CN101426506A - Novel anthraquinones and process for the preparation and method of use thereof - Google Patents
Novel anthraquinones and process for the preparation and method of use thereof Download PDFInfo
- Publication number
- CN101426506A CN101426506A CNA2005800149655A CN200580014965A CN101426506A CN 101426506 A CN101426506 A CN 101426506A CN A2005800149655 A CNA2005800149655 A CN A2005800149655A CN 200580014965 A CN200580014965 A CN 200580014965A CN 101426506 A CN101426506 A CN 101426506A
- Authority
- CN
- China
- Prior art keywords
- anthraquinone
- reactant mixture
- replaces
- hydroxyl
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000004056 anthraquinones Chemical class 0.000 title claims abstract description 97
- 238000000034 method Methods 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 25
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims abstract description 16
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 201000006353 Filariasis Diseases 0.000 claims abstract description 6
- 208000030852 Parasitic disease Diseases 0.000 claims abstract description 6
- 201000004792 malaria Diseases 0.000 claims abstract description 4
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 claims description 88
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 36
- 239000000376 reactant Substances 0.000 claims description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- -1 halide salts Chemical class 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 244000045947 parasite Species 0.000 claims description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 10
- 241000196508 Turbatrix Species 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000004744 fabric Substances 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 7
- RGCKGOZRHPZPFP-UHFFFAOYSA-N Alizarin Natural products C1=CC=C2C(=O)C3=C(O)C(O)=CC=C3C(=O)C2=C1 RGCKGOZRHPZPFP-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
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- 239000002841 Lewis acid Substances 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- 239000011260 aqueous acid Substances 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 210000001365 lymphatic vessel Anatomy 0.000 claims description 4
- 238000000638 solvent extraction Methods 0.000 claims description 4
- JIIAPRPZEBHUFV-UHFFFAOYSA-N 1,2,3,5-tetrahydroxyanthracene-9,10-dione Chemical compound O=C1C2=C(O)C=CC=C2C(=O)C2=C1C=C(O)C(O)=C2O JIIAPRPZEBHUFV-UHFFFAOYSA-N 0.000 claims description 3
- ZYWJMFALERBARD-UHFFFAOYSA-N 2,3-dihydroxy-1-methylanthracene-9,10-dione Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C=C(O)C(O)=C2C ZYWJMFALERBARD-UHFFFAOYSA-N 0.000 claims description 3
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- 238000001727 in vivo Methods 0.000 claims description 3
- 230000001035 methylating effect Effects 0.000 claims description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- ABJNJFJDICFQPE-UHFFFAOYSA-N 2,3,8-trihydroxy-1-methylanthracene-9,10-dione Chemical compound O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(O)=C2C ABJNJFJDICFQPE-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
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- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 230000004927 fusion Effects 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 2
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 claims 3
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- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 230000001629 suppression Effects 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 201000004409 schistosomiasis Diseases 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 117
- 239000000047 product Substances 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 18
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 17
- PGSWEKYNAOWQDF-UHFFFAOYSA-N 3-methylcatechol Chemical compound CC1=CC=CC(O)=C1O PGSWEKYNAOWQDF-UHFFFAOYSA-N 0.000 description 16
- CCTOEAMRIIXGDJ-UHFFFAOYSA-N 4-hydroxy-2-benzofuran-1,3-dione Chemical compound OC1=CC=CC2=C1C(=O)OC2=O CCTOEAMRIIXGDJ-UHFFFAOYSA-N 0.000 description 16
- 241000244038 Brugia malayi Species 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
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- 239000003664 filaricide agent Substances 0.000 description 9
- 230000000507 anthelmentic effect Effects 0.000 description 8
- LAOOXBLMIJHMFO-UHFFFAOYSA-N 1-[2-(diethylamino)ethylamino]-4-methylthioxanthen-9-one;hydron;chloride Chemical compound Cl.S1C2=CC=CC=C2C(=O)C2=C1C(C)=CC=C2NCCN(CC)CC LAOOXBLMIJHMFO-UHFFFAOYSA-N 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000001843 schistosomicidal effect Effects 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 241000244005 Wuchereria bancrofti Species 0.000 description 6
- FUDDLSHBRSNCBV-UHFFFAOYSA-N 4-hydroxyoxolan-2-one Chemical compound OC1COC(=O)C1 FUDDLSHBRSNCBV-UHFFFAOYSA-N 0.000 description 5
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- 239000003814 drug Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- FRASJONUBLZVQX-UHFFFAOYSA-N 1,4-naphthoquinone Chemical compound C1=CC=C2C(=O)C=CC(=O)C2=C1 FRASJONUBLZVQX-UHFFFAOYSA-N 0.000 description 4
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- ZNWUXECLSWKRRH-UHFFFAOYSA-N 8-hydroxy-2,3-dimethoxy-1-methylanthracene-9,10-dione Chemical compound O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(OC)C(OC)=C2C ZNWUXECLSWKRRH-UHFFFAOYSA-N 0.000 description 3
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B1/00—Dyes with anthracene nucleus not condensed with any other ring
- C09B1/02—Hydroxy-anthraquinones; Ethers or esters thereof
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for the preparation of hydroxyl substituted anthraquinones is described. The process couples a phthalic anhydride (substituted or unsubstituted) to benzene ring moiety substituted with at least two hydroxyl groups. Remaining hydroxy groups were converted to methoxy groups in some anthraquinones. The compounds are particularly useful for the treatment of parasitic diseases. Also, a method of treating or preventing malaria, filariasis schistosomiasis and other parasitic diseases using anthraquinones.
Description
The cross reference of related application
The application requires the priority of U.S. Provisional Application serial number 60/570109 (submission on May 11st, 2004) and provisional application serial number 60/650552 (submission on February 7th, 2005).
Federal funding research and development statement
The present invention obtains the subsidy of National Institutes of Health Cooperative Agreement (national health academy's cooperation agreement) U01-A1153877-02 (MK) NIHR21TW0662501.There are certain rights and interests in U.S. government to the present invention.
Government rights statement
Not application
Background of invention
(1) invention field
The present invention relates to the anthraquinone that new hydroxyl replaces, and the preparation method of these chemical compounds.This anthraquinone also can replace hydroxyl to replace with methoxyl group.These chemical compounds are particularly useful for treatment malaria, schistosomicide and elephantiasis (filaricide) anthelmintic and other parasitic disease.Some new anthraquinone has been described.
Description of Related Art
Many parasitic disease are arranged.Especially filariasis of lymphatic vessels (elephantiasis) is the destructive disease that is caused by Wuchereriabancrofti and Bu Lu Turbatrix malayi spp..World Health Organization (WHO) estimates that the whole world has 1.2 hundred million people to infect, and wherein at least 4,000 ten thousand people's bodies and minds are all residual.This is that one of ballistic main public health problem of social economy (Ottesen, E.A., Trop.Med.Int.Hlth.5,591-594 (2000)) is brought in Africa, Asia, West Pacific region and America.These infection of about 90% are caused that by Wuchereria bancrofti other are caused by cloth Shandong Turbatrix spp.The mankind are unique host (Anonymous, The GlobalAlliance for the Elimination of Lymphatic Filariasis-epidemiology of W.bancrofti.Http://www.filariasis.org/2002)。
Comprise dihydroxy-and many quinones of trihydroxyanthraquinone be distributed widely in vegetable kingdom, and help plant pigment to form (Thomson, R.H., Naturally Occurring Quinonones, Academic Press, pp367-535, London (1971)).It is reported that Hemerocallis fulva L. kwanzakaempfer (Radix hemerocalis plicatae) root contains several anthraquinone derivatives, naphthalene glycosides and flavone (Tetrahedron 58 for Cichewicz, R.H. etc., 8597-8606 (2002)).In our early stage research, discovery isolated some anthraquinone from hemerocallitis,radix has activity to Schistosoma mansoni, and this is Schistosoma spp. parasitic a kind of (Cichewicz, the R.H. etc. that cause schistosomicide, Tetrahedron 58,8597-8606 (2002)).Schistosomicide also is a kind of debilitating disease that the distoma by the Schistosoma that has tormented the whole world 200,000,000 people causes.These active anthraquinones from hemerocallitis,radix are chemically examined filaricide parasite (cloth Shandong Turbatrix malayi), find that they have activity.The content of these active anthraquinones in hemerocallitis,radix is very low.
Excavate these active anthraquinones and analog thereof as parasitic disease to prevent and/or treat may using of agent also very important.Therefore, need synthetic these anthraquinones, with further evaluation its in vivo effectiveness and measure its toxicity, to determine its potentiality as the medicine of filaricide and schistosomicide.
The catalytic oxidation of having reported by the anthracene that obtains from coal tar prepares anthraquinone (Nanba, Y. etc., US 3870655 (1975) and Rodriguez, E etc., Separation Science andTechnology 24 275-289 (1989)).It also prepares by the friedel-crafts acylation reaction of diels-alder cycloaddition and employing suitable agent.By 1,4-naphthoquinone and 1 obtains anthraquinone (Boisvert, L., J.Org.Chem.53 4052-4059 (1988)) with gained three ring adduct dehydrogenations behind the diels-Alder reaction between the 3-diene.Yet, 1,4-naphthoquinone and 1, the preparation of 3-diene is very complicated also very expensive.
The friedel-crafts acylation reaction is one of reaction the most frequently used in the synthetic organic chemistry, and it passes through such as AlCl
3, BF
3, FeCl
3, TiCl
4And Sc (OTf)
3Louis acid catalysis (Olah, G.A., Friedel-Crafts and related reactions, Wiley Interscience, NY, II volume, part i (1964); Bensari, A. etc., Synthesis 267-271 (2003); Kotsuki, H. etc., Synthesis 603-606 (1999); And Kobayashi, S., Eur.J.Org.Chem.15-27 (1999)).Its mechanism relates to the formation of the acyl group ion intermediate that produces by the reaction between carboxylic acid derivates and the acid catalyst.
HF and BF have been reported with equimolecular quantity
3As catalyst, by the condensation of phthalic anhydride and benzene, the another kind of method of preparation anthraquinone.By with concentrated sulphuric acid heating or other cyclisation measures, the o-benzoylbenzoic acid that obtains is changed into corresponding anthraquinone then.The shortcoming of this method be from crude reaction mixture purification o-benzoylbenzoic acid, yield is low and the formation of sulfonated products (US 4379092 (1983) for Devic, M.).For fear of these shortcomings, can attempt under gas phase through solid catalyst reaction such as aluminosilicate (Yang, P. etc., Huaxue Shijie 34 258-260 (1993)) or titanium oxide (JP 61100543 (1986) for Akazawa, Y.).Yet these methods require high temperature and expensive device.
Purpose
Therefore the object of the invention provides anthraquinone or its methoxy derivatives that new hydroxyl replaces.In addition, the object of the invention provides with the anthraquinone of hydroxyl replacement or the new method of derivatives for treatment various diseases.In addition, the object of the invention provides the preparation method of this chemical compound.These and other purposes will be by becoming clearer with reference to following description.
The accompanying drawing summary
The anthraquinone that Fig. 1,2,4 and 5 expressions prepare by method of the present invention, and the intermediate that is used for this method.
Fig. 3 is the sketch map of preparation 3-hydroxyl phthalic anhydride.
Fig. 6 is H﹠amp; The cross-sectional view of the adult female cloth Shandong Turbatrix malayi of the painted common contrast of E.Common replicon is the structure microfilament larva Hey that contains as yet many good shapings of not discharging from the uterus in utero.Amplify 400 times.Calibration marker among Fig. 6-9 is represented 100 microns.
Fig. 7 is the longitudinal section of common bull B.malayi.Sectional view shows the nuclear of epidermis deep good organization.Amplify 40 times.
Fig. 8 is the morphologic profile of the adult female B.malayi that killed by the 5ppm compd B.Attention is along with the division Hey of intrauterine microfilament, the stable epidermis and the destruction of subcutaneous area.Amplify 400 times.
The profilograph of the bull B.malayi that Fig. 9 is killed by the 5ppm compd B.Note cyto-architectural obvious loss in the subcutaneous and DEEP STRUCTURE.Amplify 400 times.
Summary of the invention
Insert claim
The present invention relates to the preparation method of anthraquinone, comprising:
(a) in the fusion anhydrous mixture of lewis acid and alkali halide salts, the phenol that the phthalic anhydride of heating molar excess and hydroxyl replace in reactant mixture makes its reaction;
(b) reactant mixture of cooling step (a);
(c) in the reactant mixture of step (b), add aqueous acids, preparation acidylate anthraquinone;
(d) reactant mixture of reflow step (c), the preparation anthraquinone; With
(e) from reactant mixture, separate anthraquinone.
Lewis acid is known as mentioned above.Preferred anhydrous Aluminum chloride.Preferred salt is sodium chloride; But also available other halogenide (Br, I).Anhydrous basically anhydrous the carrying out of reagent used in this reaction.
Reactant mixture preferably heated about 4-5 hour down at about 165 ℃-185 ℃.The preferred aqueous hydrochloric acid of aqueous acids.Anthraquinone preferably separates from reactant mixture in step (e) by solvent extraction.Solvent ethyl acetate or diethyl ether.The separation of preferred anthraquinone is undertaken by chromatography.
The anthraquinone that the invention still further relates to the hydroxyl replacement that methylates prepares the method for the anthraquinone of methoxyl group replacement, comprising:
(a) in reactant mixture, anthraquinone that hydroxyl replaces and N-nitroso-group-N-methyl urea and potassium hydroxide are reacted in diethyl ether; With
(b) from reactant mixture, separate the anthraquinone that methoxyl group replaces.The anthraquinone that the preferred methoxyl group of methyl substituted anthraquinone replaces.Reactant mixture in the step (a) preferably cools off in ice bath.
Diethyl ether preferably evaporates from reactant mixture, and the anthraquinone that methoxyl group replaces also further separates by chromatography by solvent extraction.Solvent is preferably selected from ethyl acetate and hexane.
Also can be used for preparing the dimethoxy anthraquinone with the dimethyl sulfate in the dried solvent of dihydroxyanthraquinone reaction.Remove then and desolvate.Preferred solvent is an acetone.
The description of preferred embodiment
Chemical compound of the present invention is used for suppressing parasitic method, comprises parasite is exposed in the anthraquinone of the hydroxyl replacement that suppresses consumption.US patent 6800615 and 6835443 (having transferred commonly-assigned us) has been described vermifugal anthraquinone.U.S. Patent application serial number 10723671 (having transferred commonly-assigned us) is dividing an application of US patent 6800615 (having transferred commonly-assigned us).The serial number of submitting on January 20th, 2,004 10/761071 also is one and divides an application.Parasitic nematode (nematicide), flatworm (cestode) and trematodiasis (trematodiasis) cause the billions of people in the whole world, plant and animal to infect.Relevant parasite is the reason as the main economic loss of agricultural disaster.Human parasitic nematode belongs to together with other and comprises the Filaria parasite (for example Wuchereria Wuchereria bancrofti, Onchocerca volvulus, cloth Shandong Turbatrix malayi, cloth Shandong Turbatrix timori etc.) that causes such as several hundred million human diseases cases of river blind (riverblindness) and filariasis of lymphatic vessels together.The trial that prevents or treat the Animal diseases that caused by Filaria parasite Dirofilaria immitis (for example heartworm) only is exactly the industry of millions of dollar in the U.S..The nematicide species that many other mankind or veterinary are worth comprise ancylostome, whipworm and the acarid that causes iron deficiency anemia, growth retardation, intestinal malabsorption and/or obstruction.Human fluke infection comprises the infection that is caused by the pathogen of distoma hepaticum, fasciola gigantica and schistosomicide (Schistosoma japonicum, Schistosoma mansoni, live blood schistosomicide and the public schistosomicide of river bank), and these trematodiasiss can cause from hepatitis and ulcer to occlusion of bile duct, and to the clinical disease of the granulomatosis of liver, kidney, bladder and intestinal.Human fluke infection comprises various biologies, comprises Echinococcus, taeniasis bovis genus and T.Solium, wealthy joint two leaf groove worms, and various other " cestodes " belong to.The disease that is caused by trematodiasis is from the capsule disease to intestinal malabsorption with vitamin deficiency.
Cloth Shandong Turbatrix malayi spp. is the parasite of causing lymphatic vessel trematodiasis or malaria.Find that they can suppress by hydroxyanthraquinone.This parasite can be in vitro inhibition.This parasite also can suppress in vivo.The anthraquinone that hydroxyl replaces also can be that methoxyl group replaces.
Anthraquinone also is used for the treatment of tumor.This has description in the application Ser. No of submitting on May 10th, 2,004 10/355483 (having transferred commonly-assigned us).
The synthetic phenol by selected phthalic anhydride and replacement of the single step of anthraquinone analogs (A-N) is at AlCl
3/ NaCl exists down, and reaction realizes (Fig. 1 and 4).Phthalic anhydride with such as catechol, 1, reaction between the phenol of the replacement of 4-hydroquinone and pyrogaelol has prepared 1 respectively, 2-dihydroxy-(A), 1, the 4-dihydroxy-(E) with 1,2,3-trihydroxyanthraquinone (F), and provide 1 with resorcin reaction, 3-dihydroxyanthraquinone (D) and 3 ', 6 '-dihydroxy fluoran (D1).Yet, obtained respectively as 1 of major product and time product, 2-dihydroxy-3-tectoquinone (B) and 1-methyl-2,3-dihydroxyanthraquinone (C) with the reaction of 3-methyl catechol.The yield and the various base material of product is more interesting.The reaction of phthalic anhydride and catechol obtains 50% A, is respectively 60% and 15% B and C and obtain yield with 3-methyl catechol reaction.In addition, with 1, the reaction of 4-hydroquinone and pyrogaelol obtains 80% E and 75% F, and obtains 50% D and 20% D1 with resorcin reaction.The yield difference may be since in normotopia and para-position to the acidylate of hydroxyl.Because 1, do not have free para-position in the 4-hydroquinone, therefore in normotopia to acylated hydroxy, obtain high yield product E.In the reaction of pyrogaelol and phthalic anhydride, acyl group ion or replace 1-hydroxyl or 3-hydroxyl in normotopia perhaps at para-orientation 2-hydroxyl, obtains single product F.Yet, with the reaction of 3-methyl catechol in, the possible replacement of acyl group ion both can also can be carried out methyl in normotopia in normotopia or para-position to hydroxyl, obtained two kinds of different product B of productive rate and C.In the reaction of phthalic anhydride and resorcinol, the acyl group ion is potential to be substituted on 2,4 and 6.This reaction is because the high electron density that causes of steric hindrance and can be 2 generations, but obtains D at 4 and 6.Yet excessive resorcinol can obtain another kind of by-product D1.What is interesting is that catechol is because 3 and 6 replacement and only obtain product A.Be clear that very much, though the acyl group ion in 4 or 5 reactions of catechol because 3 or 6 ring closure, A also can be unique product.Also studied in the presence of all kinds of solvents and AlCl
3Freed-Ke come the just two acylation reactions (Fig. 2) of Ford.Though can select benzene, toluene and Nitrobenzol solvent be used for acylation reaction (Huffman, J.W. etc., J.Org.Chem., 37 487-490 (1972), we discover that Nitrobenzol is that Freed-Ke is come the unique effective solvent of Ford " positive acidylate " reaction.Compare AlCl
3/ C
6H
5NO
2And AlCl
3Reactivity between/NaCI melt and product yield are very important.Even yield is very low, AlCl
3/ C
6H
5NO
2System also needs 4 hours long periods (〉) and such as the high temperature more than 215 ℃, to finish reaction.The also available o-phthaloyl chloride 1a of this reaction replaces phthalic anhydride to carry out.O-phthaloyl chloride 1a prepared by handling phthalic acid with excessive thionyl chloride down at 80 ℃ in 2 hours.AlCl is used in this reaction under the same conditions
3/ C
6H
5NO
2Carry out.Product yield does not improve.Yet, if with 165 ℃ AlCl
3/ NaCl melt, it is faster that reaction is carried out, and obtain much higher yield (Fig. 2).Because the potential decomposition of phenolic compounds also may obtain low yield under higher temperature.
Anthraquinone J naturally occurringly in the hemerocallitis,radix has one of obvious active anthraquinone (Cichewicz, R.H. etc., Tetrahedron 59 8597-8606 (2002)) to Schistosoma mansoni.Find that also it also has activity to human nematosis worm B.malayi.Therefore, it is synthetic by Friedel-Crafts reaction that J and analog thereof are generally used 3-hydroxyl phthalic anhydride and 3-methyl catechol and hydroxyl phenol.Though the 3-hydroxyl phthalic anhydride is commercially available, it is for extensive synthetic and very expensive as synthetic fibers as the evaluation of medicine.Reported by maleic anhydride and the reaction of 2-silicohetane alcoxyl base furan, then with gained ring-type adduct aromatisation, prepare the diels-alder method (Asaoka, M. etc., Chem.Lett.167-170 (1977)) of 3-hydroxyl phthalic anhydride to differ from yield.It also can be by using 3-aminophthalic acid acid anhydride (Eliel, E.L. etc., J.Am.Chem.Soc., 77,5092-5095 (1955)) or 3,6-two iodo phthalic anhydride (Pratt, D.S. etc., J.Am.Chem.Soc.40 219-214 (1918)) as the synthetic fibers preparation, but its yield is very low.Reported the 3-hydroxyl phthalic anhydride (Nasman, J-H.N., synthesis 788-789 (1985)) of higher yields, with the more cheap raw material 2-oxo-2 that is purchased, the 5-dihydrofuran prepares the 3-hydroxyl phthalic anhydride.Therefore, we have synthesized the 3-hydroxyl phthalic anhydride with the more cheap 3-hydroxybutyrolactone that is purchased as raw material, as shown in Figure 3.In the presence of the concentrated sulphuric acid of catalytic amount, under 0 ℃, handle 3-hydroxybutyrolactone (3) with acetic anhydride, handle 100 ℃ then, obtain surpassing 5-hydrogen furan-2-ketone (4) of 90%.In the presence of triethylamine, under 0 ℃, make chemical compound 4 and trimethyl-aceyl chloride reaction then, obtain 2,2-neopentanoic acid 2-furan ester (5).The mixture overnight of stirring at room 5 and maleic anhydride forms diels-alder ring-type adduct 6 (1-(2,2-dimethyl propylene acyl group)-4,10-two oxatricyclo [5.2.1.0 then
2,6] last of the ten Heavenly stems-8-alkene-3, the 5-diketone).Then under-15 ℃ with concentrated sulphuric acid with the products therefrom aromatisation, obtain 3-hydroxyl phthalic anhydride (7).
The reaction of 3-hydroxyl phthalic anhydride and catechol obtains 1,2, the 8-trihydroxy-, 1,2,5-trihydroxy-and 2,3, three kinds of products of 8-trihydroxyanthraquinone (being respectively I, H and G).Yet the 3-methyl catechol obtains 1,2,8-trihydroxy-3-tectoquinone (J) and 1-methyl-2,3, two kinds of products of 8-trihydroxyanthraquinone (K).In addition, the 3-hydroxyl phthalic anhydride with such as resorcinol, 1, the reaction of other phenol of 4-hydroquinone and pyrogaelol has prepared 1,3 respectively, 5-trihydroxy-(L), 1,4,8-trihydroxy-(M) and 1,2,3,5-tetra hydroxyanthraquinone (N).Ironically excessive resorcinol can obtain a kind of by-product 4 in the reactant mixture, 3 ', 6 '-trihydroxy fluoran (L1).
The reaction of phthalic anhydride and catechol obtains G and each 10% H and I of 30%.Equally, 3-methyl catechol and phthalic anhydride obtain the J and the K of yield 30% and 15% respectively.Equally, phthalic anhydride and resorcinol, 1, the reaction of 4-hydroquinone and pyrogaelol obtains 35% L, 55% M and 50% N respectively.Yet excessive catechol can obtain 40% L and 20% L1.The change list of yield is understood in normotopia and the para-position acyl group ionic replacement to hydroxyl.1, do not have free para-position in the 4-hydroquinone, so the acyl group ionic replacement only carries out to hydroxyl on normotopia, obtain single product M.In pyrogaelol, the acyl group ion had both replaced the 1-hydroxyl in normotopia, also replaced the 3-hydroxyl, obtained product N.Yet, in the 3-methyl catechol, possible acyl group ionic replacement otherwise in normotopia and para-position to hydroxyl, or on normotopia, methyl is carried out, thereby obtains two kinds of different product J and K.The reaction of phthalic anhydride and resorcinol shows the replacement on 2,4 and 6.Because the steric hindrance (although it has very high electron density) on 2, this reaction can not carried out on this position yet, but carries out on 4 and 6, obtains the L of normotopia and/or para-position hydroxyl.Yet resorcinol excessive in the reactant mixture can obtain by-product L1.
For the relation between research structure-activity, prepared the methyl and the methoxy derivatives of anthraquinone.Hydroxyl is protected by methylating.Anthraquinone B and J at room temperature carry out with the Azimethylene. in the ether in the selectivity monomethylization at 2-hydroxyl place, obtain 1-hydroxyl-2-methoxyl group-3-tectoquinone (O) and 1,8-dihydroxy-2-methoxyl group-3-tectoquinone (Q).Anthraquinone K and CH
2N
2Similar methylating obtain dimethyl product 1-methyl-2,3-dimethoxy-8-hydroxyanthraquinone (S).Yet, the Dimethylsulfate/K in anthraquinone B, J and K and the acetone
2CO
3At room temperature obtain 1 respectively, 2-dimethoxy-3-tectoquinone (P), 1,2-dimethoxy-8-hydroxy-3-methyl anthraquinone (R) and 1-methyl-2,3-dimethoxy-8-hydroxyanthraquinone (S).Compound C, K, N, R and S are new.
Test
Phthalic anhydride and 3-hydroxyl phthalic anhydride (can buy or synthetic), catechol, 3-methyl catechol, resorcinol, 1,4-anthraquinone, pyrogaelol, anhydrous AlCl
3All buy with NaCl from Sigma-Aldrich.At Varian VRX instrument is to write down the 500MHz place
1H and
13CNMR (DMSO-d
6Or CDCl
3).DMSO-d
6And CDCl
3From Cambridge IsotopeLaboratories, Inc., Andover, MA buys.With Shimatzu (UV-260) spectrophotometer record CH
3The UV-VIS spectrum of OH.C-18 silica gel (32-63 μ m) is from FisherScientific, and PA obtains.
The preparation of 5-hydrogen-furan-2-ketone (4):
In RB, mix 3-hydroxybutyrolactone (3) (10mmol, 0.779ml) and acetic anhydride (10mmol, 0.95ml), and at 0 ℃ of 2 dense H of adding down
2SO
4Pale yellow solution becomes buff.Stirred reaction mixture 15 minutes.Add DMAP with in and H
2SO
4, and in 100 ℃ of oil baths, heated 3 hours.The distillation reaction mixture is removed acetic acid under the normal pressure, and vacuum distilling obtains required product 4 (90% yield) subsequently.
1H NMR(CDCl
3)：δ 4.83(m，2H)、6.06(m，1H)、7.56(m，1H)。
13C NMR(CDCl
3)：72.11、121.00、153.22、173.76。
2, the preparation of 2-neopentanoic acid 2-furyl ester (5):
With triethylamine (6mmol, acetonitrile 0.83ml) (5ml) drips of solution be added to 5-hydrogen-furan-2-ketone (5mmol, 0.35ml) and trimethyl-aceyl chloride (6mmol in acetonitrile 0.74ml) (20ml) solution, and stirred 4 hours down at 60 ℃.Filter the precipitation triethylamine hydrogen chlorate who forms.With 10% sodium carbonate flushing filtrate, through MgSO
4Drying distills acetonitrile and vacuum distilling products therefrom and obtains product 5 (80%).
1-(2,2-dimethyl-propiono)-4,10-two oxatricyclo [5.2.1.0
2,6] last of the ten Heavenly stems-8-alkene-3, the preparation of 5-diketone (6):
With 2,2-neopentanoic acid 2-furyl ester (5mmol, 840mg) and maleic anhydride (5mmol 0.490g) is dissolved in the ether (1ml/mmol 5) and stirs and spend the night.Filtering-depositing (being product 6) and from chloroform crystallization (75% yield).
1H NMR(DMSO)：δ1.32(s，9H)、3.39(d，1H，J＝7.0)、3.78(d，1H，J＝7.0)、5.33(d，1H，J＝2.0)、6.70(m，2H)；
13C NMR(DMSO)：176.68、169.43、166.10、138.16、137.33、111.76、52.87、52.84、48.92、48.15、48.09、39.33、27.10。
The preparation of 3-hydroxyl phthalic anhydride (7):
(1mmol 266mg) divides aliquot to add 15 ℃ 98%H with chemical compound 6
2SO
4(2ml).Stir the cream colored mixture 5 minutes, and flow through trash ice then.Filtering precipitate, with icy water flushing and in exsiccator drying obtain product 7 (73%).
1H NMR(CD
3OD)：δ 7.40(d，1H，J＝8.1)、7.62(d，1H，J＝6.9)、7.85(t，1H，J＝7.8)。
The general preparation method of anthraquinone:
Heating (110 ℃) anhydrous AlCl in oil bath
3(5mmol, 0.667g) and the NaCl of previously baked mistake (2.5mmol, mixture 0.145g) is until fusing.The homogeneous mixture and the AlCl of the phenol (1mmol) that makes phthalic anhydride (1mmol) and replace
3/ NaCl fusant reaction.Slow intensification also kept 4 hours under 165 ℃.Reactant mixture is cooled to 0 ℃, adds 10ml 10%HCl, stirred 15 minutes down, refluxed 30 minutes down at 100 ℃ at 0 ℃.With the reactant mixture cool to room temperature and use ethyl acetate extraction.By using acetonitrile: water (1:1) is as the C of mobile phase
18MPLC post purification products therefrom.
The general preparation method of monomethyl anthraquinone:
The prepared in reaction Azimethylene. in ether by N-nitroso-group-N-methylurea and KOH.(0.1mmol) is dissolved in respectively in the 2ml dry ether with anthraquinone, in ice bath, cool off, and in ether excessive adding Azimethylene..Reactant mixture was placed several hours, solvent evaporated under reduced pressure, and pass through with the silicon oxide MPLC purification products therefrom of 30% ethyl acetate in the hexane as mobile phase.
The general preparation method of dimethyl anthraquinone:
With anthraquinone (0.1mmol) and anhydrous propanone (2ml) and K
2CO
3(0.1mmol 0.014g) stirs.Reaction mixture in ice bath.Adding dimethyl sulfate (0.2mmol) also at room temperature stirred several hours.Vacuum evaporating solvent is dissolved in residue in the water, and uses ethyl acetate extraction.By the silicon oxide MPLC purification gained residue of 20% ethyl acetate in the usefulness hexane as mobile phase.
1,2-dihydroxyanthraquinone (A)
UV λ
Max(CH
3OH) (log ∈): 205 (4.47), 246 (4.6), 275 (4.4), 431 (3.7).
1H NMR (DMSO): δ 7.27 (d, 1H, J=8.5), 7.70 (d, 1H, J=8.5), 7.95 (m, 2H), 8.23 (m, 2H).
13C NMR (DMSO): 190.25,182.03,154.2,152.28,136.57,135.51,135.04,134.16,128.59,127.95,125.26,122.70,122.31,117.73. yield: 55%.
1,2-dihydroxy-3-tectoquinone (B)
UV λ
Max(CH
3OH) (log ∈): 206 (4.46), 245 (4.36), 270 (4.39), 280 (4.39), 417 (3.57);
1H NMR (DMSO): δ 2.32 (s, 3H), 7.61 (s, 1H), 7.94 (m, 2H), 8.21 (m, 2H).
13C NMR (DMSO): 189.87,182.17,151.61,151.11,136.47,135.48,134.99,134.29,133.48,128.18,127.82,124.57,124.02,115.96,17.90. yield: 60%.
1-methyl-2,3-dihydroxyanthraquinone (C)
1H NMR (DMSO): δ 2.63 (s, 3H), 7.61 (s, 1H), 7.85 (m, 2H), 8.10 (dd, 1H, J=7.0,1.5), 8.14 (dd 1H, J=7.5,1.5);
13C NMR (DMSO): 183.76,182.07,149.64,149.39,134.65,133.89,132.24,128.00,127.48,126.55,125.74,124.90,111.12,110.96,13.61. yield: 60%.
1,3-dihydroxyanthraquinone (D)
UV λ
Max(CH
3OH) (log ∈): 211 (4.18), 282 (3.89), 311 (3.69), 410 (3.41);
1H NMR (DMSO): δ 5.73 (s, 1H), 6.59 (s, 1H), 7.72 (t, 1H, J=7.5), 7.83 (t, 1H, J=7.5), 8.07 (d, 1H, J=7.5), 8.13 (d, 1H, J=8.0). yield: 75%.
1,4-dihydroxyanthraquinone (E)
UV λ
Max(CH
3OH) (log ∈): 206 (4.51), 223, (4.54) 248 (4.64), 278 (4.20), 479 (4.02);
1H NMR (DMSO): δ 7.47 (s, 2H), 8.01 (m, 2H), 8.30 (m, 2H);
13C NMR (DMSO): 187.40,157.40,135.77,133.61,133.04,127.38,113.40. yield: 80%.
1 (F)
UV λ
Max(CH
3OH) (log ∈): 207 (4.59), 243 (4.39), 283 (4.49), 410 (3.71);
1H NMR (DMSO): δ 7.29 (s, 1H), 7.91 (m, 2H), 8.18 (m, 2H);
13C NMR (DMSO): 187.63,181.67,152.72,152.48,139.65,135.22,134.79,133.94,133.77,127.30,126.94,125.37,111.03,109.52. yield: 75%.
2,3,5-trihydroxyanthraquinone (G)
1H NMR (DMSO): δ 7.28 (dd, 1H, J=8.0,1.0), 7.47 (s, 1H), 7.51 (s, 1H), 7.61 (dd, 1H, J=7.5,1.0), 7.71 (t, 1H, J=8.0).
13C NMR (DMSO): 187.69,181.05,161.32,152.45,151.71,136.63,133.46,127.14,126.15,123.66,118.72,115.78,113.21,112.66. yield: 30%.
1,2,5-trihydroxyanthraquinone (H)
1H NMR (DMSO): δ 7.28 (d, 1H, J=8.5), 7.41 (dd, 1H, J=8.5,1.5), 7.54 (d, 1H, J=8.5), 7.79 (dd, 1H, J=7.5,1.5), 7.83 (t, 1H, J=8).
13C NMR (DMSO): 188.04,186.57,161.70,153.61,151.14,136.66,133.14,124.63,123.16,121.48,120.74,118.83,116.20,115.92. yield: 10%.
1,2,8-trihydroxyanthraquinone (I)
1H NMR (DMSO): δ 7.26 (d, 1H, J=8.5), 7.57 (dd, 1H, J=8.5,1), 7.68 (d, 1H, J=8), 7.21 (dd, 1H, J=7.5,1), 7.83 (t, 1H, J=8).
13C NMR (DMSO): 192.59,180.07,161.34,152.93,150.57,137.49,133.83,122.78,123.73,121.42,120.98,119.04,116.18,116.09. yield: 10%.
1,2,8-trihydroxy-3-tectoquinone (J)
1H NMR (DMSO): δ 2.24 (3H, s), 7.32 (d, 1H, J=8.5Hz), 7.54 (1H, s), 7.67 (d, 1H, J=7.5Hz), 7.74 (t, 1H, J=7.5).
13C NMR (DMSO): 114.35,115.94,119.05,122.87,123.11,123.73,132.32,132.75,137.40,149.38,150.27,161.26,180.19,192.26. yield: 30%.
1-methyl-2,3,8-trihydroxyanthraquinone (K)
1H NMR (DMSO): δ 2.65 (3H, s), 7.19 (d, 1H, J=8.5Hz), 7.60 (1H, s), 7.63 (d, 1H, J=7.5Hz), 7.73 (t, 1H, J=8).
13C NMR (DMSO): 111.38,116.73,117.88,123.74,124.12,127.71,128.67,132.68,135.87,149.63,150.15,161.25,181.41,190.31. yield: 15%.
1,3,5-trihydroxyanthraquinone (L)
1H NMR (DMSO): δ 6.58 (d, 1H, 2.5Hz), 7.14 (d, 1H, 2.5Hz), 7.33 (dd, 1H, J=8.5, JJ=1Hz), 7.68 (dd, 1H, J=7.5Hz, JJ=1Hz), 8.07 (d, 1H, J=7.5), 7.78 (t, 1H, J=8.0).
13C NMR (DMSO): 108.07,108.37,109.23,115.67,118.68,124.0,133.2,134.64,137.33,161.65,164.87,185.09,187.34. yield: 35%.
1,4,8-trihydroxyanthraquinone (M)
1H NMR (DMSO): δ 7.41 (dd, 1H, J=8.0,1.5Hz), 7.80 (dd, 1H, J=7.5,1.0Hz), 7.84 (t, 1H, J=8.0). yield: 55%.
1,2,3,5-tetra hydroxyanthraquinone (N)
1H NMR (DMSO): δ 6.58 (d, 1H, 2.5Hz), 7.14 (d, 1H, 2.5Hz), 7.33 (dd, 1H, J=8.5, JJ=1Hz), 7.68 (dd, 1H, J=7.5Hz, JJ=1Hz), 8.07 (d, 1H, J=7.5), 7.78 (t, 1H, J=8.0).
13C NMR (DMSO): 108.07,108.37,109.23,115.67,118.68,124.0,133.2,134.64,137.33,161.65,164.87,185.09,187.34. yield: 50%.
1-hydroxyl-2-methoxyl group-3-tectoquinone (O)
1HNMR (CDCl
3): δ 8.27 (m, 2H), 7.79 (m, 2H) 7.67 (s, 1H), 4.02 (s, 3H), 2.39 (s, 3H);
13C NMR (CDCl
3): 17.03,60.64,115.91,122.55,127.02,127.61,127.85,133.58,133.93,134.17,134.85,140.22,152.14,155.84,182.30,188.99. yield: 80%.
1,2-dimethoxy-3-tectoquinone (P)
1HNMR (CDCl
3): δ 8.26 (m, 2H), 7.77 (m, 2H) 7.99 (s, 1H), 4.06 (s, 6H), 2.41 (s, 3H);
13C NMR (CDCl
3): 17.03,61.00,61.54,125.85,126.19,126.89,127.33,129.98,132.98,133.67,134.22,135.21,139.42,153.74,158.33,182.74,183.05. yield: 75%.
1,8-dihydroxy-2-methoxyl group-3-tectoquinone (Q)
1HNMR (CDCl
3): δ 7.82 (dd, 1H, J=7.5,1.0), 7.68 (t, 1H, J=8.0) 7.30 (dd, 1H, J=8.0,1.0), 4.04 (s, 3H), 2.39 (s, 3H). yield: 75%.
1-hydroxyl-2,8-dimethoxy-3-tectoquinone (R)
1HNMR (CDCl
3): δ
1HNMR (CDCl
3): δ 7.77 (s, 1H), 7.61 (dd, 1H, J=8.4,0.9) 7.58 (t, 1H, J=7.8), 7.27 (dd, 1H, J=8.1,1.2), 4.05 (s, 3H), 3.87 (s, 3H), 2.76 (s, 3H). yield: 80%.
1-methyl-2,3-dimethoxy-8-hydroxyanthraquinone (S)
1HNMR (CDCl
3): δ 7.77 (s, 1H), 7.58 (dd, 1H, J=7.5,1.0) 7.60 (t, 1H, J=8.0), 7.27 (dd, 1H, J=8.5,1.0), 4.05 (s, 3H), 3.87 (s, 3H), 2.77 (s, 3H);
13CNMR (CDCl
3): 14.71,56.43,60.88,108.90,117.38,118.98,124.77,125.91,132.61,133.02,135.83,137.23,152.69,157.32,162.55,182.82,190.58. yield: 75%.
The C9 of the synthetic anthraquinone of table 1 expression isomery and C10 carbon
13The chemical shift of C NMR, color and fusing point.
Table 1
| Anthraquinone | C9 | C10 | Color |
| B | 189.87 | 182.17 | Darkorange |
| C | 183.76 | 182.07 | Yellow |
| G | 187.69 | 181.05 | Yellow |
| H | 188.04 | 186.57 | Darkorange |
| I | 192.59 | 180.07 | Darkorange |
| J | 192.26 | 180.19 | Darkorange |
| K | 191.05 | 182.14 | Yellow |
Table 2 expression compd A of the present invention is to fusing point and the HRMS data of S.
Table 2
| Anthraquinone | Fusing point (℃) | By the observed quality [MH of HRFAB +] | Theoretical Mass [M] |
| A | 173-174 | 241.0502 | 240.0423 |
| B | 224-225 | 255.0655 | 254.0679 |
| C | a297-299 | 255.0658 | 254.0679 |
| D | 207-208 | 241.0500 | 240.0423 |
| E | 195-196 | 241.0500 | 240.0423 |
| F | 282-284 | 257.0449 | 256.0372 |
| G | a302-304 | 257.0449 | 256.0372 |
| H | 263-264 | 257.0449 | 256.0372 |
| I | 234-235 | 257.0449 | 256.0372 |
| J | 239-240 | 271.0606 | 270.0528 |
| K | a304-305 | 271.0606 | 270.0528 |
| L | a284-286 | 257.0451 | 256.0372 |
| M | a254-256 | 257.0450 | 256.0372 |
| N | a278-279 | 273.0398 | 272.0321 |
| O | 154-155 | 269.0813 | 268.0736 |
| P | 127-128 | 283.0970 | 282.0892 |
| Q | 173-174 | 285.0761 | 284.0685 |
| R | 283-284 | 299.0920 | 298.0841 |
| S | 197-198 | 299.0920 | 298.0841 |
a: decomposition point
Filaricide is measured:
Obtain 100 female cloth Shandong Turbatrix malayi specimen of growing up by NIH subcontract, so that the test anthraquinone is as the effectiveness of filaricide agent from John doctor McCall of University of Georgia.3 anthelmintics in every hole are transferred in 6 orifice plates that fresh RPMI 1640 culture mediums are housed, and replenished with L-glutaminate and penicillin/streptomycin.The concentration of anthraquinone with 4mg/ml is dissolved among 100% DMSO, and uses the RPMI medium, obtain the ultimate density of 50ppm.Duplicate the matched group that contains 2% DMSO or do not have DMSO.Remove medium, per 48 hours with medicine being arranged among the DMSO or not having the fresh RPMI of medicine to replace.Motion and the vitality of an adult of monitoring in per 24 hours were monitored 10 days always.B.malayi anthelmintic in the control wells was finished up to 10 days also fully can be movable, and the anthelmintic death of handling with anthraquinone.
Anthraquinone A, B, D, E, F, J, Q and the R of picked at random measured mortality rate and movable inhibition of female filaricide (cloth Shandong Turbatrix malayi) adult.Under the 5ppm anthraquinone, measure, the results are shown in table 3.The result shows, anthraquinone B and R are the most effective to making B.malayi reach 100% mortality rate in 24 hours.Chemical compound J also shows very effectively, and demonstrates 100% mortality rate in 2 days.Other tested anthraquinones reached 100% mortality rate (table 3) between 3-10 days.
Table 3, anthraquinone under 5ppm to the filaricide activity of B.malayi adult
| Anthraquinone | 100% mortality rate of B.malayi (my god) |
| A | 11 |
| B | 5 |
| C | 7 |
| D | Non-activity |
| E | 10 |
| F | 5 |
| G | 5 |
| H | 9 |
| I | 14 |
| J | 5 |
| K | 3 |
| L | 7 |
| M | 9 |
| N | 5 |
| O | Non-activity |
| P | 11 |
| Q | Non-activity |
| R | 7 |
| S | 9 (50% activity) |
| RPMI | Non-activity |
| RPMI+2.5％DMSO | Non-activity |
| Albendazole positivity tester | 16 |
Even mortality rate or the activeness inhibition of tester after 20 days with the DMSO solvent processing also is 0.The anthraquinone comparison of they and other tested person repeats this test with anthraquinone B, F, J and R, because can be killed anthelmintic fast.Studies show that from the dose response of 50-3.12ppm 100% mortality rate is 6 days, the compound F 17-hydroxy-corticosterone of 3.125ppm is 5 days, is 5 days to the chemical compound J of 6.25ppm for the compd B of 3.125ppm, and be 8 days (table 4) the compound R of 6.25ppm.
Table 4, active anthraquinone B, F, J and R are to the dose response of B.malayi adult
From John McCall, University of Georgia, Athens, GA obtains bull and female B.malayi (NIH contract) alive.Adult is transferred in 6 orifice plates that fresh RPMI 1640 culture mediums that replenish with L-glutaminate and penicillin/streptomycin are housed (3 the male or female anthelmintics in each hole).Anthraquinone is dissolved in respectively among 100% DMSO (4mg/ml), and uses the RPMI medium, obtain the ultimate density of 5ppm.Duplicate the tester group that contains 2.5% DMSO or do not contain DMSO.From each hole, remove medium in per 48 hours, and be used in the fresh RPMI replacement that contains or do not contain medicine among the DMSO.Motion and the mortality rate of per 24 hours monitoring filaricides were monitored 20 days.All B.malayi anthelmintics in the tester hole all are alive in whole research, and the anthelmintic death of handling with anthraquinone.The results are shown in table 5.
Table 5,5ppm anthraquinone be female and male insect and microfilament filaricide activity Hey to B.malayi
| Anthraquinone | 100% mortality rate of female B.malayi (my god) | 100% mortality rate of male B.malayi (my god) | Hey 100% mortality rate of microfilament (my god) ＊ |
| A | 5 | NI | 3 |
| |
5 | 6 | 3 |
| |
7 | NT | 3 |
| D | The zero death rate | NT | The zero death rate |
| E | 10 | NT | The zero |
| F | |||
| 5 | NT | 3 | |
| |
5 | NT | 3 |
| H | 9 | NT | 3 |
| I | 14 | NT | 3 |
| |
5 | 5 | 3 |
| |
3 | 5 | 1 |
| |
7 | NT | 3 |
| M | 9 | NT | 5 |
| |
5 | 6 | 3 |
| O | The zero death rate | NT | The zero death rate |
| P | 11 | NT | The zero death rate |
| Q | The zero death rate | NT | The zero |
| R | |||
| 7 | NT | The zero death rate | |
| S | 9 | NT | The zero death rate |
| Albendazole | 16 | 9 | The zero death rate |
| RPMI+2.5％DMSO | The zero death rate | The zero death rate | The zero death rate |
| Has only RPMI | The zero death rate | The zero death rate | The zero death rate |
More than description only is used to illustrate the present invention, and the present invention is limited by following appended claims only.
Claims (30)
1, the preparation method of anthraquinone comprises:
(a) in the fusion anhydrous mixture of lewis acid and alkali halide salts, the phenol that the phthalic anhydride of heating molar excess and hydroxyl replace in reactant mixture makes its reaction;
(b) reactant mixture of cooling step (a);
(c) in the reactant mixture of step (b), add aqueous acids, preparation acidylate anthraquinone;
(d) reactant mixture of reflow step (c), the preparation anthraquinone; With
(e) from reactant mixture, separate anthraquinone.
2, the process of claim 1 wherein that lewis acid is an anhydrous Aluminum chloride.
3, claim 1 or 2 method, wherein alkali metal salt is dried sodium chloride.
4, claim 1 or 2 method, wherein with reactant mixture in about 165 ℃-185 ℃ heating about 4-5 hour down.
5, claim 1 or 2 method, wherein aqueous acids is an aqueous hydrochloric acid.
6, claim 1 or 2 method, wherein anthraquinone separates from reactant mixture by solvent extraction in step (e).
7, the method for claim 6, wherein solvent is selected from ethyl acetate, diethyl ether and their mixture.
8, claim 1 or 2 method, wherein the anthraquinone in the step (e) separates by chromatography.
9, claim 1 or 2 method, wherein anthraquinone is Compound C (1-methyl-2, a 3-dihydroxyanthraquinone).
10, claim 1 or 2 method, wherein anthraquinone is compound K (1-methyl-2,3, a 8-trihydroxyanthraquinone).
11, claim 1 or 2 method, wherein anthraquinone is compound N (1,2,3, the 5-tetra hydroxyanthraquinone).
12, methylate anthraquinone that dihydroxy replaces prepares the method for the anthraquinone that methoxyl group replaces, and comprises dihydroxyanthraquinone and methylating reagent are reacted in anhydrous organic solvent the anthraquinone of preparation methoxyl group replacement.
13, methylate anthraquinone that hydroxyl replaces prepares the method for the anthraquinone that methoxyl group replaces, and comprising:
(a) in reactant mixture, the anthraquinone that hydroxyl is replaced reacts in diethyl ether with N-nitroso-group-N-methyl urea and potassium hydroxide, the anthraquinone of preparation methoxyl group replacement; With
(b) from reactant mixture, separate the anthraquinone that methoxyl group replaces.
14, the method for claim 13, wherein methyl substituted anthraquinone are the anthraquinones that a methoxyl group replaces.
15, the method for claim 13, the wherein reactant mixture in the cooling step (a) in ice bath.
16, the method for claim 13 wherein evaporates diethyl ether from reactant mixture, the anthraquinone that methoxyl group replaces also further separates by chromatography by solvent extraction and separation.
17, the method for claim 16, wherein solvent is selected from ethyl acetate and hexane.
18, the method for claim 13, wherein the methoxyl group anthraquinone is S (1-methyl-2, a 3-dimethoxy-8-hydroxyanthraquinone).
19, the anthraquinone that dihydroxy replaces that methylates, the method for the anthraquinone that the preparation dimethoxy replaces comprises:
(a) in room temperature or more under the low temperature, dihydroxyanthraquinone and Dimethylsulfate in the anhydrous solvent are reacted in reactant mixture; With
(b) from reactant mixture, separate the anthraquinone that dimethoxy replaces.
20, the method for claim 19, wherein solvent is an acetone.
21, claim 19 or 20 method, wherein the anthraquinone that replaces of dimethoxy is R.
22, the method that suppresses the nematosis worm comprises parasite is exposed in the anthraquinone that the hydroxyl of amount of suppression replaces.
23, the method for claim 22, wherein parasite is to cause the cloth Shandong Turbatrix malayi spp of filariasis of lymphatic vessels or the parasite that causes malaria.
24, claim 22 or 23 method, wherein parasite is suppressed external.
25, claim 22 or 23 method, wherein parasite is suppressed in vivo.
26, the method for claim 22, wherein the anthraquinone of hydroxyl replacement also is that methoxyl group replaces.
27, the method for claim 22, wherein anthraquinone is selected from C, K, N, R and S.
28, be selected from chemical compound 1-methyl-2,3-dihydroxyanthraquinone (C), 1-methyl-2,3,8-trihydroxyanthraquinone (K), 1,2,3,5-tetra hydroxyanthraquinone (N), 1-hydroxyl-2,8-dimethoxy-3-tectoquinone (R) and 1-methyl-2, the anthraquinone of 3-dimethoxy-8-hydroxyanthraquinone (S).
29, the purposes of the anthraquinone of claim 28 treatment parasitic disease, tumor and cancer.
30, a kind of anthraquinone
R wherein
1, R
2, R
3, R
4, R
5And R
6Be selected from H, OH, CH
3And CH
3O, and at least one R wherein
1, R
2, R
3, R
4And R
5Be CH
3O.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US57010904P | 2004-05-11 | 2004-05-11 | |
| US60/570,109 | 2004-05-11 | ||
| US60/650,552 | 2005-02-07 | ||
| US11/074,227 | 2005-03-07 |
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| ZA (1) | ZA200609305B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102493218A (en) * | 2011-11-24 | 2012-06-13 | 东华大学 | Method for carrying out dyeing by structure-modified anthraquinone natural dye |
-
2005
- 2005-05-11 CN CNA2005800149655A patent/CN101426506A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102493218A (en) * | 2011-11-24 | 2012-06-13 | 东华大学 | Method for carrying out dyeing by structure-modified anthraquinone natural dye |
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