CN100999492A - Quinoline kind iriyellowsin electronic isostericmer its preparation process and use - Google Patents
Quinoline kind iriyellowsin electronic isostericmer its preparation process and use Download PDFInfo
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- CN100999492A CN100999492A CN200610161366.2A CN200610161366A CN100999492A CN 100999492 A CN100999492 A CN 100999492A CN 200610161366 A CN200610161366 A CN 200610161366A CN 100999492 A CN100999492 A CN 100999492A
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title claims description 33
- 238000002360 preparation method Methods 0.000 title claims description 13
- OBBCRPUNCUPUOS-UHFFFAOYSA-N tectorigenin Chemical compound O=C1C2=C(O)C(OC)=C(O)C=C2OC=C1C1=CC=C(O)C=C1 OBBCRPUNCUPUOS-UHFFFAOYSA-N 0.000 claims abstract description 46
- UYLQOGTYNFVQQX-UHFFFAOYSA-N psi-tectorigenin Natural products COC1=C(O)C=C(O)C(C2=O)=C1OC=C2C1=CC=C(O)C=C1 UYLQOGTYNFVQQX-UHFFFAOYSA-N 0.000 claims abstract description 23
- OYUJPVCKGSEYDD-UHFFFAOYSA-N tectorigenin Natural products COc1c(O)cc2OCC(C(=O)c2c1O)c1ccc(O)cc1 OYUJPVCKGSEYDD-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 4
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- -1 NR 2 Inorganic materials 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 5
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 3
- 229930185107 quinolinone Natural products 0.000 claims description 3
- 230000000694 effects Effects 0.000 abstract description 9
- 206010028980 Neoplasm Diseases 0.000 abstract description 8
- 201000011510 cancer Diseases 0.000 abstract description 6
- 150000003248 quinolines Chemical class 0.000 abstract description 5
- 238000002474 experimental method Methods 0.000 abstract description 4
- 229940111121 antirheumatic drug quinolines Drugs 0.000 abstract 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 3
- 150000002576 ketones Chemical class 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 67
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 67
- QKJAZPHKNWSXDF-UHFFFAOYSA-N 2-bromoquinoline Chemical class C1=CC=CC2=NC(Br)=CC=C21 QKJAZPHKNWSXDF-UHFFFAOYSA-N 0.000 description 55
- 210000004027 cell Anatomy 0.000 description 17
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 8
- 230000000452 restraining effect Effects 0.000 description 8
- 229960002949 fluorouracil Drugs 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XQXPVVBIMDBYFF-UHFFFAOYSA-N 4-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 description 4
- 241000596154 Belamcanda Species 0.000 description 4
- DSWXNIJJMOIUHA-UHFFFAOYSA-N C1=CC=C(C=C1)COC2=CC3=C(C=C2)N=C(C=C3Cl)C4=CC=CC=C4 Chemical compound C1=CC=C(C=C1)COC2=CC3=C(C=C2)N=C(C=C3Cl)C4=CC=CC=C4 DSWXNIJJMOIUHA-UHFFFAOYSA-N 0.000 description 4
- 102100026535 Fibronectin type III domain-containing protein 5 Human genes 0.000 description 4
- 101800001026 Irisin Proteins 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000001076 estrogenic effect Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- LNQCUTNLHUQZLR-OZJWLQQPSA-N iridin Chemical compound OC1=C(OC)C(OC)=CC(C=2C(C3=C(O)C(OC)=C(O[C@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O4)O)C=C3OC=2)=O)=C1 LNQCUTNLHUQZLR-OZJWLQQPSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000013019 agitation Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- PHWYGBMFZMYNEJ-UHFFFAOYSA-N 2-phenylmethoxy-5-(4,5,7-trichloroquinolin-3-yl)aniline Chemical compound C1=CC=C(C=C1)COC2=C(C=C(C=C2)C3=CN=C4C=C(C=C(C4=C3Cl)Cl)Cl)N PHWYGBMFZMYNEJ-UHFFFAOYSA-N 0.000 description 2
- LMTIGVVBRMFAMN-UHFFFAOYSA-N 3-(3-amino-4-hydroxyphenyl)-4-chloroquinolin-6-ol Chemical compound C1=CC(=C(C=C1C2=CN=C3C=CC(=CC3=C2Cl)O)N)O LMTIGVVBRMFAMN-UHFFFAOYSA-N 0.000 description 2
- BXKYBAUAOUOAFP-UHFFFAOYSA-N 3-(3-bromo-4-hydroxyphenyl)-4-chloroquinolin-6-ol Chemical compound C1=CC(=C(C=C1C2=CN=C3C=CC(=CC3=C2Cl)O)Br)O BXKYBAUAOUOAFP-UHFFFAOYSA-N 0.000 description 2
- RHFCWUXGVAPHSU-UHFFFAOYSA-N 4,5,7-trichloro-3-(4-methoxyphenyl)quinoline Chemical compound COC1=CC=C(C=C1)C2=CN=C3C=C(C=C(C3=C2Cl)Cl)Cl RHFCWUXGVAPHSU-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- ZBUCXXUMBJLLJT-UHFFFAOYSA-N C1=CC=C(C=C1)C2=NC3=C(C(=CC(=C3)Cl)Cl)C(=C2Br)Cl Chemical compound C1=CC=C(C=C1)C2=NC3=C(C(=CC(=C3)Cl)Cl)C(=C2Br)Cl ZBUCXXUMBJLLJT-UHFFFAOYSA-N 0.000 description 2
- OBOZNPUBDPVEHO-UHFFFAOYSA-N C1=CC=C(C=C1)COC2=C(C3=C(C=C(C=C3Cl)Cl)N=C2C4=CC=CC=C4)Cl Chemical compound C1=CC=C(C=C1)COC2=C(C3=C(C=C(C=C3Cl)Cl)N=C2C4=CC=CC=C4)Cl OBOZNPUBDPVEHO-UHFFFAOYSA-N 0.000 description 2
- OGYCJFVRTWZFCU-UHFFFAOYSA-N C1=CC=C(C=C1)COC2=CC3=C(C=C2)N=C(C(=C3Cl)Br)C4=CC=CC=C4 Chemical compound C1=CC=C(C=C1)COC2=CC3=C(C=C2)N=C(C(=C3Cl)Br)C4=CC=CC=C4 OGYCJFVRTWZFCU-UHFFFAOYSA-N 0.000 description 2
- REJKCVNAKHYJOZ-UHFFFAOYSA-N C1=CC=C(C=C1)COC2=CC3=C(C=C2)N=C(C(=C3Cl)OCC4=CC=CC=C4)C5=CC=CC=C5 Chemical compound C1=CC=C(C=C1)COC2=CC3=C(C=C2)N=C(C(=C3Cl)OCC4=CC=CC=C4)C5=CC=CC=C5 REJKCVNAKHYJOZ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 description 2
- 206010019668 Hepatic fibrosis Diseases 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- DZOPSTDZPXGOAN-UHFFFAOYSA-N ethyl 2-phenyl-2-phenylmethoxyacetate Chemical compound CCOC(=O)C(OCC1=CC=CC=C1)C1=CC=CC=C1 DZOPSTDZPXGOAN-UHFFFAOYSA-N 0.000 description 2
- 201000002313 intestinal cancer Diseases 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 1
- BMCOVXVPTWKZCR-UHFFFAOYSA-N 2-chloro-3H-quinolin-4-one Chemical class C1=CC=C2C(=O)CC(Cl)=NC2=C1 BMCOVXVPTWKZCR-UHFFFAOYSA-N 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- BLGWFGKTSFSRJN-UHFFFAOYSA-N C1=CC=C(C=C1)COC2C(=NC3=CC=CC=C3C2=O)C4=CC=CC=C4 Chemical compound C1=CC=C(C=C1)COC2C(=NC3=CC=CC=C3C2=O)C4=CC=CC=C4 BLGWFGKTSFSRJN-UHFFFAOYSA-N 0.000 description 1
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- 102000006587 Glutathione peroxidase Human genes 0.000 description 1
- 108700016172 Glutathione peroxidases Proteins 0.000 description 1
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- 241001465754 Metazoa Species 0.000 description 1
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- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- 102000019197 Superoxide Dismutase Human genes 0.000 description 1
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- QTTMOCOWZLSYSV-QWAPEVOJSA-M equilin sodium sulfate Chemical compound [Na+].[O-]S(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4C3=CCC2=C1 QTTMOCOWZLSYSV-QWAPEVOJSA-M 0.000 description 1
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- LGBBTPVHBZOVRF-UHFFFAOYSA-N ethyl 2-phenylacetate propan-2-one Chemical compound C(C)OC(CC1=CC=CC=C1)=O.CC(=O)C LGBBTPVHBZOVRF-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
A quinolines tectorigenin isostere, it has the right formula structure, which : R1 and R3 = Br, R2 = OR and R5=R, R4 = NO2, NR2, F, Cl, Br, OCH3 or OBn; R1 and R3 = Cl, R2 = H and R5= R, R4 = NO2, NR2, F, Cl, Br, OCH3 or OBn; R1 and R3 = F, R2 = H and R5=R, R4 = NO2, NR2, F, Cl, Br, OCH3 or OBn; R1 and R3 = H, R2=OR and R4 = OR, R5 = NO2, NR2, F, Cl or Br; the R = H, CH3 or C2H5. Experiments proved that quinolines tectorigenin isostere can inhibit the S180, EAC and HepA cells, and can inhibit five types of people cancer cells. Its activity is higher than tectorigenin itself and quinolines ketone tectorigenin isostere, so they can be used to prepare the anti-tumor drugs.
Description
Technical field
The present invention relates to method for making and their application in the preparation antitumor drug of the isostere of quinoline tectorigenin.
Technical background
Tectorigenin is the main active ingredient of Chinese medicinal materials blackberry lily, has following structure:
Blackberry lily is the dry rhizome of Iridaceae blackberry lily platymiscium blackberry lily [Belamcanda chinensis (L.) DC], has effect clearing heat and detoxicating, the relieve sore throat dissolving phlegm, is mainly used in diseases such as throat lung carbuncle, productive cough asthma, is the key medicine of treatment larynx numbness pharyngalgia.Because tectorigenin has estrogen-like effects, thereby when tectorigenin and oestrogenic hormon acted on target organ simultaneously, the two competed conjugated estrogen hormone acceptor, thereby alleviates estrogenic short cel l proliferation, reduces the pathogenesis of cancer danger relevant with oestrogenic hormon.Simultaneously tectorigenin also has to a certain degree restraining effect to non-estrogen-dependent tumour, as tectorigenin HL-60 cell (leukemia cell) is had very strong restraining effect.Tectorigenin also has to a certain degree restraining effect to the propagation of BGC cell (adenocarcinoma of stomach).
The experimentation on animals of Thelen P et al. shows that tectorigenin has the effect of obvious suppression tumour, finds that it can be used as the medicine of prevention and treatment people's prostate cancer.Saratikov; A.S.et al. studies show that; polyols such as tectorigenin can suppress hepatocellular necrosis; stop intrahepatic fat and proteinic unbalance; make the active normalizing of transaminase and glutamyl transferring enzyme; prevented the development of hepatic fibrosis, the effect that play the protection liver, recovers liver function.Act on the liver cell of mouse with tertbutyl peroxide, take tectorigenin then, find that tectorigenin can protect mouse to avoid the infringement of tertbutyl peroxide inductive liver cancer cell.Intracellular active oxygen is one of factor that causes cell carcinogenesis, tectorigenin can be removed active oxygen on the one hand, can increase the active of superoxide dismutase, catalase and glutathione peroxidase and their protein level on the other hand, strengthen the ability of cell removing active oxygen.Tectorigenin also has the effect of fine anti-hepatic fibrosis.
The inventor is in patent (publication number CN1850817A), the isostere of quinolinones tectorigenin is disclosed, the inventor synthesized the isostere of a series of substd quinolines class tectorigenin again on this basis, and carried out their inhibiting tests to cancer cells.
Summary of the invention
The objective of the invention is to the tectorigenin is guide's thing, the isostere that synthesizes a series of quinoline tectorigenins by some ultimate principles of medicinal design, on the basis of further investigation structure activity relationship, find the new drug that activity is higher, toxic side effect is lower, and the method for making of quinoline Roofirisrhizome flavin non polar isostere is provided.
Technical scheme of the present invention is as follows:
A kind of quinoline Roofirisrhizome flavin non polar isostere, it has following general structure:
Wherein:
R
1And R
3=Br, R
2=OR and R
5=R, then R
4=NO
2, NR
2, F, Cl, Br, OCH
3Or OBn;
R
1And R
3=Cl, R
2=H and R
5=R, then R
4=NO
2, NR
2, F, Cl, Br, OCH
3Or OBn;
R
1And R
3=F, R
2=H and R
5=R, then R
4=NO
2, NR
2, F, Cl, Br, OCH
3Or OBn;
R1 and R3=H, R2=OR and R4=OR, then R5=NO2, NR2, F, Cl or Br;
Described R=H, CH
3Or C
2H
5
A kind of method for preparing quinoline Roofirisrhizome flavin non polar isostere (Compound I I), it is at POCl with the isostere Compound I of tectorigenin (with reference to patent CN1850817A preparation)
3Be heated between 110～120 ℃ under existing, reacted 10-15 hour, obtain quinoline Roofirisrhizome flavin non polar isostere (Compound I I):
Experimental results show that, the quinoline Roofirisrhizome flavin non polar isostere has restraining effect to S180, EAC and HepA cell, 5 kinds of human cancer cells are had restraining effect, and its activity is higher than tectorigenin itself and quinolinones Roofirisrhizome flavin non polar isostere, so they can be used to prepare anti-tumor drug.
Embodiment
Further describe the present invention by following examples, but should notice that scope of the present invention is not subjected to any restriction of these embodiment.
Embodiment 1:3-p-methoxyphenyl-6-methoxyl group-4-chloro-5, the preparation of 7-two bromoquinolines (2)
With 5,7-two bromo-6-methoxyl group-3-(p-methoxyphenyl)-4-quinolinones (we have described its preparation method in patent CN1850817A) 43.9g under magnetic agitation, adds POCl in the single port bottle of 500mL
3200mL, reflux 12h (120 ℃ of oil bath temperatures), pressure reducing and steaming POCl
3, residue is with saturated NaHCO
3Alkalization with AcOEt (200mL * 4) extraction, is washed to neutrality with saturated common salt, uses MgSO
4Drying boils off solvent, gets yellow solid 43.9g, productive rate 99%.Mp178-179℃；ESI-MS：457.5；IR(KBr)cm
-1：2908(C-H)，3010(Ar-H)；
1H NMR(CDCl
3)δppm：3.91(s，3H)，4.03(s，3H)，7.06(d×d，2H)，7.43(d×d，2H)，8.50(s，1H)，8.75(s，1H)。
By above embodiment similar methods, utilize that the listed compound of table 3 is raw material among the patent CN1850817A, we have synthesized the listed quinoline Roofirisrhizome flavin non polar isostere 1～22 of table 1.
Each R group of quinoline Roofirisrhizome flavin non polar isostere among the table 1 general formula I I
| Sequence number | R 1 | R 2 | R 3 | R 4 | R 5 |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 | Br Br Br Br Br Br Br Br Br Br Br Br H H | OH OCH 3 OH OCH 3 OH OCH 3 OH OCH 3 OH OCH 3 OH OCH 3 OH OCH 3 | Br Br Br Br Br Br Br Br Br Br Br Br H H | OCH 3 OCH 3 NO 2 NO 2 NH 2 NH 2 F F Cl Cl Br Br OH OH | H H H H H H H H H H H H NO 2 NO 2 |
| 15 16 17 18 19 20 21 22 | H H H H H H H H | OH OCH 3 OH OCH 3 OH OCH 3 OH OCH 3 | H H H H H H H H | OH OH OH OH OH OH OH OH | NH 2 NH 2 F F Cl Cl Br Br |
Annotate: initial feed is all available from aldrich company
Embodiment 2:3-is to benzyloxy phenyl-4,5, the preparation of 7-trichloro-quinoline (24)
The preparation of A 4-hydroxyphenylacetic acid ethyl ether
The 1.50g p-hydroxyphenylaceticacid is dissolved in the 6mL ethanol, splashes into 0.5mL H
2SO
4, temperature rising reflux 22h, cooling with 100mL AcOEt extraction, is used Na successively
2CO
3Solution, saturated common salt water washing, anhydrous MgSO
4Drying boils off solvent and gets weak yellow liquid 1.65g, productive rate 92%.ESI-MS：180.2；IR(KBr)cm
-1：1678(C＝O)，3387(OH)；
1H NMR(DMSO-d
6)δppm：1.25(t，3H)，3.53(s，2H)，4.14(q，2H)，6.65(d×d，2H)，6.92(d×d，2H)，8.45(s，1H)。
B is to the preparation of benzyloxy Phenylacetic acid ethylester
4.5g is dissolved in the 100mL acetone Phenylacetic acid ethylester, under magnetic agitation, adds 1Og K2CO3, the 4.75g bromotoluene reacts 12h under reflux temperature, reclaim acetone, residue water dissolution, AcOEt extraction, anhydrous MgSO
4Drying boils off solvent, gets a white solid 6.06g, productive rate 91%.Mp32-33℃；ESI-MS：270.13；IR(KBr)cm
-1：1669(C＝O)，3407(OH)；
1H NMR(CDCl
3)δppm：1.26(t，3H)，3.56(s，2H)，4.15(q，2H)，5.06(s，2H)，6.94(d×d，2H)，7.21(d×d，2H)，7.33(t，1H)，7.39(t，2H)，7.43(d，2H)。
C 2-is to the preparation of benzyloxy phenyl-2-formyl radical ethyl acetate
5.4g is dissolved in 30mL HCO to the benzyloxy Phenylacetic acid ethylester
2Among the Et, at N
2Add 1.8g NaH under stream protection and the magnetic agitation in batches, after adding, at room temperature react 2h, reaction solution is poured into 100mL through among rare HCl of refrigerated 5%, use Et
2Saturated NaHCO is used in the O extraction successively
3With saturated salt solution washing, use anhydrous MgSO
4Drying boils off solvent, spends the night in 40 ℃ of following vacuum-dryings, gets weak yellow liquid 5.5g, productive rate 92%.ESI-MS：298.1；IR(KBr)cm
-1：1675(C＝O)；
1HNMR(CDCl
3)δppm：1.30(t，3H)，4.08(q，2H)，4.48(d，1H)，5.14(s，2H)，6.64(d×d，2H)，7.03(d×d，2H)，7.32(t，1H)，7.37(t，2H)，7.47(d，2H)，9.68(d，1H)。
D 3-[N-(3, the 5-dichlorophenyl) amino] 2-2-is to the preparation of benzyloxy ethyl phenylacrylate
With 1.62g 3, the 5-dichlorphenamide bulk powder is dissolved in the 30mL ethanol, is warming up to 70 ℃, adds 2.7g 2-to benzyloxy phenyl-2-formyl radical ethyl acetate, reaction 2h, and pressure reducing and steaming ethanol gets white solid 3.75g, productive rate 85%.Mp177-178℃；ESI-MS：441.1；IR(KBr)cm
-1：1600(C＝C)，1708(C＝O)，3458(NH)；
1H NMR(DMSO-d
6)δppm：1.19(t，3H)，3.75(s，3H)，4.16(q，2H)，6.86(d×d，2H)，7.26(d×d，2H)，7.49(d，1H)，7.60(s，2H)，9.51(s，1H)，10.4(d，1H)。
E 3-is to benzyloxy phenyl-5, the preparation of 7-two chloro-4-quinolinones
Get 15g PPA in there-necked flask, add 1.33g 3-[N-(3, the 5-dichlorophenyl) amino]-2-(to the benzyloxy phenyl) ethyl propenoate, be warming up to 110 ℃ of reaction 3h, cooling adds the 100g trash ice, separates out precipitation, filter, vacuum-drying gets faint yellow solid 1.04g, productive rate 88%.Mp245-247℃；ESI-MS：395.1；IR(KBr)cm
-1：1610(C＝C)，1723(C＝O)，3447(NH)；
1H NMR(DMSO-d
6)δppm：5.12(s，2H)，6.55(s，1H)，6.70(d×d，2H)，6.84(s，1H)，7.31(d，1H)，7.38(t，1H)，7.40(t，2H)，7.47(d，2H)，7.53(d×d，2H)，11.85(d，1H)。
F 3-is to benzyloxy phenyl-4,5, the preparation of 7-trichloro-quinoline (24)
With 1.2g 5,7-two chloro-3-are dissolved in 30mLPOCl to benzyloxy phenyl-4-quinolinone
3In, backflow 11h, cooling boils off excessive POCl
3, use NaHCO
3Precipitation is separated out in neutralization, filters, and vacuum-drying gets faint yellow solid 1.0g, productive rate 81%.Mp 165-166℃；ESI-MS：413.0；IR(KBr)cm
-1：2928(C-H)，3009(Ar-H)；
1HNMR(CDCl
3)δppm：4.73(s，2H)，6.80(d×d，2H)，7.28(t，1H)，7.32(t，2H)，7.35(d，2H)，7.52(d×d，2H)，7.70(d，1H)，7.96(d，1H)，9.52(s，1H)。
Embodiment 3:
We have synthesized the listed quinoline Roofirisrhizome flavin non polar isostere 23～60 of table 2 by above embodiment similar methods.
Table 2
| Sequence number | R 1 | R 2 | R 3 | R 4 | R 5 |
| 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 | Cl Cl Cl Cl Cl Cl Cl Cl Cl F F F F F F F F F H H H H H H H H H | H H H H H H H H H H H H H H H H H H OCH 3 OCH 3 OCH 3 OCH 3 OCH 3 OCH 3 OBn OBn OBn | Cl Cl Cl Cl Cl Cl Cl Cl Cl F F F F F F F F F H H H H H H H H H | OCH 3 OBn OCH 2CH 3 OCH 3 OBn OCH 2CH 3 OCH 3 OBn OCH 2CH 3 OCH 3 OBn OCH 2CH 3 OCH 3 OBn OCH 2CH 3 OCH 3 OBn OCH 2CH 3 OCH 3 OBn Cl Br F NO 2 OCH 3 OBn Cl | H H H NO 2 NO 2 NO 2 NH 2 NH 2 NH 2 H H H NO 2 NO 2 NO 2 NH 2 NH 2 NH 2 H H H H H H H H H |
| 50 51 52 53 54 55 56 57 58 59 60 | H H H OH OH OH F Cl Br Br Br | OBn OBn OBn OCH 3 OCH 3 OCH 3 H H H H H | H H H OH OH OH F Cl Br Br Br | Br F NO 2 Cl Br F Cl Br Cl Br F | H H H H H H H H H H H |
Annotate: initial feed is all available from aldrich company
Embodiment 4: the quinoline Roofirisrhizome flavin non polar isostere is to S180, EAC, the cytotoxicity of HepA
Method: mtt assay.The S180 that takes the logarithm and grow, the cell of EAC and HepA is diluted to 2 * 10 respectively
4Individual/ml, be sub-packed in 96 orifice plates (0.2ml/ hole).If the 5 FU 5 fluorouracil control group, the tested compounds of DMSO control group and 8 different concns, every hole 10 μ l.Each group is established 4 parallel holes, puts 37 ℃, 5%CO
24h squeezed into MTT liquid (5mg/ml) 10 μ l/ holes before the middle 72h of cultivation experiment stopped, and cultivated 4h again.Discard nutrient solution, add DMSO 100 μ l/ holes, the mixing vibration under the 570nm wavelength, is measured the OD value with BioRad produced in USA 550 type microplate reader, calculates inhibitory rate of cell growth (half-inhibition concentration, IC by following formula
50).
Growth inhibition ratio=(the average OD value of the average OD value/control group of 1-medication group) * 100%IC
50More little, the cytotoxicity of this compound is big more, the results are shown in Table 3.
The result shows: the series electronic isostere of main irisin of the present invention is to S180, EAC and HepA cell demonstrate more intense cytotoxicity, most of suitable with the positive control 5 FU 5 fluorouracil, wherein, the cytotoxicity of 1,43 pairs of S180 cells of compound, 38 pairs of EAC cells of compound, 33,53 pairs of HepA cells of compound even also being eager to excel than 5 FU 5 fluorouracil.
Embodiment 5: Roofirisrhizome flavin non polar isostere is to the restraining effect of 5 kinds of human cancer cells
Method: mtt assay.Experimental technique the results are shown in Table 4 with embodiment 9.
The series electronic isostere of table 3 irisin is to S180, the cytotoxicity (IC of EAC and HepA
50)
| Cell strain | Compound number/IC 50(μg/ml) | ||||||||
| 1 | 25 | 33 | 38 | 43 | 47 | 53 | 59 | 5 FU 5 fluorouracil | |
| S180 EAC HepA | 0.13 6.28 2.42 | 5.38 10.21 9.54 | 21.2 11.0 0.12 | 14.84 0.08 3.54 | 0.42 31.0 3.23 | 15.1 8.24 6.53 | 4.23 13.82 0.26 | 4.76 15.8 9.57 | 1.32 0.26 1.87 |
The series electronic isostere of table 4. irisin is to the restraining effect of 5 kinds of human cancer cells
| Group | Drug level (μ g/ml) | Inhibiting rate (%) | ||||
| Nasopharyngeal carcinoma (CNE2) | Mammary cancer (MCF-7) | Liver cancer (Bel-7402) | Lung cancer (GLC-82) | Large bowel cancer (HT-29) | ||
| Compound 1 | 0.8 1.4 2.0 | 53.8 64.4 87.5 | 42.1 65.9 81.4 | 56.9 77.8 96.4 | 46.7 54.3 80.7 | 29.7 53.2 81.2 |
| Compound 16 | 0.8 1.4 2.0 | 63.8 85.1 99.7 | 39.9 72.4 87.1 | 29.2 52.7 75.4 | 15.9 41.2 76.0 | 32.4 57.2 86.2 |
| Compound 33 | 0.8 1.4 2.0 | 17.5 44.5 87.1 | 38.4 62.1 83.2 | 23.8 59.6 87.4 | 35.2 55.6 84.8 | 32.7 58.8 96.3 |
| Compound 35 | 0.8 1.4 2.0 | 22.8 56.3 79.3 | 12.3 46.1 78.9 | 31.4 54.1 88.6 | 67.7 75.8 97.8 | 11.2 47.8 70.9 |
| Compound 48 | 0.8 1.4 2.0 | 47.7 76.5 89.1 | 49.4 76.4 96.7 | 13.2 45.2 66.7 | 11.7 46.2 73.1 | 23.3 51.1 79.3 |
| Compound 54 | 0.8 1.4 2.0 | 21.7 43.4 59.9 | 19.3 45.6 68.3 | 59.2 75.4 87.6 | 43.5 60.6 86.6 | 53.6 77.2 95.4 |
| 5 FU 5 fluorouracil | 0.8 1.4 2.0 | 48.8 77.6 98.2 | 39.6 69.8 92.8 | 46.8 72.2 93.6 | 43.9 68.6 95.5 | 36.6 69.8 91.7 |
The result shows that compound 16,48,1,35,33 and 54 has significant inhibitory effect to nasopharyngeal carcinoma, mammary cancer, liver cancer, lung cancer, large bowel cancer respectively, and restraining effect is higher than 5 FU 5 fluorouracil.
The above embodiment of the present invention shows: in the series electronic isostere of synthetic irisin, the antitumous effect of a part is higher than the positive control 5 FU 5 fluorouracil, anxious poison experiment to rat shows, compound 16,35,48, when 54 dosage reaches 5g/kg (this dosage is the non-toxic of pharmacopeia regulation), do not find that rat has the poisoning sign, therefore under normal dose, they are safe as medicinal application.
The fusing point of compound 1～60, mass spectrum, infrared and hydrogen spectrum data
3-p-methoxyphenyl-6-hydroxyl-4-chloro-5,7-two bromoquinolines (1):
Mp265-267℃；ESI-MS：440.9；IR(KBr)cm
-1：2910(C-H)，3011(Ar-H)，3421(OH)；
1HNMR(DMSO-d
6)δppm：3.77(s，3H)，6.93(d×d，2H)，7.57(d×d，2H)，7.83(s，1H)，7.99(d，1H)，9.70(s，1H)，11.85(d，1H)。
3-p-methoxyphenyl-6-methoxyl group-4-chloro-5,7-two bromoquinolines (2):
Mp178-179℃；ESI-MS：457.5；IR(KBr)cm
-1：2952(C-H)，3010(Ar-H)；
1HNMR(CDCl
3)δppm：3.91(s，3H)，4.03(s，3H)，7.06(d×d，2H)，7.43(d×d，2H)，8.50(s，1H)，8.75(s，1H)。
3-p-nitrophenyl-6-hydroxyl-4-chloro-5,7-two bromoquinolines (3):
Mp183-185℃；ESI-MS：455.9；IR(KBr)cm
-1：1558(N＝O)，2952(C-H)，3010(Ar-H)，3430(OH)；
1HNMR(DMSO-d
6)δppm：7.06(d×d，2H)，7.64(d×d，2H)，8.53(s，1H)，9.61(s，1H)。
3-p-nitrophenyl-6-methoxyl group-4-chloro-5,7-two bromoquinolines (4):
Mp173-174℃；ESI-MS：469.9；IR(KBr)cm
-1：549(N＝O)，2957(C-H)，3017(Ar-H)；
1HNMR(CDCl
3)δppm：3.78(s，3H)，7.82(d×d，2H)，8.31(d×d，2H)，8.49(s，1H)，9.58(s，1H)。
3-p-amino phenyl-6-hydroxyl-4-chloro-5,7-two bromoquinolines (5):
Mp194-196℃；ESI-MS：425.9；IR(KBr)cm
-1：2943(C-H)，3019(Ar-H)，3441(NH，OH)；
1HNMR(DMSO-d
6)δppm：5.85(s，2H)，6.51(d×d，2H)，7.44(d×d，2H)，8.48(s，1H)，8.82(s，1H)，9.57(s，1H)。
3-p-amino phenyl-6-methoxyl group-4-chloro-5,7-two bromoquinolines (6):
Mp177-178℃；ESI-MS：439.9；IR(KBr)cm
-1：2953(C-H)，3020(Ar-H)，3441(NH)；
1HNMR(DMSO-d
6)δppm：3.68(s，3H)，4.76(s，2H)，6.48(d×d，2H)，7.41(d×d，2H)，8.27(s，1H)，9.45(s，1H)。
3-is to fluorophenyl-6-hydroxyl-4-chloro-5,7-two bromoquinolines (7):
Mp164-166℃；ESI-MS：429.9；IR(KBr)cm
-1：2956(C-H)，3012(Ar-H)，3441(OH)；
1HNMR(DMSO-d
6)δppm：7.24(d×d，2H)，7.46(d×d，2H)，8.21(s，2H)，8.41(s，1H)，9.42(s，1H)。
3-is to fluorophenyl-6-methoxyl group-4-chloro-5,7-two bromoquinolines (8):
Mp158-159℃；ESI-MS：442.9；IR(KBr)cm
-1：2956(C-H)，3012(Ar-H)；
1HNMR(CDCl
3)δppm：3.64(s，3H)，7.16(d×d，2H)，7.42(d×d，2H)，8.37(s，1H)，9.34(s，1H)。
3-rubigan-6-hydroxyl-4-chloro-5,7-two bromoquinolines (9):
Mp167-169℃；ESI-MS：444.9；IR(KBr)cm
-1：2941(C-H)，3009(Ar-H)，3438(OH)；
1HNMR(DMSO-d
6)δppm：7.57(d×d，2H)，7.78(d×d，2H)，8.37(s，2H)，8.52(s，1H)，9.33(s，1H)。
3-rubigan-6-methoxyl group-4-chloro-5,7-two bromoquinolines (10):
Mp161-162℃；ESI-MS：458.9；IR(KBr)cm
-1：2951(C-H)，3016(Ar-H)；
1HNMR(CDCl
3)δppm：3.77(s，3H)，7.58(d×d，2H)，7.81(d×d，2H)，8.42(s，1H)，9.37(s，1H)。
3-is to bromophenyl-6-hydroxyl-4-chloro-5,7-two bromoquinolines (11):
Mp171-172℃；ESI-MS：488.8；IR(KBr)cm
-1：2929(C-H)，3021(Ar-H)，3451(OH)；
1HNMR(DMSO-d
6)δppm：7.51(d×d，2H)，7.62(d×d，2H)，8.29(s，2H)，8.47(s，1H)，9.43(s，1H)。
3-is to bromophenyl-6-methoxyl group-4-chloro-5,7-two bromoquinolines (12):
Mp161-162℃；ESI-MS：502.9；IR(KBr)cm
-1：2946(C-H)，3021(Ar-H)；
1HNMR(CDCl
3)δppm：3.65(s，3H)，7.54(d×d，2H)，7.63(d×d，2H)，8.35(s，1H)，9.43(s，1H)。
3-(3-base-4-hydroxy phenyl)-6-hydroxyl-4-chloroquinoline (13):
Mp138-140℃；ESI-MS：300.0；IR(KBr)cm
-1：1549(N＝O)，2932(C-H)，3017(Ar-H)，3437(OH)；
1HNMR(DMSO-d
6)δppm：7.37(d×d，1H)，7.45(d，1H)，7.75(d，1H)，7.80(d×d，2H)，8.21(d×d，2H)，8.47(s，1H)，9.52(s，1H)。
3-(3-base-4-hydroxy phenyl)-6-methoxyl group-4-chloroquinoline (14):
Mp133-134℃；ESI-MS：314.0；IR(KBr)cm
-11553(N＝O)，2944(C-H)，3018(Ar-H)，3431(OH)；
1HNMR(CDCl
3)δppm：3.69(s，3H)，7.38(d×d，1H)，7.47(d，1H)，7.76(d，1H)，7.83(d×d，2H)，8.26(d×d，2H)，9.73(s，1H)。
3-(3-amino-4-hydroxy phenyl)-6-hydroxyl-4-chloroquinoline (15):
Mp151-153℃；ESI-MS：270.1；IR(KBr)cm
-1：2938(C-H)，3014(Ar-H)，3441(OH，NH)；
1HNMR(DMSO-d
6)δppm：4.52(s，2H)，6.48(d×d，2H)，7.38(d×d，2H)，7.45(d×d，1H)，7.49(d，1H)，7.79(d，1H)，8.53(s，1H)，9.61(s，1H)。
3-(3-amino-4-hydroxy phenyl)-6-methoxyl group-4-chloroquinoline (16):
Mp147-149℃；ESI-MS：284.1；IR(KBr)cm
-1：2938(C-H)，3012(Ar-H)，3437(OH，NH)；
1HNMR(CDCl
3)δppm：3.75(s，3H)，4.55(s，2H)，6.43(d×d，2H)，7.35(d×d，2H)，7.46(d×d，1H)，7.48(d，1H)，7.81(d，1H)，9.64(s，1H)。
3-(4-hydroxyl-3-phenyl)-6-hydroxyl-4-chloroquinoline (17):
Mp138-139℃；ESI-MS：273.0；IR(KBr)cm
-1：2929(C-H)，3023(Ar-H)，3452(OH)；
1HNMR(DMSO-d
6)δppm：7.15(d×d，2H)，7.38(d×d，2H)，7.45(d，1H)，7.50(d×d，1H)，7.79(d，1H)，8.47(s，1H)，9.75(s，1H)。
3-(4-hydroxyl-3-phenyl)-6-methoxyl group-4-chloroquinoline (18):
Mp132-134℃；ESI-MS：287.0；IR(KBr)cm
-1：2931(C-H)，3017(Ar-H)，3447(OH)；
1HNMR(CDCl
3)δppm：3.54(s，3H)，7.04(d×d，2H)，7.40(d×d，2H)，7.48(d×d，1H)，7.50(d，1H)，7.81(d，1H)，9.57(s，1H)。
3-(4-hydroxyl-3-chloro-phenyl-)-6-hydroxyl-4-chloroquinoline (19):
Mp142-144℃；ESI-MS：289.0；IR(KBr)cm
-1：2927(C-H)，3023(Ar-H)，3446(OH)；
1HNMR(DMSO-d
6)δppm：7.38(d×d，1H)，7.45(d，1H)，7.61(d×d，2H)，7.78(d×d，2H)，7.90(d，1H)，8.52(s，1H)，9.64(s，1H)。
3-(4-hydroxyl-3-chloro-phenyl-)-6-methoxyl group-4-chloroquinoline (20):
Mp137-139℃；ESI-MS：303.0；IR(KBr)cm
-1：2935(C-H)，3024(Ar-H)，3448(OH)；
1HNMR(CDCl
3)δppm：3.65(s，3H)，7.35(d×d，1H)，7.50(d，1H)，7.63(d×d，2H)，7.76(d×d，2H)，7.89(d，1H)，9.63(s，1H)。
3-(4-hydroxyl-3-bromophenyl)-6-hydroxyl-4-chloroquinoline (21):
Mp147-146℃；ESI-MS：333.0；IR(KBr)cm
-1：2931(C-H)，3015(Ar-H)，3438(OH)；
1HNMR(DMSO-d
6)δppm：7.41(d×d，1H)，7.46(d，1H)，7.63(d×d，2H)，7.76(d×d，2H)，7.87(d，1H)，8.54(s，1H)，9.58(s，1H)。
3-(4-hydroxyl-3-bromophenyl)-6-methoxyl group-4-chloroquinoline (22):
Mp142-144℃；ESI-MS：347.0；IR(KBr)cm
-1：2928(C-H)，3012(Ar-H)，3442(OH)；
1HNMR(CDCl
3)δppm：3.58(s，3H)，7.37(d×d，1H)，7.48(d，1H)，7.61(d×d，2H)，7.75(d×d，2H)，7.91(d，1H)，9.67(s，1H)。
3-p-methoxyphenyl-4,5,7-trichloro-quinoline (23):
Mp157-159℃；ESI-MS：337.0；IR(KBr)cm
-1：2934(C-H)，3015(Ar-H)；
1HNMR(CDCl
3)δppm：3.83(s，3H)，7.08(d×d，2H)，7.64(d×d，2H)，7.74(d，1H)，7.97(d，1H)，9.56(s，1H)。
3-is to benzyloxy phenyl-4,5,7-trichloro-quinoline (24):
Mp165-166℃；ESI-MS：413.0；IR(KBr)cm
-1：2928(C-H)，3009(Ar-H)；
1HNMR(CDCl
3)δppm：4.73(s，2H)，6.80(d×d，2H)，7.28(t，1H)，7.32(t，2H)，7.35(d，2H)，7.52(d×d，2H)，7.70(d，1H)，7.96(d，1H)，9.52(s，1H)。
3-is to ethoxyl phenenyl-4,5,7-trichloro-quinoline (25):
Mp159-160℃；ESI-MS：351.0；IR(KBr)cm
-1：2937(C-H)，3018(Ar-H)；
1HNMR(CDCl
3)δppm：1.34(t，3H)，4.06(q，2H)，7.05(d×d，2H)，7.63(d×d，2H)，7.76(d，1H)，7.81(d，1H)，9.49(s，1H)。
3-(3-base-4-p-methoxy-phenyl)-4,5,7-trichloro-quinoline (26):
Mp161-162℃；ESI-MS：382.0；IR(KBr)cm
-1：1544(N＝O)，2929(C-H)，3012(Ar-H)；
1HNMR(CDCl
3)δppm：4.02(s，3H)，7.54(d×d，1H)，7.69(d，1H)，8.01(d，1H)，8.05(d，1H)，8.32(d，1H)，9.48(s，1H)。
3-(3-base-4-benzyloxy phenyl)-4,5,7-trichloro-quinoline (27):
Mp170-172℃；ESI-MS：458.0；IR(KBr)cm
-1：1552(N＝O)，2931(C-H)，3016(Ar-H)；
1HNMR(CDCl
3)δppm：4.76(s，2H)，6.80(d×d，1H)，7.28(t，1H)，7.32(t，2H)，7.35(d，2H)，7.57(d×d，1H)，7.66(d，1H)，8.03(d，1H)，8.08(d，1H)，8.31(d，1H)，9.51(s，1H)。
3-(3-base-4-ethoxyl phenenyl)-4,5,7-trichloro-quinoline (28):
Mp161-163℃；ESI-MS：396.0；IR(KBr)cm
-1：1556(N＝O)，2932(C-H)，3015(Ar-H)；
1HNMR(CDCl
3)δppm：1.32(t，3H)，3.98(q，2H)，7.51(d×d，1H)，7.68(d，1H)，8.02(d，1H)，8.07(d，1H)，8.34(d，1H)，9.53(s，1H)。
3-(3-amino-4-p-methoxy-phenyl)-4,5,7-trichloro-quinoline (29):
Mp165-167℃；ESI-MS：352.0；IR(KBr)cm
-1：2928(C-H)，3015(Ar-H)，3438(NH)；
1HNMR(CDCl
3)δppm：4.06(s，3H)，4.98(s，2H)，6.54(d×d，1H)，6.61(d，1H)，7.02(d，1H)，7.56(d，1H)，8.28(d，1H)，9.45(s，1H)。
3-(3-amino-4-benzyloxy phenyl)-4,5,7-trichloro-quinoline (30):
Mp175-176℃；ESI-MS：428.0；IR(KBr)cm
-1：2932(C-H)，3017(Ar-H)，3445(NH)；
1HNMR(CDCl
3)δppm：4.78(s，2H)，5.02(s，2H)，6.57(d×d，1H)，6.74(d，1H)，6.98(d，1H)，7.26(t，1H)，7.31(t，2H)，7.55(d，1H)，7.69(d，1H)，8.01(d，1H)，9.53(s，1H)。
3-(3-amino-4-ethoxyl phenenyl)-4,5,7-trichloro-quinoline (31):
Mp164-165℃；ESI-MS：366.0；IR(KBr)cm
-1：2933(C-H)，3017(Ar-H)，3451(NH)；
1HNMR(CDCl
3)δppm：1.37(t，3H)，4.03(q，2H)，4.96(s，2H)，6.58(d×d，1H)，7.62(d，1H)，7.02(d，1H)，7.68(d，1H)，8.27(d，1H)，9.49(s，1H)。
3-p-methoxyphenyl-5,7-two-4-chloroquinoline (32):
Mp143-145℃；ESI-MS：305.0；IR(KBr)cm
-1：2933(C-H)，3017(Ar-H)；
1HNMR(CDCl
3)δppm：3.82(s，3H)，6.94(d，1H)，7.08(d×d，2H)，7.59(d，1H)，7.64(d×d，2H)，9.24(s，1H)。
3-is to benzyloxy phenyl-5,7-two-4-chloroquinoline (33):
Mp151-153℃；ESI-MS：381.1；IR(KBr)cm
-1：2923(C-H)，3012(Ar-H)；
1HNMR(CDCl
3)δppm；4.82(s，2H)，6.81(d×d，2H)，7.08(d，1H)，7.26(t，1H)，7.30(t，2H)，7.32(d，2H)，7.57(d，1H)，7.62(d×d，2H)，9.29(s，1H)。
3-is to ethoxyl phenenyl-5,7-two-4-chloroquinoline (34):
Mp146-147℃；ESI-MS：319.1；IR(KBr)cm
-1：2935(C-H)，3021(Ar-H)；
1HNMR(CDCl
3)δppm：1.32(t，3H)，4.03(q，2H)，7.03(d×d，2H)，7.08(d，1H)，7.58(d，1H)，7.64(d×d，2H)，9.32(s，1H)。
3-(3-base-4-p-methoxy-phenyl)-5,7-two-4-chloroquinoline (35):
Mp153-154℃；ESI-MS：350.0；IR(KBr)cm
-1：1547(N＝O)，2932(C-H)，3018(Ar-H)；
1HNMR(CDCl
3)δppm：4.08(s，3H)，7.02(d，1H)，7.56(d，1H)，7.62(d，1H)，8.06(d×d，1H)，8.36(d，1H)，9.37(s，1H)。
3-(3-base-4-benzyloxy phenyl)-5,7-two-4-chloroquinoline (36):
Mp163-165℃；ESI-MS：426.1；IR(KBr)cm
-1：1548(N＝O)，2937(C-H)，3014(Ar-H)；
1HNMR(CDCl
3)δppm：4.74(s，2H)，7.05(d，1H)，6.80(d×d，1H)，7.26(t，1H)，7.3 1(t，2H)，7.36(d，2H)，7.54(d，1H)，7.61(d，1H)，7.67(d×d，1H)，8.41(d，1H)，9.38(s，1H)。
3-(3-base-4-ethoxyl phenenyl)-5,7-two-4-chloroquinoline (37):
Mp155-157℃；ESI-MS：364.0；IR(KBr)cm
-1：1551(N＝O)，2937(C-H)，3023(Ar-H)；
1HNMR(CDCl
3)δppm：1.35(t，3H)，3.95(q，2H)，7.06(d，1H)，7.54(d，1H)，7.62(d，1H)，7.94(d×d，1H)，8.37(d，1H)，9.36(s，1H)。
3-(3-amino-4-p-methoxy-phenyl)-5,7-two-4-chloroquinoline (38):
Mp154-156℃；ESI-MS：320.1；IR(KBr)cm
-1：2931(C-H)，3024(Ar-H)，3445(NH)；
1HNMR(CDCl
3)δppm：4.07(s，3H)，5.08(s，2H)，6.59(d，1H)，7.63(d，1H)，6.97(d×d，1H)，7.08(d，1H)，7.59(d，1H)，9.32(s，1H)。
3-(3-amino-4-benzyloxy phenyl)-5,7-two-4-chloroquinoline (39):
Mp165-167℃；ESI-MS：396.1；IR(KBr)cm
-1：2938(C-H)，3012(Ar-H)，3447(NH)；
1HNMR(CDCl
3)δppm：4.74(s，2H)，5.13(s，2H)，6.52(d，1H)，6.56(d，1H)，6.88(d×d，1H)，7.05(d，1H)，7.27(t，1H)，7.34(t，2H)，7.52(d，1H)，8.47(d，1H)，9.29(s，1H)。
3-(3-amino-4-ethoxyl phenenyl)-5,7-two-4-chloroquinoline (40):
Mp168-169℃；ESI-MS：334.1；IR(KBr)cm
-1：2933(C-H)，3017(Ar-H)，3451(NH)；
1HNMR(CDCl
3)δppm：1.35(t，3H)，4.08(q，2H)，4.91(s，2H)，6.53(d，1H)，6.57(d，1H)，6.78(d，1H)，6.95(d×d，1H)，7.02(d，1H)，9.31(s，1H)。
3-p-methoxyphenyl-6-methoxyl group-4-chloroquinoline (41):
Mp137-139℃；ESI-MS：299.1；IR(KBr)cm
-1：2931(C-H)，3018(Ar-H)；
1HNMR(CDCl
3)δppm：3.72(s，3H)，3.83(s，3H)，7.03(d×d，2H)，7.41(d×d，1H)，7.53(d，1H)，7.68(d×d，2H)，7.83(d，1H)，9.28(s，1H)。
3-is to benzyloxy phenyl-6-methoxyl group-4-chloroquinoline (42):
Mp145-147℃；ESI-MS：375.1；IR(KBr)cm
-1：2939(C-H)，3025(Ar-H)；
1HNMR(CDCl
3)δppm：3.71(s，3H)，4.52(s，2H)，7.28(t，1H)，7.34(t，2H)，7.40(d，2H)，7.44(d×d，1H)，6.62(d×d，2H)，7.83(d，1H)，9.26(s，1H)。
3-rubigan-6-methoxyl group-4-chloroquinoline (43):
Mp139-141℃；ESI-MS：303.0；IR(KBr)cm
-1：2935(C-H)，3013(Ar-H)；
1HNMR(CDCl
3)δppm：3.76(s，3H)，7.42(d×d，1H)，7.51(d，1H)，7.77(d×d，2H)，7.80(d×d，2H)，7.89(d，1H)，9.25(s，1H)。
3-is to bromophenyl-6-methoxyl group-4-chloroquinoline (44):
Mp142-143℃；ESI-MS：347.0；IR(KBr)cm
-1：2931(C-H)，3014(Ar-H)；
1HNMR(CDCl
3)δppm：3.72(s，3H)，7.46(d×d，1H)，7.53(d×d，2H)，7.57(d×d，2H)，7.60(d，1H)，7.82(d，1H)，9.29(s，1H)。
3-is to phenyl-6-methoxyl group-4-chloroquinoline (45):
Mp133-135℃；ESI-MS：287.1；IR(KBr)cm
-1：2937(C-H)，3025(Ar-H)；
1HNMR(CDCl
3)δppm：3.77(s，3H)，7.12(d×d，2H)，7.37(d×d，2H)，7.42(d×d，1H)，7.53(d，1H)，7.85(d，1H)，9.30(s，1H)。
3-is to basic phenyl-6-methoxyl group-4-chloroquinoline (46):
Mp138-139℃；ESI-MS：314.1；IR(KBr)cm
-1：2938(C-H)，3021(Ar-H)；
1HNMR(CDCl
3)δppm：3.71(s，3H)，7.43(d×d，1H)，7.52(d，1H)，7.79(d×d，2H)，7.82(d，1H)，8.27(d×d，2H)，9.24(s，1H)。
3-is to benzyloxy phenyl-6-methoxyl group-4-chloroquinoline (47):
Mp137-138℃；ESI-MS：375.1；IR(KBr)cm
-1：2932(C-H)，3026(Ar-H)；
1HNMR(CDCl
3)δppm：3.72(s，3H)，4.57(s，2H)，7.03(d×d，2H)，7.35(t，1H)，7.37(t，2H)，7.41(d，2H)，7.43(d×d，1H)，7.56(d，1H)，7.64(d×d，2H)，7.85(d，1H)，9.27(s，1H)。
3-is to benzyloxy phenyl-6-benzyloxy-4-chloroquinoline (48):
Mp146-148℃；ESI-MS：451.1；IR(KBr)cm
-1：2936(C-H)，3024(Ar-H)；
1HNMR(CDCl
3)δppm：4.51(s，2H)，4.57(s，2H)，6.82(d×d，2H)，7.37(t，2H)，7.38(t，4H)，7.43(d，4H)，7.46(d×d，1H)，7.54(d，1H)，7.63(d×d，2H)，7.87(d，1H)，9.21(s，1H)。
3-rubigan-6-benzyloxy-4-chloroquinoline (49):
Mp138-141℃；ESI-MS：379.1；IR(KBr)cm
-1：2931(C-H)，3027(Ar-H)；
1HNMR(CDCl
3)δppm：4.57(s，2H)，7.35(t，1H)，7.37(t，2H)，7.41(d，2H)，7.45(d×d，1H)，7.53(d，1H)，7.66(d×d，2H)，7.70(d×d，2H)，7.84(d，1H)，9.28(s，1H)。
3-is to bromophenyl-6-benzyloxy-4-chloroquinoline (50):
Mp142-143℃；ESI-MS：423.0；IR(KBr)cm
-1：2935(C-H)，3018(Ar-H)；
1HNMR(CDCl
3)δppm：4.54(s，2H)，7.32(t，1H)，7.34(t，2H)，7.38(d，2H)，7.40(d×d，1H)，7.46(d，1H)，7.58(d×d，2H)，7.61(d×d，2H)，7.87(d，1H)，9.25(s，1H)。
3-is to phenyl-6-benzyloxy-4-chloroquinoline (51):
Mp140-142℃；ESI-MS：363.1；IR(KBr)cm
-1：2927(C-H)，3033(Ar-H)；
1HNMR(CDCl
3)δppm：4.53(s，2H)，7.13(d×d，2H)，8.30(d×d，2H)，7.34(t，1H)，7.38(t，2H)，7.42(d，2H)，7.47(d×d，1H)，7.55(d，1H)，7.81(d，1H)，9.32(s，1H)。
3-is to basic phenyl-6-benzyloxy-4-chloroquinoline (52):
Mp144-145℃；ESI-MS：390.1；IR(KBr)cm
-1：1556(N＝O)，2929(C-H)，3031(Ar-H)；
1HNMR(CDCl
3)δppm：4.56(s，2H)，7.32(t，1H)，7.36(t，2H)，7.41(d，2H)，7.46(d×d，1H)，7.54(d，1H)，7.83(d，1H)，7.92(d×d，2H)，8.33(d×d，2H)，9.31(s，1H)。
3-rubigan-5,7-dihydroxyl-6-methoxyl group-4-chloroquinoline (53):
Mp178-180℃；ESI-MS：335.0；IR(KBr)cm
-1：2929(C-H)，3031(Ar-H)，3425(OH)；
1HNMR(CDCl
3)δppm：3.68(s，3H)，7.01(s，1H)，7.62(d×d，2H)，7.79(d×d，2H)，8.91(s，1H)，9.25(s，1H)，10.01(s，1H)。
3-is to bromophenyl-5,7-dihydroxyl-6-methoxyl group-4-chloroquinoline (54):
Mp181-182℃；ESI-MS：379.0；IR(KBr)cm
-1：2928(C-H)，3029(Ar-H)，3431(OH)；
1HNMR(CDCl
3)δppm：3.71(s，3H)，7.03(s，1H)，7.53(d×d，2H)，7.58(d×d，2H)，8.92(s，1H)，9.21(s，1H)，10.04(s，1H)。
3-is to phenyl-5,7-dihydroxyl-6-methoxyl group-4-chloroquinoline (55):
Mp168-170℃；ESI-MS：319.0；IR(KBr)cm
-1：2934(C-H)，3035(Ar-H)，3432(OH)；
1HNMR(CDCl
3)δppm：3.74(s，3H)，7.02(s，1H)，7.19(d×d，2H)，7.40(d×d，2H)，8.90(s，1H)，9.22(s，1H)，10.01(s，1H)。
3-rubigan-5,7-two-4-chloroquinoline (56):
Mp139-141℃；ESI-MS：309.0；IR(KBr)cm
-1：2931(C-H)，3019(Ar-H)；
1HNMR(CDCl
3)δppm：7.02(d，1H)，7.59(d，1H)，7.61(d×d，2H)，7.78(d×d，2H)，9.22(s，1H)。
3-is to bromophenyl-4,5,7-trichloro-quinoline (57):
Mp145-147℃；ESI-MS：384.9；IR(KBr)cm
-1：2929(C-H)，3023(Ar-H)；
1HNMR(CDCl
3)δppm：7.51(d×d，2H)，7.56(d×d，2H)，7.76(d，1H)，7.96(d，1H)，9.25(s，1H)。
3-rubigan-4-chloro-5,7-two bromoquinolines (58):
Mp147-148℃；ESI-MS：428.8；IR(KBr)cm
-1：2937(C-H)，3015(Ar-H)；
1HNMR(CDCl
3)δppm：7.61(d×d，2H)，7.74(d×d，2H)，8.09(d，1H)，8.31(d，1H)，9.28(s，1H)。
3-is to bromophenyl-4-chloro-5,7-two bromoquinolines (59):
Mp148-150℃；ESI-MS：472.8；IR(KBr)cm
-1：2936(C-H)，3020(Ar-H)；
1HNMR(CDCl
3)δppm：7.52(d×d，2H)，7.58(d×d，2H)，8.07(d，1H)，8.30(d，1H)，9.26(s，1H)。
3-is to phenyl-4-chloro-5,7-two bromoquinolines (60):
Mp142-143℃；ESI-MS：412.9；IR(KBr)cm
-1：2935(C-H)，3024(Ar-H)；
1HNMR(CDCl
3)δppm：7.17(d×d，2H)，7.40(d×d，2H)，8.08(d，1H)，8.32(d，1H)，9.31(s，1H)。
Claims (3)
1. quinoline Roofirisrhizome flavin non polar isostere, it has following general structure:
Wherein:
R
1And R
3=Br, R
2=OR and R
5=R, then R
4=NO
2, NR
2, F, Cl, Br, OCH
3Or OBn;
R
1And R
3=Cl, R
2=H and R
5=R, then R
4=NO
2, NR
2, F, Cl, Br, OCH
3Or OBn;
R
1And R
3=F, R
2=H and R
5=R, then R
4=NO
2, NR
2, F, Cl, Br, OCH
3Or OBn;
R
1And R
3=H, R2=OR and R4=OR, then R
5=NO
2, NR
2, F, Cl or Br;
Described R=H, CH
3Or C
2H
5
2. method for preparing the described quinoline Roofirisrhizome flavin non polar isostere of claim 1 Compound I I is characterized in that: with the isostere Compound I of quinolinone tectorigenin at POCl
3Be heated between 110～120 ℃ under existing, reacted 10-15 hour, obtain quinoline Roofirisrhizome flavin non polar isostere Compound I I:
3. the application of the described quinoline Roofirisrhizome flavin non polar isostere of claim 1 in the preparation antitumor drug.
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|---|---|
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| CN100491354C CN100491354C (en) | 2009-05-27 |
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ID=38258328
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102309479A (en) * | 2011-06-17 | 2012-01-11 | 中国人民解放军第二军医大学 | Application of isoflavone compound in preparation of medicaments or foods for resisting tumors |
| CN107417612A (en) * | 2017-07-25 | 2017-12-01 | 广州大学 | A kind of synthetic method of quinoline |
| CN107417611A (en) * | 2017-07-25 | 2017-12-01 | 广州大学 | One kind 3（4 methoxyphenyls）The synthetic method of the bromoquinoline of 6 methoxyl group, 4 chlorine 5,7 2 |
| CN107501174A (en) * | 2017-07-25 | 2017-12-22 | 广州大学 | A kind of synthetic method of quinoline |
| CN107501175A (en) * | 2017-07-25 | 2017-12-22 | 广州大学 | A kind of synthetic method of quinoline |
| CN108685921A (en) * | 2017-12-19 | 2018-10-23 | 广州大学 | A kind of application of the quinoline of N isosteres iridin in medicines resistant to liver cancer |
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2006
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102309479A (en) * | 2011-06-17 | 2012-01-11 | 中国人民解放军第二军医大学 | Application of isoflavone compound in preparation of medicaments or foods for resisting tumors |
| CN107417612A (en) * | 2017-07-25 | 2017-12-01 | 广州大学 | A kind of synthetic method of quinoline |
| CN107417611A (en) * | 2017-07-25 | 2017-12-01 | 广州大学 | One kind 3（4 methoxyphenyls）The synthetic method of the bromoquinoline of 6 methoxyl group, 4 chlorine 5,7 2 |
| CN107501174A (en) * | 2017-07-25 | 2017-12-22 | 广州大学 | A kind of synthetic method of quinoline |
| CN107501175A (en) * | 2017-07-25 | 2017-12-22 | 广州大学 | A kind of synthetic method of quinoline |
| CN108685921A (en) * | 2017-12-19 | 2018-10-23 | 广州大学 | A kind of application of the quinoline of N isosteres iridin in medicines resistant to liver cancer |
| CN108685921B (en) * | 2017-12-19 | 2020-01-17 | 广州大学 | Application of quinoline derivative of N-isostere tectoridin in anti-liver cancer drugs |
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