CN102432607A - Application of pyrazine isoquinoline derivative in preparation of medicine for treating schistosomiasis - Google Patents

Application of pyrazine isoquinoline derivative in preparation of medicine for treating schistosomiasis Download PDF

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CN102432607A
CN102432607A CN2011103158009A CN201110315800A CN102432607A CN 102432607 A CN102432607 A CN 102432607A CN 2011103158009 A CN2011103158009 A CN 2011103158009A CN 201110315800 A CN201110315800 A CN 201110315800A CN 102432607 A CN102432607 A CN 102432607A
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schistosomiasis
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杨越
孙德群
杨春华
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WEIHAI XIUSHUI PHARMACEUTICAL RESEARCH DEVELOPMENT CO LTD
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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
    • 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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Abstract

The invention relates to pyrazine isoquinoline derivatives with a general formula I, which comprise stereochemical isomers and application of the compounds in preparation of drugs for treating schistosomiasis. The structural general formula I is shown in the specification,

Description

Application of pyrazine isoquinoline derivative in preparation of medicine for treating schistosomiasis
The invention relates to a pyrazine isoquinoline derivative for preparing medicaments for treating human and animal co-morbid diseases caused by schistosome imagoes and larvae.
Background artschistosomiasis is an epidemic caused by infection with three major species of schistosoma (schistosoma mansoni, schistosoma japonicum), which is named as one of the most overlooked major infectious diseases by the world health organization. For 40 years, praziquantel is still the only effective drug widely used for preventing and treating various adult schistosomiasis infections of human and animals. Drug resistance has been developed at present due to its large and long-term use; however, there is no effective drug for schistosomiasis infected by schistosome, i.e. the patient must wait for more than one month after schistosomiasis is infected, and can be treated after the larvae grow into adults in vivo, and the injury of the patient caused by either psychology or body is not imaginable in the period. In addition, since praziquantel cannot kill larvae, the disease condition often occurs repeatedly, and thus, the drug administration must be repeated for many times.
It is disclosed by the world health organization that 2 million people worldwide are infected with schistosomiasis, about 6 million people are threatened to be infected, and 2 million people with high schistosomiasis are present, and at least 280,000 people die of schistosomiasis annually. The data of ' fifteen ' plan for comprehensive treatment of schistosomiasis nationwide ' issued by Ministry of public health and the State development and improvement Commission show that 108 counties which do not control the propagation of schistosomiasis currently are intensively distributed in the lake and marsh regions and the mountain regions, the number of animal hosts is large, the distribution of oncomelania is wide, the influence of environmental factors is great, the prevention and treatment work is particularly difficult, the repeated infection is still very serious, and the epidemic situation is in a very unstable state. In the face of such a large number of people infected with schistosomiasis, only one chemical drug of praziquantel is not suitable, so that the development of a new anti-schistosomiasis drug is urgently needed.
Because the schistosome behaviors are very tricky and foreign, parasitize on human bodies for thousands of years, and evolve very close to human bodies, great difficulty is caused in the aspect of new drug development, and high-efficiency low-toxicity drugs are often difficult to select.
The invention aims to provide an application of pyrazine isoquinoline derivatives in preparing medicaments for treating schistosomiasis, and the compounds have the effects of killing imagoes and larvae and have no cross resistance with praziquantel. Thus, the compounds are useful in the treatment of schistosomiasis, particularly in schistosome larvae infections, and in schistosome patients who are drug resistant.
The invention content is as follows:
the invention relates to a pyrazine isoquinoline compound with a general formula I, which comprises a stereochemical isomer form and application of the compound in preparing a medicament for treating schistosomiasis.
A first interesting embodiment of the present invention relates to compounds of the general structural formula I,
Figure BSA00000593486700021
wherein,
r is cyclobutane, cyclopentane, cycloheptane, and cyclooctane.
When used, the term "compound of general formula I" or "compound of the invention" is meant to also include all stereochemically isomeric forms thereof. In particular, the stereocenter may have the R-or S-configuration;
a second interesting embodiment of the present invention relates to preferred compounds of the general structural formula I:
Figure BSA00000593486700022
a third interesting embodiment of the invention relates to compounds of the general structural formula I, which are useful for killing adult and larva schistosomes in human or animal bodies, and for killing schistosomes in human or animal bodies which are resistant to existing drugs.
A fourth interesting embodiment of the invention relates to compounds of general structural formula I, which compounds are useful as medicaments.
A fifth interesting embodiment of the invention relates to compounds of general structural formula I, which are administered in combination with the existing anti-schistosomiasis drug praziquantel.
A sixth interesting embodiment of the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of general structural formula I, or in combination with the existing anti-schistosomiasis drug praziquantel.
A seventh interesting embodiment of the present invention relates to the use of the combination as described above, or of the pharmaceutical composition, for the treatment of adult, larval infections with schistosoma.
An eighth interesting embodiment of the invention relates to a product comprising any one of the compounds of general structural formula I, or in combination with the existing anti-schistosomiasis drug praziquantel, administered in the form of a preparation or a bulk drug.
An eighth interesting embodiment of the present invention relates to a formulation comprising a compound of any of the general structural formulae I and a pharmaceutical combination, which are particularly suitable for oral administration, and to the preparation thereof, which comprises tablets, oral emulsions, syrups, or parenteral administration forms, including injections, long-acting sustained release injections, liniments, implants, and suppositories.
Pharmacology of
1, action mechanism:
the compounds of the present invention have unexpectedly been shown to be suitable for the treatment of schistosomiasis, co-morbid human and livestock diseases caused by both adults and larvae, as well as for killing schistosomiasis which is resistant to existing drugs in the human or animal body. The invention also relates to the compounds of general formula I as defined above, to their pharmaceutically acceptable racemates, stereochemically isomeric forms for use as medicaments, as well as to the use of any of the following pharmaceutical compositions for the manufacture of a medicament for the treatment of schistosomiasis.
Thus, in another aspect, the present invention provides a method of treating a patient suffering from schistosomiasis, which comprises administering to the patient or to the affected animal a therapeutically effective amount of a compound or pharmaceutical composition of the present invention.
The compound of the invention shows the activity of resisting schistosome adult and larva, the action mechanism of the compound is not clearly researched, and the compound can be related to the action of the compound on a calcium ion channel of schistosome, namely, the excitation of the activity of a worm body, the contraction of muscle of the worm body and the wide damage of a cortex are quickly caused, so that the liver shift of the worm is caused, the body surface nutrient absorption, excretion and defense functions and the subsequent metabolic disorder of the worm are influenced, the damage and the peeling of the cortex destroy the concomitant immune mechanism of the worm which can survive in a host, and the exposure of the body surface antigenic determinant provides a target position for the immune attack of a host anti-schistosome specific antibody. The test shows that:
firstly, the muscles of the worm body generate tetanic contraction and paralysis; the tension of the worm is increased only 20 seconds after the schistosome contacts the low-concentration praziquantel, and the worm is instantly and strongly contractually when the concentration of the drug reaches more than 1 mug/ml; in a host body, liver migration of a worm body occurs within minutes after a patient takes the medicine orally, the medicine in the worm body does not generate metabolic transformation, so that the worm body has an insecticidal effect, and muscle contraction of the worm body is possibly related to the fact that the medicine increases the permeability of cell membranes of the worm body, so that intracellular calcium ions are lost.
Cortical damage and involvement of the body's immune mechanisms: the medicine has rapid and obvious injury effect on the cortex of the polypide, which causes the outer skin of the syncytial to swell, the vacuole changes, the bulla is formed, the body surface is protruded, finally, the epidermis is eroded and broken, the secretion almost disappears, and the circumflex and the longitudinal muscle are also rapidly dissolved in sequence. In the host body, vacuolation of the outer skin of the insect body can be seen 15 minutes after the medicine is taken. After the cortex is destroyed, the absorption and excretion functions of the polypide are affected, and more importantly, the surface antigen of the polypide is exposed, so that the polypide is easy to attack by the host, and a large number of eosinophils are attached to and invaded in the skin lesion to promote the death of the polypide. In addition to the primary changes, the medicine can cause secondary action, depolarize the surface membrane of the insect body, obviously reduce the activity of cortical alkaline phosphatase, inhibit the uptake of glucose and exhaust endogenous glycogen. In addition, the medicine can inhibit the synthesis of nucleic acid and protein of insect body. The drug is not an ionophore, does not affect ATPase activity, and is not affected by calcium channel blockers. High concentrations of potassium have similar drug-like muscle contraction properties, but differ in their mechanism of action.
Pharmacokinetics
After the oral administration, the absorption is rapid, the peak value of the blood drug reaches within 1-2 hours, the drug is metabolized quickly after entering the liver (first pass effect), mainly hydroxyl metabolites are formed, and only a small amount of unmetabolized technical drug enters the human body for circulation. The blood concentration of portal vein is 10 times higher than that of peripheral vein. The cerebrospinal fluid concentration is about 15-20% of the blood concentration. The peak value of blood medicine after oral administration of 10-15 mg/kg is about 1 mu g/ml. The drugs are mainly distributed in the liver, and secondly, in the kidney, lung, pancreas, adrenal gland, pituitary gland, salivary gland, etc. Rarely through the placenta; there was no organ-specific accumulation. 80% of serum drugs bound to protein (animal experiments). The drug T1/2 is 0.8-1.5 hours, and the metabolite T1/2 is 4-5 hours. It is mainly excreted by the kidney as a metabolite (only trace amounts of the drug in its original form), 72% within 24 hours, 80% within 4 days, 15% found in bile and 10% secreted by the intestinal mucosa. After the lactation patient takes the medicine, the medicine concentration in the milk of the lactation patient is equivalent to 25% of that in the serum.
3, pharmacy:
the invention also relates to compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the invention as an active ingredient. The compounds of the present invention may be formulated in different pharmaceutical forms for administration purposes. Illustrative of suitable compositions are all compositions commonly employed for systemic administration of drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of a particular compound as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are in particular in single dosage form suitable for oral administration or parenteral injection. For example, in the preparation of compositions in oral dosage form, in the case of oral liquid preparations such as suspensions, syrups, and emulsions and solutions, any usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, and the like; or in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral unit dosage form, in which case solid pharmaceutical carriers are employed. For parenteral compositions, the carrier will typically comprise sterile water, at least in large part, although other ingredients may be included, for example to aid solubility, or the carrier may comprise saline solution, dextrose solution, or a mixture of saline and dextrose solution, as the case may be, for injectable solutions. Also included are solid form preparations which are designed to be converted to liquid form preparations shortly before use.
Depending on the mode of administration, the pharmaceutical combination preferably comprises 0.05 to 99% by weight, more preferably 0.1 to 70% by weight of the active ingredient, and preferably 1 to 99.95% by weight, more preferably 30 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being calculated on the total composition.
The pharmaceutical compositions may also include other ingredients well known in the art, for example, lubricants, stabilizers, buffers, emulsifiers, viscosity modifiers, surfactants, preservatives, flavoring agents, or coloring agents and the like.
It is particularly preferred that the above-described pharmaceutical compositions are formulated in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient required for the desired therapeutic effect, i.e. determined by calculation of the combined amounts of the pharmaceutical carriers required. Examples of such unit dosage forms are tablets (including scored and coated tablets), capsules, pills, powder packets, wafers. Suppositories, injection solutions or suspensions, and syrups and the like. And divided multi-dose forms thereof.
In order to increase the dissolution rate of the compound, it is particularly preferable to use a preparation technique mainly including an inclusion technique and a solid dispersion technique.
By changing the administration route and adopting a non-oral administration mode, the first-pass effect can be effectively avoided and the drug effect is improved. Non-oral administration preparations for improving the therapeutic effect of the compound are mainly injections, liniments, implants, and suppositories.
The daily dosage of the compounds of the invention will of course vary with the compound used, the mode of administration, the treatment desired and the degree of schistosomiasis confirmed. Generally, satisfactory results are obtained within the range of 10-25mg/kg body weight.
The preparation of the compound:
example preparation of compound 1:
Figure BSA00000593486700071
to a round-bottomed flask equipped with magnetic stirring was added 1-1(202mg, 1mmol), cyclopentylchloride (133mg, 1mmol), triethylamine (111mg, 1.1mmol), dichloromethane (10 ml). After stirring at room temperature for 5h, the reaction mixture was poured into water, the aqueous phase was extracted 3 times with dichloromethane, the organic phases were combined and washed with water. After drying over anhydrous magnesium sulfate, concentration gave a white solid (277mg, yield 93%), Mp: 129 ℃ and 131 ℃, is stable to light, heat and air, and can be dissolved in organic solvents such as dichloromethane, ethyl acetate, acetone and the like.
1H-NMR(300M，CDCl3)δ：1.62-1.88(m，8H，CH(CH2CH2)2)，
2.77-2.99(m，2H，CH2，1H，CH)4.06-4.53(m，2H，N-CH2-CH)，
4.81-4.88(m，2H，N-CH2-CO)，5.16-5.19(dd，1H，CH)，
7.18-7.29(m，4H，Ar-H)
Example preparation of compound 2:
Figure BSA00000593486700072
to a round bottom flask equipped with magnetic stirring was added 1-1(202mg, 1mmol), cyclobutylcarbonyl chloride (119mg, 1mmol), triethylamine (111mg, 1.1mmol), dichloromethane (10 ml). After stirring at room temperature for 5h, the reaction mixture was poured into water, the aqueous phase was extracted 3 times with dichloromethane, the organic phases were combined and washed with water. After drying over anhydrous magnesium sulfate, concentration gave a white solid (256mg, yield 90.1%), Mp: 153-155 deg.C, stable to light, heat and air, and soluble in organic solvents such as dichloromethane, ethyl acetate and acetone.
1H-NMR(300M，CDCl3)δ：2.00-2.38(m，7H，CHCH2CH2CH2)
2.76-2.98(m，2H，CH2，)3.95-4.27(m，2H，N-CH2-CH)，
4.79-4.86(m，2H，N-CH2-CO)，5.10-5.15(dd，1H，CH)，
7.14-7.29(m，4H，Ar-H)
II, biological effect: the in vitro method for measuring the schistosoma japonicum resistance of the compound comprises the following steps:
example three, adult in vitro culture: live 42-day male adults were collected and placed in DMEM medium (10 strips/3 ml/dish) and dosed in groups. Adding 3ul of compound into each dish respectively, adding DMS03(1 (referring to other experimental groups with highest dose) into a control group with final concentration of 5-50 (mol/ml), adding the medicines, fully shaking, placing into an incubator with temperature of 37 ℃ and 5% CO, culturing overnight (16h), washing the insect body with normal saline for 3 times, adding fresh culture solution, observing the vitality state of the schistosome after culturing for 24-72 h under a stereoscopic microscope, and recording images, wherein the results are shown in Table 1,
example four, in vitro larval culture: live 16-day larvae were collected and placed in DMEM medium (10 strips/3 ml/dish) and dosed in groups. Adding 3ul of compound into each dish respectively, adding DMS03(1 (referring to other experimental groups with highest dose) into a control group with final concentration of 5-50 (mol/ml), adding the medicines, fully shaking, placing into an incubator with temperature of 37 ℃ and 5% CO, culturing overnight (16h), washing the insect body with normal saline for 3 times, adding fresh culture solution, observing the vitality state of the schistosome after culturing for 24-72 h under a stereoscopic microscope, and recording images, wherein the results are shown in Table 1,
TABLE 1, Compounds 1 and 2, testing of Schistosoma japonicum adult day 42 and day 16 larvae
Table 1 shows that the compounds 1 and 2 have high schistosome and larva killing activity, the activity is obviously higher than that of praziquantel, and the compounds have obvious advantage in killing larvae.
Example five, cross-resistance test:
1, establishing a schistosoma japonicum resistance induction model: the schistosoma japonicum obtained in the preliminary test of the subject group is infected with mice, and the subtherapeutic dose of praziquantel ED50 is used for insect resistance induction: mice are singly infected with Schistosoma japonicum cercaria, and 3W after infection, the mice begin to use sub-therapeutic dose, and are administered by stomach 1 time each day, and are continuously administered for 30 times, and the worm bodies are collected by portal vein infusion method three weeks after the last treatment.
2, cross resistance experiment of praziquantel derivative to insect body: and (3) carrying out a drug resistance induction test on the infected mice by using praziquantel, separating insect strains after the drug resistance is determined, then carrying out a cross resistance test by screening active candidate drugs, and observing whether the candidate drugs have cross resistance.
TABLE 2, Compounds 1 and 2, test for 42-day adult schistosome with Praziquantel resistance
MLC Schistosoma japonicum adult (42days)
Praziquantel 730μmol/ml
Compound 1 28μmol/ml
Compound 2 35μmol/ml
Table 2 shows that compounds 1 and 2 have no cross-resistance against 42-day adult schistosomes with praziquantel resistance.

Claims (9)

1. Pyrazine isoquinoline derivatives with a general formula I comprise stereochemical isomers and application of the compounds in preparation of drugs for treating schistosomiasis.
The structural general formula I is shown in the specification,
wherein,
r is cyclobutane, cyclopentane, cycloheptane, and cyclooctane.
2. The compound according to claim 1, wherein said compound is preferably selected from the group consisting of:
Figure FSA00000593486600012
3. compounds according to claims 1-2, characterized in that they are used for killing adult and larval schistosomes in humans or animals, and for killing schistosomes resistant to existing drugs in humans or animals.
4. A compound according to any one of claims 1-2, for use as a medicament.
5. Compound according to any one of claims 1-2, characterized in that it is administered in combination with the existing anti-schistosomiasis drug praziquantel.
6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound according to any one of claims 1-2, or in combination with an existing anti-schistosomiasis drug praziquantel.
7. The combination according to claim 5, or the pharmaceutical composition according to claim 6, for use in the treatment of adult, larval infections with schistosomes.
8. A product comprising a compound according to any one of claims 1-2, or administered in combination with an existing anti-schistosomiasis drug praziquantel, the product being administered as a preparation or as a bulk drug.
9. A formulation comprising a compound according to any one of claims 1-2 and a pharmaceutical combination suitable for oral or parenteral administration, transdermal administration, rectal administration-suppositories, implants, and the preparation thereof.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103910725A (en) * 2013-01-09 2014-07-09 江南大学 Praziquantel analogue, preparation method and application thereof
CN104327076A (en) * 2014-10-11 2015-02-04 山东京蓬生物药业股份有限公司 Compound

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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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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103910725A (en) * 2013-01-09 2014-07-09 江南大学 Praziquantel analogue, preparation method and application thereof
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

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Application publication date: 20120502