CN103936635B - Herba Houttuyniae derivant and the application in medicine thereof - Google Patents

Herba Houttuyniae derivant and the application in medicine thereof Download PDF

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CN103936635B
CN103936635B CN201410174713.XA CN201410174713A CN103936635B CN 103936635 B CN103936635 B CN 103936635B CN 201410174713 A CN201410174713 A CN 201410174713A CN 103936635 B CN103936635 B CN 103936635B
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alkyl
oxygen
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CN103936635A (en
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张健存
张英俊
谢洪明
关启明
官京鹏
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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Abstract

The present invention relates to a class Herba Houttuyniae derivant or this Herba Houttuyniae derivant its ester of its ester or enantiomer or diastereomer, geometric isomer, tautomer, hydrate, solvate, prodrug, or pharmaceutically acceptable salt.The invention still further relates to the preparation method of this kind of Herba Houttuyniae derivant and the application in medicine simultaneously；The invention still further relates to the pharmaceutical composition of the compounds of this invention, and can be used for being prepared in the purposes in antibacterial and antiviral drugs, it is particularly useful for treating various diseases of urinary system, its advantage is good water solubility, bioavailability is high, and purity is high, greatly reduce the toxicity because of the highest appearance of purity and stimulation.

Description

Herba Houttuyniae derivant and the application in medicine thereof
The application is filing date 2011.06.17, invention entitled " Herba Houttuyniae derivant and answering in medicine thereof With ", the divisional application of the invention of Application No. 201110172291.9.
Invention field
The invention belongs to chemical pharmacy field, particularly to class Herba Houttuyniae derivant and the application in medicine thereof.
Background technology
Herba Houttuyniae has another name called Herba Houttuyniae, Ji root, plucks youngster's root etc., for Saururaceae perennial herb, because of its stem and leaf rub with the hands broken after have Fishlike smell, therefore named Herba Houttuyniae.Herba Houttuyniae property and flavor of peppery and cold, has heat-clearing and toxic substances removing, the effects such as pouring, Herba Houttuyniae are gushed in detumescence and apocenosis, diuresis Preferable curative effect is all had for upper respiratory tract infection, bronchitis, pneumonia, chronic tracheitis, chronic cervicitis, pertussis etc., Acute conjunctivitis, urinary tract infection etc. are also had certain curative effect.It addition, Herba Houttuyniae can also enhancing human body immunity function, increase white thin Born of the same parents' phagocytic activity, has analgesia, cough-relieving, hemostasis, promotes tissue regeneration, expands the work of the aspect such as blood capillary, increase blood flow With.Therefore, Herba Houttuyniae often becomes about pneumonopathy, the principal agent of diseases of urinary system in tcm prescription.Herba Swertiae davidi element (caprinoyl second Aldehyde), its structural formula isIt is the main antimicrobial component of Herba Houttuyniae, its molecular structure pair Micrococcus catarrhalis, hemophilus influenza, streptococcus pneumoniae, staphylococcus aureus etc. have obvious inhibiting effect.
Neo-houttuyninum (Sodium New Houttuyfonate), structural formula is: It is the sodium sulfite addition product of Herba Swertiae davidi element, is the antibacterials chemically synthesized, both pharmacological actions and curative effect Basic simlarity.New houttuynine sodium bisulfite injection has recorded the most in the national drug standards at present.These product are antibiosis anti-inflammatory drug, for attached All kinds of inflammation of gynecological such as part inflammation, pelvic inflammatory disease, chronic cervicitis；And for upper respiratory tract infection, chronic bronchitis, pneumonia etc.. But owing to neo-houttuyninum raw water dissolubility is poor, neo-houttuyninum dissolubility in water is about 0.1mg/mL, only It is slightly soluble in water so that this medicine easily separates out during storing, have impact on the quality of this medicine, reduce the use of medicine to a certain extent Effect.And intramuscular injection during the use of this injection, owing to this medicine is likely to occur pain, the compliance of patient when intramuscular injection Poor.
Summary of the invention
The present invention relates to new Herba Houttuyniae derivant, be specifically related to its organic acid esters and inorganic acid ester analog derivative, and make For the purposes in anti-inflammation and antiviral drugs.
On the one hand, the present invention relates to a kind of Herba Houttuyniae derivant, its structure such as formula (I), (II), (III), (IV) or (V) institute Show:
Or its ester, enantiomer or diastereomer, geometric isomer, tautomer, hydrate, solvate, prodrug, or pharmaceutically may be used The salt accepted；Wherein, R1, R2, X1, X2And X3Shown in being defined as follows.
Wherein, X1Or X2It is each independently O or NH；X3For N；
R1For H,
R2For H, OH, SH, NH2Or-Y1-(CH2)n-Y2, wherein, n is 0～25；
Y1For CH2, O, S, arlydene, inferior heteroaryl or C=O；Y2For H, C1-C4Alkyl ,-OM ,-COOM, -NR3R4、-N+R3R4R5X-Or-NH3 +X-；
Wherein ,-(CH2)nAt least one CH in-2Can be at random by O, S, NH, arlydene, inferior heteroaryl ,-CH=CH-,-C ≡ C-or CO replaces；Described arlydene, inferior heteroaryl can be the most at random by C1-C6Chain alkylene, halogen, nitro, cyano group or Hydroxyl replaces；
X is F, Cl, Br or I；
Chain alkylene is alkyl, alkenyl or alkynyl；
M independently be H, C1-C6Alkyl, Li+、K+、Na+、Cs+Or N+R3R4R5R6；
M1Independently be Ca2+、Zn2+Or Mg2+；With
Each R3、R4、R5And R6Independently selected from H or C1-C10Alkyl；
And R1And R2At least one is not-H, and works as R1For-SO3During Na, R2It is not H；
And work as X3For N, R1For H, R2For-Y1-(CH2)2-Y2, and Y1During for O, Y2It is not NH2；
And work as X3For N, R1For H, R2For-Y1-CH2-Y2, and Y1For O, Y2For-COOM time；
M is not H or Na+。
Some embodiments wherein, the present invention relates to the compound as shown in formula (I),
Wherein, X1For O or NH；
R1For
R2For-Y1-(CH2)n-Y2, wherein, n is 1～10；
Y1For C=O；
Y2For-COOM, -NR3R4、-N+R3R4R5X-Or-NH3 +X-；
Wherein-(CH2)nAt least one CH in-2Can be at random by arlydene, inferior heteroaryl, S, NH ,-CH=CH-,-C ≡ C-or CO replaces；Described arlydene, inferior heteroaryl can be the most at random by C1-C6Chain alkylene, halogen, nitro, cyano group or Hydroxyl replaces.
In other embodiment, wherein,
X1For O；
R1For
N is 1 or 2；
Wherein-(CH2)nAt least one CH in-2Can be at random by arlydene, inferior heteroaryl, S, NH ,-CH=CH-,-C ≡ C-or CO replaces；Described arlydene, inferior heteroaryl can be the most at random by C1-C6Chain alkylene, halogen, nitro, cyano group or hydroxyl Base replaces.
Some embodiments wherein, the present invention relates to the compound as shown in formula (II),
Wherein, X2For O or NH；
R1For H,
R2For OH, NH2Or-Y1-(CH2)n-Y2, wherein, n is 0～25；
Y1For CH2, O, S, arlydene, inferior heteroaryl or C=O；
Y2For H, C1-C4Alkyl ,-OM ,-COOM, -NR3R4、-N+R3R4R5X-Or NH3 +X-；- (CH2)nAt least one or more CH in-2Can be at random by O, S, NH, arlydene, inferior heteroaryl ,-CH=CH-,-C ≡ C-or CO Replace；Described arlydene, inferior heteroaryl can be the most at random by C1-C6Chain alkylene, halogen, nitro, cyano group or hydroxyl take Generation.
In other embodiment, wherein,
X2Independently selected from O or NH；
R1Selected from H or
R2Selected from-Y1-(CH2)n-Y2, wherein, n is 1 or 2；
Y1Selected from CH2, arlydene, inferior heteroaryl or C=O；
Y2Selected from H, C1-C4Alkyl ,-OM ,-COOM, -N+R3R4R5X-Or NH3 +X-；
Wherein ,-(CH2)nAt least one CH in-2Can be at random by O, arlydene, inferior heteroaryl ,-CH=CH-,-C ≡ C- Or CO replaces；Described arlydene, inferior heteroaryl can be the most at random by C1-C6Chain alkylene, halogen, nitro, cyano group or hydroxyl Replace.
Some embodiments wherein, the present invention relates to the compound as shown in formula (III),
Wherein, X3For N；
R1For H；
R2For OH, NH2Or-Y1-(CH2)n-Y2, wherein, n is 0～25；
Y1For CH2, O, S, arlydene, inferior heteroaryl or C=O；
Y2For H, C1-C4Alkyl ,-OM ,-COOM, -N+R3R4R5X-Or NH3 +X-；-(CH2)nIn- At least one or more at random CH2Can be replaced by O, S, NH, arlydene, inferior heteroaryl ,-CH=CH-,-C ≡ C-or CO；Institute State arlydene, inferior heteroaryl can be the most at random by C1-C6Chain alkylene, halogen, nitro, cyano group or hydroxyl replace.
In other embodiment, wherein,
X3For N；
R1For H；
R2For OH, NH2Or-Y1-(CH2)n-Y2, wherein, n=0～25；
Y1For arlydene or inferior heteroaryl；
Y2For H, O, C1-C4Alkyl ,-OM ,-COOM, -N+R3R4R5X-Or NH3 + X-；-(CH2)nAt least one or more CH in-2Can at random be replaced by O ,-CH=CH-,-C ≡ C-or CO；Described arlydene, Inferior heteroaryl can be the most at random by C1-C6Chain alkylene, halogen, nitro, cyano group or hydroxyl replace.
Some embodiments wherein, the present invention relates to the compound as shown in formula (IV),
Wherein, X1Independently selected from O or NH；
R1For H,
R2For OH, SH, NH2,-Y1-(CH2)n-Y2, or there is the structure as shown in formula (V):
Wherein, n is 0～25；
Y1For CH2, O, S, arlydene, inferior heteroaryl or C=O；Y2For H, C1-C4Alkyl ,-OM ,-COOM, -NR3R4、-N+R3R4R5X-Or-NH3 +X-；
Described arlydene, inferior heteroaryl can be the most at random by C1-C6Chain alkylene, halogen, nitro, cyano group or hydroxyl Replace；
M independently be H, C1-C6Alkyl, Li+、K+、Na+、Cs+Or N+R3R4R5R6；
M1Independently be Ca2+、Zn2+Or Mg2+；With
Each R3、R4、R5And R6Independently selected from H or C1-C10Alkyl.
In other embodiment, wherein,
X1Selected from O；
R1For H,
R2For OH, SH, NH2,-Y1-(CH2)n-Y2, or there is the structure as shown in formula (V):
Wherein, n is 1,2,3,4,5 or 6；
Y1For CH2, O, S or C=O；
Y2For H, C1-C4Alkyl ,-OM ,-COOM,
Some embodiments wherein, described aryl is phenyl；With described heteroaryl be imidazole radicals, triazolyl, tetrazole radical, Thiazolyl, pyridine radicals, furyl, isoxazolyl, oxazolyl, pyrrole radicals or thienyl.
Some embodiments wherein, described M is Na+、K+Or N+R3R4R5R6；And M1For Ca2+、Zn2+Or Mg2+；Wherein, R3、R4、R5And R6Can be identical or different, it is each independently selected from H or C1-C4Alkyl.
On the other hand, the present invention relates to a kind of Pharmaceutical composition, its comprise the compound of at least one present invention or it Stereoisomer, geometric isomer, tautomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and Pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combinations thereof.
On the other hand, the present invention relates to compound or its stereoisomer, geometric isomer, the change of a kind of present invention Isomer, hydrate, solvate, pharmaceutically acceptable salt or the prodrug use in preparing anti-inflammation and antiviral drugs On the way.
On the other hand, the present invention relates to the pharmaceutical composition of a kind of present invention in preparing anti-inflammation and antiviral drugs Purposes.
Another aspect of the present invention relates to the preparation of compound, the separation that formula (I), (II), (III), (IV) or (V) is comprised Method with purification.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and The content of his aspect will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
The present invention will list the document corresponding to the content of the materialization determined in detail, and embodiment is all attended by structure Formula and the diagram of chemical formula.The present invention has and expectedly contains all of choice, variant and coordinate, and these may be as right Existing invention field it is included in like that defined in requirement.Those skilled in the art will identify many similar or equivalent to This described method and material, these can apply in the practice of the present invention.The present invention is limited to absolutely not method and material Description.Have a lot of document and similar material distinguish with the present patent application or conflict, including but be not limited to term Definition, the usage of term, the technology of description, or the scope controlled as the present patent application.
The present invention by defined below for application unless other aspects show.According to the purpose of the present invention, chemical element is according to unit Element periodic chart, CAS version and chemical drugs handbook, 75,thEd, 1994 define.It addition, organic chemistry General Principle is shown in " Organic Chemistry,"Thomas Sorrell,University Science Books,Sausalito:1999, and"March's Advanced Organic Chemistry,"by Michael B.Smith and Jerry March, John Wiley&Sons, New York:2007, the most all of content has all merged list of references.
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, as General formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention is comprised. Should be appreciated that " optionally substituted " this term and " substituted or non-substituted " this term can exchange use.It is said that in general, art Before language " optionally " is whether positioned at term " substituted ", represent that the one or more hydrogen atoms in given structure are by specifically Substituent group is replaced.Unless other aspects show, optional substituted radical can have a substituent group group each can Substituted position replaces.When in given structural formula, more than one position can be selected from the one or more of concrete group Substituent group is replaced, then substituent group can replace in each position identical or differently.Described substituent group is not it may be that but It is limited to (C1-C6) chain alkylene, halogen, nitro, cyano group or hydroxyl etc..
Terminology used in the present invention " chain alkylene ", represents straight chain (i.e. non-branched) or side chain, and substituted or non-substituted is complete Saturated or containing the hydrocarbon chain of one or more degrees of unsaturation, including alkyl, thiazolinyl and alkynyl.Unless otherwise detailed instructions, chain hydrocarbon Base group contains 1-20 carbon atom, and some of them embodiment is, chain alkylene group contains 1-10 carbon atom, and other is real Executing example is, chain alkylene group contains 1-8 carbon atom, and other embodiment is, chain alkylene group contains 1-6 carbon atom, Other embodiment is, chain alkylene group contains 1-4 carbon atom, and other embodiment is, chain alkylene group contains 1-3 Individual carbon atom.Suitably chain alkylene group includes, but is not limited to, straight or branched, substituted or non-substituted alkyl, alkylene Base, alkenyl or alkynyl group, such as methyl, ethyl, propyl group, butyl, pi-allyl, vinyl, the tert-butyl group, isopropyl etc..
Term " alkyl " all includes 1-20 carbon atom saturated straight chain or the univalence hydrocarbyl of side chain, and wherein alkyl can be independent Optionally replaced by one or more substituent groups described in the invention.Some of them embodiment is that alkyl group contains 1- 10 carbon atoms, other embodiment is, alkyl group contains 1-8 carbon atom, and other embodiment is, alkyl group Containing 1-6 carbon atom, other embodiment is, alkyl group contains 1-4 carbon atom, and other embodiment is, alkane Base group contains 1-3 carbon atom.Alkyl group further example includes, but is not limited to, methyl (Me ,-CH3), second Base (Et ,-CH2CH3), n-pro-pyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,- CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t- Bu ,-C (CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-amyl group (-CH (CH3)CH2CH2CH3), 3-amyl group (-CH (CH2CH3)2), 2-methyl-2-butyl (-C (CH3)2CH2CH3), 3-methyl-2-butyl (-CH (CH3)CH(CH3)2), 3-methyl- 1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butene base (-CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH3)CH2CH2CH2CH3), 3-hexyl (-CH (CH2CH3)(CH2CH2CH3)), 2- Methyl-2-amyl group (-C (CH3)2CH2CH2CH3), 3-methyl-2-amyl group (-CH (CH3)CH(CH3)CH2CH3), 4-methyl-2-penta Base (-CH (CH3)CH2CH(CH3)2), 3-methyl-3-amyl group (-C (CH3)(CH2CH3)2), 2-methyl-3-amyl group (-CH (CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C (CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH (CH3) C(CH3)3), n-heptyl, n-octyl, etc..Term " alkyl " and its prefix " alkane " are being used herein as, and all comprise straight chain and side chain Saturated carbon chains.Term " alkylene " is being used herein as, and represents that eliminating two hydrogen atoms from straight or branched saturated carbon hydride obtains The saturated bivalent hydrocarbon radical arrived, such example includes, but is not limited to, methylene, ethylidine, secondary isopropyl etc..
Term " alkenyl " represents 2-12 carbon atom straight chain or the monovalent hydrocarbon of side chain, and at least one of which position is not Saturation, i.e. one C-C is sp2Double bond, the group of its alkenyl groups can be individually optionally by one or more present invention Described substituent group is replaced.Some of them embodiment is, alkenyl group contains 2-10 carbon atom, other embodiment Being that alkenyl group contains 2-8 carbon atom, other embodiment is, alkenyl group contains 2-6 carbon atom, other Embodiment is, alkenyl group contains 2-4 carbon atom.Negation " just " or the location of " E " " Z " is had including group, the most concrete Example includes, but is not limited to, vinyl (-CH=CH2), acrylic, pi-allyl (-CH2CH=CH2), cyclobutenyl and 4-methyl Cyclobutenyl etc..
Term " alkynyl " represents 2-12 carbon atom straight chain or the monovalent hydrocarbon of side chain, and at least one of which position is insatiable hunger And state, i.e. one C-C is sp tri-key, and wherein alkynyl group can be individually optionally by one or more described in the invention Substituent group is replaced, and some of them embodiment is, alkynyl group contains 2-10 carbon atom, and other embodiment is, alkynyl Group contains 2-8 carbon atom, and other embodiment is, alkynyl group contains 2-6 carbon atom, other embodiment It is that alkynyl group contains 2-4 carbon atom.Concrete example includes, but is not limited to, acetenyl (-C three CH), propargyl (- CH2C tri-CH), etc..
Term " aryl " can be used alone or as the big portion of " aralkyl " " aralkoxy " or " aryloxy alkyl " Point, representing the monocycle containing 6-14 ring altogether, dicyclo, and the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic series , each of which member ring systems comprises 3-7 ring, and only one of which attachment point is connected with the remainder of molecule.Term " virtue Base " can use, as aromatic rings can include phenyl, naphthyl and anthracene with term " aromatic rings " exchange.And described aryl is permissible It is substituted or non-substituted.
Term " arlydene " represents that aryl systems has two junction points and is connected with molecule remainder.Wherein aromatic yl group Having implication as described in the present invention, such example includes, but is not limited to, phenylene, sub-fluorophenyl, xylene etc..
Term " heterocyclic radical " includes saturated containing heteroatomic ring group and heteroaryl, term " heterocycle ", " heterocyclic radical ", " miscellaneous alicyclic " or " heterocycle " are used interchangeably herein, refer both to monocycle, dicyclo, or three-ring system, on its medium ring one or Multiple atoms can be replaced by hetero atom individually optionally, and ring can be fully saturated or comprise one or more unsaturation Degree, including the fragrance same clan.One or more ring hydrogen atoms are individually optionally by one or more described in the invention taking Replaced for base.Some of them embodiment is, " heterocycle ", " heterocyclic radical ", " miscellaneous alicyclic " or " heterocycle " group are 3-7 rings Monocycle (1-6 carbon atom and selected from N, 1-3 the hetero atom of O, P, S, at this S or P optionally by one or more oxygen atoms Replaced and obtained as SO, SO2, PO, PO2Group, when described ring is three-membered ring, only one of which hetero atom), or 7- (4-9 carbon atom and selected from N, 1-3 the hetero atom of O, P, S, at this S or P optionally by one or more oxygen for the dicyclo of 10 yuan Atom is replaced to be obtained as SO, SO2, PO, PO2Group).
Heterocyclic radical can be carbon back or hetero atom base." heterocyclic radical " the most also includes heterocyclic group and saturated or part insatiable hunger With ring or heterocyclic fused formed group.The example of heterocycle includes, but is not limited to, pyrrolidinyl, tetrahydrofuran base, dihydro Furyl, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, Thiophene alkyl, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, glycidyl, Azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulfur azatropylidene base, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranose, 4H-pyranose, dioxacyclohexyl, 1,3-dioxy amyl group, pyrazolinyl, Dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinoline Base, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 3H-indyl Quinolizinyl and N-pyridine radicals carbamide.The example of heterocyclic group also includes, two carbon on 1,1-dioxidothiomorpholinyl, and its medium ring Atom is replaced such as hybar X base by oxygen atom.And described heterocyclic radical can be substituted or non-substituted, wherein substituent group It may be that but be not limited to, hydroxyl, amino, halogen, cyano group, aryl, heteroaryl, alkoxyl, alkyl, thiazolinyl, alkynyl, heterocycle Base, sulfydryl, nitro, aryloxy group etc..
The example of saturated heterocyclyl includes the saturated 3-8 unit heteromonocyclic group containing 1-4 nitrogen-atoms, such as pyrrolidinyl, Imidazolidinyl, piperidyl, pyrrolinyl, piperazinyl；The miscellaneous monocycle of saturated 3-8 unit containing 1-2 oxygen atom and 1-3 nitrogen-atoms Base, such as morpholinyl；Saturated 3-8 unit heteromonocyclic group containing 1-2 sulphur atom and 1-3 nitrogen-atoms, such as thiazolidinyl.
Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ", Representing the monocycle containing 5-14 ring altogether, dicyclo, and three-ring system, at least one of which member ring systems is aromatic, and at least One member ring systems comprises one or more hetero atom, and each of which member ring systems comprises 3-7 ring, and only one of which attachment point with Molecule remainder is connected.Term " heteroaryl " can exchange with term " heteroaromatic " or " heteroaromatics " and use.And Described heteroaryl can be substituted or non-substituted.
Other embodiment is, heteroaromatic includes following monocycle, but is not limited to these monocycles: imidazole radicals, triazole Base, tetrazole radical, thiazolyl, pyridine radicals, furyl, isoxazolyl, oxazolyl, pyrrole radicals, thienyl, 2-furyl, 3-furan Base, TMSIM N imidazole base, 2-imidazole radicals, 4-imidazole radicals, 5-imidazole radicals, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- Oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrole radicals, 2-pyrrole radicals, 3-pyrrole radicals, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, 2-pyrimidine radicals, 4-pyrimidine radicals, 5-pyrimidine radicals, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolium Base (such as 5-tetrazole radical), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl is (such as 2-pyrazoles Base), isothiazolyl, 1,2,3-di azoly, 1,2,5-di azoly, 1,2,4-di azoly, 1,2,3-triazoles base, 1,2,3- Thio biphosphole base, 1,3,4-thio biphosphole base, 1,2,5-thio biphosphole base, pyrazinyl, 1,3,5-triazines base；Also include following Dicyclo, but it is not limited to these dicyclos: benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2-indyl), Purine radicals, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl is (such as 1-isoquinolyl, 3-isoquinolyl Or 4-isoquinolyl) etc..
Term " inferior heteroaryl " represents that heteroaromatic system has two junction points and is connected with molecule remainder.Wherein heteroaryl Base group has implication as described in the present invention, and such example includes, but is not limited to, pyridylidene, sub-pyrrole radicals, sub-thiophene Oxazolyl, sub-imidazole radicals etc..
" cycloalkyl " refers to monovalence or multivalence, non-aromatic, and the unsaturated ring of saturated or part, including 3-12 carbon atom Monocycle or the bicyclo-of 7-12 carbon atom.The bicyclic carbocyclic ring with 7-12 atom can be bicyclo-[4,5], [5,5], [5,6] or [6,6] system, the bicyclic carbocyclic ring with 9 or 10 atoms can be bicyclo-[5,6] or [6,6] system.Suitably cycloalkyl Group includes, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of group of naphthene base farther includes, but never limits In, cyclopropyl, cyclobutyl, cyclopenta, 1-cyclopenta-1-thiazolinyl, 1-cyclopenta-2-thiazolinyl, 1-cyclopenta-3-thiazolinyl, hexamethylene Base, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, Ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, etc..And described " annular aliphatic ", carbocyclic ring ", " carbocylic radical " Or " cycloalkyl " can be substituted or non-substituted.
Halogen represents fluorine, chlorine, bromine or iodine atom.
Term " carboxyl ", is either used alone and is still used in conjunction, such as " carboxyalkyl ", expression-CO with other terms2H；Term " carbonyl " and " acyl group " is used interchangeably, and is either used alone and is still used in conjunction, such as " amino carbonyl " or " acyl-oxygen with other terms Base ", represent-(C=O)-.
Term " alkylthio group " includes C1-10The alkyl of straight or branched is connected on the sulphur atom of bivalence, wherein alkyl group There is implication as described in the present invention.Some of them embodiment is, alkylthio group is the C of lower level1-3Alkylthio group, such example Include, but is not limited to methyl mercapto (CH3S-), ethylmercapto group etc..
Term " aralkyl " includes the substituted alkyl group of aryl, and wherein aryl and alkyl group have as described herein Implication.Some of them embodiment is, aromatic alkyl group refers to that " aralkyl of lower level " group, i.e. aromatic yl group is connected to C1-6Alkyl group on.Other embodiment is that aromatic alkyl group refers to containing C1-3" the benzene alkylene " of alkyl.The most concrete Example includes benzyl, diphenyl methyl, phenethyl etc..And the aryl on aralkyl can be further by halogen, alkyl, alcoxyl Base, haloalkyl and halogenated alkoxy are replaced.
Term " alkyl amino " includes " N-alkyl amino " and " N, N-dialkyl amido ", and wherein amino group is independently Ground is replaced by one or two alkyl group, and wherein alkyl group has implication as described in the present invention.Some of them are implemented Example is, alkyl amino is one or two C1-6The alkylamino group of the lower level that alkyl is connected on nitrogen-atoms.Other Embodiment is, alkyl amino is C1-3The alkylamino group of lower level.Suitably alkylamino group can be monoalkyl ammonia Base or dialkyl amido, such example includes, but is not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N- Lignocaine etc..
Term " alkoxyl " used in the present invention, relates to alkyl, as defined in the present invention, by oxygen atom even Receive in main carbochain.Such example includes, but is not limited to, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, tertiary fourth Epoxide etc..
Term " alkyl acyl " includes the substituted carbonyl group of alkyl, and wherein alkyl and carboxyl groups have such as institute of the present invention The implication stated.Such example includes, but is not limited to, formoxyl, acetyl group, propiono, bytyry, tertiary bytyry etc..
Term " alkoxy acyl " includes the substituted acyl group of alkoxyl, and wherein alkoxyl and carboxyl groups have such as institute of the present invention The implication stated.Such example includes, but is not limited to, methoxyl group acyl group, ethoxyacyl, propoxyl group acyl group, butoxy acyl Base, tert-butoxy acyl group etc..
Unless other aspects show, structural formula described in the invention includes that all of isomeric forms is (as mapping is different Structure, diastereo-isomerism, and geometrical isomerism (or conformational isomerism)): such as contain R, S configuration of asymmetric center, (Z) of double bond, (E) isomer, and (Z), the conformer of (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or it is right Reflect isomer, diastereomer, or the mixture of geometric isomer (or conformer) and broadly fall into the scope of the present invention.
Term used in the present invention " prodrug ", represents a compound and is converted in vivo shown in formula (I) or (II) Compound.Such conversion hydrolyzed in blood by prodrug or blood or tissue in through enzymatic conversion be the shadow of precursor structure Ring.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class as prodrug, Aliphatic (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention A compound comprise hydroxyl, i.e. can be acylated the compound obtaining prodrug form.Other prodrug shape Formula includes phosphate ester, if these phosphate compounds are that the di on parent obtains.Complete about prodrug Whole discussion is referred to documents below: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008,51,2328-2345.
Unless other aspects show, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.It addition, unless other aspects show, the structural formula of compound described in the invention includes one or more different former The enriched isotope of son.
" metabolite " refers to that concrete compound or its salt is in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention Adopt as stating and experimentally characterize.Such product can be by passing through oxidation, reduction, water to drug compound Solving, amidated, desamido-effect, esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes compound Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.
The definition of neutral body of the present invention chemistry and the use of convention are typically referenced to documents below: S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons, Inc., New York, the compound of 1994. present invention can comprise asymmetric center or chiral centre, therefore There is different stereoisomers.The all of stereoisomeric forms in any ratio of compound of the present invention, include, but not limited to, diastereomeric Body, enantiomer, atropisomer, and their mixture, such as racemic mixture, constitute the part of the present invention. A lot of organic compound all exist with optical active forms, and i.e. they are had the ability the plane of Plane of rotation polarized light.Light is being described When learning reactive compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) use Name the symbol that compound linearly polarized light rotates, (-) or l refer to that compound is left-handed, prefix (+) or d refer to chemical combination Thing is dextrorotation.The chemical constitution of these stereoisomers is identical, but their stereochemical structure is different.Specific vertical Body isomer can be enantiomer, and the mixture of isomer is commonly referred to enantiomeric mixture.The enantiomer mixing of 50:50 Thing is referred to as racemic mixture or racemic modification, and this may cause not having stereo selectivity or three-dimensional fixed in chemical reaction process Tropism.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack light Learn activity.
Term " tautomer " or " tautomeric form " refer to that the isomers of the structure of different-energy is permissible Converted mutually by low energy barrier.Such as proton tautomer (the most prototropic tautomer) includes being migrated by proton Change, such as keto-enol and the isomerization of imine-enamine.Atomicity (quantivalence) tautomer includes Reassemble into the change of bonding electron.
Term " tautomer " or " tautomeric form " represent that the isomers of different-energy can be by relatively low The mutual inversion of phases of energy barrier.Such example includes, but is not limited to, and proton tautomer (i.e. prototropic change isomer) includes The isomerization of the change migrated by proton, such as keto-enol and imine-enamine.Atomicity tautomer bag Include the restructuring change of some bonding electronss.
" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Medicine On, acceptable salt is known to us at art, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66: 1-19,1977. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, anti-with amino group The inorganic acid salt that should be formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetate, Oxalates, maleate, tartrate, citrate, succinate, malonate, or pass through described on books document Additive method such as ion exchange obtains these salt.Other pharmaceutically acceptable salts include adipate, malic acid, 2-hydroxyl Base propanoic acid, alginate, Ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, Fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydroiodic acid Salt, 2-hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, Mesylate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- Phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, Valerate, etc..The salt obtained by suitable alkali includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.This Bright being also intended to contemplates the quaternary ammonium salt that the compound of the group of any comprised N is formed.Water solublity or oil-soluble or dispersion product Can be obtained by quaternization.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable Salt farther include suitable, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenide, hydrogen-oxygen Compound, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecule and the present invention is formed Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
The when that term " blocking group " or " Pg " referring to a substituent group and other reacted with functional groups, it is commonly used to resistance Disconnected or protect special functional.Such as, " blocking group of amino " refers to that a substituent group is connected with amino group and blocks Or amino functional in protection compound, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and 9-fluorenes Asia methoxycarbonyl group (Fmoc).Similarly, " hydroxy-protective group " refers to the replacement of hydroxyl Base is used for blocking or protect the functional of hydroxyl, suitable blocking group to include acetyl group and silicyl." carboxyl-protecting group Group " refer to the substituent group of carboxyl for blocking or protect the functional of carboxyl, general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-is (to toluene Sulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The description that group is general refers to document: T W.Greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.
Summary of the invention
The present invention carries out structure of modification to neo-houttuyninum, while keeping its pharmacologically active, improves water solublity, right The safety improving its clinical application has great importance.In order to realize this goal of the invention, present invention employs the medicine of prodrug Thing design principle, makes corresponding water solublity Herba Houttuyniae derivant, water solublity Herba Houttuyniae derivant such as formula provided by the present invention (I), shown in (II), (III), (IV) or (V):
Or its ester or enantiomer or diastereomer, geometric isomer, tautomer, hydrate, solvate, prodrug, Or pharmaceutically acceptable salt；Wherein, R1, R2, X1, X2And X3Shown in being defined as follows.
Wherein, X1Or X2It is each independently O or NH；
X3For N；
R1For H,
R2For H, OH, SH, NH2Or-Y1-(CH2)n-Y2, n is 0～25；
Y1For CH2, O, S, arlydene, inferior heteroaryl or C=O；
Y2For H, C1-C4Alkyl ,-OM ,-COOM, -NR3R4、-N+R3R4R5X-Or-NH3 +X-；- (CH2)nAt least one or more CH in-2Can be at random by O, S, NH, arlydene, inferior heteroaryl ,-CH=CH-,-C ≡ C-or CO Replace；Described arlydene, inferior heteroaryl can be the most at random by C1-C10Chain alkylene, halogen, nitro, cyano group or hydroxyl take Generation；
The above chain alkylene is alkyl, alkenyl or alkynyl；
X is F, Cl, Br or I；
Each M independently be H, C1-C6Alkyl, Li+、K+、Na+、Cs+Or N+R3R4R5R6；
Each M1Independently be Ca2+、Zn2+Or Mg2+；
R3、R4、R5And R6Can be identical or different, and each R3、R4、R5And R6It is each independently selected from H or C1-C10's Alkyl；
And R1And R2At least one is not-H, and works as R1For-SO3During Na, R2It is not H；
And work as X3For N, R1For H, R2For-Y1-CH2-Y2, and Y1For O, Y2For-COOM time；M is not H.
In some embodiments, the present invention has the compound as shown in formula (I),
Wherein, X1For O or NH；
R1For
R2For-Y1-(CH2)n-Y2, n is 1～10；
Y1For C=O；
Y2For-COOM, -NR3R4、-N+R3R4R5X-Or-NH3 +X-；
Wherein-(CH2)nAt least one or more CH in-2Can be at random by arlydene, inferior heteroaryl, S, NH ,-CH= CH-,-C ≡ C-or CO replaces；Described arlydene, inferior heteroaryl can be the most at random by C1-C6Chain alkylene, halogen, nitro, Cyano group or hydroxyl replace.
At other embodiment, X1For O；
R1For
N is 1 or 2；With
Wherein-(CH2)nAt least one or more CH in-2Can be at random by arlydene, inferior heteroaryl, S, NH ,-CH= CH-,-C ≡ C-or CO replaces；Described arlydene, inferior heteroaryl can be the most at random by C1-C6Chain alkylene, halogen, nitro, Cyano group or hydroxyl replace.
In some embodiments, the present invention has the compound as shown in formula II,
Wherein, X2For O or NH；
R1For H,
R2For H, OH, NH2Or-Y1-(CH2)n-Y2, n is 0～25；
Y1For CH2, O, S, arlydene, inferior heteroaryl or C=O；
Y2For H, C1-C4Alkyl ,-OM ,-COOM, -NR3R4、-N+R3R4R5X-Or NH3 +X-；
Wherein ,-(CH2)nAt least one CH in-2Can be at random by O, S, NH, arlydene, inferior heteroaryl ,-CH=CH-,-C ≡ C-or CO replaces；Described arlydene, inferior heteroaryl can be the most at random by C1-C6Chain alkylene, halogen, nitro, cyano group or Hydroxyl replaces.
At other embodiment, X2It is each independently O or NH；
R1For H or
Work as R1During for H, R2For-Y1-(CH2)n-Y2, n is 0～25；
Y1For CH2, arlydene, inferior heteroaryl or C=O；
Y2For H, C1-C4Alkyl ,-OM ,-COOM, -N+R3R4R5X-Or NH3 +X-；
Wherein ,-(CH2)nAt least one or more CH in-2Can at random by O, arlydene, inferior heteroaryl ,-CH=CH-,- C ≡ C-or CO replaces；Described arlydene, inferior heteroaryl can be the most at random by C1-C6Chain alkylene, halogen, nitro, cyano group Or hydroxyl replaces.
In other embodiment, wherein n is 1 or 2, and-(CH2)nAt least one CH in-2Can be at random by O, sub-virtue Base, inferior heteroaryl ,-CH=CH-,-C ≡ C-or CO replace；Described arlydene, inferior heteroaryl can be the most at random by C1-C6's Chain alkylene, halogen, nitro, cyano group or hydroxyl replace.
In some embodiments, the present invention has the compound as shown in formula III,
Wherein, X3For N；
R1For H；
R2For OH, NH2Or-Y1-(CH2)n-Y2, n is 0～25；
Y1For CH2, O, S, arlydene, inferior heteroaryl or C=O；
Y2For H, (C1-C4) alkyl ,-OM ,-COOM, -N+R3R4R5X-Or NH3 +X-；-(CH2)nIn- At least one or more at random CH2Can be replaced by O, S, NH, arlydene, inferior heteroaryl ,-CH=CH-,-C ≡ C-or CO；Institute State arlydene, inferior heteroaryl can be the most at random by C1-C6Chain alkylene, halogen, nitro, cyano group or hydroxyl replace.
At other embodiment, X3For N；
R1For H；
R2For OH, NH2Or-Y1-(CH2)n-Y2, n=0～25；
Y1For arlydene or inferior heteroaryl；
Y2For H, O, C1-C4Alkyl ,-OM ,-COOM, -N+R3R4R5X-Or NH3 +X-；
Wherein ,-(CH2)nAt least one or more CH in-2Can at random be replaced by O ,-CH=CH-,-C ≡ C-or CO；Institute State arlydene, inferior heteroaryl can be the most at random by C1-C6Chain alkylene, halogen, nitro, cyano group or hydroxyl replace.
In above-mentioned definition ,-OM ,-COOM, Described M or M1And both can be with chemical combination key key between oxygen atom With, again can with ionic bond key and, when each M independently be H, C1-C6Alkyl time, M with chemical combination key and oxygen atom key and, When M is Li+、K+、Na+、Cs+Or N+R3R4R5R6Or each M1Independently be Ca2+、Zn2+Or Mg2+Time, M or M1With oxygen atom it Between oxygen atom with ionic bond key and.
At-Y1-(CH2)n-Y2In, Y1During for arlydene, inferior heteroaryl, after "-(CH2)n-Y2" can be partly arbitrarily to close The link of reason position, such as, work as Y1During for phenylene ,-(CH2)n-Y2Can be the link of o-, m-or p-position at phenylene, i.e. Work as Y1During for pyridylidene ,-(CH2)n-Y2Permissible It is the connection being left 4 any rational positions of the position of substitution in addition to connecting parent position at pyridylidene, such asEtc..
“-(CH2)nAt least one or more CH in-2Can be at random by O, S, NH, arlydene, inferior heteroaryl ,-CH= CH-,-C ≡ C-or CO replaces " more specifically refer to as-(CH2)nA CH in-2By O, S, NH, arlydene, inferior heteroaryl ,- After CH=CH-,-C ≡ C-or CO replaces, it is respectively-(CH2)n-m-O-(CH2)m-1-,-(CH2)n-m-S-(CH2)m-1-,- (CH2)n-m-NH-(CH2)m-1-,-(CH2)n-m-(arlydene)-(CH2)m-1-,-(CH2)n-m-(inferior heteroaryl)-(CH2)m-1-,- (CH2)n-m-CH=CH-(CH2)m-1-,-(CH2)n-m-C≡C-(CH2)m-1-,-(CH2)n-m-CO-(CH2)m-1-, wherein 1≤m≤ N, the wherein remaining one or more CH in these groups2Can continue again at random by O, S, NH, arlydene, inferior heteroaryl ,- CH=CH-,-C ≡ C-or CO replaces, the like.
And as-(CH2)nCH in-2When being replaced by arlydene or inferior heteroaryl, connect arlydene or the position of inferior heteroaryl Can be any rational position, such as a CH2When being replaced by phenylene, i.e. at-(CH2)n-m-(phenylene)-(CH2)m-1 In ,-(CH2)n-mWith-(CH2)m-1-can be to be attached in six the position of substitution any two positions of phenyl ring, real at some Execute in example ,-(CH2)n-mWith-(CH2)m-1-on phenyl ring, sometimes become para-position, sometimes become meta, sometimes become ortho position；As a CH2Quilt When pyridylidene replaces, (CH2)n-m-(pyridylidene)-(CH2)m-1In ,-(CH2)n-mWith-(CH2)m-1-can be at pyridine ring 5 the position of substitution any two positions be attached.
The present invention comprises the structure of one of, or its stereoisomer, geometric isomer, tautomer, molten Agent compound, polymorph, metabolite, ester, pharmaceutically acceptable salt, prodrug, but it is not limited to following compounds:
The compositions of the compound of the present invention, preparation and administration
Another aspect of the present invention relates to pharmaceutical composition, it include at least one as formula (I), (II), (III), (IV) or (V) compound shown in, or its stereoisomer, geometric isomer, tautomer, hydrate, solvate, pharmaceutically Acceptable salt or prodrug, and pharmaceutically acceptable carrier, adjuvant, or excipient.And pharmaceutical carrier, adjuvant, or figuration Agent, described pharmaceutical composition can be prepared as various forms according to different way of administration.Compound mentioned by the present invention is also Various pharmaceutically acceptable salt can be prepared to.Present invention additionally comprises pharmaceutical composition, this pharmaceutical composition comprises as work The compound or pharmaceutically acceptable salt thereof as shown in formula (I), (II), (III), (IV) or (V) of property composition or pharmaceutically acceptable load Body.
As described in the invention, the pharmaceutically acceptable compositions of the present invention comprises pharmaceutically acceptable load further Body, adjuvant, or excipient, these are applied as the present invention, including any solvent, diluent, or other liquid excipients, point Powder or suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder or lubricant, etc., It is suitable for distinctive target formulation.As described by documents below: In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins, Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick And J.C.Boylan, 1988-1999, Marcel Dekker, New York, the most herein content of document, show different Carrier can be applicable to preparation and the preparation method known to them of pharmaceutically acceptable compositions.Carrier except any routine The scope that the compound of medium and the present invention is incompatible, such as produced any bad biological effect or with pharmaceutically can connect The interaction that any other component of the compositions being subject to produces in harmful manner, their purposes is also that the present invention is considered Scope.
Can include, but is not limited to as the material of pharmaceutically acceptable carrier, ion-exchanger, aluminum, aluminium stearate, ovum Phospholipid, serum albumin, such as human albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, saturated vegetable butter The partial glyceride mixtures of fat acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination Sodium, zinc salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymerization Body, lanoline, sugar, such as lactose, dextrose plus saccharose；Starch such as corn starch and potato starch；Cellulose and its derivant Such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate；Natural gum powder；Fructus Hordei Germinatus；Gelatin；Pulvis Talci；Adjuvant such as cacao bean Fat and suppository wax；Oil is such as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum Sesami, olive oil, Semen Maydis oil and Oleum Glycines；Glycols chemical combination Thing, such as propylene glycol and Polyethylene Glycol；Esters such as ethyl oleate and Ethyl Lauroyl acid esters；Agar；Buffer agent such as magnesium hydroxide and Aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethanol, phosphate buffer solution, and other are nontoxic Proper lubrication agent such as sodium laurylsulfate and magnesium stearate, coloring agent, releasing agent, coating agents, sweeting agent, flavoring agent and perfume (or spice) Material, preservative and antioxidant.
The compositions of the present invention can be oral administration, drug administration by injection, Aerosol inhalation, topical, and per rectum is administered, Nose administration, buccal administration, vagina administration or be administered by implantable medicine box.Term used herein " through injection " includes Subcutaneous, vein, intramuscular, IA, in synovial membrane (chamber), intrasternal, in film, ophthalmic, in liver, focus In, and the injection of intracranial or infusion techniques.Preferably compositions is oral administration, to Intraperitoneal medication or intravenous injection.This The injection system of the composition sterile of invention can be water or oleaginous suspension.These suspensions can be according to known skill Art uses suitable dispersant, wetting agent and suspending agent to press formula manufacture.Aseptic injection can be aseptic parenteral solution or suspension Liquid, is to inject nontoxic acceptable diluent or solvent, such as 1,3 butylene glycol solution.These acceptable excipient and solvents Can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, aseptic nonvolatile oil can be made by convention For solvent or suspension media.
With this end in view, the nonvolatile oil of any gentleness can be list or the DG of synthesis.Fat Acid, as oleic acid and its glyceride ester derivatives can be used for the preparation of injectable, as natural pharmaceutically acceptable oil Fat, such as olive oil or Oleum Ricini, particularly their polyoxyethylene deriv.These oil solutions or suspension can comprise long-chain Alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents, be generally used for the medicine system of pharmaceutically acceptable dosage form Agent includes emulsion and suspension.Other conventional surfactants, such as Tweens, spans and other emulsifying agents or biological medicament The hardening agent of efficiency, is generally used for pharmaceutically acceptable solid, liquid, or other dosage forms, it is possible to be applied to drug target The preparation of preparation.
The pharmaceutically acceptable compositions of the present invention can be to carry out oral administration with any acceptable peroral dosage form, its In include, but is not limited to, capsule, tablet, water suspension or solution.Orally using about tablet, carrier generally comprises breast Sugar and corn starch.Lubricant, such as magnesium stearate, is the most typically added.Capsule oral is administered, suitable diluent bag Include lactose and dry corn starch.When oral administration is water suspension, its effective ingredient is made up of emulsifying agent and suspending agent. If it is desired to obtain these dosage forms, some sweeting agent, flavoring agent or coloring agent can also be added.
It addition, the pharmaceutically acceptable compositions of the present invention can be with the form rectally of suppository.These can pass through Reagent is mixed with suitable non-perfusing accessory drugs and forms, this accessory drugs be at room temperature solid but at a temperature of rectum then For liquid, thus melt in the rectum and discharge medicine.Such material includes cocoa butter, Cera Flava, and polyethylene glycols.
Rectal suppository (see above content) or suitably enema can apply to the local application of lower intestine.Locally skin Skin speckle is it is also possible that medication.For local application, pharmaceutically acceptable compositions can be prepared as properly by formulation method Ointment, this ointment packets is suspended or dissolved in one or more carrier containing active component.Topical of the present invention supported Compound includes, but is not limited to mineral oil, liquid paraffin, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, breast Change wax and water.It addition, pharmaceutically acceptable compositions can be prepared as suitable lotion or Emulsion, this lotion or Emulsion comprise Active component is suspended in or is dissolved in one or more pharmaceutically acceptable carrier.Suitably carrier includes, but is not limited to, ore deposit Thing oil, Arlacel-60 (Arlacel-60), polysorbate60 (polysorbate 60), cetyl esters wax, palmityl alcohol, 2- Octyldodecanol, benzyl alcohol and water.
Preparation be can be prepared as, such as isotonic micronized suspension, pH for ophthalmically acceptable, pharmaceutically acceptable compositions The Sterile Saline of regulation or other aqueous solutions, it is preferable that isosmotic solution and the Sterile Saline of pH regulator or other aqueous solutions, permissible Add disinfection preservative such as benzalkonium chloride.It addition, for ophthalmically acceptable, pharmaceutically acceptable compositions can be by pharmaceutical formulation system Standby one-tenth ointment such as vaseline oil.The pharmaceutically acceptable compositions of the present invention can by the gaseous solvents of nose or inhalant carry out to Medicine.Such compositions can prepare according to the known technology of pharmaceutical formulation, or can be prepared as saline solution, uses benzene first Alcohol or other suitable preservative, absorption enhancer, fluorocarbon or other conventional solubilizing agents or dispersant improve biology Availability.
The liquid dosage form of oral administration includes, but is not limited to, pharmaceutically acceptable Emulsion, microemulsion, solution, suspends Liquid, syrup and elixir.In addition to the active compound, liquid dosage form can comprise known general inert diluent, such as, water Or other solvents, solubilizing agent and emulsifying agent, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, Propylene glycol, 1,3 butylene glycol, dimethylformamide, oils and fats (particularly Semen Gossypii, Semen arachidis hypogaeae, Semen Maydis, microorganism, Fructus Canarii albi, Semen Ricini and Oleum Sesami), glycerol, Tetrahydrofurfuryl Alcohol, Polyethylene Glycol, sorbitan alcohol fatty acid ester, and their mixture.Except lazy Outside the diluent of property, Orally administered composition can also comprise adjuvant such as wetting agent, emulsifying agent or suspending agent, sweeting agent, flavoring agent And aromatic.
Injection, as aseptic parenteral solution or oleaginous suspension can according to known technology use suitable dispersant, Wetting agent and suspending agent are prepared by pharmaceutical formulation.Aseptic injection can be nontoxic through the most acceptable diluent Or aseptic parenteral solution, suspension or the emulsion that solvent is made, such as, 1,3 butylene glycol solution.Acceptable excipient and solvent Can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.It addition, aseptic nonvolatile oil is by convention As solvent or suspension media.The nonvolatile oil of the most any gentleness can include that the list of synthesis or two glycosyl are sweet Oil diester.It addition, fatty acid such as oleic acid can apply to injection.
Injection can be aseptic, as filtered by antibacterial defence filter, or the form with aseptic solid composite Mix biocide, during biocide can be dissolved in or be scattered in disinfectant or other sterile injectable medium before use.In order to prolong The effect of the compound of the long present invention, it usually needs slowed down the absorption of compound by subcutaneous injection or intramuscular injection.So Can realize utilizing liquid suspension to solve crystal or the problem of amorphous material poorly water-soluble.The absorbance of compound depends on Its dissolution, depends on grain size and crystal shape successively.Furthermore it is possible to dissolved in oil vehicles by compound Or the delay having disperseed compound injection to be administered absorbs.
Injection storage form is to form chemical combination by biodegradable polymer, such as many lactic acid-polyglycolide The microcapsule matrix of thing completes.The controlled release ratio of compound depends on that compound forms ratio and the particular polymer of polymer Character.Other biodegradable polymers include poly-(positive esters) and poly-(anhydride).Injection storage form can also be passed through Compound embeds the liposome compatible with bodily tissue or microemulsion prepares.
The solid dosage forms of oral administration includes capsule, tablet, pill, powder and granule.In these dosage forms, active ingredient Thing mixes with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium phosphate or filler or a) Filler such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binding agent such as carboxymethyl cellulose, alginate, bright Glue, polyvidon, sucrose and arabic gum, c) wetting agent such as glycerol, d) disintegrating agent such as agar, calcium carbonate, potato starch Or tapioca, alginic acid, some silicate and sodium carbonate, e) blocker solution such as paraffin, f) absorption enhancer such as quaternary ammonium Compound, g) wetting agent such as hexadecanol and glyceryl monostearate, h) absorbent such as kaolin and Bentonite, i) lubricant such as Talcum Powder, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium laurylsulfate, and their mixture.As for capsule, tablet and ball Agent, these dosage forms can comprise buffer agent.
The solid composite of similar type can be that filler riddles soft or hard capsule, and the adjuvant used has breast Sugared and high molecular Polyethylene Glycol etc..Solid dosage forms photo agent, lozenge, capsule, pill and granule can pass through coating, shell adding Coating method as known on enteric coating and other drug preparation prepares.They can optionally comprise opacifier, or Preferably, in certain part of intestinal, at random, with the sole active agent in the method release composition of delay.As implanted Compositions can comprise multimeric species and wax.
Reactive compound can form microcapsule formulations together with one or more excipient described in the invention.Solid Dosage form photo agent, lozenge, capsule, pill and granule can pass through coating or shell adding, such as enteric coating, controlled release coat and other public affairs The drug formulation process known.In these solid dosage formss, reactive compound can mix with at least one inert diluent, such as sugarcane Sugar, lactose or starch.Such dosage form can also comprise substance besides inert diluents as general application, as Tableting lubricant and other compression aids such as magnesium stearate and microcrystalline Cellulose.As for capsule, tablet and pill, these dosage forms can To comprise buffer agent.They can optionally comprise tranquilizer, or preferably, in certain part of intestinal, with arbitrarily postpone Sole active agent in method release composition.Applicable implant compositions can include, but is not limited to, polymer and Wax.The various dosage forms of pharmaceutical composition of the present invention can be prepared according to the method known in pharmaceutical field.
Can carry out modifying to improve selectivity organism characteristic by the functional group of additional suitable by the compounds of this invention.This The modification of sample be known in the art and include to biological lacuna (such as blood, lymphsystem, central nervous system) infiltration, Improve Oral Availability, improve dissolubility so that drug administration by injection can be passed through, and changes metabolism and changes the modification of excretion.
The compound that the present invention relates to or its pharmaceutical salts or its hydrate have and prevent vascular permeability sexual abnormality from raising, and press down Erythrocyte processed and coagulating platelets, improve the effects such as microcirculation, can be used for preventing and treat adnexitis, pelvic inflammatory disease, chronic cervix uteri All kinds of inflammation of Yan Deng gynecological；And for diseases such as upper respiratory tract infection, chronic bronchitis, pneumonia.
Compound of the present invention can prepare pharmaceutical composition as effective ingredient together with pharmaceutically acceptable carrier, Its advantage is good water solubility, and bioavailability is high, and purity is high, greatly reduce because of the highest appearance of purity toxicity with Stimulation.
General building-up process
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I), (II), (III), (IV) or (V).Following reaction scheme and enforcement Example is used for being further illustrated by present disclosure.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to prepare perhaps suitably Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention , or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applicable to the preparation of other compounds of the present invention.
The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company, Alfa Chemical Company, and Sigma, the most not through being further purified, unless other aspects show during use.General reagent is from Shantou Chemical plant, western Gansu Province, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao is risen Dragon chemical reagent company limited, and Haiyang Chemical Plant, Qingdao is commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, N,N-dimethylacetamide and N, N- Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.
Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb the most suitable rubber closure, substrate is squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum with CDC13,d6-DMSO,CD3OD or d6-acetone is solvent (report is in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When multiplet occurs when, the abbreviation by following for use: s (singlet, unimodal), d (doublet, double Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant, represents with hertz (Hz).
By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) the spectrogrph of Agilent6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector Being applied to analyze, ESI source is applied to LC-MS spectrogrph.
Algorithm (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C) The spectrogrph of Agilent6120 series LC-MS measure, G1329A automatic sampler and the application of G1315D DAD detector In analysis, ESI source is applied to LC-MS spectrogrph.
Both the above spectrogrph is provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Note Beam is long-pending is to be determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength records reading.Flowing be mutually 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1:
Table 1
Compound purification is evaluated by Agilent1100 series of high efficiency liquid chromatograph (HPLC), wherein UV detection At 210nm and 254nm, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, and flow velocity is 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.
The use of brief word below runs through the present invention:
HOAc acetic acid
MeCN,CH3CN acetonitrile
BOC, Boc tert-butoxycarbonyl
DMF DMF
DMAP DMAP
DMSO dimethyl sulfoxide
DCC N, N-dicyclohexylcarbodiimide
EDC, EDCI 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
EtOAc/EA ethyl acetate
G gram
H hour
ML milliliter
MeOH,CH3OH methanol
CH2Cl2, DCM dichloromethane
HCO2Et Ethyl formate
TLC thin plate chromatographs
TFA trifluoroacetic acid
LC-Ms high performance liquid chromatography mass spectrum
PE petroleum ether (60-90 DEG C)
K2CO3Potassium carbonate
KOH potassium hydroxide
NaHCO3Sodium bicarbonate
NaOtBu sodium tert-butoxide
NaH sodium hydride
Na2SO4Sodium sulfate
THF oxolane
Et3N, TEA triethylamine
Synthetic method 1:
Compound 2 can be prepared by synthetic method 1, wherein R1, R2And X1There is implication as described in the present invention, Y For carboxyl, halogen etc., and R2-Y is alternatively anhydrides compound.Herba Houttuyniae or derivatives thereof 1 is in polarity or non-polar solven (as methanol, ethanol, oxolane, second eyeball, dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, ethyl acetate, third Ketone, hexamethylene, benzene, toluene etc. or a combination thereof), under alkaline environment, with R2-Y compounds is condensed, and through NaHCO3Solution processes, Obtain target compound 2.
Synthetic method 2:
Compound 4 can be prepared by synthetic method 2, wherein R1, R2And X2There is implication as described in the present invention. Compound 3 hendecane-2-ketone is dissolved in THF, is added thereto to sodium tert-butoxide, then add Ethyl formate, then with bromo-derivative R2There is addition condensation reaction in-Br, i.e. obtains target compound 4.
Synthetic method 3:
Compound 6 can be prepared by synthetic method 3, wherein R1, R2And X3There is implication as described in the present invention. Will R2-NH2It is dissolved in polar solvent (such as THF/H2O), in this system, Sodium Houttuyfonate 5 is then added, at 10～80 DEG C Under, stirring reaction 1～48 hour, raw material reaction is complete, i.e. obtains target compound 6.
Synthetic method 4
Compound 8 can be prepared by synthetic method 1, wherein R1, R2And X1There is implication as described in the present invention, Y For carboxyl, halogen etc., and R2-Y is alternatively anhydrides compound.New Herba Houttuyniae or derivatives thereof 7 is at polarity or non-polar solven In (as methanol, ethanol, oxolane, second eyeball, dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, ethyl acetate, Acetone, hexamethylene, benzene, toluene etc. or a combination thereof), under alkaline environment, with R2-Y compounds is condensed, and through NaHCO3At solution Reason, obtains target compound 8.
Preparation method of the present invention, parent material is known, it is possible to prepare according to known methods, or by business way Footpath obtains.Method described in the invention, its step can use alternate succession to carry out, and can carry out as required or It is followed by protection/deprotection steps.The method can additionally comprise and use suitable reaction condition, including atent solvent, additionally Reagent such as alkali, catalyst and above-mentioned salt form.Intermediate can be separated or carry out in position.
Embodiment
Embodiment 1
4-oxygen-4-((3-oxygen-1-sulfinic acid sodium dodecyl) epoxide) butanoic acid sodium salt
Taking 9.06g Sodium Houttuyfonate in four-hole bottle, nitrogen is protected.Add 150mL DMF, be stirred at room temperature.It is subsequently adding 9g succinic anhydride, instillation 21mL triethylamine, stirred overnight at room temperature.After liquid quality detection exists without raw material Sodium Houttuyfonate, in ice bath It is slowly added dropwise 5.04g saturated solution of sodium bicarbonate, after adding, is stirred at room temperature ten minutes.Filtering, in filter cake, a small amount of DMF remains with two Chloromethanes is washed off.Taking filter cake 4.2g in bottle, add 20mL water, add 20mL methanol, then it is even to be mixed after mixing, room temperature stands about 15 minutes.Filter, wash pigment with dichloromethane, drain, obtain title compound 2.66g.
MS (m/z): 379.2 [M-46]；
1H-NMR(D2O) δ 0.752 (t, 3H), 1.167 (m, 12H), 1.450 (t, 2H), 2.359 (t, 2H), 2.482 (t, 2H),2.557(t,2H),3.047(m,1H),3.163(m,1H),5.965(m,1H)。
Embodiment 2
2-(((3-oxygen-1-sulfinic acid sodium dodecyl) epoxide) carbonyl) benzoic acid sodium salt
In the round-bottomed flask of dry 100mL, 2.0g Sodium Houttuyfonate and 2.94g phthalic acid are suspended in 30mL In DMF, after stirring lower instillation 2.08g triethylamine, continue 3.5h is stirred at room temperature.After reaction completely, reaction bulb is placed in ice bath, Under stirring, saturated sodium bicarbonate solution is slowly instilled in reaction bulb, after regulation pH value is 8, continues stirring 5min, filter, filtering residue After washing with first alcohol and water (1:1,10mL) mixed liquor, it is white solid 1.0g that drying under reduced pressure obtains target compound, yield 32.2%, purity 95.7%.
MS (m/z): 425.8 [M-1]；
1H-NMR(D2O) δ 0.747 (t, 3H), 1.132 (m, 12H), 1.453 (m, 2H), 2.531 (m, 2H), 3.226 (d, 2H),6.179(t,1H),7.315(d,1H),7.381(m,1H),7.551(m,1H),7.826(d,1H)。
Embodiment 3
(Z)-4-oxygen-4-((3-oxygen-1-sodium sulfite dodecyl) epoxide) but-2-ene acid sodium-salt
Taking 906mg Sodium Houttuyfonate in four-hole bottle, nitrogen is protected.Add 15mL DMF, be stirred at room temperature.It is subsequently adding 882mg maleic anhydride, instillation 2.1mL triethylamine, stirred overnight at room temperature.Liquid quality detection exists without raw material Sodium Houttuyfonate After, ice bath is slowly added dropwise 504mgSaturated solution of sodium bicarbonate, is stirred at room temperature ten minutes after adding.Filter, a small amount of in filter cake DMF residual dichloromethane is washed off.Take filter cake 800g in bottle, add 4mL water, add 4mL methanol after mixing, then it is even to be mixed, Room temperature stands about 15 minutes, filters, washes pigment with dichloromethane, drain, obtain target compound 300mg.
1H-NMR(D2O) δ 0.750 (t, 3H), 1.132 (m, 12H), 1.453 (m, 2H), 2.531 (t, 2H), 3.226 (d, 2H),5.901(t,1H),6.491(d,1H),6.531(d,1H)。
Embodiment 4
(E)-3-oxygen 12-1-alkene-1-sodium sulfonate
In the 50mL acetone soln of 3.02g Sodium Houttuyfonate, 10g acetic anhydride and 15g Et it is separately added into when room temperature3N, Backflow reaction overnight LC-Ms detects Sodium Houttuyfonate after completion of the reaction, and cold filtration is spin-dried for filtrate acetic acid ethyl dissolution, uses Saturated NaHCO3Filtering after neutralization, obtaining target compound is 1.5g.
1H-NMR (MeOD) δ 0.898 (s, 3H), 1.300 (s, 12H), 1.597 (s, 2H), 2.665 (d, 2H), 6.687 (d,1H),7.214(d,1H)。
Embodiment 5
(Z)-2-((3-oxygen 12-1-alkene-1-base) epoxide) tert-butyl acetate
First 2.0g NaOt-Bu addition reaction bulb being done nitrogen protection, the rear 40mL THF of addition stirs 10 minutes, adds 3.4g hendecane-2-ketone is placed in room temperature reaction 15 minutes, drips 3.2mLHCO afterwards2Et, drips reaction 0.5 hour, concentrates, so After under nitrogen protection, add 40mL THF and dissolve, rear dropping 4.8mL BrCH2COOt-Bu, drips and is placed on room temperature reaction Overnight, determining reaction end with TLC, ethyl acetate extracts, and saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, and filters, reduces pressure dense Contracting, it is 930mg that residue obtains target compound by silica gel column chromatography (EtOAc/PE, 1:10 (v/v)).
1H-NMR(CDCl3) δ 0.887 (t, 3H), 1.306 (m, 21H), 1.567 (m, 2H), 2.673 (t, 2H), 4.921 (s,2H),5.146(d,1H),7.344(d,1H)。
Embodiment 6
(Z)-2-(2-methoxy ethoxy) ethyl 2-((3-oxygen 12-1-alkene-1-base) epoxide) acetas
Step 1) 2-(2-methoxy ethoxy) ethyl 2-bromacetate
In the 15mL dichloromethane solution of 1.42g bromoacetic acid, at room temperature add 2.29g DCC, after stirring ten minutes again Dripping 1.52g2-(2-methoxy ethoxy) ethanol in system, drip and be placed on room temperature reaction, TLC detection reaction is complete Rear filtration, washing filtrate is extracted with ethyl acetate, and saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, residual Stay thing to pass through silica gel column chromatography (EA:PE, 1:1 (v/v)) and obtain title compound 1.02g, yield 43%.
1H-NMR(CDCl3)δ3.304(s,3H),3.543(m,4H),3.652(t,2H),4.201(t,2H),4.261(s, 2H)。
Step 2) (Z)-2-(2-methoxy ethoxy) ethyl 2-((3-oxygen 12-1-alkene-1-base) epoxide) acetas
First 192mg NaOt-Bu addition reaction bulb being done nitrogen protection, the rear 5mL THF of addition stirs 10 minutes, adds 0.41mL hendecane-2-ketone is placed in room temperature reaction 15 minutes, rear dropping 0.16mL HCO2Et, drips reaction 0.5 hour, dense Contracting, the most under nitrogen protection, adds 5mL THF and dissolves, drip 528mg2-(2-methoxy ethoxy) ethyl 2-bromoacetic acid afterwards Ester, drips and is placed on room temperature reaction overnight, determines reaction end with TLC, and ethyl acetate extracts, and saturated sodium-chloride washs, nothing Aqueous sodium persulfate is dried, and filters, concentrating under reduced pressure, and residue obtains targeted by silica gel column chromatography (EtOAc/PE, 1:4 (v/v)) Compound 75mg.
1H-NMR(CDCl3) δ 0.893 (t, 3H), 1.311 (m, 12H), 1.367 (m, 2H), 2.891 (t, 2H), 3.301 (s,3H),3.543(m,4H),3.651(t,2H),4.201(t,2H),4.861(s,2H)5.141(d,1H),7.114(d, 1H)。
Embodiment 7
(Z)-3-oxygen 12-1-alkene-1-yl acetate
First 192mg NaOt-Bu addition reaction bulb being done nitrogen protection, the rear 5mL THF of addition stirs 10 minutes, adds 0.41mL hendecane-2-ketone is placed in room temperature reaction 15 minutes, rear dropping 0.16mL HCO2Et, drips reaction 0.5 hour, dense Contracting, the most under nitrogen protection, adds 5mL THF and dissolves, and rear dropping 0.208mL acetic anhydride drips and is placed on room temperature reaction Overnight, determining reaction end with TLC, washing ethyl acetate extraction, saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, and filters, subtracts Pressure concentrates, and residue obtains target compound 154mg by silica gel column chromatography (EtOAc/PE, 1:5 (v/v)).
1H-NMR(CDCl3) δ 0.862 (t, 3H), 1.278 (m, 12H), 1.343 (m, 2H), 2.129 (s, 3H), 2.882 (m,2H),5.567(d,1H),7.965(d,1H)。
Embodiment 8
(Z)-2-(2-(2-methoxy ethoxy) ethyoxyl) ethyl 2-((3-oxygen 12-1-alkene-1-base) epoxide) acetic acid Ester
Step 1) 2-(2-(2-methoxy ethoxy) ethyoxyl) ethyl 2-bromacetate
In the 15mL dichloromethane solution of 1.42g bromoacetic acid, at room temperature add 2.29g DCC, after stirring ten minutes again Dripping 2.80mL2-(2-(2-methoxy ethoxy) ethyoxyl) ethanol in system, drip and be placed on room temperature reaction, TLC examines Filtering after measured reaction, washing filtrate is extracted with ethyl acetate, and saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, and filters, subtracts Pressure concentrates, and residue obtains title compound 730mg by silica gel column chromatography (EA:PE, 1:1 (v/v)).
1H-NMR(CDCl3)δ3.302(s,3H),3.541(m,8H),3.648(m,2H),4.193(t,2H),4.262(s, 2H)。
Step 2) (Z)-2-(2-(2-methoxy ethoxy) ethyoxyl) ethyl 2-((3-oxygen 12-1-alkene-1-base) oxygen Base) acetas
First 192mg NaOt-Bu addition reaction bulb being done nitrogen protection, the rear 5mL THF of addition stirs 10 minutes, adds 0.41mL hendecane-2-ketone is placed in room temperature reaction 15 minutes, drips 0.16mLHCO afterwards2Et, drips reaction 0.5 hour, dense Contracting, the most under nitrogen protection, adds 5mL THF and dissolves, drip 624mg2-(2-(2-methoxy ethoxy) ethyoxyl) second afterwards Base 2-bromacetate, drips and is placed on room temperature reaction overnight, determines reaction end with TLC, and ethyl acetate extracts, saturated chlorination Sodium washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, and residue is obtained by silica gel column chromatography (EtOAc/PE, 1:4 (v/v)) To target compound 220mg.
1H-NMR(CDCl3) δ 0.893 (t, 3H), 1.310 (m, 12H), 1.365 (m, 2H), 2.911 (m, 2H), 3.301 (s,3H),3.543(m,8H),3.650(m,2H),4.203(t,2H),4.911(s,2H)5.143(d,1H),7.213(d, 1H)。
Embodiment 9
(Z)-2-(2-hydroxyl-oxethyl) ethyl 2-((3-oxygen 12-1-alkene-1-base) epoxide) acetas
Step 1) 2-(2-hydroxyl-oxethyl) ethyl 2-bromacetate
At room temperature adding 4.18mL triethylamine in the 20mL dichloromethane solution of 1.75mL bromoacetyl chloride, stirring is very Zhong Houzai drips 1.92mL2,2'-oxygen diethanol in system, drips and is placed on room temperature reaction, and TLC detects after completion of the reaction Filtering, washing filtrate is extracted with ethyl acetate, and saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, residual Thing obtains target compound 737mg, yield 16% by silica gel column chromatography (EA:PE, 1:1 (v/v)).
1H-NMR(CDCl3)δ3.402(t,2H),3.543(t,2H),3.647(t,2H),4.193(t,2H),4.264(s, 2H)。
Step 2) (Z)-2-(2-hydroxyl-oxethyl) ethyl 2-((3-oxygen 12-1-alkene-1-base) epoxide) acetas first general 313mg NaOt-Bu adds reaction bulb and does nitrogen protection, and the rear 5mL THF of addition stirs 10 minutes, add 0.67mL hendecane- 2-ketone is placed in room temperature reaction 15 minutes, drips 0.27mLHCO afterwards2Et, drips reaction 0.5 hour, concentrates, and then protects at nitrogen Protect down, add 5mL THF and dissolve, drip 737mg2-(2-hydroxyl-oxethyl) ethyl 2-bromacetate afterwards, drip and be placed on room Temperature reaction overnight, determines reaction end with TLC, and ethyl acetate extracts, and saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, and filters, Concentrating under reduced pressure, residue obtains target compound 190mg by silica gel column chromatography (EtOAc/PE, 1:2 (v/v)).
1H-NMR(CDCl3) δ 0.893 (s, 3H), 1.300 (m, 12H), 1.364 (m, 2H), 2.921 (t, 2H), 3.341 (t,3H),3.553(m,2H),3.650(t,2H),4.202(t,2H),4.917(s,2H)5.143(d,1H),7.221(d, 1H)。
Embodiment 10
(Z)-2-(2-(2-(2-hydroxyl-oxethyl) ethyoxyl) ethyoxyl) ethyl 2-((3-oxygen 12-1-alkene-1-base) oxygen Base) acetas
Step 1) 2-(2-(2-(2-hydroxyl-oxethyl) ethyoxyl) ethyoxyl) ethyl 2-bromacetate
At room temperature adding 4.18mL triethylamine in the 20mL dichloromethane solution of 1.75mL bromoacetyl chloride, stirring is very Zhong Houzai drips 4.32mL2,2'-((oxygen two (ethane-2,1-diyl)) two (oxygen)) diethanol in system, drips and is placed on Room temperature reaction, TLC detection is filtered after completion of the reaction, washes filtrate and is extracted with ethyl acetate, and saturated sodium-chloride washs, anhydrous slufuric acid Sodium is dried, and filters, concentrating under reduced pressure, and residue obtains target compound 630mg by silica gel column chromatography (EA:PE, 1:1 (v/v)).
1H-NMR(CDCl3)δ3.422(t,2H),3.551(m,10H),3.648(t,2H),4.194(t,2H),4.262 (s,2H)。
Step 2) (Z)-2-(2-(2-(2-hydroxyl-oxethyl) ethyoxyl) ethyoxyl) ethyl 2-((3-oxygen 12-1-alkene- 1-yl) epoxide) acetas
First 387mg NaOt-Bu addition reaction bulb being done nitrogen protection, the rear 5mL THF of addition stirs 10 minutes, adds 0.83mL hendecane-2-ketone is placed in room temperature reaction 15 minutes, drips 0.33mLHCO afterwards2Et, drips reaction 0.5 hour, dense Contracting, the most under nitrogen protection, adds 5mL THF and dissolves, drip 844mg2-(2-(2-(2-hydroxyl-oxethyl) ethyoxyl) afterwards Ethyoxyl) ethyl 2-bromacetate, drip and be placed on room temperature reaction overnight, determine reaction end with TLC, ethyl acetate extracts Take, saturated sodium-chloride wash, anhydrous sodium sulfate is dried, filter, concentrating under reduced pressure, residue by silica gel column chromatography (EtOAc/PE, 1:1 (v/v)) obtain target compound 177mg.
1H-NMR(CDCl3) δ 0.893 (t, 3H), 1.300 (m, 12H), 1.364 (m, 2H), 2.921 (t, 2H), 3.431 (m,2H),3.545(m,10H),3.650(t,2H),4.201(t,2H),4.921(t,2H)5.143(d,1H),7.321(d, 1H)。
Embodiment 11
(E)-2-(((3-oxygen dodecylene) amino) epoxide) ethyl acetate
Step 1) hydroxy carbamic acid tertiary butyl ester
By 61.9g Na under conditions of room temperature2CO3It is slowly dropped to 20g NH2The THF/H of OH.HCl2O (1:1, In system 300mL), 15min is stirred at room temperature.Then 76g Boc2O is slowly dropped in reaction system and in the process Keep system temperature at 25-30 DEG C, drip complete stirred overnight at room temperature.TLC detects NH2OH reaction is complete, filters, ethyl acetate Extraction filtrate, saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and filters, and concentrating under reduced pressure, residue passes through silica gel column chromatography (EtOAc/PE, 1:5 (v/v)) obtains target compound 26g.
Step 2) 2-(((tert-butoxycarbonyl) amino) epoxide) ethyl acetate
1.09g NaH is joined in batches the 40mL THF body of 3g hydroxy carbamic acid tertiary butyl ester under ice bath temperature Inside system, then 5.51mL bromoacetate is added drop-wise to this reaction system slowly, drips and complete be heated to 50 DEG C of stirred overnight. TLC detection guarantees that the reaction of hydroxy carbamic acid tertiary butyl ester is complete.It is down to room temperature and adds water until solution becomes clarification, acetic acid second Ester extracts, and saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, and filters, and concentrating under reduced pressure, residue passes through silica gel column chromatography (EtOAc/PE, 1:20 (v/v)) obtains title compound 3.6g.
Step 3) 2-(amino epoxide) ethyl acetate
9g2-(((tert-butoxycarbonyl) amino) epoxide) ethyl acetate is dissolved in 200mL dichloromethane, at room temperature 12.5mL TFA is slowly dropped to inside reaction system, drips complete continuation and stir.TLC detects after completion of the reaction, adds 200mL toluene is spin-dried for.Again with acetic acid ethyl dissolution, saturated sodium bicarbonate washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, Residue obtains target compound 4.76g by silica gel column chromatography (EtOAc/PE, 1:10 (v/v)).
Step 4) (E)-2-(((3-oxygen dodecylene) amino) epoxide) ethyl acetate
1.59g2-(amino epoxide) ethyl acetate being dissolved in 5mL THF is added dropwise to the most slowly The THF/H of 1.59g Sodium Houttuyfonate2In O (1:1 (v/v), 80mL) system, then 354mg NaHCO3Join reaction system The inside, stirred overnight at room temperature, TLC detection 2-(amino epoxide) acetic acid ethyl reaction complete good after, be extracted with ethyl acetate, saturated NaCl, anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, and residue passes through silica gel column chromatography (EtOAc/PE, 1:15 (v/ V) target compound 1.8g) is obtained.
MS(m/z):300.0[M+1]；
1H-NMR(CDCl3) δ 0.893 (t, 3H), 1.300 (m, 15H), 1.604 (m, 2H), 2.491 (m, 2H), 3.575 (d,2H),4.244(m,2H),4.641(d,2H),7.148(m,1H)。
Embodiment 12
(E)-2-(((3-oxygen dodecylene) amino) epoxide) tert-butyl acetate
Step 1) 2-(((tert-butoxycarbonyl) amino) epoxide) tert-butyl acetate
4.9g NaH is joined in batches the 150mL of 13.5g hydroxy carbamic acid tertiary butyl ester under ice bath temperature THF solution, then 43g bromo-acetic acid tert-butyl is added drop-wise to this reaction system slowly, drips and complete is heated to 50 DEG C of stirred overnight. TLC detection guarantees that the reaction of hydroxy carbamic acid tertiary butyl ester is complete.It is down to room temperature and adds water until solution becomes clarification, acetic acid second Ester extracts, and saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, and filters, and concentrating under reduced pressure, residue passes through silica gel column chromatography (EtOAc/PE, 1:5 (v/v)) obtains title compound 18.6g.
Step 2) 2-(amino epoxide) tert-butyl acetate
10g2-(((tert-butoxycarbonyl) amino) epoxide) tert-butyl acetate is dissolved in 200mL dichloromethane, in room temperature Lower 12.5mL TFA is slowly dropped to reaction system, drips complete continuation and stirs.TLC detects after completion of the reaction, adds 200mL Toluene is spin-dried for.Again with acetic acid ethyl dissolution, saturated sodium bicarbonate washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, residual Thing obtains title compound 5.6g by silica gel column chromatography (EtOAc/PE, 1:15 (v/v)).
Step 3) (E)-2-(((3-oxygen dodecylene) amino) epoxide) tert-butyl acetate
100mg2-(amino epoxide) tert-butyl acetate is dissolved in 4mL THF, and is slowly dropped at ambient temperature 513.6mg the THF/H of Sodium Houttuyfonate2In O (1:1 (v/v), 30mL) system, then 114.3mg NaHCO3Join reaction System, stirred overnight at room temperature, the complete good rear ethyl acetate extraction of TLC detection 2-(amino epoxide) tert-butyl acetate reaction, saturated NaCl, anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, and residue passes through silica gel column chromatography (EtOAc/PE, 1:15 (v/ V) title compound 790mg) is obtained.
1H-NMR(CDCl3) δ 0.887 (t, 3H), 1.300 (m, 12H), 1.386 (s, 9H), 1.594 (m, 2H), 2.480 (m,2H),2.874(d,2H),4.741(s,2H),7.488(m,1H)。
Embodiment 13
(Z)-1-((4-(hydroxymethyl) phenyl) amino) 12-1-alkene-3-ketone
When room temperature to the THF/H of 3.02g Sodium Houttuyfonate2O (1:1 (v/v), 80mL) system adds 0.615g to ammonia Base benzylalcohol, adds 1.68g NaHCO to this system after adding again3, it being stirred overnight, TLC detects to aminobenzyl alcohol after completion of the reaction Filtering, filtrate is extracted with ethyl acetate, and saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, and residue leads to Cross silica gel column chromatography (EtOAc/PE, 1:2 (v/v)) and obtain target compound 870mg.
MS(m/z):304.1[M+1]；
1H-NMR (d-DMSO) δ 0.850 (t, 3H), 1.243 (m, 12H), 1.500 (m, 2H), 2.316 (t, 1H), 2.394 (t,1H),4.416(m,2H),5.058(m,1H),5.414(m,1H),7.024(m,2H),7.231(m,1H),7.328(m, 2H),11.647(m,1H)。
Embodiment 14
(E)-4-((3-oxygen dodecylene) amino) sodium benzoate
Step 1) (E)-4-((3-oxygen dodecylene) amino) benzoic acid
At ambient temperature to the THF/H of 11g Sodium Houttuyfonate2O (1:1,200mL) system adds 2g p-aminophenyl first Acid, adds this system backward and adds 3.675g NaHCO3, it being stirred overnight, TLC detects para-amino benzoic acid mistake after completion of the reaction Filter, after neutralization, filtrate is extracted with ethyl acetate, and saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, and filters, concentrating under reduced pressure, residual Thing obtains title compound 1.1g by silica gel column chromatography (MeOH:DCM, 1:30 (v/v)).
Step 2) (E)-4-((3-oxygen dodecylene) amino) sodium benzoate
600mg (E)-4-((3-oxygen dodecylene) amino) benzoic acid is dissolved in 8mL THF, then adds full in system The NaHCO of sum3Solution regulation pH is 8, dissolves with methanol, filter, be spin-dried for after being spin-dried for solvent, and vacuum drying obtains target compound 597mg。
MS(m/z):318.1[M-23]；
1H-NMR (d-DMSO) δ 0.854 (t, 3H), 1.246 (m, 12H), 1.501 (m, 2H), 2.326 (t, 1H), 2.420 (t,1H),5.312(d,1H),5.549(d,1H),6.988(d,1H),7.076(d,1H),7.786(m,2H),7.972(m, 1H)。
Embodiment 15
(E)-1-((2-(2-hydroxyl-oxethyl) ethyl) imino group) dodecane-3-ketone
At room temperature to the THF/H of 24.16g Sodium Houttuyfonate2O (1:1,600mL) system adds 9.56mL2-(2-ammonia Base oxethyl) ethanol, add this system backward and add 3.675g NaHCO3, it being stirred overnight after adding, TLC detects 2-(2-amino Ethyoxyl) to filter after ethanol synthesis, after neutralization, filtrate is extracted with ethyl acetate, and saturated sodium-chloride washs, anhydrous sodium sulfate Being dried, filter, concentrating under reduced pressure, residue obtains target compound by silica gel column chromatography (MeOH:DCM, 1:25 (v/v)) 6.0g。
1H-NMR(CDCl3) δ 0.874 (t, 3H), 1.217 (m, 12H), 1.501 (m, 2H), 2.041 (m, 2H), 2.913 (s,2H),3.352(t,2H),3.445(t,2H),3.563(t,2H),3.631(m,3H),7.501(s,1H)。
Embodiment 16
(E)-3-oxygen dodecane oxime
At room temperature to the THF/H of 10g Sodium Houttuyfonate2O (1:1,200mL) system adds 2.76g hydramine, after adding Adding 2.8g NaOH to this system, be stirred overnight after adding, TLC detection is filtered after completion of the reaction, and filtrate extracts by ethyl acetate Take, saturated sodium-chloride wash, anhydrous sodium sulfate is dried, filter, concentrating under reduced pressure, residue by silica gel column chromatography (EA:DCM, 1: 6 (v/v)) obtain target compound 1.8g.
1H-NMR(CDCl3) δ 0.882 (t, 3H), 1.331 (m, 12H), 1.444 (m, 2H), 1.915 (m, 2H), 2.656 (s,1H),2.913(s,2H),7.245(s,1H)。
Embodiment 17
(Z)-4-oxygen-4-((4-((3-oxygen 12-1-alkene-1-base) amino) benzyl) epoxide) sodium butyrate
Step 1) (Z)-4-oxygen-4-((4-((3-oxygen 12-1-alkene-1-base) amino) benzyl) epoxide) butanoic acid
At room temperature to the 6mL CH of 200mg (Z)-1-((4-(methylol) phenyl) amino) 12-1-alkene-3-ketone2Cl2 Adding 86mg succinic anhydride, 80mg DMAP in system, be stirred overnight after adding, TLC detects (Z)-1-((4-(methylol) benzene Base) amino) wash with the citric acid of 10% after 12-1-alkene-3-reactive ketones, dichloromethane extracts, and anhydrous sodium sulfate is done Dry, filter, concentrating under reduced pressure, obtain title compound 150mg.
Step 2) (Z)-4-oxygen-4-((4-((3-oxygen 12-1-alkene-1-base) amino) benzyl) epoxide) sodium butyrate
150mg (Z)-4-oxygen-4-((4-((3-oxygen 12-1-alkene-1-base) amino) benzyl) epoxide) butanoic acid is dissolved in 6mL THF, then adds saturated NaHCO in system3Solution regulation pH is 8, dissolves with methanol, filter, be spin-dried for after being spin-dried for solvent, Vacuum drying, obtains target compound 120mg.
1H-NMR (MeOD) δ 0.885 (t, 3H), 1.291 (m, 12H), 1.497 (m, 2H), 2.739 (t, 2H), 2.836 (t,2H),2.944(m,2H),5.201(s,2H),5.362(d,1H),6.433(m,2H),7.113(d,2H),7.261(d, 1H)。
Embodiment 18
(Z)-2-(2-methoxy ethoxy) ethyl 4-((3-oxygen 12-1-alkene-1-base) amino) benzyl succinate
At room temperature to 150mg (Z)-4-oxygen-4-((4-((3-oxygen 12-1-alkene-1-base) amino) benzyl) epoxide) fourth The 6mL CH of acid2Cl2System is sequentially added into 58mg2-(2-methoxy ethoxy) ethanol, 9mgDMAP, 106mg EDCI, adds After be stirred overnight, TLC detect, wash with water after completion of the reaction, dichloromethane extract, anhydrous sodium sulfate is dried, filter, reduce pressure dense Contracting, column chromatography purification obtains target compound 139mg.
1H-NMR(CDCl3) δ 0.885 (t, 3H), 1.291 (m, 12H), 1.427 (m, 2H), 2.499 (m, 2H), 2.856 (m,4H),3.381(s,3H),3.542(m,4H),3.652(d,2H),4.211(d,2H),5.191(s,2H),5.361(d, 1H),6.521(m,2H),7.263(d,1H),7.287(m,2H)。
Embodiment 19
(Z)-2-(2-(2-methoxy ethoxy) ethyoxyl) ethyl 4-((3-oxygen 12-1-alkene-1-base) amino) benzyl Succinate
At room temperature to 150mg (Z)-4-oxygen-4-((4-((3-oxygen 12-1-alkene-1-base) amino) benzyl) epoxide) fourth The 6mL CH of acid2Cl2System is sequentially added into 79mg2-(2-(2-methoxy ethoxy) ethyoxyl) ethanol, 9mg DMAP, 106mg EDCI, is stirred overnight after adding, and TLC detects, and washes with water after completion of the reaction, and dichloromethane extracts, anhydrous sodium sulfate Being dried, filter, concentrating under reduced pressure, column chromatography purification obtains target compound 106mg.
1H-NMR(CDCl3) δ 0.886 (t, 3H), 1.291 (m, 12H), 1.484 (m, 2H), 2.493 (m, 2H), 2.858 (m,4H),3.301(s,3H),3.545(m,8H),3.652(d,2H),4.211(d,2H),5.121(s,2H)5.261(d, 1H),6.438(m,2H),7.217(m,2H),7.385(d,1H)。
Embodiment 20
2-(((3-oxygen-1-sodium sulfite myristyl) epoxide) carbonyl) sodium benzoate
In the round-bottomed flask of dry 100mL, 3.0g neo-houttuyninum and 4.03g phthalic anhydride are suspended in In 30mL DMF, after stirring lower instillation three 2.7g ethamine, continue 3.5h is stirred at room temperature.After reaction completely, reaction bulb is placed in ice In bath, under stirring, saturated sodium bicarbonate solution is slowly instilled in reaction bulb, after regulation pH value is 8, continue stirring 5min, mistake Filter, after filtering residue washs with first alcohol and water (1:1,10mL) mixed liquor, it is white solid 1.6g that drying under reduced pressure obtains target compound, receives Rate 35.1%, purity 93.3%.
MS(m/z):455.2[M-1]；
1H-NMR(D2O) δ 0.758 (t, 3H), 1.149 (m, 16H), 1.467 (m, 2H), 2.518 (m, 2H), 3.222 (d, 2H),6.179(t,1H),7.316(d,1H),7.391(m,1H),7.535(m,1H),7.821(d,1H)。
Embodiment 21
4-oxygen-4-((3-oxygen-1-sodium sulfite myristyl) epoxide) sodium butyrate
In the round-bottomed flask of dry 100mL, 3.0g neo-houttuyninum and 2.73g succinic anhydride are suspended in 30mL In DMF, after stirring lower instillation three 2.76g ethamine, continue 6.5h is stirred at room temperature.After reaction completely, reaction bulb is placed in ice bath, Under stirring, saturated sodium bicarbonate solution is slowly instilled in reaction bulb, after regulation pH value is 8, continues stirring 5min, filter, filtering residue After washing with first alcohol and water (1:1,10mL) mixed liquor, it is white solid 2.0g that drying under reduced pressure obtains target compound, yield 48.8%, purity 98.5%.
MS(m/z):407.2[M-1]；
1H-NMR(D2O) δ 0.774 (t, 3H), 1.206 (m, 16H), 1.470 (m, 2H), 2.382 (t, 2H), 2.503 (t, 2H),2.580(m,2H),3.109(m,2H),5.978(dd,1H)。
Biologic test
Following representational assay method, but it is not limited to these methods, will be used for evaluating the biology of the compounds of this invention Activity.
In vitro Bactericidal Experiments
The assay method of MIC value
1. antibacterial liquid medium within respectively is cultivated two days and one day in 25 DEG C and 37 DEG C.The bacterial strain of results is by measuring Bacteria concentration is adjusted to 105CFU/ml stand-by by OD600.
2. it is equipped with certain density testing compound with 100%DMSO.Twice dilution totally 11 concentration, last hole is 100%DMSO compares.Then by compound transfer 1ul to the Costa#3904 plate after dilution.Each bacterial strain chooses at least one Positive control.Secondary orifices is all done in all experiments.
3. by ready bacterial strain transfer 100ul/ hole to compound Costa#3904 plate.
4. brassboard is placed in 25 DEG C (antibacterials) and 37 DEG C of (antibacterial) incubators cultivate two days and one day respectively.
5. experimental result detects by an unaided eye and record.MIC value is can be with the Cmin of the compound of bacteria growing inhibiting.
Table 2 antibacterial activity in vitro (MIC50, μ g/ml)
Wherein, +++: MIC50＜ 1 μ g/ml；++: 1 μ g/ml ＜ MIC50＜ 10 μ g/ml；+: MIC50＞ 10 μ g/ml；NA: do not have There is test.
In vitro antibacterial test
Inhibitory action biosynthetic to varicella zoster virus
On 96 orifice plates, every hole adds 0.1mL5 × 104The MRC cell of concentration, 24h is after cell grows up to monolayer, with 10-6 Viral dilution liquid, every hole 50 μ L infection cell, absorption 2h after, abandon virus liquid, with cell maintain culture medium wash 1 time, according to The result of cytotoxicity experiment, selects in the range of non-toxic concn, and the pastille adding variable concentrations maintains liquid, and every day is aobvious in being inverted Observation of cell change under micro mirror.Each drug level sets two multiple holes, sets normal cell controls and virus control simultaneously.According to CPE observed result, abandons culture fluid supernatant when virus control CPE is for " +++～++++", and every hole adds the training containing 5mg/mL MTT Nutrient solution 50 μ L, after continuing to cultivate 2～3h, abandons supernatant, adds DMSO lysate every hole 50 μ L, and mixing, after 5～10 minutes, uses enzyme mark The optical density OD value at 570nm wavelength surveyed by instrument.And drug on viral suppression ratio according to the following formula.With Probit homing method Calculate medicine medium effective concentration (IC50)。
Viral suppression=drug treating group OD570 virus control group OD570 × 100%
Cell controls group OD570 virus control group OD570
Table 3 Anti-viral activity in vitro (Strain is VZV)
Embodiment IC50(μM)
01 A
02 A
03 A
04 B
05 A
06 C
07 D
08 A
09 B
10 C
11 C
12 B
13 A
21 A
Wherein, A:＜ 1 μM；B:1～10 μMs；C:20～30 μMs；D:＞ 30 μMs.
Antiviral assay in vivo
Experimental subject:
Female BAl BIc/c mice (5-7 week old, body weight 18-22 gram), mice needs 7 day laundering period, through inspecting conjunction after arriving It is grouped after lattice.
Respiratory syncytial virus (RSV) infects and drug treating flow process:
A)-6 and-1 day, mice is carried out lumbar injection Immunosuppressant Cyclophosphamide (100mg/kg).
B) RSV virus infect the same day be designated as 0 day, the previous day be-1 day, be+1 day one day after.
C) the rsv infection same day, mice is carried out pentobarbital intraperitoneal injection of anesthesia (80mg/kg).
Then the DMEM/F12 culture medium diluent using RSV carries out nasal infection to mice.
D) infect latter four days, put to death mice, take lung tissue for measuring virus titer.After mouse lung tissue takes out, make It is homogenized with 10% (wt/vol) Hanks buffer.External plaque assay measures Mus lung tissue virus titer.
E) the 0th day, inoculation HEp2 cell was in 12 orifice plates.
F) the 1st day, every part of tissue homogenate was inoculated in a cell hole.After viruses adsorption, use 0.5% agarose 12%DMEM/F12 culture medium covers in hole.12 orifice plates, at 37 DEG C, are cultivated 5 days under the conditions of 5%CO2.
G) the 6th day and the 7th day, orifice plate was also dyeed by fixing cell with immuning dyeing method.
H) 12 orifice plates are dried, and naked eyes read plaque number.Lung virus titer measurement unit is PFU/mg.
Table 4 interior resisting virus activity (Strain is RSV)
Result of the test shows, the compounds of this invention 400mg/kg gastric infusion, can significantly press down in mice rsv infection model System virus, plaque number and virus titer are below BMS-433771, show that compound antiviral activity is better than positive control chemical combination Thing BMS-433771.

Claims (9)

1. a compound, shown in its formula such as formula II or (III):
Or its pharmaceutically acceptable salt；
Wherein, R1For H or
X2When independently be O or NH, R2For H or-Y1-(CH2)n-Y2, wherein, n is 0～25；
Y1For CH2, phenylene or C=O；
X3During for N, R2For-Y1-(CH2)n-Y2, wherein, n is 0～25；
Y1For phenylene；
Y2For H, C1-C4Alkyl ,-OM or-COOM；
Wherein ,-(CH2)nAt least one CH in-2Can at random be replaced by O, S or CO；
M independently be H, K+Or Na+；
And R1And R2At least one is not-H, and works as R1For-SO3During Na, R2It is not H.
Compound the most according to claim 1, it has the compound as shown in (II),
Wherein, X2For O or NH；
R1For H or
R2For-Y1-(CH2)n-Y2, wherein, n is 0～25；
Y1For CH2, phenylene or C=O；
Y2For H, C1-C4Alkyl ,-OM or-COOM；
Wherein ,-(CH2)nAt least one or more CH in-2Can at random be replaced by O, S or CO.
Compound the most according to claim 2, wherein,
X2Independently selected from O or NH；
R1Selected from H or
R2Selected from-Y1-(CH2)n-Y2, wherein, n is 1 or 2；
Y1Selected from CH2, phenylene or C=O；
Y2Selected from H, methyl, ethyl ,-OM or-COOM；
Wherein ,-(CH2)nAt least one CH in-2Can at random be replaced by O or CO.
Compound the most according to claim 1, it has the compound as shown in formula (III),
Wherein, X3For N；
R1For H；
R2For-Y1-(CH2)n-Y2, wherein, n is 0～25；
Y1For phenylene；
Y2For H, C1-C4Alkyl ,-OM or-COOM；
Wherein ,-(CH2)nAt least one or more at random CH in-2Can be replaced by O, S or CO.
Compound the most according to claim 4, wherein,
X3For N；
R1For H；
R2For-Y1-(CH2)n-Y2, wherein, n=0～25；
Y1For phenylene；
Y2For H, methyl, ethyl ,-OM or-COOM；
Wherein ,-(CH2)nAt least one or more CH in-2Can at random be replaced by O or CO.
Compound the most according to claim 1, it is selected from following compounds:
7. a Pharmaceutical composition, it comprises the arbitrary described compound or pharmaceutically acceptable of at least one claim 1-6 Salt, and pharmaceutically acceptable carrier.
8. the compound as described in claim 1-6 is arbitrary or pharmaceutically acceptable salt are preparing anti-inflammation and disease-resistant Purposes in cytotoxic drug.
9. a pharmaceutical composition as claimed in claim 7 purposes in preparing anti-inflammation and antiviral drugs.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051803A2 (en) * 2000-12-22 2002-07-04 L'oreal Novel c-glycoside derivatives and use thereof
CN1657517A (en) * 2004-02-17 2005-08-24 李湛明 Synthesis method of new sodium decanoy acetal
WO2006072579A1 (en) * 2005-01-05 2006-07-13 Foundation For Fatal Rare Disease Pharmaceutically active antiviral peptides
CN101053566A (en) * 2006-04-14 2007-10-17 黄振华 Acetylcysteine or its salt and anti-infectious medicine composition
CN101659629A (en) * 2009-09-07 2010-03-03 广东中科药物研究有限公司 Houttuynin high water-solubility and stability prodrug and preparing method and application thereof
CN102066309A (en) * 2008-05-06 2011-05-18 西班牙高等科研理事会 Method for preparing oreganic acid

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002051803A2 (en) * 2000-12-22 2002-07-04 L'oreal Novel c-glycoside derivatives and use thereof
CN1657517A (en) * 2004-02-17 2005-08-24 李湛明 Synthesis method of new sodium decanoy acetal
WO2006072579A1 (en) * 2005-01-05 2006-07-13 Foundation For Fatal Rare Disease Pharmaceutically active antiviral peptides
CN101053566A (en) * 2006-04-14 2007-10-17 黄振华 Acetylcysteine or its salt and anti-infectious medicine composition
CN102066309A (en) * 2008-05-06 2011-05-18 西班牙高等科研理事会 Method for preparing oreganic acid
CN101659629A (en) * 2009-09-07 2010-03-03 广东中科药物研究有限公司 Houttuynin high water-solubility and stability prodrug and preparing method and application thereof

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