CN104788457B - Novel anti-parasitic pyrazine isoquinoline derivative - Google Patents
Novel anti-parasitic pyrazine isoquinoline derivative Download PDFInfo
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- CN104788457B CN104788457B CN201510117838.3A CN201510117838A CN104788457B CN 104788457 B CN104788457 B CN 104788457B CN 201510117838 A CN201510117838 A CN 201510117838A CN 104788457 B CN104788457 B CN 104788457B
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of compound such as general structure I, wherein, A is selected from phenyl ring；B is selected from saturation azacyclo-, including five yuan, hexa-atomic, seven yuan of saturation azacyclo-s；C is selected from saturation azacyclo-, including five yuan, hexa-atomic, seven yuan of saturation azacyclo-s, can be ketone or non-assimilation compound；D is selected from saturated rings, including ternary, quaternary, five yuan, hexa-atomic and seven yuan of saturated rings.And it is related to application, pharmaceutical composition and the medicine of compound as described above.
Description
Technical field
The present invention relates to a kind of new pyrazine isoquinoline derivative for treating parasitic disease, more particularly to a kind for the treatment of is posted
Infested disease includes but is not limited to blood fluke, tapeworm, cysticercus, clonorchis sinensis, lung fluke and infecting both domestic animals and human caused by fasciolopsis
Property disease include a kind of drug regimen and medicine of pyrazine isoquinoline derivative component.
Background technology
Snail fever is due to three kinds of main blood flukes (Schistosoma mansoni, Schistosoma haematobium and Schistosoma japonicum) of infection
Caused by epidemic disease.Over 40 years, praziquantel is still widely used in the various imago of blood fluke infection of preventing and treating humans and animals only
One active drug.Due to a large amount of of it and long-term use, drug resistance has been produced at present；And infected for blood fluke larva
Snail fever is still treated without active drug so far.Disclosing the whole world according to the World Health Organization has 200,000,000 people to infect snail fever, there is about 6
Hundred million people are infected to be threatened, and the high number of the infected of snail fever has 2,000 ten thousand, has at least 280000 people to die from snail fever every year.And
" comprehensive national administer snail fever ' 15 ' plan " as shown by data that the Ministry of Public Health and National Development and Reform Committee issue, China is at present not yet
108 county's integrated distributions that control schistosomiasis is propagated are in marshland endemic area and Mountainous region, and animal reservoir is numerous, and oncomelania distribution is wide
General, very big by such environmental effects, preventing and controlling are especially difficult, and superinfection is still extremely serious, and epidemic situation is in very unstable
State.It is very disproportionate in face of a kind of so numerous chemicalses of schistosomiasis infection crowd only praziquantel, therefore needs badly
Develop new antischistosomal drug.
The content of the invention
A kind of compounds of formula I, its medicinal upper various salt suitable for humans and animals, and its various isomers and nitrogen oxygen
Compound.General structure such as Formulas I,
Wherein,
A is unsaturation ring, including phenyl ring, pyridine ring and nitrogen oxygen dipole pyridine ring；
B is saturation azacyclo-, including five yuan, hexa-atomic, and seven yuan of saturation azacyclo-s, can be taken on B rings by C1-C4 alkyl
Generation, or form 3-5 members saturation and ring；
C is saturation azacyclo-, including five yuan, it is hexa-atomic, and seven yuan of saturation azacyclo-s, can be ketone or non-assimilation compound；
D is saturated rings, including ternary, and quaternary is 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：
Compound that is wherein preferred but being not limited to is：
The compounds of this invention is unexpectedly shown suitable for treatment parasitic disease, especially including blood fluke, tapeworm, capsule
The present invention also relates to by formula I defined above by worm, clonorchis sinensis, lung fluke, infecting both domestic animals and human disease caused by fasciolopsis
Compound, the acid or base addition salts that it is pharmaceutically received, including quaternary salt, stereochemistry heterogeneous forms, N- oxygen compound shapes
Formula is used as medicine, and following any pharmaceutical compositions are used to treating parasitic disease preparing, including blood fluke, tapeworm, cysticercus,
Purposes in clonorchis sinensis, lung fluke, the medicine of infecting both domestic animals and human disease caused by fasciolopsis.
Therefore, another aspect of the present invention provides a kind of method of the treatment with parasitic disease (including blood fluke disease),
The compounds of this invention or pharmaceutical composition that this method includes therapeutically effective amount give patient or suffer from storage.
The present invention also relates to composition, it includes pharmaceutically acceptable carrier and the therapeutically effective amount as active component
The compounds of this invention.The compounds of this invention can be deployed into the different pharmaceutical form for purpose to be administered.As appropriately combined
The illustration of thing is all compositions that Formulations for systemic administration medicine is generally used.To prepare pharmaceutical composition of the present invention, effective dose
Specific compound (optionally using addition salt form) closely combined as active component with drug acceptable carrier, depending on administration
Required dosage form, the carrier can take many forms.These pharmaceutical compositions be preferably particularly it is suitable oral administration or
The ingle dose form of parental injection.For example, when preparing the composition of peroral dosage form, in oral liquid as being suspended
In the case of agent, syrup, emulsion and solution, any usual drug media, such as water, ethylene glycol, oil, alcohol can be used
Deng；Or in powder agent, pill, in the case of capsule and tablet, using solid carrier such as starch, sugar, kaolin, dilution
Agent, adhesive etc..
Depending on the mode of administration, the drug regimen preferably includes 0.05-99% weight, more preferably 0.1-70% weight
Active component, and preferably 1-99.95% weight, the more preferably pharmaceutically acceptable carrier of 30-99.9% weight owns
Percentage is based on total composition calculating.
Embodiment
The typical compound 1-3 of embodiment one preparation：
The addition 1-1 (188mg, 1mmol) into the round-bottomed flask equipped with magnetic agitation, cyclohexanecarboxylic acid (128mg, 1mmol),
EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1mmol).It is stirred overnight at room temperature, with 1% hydrochloric acid water and unsaturated carbonate
Sodium solution is alternately washed, and is finally washed with water.Anhydrous magnesium sulfate is concentrated to give white solid .Mp132-135 (277mg, yield after drying
93%).
The addition 1-1 (188mg, 1mmol) into the round-bottomed flask equipped with magnetic agitation, cyclopentanecarboxylic acid (114mg, 1mmol),
EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1mmol).It is stirred overnight at room temperature, with 1% hydrochloric acid water and unsaturated carbonate
Sodium solution is alternately washed, and is finally washed with water.Anhydrous magnesium sulfate is concentrated to give white solid Mp128-130 (256mg, yield after drying
90.14%).
The addition 1-1 (188mg, 1mmol) into the round-bottomed flask equipped with magnetic agitation, cycloheptyl formic acid (142mg, 1mmol),
EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1mmol).It is stirred overnight at room temperature, with 1% hydrochloric acid water and unsaturated carbonate
Sodium solution is alternately washed, and is finally washed with water.Anhydrous magnesium sulfate is concentrated to give white solid .Mp137-139 (287mg, yield after drying
92%).
The typical compound 10-12 of embodiment two preparation：
The addition 10-1 (232mg, 1mmol) into the round-bottomed flask equipped with magnetic agitation, cyclohexanecarboxylic acid (128mg,
1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1mmol).Be stirred overnight at room temperature, with 1% hydrochloric acid water and
Saturated sodium carbonate solution is alternately washed, and is finally washed with water.Anhydrous magnesium sulfate is concentrated to give white solid .Mp143-146 after drying
(324mg, yield 95%).
The addition 10-1 (232mg, 1mmol) into the round-bottomed flask equipped with magnetic agitation, cycloheptyl formic acid (142mg,
1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1mmol).Be stirred overnight at room temperature, with 1% hydrochloric acid water and
Saturated sodium carbonate solution is alternately washed, and is finally washed with water.Anhydrous magnesium sulfate is concentrated to give white solid .Mp138--141 after drying
(295mg, yield 90%).
The addition 10-1 (232mg, 1mmol) into the round-bottomed flask equipped with magnetic agitation, cycloheptyl formic acid (142mg,
1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1mmol).Be stirred overnight at room temperature, with 1% hydrochloric acid water and
Saturated sodium carbonate solution is alternately washed, and is finally washed with water.Anhydrous magnesium sulfate is concentrated to give white solid .Mp149-153 after drying
(316mg, yield 89%).
The biological effect of embodiment three
Determine the in-vitro method of compound anti schistosoma：Adult in vitro culture：Collection male insect living is placed in
In DMEM nutrient solutions (10/3ml/ wares), dosing is grouped.It is separately added into compound each 3ul per ware, final concentration of 50 (mol/ml,
Control group adds DMS03 (1 (referring to other experimental group dosing maximum dose levels).Fully shaken up after dosing, be put into 37 DEG C, 5%CO：Training
Support in case.Overnight incubation (16h) uses brine polypide 3 times afterwards, adds fresh medium, is observed under stereomicroscope
Cultivate the blood fluke vigor state after .24h~72h, and photologging.It 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 (11)
1. a kind of compound, it is characterised in that the compound be selected from as structural formula 4,5,6,7,8,9,10,11,12,13,14,
15th, at least one of 16,17,18,22,23,24,31,32 and 33 compound,
2. purposes of the compound according to claim 1 in the medicine for preparing prevention or treatment parasitic disease, its
Described in parasite be selected from least one of blood fluke, tapeworm, cysticercus, clonorchis sinensis, lung fluke and fasciolopsis.
3. a kind of pharmaceutically acceptable salt of compound as claimed in claim 1.
4. a kind of pharmaceutical composition for having killing action to Schistosoma japonicum, it is characterised in that the activity of described pharmaceutical composition
Composition includes compound as claimed in claim 1.
5. pharmaceutical composition according to claim 4, it is characterised in that the composition is also comprising pharmaceutically acceptable
Carrier.
6. a kind of pharmaceutical composition for having killing action to Schistosoma japonicum, it is characterised in that the activity of described pharmaceutical composition
Composition includes the pharmaceutically acceptable salt of compound as claimed in claim 3.
7. pharmaceutical composition according to claim 6, it is characterised in that the composition is also comprising pharmaceutically acceptable
Carrier.
8. a kind of medicine for having killing action to Schistosoma japonicum, it is characterised in that the active component of the medicine is included as weighed
Profit requires the compound described in 1.
9. medicine according to claim 8, it is characterised in that the medicine also includes pharmaceutically acceptable carrier.
10. a kind of medicine for having killing action to Schistosoma japonicum, it is characterised in that the active component of the medicine is included as weighed
Profit requires the pharmaceutically acceptable salt of the compound described in 3.
11. medicine according to claim 10, it is characterised in that the medicine also includes 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 |
|---|---|---|---|
| CN201110154047.XA CN102267998B (en) | 2011-05-31 | 2011-05-31 | Novel anti-parasitic pyrazine isoquinoline derivative |
| CN201510117838.3A CN104788457B (en) | 2011-05-31 | 2011-05-31 | Novel anti-parasitic pyrazine isoquinoline derivative |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110154047.XA Division CN102267998B (en) | 2011-05-31 | 2011-05-31 | Novel anti-parasitic pyrazine isoquinoline derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104788457A CN104788457A (en) | 2015-07-22 |
| CN104788457B true CN104788457B (en) | 2017-08-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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 |
| CN201510117838.3A Expired - Fee Related CN104788457B (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 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0134984B1 (en) * | 1983-07-16 | 1988-07-13 | Beecham Group Plc | Benzazepine and benzoxazepine derivatives |
| DE3619030A1 (en) * | 1986-06-06 | 1987-12-10 | Bayer Ag | Compositions for topical use |
| CN100503582C (en) * | 2005-03-01 | 2009-06-24 | 江苏工业学院 | Praziquantel synthetic process |
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2011
- 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
- 2011-05-31 CN CN201510117838.3A patent/CN104788457B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN102267998A (en) | 2011-12-07 |
| CN104844606A (en) | 2015-08-19 |
| CN102267998B (en) | 2015-05-13 |
| CN104788457A (en) | 2015-07-22 |
| CN104844606B (en) | 2017-03-01 |
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