CN105037354A - Application of pyrazine isoquinoline derivatives in preparing drugs for treating schistosomes - Google Patents
Application of pyrazine isoquinoline derivatives in preparing drugs for treating schistosomes Download PDFInfo
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- CN105037354A CN105037354A CN201510296027.4A CN201510296027A CN105037354A CN 105037354 A CN105037354 A CN 105037354A CN 201510296027 A CN201510296027 A CN 201510296027A CN 105037354 A CN105037354 A CN 105037354A
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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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- 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
Abstract
The invention relates to pyrazine isoquinoline derivatives (including stereochemical isomers) disclosed as general formula I and application of the compounds in preparing drugs for treating schistosomes. The structural general formula I is disclosed in the specification, wherein R is cyclobutyl, cyclopentyl, cycloheptyl or cyclooctyl.
Description
Technical field
The present invention relates to a kind of pyrazine isoquinoline derivative at preparation treatment imago of blood fluke, and the infecting both domestic animals and human disease that larva causes.
Background technology
Schistosomicide is that this disease is by one of the most unheeded serious infectious diseases of World Health Organization's called after owing to infecting three kinds of main schistosomicide (Schistosoma mansoni, Schistosoma haematobium, 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 for schistosomicide larva infect schistosomicide so far still without active drug, that is, a wheat harvesting period must be waited for after patient infection schistosomicide, grow in vivo after adult can treat until larva, no matter psychologically period patient, or cannot imagine by the injury that health causes.In addition, because praziquantel cannot kill larva, the frequent repeatability outbreak of the state of an illness, therefore, must repeated multiple times continuous use.
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 280,000 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.
Because schistosomicide behavior is very strange, parasitizing human body has history of more than one thousand years, evolves very close with human body, therefore, can cause very large difficulty in new drug development, is often difficult to select high-efficiency low-toxicity medicine.
The object of this invention is to provide the application of a kind of pyrazine isoquinoline derivative in preparation treatment schistosomicide medicine, this compounds has kills adult and larva, with praziquantel without crossed resistance.Therefore, described compound can be used for treating schistosomicide, is specially adapted to schistosomicide larva and infects, and to having the Schistosomiasis patients of drug resistance.
Summary of the invention
The present invention relates to a kind of pyrazine isoquinoline compound of general formula I, comprise form of three-dimensional chemical isomer, and the application of described compound in preparation treatment schistosomicide medicine.
The present invention's first embodiment merited attention relates to the compound of general structure I,
Wherein,
R is tetramethylene base, pentamethylene base, suberane base, and cyclooctane base.
In use, term " compound of Formula I " or " the compounds of this invention " refer to and also comprise its all form of three-dimensional chemical isomer.Specifically, Stereocenter can have R-or S-configuration.
The present invention's second embodiment merited attention relates to preferred compound in general structure I:
The present invention's the 3rd embodiment merited attention relates to the compound of general structure I, and this compounds is used for killing imago of blood fluke and larva in human body or animal body, and for killing the schistosomicide existing medicine in human body or animal body to resistance.
The present invention's the 4th embodiment merited attention relates to the compound of general structure I, and its compound is used as medicine.
The present invention's the 5th embodiment merited attention relates to the compound of general structure I, this compound and existing antischistosomal drug praziquantel drug combination.
The present invention's the 6th embodiment merited attention relates to a kind of pharmaceutical composition, described composition comprises pharmaceutically acceptable carrier, and the compound of general structure I as the treatment significant quantity of activeconstituents, or with existing antischistosomal drug praziquantel drug combination.
The present invention's the 7th embodiment merited attention relates to above-mentioned combination medicine, or pharmaceutical composition is treating imago of blood fluke, the purposes during larva infects.
The present invention's the 8th embodiment merited attention relates to a kind of product, and described product comprises any one compound in the compound of general structure I, or with existing antischistosomal drug praziquantel drug combination, this product is with the form medication of preparation or former medicine.
The present invention's the 8th embodiment merited attention relates to a kind of preparation and preparation thereof, described preparation comprises any one compound in general structure I and drug regimen, and these pharmaceutical compositions are particularly applicable to oral administration, and said preparation comprises tablet, Orally taken emulsion, syrup, or Parenteral administration forms, comprise injection, long-acting sustained-release injection, liniment, implant, and suppository.
Pharmacology
1, mechanism of action:
The compounds of this invention shows unexpectedly and is suitable for treating schistosomicide, comprises the infecting both domestic animals and human disease that adult and larva cause, and for killing the schistosomicide existing medicine in human body or animal body to resistance.The present invention also relates to the compound of general formula I defined above, the raceme it pharmaceutically accepted, stereochemistry heterogeneous forms is used as medicine, and the purposes of following any pharmaceutical composition in the medicine for the preparation for the treatment of schistosomicide disease.
Therefore, the present invention provides a kind for the treatment of to suffer from the method for schistosomicide disease on the other hand, and the method comprises the compounds of this invention or pharmaceutical composition gives patient or suffers from the significant quantity of poultry treatment.
The compounds of this invention display schistosomicide adult, with the activity of larva, the mechanism of action of this compounds is not yet studied clear, may be relevant with the bilharzial calcium channel of such compound effects, namely cause rapidly polypide movable excited, polypide muscle contracture and cortex extensively impaired, thus cause the liver of worm to move, affect the body surface dietetic alimentation of worm, the metabolism disorder of excretion and defense function and secondary, and the infringement of cortex and peeling off, destroy the concomitant immunity mechanism that worm is able to survive in host, the immune attack appeared for host's schistosomicide specific antibody of its body surface antigenic determinant provides target site.Test shows:
1. polypide muscle generation tetanic contraction and paralysis; After schistosomicide Low Level Exposure praziquantel only 20 second polypide tension force namely increase, when concentration reaches 1 more than μ g/ml, polypide wink and strong contracture; In host, namely polypide liver occurred in after patient's oral pharmaceutical several minutes and move, metabolic conversion does not occur at worm drug disposition, therefore have insecticidal action, polypide Muscle contraction may increase polypide membrane passage with medicine, causes intracellular calcium and loses relevant.
2. the participation of Tegumental Damage and human body immune mechanism: medicine has rapidly and significantly damaging action to polypide cortex, cause the swelling of synplasm crust, occur that cavity becomes, form bleb, outstanding body surface, the rotten to the corn diabrosis of final epidermis, almost all disappearance, circular muscle and longitudinal muscle also successively dissolve rapidly body secretion.In host, the cavity of latter 15 minutes i.e. visible polypide crusts of taking medicine becomes.After cortex destroys, affect polypide and absorb and excretory function, the more important thing is its body surface antigen-exposed, thus subject to the immune attack of host, a large amount of eosinophilic granulocyte attachment skin damage place also invades, and impels polypide dead.Except above-mentioned primary change, medicine still can cause Secondary cases effect, and make the depolarize of polypide pellicle, cortex alkaline phosphatase activities obviously reduces, and the picked-up causing glucose is suppressed, and endogenous glycogen is exhausted.In addition, medicine still can suppress nucleic acid and the protein synthesis of polypide.Medicine is not ionophore, does not affect atpase activity, not by the impact of calcium channel blocker.High potassium concentration has the flesh shrinkage character of similar medicine, but its mechanism of action is different.
2, pharmacokinetics
Absorbed following oral administration is rapid, and blood medicine peak value arrived in 1 ~ 2 hour, and medicine is very fast metabolism (first-pass effect) after entering liver, and main formation hydroxy metabolite thing, the former medicine of the only non-metabolism of minute quantity enters human circulation.Portal vein blood level can comparatively PeV Plasma Concentration be high more than 10 times.Cerebrospinal fluidconcentration is about 15 ~ 20% of Plasma Concentration.Blood medicine peak value after oral 10 ~ 15mg/kg is about 1 μ g/ml.Drug main will be distributed in liver, is secondly kidney, lung, pancreas, suprarenal gland, pituitary gland, sialisterium etc.Seldom pass through placenta; Without organ specificity cumulative appearance.80% and protein binding (experimentation on animals) of serum drug.Medicine T1/2 is 0.8 ~ 1.5 hour, and the T1/2 of its metabolite is 4 ~ 5 hours.Discharge (original shape medicine is trace only) with metabolite form primarily of kidney, discharge in 72% in 24 hours, discharge in 80% in 4 days, 15% sees bile, and 10% is secreted by intestinal mucosa.After lactation patient consumes, its milk drug concentration is equivalent to 25% in serum.
3, pharmaceutics:
The present invention also relates to composition, comprise pharmaceutically acceptable carrier and the compounds of this invention significant quantity as active treatments.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 of significant quantity closely combines as activeconstituents and drug acceptable carrier, depends on the dosage form needed for administration, and described carrier can take various ways.These pharmaceutical compositions are particularly applicable to the single dose form of oral administration or parental injection.Such as, when preparing the composition of oral dosage form, at oral liquid as suspensoid, syrup, and emulsion and solution when, any usual drug media can be adopted, as water, ethylene glycol, oil, alcohol etc.; Or at pulvis, pill, when capsule and tablet, adopts solid carrier such as starch, sugar, kaolin, thinner, lubricant, tackiness agent, disintegrating agent etc.Due to convenient drug administration, Tablet and Capsula agent represents best oral unit dosage form, adopts solid pharmaceutical carriers in this case.For stomach topical composition, carrier generally includes and at least accounts for most sterilized water, although can comprise other compositions, such as to help to dissolve, or as prepared injection solution, wherein carrier comprises salt brine solution, glucose solution, or the mixture of salt solution and glucose solution.Also the Solid form preparations being designed to be converted into liquid form preparation before use is soon comprised.
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.
Described pharmaceutical composition also comprises other components well known in the art, such as, lubricant, stablizer, buffer reagent, emulsifying agent, viscosity modifier, tensio-active agent, sanitas, correctives, or tinting material etc.
For the ease of the homogeneity of administration and dosage, particularly preferably said medicine formulated in combination is become unit dosage.Refer to for unit dosage herein the physical discrete unit being suitable as single dose, constituent parts comprises the predetermined amount activeconstituents of required response to treatment, that is, draw by calculating required pharmaceutical carrier combined amount.The example of such unit dosage is tablet (comprising scored tablet and coating tablet) capsule, pill, powder packets, wafer.Suppository, injection solution or suspension, and syrup etc.And the multiple doses form separated.
In order to improve the dissolution rate of described compound, preparation technique is particularly preferably adopted to mainly contain inclusion technique and solid dispersal skill.
By changing route of administration, adopting non-oral administration mode, effectively can avoid first pass effect, improve drug effect.The non-oral administration preparation improving described compound curative effect mainly contains injection, liniment, implant, and suppository.
The per daily dose of compound of the present invention certainly with compound used, administering mode, required treatment and the schistosomicide degree confirmed and change.In general, time in 10-25mg/kg weight range, satisfied result can be obtained.
Embodiment
One, the preparation of compound
Embodiment one
The preparation of compound 1
1-1 (202mg, 1mmol) is added, ring penta formyl chloride (133mg, 1mmol), triethylamine (111mg, 1.1mmol), methylene dichloride (10ml) in the round-bottomed flask that magnetic agitation is housed.After stirred at ambient temperature 5h, poured into by reaction solution in water, aqueous phase dichloromethane extraction 3 times, merges organic phase, washing.Concentrate to obtain white solid (277mg, yield 93%) after anhydrous magnesium sulfate drying, Mp:129-131 DEG C, to light, heat, air-stable, dissolves in methylene dichloride, ethyl acetate, acetone and other organic solvent.
1H-NMR(300M，CDCl3)δ：1.62-1.88(m，8H，CH(CH
2CH
2)
2)，2.77-2.99(m，2H，CH
2，1H，CH)4.06-4.53(m，2H，N-CH
2-CH)，4.81-4.88(m，2H，N-CH
2-CO)，5.16-5.19(dd，1H，CH)，7.18-7.29(m，4H，Ar-H)
Embodiment two
The preparation of compound 2
1-1 (202mg, 1mmol) is added, ring fourth formyl chloride (119mg, 1mmol), triethylamine (111mg, 1.1mmol), methylene dichloride (10ml) in the round-bottomed flask that magnetic agitation is housed.After stirred at ambient temperature 5h, poured into by reaction solution in water, aqueous phase dichloromethane extraction 3 times, merges organic phase, washing.Concentrate to obtain white solid (256mg, yield 90.1%) after anhydrous magnesium sulfate drying, Mp:153-155 DEG C, to light, heat, air-stable, dissolves in methylene dichloride, ethyl acetate, acetone and other organic solvent.
1H-NMR(300M，CDCl3)δ：2.00-2.38(m，7H，CHCH
2CH
2CH
2)2.76-2.98(m，2H，CH
2，)3.95-4.27(m，2H，N-CH
2-CH)，4.79-4.86(m，2H，N-CH
2-CO)，5.10-5.15(dd，1H，CH)，7.14-7.29(m，4H，Ar-H)
Two, biological effect: the in vitro method measuring compound anti schistosoma
Embodiment three
Adult vitro culture: gather 42 days male insects of living and be placed in DMEM nutrient solution (10/3ml/ ware), grouping dosing.Every ware adds each 3 μ l of compound respectively, and final concentration is that (mol/ml, control group adds DMS03 (1 (with reference to other experimental group dosing maximum dose levels) to 5-50.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.
Embodiment four
Larva vitro culture: gather the 16 days larvas lived 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 (mol/ml, control group adds DMS03 (1 (with reference to other experimental group dosing maximum dose levels) to 5-50.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 1 and 2, to the test of schistosomicide 42 days adults and 16 days larvas
Table 1 shows, and compound 1 and 2 has the very high activity killing schistosomicide and larva, and its activity, apparently higher than praziquantel, especially has obvious advantage killing in larva.
Embodiment five
Crossed resistance is tested:
1, the foundation of Schistosoma japonicum induction of resistance model: to this seminar pre-stage test gained schistosoma japonicum infection mouse, polypide induction of resistance is carried out: mouse unisexuality infects schistosoma japonicum cercariae with the sub-therapeutic dose of praziquantel ED50, after infection, 3W starts to use sub-therapeutic dose, every day is through stomach administration 1 time, continuous use 30 times, after last therapeutic, three weeks portal vein perfusion methods collect polypide.
2, praziquantel derivative is tested the crossed resistance of polypide: carry out resistance induction experiment by praziquantel to the mouse infected, after determining that there is resistance, and Isolates, whether carry out crossed resistance experiment with filtering out the activated drug candidate of tool again, observing this drug candidate has crossed resistance.
Table 2, compound 1 and 2, to the test with praziquantel resistance schistosomicide 42 days adults
| MLC Schistosoma japonicum adult (42days) | |
| Praziquantel | 730μmol/ml |
| Compound 1 | 28μmol/ml |
| Compound 2 | 35μmol/ml |
Table 2 shows, and compound 1 and 2 is to having praziquantel resistance schistosomicide 42 days adults without crossed resistance.
Claims (2)
1. pyrazine isoquinoline derivative treats the application in the composition of the disease that schistosomulum causes in preparation, and it is characterized in that, described pyrazine isoquinoline derivative is the compound as chemical structural formula general formula I; Wherein, R is selected from the one in tetramethylene base, pentamethylene base, suberane base and cyclooctane base,
2. application according to claim 1, is characterized in that, described pyrazine isoquinoline derivative is selected from as chemical structural formula II with as the one in the compound of chemical structure formula III,
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| CN105566323A (en) * | 2016-03-22 | 2016-05-11 | 中国药科大学 | Pyridinopyrazine compounds and preparation method thereof, and medical application of pyridinopyrazine compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103910725B (en) * | 2013-01-09 | 2015-12-02 | 江南大学 | One class Praziquantel Analogues, Preparation Method And The Use |
| CN104327076A (en) * | 2014-10-11 | 2015-02-04 | 山东京蓬生物药业股份有限公司 | Compound |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3619030A1 (en) * | 1986-06-06 | 1987-12-10 | Bayer Ag | Compositions for topical use |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3619030A1 (en) * | 1986-06-06 | 1987-12-10 | Bayer Ag | Compositions for topical use |
Non-Patent Citations (1)
| Title |
|---|
| 余瑜等: "吡喹酮类似物的合成及其抗血吸虫活性", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566323A (en) * | 2016-03-22 | 2016-05-11 | 中国药科大学 | Pyridinopyrazine compounds and preparation method thereof, and medical application of pyridinopyrazine compounds |
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Application publication date: 20151111 |