CN109053701A - Arctiin metaclass compound, preparation method and purposes - Google Patents
Arctiin metaclass compound, preparation method and purposes Download PDFInfo
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
The invention discloses one kind based on arctiin metaclass compound and its preparation method and application.The compound of the present invention is obtained using arctigenin as parent nucleus by chemical modification unit of substituted 1,2,3-triazoles, has good resisting toxoplasmosis activity.
Description
Technical field
The present invention relates to a kind of arctiin metaclass compounds and its preparation method and application.
Background technique
Toxoplasma gondii (Toxoplasma gondii) is that obligatory parasitism causes a disease in the opportunistic of warm-blooded animal karyocyte
Protozoon can infect most of mammal and birds including people.Whole history of life of toxoplasma include tachyzoite, packet
Capsule, schizont, five stages of gametophyte and egg capsule, wherein tachyzoite (tachyzoites) is its principal causative stage.By arch
Toxoplasmosis caused by insect infection (Toxoplasmosis) is in worldwide distribution, and there are about the populations of one third in chronic in the whole world
Arch insect infection, the physiological function of the organs such as main damage host eye, brain, heart, liver, and also result in the pregnancy period
Intrauterine fetal deformity.Toxoplasmosis is in usually subclinical infection without apparent clinical symptoms, and latent time is long, it is wide to involve range, danger
Evil degree is big, seriously affects the mankind, farming animals and food safety.
Currently, the drug for the treatment of toxoplasmosis is mainly pyrimethamine (pyrimethamine), sulphadiazine
(sulfadiazine), spiramvcin (spiramycin), Atovaquone (atovaquone) etc..Clinical research shows ethamine
Pyrimidine and sulphadiazine are applied together shows apparent insect resistant effect, but the combination drug of the two can cause it is serious bad anti-
(such as allergy, does not tolerate bone marrow suppression) is answered, but also will increase the risk of liver kidney complication.Although the use of Atovaquone
Certain success is achieved, but its insect resistant effect is extremely limited.Spiramvcin is only proved to as macrolide antibacterial agents
The time-to-live of infected rodent can be extended under high dose.Taking these drugs in early pregnancy, to may cause fetus abnormal
Shape, thus all it is not suitable for pregnant woman.Therefore, there is an urgent need to develop low toxicities, efficient resisting toxoplasmosis drug.
Fructus arctii (Arctium lappa L.) is the biennial herb plant that Compositae Arctium lappa belongs to, mellow fruit fructus arctii
Sub (Fructus Arctii) is as traditional herbal medicines in existing thousands of years of the medicinal history of China.Arctiin (Arctiin) and ox
Burdock aglycon (Arctigenin) is the main active of great burdock achene.Wherein arctigenin have anti-inflammatory, antiviral, anti-Ah
Er Cihaimo disease and antitumor equal pharmacological activity.
(" arctiin is to toxoplasma heat shock protein 70 induction arch insect infection acute liver for non-patent literature 1
Protective effect ", Cheng little Yan etc., Yanbian University's medical journal, the 4th phase of volume 38, the 270-273 pages, in December, 2015), it is non-specially
Sharp document 2 (" arctiin pharmacology activity research progress ", small blueness of model etc., Shanghai Chinese magazine, the 4th phase of volume 51,2017),
Non-patent literature 3 (" progress of the effective component to liver protection in fructus arctii ", Zhang Mingyue etc., West China pharmaceutical journal, the
The phase of volume 32 the 6th, the 661-663 pages, 2017) arctiin is individually disclosed to toxoplasma heat shock protein 70 (T.g.HSP70)
It induces arch insect infection acute liver that there is protective effect, glutamic-pyruvic transaminase in mice serum can be substantially reduced
(ALT), level and inflammatory factor interleukins (IL-1 β), the tumor necrosis factor (TNF-α), blood of glutamic-oxalacetic transaminease (AST)
The expression of platelet activation factor (PAF-AH) mRNA.
CN101284823A, CN102342929A, WO2013023145A1 individually disclose the esterification of arctigenin, ether
Change, alkyl derivative improve body tolerance, anti-inflammatory, antiendotoxin, it is antitumor, in terms of application.
CN103467417A, which discloses arctigenin carboxamide derivatives and can be used for treating, to beta amyloid peptide forms relevant disease.
CN105732598A discloses application of the arctigenin ether derivative in the drug of preparation prevention and treatment neurodegenerative disease.
CN105616400A discloses arctigenin carbamate derivatives and is preparing the drug for treating Alzheimer disease
In purposes.
But currently available technology does not still have the active report of resisting toxoplasmosis about arctigenin or derivatives thereof
Road.
Summary of the invention
It is an object of the present invention to provide the compounds based on arctigenin, with resisting toxoplasmosis activity.This
Invention it is a further objective that providing above compound, have the characteristics that less toxic, efficient.
It is another object of the present invention to provide the preparation method of above compound, simple process and stabilization.
It is yet a further object of the present invention to provide above compounds to have in the active drug of resisting toxoplasmosis in preparation
Using.
On the one hand, the present invention provides a kind of compound based on arctigenin, with structure shown in formula (I):
In formula (I), R1~R5It is identical or different, separately it is selected from hydrogen, C1-C6 alkyl, C2-C6 miscellaneous alkyl, C3-C6
Naphthenic base, C1-C6 alkoxy or C1-C6 alkylthio group；R6Selected from singly-bound, C1-6 alkylidene or the Asia C2-C6 miscellaneous alkyl；R has formula
(II) structure shown in:
In formula (II), R7Selected from singly-bound, C1-6 alkylidene or the Asia C2-C6 miscellaneous alkyl；R8~R12It is identical or different, it is only respectively
On the spot it is selected from hydrogen, nitro, halogen, C1-C6 alkyl, C2-C6 miscellaneous alkyl, C3-C6 naphthenic base, C1-C6 alkoxy or C1-C6 alkane sulphur
Base.
Compound according to the present invention, it is preferable that R1~R5It is identical or different, separately it is selected from hydrogen or C1-C3
Alkyl；R6Selected from singly-bound or C1-C3 alkylidene；R7Selected from singly-bound or C1-C3 alkylidene；R8~R12It is identical or different, independently
Ground is selected from hydrogen, halogen, C1-C3 alkyl or C1-C3 alkoxy.
Compound according to the present invention, it is preferable that R1~R5It is identical or different, separately selected from hydrogen, methyl or
Ethyl；R6Selected from singly-bound, methylene or ethylidene；R7Selected from singly-bound, methylene or ethylidene；R8~R12It is identical or different, respectively
Independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy or ethoxy.
Compound according to the present invention, it is preferable that R is selected from one of following group:
Compound according to the present invention, it is preferable that R is selected from one of following group:
Compound according to the present invention, it is preferable that formula (I) compound represented is selected from one of following compound:
On the other hand, the present invention provides the preparation method of above compound, includes the following steps:
(1) formula (III) compound represented is reacted with formula (IV) compound represented, forms intermediate product A；
In formula (III), R1~R5It is identical or different, separately it is selected from hydrogen, C1-C6 alkyl, C2-C6 miscellaneous alkyl, C3-
C6 naphthenic base, C1-C6 alkoxy or C1-C6 alkylthio group；In formula (IV), R6Selected from the sub- miscellaneous alkane of singly-bound, C1-6 alkylidene or C2-C6
Base, X indicate that halogen, ≡ indicate alkynyl；
(2) intermediate product A is reacted with formula (V) compound represented, obtains formula (I) compound represented；
In formula (V), R7Selected from singly-bound, C1-6 alkylidene or the Asia C2-C6 miscellaneous alkyl；R8~R12It is identical or different, it is only respectively
On the spot it is selected from hydrogen, nitro, halogen, C1-C6 alkyl, C2-C6 miscellaneous alkyl, C3-C6 naphthenic base, C1-C6 alkoxy or C1-C6 alkane sulphur
Base；N3Indicate azido.
Preparation method according to the present invention, it is preferable that be formula (III) institute of 1:1~3 by molar ratio in step (1)
The compound shown is reacted in acetone solvent, by catalyst of potassium carbonate with formula (IV) compound represented, is formed intermediate
Product A；In step (2), by intermediate product A and formula (V) compound represented the mixing in fourth alcohol and water that molar ratio is 1:1~3
It is reacted in bonding solvent, using copper sulphate and sodium ascorbate as catalyst, obtains formula (I) compound represented.
Preparation method according to the present invention, it is preferable that comprise the following specific steps that:
It (1) is formula (III) compound represented, formula (IV) compound represented and the carbon of 1:1~3:1~4 by molar ratio
Reaction vessel is added in sour potassium and acetone solvent, reacts 5-20h in the case where temperature is 40~80 DEG C and stirring；Reaction is produced
Object pours into ice water, is extracted with ethyl acetate 2~5 times, then washs extract liquor 2~5 times with saturated brine solution；It will be organic
Layer is dried over anhydrous sodium sulfate, filters, being concentrated under reduced pressure and column chromatographs to obtain intermediate product A；
(2) mixed solvent for the fourth alcohol and water for being 1~10:1 by volume ratio, molar ratio are 1:1~3:0.05~0.2:0.1
~0.4 intermediate product A, formula (V) compound represented, cupric sulfate pentahydrate CuSO4·5H2O and sodium ascorbate VC-Na is added
Reaction vessel reacts 12~48h in the case where temperature is 20~60 DEG C and stirring；Reaction product is poured into ice water, acetic acid is used
Ethyl ester extract 2~5 times, organic layer is washed 2~5 times with saturated brine solution, be dried over anhydrous sodium sulfate, filter, depressurize it is dense
Contracting and column chromatograph to obtain formula (I) compound represented.
In another aspect, the present invention also provides above compounds to have the application in the active drug of resisting toxoplasmosis in preparation.
The present invention can be obtained living with good resisting toxoplasmosis by the way that arctigenin is used specific base group modification
The compound of property.The present invention is not only improved of the invention using the hydroxyl of the 1,2,3-triazoles modification arctigenin replaced
The synthesis technology stability of compound also improves its resisting toxoplasmosis activity.
Detailed description of the invention
Fig. 1 shows influence of the compound D1~D12 to host cell survival rate.* compared with spiramvcin group, P <
0.05.Control is control group, and Ar is arctigenin experimental group, and Spy indicates spiramvcin experimental group.
Influence Fig. 2 shows compound D4 and control compound to the host cell of toxoplasma gondii infection.
Wherein, Fig. 2 a is HeLa host cell, and Fig. 2 b is arch insect infection cell, and Fig. 2 c is the arch of compound D4 treatment
Insect infection cell, Fig. 2 d are the arch insect infection cell of spiramvcin treatment, and Fig. 2 e is the toxoplasma sense of arctigenin treatment
Contaminate cell.
Fig. 3 shows the influence of compound D4 and control compound to mouse peritoneal borer population.Control indicates control group,
Ar indicates arctigenin experimental group, and Sp indicates spiramvcin experimental group, and D4 indicates compound D4 experimental group.
Specific embodiment
The present invention is further illustrated combined with specific embodiments below, but protection scope of the present invention is not limited to
This.
Present inventor surprisingly has found during furtheing investigate arctigenin derivative, by specific base
The arctiin metaclass compound of group's modification has good resisting toxoplasmosis activity, thereby completing the present invention.
<term explanation>
In the present invention, Cm-Cn indicates there is m~n carbon atom；For example, C1-C20 alkyl indicates there is 1~20
The alkyl of a carbon atom.
In the present invention, " singly-bound " refer to two between atom or group with 1 valence covalent bond Direct Bonding." alkyl " indicates
With tie point, aliphatic hydrocarbon derived from straight chain or branch group." miscellaneous alkyl " indicates there is a tie point
, have at least one heteroatomic alkyl." alkylidene " indicate tool there are two tie point, derived from direct-connected or branch
The group of aliphatic hydrocarbon." sub- miscellaneous alkyl " indicate tool there are two tie point, have at least one heteroatomic alkylidene.Aforementioned art
The one or more carbon atoms of " miscellaneous " expression in language are by different atomic substitutions.
Unless specifically stated otherwise, all groups can be substituted or unsubstituted.Some specific embodiments according to the present invention,
Substituent group is selected from halogen, alkyl or alkoxy.
In the present invention, " click chemistry reaction " (Click Chemistry Reaction) refers to exists in catalyst
Under, make to have and reacts to form 1,2,3- tri- with azido by alkynyl between the compound of alkynyl and the compound with azido
The chemical reaction of azoles linking group.
Unless otherwise defined, the meaning of all technical and scientific terms used herein with it is of the art general
As logical technical staff is generally understood.Although similar or equivalent method and material can also with method described herein and material
For in implementation or test of the invention, but suitable method and material is described below.All publication, patent Shen
Please, patent and the other references being mentioned above are incorporated by herein.If conflict occurs, with this theory
Bright book and its including definition subject to.In addition, material, method, embodiment are merely exemplary, it is no intended to be limited.
<compound>
Compound based on arctigenin of the invention indicates a substance, and parent nucleus is arctigenin, using change
It learns synthetic method to be chemically modified on its phenyl ring hydroxyl, can also be chemically modified in the position that may replace of phenyl ring.This
The compound based on arctigenin of invention has structure shown in formula (I):
The present invention not only improves chemical combination of the invention using the hydroxyl of the 1,2,3-triazoles modification arctigenin replaced
The synthesis technology stability of object, while improving its resisting toxoplasmosis activity.
In the present invention, R1~R5It is identical or different, separately it is selected from hydrogen, C1-C6 alkyl, C2-C6 miscellaneous alkyl, C3-
C6 naphthenic base, C1-C6 alkoxy or C1-C6 alkylthio group.Preferably, R1~R5Separately it is selected from hydrogen, C1-C3 alkyl, C2-
C5 miscellaneous alkyl, C5-C6 naphthenic base, C1-C3 alkoxy, C1-C3 alkylthio group；It is highly preferred that R1~R5Separately selected from hydrogen or
C1-C3 alkyl.
In the present invention, C1-C6 alkyl can include but is not limited to straight chained alkyl or branched alkyl；Preferably C1-C3 alkane
Base, more preferably C1-C3 straight chained alkyl.The example of C1-C6 alkyl include but is not limited to methyl, ethyl, n-propyl, isopropyl,
Normal-butyl, isobutyl group, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl etc..In addition, C1-C6 alkyl of the invention can wrap
Include substituted alkyl or unsubstituted alkyl.Substituent group in substituted alkyl can contain hetero atom, such as O, S, N or halogen
Element.Halogen of the invention includes but is not limited to fluorine, chlorine, bromine, iodine.
In the present invention, C2-C6 miscellaneous alkyl can include but is not limited to linear heteroalkyl group or branched heteroalkyl groups；Preferably
C2-C5 miscellaneous alkyl, more preferably C2-C3 miscellaneous alkyl.Miscellaneous alkyl of the invention refers to the carbon atom on alkyl chain by other miscellaneous originals
Son replaces the group formed.Above-mentioned hetero atom includes O, S or N, preferably includes O or S.C2-C6 miscellaneous alkyl of the invention is specific
Example includes but is not limited to-CH2-O-CH3、-CH2-O-CH2CH3、-CH2-O-CH(CH3)CH3、-CH2-S-CH3、-CH2-S-
CH2CH3、-CH2-S-CH(CH3)CH3。
In the present invention, C3-C6 naphthenic base may include the naphthenic base and unsubstituted naphthenic base replaced；Preferably C5-
C6 naphthenic base, more preferably C5 naphthenic base.The specific example of C3-C6 naphthenic base of the invention includes but is not limited to: cyclopropyl, ring
Butyl, cyclopenta, cyclohexyl, 3- methylcyclopentyl, 3- methylcyclohexyl, 3- ethylcyclohexyl, preferably cyclopenta, hexamethylene
Base.
In the present invention, C1-C6 alkoxy can include but is not limited to unbranched alkoxy or branched alkoxy；Preferably
C1-C3 alkoxy, more preferably C1-C3 unbranched alkoxy.The example of C1-C6 alkoxy includes but is not limited to methoxyl group, ethoxy
Base, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isoamoxy, neopentyl oxygen, oneself
Oxygroup etc..
In the present invention, C1-C6 alkylthio group can include but is not limited to straight-chain alkylthio or branched alkylthio；Preferably
C1-C3 alkylthio group, more preferably C1-C3 straight-chain alkylthio.The example of C1-C6 alkylthio group includes but is not limited to methyl mercapto, second sulphur
Base, positive rosickyite base, isopropyisulfanyl, positive butylthio, isobutylthio, tertiary butylthio, positive penta sulfenyl, isopentylthio, new penta sulfenyl, oneself
Sulfenyl etc..
A specific embodiment according to the present invention, R1~R5Separately it is selected from hydrogen, methyl or ethyl.
In the present invention, R6Selected from singly-bound, C1-6 alkylidene or the Asia C2-C6 miscellaneous alkyl.Preferably, R6Selected from singly-bound, C1-3
Alkylidene or C2-C5 miscellaneous alkyl；More preferable R6Selected from singly-bound or C1-3 alkylidene.
In the present invention, singly-bound refer to two between atom or group with 1 valence covalent bond Direct Bonding.
In the present invention, C1-6 alkylidene can include but is not limited to straight-chain alkyl-sub or branched alkylidene；Preferably C1-
C3 alkylidene, more preferably C1-C3 straight-chain alkyl-sub.The example of C1-C6 alkylidene include but is not limited to methylene, ethylidene,
Sub- n-propyl, isopropylidene, sub- normal-butyl, isobutylidene, sub- tert-butyl, sub- n-pentyl, isoamylidene, sub- neopentyl, it is sub- oneself
Base etc..In addition, C1-C6 alkylidene of the invention may include the alkylidene or unsubstituted alkylidene replaced.Substituted alkylene
Substituent group in base can contain hetero atom, such as O, S, N or halogen.Halogen of the invention include but is not limited to fluorine, chlorine, bromine,
Iodine.
In the present invention, the Asia C2-C6 miscellaneous alkyl can include but is not limited to straight chain Asia miscellaneous alkyl or branch Asia miscellaneous alkyl；It is excellent
It is selected as the Asia C2-C5 miscellaneous alkyl, the more preferably Asia C2-C3 miscellaneous alkyl.Sub- miscellaneous alkyl of the invention refers to the original of the carbon on alkylidene chain
Son replaces the group to be formed by other hetero atoms.Above-mentioned hetero atom includes O, S or N, preferably includes O or S.C2-C6 of the invention
The sub- specific example of miscellaneous alkyl includes but is not limited to-CH2-O-CH2-、-CH2-O-CH2CH2-、-CH2-O-CH(CH3)CH2-、-
CH2-S-CH2-、-CH2-S-CH2CH2-、-CH2-S-CH(CH3)CH2-。
A specific embodiment according to the present invention, R6Selected from singly-bound, methylene or ethylidene.
In the present invention, R has structure shown in formula (II):
In formula (II), R7Selected from singly-bound, C1-6 alkylidene or the Asia C2-C6 miscellaneous alkyl.Preferably, R7Selected from singly-bound, C1-
C3 alkylidene or the Asia C2-C5 miscellaneous alkyl；It is highly preferred that R7Selected from singly-bound or C1-C3 alkylidene." alkylene mentioned herein
Base ", " sub- miscellaneous alkyl ", the substituent group range covered are referred to above, and details are not described herein.
A specific embodiment according to the present invention, R7Selected from singly-bound, methylene or ethylidene.
In formula (II), R8~R12It is identical or different, separately it is selected from hydrogen, nitro, halogen, C1-C6 alkyl, C2-
C6 miscellaneous alkyl, C3-C6 naphthenic base, C1-C6 alkoxy or C1-C6 alkylthio group.Preferably, R8~R12Separately selected from hydrogen,
Halogen, C1-C3 alkyl, C2-C5 miscellaneous alkyl, C5-C6 naphthenic base, C1-C3 alkoxy, C1-C3 alkylthio group；It is highly preferred that R8~
R12Separately it is selected from hydrogen, halogen, C1-C3 alkyl or C1-C3 alkoxy." halogen " mentioned herein, " alkyl ", " miscellaneous
Alkyl ", " naphthenic base ", " alkylthio group ", the substituent group range covered are referred to above, and details are not described herein.
A specific embodiment according to the present invention, R8~R12Separately selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl,
Ethyl, methoxy or ethoxy.
The example of R group includes but is not limited to following group:
In order to further increase the resisting toxoplasmosis activity of the compound of the present invention, R is selected from one of following group:
According to embodiment of the present invention, R is selected from one of following group:
Such compound selectivity index SI with higher, not only cytotoxicity is low, and resisting toxoplasmosis activity is higher,
Consider from drug safety angle, R is following group:
The compound of the present invention can be selected from one of following compound:
The synthesis technology of above compound is simple, and technology stability is good.
<preparation method>
The preparation method of the compound of the present invention includes: the synthesis step of (1) intermediate product A；(2) intermediate product A and folded
The step of nitrogen compound reaction synthesis the compound of the present invention.
In step (1) of the invention, formula (III) compound represented is reacted with formula (IV) compound represented, shape
At intermediate product A.
In formula (III), R1~R5It is identical or different, separately it is selected from hydrogen, C1-C6 alkyl, C2-C6 miscellaneous alkyl, C3-
C6 naphthenic base, C1-C6 alkoxy or C1-C6 alkylthio group.In formula (IV), R6Selected from the sub- miscellaneous alkane of singly-bound, C1-6 alkylidene or C2-C6
Base, X indicate that halogen, ≡ indicate alkynyl.
In formula (III), R1~R5Hydrogen, C1-C3 alkyl, C2-C5 miscellaneous alkyl, C5-C6 cycloalkanes can be separately selected from
Base, C1-C3 alkoxy, C1-C3 alkylthio group；It is highly preferred that R1~R5Separately it is selected from hydrogen or C1-C3 alkyl.
In formula (III), C1-C6 alkyl can include but is not limited to straight chained alkyl or branched alkyl；Preferably C1-C3 alkane
Base, more preferably C1-C3 straight chained alkyl.The example of C1-C6 alkyl include but is not limited to methyl, ethyl, n-propyl, isopropyl,
Normal-butyl, isobutyl group, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl etc..In addition, C1-C6 alkyl of the invention can wrap
Include substituted alkyl or unsubstituted alkyl.Substituent group in substituted alkyl can contain hetero atom, such as O, S, N or halogen
Element.Halogen of the invention includes but is not limited to fluorine, chlorine, bromine, iodine.C2-C6 miscellaneous alkyl can include but is not limited to linear heteroalkyl group
Or branched heteroalkyl groups；Preferably C2-C5 miscellaneous alkyl, more preferably C2-C3 miscellaneous alkyl.Miscellaneous alkyl of the invention refers on alkyl chain
Carbon atom replace the group to be formed by other hetero atoms.Above-mentioned hetero atom includes O, S or N, preferably includes O or S.Of the invention
The specific example of C2-C6 miscellaneous alkyl includes but is not limited to-CH2-O-CH3、-CH2-O-CH2CH3、-CH2-O-CH(CH3)CH3、-
CH2-S-CH3、-CH2-S-CH2CH3、-CH2-S-CH(CH3)CH3.C3-C6 naphthenic base may include the naphthenic base replaced and not take
The naphthenic base in generation；Preferably C5-C6 naphthenic base, more preferably C5 naphthenic base.The specific example packet of C3-C6 naphthenic base of the invention
It includes but is not limited to: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, 3- methylcyclopentyl, 3- methylcyclohexyl, 3- cyclohexyl
Base, preferably cyclopenta, cyclohexyl.C1-C6 alkoxy can include but is not limited to unbranched alkoxy or branched alkoxy；It is preferred that
For C1-C3 alkoxy, more preferably C1-C3 unbranched alkoxy.The example of C1-C6 alkoxy includes but is not limited to methoxyl group, second
Oxygroup, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isoamoxy, neopentyl oxygen,
Hexyloxy etc..C1-C6 alkylthio group can include but is not limited to straight-chain alkylthio or branched alkylthio；Preferably C1-C3 alkylthio group,
More preferably C1-C3 straight-chain alkylthio.The example of C1-C6 alkylthio group include but is not limited to methyl mercapto, ethylmercapto group, positive rosickyite base,
Isopropyisulfanyl, positive butylthio, isobutylthio, tertiary butylthio, positive penta sulfenyl, isopentylthio, new penta sulfenyl, own sulfenyl etc..According to
The specific embodiment of the present invention, R1~R5Separately it is selected from hydrogen, methyl or ethyl.
In formula (IV), R6Singly-bound, C1-3 alkylidene or C2-C5 miscellaneous alkyl can be selected from；More preferable R6Selected from singly-bound or
C1-3 alkylidene.
In formula (IV), singly-bound refer to two between atom or group with 1 valence covalent bond Direct Bonding.C1-6 alkylidene can
To include but is not limited to straight-chain alkyl-sub or branched alkylidene；Preferably C1-C3 alkylidene, more preferably C1-C3 straight chain alkylene
Base.The example of C1-C6 alkylidene includes but is not limited to methylene, ethylidene, sub- n-propyl, isopropylidene, sub- normal-butyl, sub- different
Butyl, sub- tert-butyl, sub- n-pentyl, isoamylidene, sub- neopentyl, hexylidene etc..In addition, C1-C6 alkylidene of the invention can
To include the alkylidene or unsubstituted alkylidene replaced.Substituent group in substituted alkylidene can contain hetero atom, such as
O, S, N or halogen.Halogen of the invention includes but is not limited to fluorine, chlorine, bromine, iodine.The Asia C2-C6 miscellaneous alkyl can include but is not limited to
Straight chain Asia miscellaneous alkyl or branch Asia miscellaneous alkyl；The preferably Asia C2-C5 miscellaneous alkyl, the more preferably Asia C2-C3 miscellaneous alkyl.Of the invention
Sub- miscellaneous alkyl refers to that the carbon atom on alkylidene chain replaces the group to be formed by other hetero atoms.Above-mentioned hetero atom include O, S or
N preferably includes O or S.Miscellaneous alkyl specific example in the Asia C2-C6 of the invention includes but is not limited to-CH2-O-CH2-、-CH2-O-
CH2CH2-、-CH2-O-CH(CH3)CH2-、-CH2-S-CH2-、-CH2-S-CH2CH2-、-CH2-S-CH(CH3)CH2-.According to this hair
A bright specific embodiment, R6Selected from singly-bound, methylene or ethylidene.
Formula (III) compound represented is that the phenyl ring of arctigenin passes through substituted or unsubstituted compound.Work as R1~R5
When being hydrogen, arctigenin is indicated；Work as R1~R5When for other substituent groups, the arctigenin of chemical modification is indicated.It can adopt
Substituent group is connected on phenyl ring with synthetic method well known in the art, details are not described herein.
Formula (IV) compound represented is halogenated acetylene compound, and one end has substituent X, can be with formula (III) institute
Condensation reaction occurs for the hydroxyl of the compound shown, and the other end has alkynyl, can send out with the azido of formula (V) compound represented
Raw click chemistry reaction.Work as R6When for singly-bound, halogenated acetylene, such as the bromo- 1- acetylene of 2- are indicated；Work as R6When for methylene, halogen is indicated
For propine, such as the bromo- 1- propine of 3-；Work as R6When for other substituent groups, other kinds of halogenated acetylene compound is indicated.It can adopt
These halogenated acetylene compounds are obtained with synthetic method well known in the art, details are not described herein.
In step (1), the molar ratio of formula (III) compound represented and formula (IV) compound represented can be 1:1
~3, preferably 1:1~2, more preferably 1:1.2.Reaction can carry out in acetone solvent.React depositing in basic catalyst
In lower progress, the example of basic catalyst includes but is not limited to potassium carbonate K2CO3Deng.Formula (III) compound represented is urged with alkalinity
The molar ratio of agent is 1:1~4, preferably 1:1.5~3, preferably 1:2.
According to embodiment of the present invention, by formula (III) compound represented, formula (IV) compound represented, carbon
Reaction vessel is added in sour potassium and acetone, reacts 5~20h in the case where temperature is 40~80 DEG C and stirring；Reaction product is poured into
In ice water, it is extracted with ethyl acetate 2~5 times, then washs extract liquor 2~5 times with saturated brine solution；By organic layer through nothing
Aqueous sodium persulfate is dry, filter, be concentrated under reduced pressure and column chromatographs to obtain intermediate product A.Formula (III) compound represented can be fructus arctii
Sub- aglycon etc..Formula (IV) compound represented can be bromo- 1- propine of 3- etc..In the reaction vessel, chemical combination shown in formula (III)
Object, formula (IV) compound represented are reacted under the catalytic action of potassium carbonate, the reaction time can be 5~20h, preferably 8~
15h.Gained reaction product is poured into after ice water, 2~5 times, preferably 2~3 times are extracted with ethyl acetate.Gained extract liquor is used
Saturated brine solution washs 2~5 times, preferably 2~3 times.Organic layer after washing is dried over anhydrous sodium sulfate, filter, is subtracted
Pressure concentration and column chromatograph to obtain intermediate product A.Dry, suction filtration, reduced pressure and column chromatography condition can use known in this field
Those of, details are not described herein.
In step (2) of the invention, intermediate product A is reacted with formula (V) compound represented, is obtained shown in formula (I)
Compound；
In formula (V), R7Selected from singly-bound, C1-6 alkylidene or the Asia C2-C6 miscellaneous alkyl；R8~R12It is identical or different, it is only respectively
On the spot it is selected from hydrogen, nitro, halogen, C1-C6 alkyl, C2-C6 miscellaneous alkyl, C3-C6 naphthenic base, C1-C6 alkoxy or C1-C6 alkane sulphur
Base；N3Indicate azido." alkylidene ", " sub- miscellaneous alkyl " mentioned herein, the substituent group range covered are above
It refers to, details are not described herein.A specific embodiment according to the present invention, R7Selected from singly-bound, methylene or ethylidene.
In formula (V), R8~R12It is identical or different, separately it is selected from hydrogen, nitro, halogen, C1-C6 alkyl, C2-C6
Miscellaneous alkyl, C3-C6 naphthenic base, C1-C6 alkoxy or C1-C6 alkylthio group.Preferably, R8~R12Separately it is selected from hydrogen, halogen
Element, C1-C3 alkyl, C2-C5 miscellaneous alkyl, C5-C6 naphthenic base, C1-C3 alkoxy, C1-C3 alkylthio group；It is highly preferred that R8~R12
Separately it is selected from hydrogen, halogen, C1-C3 alkyl or C1-C3 alkoxy." halogen ", " alkyl ", " miscellaneous alkane mentioned herein
Base ", " naphthenic base ", " alkylthio group ", the substituent group range covered are referred to above, and details are not described herein.According to this hair
A bright specific embodiment, R8~R12Separately it is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxyl group or second
Oxygroup.
In step (2) of the invention, point occurs for the alkynyl of intermediate product A and the azido of formula (V) compound represented
Chemical reaction is hit, to form the R base of formula (I) by the chemical structure in formula (V) compound represented molecule in addition to azido
Group.
The example of R group includes but is not limited to following group:
In some embodiments, R group is selected from one of following group:
According to embodiment of the present invention, R group is selected from one of following group:
The example of formula (V) compound represented includes but is not limited to compound listed by table 1.
Table 1
In step (2), the mixed solvent of fourth alcohol and water, the body of the in the mixed solvent fourth alcohol and water is can be used in reaction
Product is than being 1~10:1, preferably 1~5:1.The molar ratio of intermediate product A and formula (V) compound represented can be 1:1~3,
Preferably 1:1~2, more preferably 1:1.5.Intermediate product A is clicked in the presence of a catalyst with formula (V) compound represented
Chemical reaction, the catalyst can be the object well known in the art that can be catalyzed azido and react with alkynyl progress click chemistry
Matter, including but not limited to by cupric sulfate pentahydrate CuSO4·5H2The catalyst system of O and sodium ascorbate VC-Na composition.Work as use
Cupric sulfate pentahydrate CuSO4·5H2When O and sodium ascorbate VC-Na are as catalyst, intermediate product A and cupric sulfate pentahydrate
CuSO4·5H2O and sodium ascorbate VC-Na molar ratio can be 1:0.05~0.2:0.1~0.4, preferably 1:0.08~
0.15:0.15~0.3, more preferably 1:0.1:0.2.
According to embodiment of the present invention, step (2) are as follows: by the mixing for the fourth alcohol and water that volume ratio is 1~10:1
Solvent, molar ratio are 1:1~3:0.05~0.2:0.1~0.4 intermediate product A, formula (V) compound represented, five water sulfuric acid
Copper CuSO4·5H2Reaction vessel is added in O and sodium ascorbate VC-Na, reacts 12 in the case where temperature is 20~60 DEG C and stirring
~48h；Reaction product is poured into ice water, is extracted with ethyl acetate 2~5 times, organic layer is washed 2 with saturated brine solution~
It 5 times, is dried over anhydrous sodium sulfate, filters, being concentrated under reduced pressure and column chromatographs to obtain formula (I) compound represented.In reaction vessel, in
Between product A and formula (V) compound represented in cupric sulfate pentahydrate CuSO4·5H2It is anti-under the catalysis of O and sodium ascorbate VC-Na
It answers, reaction temperature can be 20~60 DEG C, preferably 30~50 DEG C；Reaction time can be 12~48h, preferably 15~30h.
Gained reaction product is poured into the ice water under stirring, is extracted with ethyl acetate 2~5 times, preferably extracts 2~3 times.
Gained extract liquor is washed into 2~5 times, preferably 2~3 times with saturated brine solution.Gained organic layer is done through anhydrous sodium sulfate
Dry, suction filtration, reduced pressure and column chromatograph to obtain formula (I) compound represented.Dry, suction filtration, reduced pressure and column chromatography condition
Can be using those of known in this field, details are not described herein.
<application>
Above compound of the invention has resisting toxoplasmosis activity, thus the present invention provides above compound and has in preparation
Application in the active drug of resisting toxoplasmosis.The compound of the present invention can be used for the clinical treatment of toxoplasma.By change of the invention
It closes object to mix with conventional excipient substance, obtains preparation.
<test method>
IR is using 1730 Fourier Transform Infrared Spectrometer of FT-IR (Shimadzu, Japan) measurement.
1H NMR and13C NMR is all made of the measurement of Bruker AV-300 (Bruker, Switzerland) nuclear magnetic resonance spectrometer, uses
Deuterated chloroform CDCl3As solvent.
Mass spectrum is measured using 1100-HPLC mass spectrograph (Agilent, the U.S.).
High resolution mass spec is using MALDI-TOF/TOF mass spectrograph (BrukerDaltonik, Germany) measurement.
Raw material used by following embodiments is known compound, is commercially available, or can be with known in the art
Method synthesis.
Embodiment 1
By arctigenin (100.44mg, 0.27mmol), the bromo- 1- propine (38.54mg, 0.324mmol) of 3-, potassium carbonate
(74.52mg, 0.54mmol) sequentially adds the round-bottomed flask of 25mL, and 15mL acetone solvent is then added.Reaction raw materials are slow
It is stirred to react 10h at this temperature after being heated to 60 DEG C.Reaction product is poured into ice water, is extracted with ethyl acetate 3 times (every time
With 15mL ethyl acetate).Extract liquor is washed 3 times with saturated brine.Organic layer is dried over anhydrous sodium sulfate, is filtered, depressurize it is dense
Contracting, column chromatograph to obtain intermediate product A.Intermediate product A is yellow, and the yield of intermediate product Ad is 90%.
The round-bottomed flask of 25mL is added in the mixed solvent (volume ratio of n-butanol and water is 1.5:1) of n-butanol and water,
Then intermediate product A (0.2mmol), azido compound V1 (1- (azido-methyl) benzene) (0.3mmol), five water sulfuric acid are sequentially added
Copper CuSO4·5H2O (0.02mmol) and sodium ascorbate VC-Na (0.04mmol).Reaction raw materials are heated to 38 DEG C to stir
It is reacted for 24 hours under state.Reaction product is poured into the ice water under stirring, 3 times is extracted with ethyl acetate and (uses every time
15mL ethyl acetate).Organic layer is washed 3 times with saturation NaCl aqueous solution, then with anhydrous sodium sulfate drying, suction filtration, decompression
Concentration, column chromatograph to obtain compound D1, yield 42%.
The above method is repeated 8 times, obtains identical intermediate product A and compound D1, and the yield of intermediate product A exists
Between 88~93%, the yield of compound D1 is 40~46%.This shows that preparation method technology stability of the invention is good.
D1 Structural Identification data are as follows:
1H NMR (300MHz, CDCl3): δ 7.54 (s, 1H, triazolone-H), 7.38-7.33 (m, 3H, Ar-H), 7.24 (s,
2H, Ar-H), 6.95 (d, J=8.1Hz, 1H, Ar-H), 6.75 (d, J=8.1Hz, 1H, Ar-H), 6.69 (d, J=1.6Hz,
1H, Ar-H), 6.63 (d, J=8.0Hz, 1H, Ar-H), 6.56-6.51 (m, 1H, Ar-H), 6.49 (s, 1H, Ar-H), 5.49
(s, 2H ,-CH2), 5.23 (s, 2H ,-CH2), 4.11 (dd, J=9.0,6.8Hz, 1H, 12-H), 3.89 (s, 1H, 12-H),
3.85 (s, 3H ,-OCH3), 3.82 (s, 3H ,-OCH3), 3.78 (s, 3H ,-OCH3), 2.93 (t, J=5.1Hz, 2H ,-CH2),
2.55 (ddd, J=24.9,13.7,5.1Hz, 4H ,-CH2, 8-H, 9-H).
13C NMR (75MHz, CDCl3): δ 178.67,149.71,149.03,147.88,146.53,144.62,
134.41,131.36,130.39,129.12,128.80,128.15,122.84,121.43,120.57,114.28,112.76,
111.84,111.38,71.24,63.30,55.92,55.88,55.84,54.22,46.52,41.11,38.16,34.54.
ESI-HRMS (m/z): C31H33N3NaO6[M+Na]+: calculated value 566.2267；Measured value 566.2264.
146~147 DEG C of fusing point.
Embodiment 2~12
Azido compound V1 is replaced with into azido compound V2~V12 respectively, remaining condition is same as Example 1, thus
It obtains compound D2~D12 (being detailed in Summary).Compound D2~D12 and compound D1 difference is only that R group
Difference, see Table 2 for details.
Table 2
Experimental example 1- test-compound influences viable count purpose
In order to study inhibiting effect of the compound D1~D12 to toxoplasma of embodiment 1~12, Trypan Blue has been carried out
Experiment.In order to reduce compound to the toxicity of host cell (HeLa), selecting concentration is the compound of 100 μm of ol/L for testing
Research, the morphological observation of the concentration versus cell is without influence.As shown in Figure 1, the activity of compound D1~D12 is stronger, especially
The resisting toxoplasmosis activity of compound D4, D7, D11 are stronger.
Experimental example 2- test-compound influences viable count purpose
Using the compound D1~D12 of MTT colorimetric method (T.gondii RH) testing example 1~12 to host cell
(HeLa) activity of cytotoxicity and external anti-tachyzoite.Preliminary detection difference compound administration concentration is in 100 μM/L pair
The basic fanout free region of host cell, to toxoplasma have it is preferable it is lethal on the basis of, this experiment tests 1~500 μ of every kind of compound
Cytotoxicity and resisting toxoplasmosis activity of the compound solution of M/L to host cell.From three independent experimental datas, calculatingization
Object is closed to the IC of arch insect infection HeLa cell50Value, compound are to the TD of HeLa cell50The selectivity index of value and compound
(SI).Dependence test result is recorded in table 3.
Table 3
In table 3, IC50Position inhibition concentration in expression, for measuring drug to the inhibitory effect of toxoplasma tachyzoite.TD50
Position toxicity dose in expression, for measuring the cytotoxicity to host cell.SI indicates selectivity index, therapeutic index or curative effect
Index, by TD50/IC50It calculates.Work as TD50When >=500.00, SI=500/IC50；Work as IC50When >=500.00, SI=TD50/500。
As shown in Table 1, compound D1~D12 all has resisting toxoplasmosis activity, and the selectivity of D2, D4, D7, D11 are more preferable.
The influence of experimental example 3- compound D4 and control compound to the host cell of toxoplasma gondii infection
As shown in Fig. 2, significant change has occurred in the growth conditions of the host cell through arch insect infection.Arch insect infection
There is shrinkage, rupture, death in cell, and cell quantity is significantly reduced compared with normal HeLa cells.The toxoplasma of spiramvcin treatment
The cell state of infection cell group is got well than the cell state of arch insect infection groups of cells, and cell activity is slightly restored, cell
Shrinkage degree reduces, and dead cell is reduced.Cell state in arctigenin experimental group is significantly better than spiramvcin group.Chemical combination
The cell state of object D4 experimental group restores substantially, and cell growth state is no different with normal cell.
The influence of experimental example 4- compound D4 and control compound to mouse peritoneal borer population
Resisting toxoplasmosis experiment has been carried out in Mice Body, has been commented by toxoplasma number in calculating each group mouse peritoneal
Estimate.Selection compound D4 is active further to study internal resisting toxoplasmosis.By establishing Acute Toxoplasma Gondii Infection animal model, even
Continuous administration 4 days.As shown in figure 3, compared with the control group, D4 and arctigenin can substantially reduce the number of toxoplasma tachyzoite
Amount, effect are better than the spiramvcin with dosage, and the better effect of compound D4.The inhibiting rate of compound D4 up to 75.13%, by
In arctiin tuple.When counting tachyzoite under an optical microscope, in abdominal cavity of the discovery with the mouse of compound D4 processing
Tachyzoite has wrinkle or deformity.
Present invention is not limited to the embodiments described above, without departing from the essence of the present invention, this field skill
Any deformation, improvement, the replacement that art personnel are contemplated that each fall within the scope of the present invention.
Claims (10)
1. a kind of compound based on arctigenin, which is characterized in that it is with structure shown in formula (I):
In formula (I), R1~R5It is identical or different, separately it is selected from hydrogen, C1-C6 alkyl, C2-C6 miscellaneous alkyl, C3-C6 cycloalkanes
Base, C1-C6 alkoxy or C1-C6 alkylthio group；R6Selected from singly-bound, C1-6 alkylidene or the Asia C2-C6 miscellaneous alkyl；R has formula (II)
Shown in structure:
In formula (II), R7Selected from singly-bound, C1-6 alkylidene or the Asia C2-C6 miscellaneous alkyl；R8~R12It is identical or different, separately
Selected from hydrogen, nitro, halogen, C1-C6 alkyl, C2-C6 miscellaneous alkyl, C3-C6 naphthenic base, C1-C6 alkoxy or C1-C6 alkylthio group.
2. compound according to claim 1, which is characterized in that R1~R5It is identical or different, separately selected from hydrogen or
C1-C3 alkyl；R6Selected from singly-bound or C1-C3 alkylidene；R7Selected from singly-bound or C1-C3 alkylidene；R8~R12It is identical or different, point
Not independently selected from hydrogen, halogen, C1-C3 alkyl or C1-C3 alkoxy.
3. compound according to claim 2, which is characterized in that R1~R5It is identical or different, separately selected from hydrogen,
Methyl or ethyl；R6Selected from singly-bound, methylene or ethylidene；R7Selected from singly-bound, methylene or ethylidene；R8~R12It is identical or not
Together, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, methoxy or ethoxy are separately selected from.
4. described in any item compounds according to claim 1~3, which is characterized in that R is selected from one of following group:
5. described in any item compounds according to claim 1~3, which is characterized in that R is selected from one of following group:
6. compound according to claim 1, which is characterized in that formula (I) compound represented be selected from following compound it
One:
7. the preparation method of described in any item compounds according to claim 1~6, which comprises the steps of:
(1) formula (III) compound represented is reacted with formula (IV) compound represented, forms intermediate product A；
In formula (III), R1~R5It is identical or different, separately it is selected from hydrogen, C1-C6 alkyl, C2-C6 miscellaneous alkyl, C3-C6 ring
Alkyl, C1-C6 alkoxy or C1-C6 alkylthio group；In formula (IV), R6Selected from singly-bound, C1-6 alkylidene or the Asia C2-C6 miscellaneous alkyl, X
Indicate that halogen, ≡ indicate alkynyl；
(2) intermediate product A is reacted with formula (V) compound represented, obtains formula (I) compound represented；
In formula (V), R7Selected from singly-bound, C1-6 alkylidene or the Asia C2-C6 miscellaneous alkyl；R8~R12It is identical or different, separately select
From hydrogen, nitro, halogen, C1-C6 alkyl, C2-C6 miscellaneous alkyl, C3-C6 naphthenic base, C1-C6 alkoxy or C1-C6 alkylthio group；N3
Indicate azido.
8. preparation method according to claim 7, it is characterised in that:
In step (1), by molar ratio be 1:1~3 formula (III) compound represented and formula (IV) compound represented in acetone
It is reacted in solvent, by catalyst of potassium carbonate, forms intermediate product A；
In step (2), by molar ratio be 1:1~3 intermediate product A and formula (V) compound represented fourth alcohol and water mixing
It is reacted in solvent, using copper sulphate and sodium ascorbate VC-Na as catalyst, obtains formula (I) compound represented.
9. preparation method according to claim 8, which is characterized in that comprise the following specific steps that:
(1) by molar ratio be 1:1~3:1~4 formula (III) compound represented, formula (IV) compound represented and potassium carbonate,
And reaction vessel is added in acetone solvent, reacts 5~20h in the case where temperature is 40~80 DEG C and stirring；Reaction product is fallen
Enter in ice water, is extracted with ethyl acetate 2~5 times, then washs extract liquor 2~5 times with saturated brine solution；Organic layer is passed through
Anhydrous sodium sulfate is dry, filter, be concentrated under reduced pressure and column chromatographs to obtain intermediate product A；
(2) mixed solvent for the fourth alcohol and water for being 1~10:1 by volume ratio, molar ratio be 1:1~3:0.05~0.2:0.1~
0.4 intermediate product A, formula (V) compound represented, cupric sulfate pentahydrate CuSO4·5H2O and sodium ascorbate VC-Na is added anti-
Container is answered, reacts 12~48h in the case where temperature is 20~60 DEG C and stirring；Reaction product is poured into ice water, with acetic acid second
Ester extracts 2~5 times, and organic layer is washed 2~5 times with saturated brine solution, is dried over anhydrous sodium sulfate, filters, is concentrated under reduced pressure
It chromatographs to obtain formula (I) compound represented with column.
10. described in any item compounds have answering in the active drug of resisting toxoplasmosis in preparation according to claim 1~6
With.
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