CN113995738B - Application of 2' -halogenated chalcone derivative in preparation of medicine for treating liver related diseases - Google Patents
Application of 2' -halogenated chalcone derivative in preparation of medicine for treating liver related diseases Download PDFInfo
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- CN113995738B CN113995738B CN202010734896.1A CN202010734896A CN113995738B CN 113995738 B CN113995738 B CN 113995738B CN 202010734896 A CN202010734896 A CN 202010734896A CN 113995738 B CN113995738 B CN 113995738B
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- 239000003814 drug Substances 0.000 title claims abstract description 26
- 210000004185 liver Anatomy 0.000 title abstract description 25
- 150000001788 chalcone derivatives Chemical class 0.000 title abstract description 18
- 201000010099 disease Diseases 0.000 title abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 17
- 210000003494 hepatocyte Anatomy 0.000 claims description 10
- 238000002347 injection Methods 0.000 claims description 10
- 239000007924 injection Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 230000006378 damage Effects 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- 229960005489 paracetamol Drugs 0.000 claims description 5
- 239000006187 pill Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- 238000013270 controlled release Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 77
- 229940079593 drug Drugs 0.000 abstract description 13
- 239000000178 monomer Substances 0.000 abstract 1
- -1 chalcone compound Chemical class 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 238000006467 substitution reaction Methods 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- 230000000694 effects Effects 0.000 description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 19
- 125000000217 alkyl group Chemical group 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 18
- 239000007788 liquid Substances 0.000 description 18
- 125000002252 acyl group Chemical group 0.000 description 17
- 125000003545 alkoxy group Chemical group 0.000 description 17
- 238000000034 method Methods 0.000 description 17
- GQNZGCARKRHPOH-RQIKCTSVSA-N miocamycin Chemical compound C1[C@](OC(C)=O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](OC(C)=O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C GQNZGCARKRHPOH-RQIKCTSVSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 12
- RVFXUQLUGHXKDS-FNORWQNLSA-N (E)-1-(2-bromo-3,5-dimethoxyphenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one Chemical compound COC(C=C1OC)=CC(C(/C=C/C(C=C2)=CC(OC)=C2OC)=O)=C1Br RVFXUQLUGHXKDS-FNORWQNLSA-N 0.000 description 12
- 208000029618 autoimmune pulmonary alveolar proteinosis Diseases 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 10
- WXJLEXKNEAEXTI-UHFFFAOYSA-N 1-(2-bromophenyl)-3-phenylprop-2-en-1-one Chemical compound BrC1=CC=CC=C1C(=O)C=CC1=CC=CC=C1 WXJLEXKNEAEXTI-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-MICDWDOJSA-N 1-deuteriopropan-2-one Chemical compound [2H]CC(C)=O CSCPPACGZOOCGX-MICDWDOJSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 125000004414 alkyl thio group Chemical group 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000007795 chemical reaction product Substances 0.000 description 8
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 8
- 208000019423 liver disease Diseases 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 125000005256 alkoxyacyl group Chemical group 0.000 description 7
- 229940125904 compound 1 Drugs 0.000 description 7
- 229940125782 compound 2 Drugs 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
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- 229940061627 chloromethyl methyl ether Drugs 0.000 description 6
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
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- RQTGRUWBAVOGTD-HWKANZROSA-N (E)-1-[2-bromo-3-hydroxy-5-(methoxymethyl)phenyl]-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one Chemical compound COCC(C=C1O)=CC(C(/C=C/C(C=C2)=CC(OC)=C2O)=O)=C1Br RQTGRUWBAVOGTD-HWKANZROSA-N 0.000 description 5
- GVSPXQVUXHMUMA-MDWZMJQESA-N (e)-3-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)\C=C\C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 GVSPXQVUXHMUMA-MDWZMJQESA-N 0.000 description 5
- RHCSKNNOAZULRK-APZFVMQVSA-N 2,2-dideuterio-2-(3,4,5-trimethoxyphenyl)ethanamine Chemical compound NCC([2H])([2H])C1=CC(OC)=C(OC)C(OC)=C1 RHCSKNNOAZULRK-APZFVMQVSA-N 0.000 description 5
- WQXWIKCZNIGMAP-UHFFFAOYSA-N 3',5'-Dihydroxyacetophenone Chemical compound CC(=O)C1=CC(O)=CC(O)=C1 WQXWIKCZNIGMAP-UHFFFAOYSA-N 0.000 description 5
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 235000005513 chalcones Nutrition 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 5
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 5
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 4
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- BLLRAYYUXAYOKC-SOFGYWHQSA-N (E)-1-[2-bromo-3,5-bis(methoxymethyl)phenyl]-3-[3-methoxy-4-(methoxymethyl)phenyl]prop-2-en-1-one Chemical compound COCC(C=C1COC)=CC(C(/C=C/C2=CC(OC)=C(COC)C=C2)=O)=C1Br BLLRAYYUXAYOKC-SOFGYWHQSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
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- 125000000753 cycloalkyl group Chemical group 0.000 description 4
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
Abstract
The invention belongs to the field of medicines, and discloses application of a 2' -halogenated chalcone derivative in preparation of a medicine for treating liver related diseases. In particular to application of 2' -halogenated chalcone derivatives shown in a formula (I) or pharmaceutically acceptable salts thereof in preparing medicaments for treating and/or preventing liver related diseases. Discloses application of the compound monomer and a pharmaceutical composition containing the compound in preparing medicines for treating and/or preventing liver related diseases.
Description
Technical Field
The invention belongs to the field of medicines, and in particular relates to application of 2' -halogenated chalcone derivatives or pharmaceutically acceptable salts thereof and medicinal compositions containing the derivatives in preparation of medicines for treating and/or preventing liver related diseases.
Background
The liver plays a vital detoxification and phagocytosis function in the organism, and as the most important parenchymal metabolic organ, the liver plays a non-negligible important role in the organism. However, with the continuous improvement of the living standard of people, the living rhythm is continuously accelerated, and the health of the liver is more and more threatened. At present, liver diseases become worldwide diseases, china is a large country of liver diseases, and the number of patients with liver injury and liver inflammation caused by various reasons is large, and the distribution is wide. The viral hepatitis is mainly the viral hepatitis, the incidence rate of which is always the first in the class A and class B infectious diseases in China, accounts for more than 1/3 of the class B infectious diseases, the incidence rate is increased year by year, the incidence rate of the viral hepatitis in China is up to 125.19 ten thousand in 2013, and about 30 ten thousand people die from different types of liver diseases each year. The prevalence of liver diseases relates to hundreds of millions of people and families, not only seriously harms human health and potentially interferes with social stability, but also has a non-negligible restriction on social and economic development. According to statistics, the economic loss of chronic hepatitis (including liver cirrhosis and liver cancer) in China reaches 9000 hundred million RMB each year. In recent years, with the change of the dietary structure and the increase of the alcohol intake of people, the incidence of drug-induced liver diseases, alcoholic and non-alcoholic fatty liver diseases and autoimmune liver diseases also tends to increase year by year. Epidemiological surveys from Shanghai, beijing, etc. areas show that the prevalence of non-alcoholic fatty liver disease in B-mode ultrasound diagnosis in common adults increases from 15% to over 31% over a period of 10 years. The liver disease patient is one of important groups which cannot be ignored in the medical system of China, and the search for safe and effective medicaments for preventing and treating liver disease is always a hot spot for research and development of various institute and pharmaceutical companies worldwide.
The development of new drugs based on active natural products is one of the important ways of modern drug development. The natural products and analogues thereof have the characteristics of wide sources, low toxicity, small side effects and the like. The natural lead compound with obvious activity is found from traditional Chinese herbal medicines, and through structural modification, in-vivo and in-vitro activity test and comprehensive evaluation of the pharmacy of a combination system, a safe and efficient candidate compound is searched from the natural lead compound to serve as a clinically useful proto-drug, so that the natural lead compound is an important direction of drug research and development. Chalcone is a flavonoid natural product with a 1, 3-diphenylpropenone structure, and the literature reports that the chalcone has wide biological activity. The compounds are distributed in plants such as safflower of Compositae, glycyrrhrizae radix of Leguminosae, and Sonchaceae.
The chalcone compound has a relatively flexible molecular structure, can be combined with various receptors, and shows relatively wide pharmacological activity. The chalcone compound has a relatively simple structure, is early in research and mature in synthesis method, is an important intermediate in organic synthesis, and is one of more ideal molecular structures for developing new drugs. The literature reports that the structural modification of chalcone compounds is mostly to introduce different substituent groups on 2 benzene rings of the chalcone compounds, to carry out reduction substitution on carbonyl groups on a carbon chain framework, or to modify carbon-carbon double bonds, to cyclize chalcone molecules and the like. Chalcone compounds have wide biological activities such as anti-tumor, antimalarial, antifungal, antioxidant, anti-inflammatory, anti-ulcer, antiviral and the like, and particularly have wide research on the activities such as anti-tumor, anti-infection and the like, and have the potential of being deeply researched and developed into new medicines.
Disclosure of Invention
The 2' -halogenated chalcone derivative is a natural product derivative which is found in the long-term synthesis and structure-activity relation research of polyphenols. Pharmacological experiments show that the compound has remarkable protective effect on hepatic cell injury caused by APAP. The results of literature search show that the liver protection activity of this type of compound has not been reported in the literature so far. The patent carries out systematic structural transformation and liver protection activity screening research on the compounds, and results show that the 2' -halogenated chalcone derivatives have remarkable liver protection activity and are active compounds with great development value. The invention discloses the liver protection activity of the compound for the first time, and has important significance for deep development and utilization of the compound. The invention aims to solve the technical problem of providing application of 2' -halogenated chalcone derivatives or a composition thereof in preparing medicines for preventing, treating or assisting in treating liver related diseases.
The first aspect of the technical scheme of the invention provides an application of a 2' -halogenated chalcone derivative shown in general formulas (I), (II), (III), (IV) and (V) and pharmaceutically acceptable salts thereof in preparing a medicament for preventing, treating or assisting in treating liver related diseases.
The second aspect of the technical scheme of the invention provides a pharmaceutical composition, which comprises at least one new structure 2' -halogenated chalcone derivative shown in general formulas (I), (II), (III), (IV) and (V) and pharmaceutically acceptable salts thereof, and is applied to the preparation of medicines for preventing, treating or assisting in treating liver related diseases.
A third aspect of the present invention provides a process for the preparation of the derivative of the first aspect.
The liver related diseases include hepatitis A, hepatitis B, hepatitis C, drug-induced liver disease, alcoholic liver disease, nonalcoholic liver disease, autoimmune liver disease, liver fibrosis of liver disease progression, liver cirrhosis or liver failure. The compounds of the present invention include derivatives and pharmaceutically acceptable salts thereof.
Specifically, the invention relates to application of a 2' -halogenated chalcone derivative shown in a general formula (I) or pharmaceutically acceptable salt thereof in preparation of a medicament for treating and/or preventing liver related diseases, and the application is characterized in that the compound is shown in the general formula (I):
wherein X is selected from F, cl, br, I;
R 1 、R 2 each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-6 Cycloalkyl, cyclopropylmethyl, MOM, glu, SO 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C 1-6 Alkoxy, C 3-6 Cycloalkyl, F, cl, br, I;
R 3 is mono-substituted or poly-substituted, wherein the mono-substituted is selected from ortho-, meta-, para-mono-substituted; the polysubstituted is selected from the group consisting of disubstituted, trisubstituted, tetrasubstituted; r is R 3 Selected from hydrogen, hydroxy, nitro, cyano, amino, carboxyl, phenyl, methylamino, dimethylAmino, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted benzyloxy, substituted or unsubstituted C 3-6 Is C, substituted or unsubstituted 1-6 Alkylthio, cyclopropylmethoxy, F, cl, br, I, glu, SO of (a) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substitution is selected from monosubstituted, disubstituted, trisubstituted and tetrasubstituted, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C 1-6 Alkoxy, C 3-6 Cycloalkyl, F, cl, br, I;
MOM represents methoxymethyl; glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
According to the present invention, preferred 2' -halochalcone derivatives represented by general formula (I) include, but are not limited to, the use of a compound represented by general formula (II), or a pharmaceutically acceptable salt thereof, characterized in that the compound is represented by general formula (II):
wherein X is selected from F, cl, br, I;
R 1 、R 2 each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-6 Cycloalkyl, cyclopropylmethyl, MOM, glu, SO 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution; the substituents are selected from hydroxy, nitro, cyano, amino, carboxyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, F, cl, br, I;
R 4 、R 5 each independently selected from hydrogen, hydroxy, nitro, cyano, amino, carboxy, phenyl, methylamino, dimethylamino, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted C 1-6 Acyl oxygen, substituted or unsubstituted C 1-6 Alkoxyacyl, substituted or unsubstituted C 2-6 Unsaturated alkoxy, substituted or unsubstituted benzyloxy, substituted or unsubstituted C 3-6 Is C, substituted or unsubstituted 1-6 Alkylthio, cyclopropylmethoxy, F, cl, br, I, glu, MOMO, SO of (a) 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substitution is selected from monosubstituted, disubstituted, trisubstituted and tetrasubstituted, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C 1-6 Alkoxy, C 3-6 Cycloalkyl, F, cl, br, I;
MOM represents methoxymethyl; glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
According to the present invention, preferred 2' -halochalcone derivatives represented by general formula (II) include, but are not limited to, the use of a compound represented by general formula (III):
wherein X is selected from F, cl, br, I;
R 1 、R 2 、R 6 、R 7 each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-6 Cycloalkyl, cyclopropylmethyl, MOM, glu, SO 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituent is selected from hydroxyl, nitro,Cyano, amino, carboxyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, F, cl, br, I;
MOM represents methoxymethyl; glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
According to the present invention, preferred 2' -halochalcone derivatives represented by general formula (III) include, but are not limited to, the use of a compound represented by general formula (IV), or a pharmaceutically acceptable salt thereof, characterized in that the compound is represented by general formula (IV):
wherein X is selected from F, cl, br, I;
R 1 、R 2 、R 7 each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-6 Cycloalkyl, cyclopropylmethyl, MOM, glu, SO 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C 1-6 Alkoxy, C 3-6 Cycloalkyl, F, cl, br, I;
MOM represents methoxymethyl; glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
According to the present invention, preferred 2' -halochalcone derivatives represented by the general formula (IV) include, but are not limited to, the use of a compound represented by the general formula (V):
wherein R is 1 、R 2 、R 7 Each independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Acyl, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-6 Cycloalkyl, cyclopropylmethyl, MOM, glu, SO 3 H、PO 3 H 2 The method comprises the steps of carrying out a first treatment on the surface of the The substitution is mono-substitution, di-substitution, tri-substitution and tetra-substitution, and the substituent is selected from hydroxy, nitro, cyano, amino, carboxyl and C 1-6 Alkoxy, C 3-6 Cycloalkyl, F, cl, br, I;
MOM represents methoxymethyl; glu represents a beta-D glucopyranosyl group; SO (SO) 3 H represents a sulfonyl group; PO (Positive oxide) 3 H 2 Represents a phosphoryl group.
Specifically, the application of the 2' -halogenated chalcone derivatives shown in the general formulas (I), (II), (III), (IV) and (V) or pharmaceutically acceptable salts thereof is characterized in that the compounds are selected from the following groups (the compound codes correspond to the compound codes in the examples):
the second aspect of the technical scheme of the invention provides application of a pharmaceutical composition containing a pharmaceutically effective dose of a compound as shown in each condition of general formulas (I), (II), (III), (IV) and (V) or a pharmaceutically acceptable carrier thereof in preparing a medicament for treating and/or preventing liver related diseases.
According to the present invention, the compound of the present invention may exist in the form of an isomer, and the general term "compound of the present invention" includes the isomer of the compound.
According to an embodiment of the invention, the compounds of the invention also include pharmaceutically acceptable salts, hydrates of salts or prodrugs thereof.
The invention also relates to pharmaceutical compositions containing as active ingredient a compound according to the invention and conventional pharmaceutical excipients or auxiliaries. Typically, the pharmaceutical compositions of the present invention contain 0.1 to 95% by weight of the compound of the present invention. The compounds of the invention are generally present in unit dosage forms in amounts of from 0.1 to 100mg, with preferred unit dosage forms containing from 4 to 50mg.
Pharmaceutical compositions of the compounds of the present invention may be prepared according to methods well known in the art. For this purpose, the compounds of the invention may, if desired, be combined with one or more solid or liquid pharmaceutical excipients and/or auxiliaries, in suitable administration forms or dosage forms which can be used as human or veterinary medicine.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by the enteral or parenteral route, such as oral, intramuscular, subcutaneous, nasal, oral, dermal, peritoneal or rectal, etc. The route of administration of the compounds of the invention or pharmaceutical compositions containing them may be by injection. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection, etc.
The administration dosage form may be liquid dosage form or solid dosage form. For example, the liquid dosage form may be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.
The compound of the invention can be prepared into common preparations, and can also be sustained release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
For example, in order to prepare a unit dosage form into a tablet, various carriers known in the art can be widely used. Examples of carriers include diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; humectants and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, dextrose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, and the like; disintegrants such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose, ethylcellulose, and the like; disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oils and the like; absorption promoters such as quaternary ammonium salts, sodium lauryl sulfate, and the like; lubricants such as talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer and multilayer tablets.
For example, carriers well known in the art may be widely used for the purpose of making the dosage unit into a pill. Examples of carriers are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, polyvinylpyrrolidone, glycerol monostearate, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, and the like; disintegrants such as agar powder, dry starch, alginate, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.
For example, in order to capsule the administration unit, the compounds of the invention are mixed with the various carriers described above, and the mixture thus obtained is placed in a hard gelatin capsule or a soft capsule. The active ingredient of the compound can be prepared into microcapsules, and the microcapsules can be suspended in an aqueous medium to form a suspension, or can be filled into hard capsules or prepared into injection for application.
For example, the compounds of the present invention may be formulated as injectable formulations, such as solutions, suspension solutions, emulsions, lyophilized powder for injection, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxyl isostearyl alcohol, polyoxyethylene sorbitol ester, fatty acids, and the like. In addition, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and further, a conventional cosolvent, a buffer, a pH adjuster, and the like may be added. These adjuvants are commonly used in the art.
In addition, colorants, preservatives, flavors, flavoring agents, sweeteners, or other materials may also be added to the pharmaceutical formulation, if desired.
For the purpose of administration, the drug or the pharmaceutical composition of the present invention can be administered by any known administration method to enhance the therapeutic effect.
The dosage of the pharmaceutical composition of the present invention depends on many factors such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, character and individual response of the patient or animal, the route of administration, the number of times of administration, the purpose of treatment, and thus the therapeutic dosage of the present invention may vary widely. Generally, the dosages of pharmaceutical ingredients used in the present invention are well known to those skilled in the art. The amount of the actual drug contained in the final formulation of the compound composition of the present invention may be appropriately adjusted to achieve the therapeutically effective amount thereof, thereby achieving the preventive or therapeutic object of the present invention. Daily suitable dosage range of the compounds of the invention: the amount of the compound of the present invention is 0.001 to 100mg/kg body weight, preferably 0.1 to 60mg/kg body weight, more preferably 1 to 30mg/kg body weight, most preferably 2 to 15mg/kg body weight. The compound of the invention is taken by adult patients at a daily dose of 10-500 mg, preferably 10-100 mg, and can be taken once or 2-3 times; the dose taken by children is 5-30 mg, preferably 10-20 mg/kg body weight per kg body weight. The above-mentioned dosages may be administered in a single dosage form or in divided dosage forms, for example, two, three or four dosage forms, which are limited by the clinical experience of the administering physician and the administration regimen of the therapeutic means. The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents.
According to a third aspect of the present invention, there is provided a process for the preparation of the derivative of the first aspect.
The starting materials, such as 3, 5-dihydroxyacetophenone and vanillin, used to prepare the compounds of the invention are commercially available and key intermediate 1 can be prepared by the method described in the literature [ adv. Synth. Catalyst.2019, 361,3768-3776 ]. The basic synthesis method of the key intermediate compound 1 comprises the following steps:
step one, 3, 5-dihydroxyacetophenone reacts with chloromethyl methyl ether to prepare a MOM-protected dihydroxyacetophenone 3, 5-dihydroxyacetophenone intermediate (1 a).
3, 5-dihydroxyacetophenone reacts with chloromethyl methyl ether in dichloromethane solution by using DIPEA as a catalyst at room temperature, and the reaction product is separated to prepare the MOM-protected dihydroxyacetophenone compound 1a.
And step two, performing bromination reaction on the compound 1a and NBS to prepare a brominated product (1 b) thereof.
The product obtained in the step one is subjected to bromination reaction with NBS in DMF at room temperature, and the reaction mixture is separated to obtain a brominated product 1b thereof.
Step three, vanillin reacts with chloromethyl methyl ether to prepare a vanillin intermediate compound (1 c) with MOM for protecting phenolic hydroxyl.
Vanillin reacts with chloromethyl methyl ether in dichloromethane by using DIPEA as a catalyst at room temperature, and the reaction product is separated to obtain the vanillin derivative 1c with MOM protected hydroxyl.
Step four, the brominated product 1b and the vanillin derivative 1c are subjected to aldol condensation reaction to prepare a key intermediate product 1.
In the mixed solution of methanol and water, naOH is used as a catalyst to carry out aldol condensation reaction on the brominated product 1b and the vanillin derivative 1c at room temperature, and the reaction product is separated to prepare a key intermediate product 1.
The basic synthesis method of the compound comprises the following steps:
step one, removing MOM protecting groups from MOM protected hydroxyl chalcone compounds under an acidic condition to prepare corresponding hydroxyl derivatives. .
The MOM protected chalcone derivative reacts with hydrochloric acid in methanol solution at room temperature, and the product is separated to obtain the chalcone derivative with all or part of the hydroxyl groups removed MOM protecting groups.
Step two, preparing the corresponding methylated derivative of the chalcone derivative with the hydroxyl through a method of hydroxy complete methylation and hydroxy partial methylation.
Chalcone derivatives with hydroxyl groups in acetone solution at K 2 CO 3 And (3) carrying out methylation reaction with a proper amount of methyl iodide reagent, and separating reaction products to obtain the chalcone derivative with fully or partially methylated hydroxyl groups.
And thirdly, reacting the chalcone derivative with the hydroxyl with bromomethyl cyclopropane, and synthesizing a cyclopropylmethyl product by a method of completely or partially cyclopropylmethyl the hydroxyl.
Chalcone derivatives with hydroxyl groups in anhydrous acetone solution, at K 2 CO 3 In the presence of the catalyst, cyclopropylmethyl reaction is carried out with a proper amount of bromomethyl cyclopropane, and the reaction product is separated to obtain chalcone derivatives with all cyclopropylmethyl hydroxyl groups and partial cyclopropylmethyl hydroxyl groups.
Beneficial technical effects
The inventor of the invention finds that the natural product derivative 2' -bromochalcone has remarkable protective activity on hepatic cell injury caused by APAP in the process of total synthesis and activity research of the natural product. On the basis, 2' -bromochalcone is further subjected to synthesis and structure derivatization modification, a series of structure related derivatives are synthesized, and the obtained derivatives are subjected to systematic liver protection activity evaluation, so that the liver protection activity of the compounds is confirmed. The compound has remarkable protection effect on HepG2 cell injury caused by APAP, and has potential application value of further development and research.
2' -bromochalcone is a natural product derivative with a novel structure. So far, the structure-activity relation research of the liver protection active system of the compound is not reported in the literature. No report about 2' -bromochalcone derivatives or pharmaceutically acceptable salts thereof and application of the compounds in liver related diseases is found in the prior literature and technology. The content of the invention is therefore significantly innovative.
Detailed description of the invention:
various terms and phrases used herein have the ordinary and customary meaning as understood by those skilled in the art, and even though they are still intended to be more fully described and explained herein, the terms and phrases used herein are to be understood and to have a meaning inconsistent with the ordinary and customary meaning as set forth herein. The following are definitions of various terms used in the present invention, which are applicable to terms used throughout the specification of the present application, unless otherwise specified in the specific context.
The definitions of the various groups of the compounds of the invention are provided below and are used throughout the specification and claims unless otherwise indicated.
The term "alkyl" as referred to herein means an alkyl group having the indicated number of carbon atoms, which may be a straight or branched chain alkyl group, e.g. "C" as referred to 3-6 Cycloalkyl "of (C) refers to a substituted or unsubstituted cycloalkyl group having 3,4, 5, 6 carbon atoms, and may include C 3-5 Cycloalkyl, C 3-4 Cycloalkyl, C 4-6 Cycloalkyl, C 4-5 Cycloalkyl, C 5-6 Cycloalkyl, etc., and preferred specific groups such as cyclopropane, cyclopentane, and cyclohexane.
The term "C" as referred to in the present invention 1-6 The "alkyl" of (C) refers to a straight or branched alkyl group having 1, 2, 3,4, 5, 6 carbon atoms, and may include C 1-5 Alkyl, C 1-4 Alkyl, C 2-5 Alkyl, C 2-4 Alkyl, C 2-3 Alkyl, C 3-5 Alkyl groups, etc., and preferred specific groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.
The term "C" as referred to in the present invention 1-6 Alkoxy "means a C1 group,2. 3,4, 5, 6, including C 1-5 Alkoxy, C 1-2 Alkoxy, C 2-4 Alkoxy, C 2-3 Alkoxy, C 3-4 Alkoxy, and the like, and preferred specific groups are methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy, and the like.
The term "C" as referred to in the present invention 1-6 Unsaturated alkyl "refers to an unsaturated alkyl group having 1, 2, 3,4, 5, 6 carbon atoms, and may include C 1-5 Unsaturated alkyl of (C) 1-4 Unsaturated alkyl of (C) 2-5 Unsaturated alkyl of (C) 2-4 And the like, and preferred specific groups such as vinyl, ethynyl, isopropenyl, isobutenyl, isopentenyl, 1, 4-dibutenyl.
The term "C" as referred to in the present invention 1-6 The "acyl" refers to an acyl group having 1, 2, 3,4, 5, and 6 carbon atoms, and may include C 1-5 Acyl, C 1-3 Acyl, C 2-5 Acyl, C 2-3 Acyl, C 3-4 Acyl, etc., and preferred specific groups, such as formyl, acetyl, propionyl, etc.
Reference to "C" in the present invention 1-6 The "acyloxy group" of (C) refers to a straight-chain or branched acyloxy group having 1, 2, 3,4, 5, 6 carbon atoms and may include C 1-5 Acyloxy radicals, C 1-3 Acyloxy radicals, C 2-5 Acyloxy radicals, C 2-3 Acyloxy radicals, C 3-4 Acyl groups, etc., and preferred specific groups, such as formyl, acetyl, propionyloxy, etc.
Reference to "C" in the present invention 1-6 Alkoxyacyl "of (C) is an alkanoyl group having 1, 2, 3,4, 5, 6 carbon atoms and may include C 1-5 Alkoxyacyl, C 1-3 Alkoxyacyl, C 2-5 Alkoxyacyl, C 2-3 Alkoxyacyl, C 3-4 Sub-range groups represented by alkanoyl and the like, and preferably specific groups such as methoxyacyl, ethoxylAcyl groups and the like;
the term "C" as referred to in the present invention 1-6 Alkylthio "of (C) refers to straight-chain or branched alkylthio of 1, 2, 3,4, 5, 6 carbon atoms, and may include C 1-5 Alkylthio, C 1-3 Alkylthio, C 2-5 Alkylthio, C 2-3 Alkylthio, C 3-4 Alkylthio groups and the like, and preferred specific groups, such as methylthio, ethylthio and the like.
Detailed Description
In order to further illustrate the invention, the following examples are given purely by way of illustration and are not to be construed as limiting the invention.
The synthetic route for key intermediate compound 1 in the examples is as follows:
example 1:
1- (2-bromo-3, 5-dimethoxymethylphenyl) -3- (3-methoxy-4-methoxymethylphenyl) - (2E) -2-propen-1-one (1)
Synthetic route for compound 1:
step one, 10g (65.79 mmol) of 3, 5-dihydroxyacetophenone was dissolved in 300ml of methylene chloride, DIPEA (43.42 ml,263 mmol) was added under stirring at room temperature, chloromethyl methyl ether liquid (21.2 g,263 mmol) was slowly added dropwise, and stirring was maintained at room temperature for 10 hours, and the reaction was stopped. To the reaction solution was added 300ml of water, extracted with methylene chloride, the organic phase was washed with 5% sodium hydroxide solution, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The colorless oily liquid was subjected to column chromatography separation on 200-300 mesh silica gel, and petroleum ether/acetone (10:1) was eluted to give compound 1a (15.78 g, yield 80%) as a colorless oily liquid. The physicochemical constants of compound 1a are as follows:
compound 1a: a colorless oily liquid, which is prepared from, 1 H NMR(500MHz,acetone-d 6 ):δ:7.26(d,J＝2.29Hz,2H),6.93(t,J＝2.27Hz,1H),5.19(s,4H),3.48(s,3H),2.56(s,3H)；(+)-ESI-MS:m/z 263.0[M+Na] + .
step two, compound 1a (0.7 g,2.917 mmol) was dissolved in 40ml of dry DMF, NBS (0.399 g,2.916 mmol) was added under stirring, and the reaction was stopped at room temperature for 8h in the absence of light. 50ml of water was added to the reaction solution, extraction was performed with ethyl acetate, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the obtained solid was separated by 200-300 mesh silica gel column chromatography, and petroleum ether: ethyl acetate: dichloromethane (40:1:3) was eluted to obtain oily liquid 1b (0.6 g, yield 64.5%). The physicochemical constants of compound 1b are as follows:
compound 1b: a colorless oily liquid, which is prepared from, 1 H NMR(500MHz,MeOH-d 4 )δ:6.96(d,J＝2.69Hz,1H)，6.76(d,J＝2.69Hz,1H),5.27(s,2H),5.19(s,2H),3.49(s,3H),3.46(s,3H),2.55(s,3H)； 13 C NMR(125MHz,MeOH-d 4 )δ:203.830,158.982,156.197,145.750,109.331,107.123,101.209,96.394,95.768,56.774,56.478,30.685；(+)-ESI-MS:m/z341.0[M+Na] + .
step three, 3-methoxy-4-hydroxybenzaldehyde (10 g,65.79 mmol) was dissolved in 300ml dichloromethane, DIPEA (20.28 ml,122.7 mmol) was added under stirring, chloromethyl methyl ether liquid (10 ml,132.9 mmol) was slowly added dropwise, stirring was maintained at room temperature for 10h, and TLC detection of the reaction was completed. To the reaction solution was added 300ml of water, extracted with dichloromethane, the organic phase was washed with 5% sodium hydroxide solution, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the filtrate was concentrated. The colorless oily liquid was subjected to column chromatography separation on 200-300 mesh silica gel, and petroleum ether/ethyl acetate/dichloromethane (25:1:3) was eluted to give compound 1c (11.3 g, 90%) as a colorless oily liquid. The physicochemical constants of compound 1c are as follows:
compound 1c: colorless oily liquid. 1 H NMR(500MHz,acetone-d 6 ):δ:9.89(s 1H)；7.51(dd,J＝8.19Hz,1.52Hz,1H)；7.47(d,J＝1.93Hz,1H)；7.28(d,J＝8.23Hz,1H)；5.31(s,2H).3.92(s,3H).3.43(s,3H). 13 C NMR(125MHz,MeOH-d 4 )δ:191.397,152.872,151.488,132.374,126.019,116.307,111.211,95.728,56.531,56.211.(+)-ESI-MS:m/z 197.1[M+H] + ,219.0[M+Na] + .
Step four, 1g (3.13 mmol) of compound 1b was dissolved in 30ml of a mixed solvent of methanol and water (methanol: water=2:1, v/v), and 125mg (1.2 eq) of NaOH solid was added. Stirring at room temperature for 10 min, compound 1c 313 mg (3.13 mmol) was added and the reaction was continued for 10h. The reaction solution was diluted with 30ml of water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and separated by silica gel column chromatography to give yellow oily liquid 1 (1.26 g, 80%). The physicochemical parameters of compound 1 are as follows:
compound 1: yellow oily liquid (yield=80%); 1 H NMR(500MHz,MeOH-d 4 ):δ:7.41(d,J＝2.0Hz,1H)；7.37(d,J＝16.0Hz,1H)；7.23(dd,J＝8.0Hz,2.0Hz,1H)；7.14(d,J＝8.5Hz,1H)；7.02(d,J＝16.0Hz,1H)；7.00(d,J＝2.0Hz,1H)；6.75(d,J＝2.0Hz,1H)；5.34(s,2H)；5.24(s,3H)；5.24(s,2H)；3.90(s,3H)；3.51(s,3H)；3.45(s,6H)； 13 C NMR(125MHz,MeOH-d 4 )δ:194.5,158.5,155.7,151.5,150.2,147.4,144.7,129.9,125.6,123.8,117.3,112.2,109.7,106.5,96.1,95.9,95.5,56.4,53.4,56.2,56.2；(+)-ESI-MS m/z:497.0,499.0[M+H] + .
example 2:
1- (2-bromo-3, 5-dihydroxyphenyl) -3- (3-methoxy-4-hydroxyphenyl) - (2E) -2-propen-1-one (2)
Synthetic route for compound 2:
compound 1 900mg (1.815 mmol) was dissolved in 130ml dry methanol, and a concentrated hydrochloric acid methanol solution (15 equivalents of concentrated hydrochloric acid in 2ml methanol) was slowly added at-10℃and the reaction was continued at room temperature for 24 hours under stirring at-10℃for 0.5 hour. The reaction solution was cooled to-10 ℃, the PH was adjusted to neutral with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the product mixture was separated by silica gel column chromatography using dichloromethane: methanol=10:1 as eluent to give compound 2 (428 mg, 64%) as a yellowish brown oily liquid. The physicochemical parameters of compound 2 are as follows:
compound 2: yellow oily liquid (yield=64%); 1 H NMR(400MHz,MeOH)δ H :7.74(d,J＝16.0Hz,1H)；7.64(d,J＝2.0Hz,1H)；7.54(dd,J＝8.0Hz,2.0Hz,1H)；7.30(d,J＝16.0Hz,1H)；7.25(d,J＝8.0Hz,1H)；6.93(d,J＝2.4Hz,1H)；6.72(d,J＝2.4Hz,1H)；4.31(s,3H)；3.73(s,3H)； 13 C NMR(125MHz,MeOH 4 )δ C :198.2,159.0,156.7,151.4,150.4,149.4,144.3,127.6,124.9,124.4,116.6,112.2,107.9,105.3,97.2,56.5；HRESIMS:m/z 362.9868,calcd for C 16 H 12 O 5 Br[M-H] + ,362.9874.
synthetic routes for compounds 3-5 in the examples:
compound 1 100mg (0.202 mmol) was dissolved in 16ml of dry methanol, and a methanol solution of concentrated hydrochloric acid [ 90. Mu.l (4.5 eq) of concentrated hydrochloric acid was slowly added at 0℃to 0.5ml of methanol ], followed by stirring for 0.5 hours, and then, by reaction at room temperature under dark conditions for 10 hours, the reaction was stopped. The pH was adjusted to neutrality with saturated sodium bicarbonate solution at 0deg.C, extracted with ethyl acetate, the organic phases combined, washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the resulting product was separated by eluting with petroleum ether: acetone=6:1-2:1 to give Compound 3 (21 mg, 21%), compound 4 (14.0 mg, 16%) and Compound 5 (11.2 mg, 18%).
Synthesis of end products 3 to 5 (Compound code corresponds to the Compound code in the examples)
Example 3:
1- (2-bromo-3, 5-dimethoxymethylphenyl) -3- (3-methoxy-4-hydroxyphenyl) - (2E) -2-propen-1-one (3)
Compound 3, yellow oily liquid (yield=21%); 1 H NMR(400MHz,Acetone-d 6 )δ H :7.38(d,J＝2.0Hz,1H),7.34(d,J＝16.0Hz,1H),7.18(dd,J＝8.0Hz,2.0Hz,1H),6.99(d,J＝2.0Hz,1H),6.94(d,J＝16.0Hz,1H),6.88(d,J＝8.0Hz,1H),6.74(d,J＝2.8Hz,1H),5.35(s,2H),5.24(s,2H),3.91(s,3H),3.51(s,3H),3.45(s,3H)； 13 CNMR(125MHz,Acetone-d 6 )δ C :194.6,158.4,155.6,150.8,148.9,148.0,144.8,127.5,124.8,124.3,116.2,111.7,109.7,106.4,102.0,96.1,95.4,56.7,56.4(2×C)；HRESIMS:m/z 451.0389,calcd for C 20 H 20 O 7 Br[M-H] + ,451.0398.
example 4:
1- (2-bromo-3-hydroxy-5-methoxymethylphenyl) -3- (3-methoxy-4-hydroxyphenyl) - (2E) -2-propen-1-one (4)
Compound 4: yellow oily liquid (yield=16%); 1 H NMR(400MHz,CDCl 3 )δ H :7.38(d,J＝2.3Hz,1H),7.34(d,J＝16.0Hz,1H),7.17(dd,J＝8.2Hz,2.8Hz,1H),6.99(d,J＝2.83Hz,1H),6.94(d,J＝16.06Hz,1H),6.88(d,J＝8.23Hz,1H),6.74(d,J＝2.79Hz,1H),5.35(s,2H),5.24(s,2H),3.91(s,3H),3.51(s,3H),3.45(s,3H)； 13 C NMR(125MHz,CDCl 3 )δc:191.0,151.8,150.2,144.2,143.5,142.2,138.4,122.2,120.0,119.5,119.1,110.2,105.2,104.5,100.5,95.3,90.5,51.8,51.3；HRESIMS:m/z 407.0127,calcd for C 18 H 16 O 6 Br[M-H] + ,407.0136.
example 5:
1- (2-bromo-3-methoxymethyl-5-hydroxyphenyl) -3- (3-methoxy-4-hydroxyphenyl) - (2E) -2-propen-1-one (5)
Compound 5: yellow solid (yield=18%); 1 H NMR(400MHz,CDCl 3 )δ H :7.36(d,J＝15.98Hz,1H),7.10(dd,J＝8.19Hz,1H),7.06(d,J＝1.94Hz,1H),6.93(d,J＝8.19Hz,1H),6.87(d,J＝15.98Hz,1H),6.86(d,J＝8Hz,1H),6.70(d,J＝2.84Hz,1H),5.6(s,2H),3.93(s,3H),3.47(s,3H)； 13 C NMR(125MHz,CDCl 3 )δc:194.1,157.8,153.7,148.9,148.0,147.0,142.2,126.9,124.2,123.6,115.0,109.9,109.5,105.2,99.7,94.7,56.3,56.1；HRESIMS:m/z 407.0130,calcd for C 18 H 16 O 6 Br[M-H] + ,407.0136.
example 6:
1- (2-bromo-3, 5-dimethoxyphenyl) -3- (3, 4-dimethoxyphenyl) - (2E) -2-propen-1-one (6)
100mg (0.275 mmol) of compound 2 was dissolved in 10ml of dry acetone, 228mg (1.65 mmol) of anhydrous potassium carbonate was added, and after stirring for 0.5 hour, 234mg (1.65 mmol) of methyl iodide was added, and stirring was continued at room temperature for 72 hours, and the completion of the reaction was detected by TLC. The reaction solution was filtered through celite, the filtrate was concentrated, and the product was chromatographed on a 200-300 mesh silica gel column, eluting with petroleum ether: acetone=9:1 to give 6 (97 mg, 87%) as pale yellow crystalline solid.
Compound 6, pale yellow crystals (yield=87%); 1 H NMR(400MHz,Acetone-d 6 )δ H :7.37(d,J＝2.4Hz,1H),7.32(d,J＝16.0Hz,1H),7.23(dd,J＝8.0Hz,2.0Hz,1H),7.00(d,J＝8.0Hz,1H),6.95(d,J＝16.0Hz,1H),6.75(d,J＝2.4Hz,1H),6.55(d,J＝2.4Hz,1H),3.94(s,3H),3.87(s,3H),3.86(s,3H),3.86(s,3H)； 13 C NMR(125MHz,Acetone-d 6 )δ C :206.1,194.9,161.2,157.9,153.1,150.7,147.7,144.7,128.3,125.0,124.4,112.4,111.4,105.6,101.2,99.6,56.9,56.2(2×C),56.1；HRESIMS:m/z407.0480,calcd for C 19 H 20 O 5 Br[M+H] + ,407.0489.
synthetic routes and synthetic methods of the compounds 7 to 10:
100mg (0.275 mmol) of compound 2 was dissolved in 10ml of dry acetone, 228mg (1.65 mmol) of anhydrous potassium carbonate was added, stirred for 0.5 hour, 176mg (1.24 mmol) of methyl iodide was added, and the reaction was stirred at room temperature for 72 hours, and the reaction was stopped. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the product was chromatographed on a 200-300 mesh silica gel column, eluting with petroleum ether: acetone=9:1-4:1 gradient to give compounds 7,8,9 and 10, respectively.
Synthesis of end products 7 to 10 (Compound code corresponds to the Compound code in the examples)
Example 7:
1- (2-bromo-3-hydroxy-5-methoxyphenyl) -3- (3, 4-dimethoxyphenyl) - (2E) -2-propen-1-one (7)
Compound 7: yellow solid (yield=9%); 1 H NMR(400MHz,CDCl 3 )δ H :7.34(d,J＝16.0Hz,1H),7.12(dd,J＝8.0Hz,2.0Hz,1H),7.06(d,J＝2.0Hz,1H),6.87(m,2H),6.53(d,J＝2.0Hz,1H),6.45(d,J＝2.0Hz,1H),3.91(s,3H),3.90(s,3H),3.87(s,3H)； 13 C NMR(125MHz,CDCl 3 )δc:196.2,157.1,156.9,152.0,149.3,148.4,142.9,127.3,124.2,123.9,111.1,110.1,107.7,101.7,98.8,56.6,56.2,56.1；HRESIMS:m/z393.0326,calcd for C 18 H 18 O 5 Br[M+H] + ,393.0332.
example 8:
1- (2-bromo-3-methoxy-5-hydroxyphenyl) -3- (3, 4-dimethoxyphenyl) - (2E) -2-propen-1-one (8)
Compound 8: yellow solid (yield=11%); 1 H NMR(400MHz,CDCl 3 )δ H :7.31(d,J＝16.0Hz,1H),7.09(dd,J＝8.0Hz,2.0Hz,1H),7.06(d,J＝2.0Hz,1H),6.92(m,2H),6.57(d,J＝2.0Hz,1H),6.50(d,J＝2.0Hz,1H),3.93(s,3H),3.92(s,3H),3.82(s,3H)； 13 C NMR(125MHz,CDCl 3 )δc:195.4,178.6,160.1,156.9,148.8,147.6,147.0,143.4,127.1,124.2,124.1,115.0,109.8,104.5,101.0,77.2,56.6,56.1,55.9；HRESIMS:m/z 393.0324,calcd for C 18 H 18 O 5 Br[M+H] + ,393.0332.
example 9:
1- (2-bromo-3-hydroxy-5-methoxyphenyl) -3- (3-methoxy-4-hydroxyphenyl) - (2E) -2-propen-1-one (9)
Compound 9: yellow solid (yield=23%); 1 H NMR(400MHz,CDCl 3 )δ H :7.37(d,J＝16.0Hz,1H),7.12(dd,J＝8.0Hz,2.00Hz,1H),7.06(d,J＝2.0Hz,1H),6.88(d,J＝8.0Hz,1H),6.85(br s,1H),6.66(br s,1H),6.50(br s,1H),3.90(s,6H)； 13 C NMR(125MHz,CDCl 3 )δc:195.0,156.8,154.0,152.0,149.4,148.3,142.2,127.3,123.9(2×C),111.2,110.1,108.7,104.9,98.1,56.2,56.1；HRESIMS:m/z 379.0171,calcd forC 17 H 16 O 5 Br[M+H] + ,379.0176.
example 10:
1- (2-bromo-3-methoxy-5-hydroxyphenyl) -3- (3-methoxy-4-hydroxyphenyl) - (2E) -2-propen-1-one (Z10)
Compound 10: yellow solid (yield=16%); 1 H NMR(400MHz,CDCl 3 )δ H :7.34(d,J＝16.0Hz,1H),7.08(dd,J＝8.0Hz,2.00Hz,1H),7.04(d,J＝2.0Hz,1H),6.91(d,J＝8.0Hz,1H),6.85(d,J＝16.0Hz,1H),6.53(d,J＝2.0Hz,1H),6.45(d,J＝2.0Hz,1H),3.91(s,3H),3.90(s,3H)； 13 C NMR(125MHz,CDCl 3 )δc:196.31,157.1,157.0,149.0,148.6,145.0,142.9,126.9,124.3,123.9,115.0,110.0,107.7,101.7,98.7,56.6,56.1；HRESIMS:m/z 379.0169,calcd for C 17 H 16 O 5 Br[M+H] + ,379.0176.
example 11:
1- (2-bromo-3, 5-diphenylmethoxyphenyl) -3- (3-methoxy-4-benzyloxyphenyl) - (2E) -2-propen-1-one (11)
20g (48.8 mmol) of 2-bromo-3, 5-dibenzyloxy acetophenone was dissolved in 2000ml of a mixed solvent of methanol and water (methanol: water=2:1, v/v), and 20g (48.8 mmol) of NaOH solid was added. Stirring at room temperature for 10 min, then adding 14.2g (58.6 mmol) of 3-methoxy-4-benzyloxy benzaldehyde, and continuing the reaction for 10h, wherein TLC detection showed that the reaction was complete. The reaction mixture was filtered through celite to give compound 11 (27.5 g, 87%) as a yellow solid.
Compound 11: a yellow solid was used as the starting material, 1 H NMR(400MHz,acetone-d 6 ):δ H :7.31-7.57(m,17H),7.19(dd,J＝8.0Hz,2Hz,1H),7.09(d,J＝8.0Hz,1H),6.97(d,J＝16Hz,1H),6.96(d,J＝2.6Hz,1H),5.29(s,2H),5.19(s,2H),5.18(s,2H),3.89(s,3H)； 13 C NMR(100MHz,acetone-d 6 ):δ C :194.8,160.2,156.9,152.1,151.1,147.7,144.7,138.0,137.6(2×C),129-128.2(12×C),125.2,124.3,114.3,111.9,107.1,103.6,71.6,71.2,71.1,56.3；HRESIMS:m/z 635.1424,calcd for C 37 H 32 O 5 Br[M+H] + ,635.1428.
the synthesis method of the compounds 12 to 15 comprises the following steps:
100mg of Compound 2 (0.275 mmol) was dissolved in 10ml of dry acetone, 228mg (1.65 mmol) of anhydrous potassium carbonate was added, followed by stirring for 0.5 hour, 168mg (1.24 mmol) of bromomethylcyclopropane was added, and the reaction was stopped by stirring at 100℃for 12 hours. The reaction solution is filtered by diatomite, the filtrate is concentrated under reduced pressure, and the obtained product is separated by silica gel column chromatography by using petroleum ether and ethyl acetate, wherein dichloromethane=6:1:2-3:1:2 as eluent to obtain the compounds 12,13,14 and 15.
Synthesis of end products 12 to 15 (Compound code corresponds to the Compound code in the examples)
Example 12:
1- (2-bromo-3, 5-dicyclohexylmethoxyphenyl) -3- (3-methoxy-4-cyclopropylmethoxyphenyl) - (2E) -2-propen-1-one (12)
Compound 12: yellow solid (yield=32%); 1 H NMR(400MHz,CDCl 3 )δ H :7.32(d,J＝16.0Hz,1H),7.08(dd,J＝8.0Hz,2Hz,1H),7.07(d,J＝2.0Hz,1H),6.89(d,J＝16.0Hz,1H),6.84(d,J＝8.0Hz,1H),6.56(d,J＝2.4Hz,1H),6.47(d,J＝2.4Hz,1H),3.89(d,J＝6.4Hz,2H),3.88(s,3H),3.87(d,J＝6.4Hz,2H),3.78(d,J＝6.4Hz,2H)； 13 C NMR(125MHz,CDCl 3 )δc:195.3,159.3,156.5,151.4,149.7,147.2,143.4,127.4,124.3,123.5,112.8,110.5,105.4,103.0,100.5,74.1,74.0,73.4,56.1,29.8,10.2(2×C),3.6,3.4,3.3；HRESIMS:m/z 527.1419,calcd for C 28 H 32 O 5 Br[M+H] + ,527.1428.
example 13:
1- (2-bromo-3-cyclopropylmethoxy-5-hydroxyphenyl) -3- (3-methoxy-4-cyclopropylmethoxyphenyl) - (2E) -2-propen-1-one (13)
Compound 13 as yellow solid (yield=16%); 1 H NMR(400MHz,CDCl 3 )δ H :7.33(d,J＝16.0Hz,1H),7.07(m,2H),6.87(d,J＝16.0Hz,1H),6.83(d,J＝8.0Hz,2H),6.48(d,J＝2.0Hz,1H),6.44(d,J＝2.0Hz,1H),3.87(m,7H),0.69-0.31(m,5H)； 13 C NMR(125MHz,CDCl 3 )δc:196.3,156.61 151.6,149.6,148.4,142.9,127.2,124.1,123.8,112.6,110.5,107.7,103.0,99.6,74.0,56.1,10.2(2×C),3.7(2×C),3.4(2×C)；HRESIMS:m/z 473.0951,calcd for C 24 H 26 O 5 Br[M+H] + ,473.0958.
example 14:
1- (2-bromo-3-hydroxy-5-cyclopropylmethoxyphenyl) -3- (3-methoxy-4-cyclopropylmethoxyphenyl) - (2E) -2-propen-1-one (14)
Compound 14, yellow solid (yield=15%); 1 H NMR(400MHz,CDCl 3 )δ H :7.32(d,J＝16.0Hz,1H),7.07(m,2H),6.97(d,J＝16.0Hz,1H),6.85(d,J＝8.0Hz,2H),6.56(d,J＝2.0Hz,1H),6.47(d,J＝2.0Hz,1H),3.87(m,7H),0.69-0.31(m,5H)； 13 C NMR(125MHz,CDCl 3 )δc:196.3,156.61 151.6,149.6,148.4,142.9,127.2,124.1,123.8,112.6,110.5,107.7,103.0,99.6,74.0,56.1,10.2(2×C),3.7(2×C),3.4(2×C)；HRESIMS:m/z 473.0954,calcd for C 24 H 26 O 5 Br[M+H] + ,473.0958.
example 15:
1- (2-bromo-3, 5-dihydroxyphenyl) -3- (3-methoxy-4-cyclopropylmethoxyphenyl) - (2E) -2-propen-1-one (15)
Compound 15, yellow solid (yield=13%); 1 H NMR(400MHz,CDCl 3 )δ H :7.33(d,J＝16.0Hz,1H),7.08(dd,J＝8.0Hz,2.0Hz,1H),7.04(d,J＝2.0Hz,1H),6.88(m,2H),6.49(d,J＝2.0Hz,1H),6.44(d,J＝2.0Hz,1H),3.91(s,3H),3.86(d,J＝6.4Hz,2H),0.88-0.39(m,5H)； 13 C NMR(125MHz,CDCl 3 )δc:196.4,156.7,156.6,148.9,148.5,147.0,142.9,127.0,124.3,123.9,115.0,110.0,107.7,103.0,99.5,74.0,56.1,10.2,3.4(2×C)；HRESIMS:m/z 419.0479,calcd for C 20 H 20 O 5 Br[M+H] + ,419.0489.
pharmacological experiments
The invention provides application of 2' -bromochalcone derivatives and pharmaceutically acceptable salts thereof in preparing medicaments for treating and/or preventing liver-related diseases, and the invention is further described by the following experimental examples, but is not limited in any way.
The pharmacological test method and result of the liver protection activity of the compound of the present invention are as follows (the compound code of the pharmacological test part corresponds to the compound code in the test example):
experimental example 1: evaluation of protection effect of 2' -bromochalcone derivative on in vitro hepatocyte injury caused by paracetamol (APAP)
1. The experimental method comprises the following steps:
1) Cytotoxicity of compounds against human hepatocyte HepG2 cells
The MTT method is employed. HepG2 cells were inoculated into 96-well cell culture plates, after 24h of culture, the test compounds were added at different concentrations, and a solvent control group was set up, with 3 parallel wells for each drug concentration. After the cells were allowed to act for 48 hours, the culture broth was discarded, 100. Mu.l of MTT (0.5 mg/ml) was added to each well, the culture was continued for 4 hours, MTT was discarded, 150. Mu.l of DMSO was added to each well, and the mixture was shaken with a mixer, and the absorbance was measured at 570nm wavelength of the microplate reader. Cell viability (%) = (mean of dosed cells OD/mean of solvent control cells OD) ×100%.
2) Protection of paracetamol (APAP) against in vitro hepatocyte damage by compounds
The MTT method is employed. HepG2 cells were inoculated into 96-well cell culture plates, and after 24 hours of culture, a non-toxic concentration of the test compound and paracetamol (APAP, final concentration of 8 mM) were added, together with a positive drug control group (bicyclol), a solvent blank control group and a model group. The cells were allowed to continue to function for 48h. The culture broth was discarded, 100. Mu.l of MTT (0.5 mg/ml) was added to each well, the culture was continued for 4 hours, MTT was discarded, 150. Mu.l of DMSO was added to each well, and the mixture was shaken by a mixer and absorbance was measured at 570nm wavelength in a microplate reader. Cell survival (%) = 100 x mean OD of dosing group/mean OD of blank group, percent increase in cell survival (%) = 100 x (dose group cell survival-model group cell survival)/model group cell survival.
2. Experimental results:
1) Cytotoxicity: the 2' -bromochalcone derivative was allowed to act on HepG2 cells at a concentration of 10 μm for 48h. At this concentration, no significant toxicity was observed for HepG2 cells, with a cell viability of greater than 90% (data not shown), and a concentration of 10 μm of test compound was selected for the subsequent experiments.
2) Protection against APAP induced human hepatocyte damage: the results are shown in Table 1, APAP 8mM acts on HepG2 cells for 48 hours, and causes remarkable damage to the HepG2 cells, and the cell survival rate is 50.92%. Under the current experimental scheme, the 2' -bromochalcone derivatives 11,14 and 15 are combined with APAP at the concentration of 10 mu M, so that the compound has obvious protection effect on hepatic cell injury caused by the APAP, and compared with a model group, the compound has statistical difference, and the cell survival rate is respectively improved by 28.43%,16.06% and 9.78%. The concentration of the positive control medicine, namely the bicyclo alcohol (Bicyclol) with the concentration of 10 mu M, has a remarkable protection effect on hepatic cell injury caused by APAP.
TABLE 1 protection of APAP-induced HepG2 cell injury by 2' -bromochalcone derivatives * .
* *** P < 0.001, compared with the blank control group; # P＜0.05， ## p < 0.01, compared with APAP model group; the concentration was 10. Mu.M.
Claims (4)
1. Use of a 2' -halochalcone derivative or a pharmaceutically acceptable salt thereof as shown below for the manufacture of a medicament for the treatment and/or prevention of hepatocyte damage caused by paracetamol:
。
2. use of a pharmaceutical composition consisting of an effective dose of a 2' -halochalcone derivative according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or adjuvant for the manufacture of a medicament for the treatment and/or prevention of hepatocyte damage caused by paracetamol.
3. Use according to claim 2, characterized in that said pharmaceutical composition is selected from the group consisting of tablets, capsules, pills or injections.
4. Use according to claim 2, characterized in that the pharmaceutical composition is selected from a slow release formulation, a controlled release formulation or various particulate delivery systems.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1559398A (en) * | 2004-02-19 | 2005-01-05 | 北京大学 | Application of chalcone for preparing medicnes for treating hepatitis and hepatoma |
| CN110240583A (en) * | 2018-03-10 | 2019-09-17 | 中国医学科学院药物研究所 | A kind of benzopyrans compounds, and preparation method thereof and pharmaceutical composition and purposes |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1559398A (en) * | 2004-02-19 | 2005-01-05 | 北京大学 | Application of chalcone for preparing medicnes for treating hepatitis and hepatoma |
| CN110240583A (en) * | 2018-03-10 | 2019-09-17 | 中国医学科学院药物研究所 | A kind of benzopyrans compounds, and preparation method thereof and pharmaceutical composition and purposes |
Non-Patent Citations (2)
| Title |
|---|
| "Stereoselective Palladium-Catalyzed r-Arylation of 3-Aryl- 1-Indanones: An Asymmetric Synthesis of (+)-Pauciflorol F";Bong Hyang Lee，等;《The Journal of Organic Chemistry》;第76卷(第16期);6611–6618 * |
| "Versatile and Enantioselective Total Synthesis of Naturally Active Gnetulin";Changhui Shang 等;《Adv. Synth. Catal.》;3768 – 3776 * |
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