CN104876899A - Dimethylamino sphaelactone fumarate and use thereof - Google Patents

Dimethylamino sphaelactone fumarate and use thereof Download PDF

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Publication number
CN104876899A
CN104876899A CN201410071673.6A CN201410071673A CN104876899A CN 104876899 A CN104876899 A CN 104876899A CN 201410071673 A CN201410071673 A CN 201410071673A CN 104876899 A CN104876899 A CN 104876899A
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China
Prior art keywords
cancer
carcinoma
formula
compound
fumarate
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Pending
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CN201410071673.6A
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Chinese (zh)
Inventor
邱传将
齐杰
王桂燕
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Accendatech Co Ltd
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Accendatech Co Ltd
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Priority to CN201410071673.6A priority Critical patent/CN104876899A/en
Publication of CN104876899A publication Critical patent/CN104876899A/en
Pending legal-status Critical Current

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a compound represented by formula (I), that is, dimethylamino sphaelactone fumarate, and a use thereof. The compound of formula (I) has the advantages of high stability and low hygroscopicity.

Description

Dimethylamine has a smile on one's face lactone fumarate and uses thereof
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to dimethylamine and have a smile on one's face lactone fumarate and uses thereof.
 
Background technology
Document (J. Med. Chem. 2012,55,8757 8769) in, report formula II compound is used for the treatment of leukemia, but further research find formula II compound exist unstable, draw the moist defect such as seriously, limit its further medicament research and development.
(Ⅱ)
Compound provided by the invention overcome formula II compound exist unstable, draw the moist defect such as seriously, have stability high, draw moist low advantage.
Summary of the invention
The invention provides formula I compound, dimethylamine has a smile on one's face lactone fumarate and uses thereof.
 
(Ⅰ)
Described formula I compound is being used for the treatment of the purposes in cancer.Wherein said cancer comprises acute myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, skin carcinoma, mammary cancer, ovarian cancer, cerebral tumor, prostate cancer, head and neck scale carcinoma, laryngocarcinoma, carcinoma of the pancreas, retinoblastoma cell cancer, children liver parent cell cancer, liver cancer, melanoma, large bowel cancer, adenocarcinoma of colon, glioma, esophagus cancer, nasopharyngeal carcinoma, cerebral glioma, cancer of the stomach, lung cancer, kidney, bladder cancer, thyroid carcinoma.
Embodiment
In order to understand the present invention, further illustrate the present invention with embodiment below, but do not limit the present invention.
embodiment 1 dimethylamine has a smile on one's face the preparation of lactone fumarate
To in the 250mL round-bottomed flask being equipped with mechanical stirring, thermometer, reflux condensing tube, add fumaric acid (1.98g, 17mmol), ethyl acetate (2.5 mL), stir, be heated to 77 DEG C; Dimethylin being had a smile on one's face lactone (5.0g, 17mmol) mixes with ethyl acetate (15 mL), drops in the middle of reaction, vigorous stirring; After dropwising, reaction solution was in 77 DEG C of insulations 3 hours; Stop heating, under whipped state, be naturally down to room temperature, filter, ethyl acetate is washed, and vacuum-drying 24 hours, namely obtains formula (I) compound, white solid 6.3g, yield 90%.
Prepare the data of formula (I) compound:
Molecular formula: C 21h 31nO 7
Molecular weight: 409
Proterties: white solid powder
Elemental analysis data:
Element Calculated value/% Test value/%
C 61.60 61.41
H 7.63 7.37
N 3.42 3.54
Nuclear magnetic resonance data (NMR):
1H NMR (DMSO, 500 MHz)6.58 (s, 2H), 3.80 (t , J = 10.3 Hz, 1H ), 2.64(s, 3H), 2.49-2.53 (m, 3H), 2.26-2.27 (m, 1H), 2.23 (s, 6H), 1.96-2.10 (m, 6H),1.60 (s, 3H), 1.57-1.59 (m, 2H), 1.23-1.25 (m, 1H), 1.15 (s, 3H);
13C NMR(DMSO, 125 MHz)177.8, 167.6(2C), 135.2(2C), 133.7, 131.4, 83.4, 80.31, 58.0, 57.1, 51.7, 45.2(2C), 43.6, 41.0, 35.3, 30.2, 27.0, 24.2, 23.2.
High resolution mass spectrum data (HRMS): [C 17h 27nO 3+ H +]: calculated value, 294.2064; Test value, 294.2067.
embodiment 2 dimethylamine have a smile on one's face lactone fumarate pharmacological action
Various cancer cells is made into 2 × 10 5/ mL cell suspension, add in 24 orifice plate round bottom Tissue Culture Plates, add test compounds respectively, every test concentrations 5 hole, put 37 degree, 5% carbonic acid gas saturated humidity regulates lower cultivation 18 hours, records absorbancy and refers to, calculate the restraining effect of the compounds of this invention to test cancer cells with mtt assay at enzyme connection detector 570nm wavelength.
  
Table 1 formula I compound is to the restraining effect of various cancer cells
Clone Formula I compound
HL-60 31.5
K562 22.3
MCF-7 19.5
CNE-1 26.3
CNE-2 26.5
SW620 33.4
A549 28.3
HepG-2 17.7
Ec9706 23.2
SGC7901 14.7
SW1116 37.1
A498 24.1
ASPC-1 31.5
HT-29 19.2
HeLa 29.4
GL15 45.2
B16F1 28.3
T24 32.4
SKOV3 25.5
SW579 42.3
PC-3 33.4
HL-60, K562, MCF-7, CNE-1, CNE-2 in table 1, SW620, A549, HepG2, Ec9706, SGC7901, SW1116, A498, ASPC-1, HT-29, HeLa, GL15, B16F1, T24, SKOV3, SW579, PC-3, represent acute myeloid leukemia respectively, chronic myelogenous leukemia, mammary cancer, nasopharyngeal carcinoma, colorectal carcinoma, lung cancer, liver cancer, the esophageal carcinoma, cancer of the stomach, colorectal carcinoma, carcinoma of the pancreas, prostate cancer, colorectal carcinoma, cervical cancer, neuroblastoma, melanoma, bladder cancer, ovarian cancer, thyroid tumor, prostate cancer.
embodiment 3 formula I compound compares with the stability of formula II compound
1. high temperature test
Get formula I compound and formula II compound is put in open container, in the thermostat container of 60 DEG C, place 10 days, in sampling in 0 day, 5 days, 10 days, observe proterties, measure content.
   
Table 2 high temperature test result (60 DEG C)
2. high wet test
Get formula I compound and formula II compound is put in open container, be placed on relative humidity 90 ± 5%(saltpetre saturated solution) encloses container in, place 10 days, in 0 day, 5 days, 10 days sampling, observe proterties, measure content.
Table 3 high humidity test-results (90 ± 5%)
Result shows: no matter under high temperature or super-humid conditions, formula I compound is all more stable than formula II compound.
 
embodiment 4 formula I compound draws moist comparison with formula II compound
Table 4 draws moist comparison
Formula I compound Formula II compound
Draw moist 0.5% 15.6%
Result shows: drawing of formula I compound is moist moist lower than drawing of (II) compound.
Purposes of the present invention and method are described by specific embodiment.Those skilled in the art can use for reference the links such as content appropriate change raw material of the present invention, processing condition and realize other object corresponding, its relevant change does not all depart from content of the present invention, all similar replacements and change will become apparent to those skilled in the art that and be all deemed to be included within scope of the present invention.

Claims (2)

1. dimethyl amine has a smile on one's face the form of fumarate of lactone, formula I compound.
2. (I) is being used for the treatment of the purposes in cancer, and described cancer comprises acute myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, skin carcinoma, mammary cancer, ovarian cancer, cerebral tumor, prostate cancer, head and neck scale carcinoma, laryngocarcinoma, carcinoma of the pancreas, retinoblastoma cell cancer, children liver parent cell cancer, liver cancer, melanoma, large bowel cancer, adenocarcinoma of colon, glioma, esophagus cancer, nasopharyngeal carcinoma, cerebral glioma, cancer of the stomach, lung cancer, kidney, bladder cancer, thyroid carcinoma.
CN201410071673.6A 2014-02-28 2014-02-28 Dimethylamino sphaelactone fumarate and use thereof Pending CN104876899A (en)

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Cited By (12)

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CN105726520A (en) * 2016-02-02 2016-07-06 南开大学 Sphaelactone dimethylamine lipidosome atomizing inhalant and application thereof
WO2017128163A1 (en) * 2016-01-28 2017-08-03 天津国际生物医药联合研究院 Application of dimethylamino micheliolide
CN108484550A (en) * 2018-05-07 2018-09-04 中国人民解放军第四军医大学 One kind having a smile on one's face lactone derivatives and its preparation method and application
CN109276553A (en) * 2017-07-21 2019-01-29 天津尚德药缘科技股份有限公司 Dimethylamine has a smile on one's face lactone fumarate preparation, preparation method and use
CN111303100A (en) * 2018-12-12 2020-06-19 天津尚德药缘科技股份有限公司 Hydrate of michelia lactone dimethylamine fumarate, preparation method and application thereof
CN111303097A (en) * 2018-12-12 2020-06-19 天津尚德药缘科技股份有限公司 Crystal form C of michelia lactone fumarate dimethylamine and preparation method thereof
CN111303099A (en) * 2018-12-12 2020-06-19 天津尚德药缘科技股份有限公司 Sphaelactone dimethylamine fumarate crystal form F and preparation method thereof
CN111803489A (en) * 2020-07-10 2020-10-23 温州医科大学附属第一医院 Application of michelia lactone and derivatives thereof in treatment of pituitary adenoma
CN113149946A (en) * 2021-04-16 2021-07-23 天津大学 Michellac dimethylamine lactone-m-hydroxybenzoate and preparation method and application thereof
CN113200949A (en) * 2021-04-16 2021-08-03 天津大学 Sphaelactone-salicylate dimethylamine and preparation method and application thereof
WO2021189343A1 (en) * 2020-03-26 2021-09-30 天津尚德药缘科技股份有限公司 Hydrate of dimethylaminomicheliolide fumarate and preparation method therefor and use thereof
US11389422B2 (en) 2018-04-13 2022-07-19 The University Of Chicago Combination of micheliolide derivatives or nanoparticles with ionizing radiation and checkpoint inhibitors for cancer therapy

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2016390488B9 (en) * 2016-01-28 2020-09-17 Accendatech Application of dimethylamino micheliolide
WO2017128163A1 (en) * 2016-01-28 2017-08-03 天津国际生物医药联合研究院 Application of dimethylamino micheliolide
JP2019503335A (en) * 2016-01-28 2019-02-07 天津国際生物医薬聯合研究院 Use of Dimethylamino Micheliolide
US10220019B2 (en) 2016-01-28 2019-03-05 Tianjin International Joint Academy Of Biotechnology & Medicine Method for treating pulmonary fibrosis comprising application of dimethylamino micheliolide
AU2016390488B2 (en) * 2016-01-28 2019-12-12 Accendatech Application of dimethylamino micheliolide
CN105726520B (en) * 2016-02-02 2019-04-09 南开大学 Lactone dimethylamine liposome atomized inhalation and its application with a smile
CN105726520A (en) * 2016-02-02 2016-07-06 南开大学 Sphaelactone dimethylamine lipidosome atomizing inhalant and application thereof
CN109276553A (en) * 2017-07-21 2019-01-29 天津尚德药缘科技股份有限公司 Dimethylamine has a smile on one's face lactone fumarate preparation, preparation method and use
CN109276553B (en) * 2017-07-21 2023-01-13 天津尚德药缘科技股份有限公司 Preparation of michelia lactone fumarate of dimethylamine, preparation method and application thereof
US11389422B2 (en) 2018-04-13 2022-07-19 The University Of Chicago Combination of micheliolide derivatives or nanoparticles with ionizing radiation and checkpoint inhibitors for cancer therapy
CN108484550A (en) * 2018-05-07 2018-09-04 中国人民解放军第四军医大学 One kind having a smile on one's face lactone derivatives and its preparation method and application
CN111303099A (en) * 2018-12-12 2020-06-19 天津尚德药缘科技股份有限公司 Sphaelactone dimethylamine fumarate crystal form F and preparation method thereof
CN111303097A (en) * 2018-12-12 2020-06-19 天津尚德药缘科技股份有限公司 Crystal form C of michelia lactone fumarate dimethylamine and preparation method thereof
CN111303097B (en) * 2018-12-12 2022-09-30 天津尚德药缘科技股份有限公司 Crystal form C of michelia lactone fumarate dimethylamine and preparation method thereof
CN111303100B (en) * 2018-12-12 2022-10-04 天津尚德药缘科技股份有限公司 Hydrate of michelia lactone dimethylamine fumarate, preparation method and application thereof
CN111303099B (en) * 2018-12-12 2022-12-02 天津尚德药缘科技股份有限公司 Sphaelactone dimethylamine fumarate crystal form F and preparation method thereof
CN111303100A (en) * 2018-12-12 2020-06-19 天津尚德药缘科技股份有限公司 Hydrate of michelia lactone dimethylamine fumarate, preparation method and application thereof
WO2021189343A1 (en) * 2020-03-26 2021-09-30 天津尚德药缘科技股份有限公司 Hydrate of dimethylaminomicheliolide fumarate and preparation method therefor and use thereof
CN111803489A (en) * 2020-07-10 2020-10-23 温州医科大学附属第一医院 Application of michelia lactone and derivatives thereof in treatment of pituitary adenoma
CN113149946A (en) * 2021-04-16 2021-07-23 天津大学 Michellac dimethylamine lactone-m-hydroxybenzoate and preparation method and application thereof
CN113200949A (en) * 2021-04-16 2021-08-03 天津大学 Sphaelactone-salicylate dimethylamine and preparation method and application thereof
CN113200949B (en) * 2021-04-16 2022-11-29 天津大学 Dimethylamine michelia lactone-salicylate and preparation method and application thereof

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