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CN104844606B - Parasiticide pyrazine isoquinoline derivative - Google Patents

Parasiticide pyrazine isoquinoline derivative Download PDF

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Publication number
CN104844606B
CN104844606B CN201510117197.1A CN201510117197A CN104844606B CN 104844606 B CN104844606 B CN 104844606B CN 201510117197 A CN201510117197 A CN 201510117197A CN 104844606 B CN104844606 B CN 104844606B
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Prior art keywords
compound
pharmaceutically acceptable
yuan
schistosomiasis
active ingredient
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Expired - Fee Related
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CN201510117197.1A
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CN104844606A (en
Inventor
孙德群
杨越
杨春华
罗敏
张凌子
孙丽
张文龙
苟招聘
王锦
胡长燕
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Shandong University Weihai
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Shandong University Weihai
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic 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
    • C07D487/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/12Heterocyclic 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
    • C07D471/14Ortho-condensed systems
    • YGENERAL 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
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against 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

Novel anti-parasitic pyrazine isoquinoline derivative.The present invention relates to a kind of compound as general structure I, wherein, A is selected from B and 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;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

Antiparasitic pyrazine isoquinoline derivatives
Technical Field
The invention relates to a novel pyrazine isoquinoline derivative for treating parasitic diseases, in particular to a medicine composition and a medicine comprising a pyrazine isoquinoline derivative component for treating zoonosis diseases caused by schistosomiasis, tapeworm, cysticercus, clonorchis sinensis, paragonimiasis pulmonalis and fasciola zingiberis.
Background
Schistosomiasis is an epidemic caused by infection with three major species of schistosomiasis (Schistosoma mansoni, Schistosoma japonicum and Schistosoma japonicum). 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 therapy for schistosomiasis infected by schistosome. According to the disclosure of the world health organization, there are 2 hundred million people infected with schistosomiasis worldwide, about 6 hundred million people are threatened to be infected, and 2 million people with high schistosomiasis are present, and at least 280000 people die of schistosomiasis every year. 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.
Disclosure of Invention
A compound of formula I, its pharmaceutically acceptable salts, its isomers and oxynitrides suitable for use in humans and animals. The structural general formula is shown as formula I,
wherein,
a is an unsaturated ring including a benzene ring, a pyridine ring and a nitroxide dipolar pyridine ring;
b is saturated nitrogen heterocycle, including five-membered, six-membered and seven-membered saturated nitrogen heterocycle, which can be substituted by C1-C4 alkyl or form 3-5-membered saturated fused ring;
c is a saturated nitrogen heterocycle including five-, six-, and seven-membered saturated nitrogen heterocycles, which may be a ketone or non-ketone compound;
d is a saturated ring, including ternary, quaternary, quinary, senary, and heptatomic saturated rings;
a is selected from the following groups:
b + C is selected from the following groups:
d is selected from the following groups:
among the preferred but not limiting compounds are:
the compounds of the present invention have unexpectedly been shown to be suitable for the treatment of parasitic diseases, especially human and animal comorbidity diseases caused by schistosomiasis, cestode, cysticercus, clonorchis sinensis, paragonimiasis zingiberis the present invention also relates to the use of a compound of formula I as defined above, pharmaceutically acceptable acid or base addition salts thereof, including quaternary salts, stereochemically isomeric forms, N-oxide compounds, as a medicament, and the use of any of the following pharmaceutical compositions for the manufacture of a medicament for the treatment of parasitic diseases, including human and animal comorbidity diseases caused by schistosomiasis, cestode, cysticercus, clonorchis sinensis, paragonimiasis zingiberis.
Thus, in another aspect, the invention provides a method of treating a subject suffering from a parasitic disease, including schistosomiasis, which comprises administering to the subject or subject a therapeutically effective amount of a compound or pharmaceutical composition of the invention.
The invention also relates to compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of the invention. 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 the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate association 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 preferably in single dosage form, especially 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, 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, binders and the like.
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.
Detailed Description
Examples preparation of typical compounds 1-3:
to a round bottom flask equipped with magnetic stirring was added 1-1(188mg, 1mmol), cyclohexanecarboxylic acid (128mg, 1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1 mmol). Stirred at room temperature overnight, washed alternately with 1% hydrochloric acid water and saturated sodium carbonate solution and finally with water. The residue was dried over anhydrous magnesium sulfate and concentrated to give MP132-135(277mg, yield 93%) as a white solid.
To a round bottom flask equipped with magnetic stirring was added 1-1(188mg, 1mmol), cyclopentanecarboxylic acid (114mg, 1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1 mmol). Stirred at room temperature overnight, washed alternately with 1% hydrochloric acid water and saturated sodium carbonate solution and finally with water. After drying over anhydrous magnesium sulfate, concentration gave Mp128-130 as a white solid (256mg, yield 90.14%).
To a round bottom flask equipped with magnetic stirring was added 1-1(188mg, 1mmol), cycloheptanecarboxylic acid (142mg, 1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1 mmol). Stirred at room temperature overnight, washed alternately with 1% hydrochloric acid water and saturated sodium carbonate solution and finally with water. The anhydrous magnesium sulfate was dried and concentrated to give a white solid, Mp137-139(287mg, 92% yield).
Example two preparation of representative Compounds 10-12:
a round-bottomed flask equipped with magnetic stirring was charged with 10-1(232mg, 1mmol), cyclohexanecarboxylic acid (128mg, 1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1 mmol). Stirred at room temperature overnight, washed alternately with 1% hydrochloric acid water and saturated sodium carbonate solution and finally with water. The mixture was dried over anhydrous magnesium sulfate and concentrated to give Mp143-146(324mg, yield 95%) as a white solid.
To a round bottom flask equipped with magnetic stirring was added 10-1(232mg, 1mmol), cycloheptanecarboxylic acid (142mg, 1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1 mmol). Stirred at room temperature overnight, washed alternately with 1% hydrochloric acid water and saturated sodium carbonate solution and finally with water. The anhydrous magnesium sulfate was dried and concentrated to give MP 138-141 (295mg, yield 90%) as a white solid.
To a round bottom flask equipped with magnetic stirring was added 10-1(232mg, 1mmol), cycloheptanecarboxylic acid (142mg, 1mmol), EDCI (211mg, 1.1mmol) and DMAP (139mg, 1.1 mmol). Stirred at room temperature overnight, washed alternately with 1% hydrochloric acid water and saturated sodium carbonate solution and finally with water. Dry over anhydrous magnesium sulfate and concentrate to give a white solid Mp149-153(316mg, 89% yield).
Examples three biological effects
The in vitro method for measuring the schistosoma japonicum resistance of the compound comprises the following steps: adult in-vitro culture: live 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 for adding the highest dose) into a control group with the final concentration of 50 mol/ml, adding the DMS03, fully shaking up after adding the DMS, placing the DMS into an incubator with the temperature of 37 ℃ and the CO content of 5 percent, washing the worm body for 3 times by using physiological saline after culturing overnight (16h), adding a fresh culture solution, observing the vitality state of the schistosome after culturing for 24h to 72h under a stereoscopic microscope, and recording images, wherein the results are shown in a table 1.
TABLE 1
Compound (I) Number of insects Mortality grade Compound (I) Number of insects Mortality grade
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 rating in table: a is 100-80%.

Claims (11)

1. A compound selected from at least one of the compounds of formulae 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 and 69,
2. use of a compound according to claim 1 for the preparation of a medicament for the prevention or treatment of a parasitic disease, wherein the parasite is selected from at least one of schistosoma, cestode, cysticercus, clonorchis sinensis, fluke scuba and fasciola.
3. A pharmaceutically acceptable salt of the compound of claim 1.
4. A pharmaceutical composition having a killing effect on schistosoma japonicum, wherein the active ingredient of the pharmaceutical composition comprises the compound of claim 1.
5. The composition of claim 4, further comprising a pharmaceutically acceptable carrier.
6. A pharmaceutical composition having a killing effect on schistosoma japonicum, wherein the active ingredient of the pharmaceutical composition comprises a pharmaceutically acceptable salt of the compound of claim 3.
7. The composition of claim 6, further comprising a pharmaceutically acceptable carrier.
8. A drug having a killing effect on schistosoma japonicum, wherein the active ingredient of the drug comprises the compound according to claim 1.
9. The medicament of claim 8, further comprising a pharmaceutically acceptable carrier.
10. A drug having a killing effect on schistosoma japonicum, wherein the active ingredient of the drug comprises a pharmaceutically acceptable salt of the compound according to claim 3.
11. The medicament of claim 10, further comprising a pharmaceutically acceptable carrier.
CN201510117197.1A 2011-05-31 2011-05-31 Parasiticide pyrazine isoquinoline derivative Expired - Fee Related CN104844606B (en)

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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 (2)

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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
CN1683346A (en) * 2005-03-01 2005-10-19 江苏工业学院 Praziquantel synthetic process

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Publication number Priority date Publication date Assignee Title
DE3619030A1 (en) * 1986-06-06 1987-12-10 Bayer Ag Compositions for topical use

Patent Citations (2)

* Cited by examiner, † Cited by third party
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
CN1683346A (en) * 2005-03-01 2005-10-19 江苏工业学院 Praziquantel synthetic process

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
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;胡玉琴,等;《中国药物化学杂志》;19970331;第7卷(第1期);第37-42页 *

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CN104844606A (en) 2015-08-19
CN102267998B (en) 2015-05-13
CN104788457A (en) 2015-07-22
CN102267998A (en) 2011-12-07

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