CN104892514A - Novel imidazole compound - Google Patents
Novel imidazole compound Download PDFInfo
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- CN104892514A CN104892514A CN201510259338.3A CN201510259338A CN104892514A CN 104892514 A CN104892514 A CN 104892514A CN 201510259338 A CN201510259338 A CN 201510259338A CN 104892514 A CN104892514 A CN 104892514A
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The invention relates to a novel imidazole compound (represented as the formula I) and salt thereof. It is proved by the experiment that the novel imidazole compound and the salt of the compound can inhibit growth of cancer cells and are used for preparation of antineoplastic drugs.
Description
Technical field
The present invention relates to a kind of new compound with inhibition tumor cell growth.
Background technology
Tumour is the serious disease of harm humans health, and the preventing and controlling of tumour are the emphasis in medical research field always.At present, due to problems such as the environmental pollutions that brings in industrial development, the living environment quality of the mankind constantly declines, and causes the sickness rate of tumor disease and lethality rate constantly to rise.Radiotherapy, chemotherapy are the Main Means for the treatment of tumour at present.But chemotherapy, radiotherapy also inhibits Normocellular growth while inhibit cancer cell development, reduce immunity of organisms, cause new complication.The specifics for the treatment of tumor disease can not be satisfactory, and current clinical cytotoxic drug selectivity used is not high, causes perniciously killing and wounding Normocellular, limits its application.Therefore, find new, hurtless measure, acellular toxic action antitumor drug and become the important directions of international field of medicaments.
The present invention relates to a kind of new compound, through external, anti-tumor in vivo experiment proof, there is good activity.
disclosure of the invention
The invention provides a kind of antineoplastic compound, is a kind of new compound and salt thereof, is specially formula (I) compound or its pharmacy acceptable salt:
And above-claimed cpd and basic metal or organic bases react the salt of gained, particular certain cancers.
Series compound synthesized by us can be obtained by reaction scheme below.
Sodium-salt form 5a, 5b, 5c of above-claimed cpd 1a, 1b, 1c are carried out external inhibition test, find that the sodium salt 5c for the restraining effect 1c of melanin tumour b16 is optimum, effect power is followed successively by: 5c > 5b > 5a.
Specific embodiment:
Embodiment 1: the preparation of series compound:
1a, 1b, 1c and sodium salt 5a, 5b, 5c obtain according to following formula:
(1) synthesis of compound 3:
Accurately taking 32.4 grams of sodium methylates joins in 100.0mLDMF, at room temperature stirring reaction 10 minutes, and reaction solution is cooled to 5-10 DEG C, slowly drips 67.0 grams of p-methyl aceto phenone, 30 minutes used times, dropwises rear continuation reaction 30 minutes.76.8 grams of trifluoro-acetates are dissolved in the DMF of 100mL, slowly be added drop-wise in above-mentioned reaction solution, 30 minutes used times, after dropwising, at room temperature continue reaction 1 hour, stopped reaction, in reaction solution, add 300mL frozen water, the hydrochloric acid with 37% regulates pH=3-5, fully stirs 30 minutes, suction filtration, filter cake distilled water wash (200mL × 3), vacuum-drying obtains 101.8 grams of flaxen compounds 3, and productive rate is 87.7%.HNMR(400Hz，DMSO)：7.74-7.72(d，J＝4.4Hz，2H)，7.18-7.16 (d，J＝4.4Hz，2H)，3.71(s，2H)，2.35(s，3H)；MS(m/z)：231.3。
(2) synthesis of compound 4:
The hydrochloric acid accurately taking 89.4 grams of 4-(amino-sulfonyl) phenylhydrazines and 30.0mL37% joins in the DMF of 200.0mL; stirring reaction 30 minutes, to add at 100 g of compound 3,60 DEG C stirring reaction 2 hours in reaction solution; stopped reaction; reaction solution is cooled to room temperature, adds 500mL distilled water in reaction solution, fully stirs 1 hour; suction filtration; filter cake, with distilled water wash (200mL × 3), obtains 149.8 g of compound 4 after vacuum-drying, productive rate is 90.3%.HNMR(400Hz，DMSO)：7.92-7.90(d，J＝4.8Hz，2H)，7.50-7.48(d，J＝4.8Hz，2H)，7.37-7.35(d，J＝4.4Hz，2H)，7.18-7.16(d，J＝4.4Hz，2H)，6.55(s，2H)，2.35(s，3H)；MS(m/z)：382.3。
(3) synthesis of compound 5a, 5b, 5c:
Accurately take 38.1 g of compound 4 and 15.0 grams of triethylamines join in the DCM of 200.0mL, stirring reaction 30 minutes, 11.0 grams of propionyl chlorides are dripped in reaction solution, dropwise in 10 minutes, stirring reaction 2 hours at being warming up to 60 DEG C, stopped reaction, reaction solution is cooled to room temperature, 500mL distilled water is added in reaction solution, abundant stirring 1 hour, stratification, separate organic layer, water layer DCM extraction (100mL × 3), merge organic phase, with distilled water wash (200mL × 3), underpressure distillation removes desolventizing and obtains 35.6 g of compound 5a, productive rate is 81.3%.HNMR(400Hz，DMSO)：8.00(s，1H)，7.92-7.90(d，J＝4.8Hz，2H)，7.50-7.48(d，J＝4.8Hz，2H)，7.37-7.35(d，J＝4.4Hz，2H)，7.18-7.16(d，J＝4.4Hz，2H)，6.55(s，2H)，2.35(s，3H)，2.24-2.20(m，2H)，1.14(t，J＝3.6Hz，3H)；MS(m/z)：438.3。
Repeat above-mentioned reactions steps, obtain 36.4 g of compound 5b, productive rate is 80.3%.HNMR(400Hz，DMSO)：8.00(s，1H)，7.92-7.90(d，J＝4.8Hz，2H)，7.50-7.48(d，J＝4.8Hz，2H)，7.37-7.35(d，J＝4.4Hz，2H)，7.18-7.16(d，J＝4.4Hz，2H)，6.55(s，2H)，2.35(s，3H)，2.19-2.17(m，2H)，1.63-1.61(m，2H)，0.96(t，J＝3.2Hz，3H)；MS(m/z)：453.3。
Repeat above-mentioned reactions steps, obtain 33.8 g of compound 5c, productive rate is 74.9%.HNMR(400Hz，DMSO)：8.00(s，1H)，7.92-7.90(d，J＝4.8Hz，2H)，7.50-7.48(d，J＝4.8Hz，2H)，7.37-7.35(d，J＝4.4Hz，2H)，7.18-7.16(d，J＝4.4Hz，2H)，6.55(s，2H)，2.35(s，3H)，1.19-1.17(m，1H)，0.71-0.68(m，2H)，0.56-0.52(m，2H)；MS(m/z)：451.3。
(4) synthesis of compound 1a, 1b, 1c:
Accurately taking 30.0 g of compound 5a joins in the ethanol of 100.0mL, stirred at ambient temperature 30 minutes.2.9 grams of sodium hydroxide are dissolved in 50.0mL ethanol, be added drop-wise in above-mentioned reaction solution, dropwise in 10 minutes, stirred at ambient temperature reacts 2 hours, stopped reaction, in reaction solution, slowly drip 300mL ether, at this moment have a large amount of Precipitations, fully stir 1 hour, suction filtration, filter cake, with washed with diethylether (50.0mL × 3), obtains 25.3 g of compound 1a after vacuum-drying, productive rate is 80.3%.HNMR(400Hz，DMSO)：7.92-7.90(d，J＝4.8Hz，2H)，7.50-7.48(d，J＝4.8Hz，2H)，7.37-7.35(d，J＝4.4Hz，2H)，7.18-7.16(d，J＝4.4Hz，2H)，6.55(s，2H)，2.35(s，3H)，2.24-2.20(m，2H)，1.14(t，J＝3.6Hz，3H)；MS(m/z)：460.4。
Repeat above-mentioned reactions steps, obtain 24.2 g of compound 1b, productive rate is 77.1%.HNMR(400Hz，DMSO)：7.92-7.90(d，J＝4.8Hz，2H)，7.50-7.48(d，J＝4.8Hz，2H)，7.37-7.35(d，J＝4.4Hz，2H)，7.18-7.16(d，J＝4.4Hz，2H)，6.55(s，2H)，2.35(s，3H)，2.19-2.17(m，2H)，1.63-1.61(m，2H)，0.96(t，J＝3.2Hz，3H)；MS(m/z)：474.3。
Repeat above-mentioned reactions steps, obtain 23.7 g of compound 1c, productive rate is 75.4%.HNMR(400Hz，DMSO)：7.92-7.90(d，J＝4.8Hz，2H)，7.50-7.48(d，J＝4.8Hz，2H)，7.37-7.35(d，J＝4.4Hz，2H)，7.18-7.16(d，J＝4.4Hz，2H)，6.55(s，2H)，2.35(s，3H)，1.19-1.17(m，1H)，0.71-0.68(m，2H)，0.56-0.52(m，2H)；MS(m/z)：472.6。
Embodiment 2:B16 melanoma restraining effect compares:
B16 melanoma to go down to posterity preservation in the oxter subcutaneous vaccination of C57BL/6 mouse.The B16 melanoma tumor-bearing mice of preservation that selection tumor growth is good, nothing is downright bad or go down to posterity in oxter that is liquefaction, de-cervical vertebra puts to death mouse, after 75% alcohol-pickled sterilization, asepticly get tumor tissue, add the injection physiological saline of 5 times of volumes (W/V), grind to form homogenate by tissue homogenizer system, obtain tumor cell suspension with 200 order stainless steel sift net filtrations of sterilizing.The same to be inoculated in C57BL/6 mouse armpit subcutaneous, conventionally raises.
Grouping and administration: tumor-bearing mice 50,5 groups are divided at random by body weight, often organize 10, be respectively model group, endoxan group, 5a, 5b, 5c group, dosage is 60mg/kg (5a, 5b, 5c are respectively the sodium salt of 1a, 1b, 1c), adopts normal saline to become 3mg/ml solution.Each group of mouse presses dosage shown in table 3 and mode administration, and endoxan group only gives an endoxan in abdominal cavity in lotus knurl second day, each group of experimental group tail intravenously administrable equal every day 1 time, continuous 10 days.Administration volume 20ml/kg body weight.After last administration 24 hours, de-cervical vertebra put to death mouse, weighs, strips tumor tissue and weigh, and calculates tumour inhibiting rate.
Result with
represent, between organizing with t inspection, significant difference compares.
Result shows, three experimental group continuous intravenous injections 10 days, all inhibited to the melanomatous growth of mice transplanted tumor B16, and compound 5c group optimum, is followed successively by 5c > 5b > 5a.
Table 2ZONK002 is to the restraining effect of mouse B16 Melanoma Growth
Compare with model group:
*, P < 0.05;
*, P < 0.01.
Claims (4)
1. such as formula the compound of structure (I) Suo Shi:
。
2. compound according to claim 1, the salt be obtained by reacting with basic metal, organic bases.
3. be sodium salt according to the salt of compound described in claim 2.
4. the purposes of compound described in claim 1,2,3 in preparation tumor.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510259338.3A CN104892514A (en) | 2015-05-19 | 2015-05-19 | Novel imidazole compound |
| PCT/CN2016/000143 WO2016184122A1 (en) | 2015-05-19 | 2016-03-18 | Pyrazoles compounds |
| CN201610163381.4A CN105646354B (en) | 2015-05-19 | 2016-03-19 | A kind of glyoxaline compound |
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| CN201510259338.3A CN104892514A (en) | 2015-05-19 | 2015-05-19 | Novel imidazole compound |
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| CN104892514A true CN104892514A (en) | 2015-09-09 |
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| CN201510259338.3A Pending CN104892514A (en) | 2015-05-19 | 2015-05-19 | Novel imidazole compound |
| CN201610163381.4A Expired - Fee Related CN105646354B (en) | 2015-05-19 | 2016-03-19 | A kind of glyoxaline compound |
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| WO (1) | WO2016184122A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2016184122A1 (en) * | 2015-05-19 | 2016-11-24 | 广州诺威生物技术有限公司 | Pyrazoles compounds |
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| CN106279353A (en) * | 2016-03-18 | 2017-01-04 | 广州诺威生物技术有限公司 | A kind of compound for antiinflammatory |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1259504A1 (en) * | 2000-03-03 | 2002-11-27 | Pfizer Products Inc. | Pyrazole ether derivatives as anti-inflammatory/analgesic agents |
| US20030105144A1 (en) * | 2001-04-17 | 2003-06-05 | Ping Gao | Stabilized oral pharmaceutical composition |
| EP1562914A1 (en) * | 2002-10-22 | 2005-08-17 | Merck Frosst Canada & Co. | Nitric oxide releasing selective cyclooxygenase-2 inhibitors |
| US20040092566A1 (en) * | 2002-11-12 | 2004-05-13 | Graneto Matthew J. | Celecoxib prodrug |
| ES2691671T3 (en) * | 2010-06-24 | 2018-11-28 | Alkermes Pharma Ireland Limited | Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives |
| CN104892514A (en) * | 2015-05-19 | 2015-09-09 | 广州诺威生物技术有限公司 | Novel imidazole compound |
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| WO2016184122A1 (en) * | 2015-05-19 | 2016-11-24 | 广州诺威生物技术有限公司 | Pyrazoles compounds |
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| WO2016184122A1 (en) | 2016-11-24 |
| CN105646354B (en) | 2018-04-10 |
| CN105646354A (en) | 2016-06-08 |
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Application publication date: 20150909 |