Preparation and application of six PARP1 inhibitors

A technology of inhibitors and excipients, applied in the field of medicine, can solve the problems of no reports of six compounds, and achieve the effects of good industrial production prospects, strong inhibitory activity, and good application prospects

Active Publication Date: 2018-11-09
INST OF OCEANOLOGY - CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The present invention uses the principle of hybrid design of drug molecules to couple bromophenol and thiosemicarbazide compound anti-tumor active groups to design and synthesize six compounds 1-6. There are no six compounds 1-6 provided by the present invention in the prior art. 6 and its reports as PARP1 inhibitors, and there is no report on the application of such derivatives or their pharmaceutical compositions in the preparation or treatment of drugs for diseases such as tumors or cancers caused by various factors

Method used

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  • Preparation and application of six PARP1 inhibitors
  • Preparation and application of six PARP1 inhibitors
  • Preparation and application of six PARP1 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1: 2,2'-(((butane-1,4-diyldioxy)bis(3-bromo-5-methoxy-4-phenyl))dimethylene)bis(N -methylhydrazine-1-thioamide)(2,2'-((((butane-1,4-diylbis(oxy)) bis(3-bromo-5-methoxy-4, 1-phenylene))bis( methanelylylidene))bis(N-methylhydrazine-1-carbothioamide), compound 1) preparation;

[0041] (1) Weigh 5-bromovanillin (13.9g, 60mmol) and potassium carbonate (2.8g, 20mmol) into a 1L flask, add 20mL of DMF to dissolve, stir for 10min, add 1,4-dibromobutane dropwise while stirring (2mL, 20mmol), heated and condensed at 80°C for reflux for 10h, added 500mL of water, a white flocculent precipitate precipitated, filtered the precipitate, washed the precipitate with saturated sodium bicarbonate, washed the precipitate with a small amount of ethyl acetate, and dried to obtain intermediate compound II .

[0042] (2) Weigh 0.2mmol of intermediate compound II (100mg) and 0.44mmol of 4-methylthiosemicarbazide (46.3mg) into a 100mL reaction flask, add 10mL of 95% ethanol, stir for 10...

Embodiment 2

[0043] Example 2: 2,2'-(((propane-1,3-diyldioxy)bis(3-bromo-5-methoxy-4-phenyl))dimethylene)bis(N- (3-morpholino)hydrazine-1-thioamide)(2,2'-(((propane-1,3-diylbis(oxy))bis (3-bromo-5-methoxy-4,1-phenylene ))bis(methanelylylidene))bis(N-(3-morpholinopropyl)hydrazine-1-carbothioamide),compound 2)

[0044] The preparation method of compound 2 is similar to the preparation method of compound 1, and its difference from example 1 is that the raw material 1,4-dibromobutane is replaced by 1,3-dibromopropane to prepare intermediate compound I, and then By replacing 4-methylaminothio with 4-[3-(4-morpholine)propyl]-3-thiosemicarbazide, a white solid compound 2 was prepared with a yield of 83.2%. 1H-NMR (500MHz, DMSO- d6 )δ: 11.50(s, 2H, CH), 8.56(t, J=6Hz, 2H, NH), 7.94(s, 2H, NH), 7.68(s, 2H, ArH), 7.35(d, J=1.5 Hz, 2H, ArH), 4.19 (t, J=6.5Hz, 4H, OCH2), 3.85 (s, 6H, OCH3), 3.59 (dd, 4H, CH2), 3.54 (s, 8H, CH2), 2.31 ( m, 10H, CH2), 2.12 (m, 2H, CH2), 1.74 (m, 4H, CH2); 13C NMR (1...

Embodiment 3

[0045] Example 3: 2,2'-(((butane-1,4-diyldioxy)bis(3-bromo-5-methoxy-4-phenyl))dimethylene)bis(N -(3-morpholino)hydrazine-1-thioamide)(2,2'-(((butane-1,4-diylbis(oxy))bis (3-bromo-5-methoxy-4,1- phenylene))bis(methanelylidene))bis (N-(3-morpholinopropyl)hydrazine-1-carbothioamide),compound 3)

[0046] The preparation method of compound 3 is similar to the preparation method of compound 1, which is prepared in the same way as in Example 1 to obtain intermediate compound II, and then 4-methylaminosulfur is replaced by 4-[3-(4-morpholine) propyl ]-3-thiosemicarbazide, a white solid compound 3 was prepared with a yield of 84.6%. 1H-NMR (500MHz, DMSO-d 6 )δ: 11.49(s, 2H, CH), 8.55(t, J=6Hz, 2H, NH), 7.94(s, 2H, NH), 7.68(s, 2H, ArH), 7.35(s, 2H, ArH ), 4.02(s, 4H, OCH 2 ), 3.86(s, 6H, OCH 3 ), 3.59 (dd, 4H, CH 2 ), 3.54(s, 6H, CH 2 ), 2.31 (m, 10H, CH 2 ), 1.90(s, 4H, CH 2 ), 1.74 (m, 4H, CH 2 ); 13 C NMR (125MHz, DMSO-d 6 )δ: 177.3, 154.0, 146.3, 140.7, 131.8, 122.9, 1...

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Abstract

The invention relates to preparation of six novel PARP1 inhibitors, combinations of the compounds and applications of the compounds in antitumor and / or anticancer medicines. The invention also relatesto a preparation method of the compounds. Chemical structures of the compounds are shown in the description. The invention further relates to medicines containing at least one of the compounds or salts formed by the compounds with physiologically acceptable inorganic acid or organic acid, and if suitable, medicinal excipients and / or diluents or excipients. The invention further relates to administration dosage forms of at least one of the compounds of the structures or salts thereof, and the dosage forms are tablets, capsules, solutions for infusion, suppositories, plasters, powder, suspensions, and the like.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to six PARP1 inhibitors and their pharmacological activities and pharmaceutical applications. The compound and its derivatives can be used to prevent and / or treat diseases such as tumors or cancers caused by various factors. Background technique [0002] Malignant tumors seriously affect people's health and have become the second leading cause of human death, second only to cardiovascular and cerebrovascular diseases. According to the statistics of the World Health Organization, more than 10 million cancer patients are newly diagnosed every year in the world, and the total number of cancer deaths worldwide reaches 7 million people every year. With the aggravation of environmental pollution, the incidence of cancer is increasing year by year, showing a trend of multiple occurrences. The WHO 2014 report predicted that global cancer cases will show a rapid growth trend, from 14 mill...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C337/06C07D295/13A61K31/5375A61K31/175A61P35/00
CPCA61P35/00C07C337/06C07D295/13
Inventor 史大永王立军郭传龙李祥乾江波李晓伟
Owner INST OF OCEANOLOGY - CHINESE ACAD OF SCI
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