WO2023011276A1 - Hétérocomplexes d'alcool de cddo/tétraméthylpyrazine ayant un effet thérapeutique combiné, leur procédé de préparation et leur utilisation - Google Patents
Hétérocomplexes d'alcool de cddo/tétraméthylpyrazine ayant un effet thérapeutique combiné, leur procédé de préparation et leur utilisation Download PDFInfo
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- WO2023011276A1 WO2023011276A1 PCT/CN2022/108166 CN2022108166W WO2023011276A1 WO 2023011276 A1 WO2023011276 A1 WO 2023011276A1 CN 2022108166 W CN2022108166 W CN 2022108166W WO 2023011276 A1 WO2023011276 A1 WO 2023011276A1
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- FINHMKGKINIASC-UHFFFAOYSA-N Tetramethylpyrazine Chemical compound CC1=NC(C)=C(C)N=C1C FINHMKGKINIASC-UHFFFAOYSA-N 0.000 title claims abstract description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 title claims abstract description 10
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
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- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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 technical field of biomedicine, in particular to a CDDO/ligustrazinol hybrid compound with combined therapeutic effect and its preparation method and application.
- Hepatitis is a general term for inflammation of the liver, mainly caused by alcohol consumption, drugs and viral infections. If hepatitis cannot be properly treated in time, it may even develop into liver fibrosis, cirrhosis, or even liver cancer. Therefore, finding effective drugs for treating hepatitis has become one of the research hotspots.
- Pentacyclic triterpenoids have a wide range of biological activities, especially in anti-tumor, anti-inflammatory and immune regulation.
- OA oleanolic acid
- CDDO-Me methyl 2-cyano-3,12-dioxooleanolic acid-1,9(11)-diene-28-carboxylate
- CDDO-Me received the most Attention, and has been conducted by Reata Company for the treatment of viral hepatitis and non-alcoholic fat in clinical trials
- the same series of CDDO drugs have shown good anti-hepatitis activity, but the clinical results show that this type of drug has serious cardiotoxicity, which is serious Limiting its clinical application, follow-up molecular mechanism research found that ⁇ -cyano- ⁇ , ⁇ -unsaturated ketone (CUK) of CDDO drugs can activate Nrf2 signaling pathway to produce anti-inflammatory effects by combining with Keap, but The activity of CUK
- Ligustrazine (tetramethylpyrazine, TMP) is an alkaloid, also known as tetramethylpyrazine, widely exists in the traditional Chinese medicine Ligusticum chuanxiong.
- TMP has a wide range of pharmacological effects, such as anti-inflammation, anti-oxidation, myocardial protection, liver protection, etc., and has a good clinical application prospect.
- Mechanistic studies have shown that the anti-inflammatory and antioxidant functions of TMP are also related to its activation of Nrf2 signaling pathway.
- 2-Hydroxymethyl-3,5,6-trimethylpyrazine (Ligustrazinol) is a metabolite of TMP in vivo, which has similar anti-inflammatory and antioxidant activities to TMP.
- the object of the present invention is to solve the shortcomings in the prior art, and propose a CDDO/ligustrazinol hybrid compound with combined therapeutic effect and its preparation method and application.
- a class of CDDO/ligustrazinol hybrid compound with combined therapeutic effect having the structure shown in general formula I:
- R represents one of H and tert-butoxycarbonyl
- R' represents OMe, NHMe, One of them
- n 0 or 1.
- R, R' and n are selected from the following combinations:
- I 1 (4aS, 6aR, 6bS, 8aS, 12aS, 14aR, 14bS)-10-(2-amino-4-methylpentanamide)-11-cyano-N,2,2,6a,6b ,9,9,12a-octamethyl-14-oxo-12-((3,5,6-trimethylpyrazin-2-yl)methoxy)-1,2,3,4,4a ,5,6,6a,6b,7,8,8a,9,12,12a,14,14a,14b-octadecylhydropyran-4a-carbamate;
- the present invention also provides a preparation method of a CDDO/ligustrazine alcohol hybrid compound with combined therapeutic effect, comprising the following steps:
- CDDO original drug 4 and ligustrazinol are treated with DMF/K 2 CO 3 to obtain enol intermediate 8, and then enol intermediate 8 is etherified with compound 5 to obtain CDDO-Me and ligustrazinol
- enol ether compound 6 or I a on the other hand, the enol intermediate 8 and N-tert-butoxycarbonyl-L-leucine 2 are condensed and acylated by EDCI and DMAP to obtain compound I a ;
- the synthetic route is as follows:
- R represents one of H and tert-butoxycarbonyl
- R' represents OMe, NHMe, One of them
- n 0 or 1.
- the present invention also provides the application of a CDDO/ligustrazinol hybrid compound with combined therapeutic effect for selective targeted therapy in liver injury inflammatory tissue.
- the selective release of the original drug of CDDO and ligustrazinol in the inflamed tissue of liver injury in vivo can be realized; the combined therapeutic effect of the original drug of CDDO and ligustrazinol in the inflamed tissue of liver injury in vivo can be realized.
- the present invention has the following beneficial effects:
- the present invention adopts a double prodrug strategy, uses the leucine acyl group of the LAP response fragment to protect the CUK of CDDO drugs as a prodrug, and couples with the ligustrazinol active fragment to form a CDDO/ligustrazinol hybrid.
- the present invention uses the prodrug to selectively cleave the leucine amide bond fragment in the liver inflammatory tissue overexpressed by LAP, releasing CDDO drugs and ligustrazinol, thereby increasing the concentration of the two drugs in the liver injury inflammatory tissue , increase the therapeutic effect of inflammation, reduce the dosage of drugs, improve the toxic and side effects of CDDO drugs, and improve the safety of drugs.
- Example 1 (4aS, 6aR, 6bS, 8aS, 12aS, 14aR, 14bS)-10-(2-amino-4-methylpentanamide)-11-cyano-N,2,2,6a,6b,9 ,9,12a-octamethyl-14-oxo-12-((3,5,6-trimethylpyrazin-2-yl)methoxy)-1,2,3,4,4a,5 ,6,6a,6b,7,8,8a,9,12,12a,14,14a,14b-octadecylhydropyran-4a-carbamate (I 1 )
- Example 2 (4aS, 6aR, 6bS, 8aR, 12aS, 14aR, 14bS)-methyl-10-((4-(2-amino-4-methylpentanamide) benzyl)oxy)-11-cyano Base-2,2,6a,6b,9,9,12a-heptamethyl-14-oxo-12-((3,5,6-trimethylpyrazin-2-yl)methoxy)- 1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,14,14a,14b-octadecylhydropyran-4a-carboxylate ( I 2 )
- Example 4 Compounds of the present invention protect liver cells from inflammation
- the protective effect of the compound of the present invention on the human hepatocyte LO2 cell line was evaluated by using the tetramethylazolidine blue colorimetric method (MTT) in vitro toxicity test.
- MTT tetramethylazolidine blue colorimetric method
- Example 5 Compounds of the present invention are tested in vivo on mouse liver injury
- the mice with liver injury were divided into four groups, namely model group, positive drug CDDO+ligustrazinol group (34 ⁇ mol/kg), I 2 (17 ⁇ mol/kg), I 2 (34 ⁇ mol/kg).
- a blank control group injection of PBS at the same frequency and volume was also set up. The drug was given three times within 5 days, intraperitoneally injected, and the liver function indexes ALT and AST in the blood were measured the next day after the administration.
- the compound I 2 of the present invention has a strong therapeutic effect on the mouse model of liver injury.
- the compound I of the present invention 2 (17 and 34 ⁇ mol/kg) groups had both It has a significant therapeutic effect on liver injury.
- the AST index of liver function is 6-7 times lower than that of the model group, and the ALT index is nearly 7 times lower than that of the model group.
- the compound of the present invention has better therapeutic effects, and the liver function indexes basically returned to normal levels. Therefore, the compound of the present invention has the effect of significantly treating liver injury inflammation in vivo.
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- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention relève du domaine technique de la biomédecine, et concerne en particulier une classe d'hétérocomplexes d'alcool de CDDO/tétraméthylpyrazine ayant un effet thérapeutique combiné, leur procédé de préparation et leur utilisation, le complexe d'alcool de CDDO/tétraméthylpyrazine ayant une structure telle que représentée par la formule générale I. Selon la présente invention, une stratégie à double promédicament est utilisée, en particulier, CUK d'un médicament CDDO est soumis à une protection de promédicament avec un groupe acyle leucine d'un fragment de réponse LAP, et est couplé à un fragment actif d'alcool de tétraméthylpyrazine pour former un hétérocomplexe d'alcool CDDO/tétraméthylpyrazine. Selon la présente invention, dans un tissu inflammatoire du foie ayant une surexpression de LAP, le promédicament libère le médicament CDDO et l'alcool tétraméthylpyrazine par clivage sélectif d'un fragment de liaison amide de la leucine, ce qui permet d'augmenter les concentrations des deux médicaments dans le tissu inflammatoire de lésion hépatique, d'augmenter l'effet thérapeutique sur l'inflammation, de réduire le dosage de médicament, de réduire la toxicité et les effets secondaires du médicament CDDO, et d'améliorer la sécurité du médicament.
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| AU2022322810A AU2022322810B2 (en) | 2021-08-06 | 2022-07-27 | Class of cddo/tetramethylpyrazine alcohol heterocomplexes having combination therapy effect, and preparation method therefor and use thereof |
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| CN202110899750.7 | 2021-08-06 | ||
| CN202110899750.7A CN113603743B (zh) | 2021-08-06 | 2021-08-06 | 一类具有联合治疗作用的cddo/川芎嗪醇杂合物及其制备方法和用途 |
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| WO2023011276A1 true WO2023011276A1 (fr) | 2023-02-09 |
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| PCT/CN2022/108166 WO2023011276A1 (fr) | 2021-08-06 | 2022-07-27 | Hétérocomplexes d'alcool de cddo/tétraméthylpyrazine ayant un effet thérapeutique combiné, leur procédé de préparation et leur utilisation |
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| CN (1) | CN113603743B (fr) |
| AU (1) | AU2022322810B2 (fr) |
| WO (1) | WO2023011276A1 (fr) |
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| CN113603743B (zh) * | 2021-08-06 | 2022-07-15 | 南通大学 | 一类具有联合治疗作用的cddo/川芎嗪醇杂合物及其制备方法和用途 |
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| CN113603743A (zh) * | 2021-08-06 | 2021-11-05 | 南通大学 | 一类具有联合治疗作用的cddo/川芎嗪醇杂合物及其制备方法和用途 |
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| CN102675403B (zh) * | 2011-03-09 | 2014-08-13 | 雷海民 | 抗乙肝药物lqc-x的合成及其应用 |
| CN104151388B (zh) * | 2011-03-09 | 2016-08-31 | 思路迪（北京）医药科技有限公司 | 抗肿瘤药物lqc-y的制备及其应用 |
| CN105315321B (zh) * | 2014-07-01 | 2018-10-16 | 思路迪（北京）医药科技有限公司 | 具有抗肿瘤作用的化合物及其制备方法和应用 |
| CN107118250B (zh) * | 2017-06-01 | 2019-06-21 | 中国药科大学 | 一种no供体型齐墩果酸衍生物及其制备方法和用途 |
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- 2021-08-06 CN CN202110899750.7A patent/CN113603743B/zh active Active
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- 2022-07-27 AU AU2022322810A patent/AU2022322810B2/en active Active
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| WO2004064723A2 (fr) * | 2002-05-13 | 2004-08-05 | Trustees Of Dartmouth College | Inhibiteurs et procedes d'utilisation de ceux-ci |
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| CN113603743A (zh) * | 2021-08-06 | 2021-11-05 | 南通大学 | 一类具有联合治疗作用的cddo/川芎嗪醇杂合物及其制备方法和用途 |
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Also Published As
| Publication number | Publication date |
|---|---|
| AU2022322810A9 (en) | 2024-10-03 |
| CN113603743A (zh) | 2021-11-05 |
| AU2022322810A1 (en) | 2023-06-15 |
| AU2022322810B2 (en) | 2023-06-29 |
| CN113603743B (zh) | 2022-07-15 |
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