogs were tested on four cancer cell lines (HepG-2, HT-29, Hela, MCF-7), respectively.
  • NGF-induced PC12 cells renal epithelial cells MDCK, mouse embryonic fibroblasts 3T3 Cytotoxic activity.
  • a first object of the present invention is to provide a compound having the structure of Formula 1 and a process for the preparation thereof.
  • a second object of the present invention is to provide the use of a compound of formula 1 for the preparation of an anticancer drug.
  • a third object of the present invention is to provide a kit having an anticancer effect.
  • R 1 - R 4 are -OH, -H or Any of the substituents
  • R5 is -COOH, Any of the substituents
  • the present application further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-described compound, pharmaceutically acceptable salt, stereoisomer, isotope label, solvate, polymorph or prodrug thereof, and pharmaceutically acceptable a.
  • the pharmaceutical compositions include, but are not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, and rectal administration dosage forms.
  • the pharmaceutical composition may be an oral tablet, capsule, pill, powder, sustained release preparation, solution or suspension, sterile solution, suspension or emulsion for parenteral injection, A topical ointment or cream, or a suppository for rectal administration.
  • Reaction Scheme 1 The cholic acid component is dissolved in an organic solvent and reacted with 2-bromomethyl-3,5,6-trimethylpyrazine (intermediate compound 1) under basic conditions to obtain the present invention.
  • Intermediate compound 1 2-bromomethyl-3,5,6-trimethylpyrazine
  • Compound I is further reacted with ligustrazine acid (intermediate compound 2) under the action of a catalyst and a condensing agent to give a compound II of the present invention.
  • Reaction conditions and reagents (a) Benzene, reflux, 10h; (b) CCl 4 , NBS, hv, reflux, 12h; (c) DMF, K 2 CO 3 , N 2 , 85 ° C, 1.5 h; H 2 O, KMnO 4 , 37 ° C, 6 h; (e) dry CH 2 Cl 2 , EDCI, DMAP, 12h.
  • R 1 - R 4 are each -OH or -H, and at least one of R 1 , R 2 and R 4 is -OH;
  • R 3 is -OH or -H
  • R 1 , R 2 and R 4 are -OH, -H or And at least one of R 1 , R 2 , and R 4
  • Reaction Scheme 2 The cholic acid component is dissolved in an organic solvent, and reacted with benzyl bromide under basic conditions to obtain an intermediate compound 3; the intermediate compound 3 is further reacted with ligustrazine by a catalyst and a condensing agent (middle) The compound 2) is reacted to obtain the compound III of the present invention; the compound III is further reduced by hydrogen to obtain the compound IV of the present invention.
  • R 3 is -OH or -H
  • R 1 , R 2 and R 4 are -OH, -H or And at least one of R 1 , R 2 , and R 4
  • the above reaction is carried out at -20 ° C to 250 ° C;
  • the organic solvent is an ether, an alcohol, an alkane, an aromatic hydrocarbon, a ketone, an alkyl halide, an amide, a nitrile, an ester having 1 to 20 carbon atoms or various ratios thereof a mixture;
  • the base used is triethylamine or potassium carbonate;
  • the catalyst is 1-hydroxybenzotriazole (HOBT);
  • the condensing agent is 1-ethyl-3-(3-dimethylaminopropyl) carbon Any one or more of diimine hydrochloride (EDCI), 1,3-dicyclohexylcarbodiimide (DCC) or 4-dimethylaminopyridine (DMAP).
  • EDCI diimine hydrochloride
  • DCC 1,3-dicyclohexylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • the molar ratio of the cholic acid component to the 2-bromomethyl-3,5,6-trimethylpyrazine is 1:0.1 to 1:10;
  • the molar ratio of the component to the base is 1:0.1 to 1:10;
  • the molar ratio of the compound II to the ligustrazine acid is 1:0.1 to 1:10;
  • the molar ratio of the compound II to the condensing agent is 1:0.1 to 1:10;
  • the molar ratio to the catalyst is 1:0.1 to 1:10.
  • the invention further provides the use of a compound of formula 1, a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph or prodrug thereof for the preparation of an anticancer drug.
  • the cancer is liver cancer, colon cancer, cervical cancer, breast cancer.
  • the invention also provides a method of treating cancer, the method comprising administering an effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph or prodrug thereof For individuals with this need.
  • the individual can be a mammal, such as a human.
  • the effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt, stereoisomer, isotope label, solvate, polymorph or prodrug thereof is from 1 to 10 mg/kg ⁇ day.
  • the cancer is liver cancer, colon cancer, cervical cancer, breast cancer.
  • the pharmaceutical composition and the at least one therapeutic agent are each combined in a separate dosage form into a combined product, such as a kit.
  • the effective amount of the combination product of a therapeutically effective amount of a compound of Formula 1, or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph or prodrug thereof, is from 1 to 10 mg/kg day. .
  • the anticancer drug is any one or more of cyclophosphamide, 5-fluorouracil, paclitaxel, doxorubicin, etoposide, irinotecan, oxaliplatin, cisplatin or japonica.
  • “Pharmaceutically acceptable” as used herein refers to molecular entities and compositions that are physiologically tolerable in humans and that generally do not produce an allergic or similar untoward reaction.
  • therapeutically effective amount is meant an amount sufficient to cause an improvement in a clinically significant condition/symptom in a host.
  • solvate refers to a combination of a compound of the present application and a solvent molecule formed by solvation.
  • polymorph is meant a compound of the present application that exists in a different lattice form.
  • isotopic label is meant a compound of the present application that is labeled by an isotope.
  • the "pharmaceutically acceptable prodrug” refers to any pharmaceutically acceptable salt, ester, ester salt or other derivative of a compound of the present application which can be provided directly or indirectly after use to a recipient. a compound or a pharmaceutically active metabolite or residue thereof.
  • the "stereoisomer” refers to an isomer produced by the arrangement of atoms in a molecule in a spatially different manner.
  • the compound of the invention has an inhibitory effect on various cancer cells.
  • the inhibition rate of intraperitoneal injection of 30 mg/kg on H22 tumor-bearing mice is 60.16%, which is equivalent to the positive drug cyclophosphamide; and for such as nerve cell kidney cells, mouse embryos Normal cytotoxicity such as fibroblasts is very small.
  • Normal mice have an intraperitoneal injection of LD 50 >900 mg/kg, indicating that the drug is safe and can be used for the prevention and treatment of cancers such as liver cancer, colon cancer and cervical cancer.
  • Human breast cancer cell line MCF-7 Human breast cancer cell line MCF-7; human hepatoma cell line HepG-2; mouse embryonic fibroblast 3T3; human colon cancer cell line HT-29; human cervical cancer cell line Hela; canine renal epithelial cell MDCK; mouse adrenal gland Chromosome cell PC12;
  • Experimental drug Compound (1-30) of the present invention (prepared as in Example 3-32); ligustrazine (TMP), cholic acid (CA), deoxycholic acid (DCA), ursodeoxycholic acid (UCA), Hyodeoxycholic acid (HCA), chenodeoxycholic acid (CDCA), lithocholic acid (LCA); positive drug doxorubicin (HY-15142; Shanghai Qianyuan Biomedical Technology Co., Ltd.).
  • MCF-7, HepG2, 3T3, HT-29, Hela, MDCK, and NGF-PC12 cells were cultured in 1640 medium containing 10% fetal bovine serum, and incubated at 37 ° C in a 5% CO 2 incubator. The cells were all grown in an adherent state, and the growth was observed under an inverted microscope, and subcultured when the number of cells was appropriate.
  • the compound of the present invention exhibits proliferation-inhibiting activity against various cancer cells, especially Compound 10, and its antitumor activity is not only superior to the raw material, but also to human colon cancer cell line HT-29 and human cervical cancer cells.
  • the anti-proliferative activity of Hela was better than that of the positive drug doxorubicin; the cytotoxicity of NGF-induced PC12 cells, canine renal epithelial cells MDCK and mouse embryonic fibroblasts 3T3 was significantly lower than that of the positive drug doxorubicin.
  • the compound of the present invention has good inhibitory activity against various cancer cells (IC 50 ⁇ 5.7 ⁇ M), but does not have any killing effect on various normal cells at a higher dose (IC 50 >80 ⁇ M), and has good cytotoxicity selection. Sexual effect.
  • the primary liver cancer cell lines (human hepatoma cell lines HCC3787C1, HCC4172A2, HCC4477B2, HCC4484B1, HCC5850A1, HCC5864D1, HCC5953B1, HCC633A5 and HCC061A2) were prepared as follows from the liver cancer tissues of 9 independent liver cancer patients according to the following method.
  • the fresh liver cancer tissue after surgical resection was washed in PBS (GIBCO, 10010-23), and cut into 0.5-1 mm3 pieces in a 100 mm culture dish using an ophthalmic forceps, scissors, etc., and laid flat on the bottom of the dish.
  • fibroblasts and tumor cells were digested with 0.25% trypsin solution (GIBCO, 25200056) to continuously remove fibroblasts. After multiple passages, fibroblasts were not visible to the naked eye in the culture dish and could be used for subsequent experiments when they were continuously grown for passage.
  • GEBCO trypsin solution
  • Experimental drug compound of the present invention (prepared according to Example 10); chemotherapeutic drug Doxorubicin (HY-15142; Shanghai Qianyuan Biomedical Technology Co., Ltd.).
  • liver cancer cell lines HCC3787C1, HCC4172A2, HCC4477B2, HCC4484B1, HCC5850A1, HCC5864D1, HCC5953B1, HCC633A5 and HCC061A2 were cultured in DMEM/F12 medium containing 10% fetal bovine serum and placed in a 5% CO 2 incubator at 37 °C. Medium temperature education. The cells were all grown in an adherent state, and the growth was observed under an inverted microscope, and subculture was performed when the cell confluence rate reached 80%-90%. The proportion and quantity of passages are subject to the experimental needs. The ratio of subculture of this liver cancer cell line is generally 1:2 ⁇ 1:3.
  • the optimal seeding density of the strain was inoculated in a 96-well culture plate, and after incubation at 37 ° C for 4 hours in a humidified incubator containing 5% CO 2 , 10 ⁇ L of the compound of the present invention was added to each well to test 9 drug concentrations.
  • the final drug concentration was 100, 31.6, 10, 3.1, 1, 0.3, 0.1, 0.03 and 0.01 ⁇ M, respectively, and the QC reference compound Doxorubicin was added simultaneously in the test of each liver cancer cell line, and the final drug concentration was 10 in turn. , 3.16, 1, 0.31, 0.1, 0.03, 0.01, 0.003, and 0.001 ⁇ M.
  • a positive control group (100% inhibition) and a negative control group (0% inhibition) were set at the same time. The drug group was repeated for 2 wells per concentration, and the positive control group and the negative control group were repeated for 6 wells. After the culture was continued for 6 days in the incubator, follow-up AlamarBlue test operation;
  • HCC5850A1 4.51 HCC5864D1 9.46 HCC5953B1 6.46 HCC633A5 4.44 HCC061A2 6.85
  • the compound 10 of the present invention has a good inhibitory activity against 7 liver cancer cell lines (HCC4477B2, HCC4484B1, HCC5850A1, HCC5864D1, HCC5953B1, HCC633A5 and HCC061A2) (IC 50 ⁇ 10 ⁇ M), and 2 liver cancer cells.
  • the inhibitory activity of HCC4172A2 and HCC3787C1 is about 50 ⁇ M. Therefore, the compound of the present invention has a good inhibitory effect on proliferation of liver cancer cells and has a good response rate in liver cancer cells.
  • Healthy male ICR mice weighing 18-22 g, were purchased from the Experimental Animal Center of Weitonglihua Experimental Animal Technology Co., Ltd. (Qualification No. SCXK (Beijing) 2011-0004); Mouse sarcoma H22 was donated by Xi'an Jiaotong University. Tumor-bearing H22 mice were passaged every 5 days.
  • the compound 10 of the present invention was subjected to liquid chromatography (HPLC) analysis for purity identification, and the purity was ⁇ 98%, which met the experimental requirements.
  • HPLC liquid chromatography
  • the powder was sealed and stored at 4 °C.
  • mice that had been inoculated for 7 days were sacrificed by cervical dislocation.
  • the ascites was taken under aseptic conditions, washed twice with RPMI1640 medium, and then made into 2 ⁇ 10 7 /ml cell suspension with sterile physiological saline.
  • H22 cell suspension The mice were inoculated subcutaneously in the right flank of the mice, and each of them was 0.1 ml, and 72 cells were inoculated to prepare a solid tumor model.
  • mice Seventy-two mice were randomly divided into 6 groups according to body weight, namely normal control group, positive drug (cyclophosphamide) group, model group, low-dose group, medium-dose group and high-dose group of the present invention; 12 rats in each group.
  • the compound 10 of the present invention is prepared by using soybean oil for injection, the low dose group is 10 mg/kg, the middle dose group is 30 mg/kg, the high dose group is 90 mg/kg, and the negative control group is injected with the same volume of injection soybean oil.
  • the positive control group was injected with cyclophosphamide injection 30 mg/kg, and intraperitoneally injected every other day for 12 days. During the period, the general activity, fur, feces, body weight, etc. of the mice were observed daily. 24 hours after the last administration, mice subcutaneously inoculated with H22 were sacrificed by cervical dislocation, and tumors, liver, spleen and kidney were taken.
  • the spleen index is the spleen weight (mg) of each group of mice/body weight (g)
  • liver index is liver weight (100 g) / mouse body weight (g)
  • kidney index is kidney weight (mg) / mouse Weight (g).
  • the solid tumor-negative control group was weighed the next day, and the mice were sacrificed (the blood was collected from the eyeball, and the serum was collected for subsequent experiments). The mice were sacrificed by cervical dislocation, the tumor tissues were dissected, and the electronic balance was weighed to calculate the tumor inhibition rate.
  • Cyclophosphamide group 4.37 ⁇ 1.26 0.49 ⁇ 0.29* 61.72%
  • Low dose group of the composition of the invention 4.21 ⁇ 1.08 0.69 ⁇ 0.30 46.09%
  • Dosage group in the composition of the invention 4.52 ⁇ 1.78 0.51 ⁇ 0.26* 60.16%
  • High dose group of the composition of the invention 5.49 ⁇ 0.97 0.63 ⁇ 0.35* 50.78%
  • the compound 10 of the present invention had no effect on the weight gain of H22 sarcoma mice, and the tumor inhibition effect was obvious.
  • the tumor growth inhibition rates of the low, medium and high dose groups on H22 sarcoma mice were 46.09% and 60.16%, respectively. And 50.78%, and the high-dose group has an anti-tumor effect comparable to the positive drug cyclophosphamide.
  • cyclophosphamide and the compound of the present invention can reduce the liver and spleen index of H22 sarcoma mice to near normal levels.
  • the compound 10 of the present invention can modulate the liver and spleen index of H22 sarcoma mice.
  • Healthy ICR mice 12 males and 12 females, weighing 18-22 g, purchased from the Laboratory Animal Center of Vitallihua Laboratory Animal Technology Co., Ltd. (Qualification No. SCXK (Beijing) 2006-0009)
  • the compound 10 of the present invention was subjected to liquid chromatography (HPLC) analysis for purity identification, and the purity was ⁇ 98%, which met the experimental requirements.
  • HPLC liquid chromatography
  • the powder was sealed and stored at 4 °C. 450 mg of this compound was dissolved in an appropriate amount of ethyl acetate, and then ultrasonically suspended with 5.0 ml of soybean oil for injection, and the solvent ethyl acetate was recovered to be tasteless. Now available.
  • mice Forty mice were randomly divided into 4 groups according to their body weight, with 10 rats in each group.
  • the experimental group was administered intraperitoneally with the mice, and the control group was given the same amount of soybean oil for injection. Before the administration, the mice were fasted to avoid overnight water (12 hours in a row), and the administration was started at 9:00 am on the day of administration (900 mg/kg), and the rats were fed for 6 hours after continuous observation for 14 days.
  • mice After intraperitoneal administration (900 mg/kg), individual mice showed mild writhing, and the symptoms disappeared within 1 hour. No death occurred within 12 hours after administration, and no obvious side effects were observed in the blank group. After 14 days, the mice in each group were in good condition and no death was observed. After the cervical spine was dislocated, the organs such as heart, liver, spleen, lung, kidney, adrenal gland and thyroid were observed. No abnormal changes were observed. Acute toxicity test of compound 26 mice by intraperitoneal injection showed that the drug had an LD 50 >900 mg/kg.
  • the compound of the present invention 10 has a high safety by intraperitoneal injection of LD 50 >900 mg/kg into normal mice.
  • benzyl hyodeoxycholate 5.0 mmol of benzyl bromide and 5.0 mmol of hyodeoxycholic acid were placed in a 50 ml round bottom flask, and 25 ml of DMF was added. After the mixture was dissolved, 5 mmol of potassium carbonate was added, and the mixture was stirred at 85 ° C for 2 h, stirring at 85 ° C. 2h, TLC monitoring the reaction material disappeared, the reaction was stopped, the reaction solution was added to a large amount of saturated NaCl solution, and 400 ml of ethyl acetate was extracted twice. The ethyl acetate layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.

Abstract

La présente invention concerne un composé ayant la structure (I), et un sel pharmaceutiquement acceptable, un stéréoisomère, un solvate, un polymorphe, ou un promédicament de celui-ci, et un procédé de préparation dudit composé; ainsi qu'une application d'une composition pharmaceutique contenant les substances décrites dans la préparation d'un médicament anticancéreux.
PCT/CN2016/109950 2015-12-14 2016-12-14 Composé ayant un effet anticancéreux, son procédé de préparation et application WO2017101789A1 (fr)

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CN201680053558.3A CN108350023B (zh) 2015-12-14 2016-12-14 一种具有抗癌作用的化合物及其制备方法和应用

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CN201610473424.9 2016-06-24

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20190094671A (ko) * 2018-02-05 2019-08-14 전북대학교산학협력단 Udca를 포함하는 신규한 고분자 화합물 및 그 용도
ES2769905A1 (es) * 2018-12-28 2020-06-29 Univ Santiago Compostela Compuestos de interes farmaceutico
WO2020260558A1 (fr) 2019-06-27 2020-12-30 Phenex Pharmaceuticals Ag Dérivés d'acide iso-/isoallo-lithocholique 3-modifiés ou leurs homo-analogues pour la prévention et le traitement de maladies associées à clostridioides difficile
CN114195853A (zh) * 2021-12-28 2022-03-18 中山百灵生物技术股份有限公司 一种别鹅去氧胆酸衍生物、其合成方法及用途

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20190094671A (ko) * 2018-02-05 2019-08-14 전북대학교산학협력단 Udca를 포함하는 신규한 고분자 화합물 및 그 용도
KR102106943B1 (ko) 2018-02-05 2020-05-06 전북대학교 산학협력단 Udca를 포함하는 신규한 고분자 화합물 및 그 용도
ES2769905A1 (es) * 2018-12-28 2020-06-29 Univ Santiago Compostela Compuestos de interes farmaceutico
WO2020136292A1 (fr) * 2018-12-28 2020-07-02 Universidade De Santiago De Compostela Composés d'intérêt pharmaceutique
WO2020260558A1 (fr) 2019-06-27 2020-12-30 Phenex Pharmaceuticals Ag Dérivés d'acide iso-/isoallo-lithocholique 3-modifiés ou leurs homo-analogues pour la prévention et le traitement de maladies associées à clostridioides difficile
CN114195853A (zh) * 2021-12-28 2022-03-18 中山百灵生物技术股份有限公司 一种别鹅去氧胆酸衍生物、其合成方法及用途
CN114195853B (zh) * 2021-12-28 2022-12-30 中山百灵生物技术股份有限公司 一种别鹅去氧胆酸衍生物、其合成方法及用途

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