CN101830819B - Phenylbutyryl curcumin derivate and application thereof in anti-tumor drug preparation - Google Patents
Phenylbutyryl curcumin derivate and application thereof in anti-tumor drug preparation Download PDFInfo
- Publication number
- CN101830819B CN101830819B CN2010101835096A CN201010183509A CN101830819B CN 101830819 B CN101830819 B CN 101830819B CN 2010101835096 A CN2010101835096 A CN 2010101835096A CN 201010183509 A CN201010183509 A CN 201010183509A CN 101830819 B CN101830819 B CN 101830819B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- chloroethyl
- amino
- cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- VFLDPWHFBUODDF-FCXRPNKRSA-N Curcumin Natural products C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- -1 Phenylbutyryl curcumin Chemical compound 0.000 title claims abstract description 23
- 235000012754 curcumin Nutrition 0.000 title claims abstract description 23
- 229940109262 curcumin Drugs 0.000 title claims abstract description 21
- 239000004148 curcumin Substances 0.000 title claims abstract description 17
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 10
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 10
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims abstract description 29
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims abstract description 29
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 17
- 201000007270 liver cancer Diseases 0.000 claims abstract description 15
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 15
- 208000032839 leukemia Diseases 0.000 claims abstract description 7
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 4
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 4
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 4
- 201000000849 skin cancer Diseases 0.000 claims abstract description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 58
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 48
- 229940125904 compound 1 Drugs 0.000 claims description 44
- 229940125782 compound 2 Drugs 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 13
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 201000010989 colorectal carcinoma Diseases 0.000 claims description 3
- 201000008261 skin carcinoma Diseases 0.000 claims description 3
- 201000000498 stomach carcinoma Diseases 0.000 claims description 3
- 238000007445 Chromatographic isolation Methods 0.000 claims description 2
- 238000011097 chromatography purification Methods 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 2
- 150000002148 esters Chemical class 0.000 claims 2
- 206010025323 Lymphomas Diseases 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 31
- 241000699670 Mus sp. Species 0.000 abstract description 10
- 238000011789 NOD SCID mouse Methods 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 8
- 241001465754 Metazoa Species 0.000 abstract description 7
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- 231100000419 toxicity Toxicity 0.000 abstract description 3
- 230000001988 toxicity Effects 0.000 abstract description 3
- 210000004881 tumor cell Anatomy 0.000 abstract description 3
- 208000000453 Skin Neoplasms Diseases 0.000 abstract 1
- 208000029742 colonic neoplasm Diseases 0.000 abstract 1
- 206010017758 gastric cancer Diseases 0.000 abstract 1
- 201000011549 stomach cancer Diseases 0.000 abstract 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 33
- 230000002401 inhibitory effect Effects 0.000 description 24
- 241000699660 Mus musculus Species 0.000 description 15
- 238000011580 nude mouse model Methods 0.000 description 15
- 230000037396 body weight Effects 0.000 description 11
- 239000002504 physiological saline solution Substances 0.000 description 10
- 230000000452 restraining effect Effects 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 238000011081 inoculation Methods 0.000 description 7
- 230000035479 physiological effects, processes and functions Effects 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 210000000265 leukocyte Anatomy 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 210000002798 bone marrow cell Anatomy 0.000 description 5
- 238000010172 mouse model Methods 0.000 description 5
- 230000002093 peripheral effect Effects 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- 210000003484 anatomy Anatomy 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 230000000366 juvenile effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 2
- 244000163122 Curcuma domestica Species 0.000 description 2
- 235000003392 Curcuma domestica Nutrition 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000011579 SCID mouse model Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 235000003373 curcuma longa Nutrition 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002169 ethanolamines Chemical class 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 210000005259 peripheral blood Anatomy 0.000 description 2
- 239000011886 peripheral blood Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000003757 reverse transcription PCR Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 235000013976 turmeric Nutrition 0.000 description 2
- 241000407170 Curcuma Species 0.000 description 1
- 235000014375 Curcuma Nutrition 0.000 description 1
- 240000009138 Curcuma zedoaria Species 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 238000002738 Giemsa staining Methods 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 206010041660 Splenomegaly Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 241000234314 Zingiber Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000003627 anti-cholesterol Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Images
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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to phenylbutyryl curcumin derivate and application thereof in anti-tumor drug preparation, in particular to 4-(di(2-chloroethyl) amino) phenylbutyryl curcumin, 4,4'-(di(2-chloroethyl)amino) diphenylbutyryl curcumin, pharmaceutically acceptable salts and a preparation method thereof, and applications of 4-(di(2-chloroethyl) amino) phenylbutyryl curcumin, and 4,4'-(di(2-chloroethyl)amino) di phenylbutyryl curcumin in anti-tumor drug preparation. The phenylbutyryl curcumin derivate can be used for (but not limited to) preparing drugs for treating leukemia, skin cancer, gastric cancer, colon cancer, liver cancer, breast cancer or prostatic cancer. The derivate has obvious inhibition on a plurality of animal tumor cell transplanting modules, especially for the human chronic granulocytic leukemia model constructed by NOD-SCID mice inoculated with the human chronic granulocytic leukemia K562 cell stain, the life prolonging rate is obviously enhanced, and the serious toxicity to mice does not exist.
Description
Technical field
The invention belongs to pharmacy field, relate in particular to benzene butyryl radicals curcumin derivate and preparation method thereof, with and in the application of preparation in the antitumor drug.
Background technology
Curcumine (Curcumin, be called for short Cur) be the effective constituent of from rhizome such as Zingiber curcuma turmeric, curcuma zedoary, root tuber of aromatic turmeric, extracting, have antitumor, anti-inflammatory, anti-human immunodeficiency virus, anti-cholesterol, multiple pharmacological effect such as anti-oxidant, have good clinical application potentiality.But the Cur instability, metabolism is rapid in vivo, and bioavailability is low, is difficult to reach effective concentration in the body, has seriously restricted curcumine and has been developed to effective anticarcinogen.By the synthetic curcumin derivate of structure of modification, improve bioavailability, prolong the biological transformation period t of elimination
1/2Significant.
Summary of the invention
One of purpose of the present invention is to provide 4-[two (2-chloroethyl) amino] benzene butyryl radicals curcumine and 4,4 '-[two (2-chloroethyl) amino] two benzene butyryl radicals curcumines and pharmacy acceptable salt thereof.
Two of purpose of the present invention is to provide 4-[two (2-chloroethyl) amino] benzene butyryl radicals curcumine and 4, the preparation method of 4 '-[two (2-chloroethyl) amino] two benzene butyryl radicals curcumines and pharmacy acceptable salt thereof.
As follows for realizing the technical scheme that purpose of the present invention adopts: two (2-chloroethyl) amino of 4-[of the present invention] its structural formula of benzene butyryl radicals curcumine is shown in following compound 1; 4,4 '-[two (2-chloroethyl) amino] two its structural formulas of benzene butyryl radicals curcumine are shown in following compound 2, and the salt of curcumin derivate of the present invention is the compound 1 of following formula structure and compound 2 in the pharmacy acceptable salt class:
Comprise an alkali metal salt, alkaline earth salt at pharmaceutically-acceptable salts, contain organic bases salt, contain the salt of organic bases.This acceptable salt comprises calcium salt, magnesium salts, ammonium salt, triethyl amine salt, ethanolamine salt.
The preparation method of curcumin derivate of the present invention and salt, concrete steps are as follows: curcumine is dissolved in the dry methylene dichloride of crossing, add catalytic amount DMAP (N, the N-4-dimethyl aminopyridine), then add two (2-chloroethyl) amino of the 4-[be dissolved in methylene dichloride] benzenebutanoic acid carries out esterification, then with product through column chromatographic isolation and purification.In the method for the invention described above, can add dewatering agent DCC (dicyclohexylcarbodiimide) or EDCI (1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride) earlier, add the DMAP of the general catalytic amount of chemical field again.
The curcumin derivate of the compound 1 that the present invention synthesized and compound 2 structures, all obtain NMR (Nuclear Magnetic Resonance) spectrum (NMR), infrared spectrum (IR), ultraviolet spectrogram (UV), liquid chromatography-mass spectrography (HPLC-Mass) evaluation, compound 1 after evaluation and compound 2 are made the formulation on the suitable pharmacology according to needing.
The present invention is medicine or its pharmacy acceptable salt of protection compound 1 or compound 2, or contains the medicine of compound 1 or compound 2 or pharmaceutical composition or the preparation that its pharmacy acceptable salt is formed.
In the formulation on preparation pharmacology, its carrier is the pharmaceutical carrier of pharmaceutical field routine, for example thinner, vehicle, weighting agent, tackiness agent, disintegrating agent, tensio-active agent, lubricant etc.; It can make oral and various formulations other administering modes, as oral liquid, suspension, capsule, tablet, pill, granule, and powder pin injection liquid etc.; Press the conventional production method preparation of pharmaceutical field, it is selected for use and contains compound 1 or the compound 2 that weight percent is the 0.1%-99.5% activeconstituents.Also can contain the compound 1 of 0.1%-99.5% or the pharmaceutical composition of compound 2; The technology that can realize for the same domain those skilled in the art.
Usage quantity of the present invention can be according to route of administration, variation such as the type of patient's age, body weight, the disease for the treatment of and severity, and its dose can be the 0.001-10g/kg body weight, can be in single or divided doses.
Three of the object of the invention is two (2-chloroethyl) amino of 4-[] benzene butyryl radicals curcumine and 4,4 '-[two (2-chloroethyl) amino] two benzene butyryl radicals curcumines are for the preparation of the application of antitumor drug.
Curcumin derivate can be used for but be not limited to preparation treating leukemia, skin carcinoma, cancer of the stomach, colorectal carcinoma, liver cancer, mammary cancer or prostate cancer medicine.The preferred human chronic myelogenous leukemia of leukemia.
Beneficial effect of the present invention: two (2-chloroethyl) amino of compound 1 curcumine 4-[of the present invention] the benzenebutanoic acid ester all has obvious inhibition to multiple animal tumor cell transplantation model in vivo, especially can be up to 60% to the restraining effect of human chronic myelogenous leukemia K562 cell transplanted tumor in nude mice, and administration group nude mice body weight does not have obvious decline, no animal generation death.1 couple of human chronic myelogenous leukemia K562 of compound cell strain inoculation NOD-SCID mouse makes up human chronic myelogenous leukemia's model, and increase in life span has also improved, and does not see the serious toxicity that pair mouse is arranged.Be 40-75% to rat liver cancer H22 at the body tumour inhibiting rate, same compound 2 is because structural similitude, and experimental results show that also has same effect.Therefore, this compounds has the tumor-inhibiting action stronger than curcumine.
Description of drawings
Fig. 1 is that compound 1 intravenously administrable is to the restraining effect figure of rat liver cancer H22 transplanted tumor
Fig. 2 is that compound 1 oral administration is to the restraining effect figure of rat liver cancer H22 transplanted tumor
Fig. 3 is 1 couple of human chronic myelogenous leukemia K562 of compound cell transplanted tumor in nude mice growth curve chart
Fig. 4 is the action diagram of 1 couple of human chronic myelogenous leukemia K562 of compound cell transplanted tumor in nude mice
Fig. 5 and Fig. 6 are mouse gross anatomy and the mouse bone marrow cells bcr-ab1 genetic expression figure of 1 pair of human chronic myelogenous leukemia's mouse model of compound
Fig. 7 and Fig. 8 are that NS group and compound 1 administration are to human chronic myelogenous leukemia's model mice peripheral hemogram figure
Fig. 9 is the restraining effect figure of 2 couples of rat liver cancer H22 of compound transplanted tumor;
As shown in Figure 1, set up the H22 mice-transplanted tumor, vein gives mouse physiology salt (control group) respectively, compound 1:50,70mg/kg (administration group).Tumour inhibiting rate is up to 60%.
As shown in Figure 2, set up the H22 mice-transplanted tumor, difference orally give mouse physiology salt (control group), compound 1:50,75,100mg/kg (administration group), curcumine 50mg/kg (curcumine control group).Administration group tumour inhibiting rate is respectively 41.21%, 52.93%, 75.06%.Curcumine control group (with mole such as compound 100mg/kg) tumour inhibiting rate only is 16.58%, and visible compound tumor-inhibiting action obviously is eager to excel than curcumine.
As shown in Figure 3, set up human chronic myelogenous leukemia K562 cell transplanted tumor in nude mice model, difference orally give nude mice physiology salt (control group), compound 1:40,60mg/kg (administration group).In the 0th, 4,8, the 11 day length with vernier callipers survey mouse tumor, calculate knurl volume=length * wide * high * 1/2, increase percentage (%)=(the average knurl volume of the average knurl volume-control group of the experimental group)/average knurl volume of control group * 100%.From Fig. 3 as seen, administration group growth of tumor is subjected to obvious inhibition.
As shown in Figure 4, set up K562 cell transplanted tumor in nude mice model, difference orally give nude mice physiology salt (control group), compound 1:40,60mg/kg (administration group).Tumour inhibiting rate is respectively 66.6%, 56.7%.
As Fig. 5, shown in Figure 6, make up human chronic myelogenous leukemia's model with the NOD-SCID mouse, the control group mice gross anatomy, intraperitoneal is seen a large amount of bloody ascites, and solid tumor occurs.Bone marrow cells in mice RT-PCR all examines people human chronic myelogenous leukemia's characterizing gene bcr-abl, illustrates that human chronic myelogenous leukemia's cell K562 goes back to the nest to the NOD-SCID mouse bone marrow cells.
As Fig. 7, shown in Figure 8, NOD-SCID mouse human chronic myelogenous leukemia model, difference orally give mouse physiological saline (control group), compound 1:60mg/kg (administration group), administration group peripheral hemogram juvenile cell also obviously is less than control group.
As shown in Figure 9, difference orally give mouse physiology salt (control group), compound 2:35,50,75,115mg/kg (administration group), curcumine 50mg/kg (curcumine control group).Administration group tumour inhibiting rate is respectively 27.43%, 32.25%, 62.60%, 58.39%.Curcumine control group (with mole such as compound 100mg/kg) tumour inhibiting rate only is 13.42%, and the tumor-inhibiting action of visible compound 2 obviously is eager to excel than curcumine.
Embodiment
It is following that the present invention is described in detail with example by reference to the accompanying drawings
Two (2-chloroethyl) amino of embodiment 14-[] benzene butyryl radicals curcumine (compound 1) synthetic
EDCI 1.92g (10mmol) is dissolved among the anhydrous methylene chloride 200ml, under ice bath, stir and adding curcumine 7.36g (20mmol), DMAP 0.244g (2mmol), slowly drip again and be dissolved with two (2-chloroethyl) amino of 4-[] the methylene dichloride 200ml of benzenebutanoic acid 3.04g (10mmol), continued stirring reaction 6 hours under the room temperature.Use distilled water wash; organic phase with anhydrous magnesium sulfate drying after; filtering and concentrating gets crude product; compacting was equipped with chromatographic separation during crude product was used; reverse C18 post, mobile phase methanol: water 50% → 100% (volume percent) gradient elution obtains two (2-chloroethyl) amino of 4-[] the pure product 1.30g of benzene butyryl radicals curcumine; productive rate 20%, chemical structural formula is as follows:
Molecular formula C
35H
37Cl
2NO
7, mp100-102 ℃
1H?NMR(D6-DMSO)：δ1.88(t，2H，-COCH
2CH
2CH
2Ph)，2.51(t，2H，-COCH
2CH
2CH
2Ph)，2.58(m，2H，-COCH
2CH
2CH
2Ph)，3.62(t，4H，-NCH
2CH
2Cl)，3.71(t，4H，-NCH
2CH
2Cl)，3.85(s，6H，2Ar-OCH3)，6.14(s，1H，-COCH＝C(OH)-)，6.70(d，2H，2-CH＝CH-Ar)，6.78-6.99(m，2H)，7.13-7.19(m，2H)，7.33(m，2H)，7.51(d，2H)，7.58(d，2H)，7.62(d，2H，2Ar-CH＝)，9.72(s，1H，Ar-OH)；HPLC-MS?m/z：654.2(M+1)
Synthesizing of embodiment 24,4 '-[two (2-chloroethyl) amino] two benzene butyryl radicals curcumines (compound 2)
EDCI 1.92g (10mmol) is dissolved among the anhydrous methylene chloride 100ml, under ice bath, stir and adding curcumine 1.84g (5mmol), DMAP 0.122g (1mmol), slowly drip again and be dissolved with two (2-chloroethyl) amino of 4-[] the methylene dichloride 200ml of benzenebutanoic acid 3.04g (10mmol), continued stirring reaction 6 hours under the room temperature.Use distilled water wash; organic phase with anhydrous magnesium sulfate drying after; filtering and concentrating gets crude product; compacting was equipped with chromatographic separation during crude product was used, reverse C18 post, mobile phase methanol: water 50% → 100% (volume percent) gradient elution; obtain 4; 4 '-[two (2-chloroethyl) amino] the pure product of two benzene butyryl radicals curcumines (compound 2) 1.88g, productive rate 40%, chemical structural formula is as follows:
C
49H
54C
14N
2O
8，mp58-60℃，
1H?NMR(CDCl
3)：δ2.04(m，4H，-COCH
2CH
2CH
2Ph)，2.29(t，4H，-COCH
2CH
2CH
2Ph)，2.60(m，4H，-COCH
2CH
2CH
2Ph)，3.63(t，4H，-NCH
2CH
2Cl)，3.70(t，4H，-NCH
2CH
2Cl)，3.87(s，6H，2Ar-OCH3)，6.58(d，2H，J＝16Hz，2-CH＝CH-Ar)，6.63(d，4H，J＝8Hz)，6.66(s，1H，-COCH＝C(OH)-)，7.03(s，2H)，7.05(m，2H)，7.08(m，2H)，7.12(d，4H，J＝8Hz)，7.17(m，2H)，7.51(d，2H)，7.53(d，2H)，7.62(d，2H，J＝16Hz，2Ar-CH＝)；HPLC-MS?m/z：941.3(M+1)
The effect of 1 couple of rat liver cancer H22 of embodiment 3 compounds transplanted tumor model
3.1 material
8～12 the week age Kunming kind healthy mice, female, body weight is (20 ± 2) g; Mouse provides (conformity certification SCXK (Fujian) 200420002) by Medical University Of Fujian's Experimental Animal Center.Rat liver cancer cell strain H22.Compound 1 uses preceding with being made into desired concn.
3.2 method
3.2.1 the foundation of bearing mouse model
The H22 tumour cell passed more than two generations, adjusted cell count to 10
7It is subcutaneous that/ml, 0.2mL/ only are inoculated in the mouse right fore, inoculates 2, treats about two weeks, the stripping knurl, and homogenate inoculates 80.
3.2.2 grouping
A: being divided into is 3 groups: the mouse behind the inoculation knurl strain 24h is divided into 3 groups at random: the I group is physiology saline control group, compound 1 adopts above-described embodiment method to make, as follows, the II group is compound 1 low dose group (compound 150mg/kg), the III group is compound 1 high dose group (70mg/kg), medication is tail vein injection, 0.1ml/10g.
B: being divided into is 5 groups: the mouse behind the inoculation knurl strain 24h is divided into 5 groups at random: the I group is physiological saline group (being the tumour control group), the II group is compound 1 low dose group (dosage is 50mg/kg), the III group is dosage group (dosage is 75mg/kg) in the compound 1, the IV group is compound 1 high dose group (dosage is 100mg/kg), (dosage is 50mg/kg to the V group for the Cur group, wait mole with high dosage IV group), medication is for irritating stomach, 0.1ml/10g.
3.2.3 tumour inhibiting rate
The stripping knurl claims the knurl quality after putting to death mouse, calculates tumour inhibiting rate. the average knurl quality of the average knurl quality/control group of the average knurl quality-experimental group of tumor control rate (%)=control group * 100%.
3.3 result
3.3.1 the tumor-inhibiting action of compound 1 intravenously administrable
Observe the tumor-inhibiting action of different dosing dosage, 1 couple of rat liver cancer H22 of visible compound transplants ratio of outflow and has obvious suppression effect (seeing Table 1, Fig. 1 of Figure of description).
Table 1 compound 1 intravenously administrable is to rat liver cancer H22 transplanted tumor restraining effect
Annotate: NS (physiological saline control group), compare with the NS group,
*P＜0.05;
*P＜0.01.
3.3.2 the tumor-inhibiting action of compound 1 oral administration
Observe 6 days tumor-inhibiting action of oral administration.As seen the increase tumour inhibiting rate with dosage improves gradually, presents good dose-effect relationship.Administration group (100mg/kg) is significantly increased than equimolar contrast medicine curcumine (50mg/kg) tumour inhibiting rate, and heavy dose do not see that dead mouse is arranged, and visible compound 1 is safer.(see Table 2 and Fig. 2 of Figure of description)
Table 2 oral administration is to the restraining effect of rat liver cancer H22 transplanted tumor
Annotate: compare with the NS group,
*P＜0.05;
*P＜0.01.Cur is curcumine
The effect of 1 couple of human chronic myelogenous leukemia K562 of embodiment 4 compounds cell transplanted tumor in nude mice model
4.1 material
4-6 SPF level nude mice in age in week, male, available from (credit number: SCXX (Shanghai) 2007-0005) is provided by Shanghai Slac Experimental Animal Co., Ltd., at the SPF laboratory rearing.Human chronic myelocytic leukemia K562 cell is available from Shanghai Inst. of Cytobiology, Chinese Academy of Sciences's cell bank.Before using, compound 1 is made into desired concn.
4.2 method
4.2.1 the foundation of bearing mouse model
The K562 cell passed more than two generations, adjusted cell count to 5 * 10
7It is subcutaneous that/ml, 0.2mL/ only are inoculated in the nude mice right fore, inoculates 30.
4.2.2 grouping
Be divided into is 3 groups: the strain of inoculation knurl is after 6 days, according to the mouse tumor size, the mouse stratified random is divided into 3 groups at random: the I group is physiology saline control group, the II group is compound 1 low dose group (40mg/kg), the III group is compound 1 high dose group (60mg/kg), medication is gastric infusion, 0.1ml/10g.
4.2.3 knurl increases percentage
Respectively at the length of surveying mouse tumor on the the 0th, 4,8,11 day with vernier callipers, calculate knurl volume=length * wide * high * 1/2, increase percentage (%)=(the average knurl volume of average knurl volume one control group of the experimental group)/average knurl volume of control group * 100%.
4.2.4 tumour inhibiting rate
The stripping knurl claims the knurl quality after putting to death mouse, calculates tumour inhibiting rate. tumor control rate (%)=(the average knurl quality of average knurl quality one experimental group of the control group)/average knurl quality of control group * 100%.
4.3 result
4.3.1 knurl increases percentage
Fig. 3 of Figure of description is seen in each dynamic change of organizing the tumor-bearing mice tumor growth, and the tumor propagation speed of visible administration group is obviously low than NS control group.
4.3.2 the tumor-inhibiting action of oral administration
Observe 11 days tumor-inhibiting action of oral administration.The result shows that compound 1 can obviously suppress the growth of K562 cell transplanted tumor in nude mice, and its tumour inhibiting rate is respectively 66.6%, 56.7%, learns processing (t check) by statistics and has significant difference, has certain dose-effect relationship (seeing Table 3, Fig. 4 of Figure of description).Compare with the physiological saline group, administration group nude mice body weight does not have obvious decline, and no animal is taken place dead, and the prompting compound does not increase the toxicity of medicine when improving the medicine antitumous effect.Test shows that 1 couple of human chronic myelogenous leukemia K562 of compound cell transplanted tumor in nude mice model has significant tumor-inhibiting action.
Table 3 oral administration is to the restraining effect of human chronic myelogenous leukemia K562 cell transplanted tumor in nude mice
Annotate: compare with the NS group,
*P＜0.05;
*P＜0.01.
The effect of 1 pair of human chronic myelogenous leukemia's mouse model of embodiment 5 compounds
5.1 material
5.1.1NOD-SCID mouse
Female and male dual-purpose, 4～6 ages in week, body weight 18～22g, Institute of Experimental Animals, Chinese Academy of Medical Sciences provides, license licensed licenser licence numbering: SCXK (capital) 2005-0013.The NOD-SCID mouse is raised (meeting the SPF standard) in the mouse box with cover in the laminar-flow rack of SPF laboratory.The standard particle feed, drinking-water, bedding and padding and all contact article all through sterilising treatment with mouse.
5.1.2 human leukemia cell line (K562)
Available from Shanghai Inst. of Cytobiology, Chinese Academy of Sciences's cell bank, the cultivation of going down to posterity of this chamber routine is adopted the cell of logarithmic phase to do in the animal body and is transplanted.
5.1.3 be made into desired concn before compound 1 uses.
5.2 method
5.2.1 the foundation of mouse chronic myelocytic leukemia model
The NOD-SCID mouse is accepted the full-body exposure of 2.0Gy X ray, and the vegetative period K562 cell of taking the logarithm next day be used for to be transplanted the disposable injection 1 * 10 of tail vein
7The cell/ mouse.
5.2.2 1 pair of NOD-SCID mouse of compound chronic myelocytic leukemia model effect
After the NOD-SCID mouse was transplanted the K562 cell, random packet set up physiological saline control group and drug treatment group separately, four every group.The blank group gives physiological saline 0.2ml/ and only irritates stomach, and the drug treatment group gives compound 160mg/kg and irritates stomach, in transplanting the beginning administrations of two week of back, and successive administration 5 days, drug treatment group drug withdrawal continuous use 8 days again after 5 days.Close observation mouse generalized case, body weight and appetite during the administration, assessment drug toxicity and animal to the tolerance degree of medicine to adjust dosage regimen.Record each experimental mice survival time, be three months observing time, and surviving after the K562 Transplanted cells, the person is long-term survival more than two months.
5.2.3 peripheral blood film and white blood cell count(WBC)
Each experimental mice respectively at inoculation before and 1 week of inoculation back, 2 weeks, 3 weeks, 4 weeks, 5 weeks, get tail vein counting total white blood cells, and the preparation blood smear, through Rui Shi-Giemsa staining, classification under the oily mirror, counting.
5.3 result
5.3.1NOD-SCID mouse human chronic myelogenous leukemia model construction
After the physiological saline control group mice was transplanted human chronic myelogenous leukemia's cell K562, the nature survival time was 32.5 ± 9.0 days.Animal skin is wrinkling, the Mi Shaodong that withers, instability of gait, and body weight alleviates gradually.Transplant back three all peripheral blood leucocyte and obviously raise, can reach and transplant preceding 2-10 doubly, peripheral blood film is seen a large amount of juvenile cells.Dead mouse gross anatomy, intraperitoneal is seen a large amount of bloody ascites, and solid tumor occurs, splenomegaly not obvious (seeing Figure of description 5).Physiological saline control group NOD-SCID bone marrow cells in mice RT-PCR all examines people bcr-abl gene (seeing Figure of description 6), illustrates that human chronic myelogenous leukemia's cell K562 goes back to the nest to the NOD-SCID mouse bone marrow cells.The white blood model construction success of reference's chronic granulocyte.
5.3.2 oral administration is to the effect of mouse chronic myelocytic leukemia
The drug treatment group has 2 to remain work in 4 mouse till finishing, survival time has reached 85 days, realize long-term survival, all the other mouse survival times obviously prolong than the physiological saline control group, peripheral white blood cell is starkly lower than the physiological saline control group, and the peripheral hemogram juvenile cell also obviously is less than control group.(see Table 4,5, and Figure of description 7,8), test shows that 1 pair of mouse chronic myelocytic leukemia of compound that embodiment 1 is synthesized has effect.
Table 4 oral administration influences chronic myelocytic leukemia mouse survival time
*: P＜0.05, VS NS group.
Each experimental mice peripheral white blood cell (* 10 of table 5
9/ L)
The restraining effect of 2 couples of rat liver cancer H22 of embodiment 6 compounds transplantation tumor
Table 6 compound 2 oral restraining effect of giving rat liver cancer H22 transplanted tumor
Annotate: compare with the NS group,
*P＜0.05; * P＜0.01.
The present invention also can verify in the same mode of above-described embodiment and comprise compound 1 or compound 2 or its at pharmaceutically-acceptable salts and contain compound 1 or compound 2 or its pharmaceutical composition in the pharmaceutically-acceptable salts form have similar characteristic; The example of pharmaceutically-acceptable salts comprises an alkali metal salt such as sodium salt or sylvite, and alkaline earth salt such as calcium salt or magnesium salts contain salt such as the ammonium salt of organic bases, or gives up salt such as triethyl amine salt or the ethanolamine salt of organic bases.
Claims (10)
1. structural formula is two (2-chloroethyl) amino of 4-[of following compound 1] benzene butyryl radicals curcumine and structural formula be 4,4 ' of following compound 2-[two (2-chloroethyl) amino] two benzene butyryl radicals curcumines and pharmacy acceptable salt thereof:
2. the preparation method of the described compound 1 of claim 1 or compound 2, it is characterized in that: curcumine is dissolved in the dry methylene dichloride of crossing, add catalytic amount DMAP, then adding two (2-chloroethyl) amino of the 4-[be dissolved in methylene dichloride] benzenebutanoic acid carries out esterification and obtains compound 1 or compound 2 products, then compound 1 or compound 2 products obtained compound 1 or compound 2 products of purifying through column chromatographic isolation and purification.
3. according to the preparation method of compound 1 or the compound 2 of claim 2, it is characterized in that dissolving curcumine again behind described methylene dichloride dissolving dewatering agent DCC or the EDCI, then add the DMAP of catalytic amount.
4. the curcumin derivate of the described compound 1 of claim 1 or compound 2 and pharmacy acceptable salt thereof the application in the preparation antitumor drug.
5. contain pharmaceutically acceptable pharmaceutical composition that the described compound 1 of claim 1 or compound 2 curcumin derivates or its pharmacy acceptable salt be combined into or preparation in the application of preparation antitumor drug.
6. according to claim 4 or 5 described application, it is characterized in that: described antitumor drug is for the preparation of the medicine for the treatment of leukemia, lymphoma, skin carcinoma, cancer of the stomach, colorectal carcinoma, liver cancer, mammary cancer, prostate cancer or other malignant tumours.
7. one kind contains pharmaceutical composition or the preparation that the described compound of claim 1 or its pharmacy acceptable salt are formed.
8. two (2-chloroethyl) amino of the described 4-[of claim 1] benzene butyryl radicals curcumine monoesters or dibasic acid esters or its pharmacy acceptable salt or contain two (2-chloroethyl) amino of 4-[] monoesters of benzene butyryl radicals curcumine or dibasic acid esters and pharmacy acceptable salt thereof the pharmaceutical composition or the application of preparation in the preparation antitumor drug that are combined into.
9. according to claim 4 or 5 or 8 described application, it is characterized in that: described tumour is leukemia, skin carcinoma, cancer of the stomach, colorectal carcinoma, liver cancer, mammary cancer or prostate cancer medicine.
10. application according to claim 9 is characterized in that: leukemia is the human chronic myelogenous leukemia.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101835096A CN101830819B (en) | 2010-05-26 | 2010-05-26 | Phenylbutyryl curcumin derivate and application thereof in anti-tumor drug preparation |
| PCT/CN2011/073844 WO2011147254A1 (en) | 2010-05-26 | 2011-05-09 | Phenylbutyryl curcumin derivatives and uses for preparing anti-tumor drugs thereof |
| GB1223251.8A GB2494595B (en) | 2010-05-26 | 2011-05-09 | Phenylbutyryl curcumin derivatives and use thereof in manufacturing medicaments for preventing tumors |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101835096A CN101830819B (en) | 2010-05-26 | 2010-05-26 | Phenylbutyryl curcumin derivate and application thereof in anti-tumor drug preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101830819A CN101830819A (en) | 2010-09-15 |
| CN101830819B true CN101830819B (en) | 2013-08-28 |
Family
ID=42715062
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010101835096A Expired - Fee Related CN101830819B (en) | 2010-05-26 | 2010-05-26 | Phenylbutyryl curcumin derivate and application thereof in anti-tumor drug preparation |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101830819B (en) |
| GB (1) | GB2494595B (en) |
| WO (1) | WO2011147254A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830819B (en) * | 2010-05-26 | 2013-08-28 | 福建医科大学 | Phenylbutyryl curcumin derivate and application thereof in anti-tumor drug preparation |
| CN102552224A (en) * | 2011-12-16 | 2012-07-11 | 西安交通大学 | Application of curcumin derivative C2 in anti-colon cancer medicaments |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101003470A (en) * | 2007-01-22 | 2007-07-25 | 温州医学院生物与天然药物开发中心有限公司 | Analog of mono carbonyl structure of curcumin, and usage |
| CN101076336A (en) * | 2004-10-15 | 2007-11-21 | 北卡罗来纳查佩尔山大学 | Novel curcumin analogues and uses thereof |
| CN101255119A (en) * | 2008-01-07 | 2008-09-03 | 沈阳药科大学 | Novel tetrahydro curcumin derivatives and salt |
| CN101434524A (en) * | 2008-06-05 | 2009-05-20 | 福建医科大学 | 4-(4-hydroxy-3-methoxybenzene methylene) curcumin, preparation thereof and use in preparing anti-cancer medicament |
| CN101524546A (en) * | 2008-11-07 | 2009-09-09 | 浙江中医药大学 | Conjugate conjugated from polyethylene glycol and curcumin derivative |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003270283A1 (en) * | 2002-10-01 | 2004-04-23 | Dr. Andre Rieks - Labor Fur Enzymtechnologie Gmbh | Novel curcumin/tetrahydrocurcumin derivatives for using in cosmetics, pharmaceuticals and for nutrition |
| CA2665916C (en) * | 2006-10-12 | 2015-12-08 | The Research Foundation Of The City University Of New York | Novel curcumin and tetrahydrocurcumin derivatives |
| CN101669931B (en) * | 2008-09-08 | 2012-07-04 | 北京鼎国昌盛生物技术有限责任公司 | Application of long effective curcumin derivative in preparing anti-tumor disease drug |
| CN101830819B (en) * | 2010-05-26 | 2013-08-28 | 福建医科大学 | Phenylbutyryl curcumin derivate and application thereof in anti-tumor drug preparation |
-
2010
- 2010-05-26 CN CN2010101835096A patent/CN101830819B/en not_active Expired - Fee Related
-
2011
- 2011-05-09 WO PCT/CN2011/073844 patent/WO2011147254A1/en active Application Filing
- 2011-05-09 GB GB1223251.8A patent/GB2494595B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101076336A (en) * | 2004-10-15 | 2007-11-21 | 北卡罗来纳查佩尔山大学 | Novel curcumin analogues and uses thereof |
| CN101003470A (en) * | 2007-01-22 | 2007-07-25 | 温州医学院生物与天然药物开发中心有限公司 | Analog of mono carbonyl structure of curcumin, and usage |
| CN101255119A (en) * | 2008-01-07 | 2008-09-03 | 沈阳药科大学 | Novel tetrahydro curcumin derivatives and salt |
| CN101434524A (en) * | 2008-06-05 | 2009-05-20 | 福建医科大学 | 4-(4-hydroxy-3-methoxybenzene methylene) curcumin, preparation thereof and use in preparing anti-cancer medicament |
| CN101524546A (en) * | 2008-11-07 | 2009-09-09 | 浙江中医药大学 | Conjugate conjugated from polyethylene glycol and curcumin derivative |
Non-Patent Citations (4)
| Title |
|---|
| 姜黄素的构效关系及以其为先导物的抗肿瘤化合物研究进展;梁广 等;《化学通报》;20081231(第2期);110-117 * |
| 姜黄素衍生物生物活性的研究进展;张磊等;《沈阳药科大学学报》;20081231;第25卷(第4期);第331-336页 * |
| 张磊等.姜黄素衍生物生物活性的研究进展.《沈阳药科大学学报》.2008,第25卷(第4期),第331-336页. |
| 梁广 等.姜黄素的构效关系及以其为先导物的抗肿瘤化合物研究进展.《化学通报》.2008,(第2期),110-117. |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011147254A1 (en) | 2011-12-01 |
| CN101830819A (en) | 2010-09-15 |
| GB201223251D0 (en) | 2013-02-06 |
| GB2494595B (en) | 2018-03-21 |
| GB2494595A (en) | 2013-03-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101311187B (en) | Tripterine derivate, preparation method and use thereof | |
| CN109021026A (en) | Cisplatin medicine precursor, preparation method and application | |
| CN104961786B (en) | Pro-drug based on gemcitabine structure and its application | |
| CN110938032A (en) | Organic selenium compound and use thereof | |
| CN101830819B (en) | Phenylbutyryl curcumin derivate and application thereof in anti-tumor drug preparation | |
| CN108836937A (en) | Cisplatin nano pharmaceutical preparation, preparation method and application | |
| CN110092808A (en) | A kind of sterol compound and pharmaceutically acceptable salt or prodrug and its application | |
| CN103040864A (en) | Medical application of selenium phosphate compound | |
| CN106554330A (en) | Water-soluble docetaxel anti-cancer drug compounds and its preparation method and application | |
| KR101135789B1 (en) | Potentiator for radiation therapy comprising pyridine derivative as active ingredient | |
| CN103893168A (en) | Application of isopimpinellin in preparation of antitumor drugs and anticancer reversal agents | |
| CN102030765B (en) | Ether-linked porphyrin dimer salt and preparation method thereof | |
| CN101402667A (en) | Glycosylation modified nitric oxide donor type oleaolic acid compounds, preparation and uses thereof | |
| CN110938033A (en) | Selenocyanine compounds and uses thereof | |
| CN106631957A (en) | Antitumor compound targeting FAP-alpha enzyme and preparation method and application thereof | |
| CN110882251A (en) | Synthesis method and anti-tumor application of 10-HCPT and Crizotinib coupled compound | |
| CN104225611B (en) | The conjugate of Dasatinib and non-linear configurations polyethylene glycol | |
| CN106854223B (en) | Mustargen quercetin derivative and its preparation method and application | |
| CN104744518B (en) | Ruthenium complex and its preparation method and application | |
| CN102617679B (en) | Preparation method and application of connected conjugated linoleic acid and gemcitabine prodrug | |
| CN104262455B (en) | Tumor microenvironment targeted activation docetaxel derivatives, preparation thereof and uses of the derivatives | |
| CN111773388B (en) | Combined application of A-nor-5 alpha androstane compound medicine and anticancer medicine | |
| CN112794853B (en) | Organic selenium compound and preparation method and application thereof | |
| CN112794852B (en) | Selenium-containing organic compound and preparation method and application thereof | |
| CN109369727A (en) | A kind of anti cancer target complex and its preparation method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130828 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |