CN102746292A - Cyclized berberine derivatives, preparation method and uses thereof - Google Patents
Cyclized berberine derivatives, preparation method and uses thereof Download PDFInfo
- Publication number
- CN102746292A CN102746292A CN201210101607XA CN201210101607A CN102746292A CN 102746292 A CN102746292 A CN 102746292A CN 201210101607X A CN201210101607X A CN 201210101607XA CN 201210101607 A CN201210101607 A CN 201210101607A CN 102746292 A CN102746292 A CN 102746292A
- Authority
- CN
- China
- Prior art keywords
- dioxole
- dihydro
- phenanthridines
- cde
- isoquino
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000003832 berberine derivatives Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 100
- -1 nitro, cyano, amino, hydroxy Chemical group 0.000 claims abstract description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 14
- 150000002367 halogens Chemical group 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
- 239000012453 solvate Substances 0.000 claims abstract description 11
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 70
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims description 50
- 239000002904 solvent Substances 0.000 claims description 38
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 claims description 33
- 229940093265 berberine Drugs 0.000 claims description 31
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 30
- 150000001263 acyl chlorides Chemical class 0.000 claims description 24
- 206010028980 Neoplasm Diseases 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 239000002585 base Substances 0.000 claims description 12
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- 208000014018 liver neoplasm Diseases 0.000 claims description 9
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- 239000003513 alkali Substances 0.000 claims description 7
- FZAGOOYMTPGPGF-UHFFFAOYSA-N Lambertine Chemical compound C1=C2C3=CC4=CC=C(OC)C(OC)=C4CN3CCC2=CC2=C1OCO2 FZAGOOYMTPGPGF-UHFFFAOYSA-N 0.000 claims description 6
- 201000007270 liver cancer Diseases 0.000 claims description 6
- IBGCXOFOCKCBNQ-UHFFFAOYSA-N nitro cyanate Chemical compound [O-][N+](=O)OC#N IBGCXOFOCKCBNQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Chemical group 0.000 claims description 4
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- 125000006332 fluoro benzoyl group Chemical group 0.000 claims description 4
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- GLGSZERYOLHNML-UHFFFAOYSA-N $l^{1}-oxidanyl(phenyl)methanone Chemical compound [O]C(=O)C1=CC=CC=C1 GLGSZERYOLHNML-UHFFFAOYSA-N 0.000 claims description 2
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- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 125000005257 alkyl acyl group Chemical group 0.000 abstract 1
- 230000009286 beneficial effect Effects 0.000 abstract 1
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Abstract
The present invention relates to cyclized berberine derivatives, a preparation method and uses thereof. The present invention specifically relates to compounds represented by a formula I or a pharmaceutically-acceptable salt or a solvate thereof, wherein X is a halogen, R is selected from hydrogen, C1-6 alkyl, phenyl substituted C1-6 alkyl, C1-18 alkylacyl, benzoyl, benzenesulfonyl, and 3,4-C1-3alkylidene dioxybenzoyl, the phenyl is optionally substituted by 1-4 substituents selected from halogen, C1-6 alkyl, C1-6 alkoxy, nitro, cyano, amino, hydroxy, C1-4 alkyl acylamino. The compounds of the present invention have beneficial physiological activities.
Description
Technical field
The invention belongs to the medical chemistry field; Be specifically related to one type of new compound that can be used as antineoplastic agent; Be particularly related to one type and have cyclisation berberinc derivate of anti-tumor activity and preparation method thereof, and this compounds as medicine particularly as the for example application aspect the medicine of anti-liver neoplasm of antitumor drug.
Background technology
Tumour and cancer are one of healthy major diseases of harm humans.Tumour be body under various carcinogenic factor effects, some cells of local organization lose the normal regulation to its growth on gene level, cause its clonal abnormality hyperplasia and the true tumor that forms.It is generally acknowledged that tumour cell is a monoclonicity, promptly all oncocytes in tumour all are offsprings of the cell of a sudden change.Generally tumour is divided into optimum and pernicious two big types.All malignant tumours are generically and collectively referred to as cancer.The physician points out that cancer is because of being: body in environmental pollution, chemical pollution (chemical toxicant), ionizing rays, radical toxin, mikrobe (bacterium, fungi, virus etc.) and metabolism toxin, hereditary property, internal secretion is unbalance, cause the result of health normal cell generation canceration under the effect of the various carcinogenic substances of immunologic function disorder or the like, carcinogenic factor, often show as: the cellular abnormality hyperplasia of local organization and the local lump that forms.Cancer is that organism normal cell is in many reasons, multistage and the caused one big type of disease of repeatedly suddenling change.
Know that (Berberine BBR), is called Umbellatine again to Berberine, is a kind of common morphinane alkaloid, and its molecular formula is [C
20H
18NO
4]
+It is present in many plants of ten genus of four sections such as Berberidaceae, and M.-E. Xia Waliai in 1826 and G. Pei Ertan obtain from the Xanthoxylonclava bark first first.Berberine is a kind of quartermary ammonium alkaloids, from ether, can separate out yellow needle-like crystal; 145 ℃ of fusing points; Water-soluble, be insoluble in benzene, EC.The solubleness of its esters in water is all smaller, and for example hydrochloride is 1: 500, and vitriol is 1: 30.Berberine has restraining effect to dysentery bacterium, intestinal bacteria, pneumococcus, golden Portugal bacterium, suis, Corynebacterium diphtheriae and ameba.Clinical berberine hydrochloride commonly used is its 2 hydrate, is mainly used in intestinal tract infections and bacillary dysentery etc.Recently find also that Berberine has antiarrhythmic effect and can be used to treat mellitus.The has a broad antifungal spectrum of Berberine, external to multiple gram-positive and the equal tool bacteriostatic action of negative bacterium, wherein to Hemolytic streptococcus, golden Portugal bacterium, vibrio cholerae.Meningococcus, shigella, Corynebacterium diphtheriae, diphtheria corynebacterium etc. have stronger restraining effect, and be antibacterial during lower concentration, sterilization during high density.Influenza virus, ameba, leptospiral, some dermatophytes also there is certain restraining effect.Experiment in vitro confirms that Umbellatine can strengthen the phagocytic activity of white corpuscle and liver reticuloendothelial system.Dysentery bacterium, Hemolytic streptococcus, golden Portugal bacterium etc. very easily produce resistance to these article.Berberine and penicillium mould, Streptomycin sulphate etc. do not have cross resistance.Berberine is mainly used in intestinal tract infectionss such as treatment gastro-enteritis, bacillary dysentery clinically at present, and is effective for eye conjunctivitis, suppurative otitis media etc.
People still expect novelty is arranged and the effective antitumour medicine for example the medicine of anti-liver neoplasm be used for clinical.
Summary of the invention
The objective of the invention is to seek and have the for example new compound of anti-liver neoplasm of effective antitumour.The wonderful discovery of the inventor, the cyclisation berberinc derivate with formula I structure has wonderful effect.The present invention is based on this discovery and be accomplished.
For this reason, first aspect present invention provides with the following formula I compound:
Or its pharmacologically acceptable salts or solvate, wherein
X is a halogen;
R
1Be selected from: hydrogen, C
1-6Alkyl, the substituted C of phenyl
1-6Alkyl, C
1-18Alkyl acyl, benzoyl-, benzenesulfonyl, 3,4-C
1-3The alkylenedioxy group benzoyl-, wherein said phenyl is optional to be selected from following substituting group replacement by 1 to 4: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, nitro, cyanic acid, amino, hydroxyl, C
1-4Alkyl acyl is amino;
R
2And R
3Be selected from independently of one another: hydrogen, C
1-6Alkyl, benzoyl-, wherein said phenyl is optional to be replaced by 1 to 4 halogen; Perhaps R
2And R
3Be together-CH
2-(be R
2And R
3The Sauerstoffatom that connects with their forms the ring of a dioxole).
According to the compound of first aspect present invention, wherein R
2And R
3Be selected from independently of one another: hydrogen, C
1-4Alkyl, halogeno-benzene formyl radical; Perhaps R
2And R
3Be together-CH
2-(be R
2And R
3The Sauerstoffatom that connects with their forms the ring of a dioxole).
According to the compound of first aspect present invention, it is the compound with Formula Il:
Or its pharmacologically acceptable salts or solvate, wherein
X is a halogen;
R is selected from: hydrogen, C
1-6Alkyl, the substituted C of phenyl
1-6Alkyl, C
1-18Alkyl acyl, benzoyl-, benzenesulfonyl, 3,4-C
1-3The alkylenedioxy group benzoyl-, wherein said phenyl is optional to be selected from following substituting group replacement by 1 to 4: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, nitro, cyanic acid, amino, hydroxyl, C
1-4Alkyl acyl is amino.
According to the compound of first aspect present invention, wherein X is selected from fluorine, chlorine, bromine, iodine.In one embodiment, X is selected from chlorine, bromine, iodine.
According to the compound of first aspect present invention, wherein R is selected from hydrogen, C
1-4Alkyl, the substituted C of phenyl
1-4Alkyl, C
1-16Alkyl acyl, benzoyl-, benzenesulfonyl, 3,4-C
1-2The alkylenedioxy group benzoyl-, wherein said phenyl is optional to be selected from following substituting group replacement by 1 to 4: halogen, C
1-4Alkyl, C
1-4Alkoxyl group, nitro, cyanic acid, amino, hydroxyl, C
1-4Alkyl acyl is amino.
According to the compound of first aspect present invention, wherein R is selected from hydrogen, C
1-4Alkyl, the substituted C of phenyl
1-4Alkyl, C
1-16Alkyl acyl, benzoyl-, benzenesulfonyl, 3,4-methylene-dioxy benzoyl-, wherein said phenyl is optional to be selected from following substituting group replacement by 1 to 4: halogen, C
1-4Alkyl, C
1-4Alkoxyl group, nitro, cyanic acid, amino, hydroxyl, C
1-4Alkyl acyl is amino.
According to the compound of first aspect present invention, it is a following formula: compound,
R wherein
1, R
2, R
3Have each said implication of following numbering (No1 to No51) with X:
According to the compound of first aspect present invention, it is to be selected from following compound:
9,10-dimethoxy-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-hydroxyl-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-oxyethyl group-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide;
9-butoxy-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-iodide;
9-benzyloxy-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide;
9-(2,4 difluorobenzene base) methoxyl group-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide;
9-ethanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-benzoyl-Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methyl benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to anisoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to fluoro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to fluorine m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methyl m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methoxyl group m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(3,4-methylene-dioxy benzoyl-oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(3,4,5-trimethoxy benzoyl-oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
The adjacent fluoro benzoyl Oxy-1 of 9-0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
The adjacent chlorobenzene formacyl Oxy-1 of 9-0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(2,4 difluorobenzene formyl radical oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to acetamido benzenesulfonyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-benzenesulfonyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-decanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-lauroyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-hexadecanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
Or its pharmacologically acceptable salts or solvate.
According to the compound of first aspect present invention, it is like the embodiment of the invention prepared compound or its pharmacologically acceptable salts or solvate.
Second aspect present invention provides the method for preparing each said formula I compound of first aspect present invention, and it may further comprise the steps:
A) in solvent (for example methyl alcohol), in the presence of alkali (for example salt of wormwood, sodium hydroxide etc. or its combination), make the reaction of Peng Qinghuana and Berberine, obtain dihydroberberine;
B) in solvent (for example acetonitrile), exist down in acid (for example organic acid, for example acetate), make dihydroberberine and glyoxal reaction, obtain the cyclisation Berberine shown in the formula Ia:
Choose wantonly, formula Ia cyclisation Berberine handled down under vacuum (for example 10-60mmHg, for example 20-40mmHg), at high temperature (for example 150～250 ℃, for example 180～230 ℃) obtained the 9-hydroxyl cyclisation Berberine shown in the formula Ib:
Choose wantonly; D) in organic solvent (for example DMF); In the presence of alkali (for example sodium hydroxide, Pottasium Hydroxide), make 9-hydroxyl cyclisation Berberine and suitable reagent (for example halohydrocarbon, for example halogenated alkane, the substituted halogenated alkane of the phenyl) reaction of formula Ib; Obtain 9-alkyl oxy cyclisation Berberine, alkyl wherein is optional to be replaced by phenyl or substituted phenyl;
Choose wantonly; E) in organic solvent (for example acetonitrile); In the presence of reagent (for example pyridine); Make 9-hydroxyl cyclisation Berberine and acyl chlorides or the SULPHURYL CHLORIDE reaction of formula Ib, obtain 9-acyloxy cyclisation Berberine or 9-alkylsulfonyl oxygen basic ring Berberine, acyl group wherein is alkyloyl or benzoyl-.
In the preparation method of second aspect present invention, under necessary situation, in formula I compound process; For preventing that some group (like amino, hydroxyl etc.) from undesirable reaction taking place; Need protect these groups, simultaneously, remove the protection base in due course.These embodiment are too numerous to enumerate, and the use of the protection base of specifically not mentioning and the method for deprotection also belong within the scope of the present invention.
Third aspect present invention relates to a kind of pharmaceutical composition, and it comprises each described formula I compound of first aspect present invention, and optional one or more pharmaceutically acceptable carriers or vehicle.
Fourth aspect present invention relates to each described formula I compound of first aspect present invention is used for treating and/or preventing the medicine of Mammals (comprising the people) tumour or cancer property disease (for example liver cancer) in preparation purposes.
Fifth aspect present invention relates to a kind of method that in the Mammals of needs is arranged, treats and/or prevents Mammals (comprising the people) tumour or cancer property disease (for example liver cancer), and this method comprises each the described formula I compound of first aspect present invention to the administration treatment significant quantity that needs are arranged.
Sixth aspect present invention relates to the pharmaceutical composition that is used to treat and/or prevent Mammals (comprising the people) tumour or cancer property disease (for example liver cancer); This pharmaceutical composition comprises each described formula I compound of first aspect present invention, and optional one or more pharmaceutically acceptable carriers or vehicle.
Seventh aspect present invention also relates to each the described formula I compound of first aspect present invention that is used to treat and/or prevent Mammals (comprising the people) tumour or cancer property disease (for example liver cancer).
Arbitrary embodiment of arbitrary aspect of the present invention can make up with other embodiment, as long as they contradiction can not occur.In addition, in the arbitrary embodiment aspect the present invention is arbitrary, arbitrary technical characterictic goes for this technical characterictic in other embodiment, as long as they contradiction can not occur.
Do further description in the face of the present invention down.
All documents that the present invention quoted from, their full content is incorporated this paper by reference into, and if the expressed implication of these documents and the present invention when inconsistent, be as the criterion with statement of the present invention.In addition; Various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art; Nonetheless; The present invention still hopes at this more detailed explanation and explanation to be done in these terms and phrase, and term of mentioning and phrase are as the criterion with the implication that the present invention was explained if any inconsistent with known implication.
Those skilled in the art know, and the main ring of Berberine and annular atoms can be by following exemplary serial numbers:
Similarly, for formula I compound of the present invention, for example for for formula Ia compound of the present invention, wherein corresponding five rings and the numbering of part annular atoms are can example following:
Therefore in the present invention, when mentioning " cyclisation Berberine ", be meant berberinc derivate with following formula Ia.Further, when mentioning " 9-hydroxyl cyclisation Berberine ", be meant with the berberinc derivate shown in the following formula Ib:
Again for example, when mentioning " 9-oxyethyl group cyclisation Berberine ", be meant that the 9-position is the The compounds of this invention of oxyethyl group.
In the present invention, term " halogen " or " halo " are meant fluorine, chlorine, bromine and iodine.In the present invention, and group " 3,4-C
1-3The alkylenedioxy group benzoyl-" in group part " C
1-3Alkylidene group " be meant alkylidene group with 1 to 3 carbon atom.
Among the present invention, when mentioning, the term that is adopted " alkyl " comprises alkyl, thiazolinyl and alkynyl, and cyclic group, for example the group of aromatic ring (like phenyl ring) or non-aromatic ring (for example cyclohexane ring).In the present invention, mention C
1-6During alkyl, it comprises its any subset, for example comprises C
1-5Alkyl, C
1-4Alkyl, C
1-3Alkyl, and methyl, ethyl, n-propyl, sec.-propyl, normal-butyl etc.
In the method for synthetic compound of formula i of the present invention, the various starting material that react used are that those skilled in the art can prepare according to existing knowledge, or can make through the document known method, or can buy through commerce.Used midbody, starting material, reagent, reaction conditions etc. all can be made appropriate change according to those skilled in the art existing knowledge in the above reaction scheme.Perhaps, those skilled in the art also can synthesize other formula I compound that the present invention does not specifically enumerate according to the second aspect present invention method.
Formula I compound of the present invention can use with other activeconstituents combination, as long as it does not produce other detrimental actions, for example anaphylaxis.
Active compound shown in the formula I of the present invention can be used as unique antitumor/cancer therapy drug and uses, and perhaps can unite use with one or more other antibacterials.Combination therapy realizes through each being treated component while, order or separating administration.
Term used herein " compsn " means and comprises the product of respectively specifying composition that comprises specified amount, and directly or indirectly from any product of the combination results of respectively specifying composition of specified amount.In the present invention, term " compsn " can exchange with " pharmaceutical composition " and use.
Compound of the present invention can use with the form derived from mineral acid or organic acid pharmacologically acceptable salts.Word " pharmacologically acceptable salts " refers in reliable medical judgment scope, be suitable for contacting with zootic tissue and over-drastic toxicity, stimulation, anaphylaxis etc. do not occur with the mankind, and with rational effect/risk than the salt that matches.Pharmacologically acceptable salts is well known in the art.For example, S.M.Berge, et al., J.Pharmaceutical Sciences, 1977, among the 66:1 pharmacologically acceptable salts is described in detail.Said salt can be through free alkali functionality and the appropriate organic reaction that makes The compounds of this invention, in final separation and the purge process made acid-stable in situ or the preparation separately of The compounds of this invention.Representational acid salt include but not limited to acetate, adipate, alginates, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (different thiosulphate, isothionate), lactic acid salt, PHENRAMINE MALEATE, mesylate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, SUMATRIPTAN SUCCINATE, tartrate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecane hydrochlorate.Equally, alkaline nitrogen-containing group can use following material quaternized: the muriate of elementary alkyl halide such as methyl, ethyl, propyl group and butyl, bromide and iodide; Sulfuric acid dialkyl such as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; The muriate of long-chain halogenide such as decyl, dodecyl, tetradecyl and octadecyl, bromide and iodide; Arylalkyl halogenide such as bromotoluene and phenethyl bromide and other.Therefore dissolved in or be scattered in the product of water or oil.The sour instance that can be used to form the acceptable acid salt of pharmacy comprises mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid, and organic acid such as oxalic acid, toxilic acid, succsinic acid and Hydrocerol A.
Base addition salt can contain carboxylic moiety and suitable alkali reaction through what make The compounds of this invention; Final separation and purge process made acid-stable in situ at The compounds of this invention; Described alkali is oxyhydroxide, carbonate and the supercarbonate of the acceptable metallic cation of pharmacy for example, perhaps ammonia or organic primary amine, secondary amine or tertiary amine.
Pharmacologically acceptable salts includes but not limited to based on the positively charged ion of basic metal or earth alkali metal such as lithium, sodium, potassium, calcium, magnesium and aluminium salt etc.; And nontoxic quaternary ammonium and amine positively charged ion, comprise ammonium, tetramethyl-ammonium, tetraethyl ammonium, ammonium methyl, Dimethyl Ammonium, trimethyl ammonium, triethyl ammonium, diethyl ammonium and ethyl ammonium etc.Other representative organic amines that can be used for forming base addition salt comprise quadrol, thanomin, diethylolamine, piperidines, piperazine etc.
Formula I compound of the present invention also comprises its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester; Formula I compound of the present invention and its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester can also form solvate, for example hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that discharges said activeconstituents in vivo after the metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.In general, for the object of the invention, suitable with non-solvent compound form with the solvate form thereof of pharmacy acceptable solvent such as water, ethanol etc.
Below the activity of the structure of certain exemplary compound of the present invention and anti-HepG2 cell proliferation thereof was listed in, antiproliferative activity measuring method was wherein seen Test Example 1.
| Embodiment number | The compound code name | Inhibiting rate % |
| Embodiment 1 | A | 33.4±3.2 a |
| Embodiment 2 | A-30 | 50.0±3.1 a |
| |
A-31 | 41.9±3.3 a |
| Embodiment 4 | A-32 | 62.6±1.8 a |
| |
A-33 | 53.3±11.5 a |
| Embodiment 6 | A-43 | 50.7±11.7 a |
| Embodiment 7 | A-34 | 88.7±1.1 a |
| Embodiment 8 | A-35 | 86.6±2.4 a |
| Embodiment 9 | A-38 | 63.7±2.0 a |
| Embodiment 10 | A-40 | 84.5±1.9 a |
| Embodiment 11 | A-39 | 70.3±2.6 a |
| Embodiment 12 | A-44 | 69.6±2.5 a |
| Embodiment 13 | A-45 | 50.9±4.3 a |
| Embodiment 14 | A-46 | 53.6±2.2 a |
| Embodiment 15 | A-56 | 88.6±10.8 a |
| Embodiment 16 | A-49 | 86.5±10.6 a |
| Embodiment 17 | A-55 | 93.7±16.1 a |
| Embodiment 18 | A-37 | 62.3±2.0 a |
| Embodiment 19 | A-58 | 92.5±11.4 a |
| Embodiment 20 | A-41 | 8.9±5.1 a |
| Embodiment 21 | A-42 | 56.2±2.0 a |
| Embodiment 22 | A-50 | 87.3±55.5 a |
| Embodiment 23 | A-53 | 87.6±9.8 a |
| Embodiment 24 | A-54 | 93.5±2.5 a |
| Embodiment 25 | A-61 | 86.5±10.6 a |
| Embodiment 26 | A-64 | 79.0±9.9 a |
| Embodiment 27 | A-67 | 70.5±2.5 a |
| Embodiment 28 | A-68 | 63.7±6.1 a |
| Embodiment 29 | A-69 | 88.6±9.1 a |
| Embodiment 30 | A-70 | 76.5±8.4 a |
| Embodiment 31 | A-71 | 58.6±5.3 b |
| Embodiment 32 | A-72 | 49.7±6.1 b |
| Embodiment 33 | A-73 | 58.0±5.6 b |
| Embodiment 34 | A-74 | 59.3±5.1 b |
| Embodiment 35 | A-75 | 57.6±3.6 b |
| Embodiment 36 | A-76 | 52.4±2.3 b |
| Embodiment 37 | A-77 | 52.8±4.1 b |
| Embodiment 38 | A-78 | 50.9±3.5 b |
| Embodiment 39 | A-79 | 48.5±4.3 b |
| Embodiment 40 | A-80 | 49.5±6.0 b |
| Embodiment 41 | A-81 | 57.3±3.6 b |
| Embodiment 42 | A-82 | 43.4±3.2 b |
| Embodiment 43 | A-83 | 56.6±1.2 b |
| Embodiment 44 | A-84 | 53.5±5.6 b |
| Embodiment 45 | A-85 | 60.6±1.2 b |
| Embodiment 46 | A-86 | 54.1±6.0 b |
| Embodiment 47 | A-87 | 13.0±1.3 b |
| Embodiment 48 | A-36 | 32.9±3.0 a |
| Embodiment 49 | A-60 | 5.4±0.9 a |
| Embodiment 50 | A-65 | 87.3±55.5 a |
| Embodiment 51 | A-66 | 87.6±9.8 a |
Annotate a:0.6 μ g/mL b:0.1 μ g/mL
Can change the actual dose level of each activeconstituents in the pharmaceutical composition of the present invention, obtain required therapeutic response so that the active compound amount of gained can effectively be directed against concrete patient, compsn and administering mode.The dosage level fibrous root is according to the severity of the activity of particular compound, route of administration, the patient's condition of treating and wait that the patient's condition and the medical history of treating the patient select.But the way of this area is, the dosage of compound begins from being lower than for obtaining the level that required result of treatment requires, and increases dosage gradually, up to obtaining required effect.
When being used for above-mentioned treating and/or preventing or other treatment and/or when prevention, a kind of The compounds of this invention that treats and/or prevents significant quantity can be used with pure form, perhaps uses with acceptable ester of pharmacy or prodrug forms (under the situation that has these forms).Perhaps, said compound can be accepted the pharmaceutical composition administration of vehicle to contain this purpose compound and one or more medicines.The The compounds of this invention that word " treats and/or prevents significant quantity " refers to the compound of the reasonable effect that is applicable to any therapeutic treatment and/or prevention/risk than the q.s of treatment obstacle.But the total daily dosage portion that it should be understood that The compounds of this invention and compsn must be examined the doctor by the master and maked decision in the medical judgment scope reliably.For any concrete patient, the horizontal fibrous root of concrete treatment effective dose decide according to multiple factor, and said factor comprises the obstacle of being treated and the severity of this obstacle; The activity of the particular compound that is adopted; The concrete compsn that is adopted; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound that is adopted, route of administration and excretion rate; The treatment time length; With particular compound combination use of being adopted or the medicine that uses simultaneously; And the known similar factor of medical field.For example, the way of this area is, the dosage of compound begins from being lower than for obtaining the level that required result of treatment requires, and increases dosage gradually, up to obtaining required effect.Generally speaking, formula I compound of the present invention is used for Mammals particularly people's dosage can be between 0.001～1000mg/kg body weight/day, for example between 0.01～100mg/kg body weight/day, for example between 0.01～10mg/kg body weight/day.
The pharmaceutical carrier that utilization those skilled in the art are familiar with can be prepared into the pharmaceutical composition of the The compounds of this invention that contains effective dosage.Therefore the present invention also provides the pharmaceutical composition that comprises with one or more nontoxic drug acceptable carriers The compounds of this invention formulated together.That said pharmaceutical composition can be mixed with especially specially is for oral administration with solid or liquid form, supply the parenteral injection or supply rectal administration.
Described pharmaceutical composition can be mixed with many formulations, is convenient to administration, for example, and oral prepns (like tablet, capsule, solution or suspension); Injectable preparation (like injectable solution or suspension, or injectable dried powder, before injection, adding injection water can use immediately).Carrier comprises in the described pharmaceutical composition: the tackiness agent that oral prepns uses (like starch, normally corn, wheat or rice starch, gelatin, methylcellulose gum, Xylo-Mucine and/or Vinylpyrrolidone polymer), and thinner is (like lactose, Vadex, sucrose, N.F,USP MANNITOL, sorbyl alcohol, Mierocrystalline cellulose; And/or glycerine), lubricant is (like silicon-dioxide, talcum, Triple Pressed Stearic Acid or its salt, normally Magnesium Stearate or calcium stearate; And/or polyoxyethylene glycol); And if desired, also contain disintegrating agent, like starch, agar, Lalgine or its salt; Sodiun alginate normally; And/or effervescent mixture, solubility promoter, stablizer, suspension agent, non-pigment, correctives etc., the sanitas that injectable preparation uses, solubilizing agent, stablizer etc.; The matrix that topical formulations is used, thinner, lubricant, sanitas etc.Pharmaceutical prepn can oral administration or parenteral mode (for example intravenously, subcutaneous, intraperitoneal or part) administration, if some drugs is unsettled under the stomach condition, can it be mixed with enteric coated tablets.
More particularly; But in pharmaceutical composition administered through oral of the present invention, rectum, parenteral, the pond, intravaginal, intraperitoneal, part (as through powder, ointment or drops), a mouthful cheek give the mankind and other Mammalss, perhaps give as oral spray or nasal mist.Term used herein " parenteral " refers to comprise intravenously, intramuscular, intraperitoneal, breastbone is interior, subcutaneous and the administering mode of intra-articular injection and transfusion.
The compsn that is suitable for the parenteral injection can comprise physiologically acceptable aseptic moisture or non-aqueous solution agent, dispersion agent, suspensoid or emulsion, and supplies to reconstitute the aseptic powder of sterile injectable solution agent or dispersion agent.Suitable moisture or nonaqueous carrier, thinner, solvent or vectorial instance comprise water, ethanol, polyvalent alcohol (Ucar 35, polyoxyethylene glycol, glycerine etc.), vegetables oil (like sweet oil), injectable organic ester such as OE and their suitable mixture.
These compsns also can contain auxiliary material, like sanitas, wetting agent, emulsifying agent and dispersion agent.Through various antibacterial agents and anti-mycotic agent, for example parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc. can guarantee to prevent action of microorganisms.Also expectation comprises isotonic agent, for example carbohydrate, sodium-chlor etc.Through using the material that can postpone absorption, for example aluminum monostearate and gelatin can reach the prolongation absorption of injectable drug form.
Remove the active ingredient beyond the region of objective existence in the suspensoid and also can contain suspension agent, for example ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, the mixture etc. of white lake, wilkinite, agar and tragacanth gum or these materials partially.
In some cases, be the effect of prolong drug, expect to slow down absorption subcutaneous or the intramuscularly medicine.This can realize through the crystal of use poorly water-soluble or the liquid suspension of amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be depending on crystallographic dimension and crystal formation.Perhaps, the delay of the medicament forms of parenteral admin absorb through with this medicine dissolution in or be suspended in the oily vehicle and realize.
The injectable depot formulations form can be through at biodegradable polymer such as polylactide-gather the microcapsule matrix that forms medicine in the NSC 403079 (polylactide-polyglycolide) to prepare.Can drug releasing rate be controlled according to the character of medicine with ratio with the concrete polymkeric substance that is adopted of polymkeric substance.The instance of other biological degradable polymer comprises poe class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations also can through pharmaceutical pack is embedded in can be compatible with bodily tissue liposome or micro emulsion in prepare.
Injectable formulation can be for example through filtering with bacterial filter or sterilizing through the disinfectant that mixes the aseptic solid composite form, and said solids compsn can face with before being dissolved or dispersed in sterilized water or other sterile injectable medium.
The compounds of this invention or its compsn can be with oral methods or parenteral administration modes.Oral administration can be tablet, capsule, seed dressing agent, and the enteron aisle external application preparation has injection and suppository etc.These preparations prepare according to method appreciated by those skilled in the art.In order to make tablet, capsule, the used auxiliary material of seed dressing agent is the auxiliary material of conventional usefulness; For example starch, gelatin, gum arabic; Silica, polyoxyethylene glycol, solvent that liquid dosage form is used such as water, ethanol, Ucar 35, vegetables oil (like Semen Maydis oil, peanut oil, olive wet goods).Contain and also have other auxiliary material in the preparation of The compounds of this invention, tensio-active agent for example, lubricant, disintegrating agent, sanitas, correctives and pigment etc.The dosage that in tablet, capsule, seed dressing agent, injection and suppository, contains formula I compound of the present invention is that the compound amount that exists in unit dosage form is calculated.The general content of formula I compound of the present invention is 0.01-5000mg in unit dosage form, and preferred unit dosage form contains 0.1-500mg, and preferred unit dosage form contains 1-300mg.Specifically, the present invention's solid dosage for oral administration that can provide comprises capsule, tablet, pill, powder and granule.In this type of solid dosage, active compound can be accepted vehicle or carrier such as Trisodium Citrate or Lin Suanergai and/or following material with at least a inert medicine and mix: a) weighting agent or extender such as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent such as CMC 99.5, alginates, gelatin, Vinylpyrrolidone polymer, sucrose and Sudan Gum-arabic; C) wetting Agent for Printing Inks such as glycerine; D) disintegrating agent such as agar, lime carbonate, yam or tapioca(flour), Lalgine, some silicate and yellow soda ash; E) solution retarding agent such as paraffin; F) absorb accelerator such as quaternary ammonium compound; G) wetting agent such as Tego Alkanol 16 and Zerol; H) sorbent material such as kaolin and wilkinite and i) lubricant such as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.Under the situation of capsule, tablet and pill, also can comprise buffer reagent in the said formulation.
The solids compsn of similar type uses vehicle for example lactose and high molecular weight polyethylene glycol etc., also can be used as the weighting material in soft capsule and the hard capsule.
The solid dosage of tablet, dragee (dragees), capsule, pill and granule can prepare with dressing and shell material such as enteric coating material and known other clothing materials of field of medicine preparations.These solid dosages can be chosen wantonly and contain opalizer, and its composition also can make it just or preferentially choose wantonly with the delayed mode release of active ingredients at certain position of enteron aisle.The instance of operable embedding composition comprises polymer substance and wax class.If be fit to, active compound also can be made into the micro-capsule form with one or more above-mentioned vehicle.
Liquid dosage form for oral administration comprises the acceptable emulsion of pharmacy, solution, suspensoid, syrup and elixir.Liquid dosage form also can contain this area inert diluent commonly used except that containing the active ingredient beyond the region of objective existence; For example water or other solvents; Solubilizing agent and emulsifying agent be ethanol, Virahol, ethyl-carbonate, ETHYLE ACETATE, benzylalcohol, peruscabin, Ucar 35,1,3 butylene glycol, N, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and til), glycerine, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), polyoxyethylene glycol and the fatty ester of sorbitan and their mixture for example.Oral compsns also can comprise auxiliary material except that comprising inert diluent, for example wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and flavouring agent.
The compsn of confession rectum or vagina administration is suppository preferably.Suppository can be through for example theobroma oil, polyoxyethylene glycol or suppository wax are mixed and prepared with The compounds of this invention and suitable non-irritating excipient or carrier; They at room temperature are solid; Therefore but next at body temperature is liquid, can in rectal cavity or vaginal canal, melt and discharges active compound.
Compound of the present invention and compsn thereof also consider to be used for topical.Supply the dosage form of topical administration The compounds of this invention to comprise powder, sprays, ointment and inhalation.Under aseptic condition with active compound and pharmaceutically acceptable carrier and any required sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, eye ointment, powder and solution also are considered within the scope of the present invention.
The compounds of this invention also can the liposome form administration.As well known in the art, liposome makes with phosphatide or other lipid materials usually.Liposome is formed by the single or multiple lift aquation liquid crystal that is scattered in the water-bearing media.Can accept on any nontoxic, physiology that can form liposome and metabolizable lipid all can use.The present composition of liposome form also can contain stablizer, sanitas, vehicle etc. except that containing The compounds of this invention.Preferred lipid is natural and synthetic phosphatide and phosphatidylcholine (Yelkin TTS), and their can use separately or together.The method that forms liposome is well known in the art.Referring to for example Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p.33.
The inventor is surprised to find, and the cyclisation berberinc derivate shown in the structural formula I has produced the obvious suppression effect to the propagation of HepG2 cell.Therefore, compound of the present invention can be used for treating and/or preventing Mammals (comprising the people) tumour or cancer property disease (for example liver cancer).
Description of drawings
Fig. 1 has described The compounds of this invention the drug-resistant tumor cell activity has been measured the result.
Fig. 2 has described the cell cycle analysis of The compounds of this invention and has measured the result.
Fig. 3 has described the inhibition determination of activity result of The compounds of this invention to topoisomerase I.
Embodiment
Further specify the present invention through concrete preparation embodiment and biological test example below, still, be to be understood that into, these embodiment and Test Example are only used for the usefulness of explanation more in detail particularly, are used for limiting in any form the present invention and should not be construed as.
The present invention carries out generality and/or concrete description to the material and the TP that are used in the test.Though for realizing that employed many materials of the object of the invention and working method are well known in the art, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if do not specify that material therefor of the present invention and working method are well known in the art.
Embodiment 1: compd A synthetic
To be dissolved with Peng Qinghuana (1.2g, 5% sodium hydroxide solution (10ml) 32mmol) dropwise be added to contain Berberine (7.4g, 20mmol) and salt of wormwood (8.3g; In methyl alcohol 60mmol) (250ml) solution system; Stirring at room 2 hours, suction filtration is collected the yellow-green colour solid of separating out, and filter cake is used zero(ppm) water (100ml) and 80% ethanol (100ml) washing successively; Obtain midbody dihydroberberine (4.2g, 62%).(4.0g 12mmol) is dissolved in the acetonitrile (160ml), adds the oxalic dialdehyde (2ml) of acetate (40ml) and 40% then, is heated to 85～95 ℃ and refluxes 5 hours with the midbody dihydroberberine; The flaggy monitoring reaction is complete, and reaction solution is concentrated, and obtains scarlet oily matter, adds 2% hydrochloric acid soln (200ml); Stirring at room 1 hour is filtered, filtrating stirring at room 5 days; Reaction solution is concentrated, use 95% ethyl alcohol recrystallization, products therefrom washs with ether; Get orange solids A (1.8g, 38%), fusing point: 185～187 ℃.
HRMS-ESI(M/Z)：360.1216【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.8Hz，2H)，4.12(s，3H)，4.16(s，3H)，5.24(t，J＝6.8Hz，2H)，6.39(s，2H)，7.59(s，1H)，8.21(d，J＝9.2Hz，1H)，8.31(d，J＝9.6Hz，1H)，8.85(d，J＝9.6Hz，1H)，8.89(d，J＝9.2Hz，1H)，10.14(s，1H).
Embodiment 2: compd A-30 synthetic
(3.6g 9.1mmol) places the 250ml round-bottomed flask, and maintenance vacuum tightness is 30～40mmHg with A; Be heated to 195～210 ℃ of reactions 30 minutes; The solid color is deepened gradually, all becomes scarlet at last, and (5ml: 95ml) acidifying obtains red product A-30 (3.2g to acidic alcohol; 92%) fusing point: 269～271 ℃.
HRMS-ESI(M/Z)：346.1069【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.56(t，J＝6.8Hz，2H)，4.03(s，3H)，5.10(t，J＝6.8Hz，2H)，6.36(s，2H)，7.52(s，1H)，8.02(d，J＝8.8Hz，1H)，8.10(d，J＝9.2Hz，1H)，8.26(d，J＝8.4Hz，1H)，8.75(d，J＝9.2Hz，1H)，9.96(s，1H).
Embodiment 3: compd A-31 synthetic
With A-30 (198mg 0.52mmol) is dissolved in DMF (10ml), add then porphyrize Pottasium Hydroxide (60mg, 1.04mmol) and monobromethane (2ml; 27mmol), be heated to 60 ℃ of reactions 12 hours, concentrating under reduced pressure removes and desolvates, and resistates is transferred PH to 3 with Hydrogen chloride; Suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column; Obtain red product A-31 (52mg, 22%), fusing point: 216～218 ℃.
HRMS-ESI(M/Z)：374.1397【M-Br】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ1.49(t，J＝7.2Hz，3H)，3.62(t，J＝6.8Hz，2H)，4.10(s，3H)，4.44(q，J＝7.2Hz，2H)，5.26(t，J＝6.8Hz，2H)，6.39(s，2H)，7.58(s，1H)，8.20(d，J＝9.2Hz，1H)，8.29(d，J＝9.2Hz，1H)，8.83(d，J＝9.2Hz，1H)，8.88(d，J＝9.2Hz，1H)，10.05(s，1H).
Embodiment 4: compd A-32 synthetic
With A-30 (198mg 0.52mmol) is dissolved in DMF (10ml), add then porphyrize Pottasium Hydroxide (60mg, 1.04mmol) with 1-butyl iodide (236 μ l; 2.08mmol), being heated to 60 ℃ of reactions 12 hours, concentrating under reduced pressure removes and desolvates, and resistates is transferred PH to 3 with Hydrogen chloride; Suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column; Obtain red product A-32 (75mg, 27%), fusing point: 202～204 ℃.
HRMS-ESI(M/Z)：402.1702【M-I】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ1.00(t，J＝7.2Hz，3H)，1.51-1.57(m，2H)，1.87-1.94(m，2H)，3.62(t，J＝6.8Hz，2H)，4.10(s，3H)，4.37(t，J＝6.8Hz，2H)，5.25(t，J＝6.8Hz，2H)，6.40(s，2H)，7.59(s，1H)，8.22(d，J＝9.2Hz，1H)，8.30(d，J＝9.2Hz，1H)，8.84(d，J＝9.2Hz，1H)，8.89(d，J＝9.2Hz，1H)，9.98(s，1H).
Embodiment 5: compd A-33 synthetic
With A-30 (99mg 0.26mmol) is dissolved in DMF (5ml), add then porphyrize Pottasium Hydroxide (30mg, 0.52mmol) and cylite (124 μ l; 1.04mmol), being heated to 60 ℃ of reactions 12 hours, concentrating under reduced pressure removes and desolvates, and resistates is transferred PH to 3 with Hydrogen chloride; Suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column; Obtain orange product A-33 (81mg, 60%), fusing point: 131～133 ℃.
HRMS-ESI(M/Z)：436.1562【M-Br】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.8Hz，2H)，4.14(s，3H)，5.22(t，J＝6.8Hz，2H)，5.43(s，2H)，6.39(s，2H)，7.35-7.43(m，3H)，7.59(s，1H)，7.62(d，J＝6.8Hz，2H)，8.21(d，J＝9.2Hz，1H)，8.32(d，J＝9.6Hz，1H)，8.86(t，J＝9.2Hz，2H)，9.98(s，1H).
Embodiment 6: compd A-43 synthetic
(99mg 0.26mmol) is dissolved in DMF (5ml), and (30mg is 0.52mmol) with 2 to add the Pottasium Hydroxide of porphyrize then with A-30; (134 μ l 1.04mmol), are heated to 60 ℃ of reactions 12 hours to 4-difluoro bromobenzyl, and concentrating under reduced pressure removes and desolvates; Resistates is transferred PH to 3 with Hydrogen chloride, and suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column; Obtain red product A-43 (79mg, 55%), fusing point: 138～140 ℃.
HRMS-ESI(M/Z)：472.1347【M-Br】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.8Hz，2H)，4.11(s，3H)，5.22(t，J＝6.8Hz，2H)，5.47(s，2H)，6.40(s，2H)，7.14-7.19(m，1H)，7.28-7.33(m，1H)，7.60(s，1H)，7.81(q，J＝8.4Hz，1H)，8.22(d，J＝9.2Hz，1H)，8.33(d，J＝9.6Hz，1H)，8.88(d，J＝4.4Hz，1H)，8.90(d，J＝4.0Hz，1H)，9.93(s，1H).
Embodiment 7: compd A-34 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l, 1.04mmol), (74 μ l 1.04mmol), continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add Acetyl Chloride 98Min. then to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-34 (70mg, 64%), fusing point: 183～185 ℃.
HRMS-ESI(M/Z)：388.1188【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ2.56(s，3H)，3.64(t，J＝6.8Hz，2H)，4.09(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.2Hz，1H)，8.40(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.09(d，J＝9.2Hz，1H)，10.15(s，1H).
Embodiment 8: compd A-35 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l, 1.04mmol), (120 μ l 1.04mmol), continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add Benzoyl chloride 99min. then to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains orange product A-35 (84mg, 67%), fusing point: 228～230 ℃.
HRMS-ESI(M/Z)：450.1336【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.8Hz，2H)，4.07(s，3H)，5.22(t，J＝6.8Hz，2H)，6.41(s，2H)，7.60(s，1H)，7.71(t，J＝7.6Hz，2H)，7.86(t，J＝7.6Hz，1H)，8.26-8.31(m，3H)，8.46(d，J＝9.6Hz，1H)，8.98(d，J＝9.6Hz，1H)，9.15(d，J＝9.2Hz，1H)，10.24(s，1H).
Embodiment 9: compd A-38 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes with A-30; (84 μ l 1.04mmol), add methyl benzoyl chloride (139 μ l then to add anhydrous pyridine; 1.04mmol), continuing to reflux 6 hours, the flaggy monitoring reaction is complete.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-38 (53mg, 41%), fusing point: 221～223 ℃.
HRMS-ESI(M/Z)：464.1489【M-Cl】
+
1H?NMR(CD
3OD，400MHz)：δ2.47(s，3H)，3.60(t，J＝6.8Hz，2H)，4.06(s，3H)，5.17(t，J＝6.8Hz，2H)，6.29(s，2H)，7.40(s，1H)，7.43(d，J＝8.0Hz，2H)，8.19(d，J＝8.0Hz，2H)，8.27(d，J＝9.6Hz，1H)，8.32(d，J＝9.6Hz，1H)，8.76(d，J＝9.2Hz，1H)，8.96(d，J＝9.2Hz，1H)，9.89(s，1H).
Embodiment 10: compd A-40 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes with A-30; (84 μ l 1.04mmol), add anisoyl chloride (141 μ l then to add anhydrous pyridine; 1.04mmol), continuing to reflux 6 hours, the flaggy monitoring reaction is complete.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains orange product A-40 (69mg, 51%), fusing point: 202～204 ℃.
HRMS-ESI(M/Z)：480.1442【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.8Hz，2H)，3.92(s，3H)，4.06(s，3H)，5.22(t，J＝6.8Hz，2H)，6.41(s，2H)，7.22(d，J＝8.8Hz，2H)，7.59(s，1H)，8.24(d，J＝8.8Hz，2H)，8.27(d，J＝9.6Hz，1H)，8.44(d，J＝9.2Hz，1H)，8.98(d，J＝9.6Hz，1H)，9.13(d，J＝9.6Hz，1H)，10.20(s，1H).
Embodiment 11: compd A-39 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), being warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add then that (123 μ l 1.04mmol), continue to reflux 6 hours, and the flaggy monitoring reaction is complete to fluorobenzoyl chloride to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains orange product A-39 (40mg, 31%), fusing point: 218～220 ℃.
HRMS-ESI(M/Z)：468.1256【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.08(s，3H)，5.21(t，J＝6.4Hz，2H)，6.41(s，2H)，7.56(t，J＝8.8Hz，2H)，7.60(s，1H)，8.28(d，J＝9.2Hz，1H)，8.35-8.39(m，2H)，8.46(d，J＝9.6Hz，1H)，8.99(d，J＝9.2Hz，1H)，9.16(d，J＝9.6Hz，1H)，10.24(s，1H).
Embodiment 12: compd A-44 synthetic
(193mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with 4-fluoro-3-nitrobenzoic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-44 (35mg, 25%), fusing point: 187～189 ℃.
HRMS-ESI(M/Z)：513.1083【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.09(s，3H)，5.20(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，7.93-7.98(m，1H)，8.29(d，J＝9.2Hz，1H)，8.48(d，J＝9.2Hz，1H)，8.67-8.68(m，1H)，8.94(dd，J＝2.0，7.2Hz，1H)，8.99(d，J＝9.2Hz，1H)，9.18(d，J＝9.6Hz，1H)，10.29(s，1H).
Embodiment 13: compd A-45 synthetic
(188mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with 4-methyl-3-nitro phenylformic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains scarlet product A-45 (36mg, 25%), fusing point: 165～167 ℃.
HRMS-ESI(M/Z)：509.1343【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ2.70(s，3H)，3.62(t，J＝6.8Hz，2H)，4.08(s，3H)，5.20(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，7.87(d，J＝8.0Hz，1H)，8.28(d，J＝9.2Hz，1H)，8.47(d，J＝9.2Hz，2H)，8.79(d，J＝1.2Hz，1H)，8.99(d，J＝9.6Hz，1H)，9.17(d，J＝9.2Hz，1H)，10.27(s，1H).
Embodiment 14: compd A-46 synthetic
(205mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with 4-methoxyl group-3-nitrobenzoic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains scarlet product A-46 (22mg, 15%), fusing point: 158～160 ℃.
HRMS-ESI(M/Z)：525.1295【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.08(s，3H)，4.11(s，3H)，5.20(t，J＝6.4Hz，2H)，6.41(s，2H)，7.60(s，1H)，7.68(d，J＝8.8Hz，1H)，8.28(d，J＝9.2Hz，1H)，8.46(d，J＝9.6Hz，1H)，8.51(dd，J＝2.4，8.8Hz，1H)，8.74(d，J＝2.4Hz，1H)，8.98(d，J＝9.6Hz，1H)，9.16(d，J＝9.2Hz，1H)，10.25(s，1H).
Embodiment 15: compd A-56 synthetic
(173mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with piperinic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains orange product A-56 (29mg, 21%), fusing point: 192～194 ℃.
HRMS-ESI(M/Z)：494.1239【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.07(s，3H)，5.23(t，J＝6.4Hz，2H)，6.25(s，2H)，6.41(s，2H)，7.22(d，J＝8.0Hz，1H)，7.60(s，1H)，7.73(d，J＝1.6Hz，1H)，7.91(dd，J＝1.6，8.4Hz，1H)，8.27(d，J＝9.2Hz，1H)，8.44(d，J＝9.6Hz，1H)，8.97(d，J＝9.6Hz，1H)，9.13(d，J＝9.6Hz，1H)，10.19(s，1H).
Embodiment 16: compd A-49 synthetic
With 3,4, (221mg 1.04mmol) is added in the thionyl chloride (5ml) the 5-trimethoxybenzoic acid, refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains orange product A-49 (31mg, 21%), fusing point: 210～212 ℃.
HRMS-ESI(M/Z)：540.1685【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，3.83(s，3H)，3.92(s，6H)，4.08(s，3H)，5.24(t，J＝6.4Hz，2H)，6.41(s，2H)，7.56(s，2H)，7.60(s，1H)，8.28(d，J＝9.2Hz，1H)，8.46(d，J＝9.6Hz，1H)，8.99(d，J＝9.2Hz，1H)，9.16(d，J＝9.6Hz，1H)，10.20(s，1H).
Embodiment 17: compd A-55 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l, 1.04mmol), (124 μ l 1.04mmol), continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add o-fluoro-benzoyl chloride then to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-55 (35mg, 27%), fusing point: 181～183 ℃.
HRMS-ESI(M/Z)：468.1247【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.8Hz，2H)，4.10(s，3H)，5.22(t，J＝6.8Hz，2H)，6.41(s，2H)，7.51-7.57(m，2H)，7.60(s，1H)，7.88-7.92(m，1H)，8.28(d，J＝9.2Hz，1H)，8.30-8.32(m，1H)，8.46(d，J＝9.2Hz，1H)，8.98(d，J＝9.2Hz，1H)，9.16(d，J＝9.2Hz，1H)，10.25(s，1H).
Embodiment 18: compd A-37 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l, 1.04mmol), (132 μ l 1.04mmol), continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add NSC 93897 then to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-37 (31mg, 23%), fusing point: 164～166 ℃.
HRMS-ESI(M/Z)：484.0952【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.63(t，J＝6.8Hz，2H)，4.11(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，7.66-7.69(m，1H)，7.79-7.81(m，2H)，8.28(d，J＝9.2Hz，1H)，8.45-8.48(m，2H)，8.99(d，J＝9.6Hz，1H)，9.16(d，J＝9.2Hz，1H)，10.24(s，1H).
Embodiment 19: compd A-58 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and adds anhydrous pyridine (84 μ l with A-30; 1.04mmol), add 2,4 difluorobenzene formyl chloride (128 μ l then; 1.04mmol), continuing to reflux 6 hours, the flaggy monitoring reaction is complete.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-58 (23mg, 17%), fusing point: 191～193 ℃.
HRMS-ESI(M/Z)：486.1151【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.10(s，3H)，5.21(t，J＝6.4Hz，2H)，6.41(s，2H)，7.41-7.46(m，1H)，7.61(s，1H)，7.62-7.68(m，1H)，8.28(d，J＝9.2Hz，1H)，8.39(q，J＝8.4Hz，1H)，8.46(d，J＝9.6Hz，1H)，8.98(d，J＝9.6Hz，1H)，9.16(d，J＝9.6Hz，1H)，10.24(s，1H).
Embodiment 20: compd A-41 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes with A-30; (84 μ l 1.04mmol), add 4-acetamido benzene sulfonyl chloride (243mg then to add anhydrous pyridine; 1.04mmol), continuing to reflux 6 hours, the flaggy monitoring reaction is complete.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-41 (23mg, 15%), fusing point: 205～207 ℃.
HRMS-ESI(M/Z)：543.1203【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ2.12(s，3H)，3.60(t，J＝6.4Hz，2H)，3.81(s，3H)，5.18(t，J＝6.4Hz，2H)，6.42(s，2H)，7.63(s，1H)，7.86(s，4H)，8.28(d，J＝9.2Hz，1H)，8.34(d，J＝9.6Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.15(d，J＝9.6Hz，1H)，9.74(s，1H)，10.61(s，1H).
Embodiment 21: compd A-42 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l, 1.04mmol), (133 μ l 1.04mmol), continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add benzene sulfonyl chloride then to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-42 (38mg, 28%), fusing point: 223～225 ℃.
HRMS-ESI(M/Z)：486.1001【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.8Hz，2H)，3.76(s，3H)，5.20(t，J＝6.8Hz，2H)，6.42(s，2H)，7.63(s，1H)，7.73(t，J＝8.0Hz，2H)，7.91(t，J＝7.6Hz，1H)，7.97(d，J＝7.2Hz，2H)，8.28(d，J＝9.6Hz，1H)，8.33(d，J＝9.6Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.16(d，J＝9.6Hz，1H)，9.79(s，1H).
Embodiment 22: compd A-50 synthetic
(179mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with n-capric acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-50 (25mg, 18%), fusing point: 180～182 ℃.
HRMS-ESI(M/Z)：500.2444【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ0.85-0.88(m，3H)，1.23-1.49(m，12H)，1.73-1.80(m，2H)，2.89(t，J＝7.2Hz，2H)，3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.2Hz，1H)，8.40(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.08(d，J＝9.6Hz，1H)，10.11(s，1H).
Embodiment 23: compd A-53 synthetic
(208mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with LAURIC ACID 99 MIN.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-53 (21mg, 14%), fusing point: 184～186 ℃.
HRMS-ESI(M/Z)：528.2718【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ0.85(t，J＝6.8Hz，3H)，1.25-1.47(m，16H)，1.74-1.78(m，2H)，2.89(t，J＝7.2Hz，2H)，3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.23(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.6Hz，1H)，8.40(d，J＝9.6Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.09(d，J＝9.6Hz，1H)，10.09(s，1H).
Embodiment 24: compd A-54 synthetic
(267mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with palmitinic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-54 (52mg, 32%), fusing point: 184～186 ℃.
HRMS-ESI(M/Z)：584.3337【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ0.84(t，J＝6.8Hz，3H)，1.23-1.47(m，24H)，1.74-1.78(m，2H)，2.89(t，J＝7.2Hz，2H)，3.64(t，J＝6.4Hz，2H)，4.07(s，3H)，5.23(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.2Hz，1H)，8.40(d，J＝9.6Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.09(d，J＝9.6Hz，1H)，10.09(s，1H).
Embodiment 25: compd A-61 synthetic
(99mg 0.26mmol) is dissolved in DMF (5ml), and (30mg is 0.52mmol) with 1 to add the Pottasium Hydroxide of porphyrize then with A-30; (90 μ l 1.04mmol), are heated to 60 ℃ of reactions 12 hours to the 2-ethylene dibromide, and concentrating under reduced pressure removes and desolvates; Resistates is transferred PH to 3 with Hydrogen chloride, and suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column; Obtain red product A-61 (40mg, 29%), fusing point: 142～144 ℃.
HRMS-ESI(M/Z)：452.0476【M-Br】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.65(t，J＝6.4Hz，2H)，4.02(t，J＝6.0Hz，2H)，4.13(s，3H)，4.70(t，J＝6.0Hz，2H)，5.25(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.24(d，J＝9.2Hz，1H)，8.34(d，J＝9.2Hz，1H)，8.90(d，J＝8.8Hz，1H)，8.92(d，J＝8.8Hz，1H)，10.11(s，1H).
Embodiment 26: compd A-64 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l, 1.04mmol), (91 μ l 1.04mmol), continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add bromoacetyl bromide then to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-64 (42mg, 30%), fusing point: 154～156 ℃.
HRMS-ESI(M/Z)：466.0293【M-Br】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.65(t，J＝6.8Hz，2H)，4.10(s，3H)，4.78(s，2H)，5.20(t，J＝6.8Hz，2H)，6.41(s，2H)，7.62(s，1H)，8.27(d，J＝9.2Hz，1H)，8.42(d，J＝9.2Hz，1H)，8.96(d，J＝9.2Hz，1H)，9.13(d，J＝9.6Hz，1H)，10.17(s，1H).
Embodiment 27: compd A-67 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l, 1.04mmol), (144 μ l 1.04mmol), continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add caproyl chloride then to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-67 (54mg, 43%), fusing point: 125～127 ℃.
HRMS-ESI(M/Z)：444.1824【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ0.94(t，J＝7.2Hz，3H)，1.38-1.46(m，4H)，1.76-1.79(m，2H)，2.89(t，J＝7.2Hz，2H)，3.64(t，J＝6.4Hz，2H)，4.08(s，3H)，5.23(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.2Hz，1H)，8.40(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.09(d，J＝9.2Hz，1H)，10.10(s，1H).
Embodiment 28: compd A-68 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l, 1.04mmol), (161 μ l 1.04mmol), continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add oenanthyl chloro then to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains orange product A-68 (46mg, 36%), fusing point: 117～119 ℃.
HRMS-ESI(M/Z)：458.1953【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ0.91(t，J＝7.2Hz，3H)，1.34-1.38(m，4H)，1.46-1.50(m，2H)，1.75-1.78(m，2H)，2.90(t，J＝7.2Hz，2H)，3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.25(d，J＝9.2Hz，1H)，8.39(d，J＝9.2Hz，1H)，8.94(d，J＝9.6Hz，1H)，9.08(d，J＝9.2Hz，1H)，10.13(s，1H).
Embodiment 29: compd A-69 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l, 1.04mmol), (178 μ l 1.04mmol), continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add capryl(yl)chloride then to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains orange product A-69 (69mg, 52%), fusing point: 118～120 ℃.
HRMS-ESI(M/Z)：472.2121【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ0.89(t，J＝6.8Hz，3H)，1.31-1.39(m，6H)，1.45-1.49(m，2H)，1.75-1.79(m，2H)，2.90(t，J＝7.2Hz，2H)，3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.24(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.26(d，J＝9.6Hz，1H)，8.40(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.08(d，J＝9.2Hz，1H)，10.11(s，1H).
Embodiment 30: compd A-70 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l, 1.04mmol), (195 μ l 1.04mmol), continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add pelargonyl chloride then to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-70 (39mg, 29%), fusing point: 126～128 ℃.
HRMS-ESI(M/Z)：486.2262【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ0.88(t，J＝6.8Hz，3H)，1.23-1.47(m，10H)，1.75-1.78(m，2H)，2.90(t，J＝7.2Hz，2H)，3.64(t，J＝6.4Hz，2H)，4.07(s，3H)，5.25(t，J＝6.4Hz，2H)，6.40(s，2H)，7.60(s，1H)，8.23(d，J＝9.2Hz，1H)，8.38(d，J＝9.6Hz，1H)，8.92(d，J＝9.6Hz，1H)，9.06(d，J＝9.6Hz，1H)，10.14(s，1H).
Embodiment 31: compd A-71 synthetic
(209mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with 3-nitro-4-chloro-benzoic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-71 (63mg, 46%), fusing point: 211～213 ℃.
HRMS-ESI(M/Z)：529.07968【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.08(s，3H)，5.19(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.15(d，J＝8.4Hz，1H)，8.28(d，J＝9.6Hz，1H)，8.48(d，J＝9.6Hz，1H)，8.53(dd，J＝2.0，8.4Hz，1H)，8.91(d，J＝1.6Hz，1H)，8.99(d，J＝9.6Hz，1H)，9.18(d，J＝9.6Hz，1H)，10.28(s，1H).
Embodiment 32: compd A-72 synthetic
(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes with A-30; (84 μ l 1.04mmol), add 4-cyanic acid benzene sulfonyl chloride (210mg then to add anhydrous pyridine; 1.04mmol), continuing to reflux 6 hours, the flaggy monitoring reaction is complete.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-72 (74mg, 56%), fusing point: 216～219 ℃.
HRMS-ESI(M/Z)：511.09638【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.64(t，J＝6.4Hz，2H)，3.75(s，3H)，5.25(t，J＝6.4Hz，2H)，6.42(s，2H)，7.64(s，1H)，8.16-8.24(m，4H)，8.28(d，J＝9.2Hz，1H)，8.33(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.18(d，J＝9.6Hz，1H)，9.88(s，1H).
Embodiment 33: compd A-73 synthetic
(254mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with 2-bromo-5-nitrobenzoic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes with A-30; (84 μ l 1.04mmol), divide cooling to add anhydrous pyridine; Suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column; Obtain red product A-73 (62mg, 46%), fusing point: 180～183 ℃.
HRMS-ESI(M/Z)：573.02972【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.64(t，J＝6.8Hz，2H)，4.07(s，3H)，5.23(t，J＝6.8Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.23(d，J＝7.8Hz，1H)，8.28(d，J＝9.6Hz，1H)，8.48(d，J＝9.6Hz，1H)，8.51(dd，J＝1.6，7.8Hz，1H)，8.93(d，J＝1.6Hz，1H)，8.96(d，J＝9.6Hz，1H)，9.18(d，J＝9.6Hz，1H)，10.36(s，1H).
Embodiment 34: compd A-74 synthetic
(192mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with 2-fluoro-5-nitrobenzoic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-74 (40mg, 30%), fusing point: 209～211 ℃.
HRMS-ESI(M/Z)：513.11096【M-Cl】
+
1H?NMR(CD3SOCD
3，400MHz)：δ3.63(t，J＝6.4Hz，2H)，4.11(s，3H)，5.20(t，J＝6.4Hz，2H)，6.42(s，2H)，7.61(s，1H)，7.89(t，J＝10.0Hz，1H)，8.28(d，J＝9.2Hz，1H)，8.48(d，J＝9.2Hz，1H)，8.74-8.76(mm，1H)，8.99(d，J＝9.2Hz，1H)，9.02(d，J＝3.2Hz，1H)，9.19(d，J＝9.6Hz，1H)，10.30(s，1H).
Embodiment 35: compd A-75 synthetic
(117mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with the 2-furancarboxylic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-75 (29mg, 26%), fusing point: 186～188 ℃.
HRMS-ESI(M/Z)：529.07968【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.08(s，3H)，5.23(t，J＝6.4Hz，2H)，6.40(s，2H)，6.93(q，J＝1.6Hz，1H)，7.59(s，1H)，7.77(d，J＝3.6Hz?1H)，8.21-8.25(m，2H)，8.42(d，J＝9.6Hz，1H)，8.92(d，J＝9.6Hz，1H)，9.11(d，J＝9.2Hz，1H)，10.22(s，1H).
Embodiment 36: compd A-76 synthetic
(174mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with the 3-nitrobenzoic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-76 (52mg, 41%), fusing point: 221～223 ℃.
HRMS-ESI(M/Z)：495.12041【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.09(s，3H)，5.20(t，J＝6.4Hz，2H)，6.41(s，2H)，7.60(s，1H)，8.01-8.05(m，1H)，8.28(d，J＝9.2Hz，1H)，8.48(d，J＝9.2Hz，1H)，8.69-8.71(m，2H)，8.97-9.0(m，2H)9.18(d，J＝9.2Hz，1H)，10.32(s，1H).
Embodiment 37: compd A-77 synthetic
(163mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with the 4-chloro-benzoic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-77 (48mg, 38%), fusing point: 198～201 ℃.
HRMS-ESI(M/Z)：484.09596【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.07(s，3H)，5.21(t，J＝6.4Hz，2H)，6.30(s，2H)，7.60(s，1H)，7.80(d，J＝8.4Hz，2H)，8.24(d，J＝9.2Hz，1H)，8.30(d，J＝8.4Hz，2H)，8.44(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.13(d，J＝9.6Hz，1H)，10.25(s，1H).
Embodiment 38: compd A-78 synthetic
(141mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with the 3-tolyl acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-78 (57mg, 48%), fusing point: 205～208 ℃.
HRMS-ESI(M/Z)：464.15097【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ2.49(s，3H)，3.62(t，J＝6.8Hz，2H)，4.07(s，3H)，5.23(t，J＝6.4Hz，2H)，6.41(s，2H)，7.60(s，1H)，7.62-769.(m，2H)，8.09-8.13(m，2H)，8.23(d?J＝8.4Hz，1H)，8.43(d，J＝8.4Hz，1H)，8.94(d，J＝8.4Hz，1H)，9.11(d，J＝8.4Hz，1H)，10.24(s，1H).
Embodiment 39: compd A-79 synthetic
(141mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with the 2-tolyl acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-79 (50mg, 42%), fusing point: 200～202 ℃.
HRMS-ESI(M/Z)：464.15110【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ2.66(s，3H)，3.62(t，J＝6.0Hz，2H)，4.09(s，3H)，5.24(t，J＝6.0Hz，2H)，6.40(s，2H)，7.51-7.54(m，2H)，7.59(s，1H)，7.69(t，J＝7.6Hz，1H)，8.24(d?J＝9.2Hz，1H)，8.37(d?J＝7.6Hz，1H)，8.44(d，J＝9.2Hz，1H)，8.95(d，J＝9.6Hz，1H)，9.11(d，J＝9.6Hz，1H)，10.24(s，1H).
Embodiment 40: compd A-80 synthetic
(163mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with 5-nitro-2-furancarboxylic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-80 (29mg, 27%), fusing point: 190～192 ℃.
HRMS-ESI(M/Z)：485.09969【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.63(t，J＝6.4Hz，2H)，4.11(s，3H)，5.20(t，J＝6.4Hz，2H)，6.41(s，2H)，7.61(s，1H)，8.02-8.06(m，2H)，8.25(d，J＝8.4Hz，1H)，8.46(d，J＝8.4Hz，1H)，8.96(d，J＝8.4Hz，1H)，9.17(d，J＝8.4Hz，1H)，10.30(s，1H).
Embodiment 41: compd A-81 synthetic
(222mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with the 4-phenoxy benzoic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-81 (59mg, 42%), fusing point: 199～202 ℃.
HRMS-ESI(M/Z)：529.07968【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.06(s，3H)，5.23(t，J＝6.4Hz，2H)，6.40(s，2H)，7.20-7.23(m，4H)，7.30(t，J＝7.6Hz，1H)，7.52(t，J＝8Hz，2H)，7.59(s，1H)，8.22(d，J＝8.8Hz，1H)，8.30(d，J＝8.4Hz，2H)，8.42(d，J＝9.2Hz，1H)，8.92(d，J＝8.8Hz，1H)，9.09(d，J＝9.2Hz，1H)，10.22(s，1H).
Embodiment 42: compd A-82 synthetic
(160mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with the 4-fluorophenylacetic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-82 (43mg, 34%), fusing point: 195～198 ℃.
HRMS-ESI(M/Z)：482.14194【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.66(t，J＝6.8Hz，2H)，4.08(s，3H)，4.31(s，2H)，5.26(t，J＝6.8Hz，2H)，6.41(s，2H)，7.23-7.30(m，2H)，7.51-7.55(m，2H)，7.62(s，1H)，8.26(d，J＝9.6Hz，1H)，8.38(d，J＝9.6Hz，1H)，8.94(d，J＝9.2Hz，1H)，9.09(d，J＝9.6Hz，1H)，10.20(s，1H).
Embodiment 43: compd A-83 synthetic
(162mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with the 3-chloro-benzoic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-83 (63mg, 50%), fusing point: 183～185 ℃.
HRMS-ESI(M/Z)：484.09598【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.08(s，3H)，5.22(t，J＝6.4Hz，2H)，6.40(s，2H)，7.60(s，1H)，7.74-7.79(m，1H)，7.94-7.97(m，1H)，8.22-8.26(m，2H)，8.30(s，1H)，8.43(d，J＝9.2Hz，1H)，8.93(d，J＝9.2Hz，1H)，9.12(d，J＝9.2Hz，1H)，10.28(s，1H).
Embodiment 44: compd A-84 synthetic
(162mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with the 3-methoxybenzoic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-84 (40mg, 32%), fusing point: 205～208 ℃.
HRMS-ESI(M/Z)：484.14417【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，3.90(s，3H)，4.07(s，3H)，5.23(t，J＝6.4Hz，2H)，6.41(s，2H)，7.74-7.79(m，1H)，7.60-7.65(m，2H)，7.76(s，1H)，7.89(d，J＝7.6Hz，1H)8.26(d，J＝9.2Hz，1H)，8.44(d，J＝9.6Hz，1H)，8.96(d，J＝9.2Hz，1H)，9.14(d，J＝9.2Hz，1H)，10.23(s，1H).
Embodiment 45: compd A-85 synthetic
(146mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with the 3-fluorobenzoic acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-85 (46mg, 38%), fusing point: 198～201 ℃.
HRMS-ESI(M/Z)：468.12509【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，4.06(s，3H)，5.23(t，J＝6.4Hz，2H)，6.39(s，2H)，7.59(s，1H)，7.75-7.79(m，2H)，8.09(d，J＝9.2Hz，1H)，8.14-8.19(m，2H)，8.40(d，J＝9.2Hz，1H)，8.87(d，J＝9.2Hz，1H)，9.07(d，J＝9.6Hz，1H)，10.27(s，1H).
Embodiment 46: compd A-86 synthetic
(162mg 1.04mmol) is added in the thionyl chloride (5ml), refluxes 2 hours, and unnecessary solvent thionyl chloride is removed in underpressure distillation with O-Anisic Acid.(99mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes, and (84 μ l 1.04mmol), add above-mentioned acyl chlorides then, continue to reflux 6 hours, and the flaggy monitoring reaction is complete to add anhydrous pyridine with A-30.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains red product A-86 (30mg, 24%), fusing point: 183～185 ℃.
HRMS-ESI(M/Z)：484.14358【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.61(t，J＝6.4Hz，2H)，3.93(s，3H)，4.08(s，3H)，5.24(t，J＝6.4Hz，2H)，6.40(s，2H)，7.18-7.22(m，1H)，7.33-7.35(m，1H)，7.59(s，1H)，7.75-7.79(m，1H)，8.21-8.26(m，2H)，8.43(d，J＝9.2Hz，1H)，8.95(d，J＝9.2Hz，1H)，9.10(d，J＝9.2Hz，1H)，10.12(s，1H).
Embodiment 47: compd A-87 synthetic
With A-30 (99mg 0.26mmol) is dissolved in DMF (5ml), add then porphyrize Pottasium Hydroxide (30mg, 0.52mmol) with 4-nitrobenzyl chlorine (134 μ l; 1.04mmol), being heated to 60 ℃ of reactions 12 hours, concentrating under reduced pressure removes and desolvates, and resistates is transferred PH to 3 with Hydrogen chloride; Suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column; Obtain orange product A-87 (72mg, 57%), fusing point: 208～210 ℃.
HRMS-ESI(M/Z)：481.13863【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.62(t，J＝6.4Hz，2H)，4.11(s，3H)，5.24(t，J＝6.4Hz，2H)，5.57(s，2H)，6.40(s，2H)，7.60(s，1H)，7.92(d，J＝8.4Hz，2H)，8.22(d，J＝9.2Hz，1H)，8.30(d，J＝8.8Hz，2H)，8.34(d，J＝9.2Hz，1H)，8.88-8.91(m，2H)，10.10(s，1H).
Embodiment 48: compd A-36 synthetic
Under 90 ℃ with Phloroglucinol (3.0g, 18.5mmol) repeatedly be added in batches 60% sulfuric acid (60ml, v/v) in until forming colorless cleared solution; Add A (3.0g then in batches; 7.6mmol) form the scarlet suspension, add the insulation of material back and continue reaction 10 hours, the flaggy monitoring reaction is complete.Under the vigorous stirring, reacting liquor while hot is inclined to saturated aqueous common salt (50ml), stirring at room 2 hours is put into negative 20 ℃ of refrigerators then and is fully cooled off.Suction filtration, solid is used distilled water wash, and it is dissolved in 1NNaOH (100ml); Use 2N HCl (100ml) that the system furnishing is acid subsequently, fully stir, suction filtration is collected the solid of separating out; With the methylene chloride is moving phase, and with the separation and purification of decompression silicagel column, the gained solid is used ethanol again: concentrated hydrochloric acid (V: V=95: 5) system recrystallization; Obtain red product A-36 (1.8g, 62%), fusing point: 225～227 ℃.
HRMS-ESI(M/Z)：348.1240【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.54(t，J＝6.4Hz，2H)，4.11(s，3H)，4.15(s，3H)，5.21(t，J＝6.4Hz，2H)，7.34(s，1H)，8.28(d，J＝9.2Hz，1H)，8.48(d，J＝9.2Hz，1H)，8.77(d，J＝9.6Hz，1H)，8.82(d，J＝9.2Hz，1H)，9.61(s，1H)，10.07(s，1H)，10.36(s，1H).
Embodiment 49: compd A-60 synthetic
(100mg 0.26mmol) is suspended in the dry acetonitrile (5ml), is warming up to the basic dissolving that refluxes with A-36; (84 μ l 1.04mmol), add fluorobenzoyl chloride (185 μ l then to add anhydrous pyridine; 1.56mmol), continuing to reflux 6 hours, the flaggy monitoring reaction is complete.Fully cooling, suction filtration is collected the solid of separating out, and is moving phase with the methylene chloride, with the separation and purification of decompression silicagel column, obtains yellow product A-60 (18mg, 11%), fusing point: 169～171 ℃.
HRMS-ESI(M/Z)：592.1569【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.80(t，J＝6.4Hz，2H)，4.14(s，3H)，4.20(s，3H)，5.38(t，J＝6.4Hz，2H)，7.34-7.44(m，4H)，8.03(s，1H)，8.07(dd，J＝5.6，8.8Hz，2H)，8.23(dd，J＝5.2，8.8Hz，2H)，8.37(d，J＝9.2Hz，1H)，8.48(d，J＝9.6Hz，1H)，8.96(d，J＝9.6Hz，1H)，9.08(d，J＝9.6Hz，1H)，10.31(s，1H).
Embodiment 50: compd A-65 synthetic
To be dissolved with Peng Qinghuana (1.2g, 5% sodium hydroxide solution (10ml) 32mmol) dropwise be added to contain Fibrauretin (7.8g, 20mmol) and salt of wormwood (8.3g; In methyl alcohol 60mmol) (250ml) solution system; Stirring at room 2 hours, suction filtration is collected the yellow-green colour solid of separating out, and filter cake is used zero(ppm) water (100ml) and 80% ethanol (100ml) washing successively; Obtain midbody dihydro Fibrauretin (4.4g, 62%).(4.2g 12mmol) is dissolved in the acetonitrile (160ml), adds the oxalic dialdehyde (2ml) of acetate (40ml) and 40% then, is heated to 85～95 ℃ and refluxes 5 hours with midbody dihydro Fibrauretin; The flaggy monitoring reaction is complete, and reaction solution is concentrated, and obtains scarlet oily matter, adds 2% hydrochloric acid soln (200ml); Stirring at room 1 hour is filtered, filtrating stirring at room 5 days; Reaction solution is concentrated, use 95% ethyl alcohol recrystallization, products therefrom washs with ether; Get yellow product A-65 (2.9g, 59%), fusing point: 105～107 ℃.
HRMS-ESI(M/Z)：376.1564【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.67(t，J＝6.8Hz，2H)，3.97(s，3H)，4.06(s，3H)，4.12(s，3H)，4.17(s，3H)，5.27(t，J＝6.8Hz，2H)，7.72(s，1H)，8.32(d，J＝9.2Hz，1H)，8.45(d，J＝9.2Hz，1H)，8.88(d，J＝9.2Hz，1H)，8.92(d，J＝9.6Hz，1H)，10.15(s，1H).
Embodiment 51: compd A-66 synthetic
(2.0g 4.9mmol) places the 250ml round-bottomed flask, and maintenance vacuum tightness is 30～40mmHg, is heated to 195～210 ℃ of reactions 30 minutes, and the solid color is deepened gradually, all becomes scarlet at last with A-65.With the methylene chloride is moving phase, and with the separation and purification of decompression silicagel column, ethanol: (V: V=95: 5) the system acidifying obtains red product A-66 (1.5g, 77%), fusing point: 110～112 ℃ to concentrated hydrochloric acid.
HRMS-ESI(M/Z)：362.1395【M-Cl】
+
1H?NMR(CD
3SOCD
3，400MHz)：δ3.56(t，J＝6.4Hz，2H)，3.94(s，3H)，3.95(s，3H)，4.02(s，3H)，5.02(t，J＝6.4Hz，2H)，7.61(s，1H)，7.79(d，J＝8.0Hz，1H)，7.92(s，1H)，8.27(d，J＝9.2Hz，1H)，8.66(d，J＝9.2Hz，1H)，9.74(s，1H).
Test Example 1: the The compounds of this invention antiproliferative activity is measured
Material and method
1, receive the reagent thing: the compound of certain exemplary of the present invention, contrast medicine be NSC 107124 (10-hydroxycamptothecin, HCPT).
2, cell strain: HepG2 cell.
3, liquor strength is 0.6 μ g/mL.
4, method: be inoculated in 96 well culture plates behind the HepG2 cell dissociation counting with logarithmic phase, 5000/hole/200 μ L, dosing behind the 24h, every group of medicine established 5 multiple holes, and establishes DMSO solvent control wells and acellular zeroing hole.In 37 ℃, 5%CO
2Cultivate 48h under the condition, every hole, PBS washing back adds 200 μ L PBS again, and trichoroacetic acid(TCA) (TCA) fixed cell of Dropwise 50 μ L 50% (m/v), TCA final concentration are 10%, 4 ℃ and placed 1 hour.Abandon stationary liquid, with distilled water wash 5 times, seasoning in the air.Every hole adds the sulphonyl rhodamine solution of 50 μ L, room temperature held 10-30min.Remove supernatant, the acetic acid washing with 1% 5 times, dry air.Add Tris solution (pH=10.5) the 150 μ L of 10mmol/l at last, 5min vibrates on oscillator plate.(Model3550 Bio-Rad) measures the OD value, and with the blank zeroing, used wavelength is 570nm at enzyme-linked immunosorbent assay instrument.Calculate the inhibiting rate of growth of tumour cell by following formula:
Inhibiting rate=[(OD
570 control wells-OD
570 dosing holes)/OD
570 control wells] * 100%.
More than test triplicate, obtain average inhibiting rate.
Under the same measured condition, the inhibiting rate of contrast medicine HCPT is 85.4%.The result shows that The compounds of this invention has positive effect aspect antiproliferative.
Test Example 2: with MCF-7, Hela, HT1080 and four kinds of tumour cell SCREENED COMPOUND of HCT116
Material and method
1, receive the reagent thing: the compound of certain exemplary of the present invention, contrast medicine be NSC 107124 (10-hydroxycamptothecin, HCPT).
2, cell strain: MCF-7, Hela, HT1080 and HCT116.
3, liquor strength is 0.6 μ g/mL.
4, method: be inoculated in 96 well culture plates behind the cell dissociation counting with logarithmic phase, 5000/hole/200 μ L, dosing behind the 24h, every group of medicine established 5 multiple holes, and establishes DMSO solvent control wells and acellular zeroing hole.Under 37 ℃, 5%CO2 condition, cultivate 48h, every hole, PBS washing back adds 200 μ L PBS again, and trichoroacetic acid(TCA) (TCA) fixed cell of Dropwise 50 μ L 50% (m/v), TCA final concentration are 10%, 4 ℃ and placed 1 hour.Abandon stationary liquid, with distilled water wash 5 times, seasoning in the air.Every hole adds the sulphonyl rhodamine solution of 50 μ L, room temperature held 10-30min.Remove supernatant, the acetic acid washing with 1% 5 times, dry air.Add Tris solution (pH=10.5) the 150 μ L of 10mmol/l at last, 5min vibrates on oscillator plate.(Model3550 Bio-Rad) measures the OD value, and with the blank zeroing, used wavelength is 570nm at enzyme-linked immunosorbent assay instrument.Calculate the inhibiting rate of growth of tumour cell by following formula:
Inhibiting rate=[(OD570 control wells-OD570 dosing holes)/OD570 control wells] * 100%.
More than test triplicate, obtain average inhibiting rate.Part of compounds of the present invention sees the following form to the activity of tumor cell proliferation:
The result shows that under the same measured condition, The compounds of this invention has positive effect aspect antiproliferative.
Test Example 3: the IC of compd A-35, A-55, A-40 and A-56 pair cell HepG2 and HCT116
50Measure
Material and method
1, receives the reagent thing: the compound of certain exemplary of the present invention.
2, cell strain: HepG2 and HCT116.
3, liquor strength is 2 μ g/mL, 1 μ g/mL, 0.5 μ g/mL, 0.25 μ g/mL and 0.125 μ g/mL.
4, method: be inoculated in 96 well culture plates behind the cell dissociation counting with logarithmic phase, 5000/hole/200 μ L, dosing behind the 24h, every group of medicine established 5 multiple holes, and establishes DMSO solvent control wells and acellular zeroing hole.Under 37 ℃, 5%CO2 condition, cultivate 48h, every hole, PBS washing back adds 200 μ L PBS again, and trichoroacetic acid(TCA) (TCA) fixed cell of Dropwise 50 μ L 50% (m/v), TCA final concentration are 10%, 4 ℃ and placed 1 hour.Abandon stationary liquid, with distilled water wash 5 times, seasoning in the air.Every hole adds the sulphonyl rhodamine solution of 50 μ L, room temperature held 10-30min.Remove supernatant, the acetic acid washing with 1% 5 times, dry air.Add Tris solution (pH=10.5) the 150 μ L of 10mmol/l at last, 5min vibrates on oscillator plate.(Model3550 Bio-Rad) measures the OD value, and with the blank zeroing, used wavelength is 570nm at enzyme-linked immunosorbent assay instrument.Calculate the inhibiting rate of growth of tumour cell by following formula:
IC50 adopts the IC among the sigmaplot
50Calculation formula obtains.
More than test triplicate, obtain IC
50Part of compounds of the present invention is to the IC of tumour cell
50Be listed in the table below:
The IC of The compounds of this invention
50All lower, numerical value all below 1 μ M, has positive effect aspect antiproliferative.
Test Example 4: compd A-35 couple mdr cell IC
50Mensuration
Material and method
1, receives the reagent thing: compd A of the present invention-35 and Zorubicin.
The cell strain MCF-7/DOX of 2, cell strain: MCF-7 and adriamycin-resistant.
3, liquor strength is 0.5 μ g/mL, 1 μ g/mL, 2 μ g/mL, 4 μ g/mL, 8 μ g/Ml, 16 μ g/mL, 32 μ g/mL and 64 μ g/mL.
4, method: be inoculated in 96 well culture plates behind the cell dissociation counting with logarithmic phase, 5000/hole/200 μ L, dosing behind the 24h, every group of medicine established 5 multiple holes, and establishes DMSO solvent control wells and acellular zeroing hole.Under 37 ℃, 5%CO2 condition, cultivate 48h, every hole, PBS washing back adds 200 μ L PBS again, and trichoroacetic acid(TCA) (TCA) fixed cell of Dropwise 50 μ L 50% (m/v), TCA final concentration are 10%, 4 ℃ and placed 1 hour.Abandon stationary liquid, with distilled water wash 5 times, seasoning in the air.Every hole adds the sulphonyl rhodamine solution of 50 μ L, room temperature held 10-30min.Remove supernatant, the acetic acid washing with 1% 5 times, dry air.Add Tris solution (pH=10.5) the 150 μ L of 10mmol/l at last, 5min vibrates on oscillator plate.(Model3550 Bio-Rad) measures the OD value, and with the blank zeroing, used wavelength is 570nm at enzyme-linked immunosorbent assay instrument.Calculate the inhibiting rate of growth of tumour cell by following formula:
IC50 adopts the IC among the sigmaplot
50Calculation formula obtains.
More than test triplicate, obtain IC
50The result sees Fig. 1.
Visible by the result, The compounds of this invention can reverse the resistance of the cell of adriamycin-resistant.
Test Example 5: cell cycle analysis
Material and method
1, receives the reagent thing: compd A of the present invention-35.
2, cell strain: HCT116 cell.
3, liquor strength is 0.5 μ g/mL.
4, method: handle the HCT116 cell with 0.5 μ g/mL, the cell after 4h, 12h and 24h collect drug-treated respectively, PBS washes twice; 75% ethanol that adds precooling ,-20 ℃ of fixed overnight, the centrifugal ethanol of removing; PBS washes twice, adds the 200mgmL-1RNA enzyme, 37 ℃ of digestion 30min; Add iodate pyridine 25mgmL-1,4 ℃ of lucifuges.
The result sees Fig. 2.The result shows that The compounds of this invention is arrested in the G2/M phase with cell.
Test Example 6: topoisomerase experiment
Material and method
1, receives the reagent thing: compd A of the present invention-35.
2, experimental subjects: topoisomerase I with and substrate pBR322DNA.
3, liquor strength is 30 μ g/mL, 3 μ g/mL and 0.3 μ g/mL.
4, method: topoisomerase I is active to be determined in the reaction system of 20 μ l and to contain 10 * reaction buffer (350mmol/L Tris-HCl pH8.0mmol/L, 720mmol/L Repone K, 5mmol/L magnesium chloride; 50mmol/L DTT; 50mmol/L Spermidine) 2 μ l, 0.1%BAS 2 μ l, PBR3220.36 μ g; Positive control pipe (NSC 107124) final concentration is 212.5 μ g/ml, 10.6 μ g/ml.Each test tube adds the A-35 (final concentration is respectively 30 μ g/mL, 3 μ g/mL and 0.3 μ g/mL) of different concns respectively.Topoisomerase I, each effective zero(ppm) water is supplemented to 20 μ l, and the rearmounted 37 ℃ of reaction 30min of mixing add 5 μ l stop buffers (5% SDD, 40% sucrose, 0.25mg/ml bromjophenol blue) termination reaction.In the TBE electrophoretic buffer, carry out agarose electrophoresis, under the 40V voltage, electrophoresis 4h.Bromination second pyridine solution (1 μ g/ μ l) dyeing 30min puts the Zone electophoresis band of observing DNA under the 260nm ultraviolet ray, and takes the photograph the sheet record.
The result sees Fig. 3.The result shows that The compounds of this invention is inhibited to topoisomerase I.
Claims (10)
1. formula I compound:
Or its pharmacologically acceptable salts or solvate, wherein
X is a halogen;
R
1Be selected from: hydrogen, C
1-6Alkyl, the substituted C of phenyl
1-6Alkyl, C
1-18Alkyl acyl, benzoyl-, benzenesulfonyl, 3,4-C
1-3The alkylenedioxy group benzoyl-, wherein said phenyl is optional to be selected from following substituting group replacement by 1 to 4: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, nitro, cyanic acid, amino, hydroxyl, C
1-4Alkyl acyl is amino;
R
2And R
3Be selected from independently of one another: hydrogen, C
1-6Alkyl, benzoyl-, wherein said phenyl is optional to be replaced by 1 to 4 halogen; Perhaps R
2And R
3Be together-CH
2-.
2. the compound of claim 1, wherein X is selected from fluorine, chlorine, bromine, iodine.
3. each compound of claim 1 to 2, wherein R is selected from hydrogen, C
1-4Alkyl, the substituted C of phenyl
1-4Alkyl, C
1-16Alkyl acyl, benzoyl-, benzenesulfonyl, 3,4-C
1-2The alkylenedioxy group benzoyl-, wherein said phenyl is optional to be selected from following substituting group replacement by 1 to 4: halogen, C
1-4Alkyl, C
1-4Alkoxyl group, nitro, cyanic acid, amino, hydroxyl, C
1-4Alkyl acyl is amino.
4. each compound of claim 1 to 3, wherein R
2And R
3Be selected from independently of one another: hydrogen, C
1-4Alkyl, halogeno-benzene formyl radical; Perhaps R
2And R
3Be together-CH
2-.
5. each compound of claim 1 to 4, it is a following formula: compound,
R wherein
1, R
2, R
3Have following each said implication of numbering No1 to No51 with X:
6. each compound of claim 1 to 5, it is to be selected from following compound:
9,10-dimethoxy-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-hydroxyl-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-oxyethyl group-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide;
9-butoxy-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-iodide;
9-benzyloxy-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide;
9-(2,4 difluorobenzene base) methoxyl group-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-bromide;
9-ethanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-benzoyl-Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methyl benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to anisoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to fluoro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to fluorine m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methyl m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to methoxyl group m-nitro benzoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(3,4-methylene-dioxy benzoyl-oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(3,4,5-trimethoxy benzoyl-oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
The adjacent fluoro benzoyl Oxy-1 of 9-0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
The adjacent chlorobenzene formacyl Oxy-1 of 9-0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-(2,4 difluorobenzene formyl radical oxygen base)-10-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-is to acetamido benzenesulfonyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole and 4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-benzenesulfonyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquinoline 99.9 [8,1,2-cde] phenanthridines-7-muriate;
9-decanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-lauroyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
9-hexadecanoyl Oxy-1 0-methoxyl group-5,6-dihydro-[1,3] dioxole also [4 ', 5 ': 6,7] isoquino [8,1,2-cde] phenanthridines-7-muriate;
Or its pharmacologically acceptable salts or solvate.
7. prepare the method for each said compound of claim 1 to 6, it may further comprise the steps:
A) in solvent, in the presence of alkali, make the reaction of Peng Qinghuana and Berberine, obtain dihydroberberine;
B) in solvent, in the presence of acid, make dihydroberberine and glyoxal reaction, obtain the cyclisation Berberine shown in the formula Ia:
Choose wantonly, c) make formula Ia cyclisation Berberine under vacuum, at high temperature handle and to obtain the 9-hydroxyl cyclisation Berberine shown in the formula Ib:
Choose wantonly, d) in organic solvent, in the presence of alkali, make 9-hydroxyl cyclisation Berberine and the suitable reagent reaction of formula Ib, obtain 9-alkyl oxy cyclisation Berberine, alkyl wherein is optional to be replaced by phenyl or substituted phenyl;
Choose wantonly; E) in organic solvent, in the presence of reagent, make 9-hydroxyl cyclisation Berberine and acyl chlorides or the SULPHURYL CHLORIDE reaction of formula Ib; Obtain 9-acyloxy cyclisation Berberine or 9-alkylsulfonyl oxygen basic ring Berberine, acyl group wherein is alkyloyl or benzoyl-.
8. pharmaceutical composition, it comprises each said compound of claim 1 to 6, and optional one or more pharmaceutically acceptable carriers or vehicle.
9. each said compound of claim 1 to 6 is used for treating and/or preventing the purposes of the medicine of mammal tumor or cancer property disease in preparation.
10. the purposes of claim 9, wherein said tumour or cancer property disease are liver cancer.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188035A (en) * | 2016-06-30 | 2016-12-07 | 合肥华方医药科技有限公司 | The Preparation method and use of 9 substituted double-functional group berberinc derivates |
| CN107722000A (en) * | 2017-11-03 | 2018-02-23 | 中国药科大学 | The preparation of the berberinc derivate of 9-substitution and its medical usage |
| WO2018068769A1 (en) * | 2016-10-14 | 2018-04-19 | 中国医学科学院药物研究所 | Use of dihydroberberine type compounds in preparation of product for treating tumour diseases associated with stat3 signaling pathway |
| CN108822095A (en) * | 2018-07-25 | 2018-11-16 | 山东大学 | Benzo [h] chromene compound and its application as AcrB efflux pump inhibitor in antibacterial |
| CN109928967A (en) * | 2017-11-28 | 2019-06-25 | 中国医学科学院医药生物技术研究所 | A kind of cyclisation berberinc derivate and its preparation method and application |
| CN114736202A (en) * | 2022-04-20 | 2022-07-12 | 四川大学 | Preparation and application of berberine derivative with IDO1/TDO inhibitory activity |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1211252A (en) * | 1996-02-12 | 1999-03-17 | 新泽西州州立大学(拉特格斯) | Coralyne analogs as topoisomerase inhibitors |
| CN101255158A (en) * | 2008-03-28 | 2008-09-03 | 中山大学 | 9-N-substituted berberine derivatives as well as preparation method and use as anti-cancer drugs |
| US20110015222A1 (en) * | 2009-07-20 | 2011-01-20 | Naxospharma S.R.L. | Benzoquinolizinium salt derivatives as anticancer agents |
-
2012
- 2012-04-09 CN CN201210101607.XA patent/CN102746292B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1211252A (en) * | 1996-02-12 | 1999-03-17 | 新泽西州州立大学(拉特格斯) | Coralyne analogs as topoisomerase inhibitors |
| CN101255158A (en) * | 2008-03-28 | 2008-09-03 | 中山大学 | 9-N-substituted berberine derivatives as well as preparation method and use as anti-cancer drugs |
| US20110015222A1 (en) * | 2009-07-20 | 2011-01-20 | Naxospharma S.R.L. | Benzoquinolizinium salt derivatives as anticancer agents |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188035A (en) * | 2016-06-30 | 2016-12-07 | 合肥华方医药科技有限公司 | The Preparation method and use of 9 substituted double-functional group berberinc derivates |
| WO2018068769A1 (en) * | 2016-10-14 | 2018-04-19 | 中国医学科学院药物研究所 | Use of dihydroberberine type compounds in preparation of product for treating tumour diseases associated with stat3 signaling pathway |
| CN107722000A (en) * | 2017-11-03 | 2018-02-23 | 中国药科大学 | The preparation of the berberinc derivate of 9-substitution and its medical usage |
| CN109928967A (en) * | 2017-11-28 | 2019-06-25 | 中国医学科学院医药生物技术研究所 | A kind of cyclisation berberinc derivate and its preparation method and application |
| CN109928967B (en) * | 2017-11-28 | 2020-09-04 | 中国医学科学院医药生物技术研究所 | Cyclized berberine derivative and preparation method and application thereof |
| CN108822095A (en) * | 2018-07-25 | 2018-11-16 | 山东大学 | Benzo [h] chromene compound and its application as AcrB efflux pump inhibitor in antibacterial |
| CN108822095B (en) * | 2018-07-25 | 2020-05-01 | 山东大学 | Benzo [ h ] chromene compound and application thereof as AcrB efflux pump inhibitor in antibiosis |
| CN114736202A (en) * | 2022-04-20 | 2022-07-12 | 四川大学 | Preparation and application of berberine derivative with IDO1/TDO inhibitory activity |
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