CN104788457A - Novel anti-parasite pyrazine isoquinoline derivative - Google Patents
Novel anti-parasite pyrazine isoquinoline derivative Download PDFInfo
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- CN104788457A CN104788457A CN201510117838.3A CN201510117838A CN104788457A CN 104788457 A CN104788457 A CN 104788457A CN 201510117838 A CN201510117838 A CN 201510117838A CN 104788457 A CN104788457 A CN 104788457A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Organic Chemistry (AREA)
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Abstract
A novel anti-parasite pyrazine isoquinoline derivative is provided. The invention relates to the compound represented by the structural general formula I, wherein A is selected from a phenyl ring, B is selected from saturated nitrogen heterocyclic rings including five-membered, six-membered and seven-membered saturated nitrogen heterocyclic rings; C is selected from saturated nitrogen heterocyclic rings including five-membered, six-membered and seven-membered saturated nitrogen heterocyclic rings, and can be ketone or non-ketone compounds; and D is selected from saturated rings including three-membered, four-membered, five-membered, six-membered and seven-membered saturated rings. In addition, the invention relates to an application, a pharmaceutical composition and a drug of the compound.
Description
Technical field
The present invention relates to a kind of novel pyrazine isoquinoline derivative for the treatment of parasitic disease, particularly a kind ofly treat the drug regimen comprising a kind of pyrazine isoquinoline derivative component and the medicine that parasitic disease includes but not limited to the infecting both domestic animals and human disease that schistosomicide, tapeworm, cysticercus, clonorchis sinensis, lung fluke and fasciloopsis cause.
Background technology
Schistosomicide is owing to infecting three kinds of main schistosomicide (Schistosoma mansoni, Schistosoma haematobium and Schistosoma japonicum) and the prevailing disease caused.Over 40 years, praziquantel remains the unique active drug being widely used in the various imago of blood fluke of control humans and animals and infecting.Due to a large amount of of it and life-time service, produce drug resistance at present; And still treat without active drug so far for the schistosomicide that schistosomicide larva infects.Disclosing the whole world according to the World Health Organization has 200,000,000 people to infect schistosomicide, and the infected threat of 600,000,000 people of having an appointment, the high number of the infected of schistosomicide has 2,000 ten thousand, has at least 280000 people to die from schistosomicide every year.And " comprehensive national administers schistosomicide ' 15 ' plan " data that the Ministry of Health and National Development and Reform Committee issue show, 108 county's integrated distribution of China's not yet control schistosomiasis propagation are at present at marshland endemic area and Mountainous region, animal host is numerous, snail distribution is extensive, very large by such environmental effects, preventing and controlling are difficult especially, and superinfection is still very serious, and epidemic situation is in very unsteady state.In the face of so numerous schistosomiasis infection crowd only a kind of chemicals of praziquantel be very disproportionate, therefore need the antischistosomal drug that development is new badly.
Summary of the invention
A compound for general formula I, is applicable to the various salt of humans and animals on it is medicinal, and various isomer and oxynitrides.General structure such as formula I,
Wherein,
A is unsaturated ring, comprises phenyl ring, pyridine ring and nitrogen oxygen dipole pyridine ring;
B is saturated nitrogen heterocyclic, comprises five yuan, hexa-atomic, and seven yuan of saturated nitrogen heterocyclics, and B ring can be replaced by C1-C4 alkyl, or forms the saturated and ring of 3-5 unit;
C is saturated nitrogen heterocyclic, comprises five yuan, hexa-atomic, and seven yuan of saturated nitrogen heterocyclics, can be ketone or non-ketone compound;
D is saturated rings, comprises ternary, quaternary, five yuan, hexa-atomic, and seven yuan of saturated rings;
A is selected from following group:
B+C is selected from following group:
D is selected from following group:
The wherein preferred but compound be not limited to is:
The compounds of this invention show unexpectedly be suitable for treat parasitic disease, especially schistosomicide is comprised, tapeworm, cysticercus, clonorchis sinensis, lung fluke, the infecting both domestic animals and human disease that fasciloopsis causes. the present invention also relates to the compound of general formula I defined above, the acid that it is pharmaceutically accepted or base addition salt, comprise quaternary salt, stereochemistry heterogeneous forms, N-oxygen compound form is used as medicine, and following any pharmaceutical composition for the preparation for the treatment of parasitic disease, comprise schistosomicide, tapeworm, cysticercus, clonorchis sinensis, lung fluke, purposes in the medicine of the infecting both domestic animals and human disease that fasciloopsis causes.
Therefore, the present invention provides a kind for the treatment of to suffer from the method for parasitic disease (comprising schistosomicide disease) on the other hand, and the method comprises the compounds of this invention for the treatment of significant quantity or pharmaceutical composition gives patient or trouble stores.
The present invention also relates to composition, it comprises the compounds of this invention of pharmaceutically acceptable carrier and the treatment significant quantity as activeconstituents.The compounds of this invention can be deployed into the different pharmaceutical form for administration object.As appropriately combined thing illustration be usual the adopted all compositions of Formulations for systemic administration medicine.For preparation pharmaceutical composition of the present invention, the specific compound (optionally using addition salt form) of significant quantity closely combines as activeconstituents and drug acceptable carrier, and depend on the dosage form needed for administration, described carrier can take various ways.These pharmaceutical compositions are preferably the single dose form being particularly applicable to oral administration or parental injection.Such as, when preparing the composition of oral dosage form, at oral liquid as suspensoid, syrup, when emulsion and solution, can adopt any usual drug media, as water, and ethylene glycol, oil, alcohol etc.; Or at powder agent, pill, when capsule and tablet, adopts solid carrier such as starch, sugar, kaolin, thinner, tackiness agent etc.
Depend on the mode of administration, described drug regimen preferably includes 0.05-99% weight, more preferably the activeconstituents of 0.1-70% weight, and preferred 1-99.95% weight, more preferably the pharmaceutically acceptable carrier of 30-99.9% weight, all per-cent all calculates based on total composition.
Embodiment
The preparation of embodiment one typical compound 1-3:
1-1 (188mg, 1mmol) is added, heptanaphthenic acid (128mg, 1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1mmol) in the round-bottomed flask that magnetic agitation is housed.Room temperature for overnight, with 1% hydrochloric acid water and saturated sodium carbonate solution alternately washing, finally washes with water.White solid .Mp132-135 (277mg, yield 93%) is concentrated to obtain after anhydrous magnesium sulfate drying.
1-1 (188mg, 1mmol) is added, cyclopentanecarboxylic acid (114mg, 1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1mmol) in the round-bottomed flask that magnetic agitation is housed.Room temperature for overnight, with 1% hydrochloric acid water and saturated sodium carbonate solution alternately washing, finally washes with water.White solid Mp128-130 (256mg, yield 90.14%) is concentrated to obtain after anhydrous magnesium sulfate drying.
1-1 (188mg, 1mmol) is added, ring formic acid in heptan (142mg, 1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1mmol) in the round-bottomed flask that magnetic agitation is housed.Room temperature for overnight, with 1% hydrochloric acid water and saturated sodium carbonate solution alternately washing, finally washes with water.White solid .Mp137-139 (287mg, yield 92%) is concentrated to obtain after anhydrous magnesium sulfate drying.
The preparation of embodiment two typical compound 10-12:
10-1 (232mg, 1mmol) is added, heptanaphthenic acid (128mg, 1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1mmol) in the round-bottomed flask that magnetic agitation is housed.Room temperature for overnight, with 1% hydrochloric acid water and saturated sodium carbonate solution alternately washing, finally washes with water.White solid .Mp143-146 (324mg, yield 95%) is concentrated to obtain after anhydrous magnesium sulfate drying.
10-1 (232mg, 1mmol) is added, ring formic acid in heptan (142mg, 1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1mmol) in the round-bottomed flask that magnetic agitation is housed.Room temperature for overnight, with 1% hydrochloric acid water and saturated sodium carbonate solution alternately washing, finally washes with water.White solid .Mp138--141 (295mg, yield 90%) is concentrated to obtain after anhydrous magnesium sulfate drying.
10-1 (232mg, 1mmol) is added, ring formic acid in heptan (142mg, 1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1mmol) in the round-bottomed flask that magnetic agitation is housed.Room temperature for overnight, with 1% hydrochloric acid water and saturated sodium carbonate solution alternately washing, finally washes with water.White solid .Mp149-153 (316mg, yield 89%) is concentrated to obtain after anhydrous magnesium sulfate drying.
Embodiment three biological effect
Measure the in vitro method of compound anti schistosoma: adult vitro culture: gather the male insect of living and be placed in DMEM nutrient solution (10/3ml/ ware), grouping dosing.Every ware adds each 3ul of compound respectively, and final concentration is that 50 (mol/ml, control group adds DMS03 (1 (with reference to other experimental group dosing maximum dose levels).Fully shake up after dosing, put into 37 DEG C, 5%CO: incubator.Overnight incubation (16h) uses brine polypide 3 times afterwards, adds fresh medium, observes the schistosomicide vigor state after cultivating .24h ~ 72h under stereoscopic microscope, and photologging.The results are shown in Table 1.
Table 1
| Compound | Borer population | Mortality levels | Compound | Borer population | Mortality levels |
| 1 | 20 | A | 35 | 20 | A |
| 4 | 20 | A | 37 | 20 | A |
| 7 | 20 | A | 40 | 20 | A |
| 13 | 20 | A | 43 | 20 | A |
| 18 | 20 | A | 46 | 20 | A |
| 19 | 20 | A | 50 | 20 | A |
| 21 | 20 | A | 54 | 20 | A |
| 22 | 20 | A | 57 | 20 | A |
| 24 | 20 | A | 62 | 20 | A |
| 28 | 20 | A | 64 | 20 | A |
| 29 | 20 | A | 66 | 20 | A |
| 30 | 20 | A | 67 | 20 | A |
| 34 | 20 | A | 69 | 20 | A |
Mortality levels in table: A is 100-80%.
Claims (10)
1. a compound, described compound is the compound as general structure I;
Wherein,
A is selected from phenyl ring;
B is selected from saturated nitrogen heterocyclic, comprises five yuan, hexa-atomic and seven yuan of saturated nitrogen heterocyclics;
C is selected from saturated nitrogen heterocyclic, comprises five yuan, hexa-atomic and seven yuan of saturated nitrogen heterocyclics;
D is selected from saturated rings, comprises ternary, quaternary, five yuan, hexa-atomic and seven yuan of saturated rings.
2. compound according to claim 1, is characterized in that, described B ring also comprises C1-C4 alkyl substituent, or the saturated and ring substituents of 3-5 unit.
3. compound according to claim 1 and 2, is characterized in that, B+C is selected from such as formula the one in II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII group,
4. compound according to claim 3, it is characterized in that, described compound is selected from as at least one in the compound of structural formula 4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32 and 33
5. the purposes of the compound according to claim 1-4 any one in the medicine for the preparation of prevention or treatment parasitosis, wherein said parasite is selected from least one in schistosomicide, tapeworm, cysticercus, clonorchis sinensis, lung fluke and fasciloopsis.
6. the pharmacy acceptable salt of the compound as described in claim 1-4 any one.
7. Schistosoma japonicum is had to a pharmaceutical composition for killing action, it is characterized in that, the activeconstituents of described pharmaceutical composition comprises the compound as described in claim 1-4 any one, and preferred described composition also comprises pharmaceutically acceptable carrier.
8. one kind has the pharmaceutical composition of killing action to Schistosoma japonicum, it is characterized in that, the activeconstituents of described pharmaceutical composition comprises the pharmacy acceptable salt of compound as claimed in claim 6, and preferred described composition also comprises pharmaceutically acceptable carrier.
9. Schistosoma japonicum is had to a medicine for killing action, it is characterized in that, the activeconstituents of described medicine comprises the compound as described in claim 1-4 any one, and preferred described medicine also comprises pharmaceutically acceptable carrier.
10. Schistosoma japonicum is had to a medicine for killing action, it is characterized in that, the activeconstituents of described medicine comprises the pharmacy acceptable salt of compound as claimed in claim 6, and preferred described medicine also comprises pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510117838.3A CN104788457B (en) | 2011-05-31 | 2011-05-31 | Novel anti-parasitic pyrazine isoquinoline derivative |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510117838.3A CN104788457B (en) | 2011-05-31 | 2011-05-31 | Novel anti-parasitic pyrazine isoquinoline derivative |
| CN201110154047.XA CN102267998B (en) | 2011-05-31 | 2011-05-31 | Novel anti-parasitic pyrazine isoquinoline derivative |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN201110154047.XA Division CN102267998B (en) | 2011-05-31 | 2011-05-31 | Novel anti-parasitic pyrazine isoquinoline derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104788457A true CN104788457A (en) | 2015-07-22 |
| CN104788457B CN104788457B (en) | 2017-08-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510117838.3A Expired - Fee Related CN104788457B (en) | 2011-05-31 | 2011-05-31 | Novel anti-parasitic pyrazine isoquinoline derivative |
| CN201510117197.1A Expired - Fee Related CN104844606B (en) | 2011-05-31 | 2011-05-31 | Parasiticide pyrazine isoquinoline derivative |
| CN201110154047.XA Expired - Fee Related CN102267998B (en) | 2011-05-31 | 2011-05-31 | Novel anti-parasitic pyrazine isoquinoline derivative |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510117197.1A Expired - Fee Related CN104844606B (en) | 2011-05-31 | 2011-05-31 | Parasiticide pyrazine isoquinoline derivative |
| CN201110154047.XA Expired - Fee Related CN102267998B (en) | 2011-05-31 | 2011-05-31 | Novel anti-parasitic pyrazine isoquinoline derivative |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321088A (en) * | 2011-08-03 | 2012-01-18 | 威海秀水药物研发有限公司 | Novel anti-schistosomiasis compound |
| CN113754666A (en) * | 2021-09-07 | 2021-12-07 | 凯美克(上海)医药科技有限公司 | Benzopyrazine compound and synthesis method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4661489A (en) * | 1983-07-16 | 1987-04-28 | Beecham Group P.L.C. | Benzazepines, and their use as anthelminthics |
| DE3619030A1 (en) * | 1986-06-06 | 1987-12-10 | Bayer Ag | Compositions for topical use |
| CN1683346A (en) * | 2005-03-01 | 2005-10-19 | 江苏工业学院 | Praziquantel synthetic process |
-
2011
- 2011-05-31 CN CN201510117838.3A patent/CN104788457B/en not_active Expired - Fee Related
- 2011-05-31 CN CN201510117197.1A patent/CN104844606B/en not_active Expired - Fee Related
- 2011-05-31 CN CN201110154047.XA patent/CN102267998B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4661489A (en) * | 1983-07-16 | 1987-04-28 | Beecham Group P.L.C. | Benzazepines, and their use as anthelminthics |
| DE3619030A1 (en) * | 1986-06-06 | 1987-12-10 | Bayer Ag | Compositions for topical use |
| CN1683346A (en) * | 2005-03-01 | 2005-10-19 | 江苏工业学院 | Praziquantel synthetic process |
Non-Patent Citations (1)
| Title |
|---|
| 胡玉琴，等: "血吸虫病化学预防药物4H-吡嗪并〔2,1-a〕异喹啉衍生物的合成", 《中国药物化学杂志》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102267998A (en) | 2011-12-07 |
| CN104788457B (en) | 2017-08-25 |
| CN104844606A (en) | 2015-08-19 |
| CN104844606B (en) | 2017-03-01 |
| CN102267998B (en) | 2015-05-13 |
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Granted publication date: 20170825 Termination date: 20180531 |